EP1984332A2 - Methods for treating hepatitis c - Google Patents
Methods for treating hepatitis cInfo
- Publication number
- EP1984332A2 EP1984332A2 EP07718004A EP07718004A EP1984332A2 EP 1984332 A2 EP1984332 A2 EP 1984332A2 EP 07718004 A EP07718004 A EP 07718004A EP 07718004 A EP07718004 A EP 07718004A EP 1984332 A2 EP1984332 A2 EP 1984332A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- optionally substituted
- alkyl
- independently selected
- substituents independently
- substituted
- 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- Withdrawn
Links
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- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 102000004337 ribosomal protein S5 Human genes 0.000 description 1
- 108090000902 ribosomal protein S5 Proteins 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000006656 viral protein synthesis Effects 0.000 description 1
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 Three distinct elements have been shown to be involved in HCV IRES-mediated translation: (1) integrity of the global structure of HCV IRES, (2) the 3'-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV IRES 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 y 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).
- domains II and III consist of multiple stems, loops, and bulges and are important for ERES 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).
- subdomain HId 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 4OS 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 40S ribosomal subunit and eIF3 to bind directly to the RNA.
- Subdomain HId of the HCV IRES harbors the binding site for the 4OS ribosomal subunit and the only initiation factors required for translation initiation are eIF2, e ⁇ F3, and eIF4E (15, 58, 94, 100, 120, 124).
- the polypyrimidine track-binding protein (PTB) and La autoantigen are noncanor ⁇ cal translation initiation factors that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53).
- PTB 5 a 57-kDa protein involved in RNA splicing is also necessary for efficient IRES- mediated translation initiation of picornavirus mRNA, and some cellular mRNAs (10, 11, 36, 53, 59, 89, 92).
- the La autoantigen a 52 kDa double-stranded RNA unwinding protein, also increases the activity of polio virus 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
- IFN ⁇ and the nucleoside analogue ribavirin 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, 84, 138).
- 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 -stimulated genes (ISGs), many of which have an antiviral function. ISG action can limit virus replication at multiple points within the replicative cycle.
- ISGs IFN -stimulated genes
- 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.
- the present invention includes a compound of Formula (I)
- X is:
- R x is a Ci to C O alkyl
- -an alkyne optionally substituted with a Ci to C 6 alkyl optionally substituted with one or more independently selected halo or cyano groups; -an oxime;
- R b is a hydrogen or a Ci to C ⁇ alkyl, and n is 0 or 1 ;
- R c is a hydrogen, a -CONHR x , where R x is a Ci to C 6 alkyl, or an -SOaR x , where R x is a C 1 to C 6 alkyl; or
- Rd is a Ci to Ce alkyl or a C 6 to Cg aryl; -a -NHCOR e group, where Re is: -a Ci to C 6 alkyl;
- -a C 6 to Cs aryl optionally substituted with: -a Ci to C 6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or
- R x is a Ci to C 6 alkyl
- R g is a C] to C 6 alkyl or a hydrogen and R h is a hydrogen, Ci to C 6 alkyl, or C 6 to Cs aryl, the Ci to C 6 alkyl or C 6 to C 8 aryl optionally substituted with an alkoxy; -a Ci to C 6 alkyl;
- -a 5 or 6 membered heteroaryl optionally substituted with one or more of the following: -a Ci to C 6 alkyl, optionally substituted with one or more halos or a C 6 to CR aryl, -a C 6 to Cs aryl, optionally substituted with -COOR x , where R x is a Ci to C 6 alkyl, -an amino group, or -a substituent from Group A;
- -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:
- R x is a Ci to Ce alkyl and R,- is: -a hydrogen, -a Ci to C 6 alkyl,
- R k is: -a C 1 to C 6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Cj to C 6 alkyls, and R j is:
- R x is a Ci to Ce alkyl, -a haloalkyl, or
- Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino
- Ci to Cg alkyl group optionally substituted with:
- Rab is a 5 or 6 membered heterocycle group, -a -COOR x group, where R x is a Ci to Ce alkyl, -a -COR n , group, where R 1n is: -an amino optionally substituted with one or more Ci to Ce alkyls, where the Cj to Ce alkyls are optionally substituted with: -a hydroxy
- Ci to C O alkyl optionally substituted with: -a halo, -an alkoxy, or -a Ce to Cg aryl, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to
- R 0 is:
- R x is a Ci to C 6 alkyl
- Ci to C ⁇ alkyl optionally and independently substituted with one or more Ce to C 8 aryl, halo and/or C 1 to Cg alkoxy groups, -a Ci to C 6 alkoxy, -a Ci to C ⁇ haloalkoxy, -a -OR S group, where R s is a C O to C 8 aryl, or -a -COOR x group, where R x is as defined above, -a Ci to Ce alkyl optionally substituted with one or more of the following:
- -a 5 or 6 membered heterocycle optionally substituted with one or more halo, Ci to C 6 alkyl, C t to C 6 haloalkyl, Ci to C 6 alkoxy, Ci to C 6 haloalkoxy,
- Ci to C 6 alkyl Ci to C 6 haloalkyl
- Ci to C 6 alkoxy Ci to C 6 haloalkoxy
- -an alkylene -an alkoxy
- -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to Ce alkyl, -halo, or -a 5 or 6 membered heterocycle,
- -a C 6 to Cg aryl optionally substituted with: -an alkoxy, -a halo, or -a C 1 to C 6 alkyl, or -a 5 or 6 membered heterocycle,
- R x is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR v SO 2 R w group, where Rv is:
- R x is as defined above, or -a Ci to C O alkyl, optionally substituted with:
- R x is as defined above, -a hydroxyl, or -an alkoxy, and where R w is: -a C) to C 6 alkyl optionally substituted with:
- Ci Ci to C 6 alkyl, -Ci to C 6 haloalkyl, -C] to Cg alkoxy, - Ci to Ce haloalkoxy, -a 5 or 6 membered heterocycle, or
- R y is a hydrogen, Ci to Ce alkyl optionally substituted with a Ci to Ce alkoxy, Ci to Ce haloalkyl, Ce to Cs aryl, 5 or 6 membered heteroaryl, or 5 or 6 membered heterocycle, where the Ce to Cg aryl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocycle are each optionally and independently substituted with one or more halo, Ci to C 6 alkyl, Cj to C 6 alkoxy, Ci to Cg haloalkyl,
- R y is as described above and R 2 is hydrogen or a Ci to
- R y is as described above, -a -SR x group, where R x is as defined above,
- -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy, a 5 or 6 membered heterocycle, a 5 or 6 membered heteroaryl, or a -COOR x group, where R x is as defined above, -a 5 or 6 membered heteroaryl,
- -a 5 or 6 heterocycle optionally substituted with hydroxy, a Ci to Ce alkoxy, or a a Ci to Ce alkyl, where the alkyl is optionally substituted with one or more hydroxy, -a Ce to Cs aryl, or
- Ci to C 6 alkyl optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Ce alkyls, -a -NHPOR x R x , where R x is as defined above, -a -NReeCONR ff Rff group, where R 03 is a hydrogen or a Ci to C 6 alkyl, optionally substituted with a halo, and R ⁇ is: -a hydrogen, -a haloalkyl, -a haloalkoxy, -a Ci to C 6 alkyl, or
- Ci to CO alkyl optionally substituted with: -an alkoxy
- Ci to Ce alkyl optionally substituted with: -an alkoxy, -one or more halos, - a 5 or 6 membered heterocycle, or
- R is a hydrogen, a halo or an alkoxy
- Ci to C 6 alkyl Ci to C 6 alkoxy, Ci to C 6 haloalkyl, Cj to Cg haloalkoxy, Cj to Ce hydroxy, and/or SO ⁇ R X groups,
- -a 5 or 6 membered heterocycle optionally substituted with one or more halo, Cj to Cg alkyl, C 1 to C 6 alkoxy, Ci to Ce haloalkyl, Ci to C 6 haloalkoxy, Ci to C 6 hydroxy, and/or SO 2 R x groups,
- R 2 is:
- Ci to Ce alkyl group optionally substituted with one or more of the following:
- -5 or 6 membered heteroaryl group is optionally substituted with one or more halo, Ci to CO alkyl, Ci to Ce alkoxy, Ci to C 6 haloalkyl, Ci to Ce haloalkoxy, Ci to Cg hydroxy, and/or SO 2 R x groups,
- -C ⁇ to C 8 aryl group is optionally substituted with one or more halo, Ci to C ⁇ alkyl, Ci to C 6 alkoxy, Ci to Ce haloalkyl, Ci to C O haloalkoxy, Ci to Ce hydroxy, and/or SO 2 R x groups, -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an amino group optionally substituted with one or more C] to Ce alkyl groups;
- -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halos,
- -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or - an amino optionally substituted with one or more alkyl groups; -a dialkyl-amino optionally substituted with an alkoxy, -a 4 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C 6 alkyl group, the Ci to Ce alkyl group optionally substituted with one or more independently selected Ci to C 6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more independently selected halo, Ci to C O alkyl, Ci to C O alkoxy, Cj to C O haloalkyl, Ci to C 6 haloalkoxy, Ci to Ce hydroxy, and/or SO 2 R x groups, or -a C 6 to Cg aryl group
- -Ci to C 6 alkyl groups optionally substituted with one or more independently selected halo, Ci to C 6 alkoxy, Cj to C 6 hydroxy, a 5 or 6 membered heterocycle and/or a 5 or 6 membered heteroaryl, -hydroxy groups, or -C 6 to Cs aryl groups;
- -a 5 or 6 membered heterocycle optionally substituted with one or more of the following: -Ci to C 6 alkyl,
- -a -OCOR x group where R x is as defined above; -a -NHCOR jj group, where RJJ is: -an alkyl, -a C 6 to C 8 aryl, -an alkoxy, or
- Ci to Ce alkyl optionally substituted with one or more independently selected halo, Ci to Ce alkyl, Ci to Ce alkoxy, Ci to C O haloalkyl, Ci to Ce haloalkoxy, Ci to C O hydroxy, and/or SO 2 R x groups,
- R3 is:
- Ci to C 6 alkyl optionally substituted with:
- R 0 is:
- R x is a Ci to Ce alkyl
- Ci to Ce alkyl optionally and independently substituted with one or more Ce to C 8 aryl, halo and/or Ci to C O alkoxy groups, -a Ci to C ⁇ alkoxy,
- R s is a C 6 to Cs aryl
- R x is as defined above, -a C 2 to C 6 alkylene group, -a Ci to C 6 alkoxy group,
- -a 5 or 6 membered heterocycle group optionally substituted with with one or more halo, Ci to C 6 alkyl, Ci to C 6 haloalkyl, Ci to C 6 alkoxy, Ci to C 6 haloalkoxy,
- Ci to C 6 alkyl Ci to C 6 haloalkyl
- Ci to C 6 alkoxy Ci to C 6 haloalkoxy
- -an alkylene a C 6 to Cs aryl optionally substituted with one or more halo, Ci to C 6 alkyl, Ci to C 6 haloalkyl, Ci to C 6 alkoxy, Ci to C 6 haloalkoxy, -an alkylene,
- R t is:
- R x is as defined above, or -a Ci to C 6 alkyl, optionally substituted with: -a halo,
- Ci to Ce alkyl optionally substituted with: -a halo, -a haloalkyl, -a C ⁇ to Cs aryl, or -a 5 or 6 membered heterocycle,
- Raa is: -a Ci to C 6 alkyl, -an amino group
- Ci to Ce alkyls optionally substituted with: -a hydroxy
- R n is: -a -CH 2 CONH 2 , or
- L is a direct bond, Cj to Q 2 alkylene, C 2 to C 12 alkenylene or C 2 to Ci 2 alkynylene, wherein one or more — CH 2 — group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with — O — , — S — , — SO 2 — and/or — NR mm — , and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s), halos, and/or hydroxy(s), where R mm is hydrogen or Ci to Ce alkyl; or a pharmaceutical salt thereof.
- the present invention includes compounds of Formula I, with the proviso that at least one of Y, Z, R t and R 2 is selected from the following: Y is:
- -an amino optionally substituted with one or more of the following: -SO 2 R x , or
- R a b is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is:
- Ci to Ce alkyl groups optionally substituted with one or more Ci to Ce alkyl groups where the Ci to C ⁇ alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Ci to C 6 alkyl or C ⁇ to C 8 aryl groups, -a -NRqCONRqR r group, where R r is:
- Ci to C 6 alkyl substituted with one or more of the following: -a hydroxyl,
- Ci to C12 alkyl substituted with one or more of the following: -an alkoxy group substituted with one or more alkoxy groups,
- Ci Ci to Cg alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
- Ri is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle; R 2 is:
- Ci to C ⁇ alkyl group substituted with one or more of the following: -5 or 6 membered heterocycle groups, or
- -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following: -a hydroxy group,
- Ce alkyl groups substituted with Ci to Ce alkoxy, or
- a compound of Formula I is included, with the proviso that at least one of X, Y, Z, Ri, and R 2 is selected from the following: X is:
- -an alkyl optionally substituted with one or more halo
- -an alkyne optionally substituted with a Cj to Ce alkyl optionally substituted with one or more halo or cyano groups
- -a Ce to Cs aryl group substituted with one or more of the following: -Ci to Ce alkyl optionally substituted with one or more halos,
- Y is:
- -an amino optionally substituted with one or more of the following: -SO 2 R x , or -Ci to C 6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHR x , -OC(O)NH(OR x ), -OC(O)NR x (OR x ),
- R a b is a 5 or 6 membered heterocycle group, -a -NR 0 CORp group, where R p is:
- R 1 is: -a Ci to Cu alkyl, substituted with one or more groups independently selected from the following:
- -an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to C$ alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to Ce alkylene, or
- Ci -a Ci to Ce alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
- Ri is: -a Ci to Ce alkyl substituted with:
- -an amide optionally substituted with a Ci to C 6 alkyl, or -a 5 or 6 membered heteroaryl; -a Ci to C 6 alkoxy substituted with:
- R 2 is:
- Ci to C ⁇ alkyl group substituted with one or more of the following: -5 or 6 membered heterocycle groups,
- -an alkylthio group optionally substituted with a C 6 to C 8 aryl group
- -an alkylthio group optionally substituted with a C] to C 6 alkyl group
- -an SO2R* group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C 6 alkyl groups
- -an SO 2 R X group optionally substituted with a 5 or 6 membered heterocycle group; -an SO2R.
- X group optionally substituted with a C O to Cg aryl group; -an SC ⁇ Rx group optionally substituted with a Ci to C 6 alkyl group; -an S(O)R x group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)R x group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)R x group optionally substituted with a Ce to Cs aryl group; -an S(O)R x group optionally substituted with a Ci to C 6 alkyl group; -an alkoxy group substituted with an alkoxy group,
- -an amino group substituted with one or more 5 or 6 membered heteroaryl, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or
- -S-5 or 6 membered heteroaryl optionally substituted with a Ci to Ce alkyl, -S-Ci to C 6 alkyl,
- -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ci to C(, alkyl, -sulfonyl- Ci to Ce alkyl, -sulfonyl- C 6 to C 8 aryl, -a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Ci to C ⁇ alkyl groups substituted with Ci to Ce alkoxy, or
- the present invention includes compounds of Formula I, with the proviso that with the proviso that at least one of Y, Z, and R 2 is selected from the following: Y is: -a benzothiazole substituted with an amino group optionally substituted with one or more Ci to C 6 alkyls;
- -an amino optionally substituted with one or more of the following: -SO 2 R x , or
- R a b is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is: -an amino group optionally substituted with one or more Cj to C 6 alkyl groups where the C) to C ⁇ alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, substituted with one or more Ci to Ce alkyl or Ce to Cg aryl groups, -a -NR q CONRqR r group, where R 1 - is:
- Ci to Ce alkyl substituted with one or more of the following: -a hydroxyl, -an alkoxy,
- Ci to Ci 2 alkyl substituted with one or more groups independently selected from the following:
- R 2 is: -a C 1 to C O alkyl group, substituted with one or more of the following: -5 or 6 membered heterocycle groups,
- -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following:
- -an amino optionally substituted with one or more alkyl groups; -a 7 membered heterocycle group; -a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Ci to C 6 alkyl groups substituted with Ci to Ce alkoxy, or
- -an amide group substituted with one or more Ci to Ce alkyl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Ci to C 6 alkyl,
- R x group -C(O)-C 6 to C 8 aryl, or -C(O)OR x groups
- -an -ORkk group where R kk is: -a 5 to 6 membered heterocycle, optionally substituted with a Ci to C 6 alkyl, optionally substituted with a C$ to Cs aryl group, or -an -Si(Rx) 3 ; or a pharmaceutically acceptable salt thereof.
- 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.
- alkyl substituents may be Ci to Cn, or Ci to C 8 or Ci to C 6 alkyl groups.
- alkylene generally refers to straight, branched or cyclic alkene radicals having one or more carbon-carbon double bonds, such as C 2 to Q alkylene groups including 3-pro ⁇ enyl.
- 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, fiuorenyl, indenyl, azulenyl, phenanthrenyl ⁇ i.e., phenanthrene), and napthyl (i.e., napthalene) ring structures. In certain embodiments, the aryl group may be optionally substituted.
- heteroaryl refers to cyclic aromatic 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 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.
- 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.
- heteroaryl ring structures include: acridine, benzimidazole, benzoxazole, benzodioxole, benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene, furan, furazan, 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.
- 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.
- heterocyclo groups include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl or tetrahydrothiopyranyl and the like.
- the heterocycle may optionally be substituted.
- alkoxy generally refers to a group with the structure -O-R, where R is an alkyl group as defined above.
- 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.
- each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently substituted.
- 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.
- 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.
- the present invention includes compounds of Formula (I-X)
- Y is:
- Rb is a hydrogen or a Cj to Ce alkyl, and n is 0 or 1 ;
- R 0 is a hydrogen, a -CONHR x , where R x is a Ci to Ce alkyl, or an -S ⁇ 2R x , where R x is a Ci to C 6 alkyl; or where Ra is a Ci to C 6 alkyl or a C 6 to Cg aryl; -a -NHCOR e group, where R 6 is: -a C 1 to C 6 alkyl;
- R 8 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 5 or 6 membered heterocycle optionally substituted with: -a C i to C 6 alkyl, or -a hydroxy, -an amino optionally substituted with one or more Ci to C 6 alkyls, -a -NRiSO 2 R x group, where R x is a Ci to Ce alkyl and R 1 - is: -a hydrogen, -a Ci to C 6 alkyl,
- Rk is: -a Ci to C 6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Q to Cg alkyls, and Rj is:
- R x is a Cj to Ce alkyl, -a haloalkyl, or
- Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more of the following:
- Cj to Ce alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -a nitro group, -a Ci to Ce alkyl group, optionally substituted with:
- R ab is a 5 or 6 membered heterocycle group, -a -COOR x group, where R x is a Ci to Ce alkyl, -a -COR m group, where R m is: -an amino optionally substituted with one or more Ci to C 6 alkyls, where the Ci to Ce alkyls are optionally substituted with: -a hydroxy,
- Ci to Ce alkyl optionally substituted with: -a halo, -an alkoxy, or -a Cg to C 8 aryl, -an amino group optionally substituted with one or more Ci to Cg alkyl groups where the Ci to Ce alkyl groups are optionally and independently substituted with one or more C 6 to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Cj to Ce alkyl or C ⁇ to Cg aryl groups, -a Ce to C 8 aryl, optionally substituted with a halo,
- R 0 is:
- R x is a Ci to C O alkyl
- -a Ci to Ce alkyl optionally substituted with one or more of the following: -a halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, -a C 6 to Cg aryl optionally substituted with a halo, or -a -COOR x group, where R x is as defined above, -a C 2 to C 6 alkylene group, -a Ci to C ⁇ alkoxy group,
- Ci to Ci 2 alkyl optionally substituted with one or more groups independently selected from the following:
- -a Ce to Cs aryl optionally substituted with: -an alkoxy, -a halo, or -a Ci to C 6 alkyl, or
- R v is: -a hydrogen, -a -COR x , where R x is as defined above, or -a Ci to Cg alkyl, optionally substituted with:
- Ci to C O alkyl optionally substituted with a Ci to C O alkyl, where R y is a C 1 to C 6 alkyl or hydrogen,
- R 2 is hydrogen or a Ci to Cs alkyl, optionally substituted with a Ce to Cs aryl,
- R x is as defined above, or -a 5 or 6 membered heteroaryl, -a Ce to Cg aryl, or -a -NHRbb group, where R b b is:
- Ci to C O alkyl optionally substituted with a cyano group, . -an amino optionally substituted with one or more Ci to Ce alkyls,
- R ⁇ is a hydrogen or a Ci to C ⁇ alkyl. optionally substituted with a halo, and Rn- is:
- Ci to Ce alkyl optionally substituted with: -an alkoxy, -a halo, or
- R gg is:
- Ci to C 6 alkyl optionally substituted with: -an alkoxy, -one or more halos, -a 5 or 6 membered heterocycle, or
- R is a hydrogen, a halo or an. alkoxy
- -an alkoxy optionally substituted with: -one or more halos, -a C ⁇ to Cs aryl,
- R 2 is:
- -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halos, -a hydroxy group,
- -an amino optionally substituted with one or more alkyl groups
- dialkyl-amino optionally substituted with an alkoxy, -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C ⁇ alkyl group
- the Ci to Ce alkyl group optionally substituted with one or more independently selected Ci to Ce alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to C 6 alkyl groups, or -a C ⁇ to Cg aryl group
- -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more Cg to C 8 aryl groups
- -a -COOR x group where R x is as defined above; -a haloalkyl; -an amide group optionally substituted with one or more of the following: -Ci to C 6 alkyl groups, -hydroxy groups, or -C 6 to Cg aryl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Ci to C 6 alkyl,
- R 3 is:
- R x is as defined above; or a pharmaceutically acceptable salt thereof.
- the present invention includes compounds of Formula (I-Xa)
- Y is:
- R b is a hydrogen or a Ci to C 6 alkyl, and n is 0 or 1;
- R 0 is a hydrogen, a -CONHR x , where R x is a Ci to Ce alkyl, or an -SO 2 R x , where R x is a Ci to C O alkyl; or where Rd is a Ci to C 6 alkyl or a C 6 to Cs aryl; -a -NHCORe group, where R e is: -a C] to C 6 alkyl;
- R g is a Ci to Ce alkyl or a hydrogen and Rh is a C 6 to Cs aryl optionally substituted with an alkoxy; -a Ci to Ce alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
- Ci to C 6 alkyl optionally substituted with a C 6 to C 8 aryl
- -a 5 or 6 membered heterocycle optionally substituted with: -a Ci to C 6 alkyl, or -a hydroxy, -an amino optionally substituted with one or more Ci to C 6 alkyls, -a -NRiSO 2 R x group, where R x is a Ci to C 6 alkyl and Rj is: -a hydrogen, -a C 1 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 alkyls, and R j is:
- R x is a Ci to C 6 alkyl, -a haloalkyl, or
- Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more of the following:
- Ci to C 6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -a nitro group, -a Ci to C 6 alkyl group, optionally substituted with:
- R ab is a 5 or 6 membered heterocycle group, -a -COOR x group, where R x is a Ci to C 6 alkyl, -a -COR m group, where R m is: -an amino optionally substituted with one or more Ci to Ce alkyls, where the Ci to Ce alkyls are optionally substituted with: -a hydroxy
- Ci to C O alkyl optionally substituted with: -a halo, -an alkoxy, or -a C ⁇ to Cg aryl, -an amino group optionally substituted with one or more Ci to C f , alkyl groups where the Cj to C& alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to Ce alkyl or Ce to Cs aryl groups, -a Ce to Cs aryl, optionally substituted with a halo,
- R 0 is:
- R x is a Ci to Ce alkyl
- -a Ci to Ce alkyl optionally substituted with one or more of the following: -a halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, -a C 6 to C 8 aryl optionally substituted with a halo, or -a -COOR x group, where R x is as defined above, -a C 2 to C ⁇ alkylene group, -a Ci to C O alkoxy group,
- Ci to C 12 alkyl optionally substituted with one or more of the following: -a C ⁇ to Cs aryl optionally substituted with halo, Ci to Ce alkyl, or alkoxy,
- -a Ce to Cs aryl optionally substituted with: -an alkoxy, -a halo, or -a C) to C 6 alkyl, or -a 5 or 6 membered heterocycle,
- R v is: -a hydrogen, -a -COR x , where R x is as defined above, or -a Ci to C ⁇ alkyl, optionally substituted with:
- R y is a C 1 to Ce alkyl or hydrogen
- R x is hydrogen or a Ci to C O alkyl, optionally substituted with a C O to C 8 aryl,
- R aa is:
- R x is as defined above, or -a 5 or 6 membered heteroaryl, -a Ce to Cs aryl, or -a -NHRbb group, where Rbb is:
- -a Ce to Cg aryl optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halo,
- Ci to Ce alkyl optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to C ⁇ alkyls, -a -NHPOR x R x , where R x is as defined above,
- R 00 is a hydrogen or a Ci to Ce alkyl, optionally substituted with a halo, and Rn- is:
- R x is as defined above, -a -NRggCORhh group, where Rhh is: -a hydrogen, -a C] to C ⁇ alkyl optionally substituted with:
- R x is as defined above, and R U is: -a hydrogen, -a Ci to C 6 alkyl, -a haloalkyl, -a haloalkoxy., or
- Ci to C 6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
- R 2 is:
- -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an amino group; -an alkoxy group optionally substituted with one or more of the following: -halos,
- -an alkoxy group optionally substituted with an alkoxy group, -an -OCOR x group, where R x is as defined above, -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
- Ci to C& alkyl group optionally substituted with one or more independently selected hydroxy group or Ci to C& alkyl group
- the Ci to C ⁇ alkyl group optionally substituted with one or more independently selected Ci to Ce alkoxy group
- -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to C 6 alkyl groups
- -an amide group optionally substituted with one or more of the following: -Ci to Ce alkyl groups, -hydroxy groups, or -C 6 to C 8 aryl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
- -C(O)OR x groups ; -a 5 or 6 membered heteroaryl; -a -OCOR x group, where R x is as defined above; -a -NHCORjj group, where Rjj is: -an alkoxy, or
- R 3 is:
- Y 5 Z, Ri and R 2 is selected from the following:
- Y is: -a benzothiazole substituted with an amino group optionally substituted with one or more Ci to
- -an amino optionally substituted with one or more of the following: -SO 2 R x , or -Ci to C(, alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHR x , -OC(O)N(R X ) 2> -OC(O)NH(OR x ), -OC(O)NR x (OR x ),
- Rab is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is:
- Ci to Ce alkyl groups are optionally and independently substituted with one or more C 6 to Cs aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Ci to Ce alkyl or Ce to Cg aryl groups, -a -NR q CONRqRr group, where R r is: -a Ci to Ce alkyl substituted with one or more of the following:
- R u is: -a Ci to C 12 alkyl, substituted with one or more of the following:
- Ci to C 6 alkyl substituted with a 5 or 6 membered heterocycle or
- Ri is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle
- R 2 is:
- Ci to C 6 alkyl group substituted with one or more of the following: -5 or 6 membered heterocycle groups, or
- alkoxy group optionally substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
- -an amide group substituted with one or more Ci to C 6 alkyl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Cj to C 6 alkyl, -SO 2 R x ,
- R is selected from the R substituents of compounds 1330-2128 and 2600-3348.
- R is selected from the following non-limiting substituents:
- R is hydrogen
- Ri is selected from the following non-limiting substituents:
- R 2 is selected from the following non-limiting substituents:
- R 3 is selected from the R 3 substituents of compounds 1330- 2128, and 2600-3348. In some embodiments of the invention, compounds are provided wherein R 3 is selected from the following non-limiting subsituents:
- the present invention includes a compound of Formula (I-XI)
- -an alkyne optionally substituted with a Ci to Cg alkyl optionally substituted with one or more independently selected halo or cyano groups; -an oxime; -SO 2 R x ; -SO 2 NH 2 ; -SO 2 NH(R x ); -SO 2 N(Rx) 2 ;
- -an indole optionally substituted on the nitrogen with an -SO 2 R x group; or -a Ce to Cg aryl, optionally substituted with one or more of the following: -halo;
- R ab is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is:
- Ci to Ce alkyl groups optionally substituted with one or more Ci to Ce alkyl groups where the Ci to C 6 alkyl groups are optionally and independently substituted with one or more C ⁇ to Cs aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to
- Ce alkyl optionally substituted with one or more of the following: -halo, -hydroxyl, -an alkoxy,
- Ci to Ci 2 alkyl optionally substituted with one or more groups independently selected from the following: -a C 6 to C 8 aryl optionally substituted with halo,
- -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C] to C 6 alkyl, -halo, or -a 5 or 6 membered heteroaryl, -a C 2 to Ce alkylene, or
- Ci Ci to C ⁇ s alkyl optionally substituted with a 5 or 6 membered heterocycle, or
- R is a hydrogen
- Ri is:
- -an amino optionally substituted with a heterocycle
- -an amide optionally substituted with a Ci to Ce alkyl
- -a 5 or 6 membered heterocycle optionally substituted with a Ci to Ce alkyl
- -a 5 or 6 membered heterocycle optionally substituted with a Ci to C ⁇ alkyl, -a 5 or 6 membered heteroaryl, or
- R 2 is:
- Ci to Ce alkyl group optionally substituted with one or more of the following: -5 or 6 membered heterocycle groups,
- -an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group; -an alkylthio group optionally substituted with a C 6 to C 8 aryl group; -an alkylthio group optionally substituted with a Ci to C ⁇ alkyl group;
- -an SO 2 R x group optionally substituted with a 5 or 6 membered heterocycle group; -an SO 2 R x group optionally substituted with a Ce to Cs aryl group; -an SO 2 R x group optionally substituted with a Ci to Ce alkyl group;
- -an S(O)R x group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)R x group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)R x group optionally substituted with a Ce to C 8 aryl group; -an S(O)R x group optionally substituted with a Ci to C 6 alkyl group; -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halo,
- -an amino group optionally substituted with one or more 5 or 6 mernbered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
- -S-5 or 6 membered heteroaryl optionally substituted with a Ci to C 6 alkyl, -S-Ci to C 6 alkyl, -S-C 6 to C 8 aryl,
- -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ci to C 6 alkyl, -sulfonyl- Ci to Ce alkyl, -sulfonyl- C 6 to Cs aryl,
- -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C 6 alkyl group
- the Cj to C 6 alkyl group optionally substituted with one or more independently selected Ci to C 6 alkoxy group
- -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to Ce alkyl groups, -a C 6 to Cs aryl group; -a C 6 to C 8 aryl group;
- -an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Cj to C 6 alkyl groups
- -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more Ce to Cg aryl groups
- R3 is a hydrogen; or a pharmaceutically acceptable salt thereof.
- compounds of the present invention include compounds of Formula (I-XIa)
- X is: -hydrogen; -a cyano group; -a nitro group; -a formyl group; -a -COOH group;
- R x is a Ci to C 6 alkyl
- -an amino optionally substituted with one or more Cj to C 6 alkyl groups or C(O)- Ci to Cg alkyl groups;
- -an amide group optionally substituted with one or more independently selected Cj to Cg alkyl group;
- -a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C 6 alkyl groups optionally substituted with one or more halos
- -a Ce to C 8 aryl group optionally substituted with one or more of the following: -Ci to Ce alkyl optionally substituted with one or more halos, -halo, or -cyano;
- Y is: -a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to Ce alkyls;
- -an indole optionally substituted on the nitrogen with a -SO 2 R x group
- -a CO to Cg aryl optionally substituted with one or more of the following: -halo;
- -SO 2 R x groups -Ci to C ⁇ alkyl, the C] to C 6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, or -PO 2 R x groups, -OC(O)NHR x , -OC(O)N(R X ) 2 , -OC(O)NH(OR x ),
- R 30 is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is: -a Ci to C 6 alkyl,
- Ci to Ce alkyl groups are optionally and independently substituted with one or more C O to C 8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to Ce alkyl or C ⁇ to Cg aryl groups, and where R 0 is:
- Ci to Ce alkyl optionally substituted with one or more of the following: -halo, -hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a Cg to C 8 aryl optionally substituted with a halo, -a C 2 to Ce atkylene group optionally substituted with one or more halo, -a C i to C O alkoxy group, or
- Ci to Cu alkyl optionally substituted with one or more groups independently selected from the following: -a Ce to Ci aryl optionally substituted with halo,
- Z is: -a C J to C 6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; R is a hydrogen;
- Ri is:
- Ci to Q alkyl optionally substituted with: -an amino optionally substituted with a heterocycle
- -an amide optionally substituted with a Cj to C 6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a Ci to C ⁇ alkyl, -a 5 or 6 membered heteroaryl, or -a Ce to C 8 aryl; -a C] to C(, alkoxy optionally substituted with:
- -an amino optionally substituted with a heterocycle
- -an amide optionally substituted with a Ci to C 6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a Ci to Ce alkyl, -a 5 or 6 membered heteroaryl, or -a C 6 to C 8 aryl;
- -a 5 or 6 membered heteroaryl or -alkylthio optionally substituted with the following: -a 5 or 6 membered heterocycle, -a Cs to C 8 aryl, -a 5 or 6 membered heteroaryl;
- -amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
- -an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
- -an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group; -an alkylthio group optionally substituted with a C 6 to Cs aryl group; -an alkylthio group optionally substituted with a Cj to C 6 alkyl group;
- -an SO 2 R x group optionally substituted with a 5 or 6 membered heterocycle group; -an SO 2 R x group optionally substituted with a C 6 to Cg aryl group; -an SO 2 R x group optionally substituted with a Ci to Cg alkyl group;
- -an S(O)R x group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)R x group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)R x group optionally substituted with a Cg to Cs aryl group; -an S(O)R x group optionally substituted with a Ci to C O alkyl group; -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halo,
- -an alkoxy group optionally substituted with an alkoxy group
- -an amino group optionally substituted with one or more 5 or 6 membered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups
- the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or
- -S-5 or 6 membered heteroaryl optionally substituted with a C 1 to C6 alkyl, -S-Ci to C 6 alkyl, -S-C 6 to C 8 aryl, -sulfinyl-5 or 6 membered heterocycle,
- -sulfinyl-5 or 6 membered heteroaryl -sulfinyl-Ci to C 6 alkyl, -sulfinyl-C ⁇ to Cg aryl, -sulfonyl-5 or 6 membered heterocycle, -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ci to Cg alkyl,
- Ci to C 6 alkyl group optionally substituted with one or more independently selected Ci to C 6 alkoxy group
- -an amide group optionally substituted with one or more of the following: -Ci to C O alkyl groups optionally substituted with one or more C] to C 6 alkoxy,
- R 3 is a hydrogen; with the proviso that at least one of X, Y, Z, Ri, and R 2 is selected from the following: X is:
- N amino optionally substituted with one or more C ⁇ to C ⁇ alkyl _ a groups ; -a halo;
- Y is:
- Rab is a 5 or 6 membered heterocycle group, -a -NR 0 CORp group, where R p is:
- Ci to Ce alkyl groups optionally substituted with one or more Ci to Ce alkyl groups where the Ci to C 6 alkyl groups are optionally and independently substituted with one or more Ce to Ce aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Ci to Ce alkyl or Ce to C 8 aryl groups,
- Ci to C O alkyl substituted with one or more of the following: -a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle,
- Ci to Ci 2 alkyl substituted with one or more groups independently selected from the following:
- R 2 is: —a Ci to C ⁇ alkyl group, substituted with one or more of the following: -5 or 6 membered heterocycle groups, -5 or 6 membered heteroaryl groups, -Ce to Cg aryl groups, -an amide optionally substituted with a Ci to C 6 alkyl, or -amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
- -an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group; -an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group; -an alkylthio group optionally substituted with a C ⁇ to Ce aryl group; -an alkylthio group optionally substituted with a C] to CO alkyl group; -an SOaR x group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C 6 alkyl groups; -an SO 2 R x group optionally substituted with a 5 or 6 membered heterocycle group; -an SOaR x group optionally substituted with a Ce to Cg aryl group; -an SOaR x group optionally substituted with a Ci to C$ alkyl group; -an S(O)R x group optionally substituted with a 5 or 6 member
- -an amino optionally substituted with one or more alkyl groups
- -an amide optionally substituted with a Ci to Ce alkyl, -S-5 or 6 membered heterocycle, -S-5 or 6 membered heteroaryl optionally substituted with a Ci to Ce alkyl
- -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Cj to Cg alkyl, -sulfonyl- Ci to Ce alkyl, -sulfonyl- C 6 to C 8 aryl,
- Formula I-XIb a compound is provided wherein all substituents except X are as stated for Formula I-XI, and X is an electron withdrawing group.
- Formula I-XIc a compound is provided wherein all substituents except X are as stated for Formula I-XIa, and X is an electron withdrawing group.
- an electron withdrawing group includes any electronegative element, which may be attached to or adjacent to an aromatic ring.
- an electron withdrawing group can include a cyano group, an alkynyl group, a nitro group, an oxime, a halo, a halosubstituted alkyl, a carbonyl group, a sulfonyl group, and a heterooycle.
- X is a cyano group.
- Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, Hc, Hd, or lie X is a halo.
- X is a fluorine, chlorine, bromine or iodine.
- I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, Hc, Hd, or He X is a fluorine, bromine or iodine.
- I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, lie, Hd, or lie X is a fluorine or chlorine.
- X is a fluorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, Hb, Hc, Hd, or He, X is a chlorine. In an embodiment of Formulas I, I-XI, I-XIa, I- XIb, I-XIc, Ha, Hb 3 He, Hd, or He, X is bromine.
- X is iodine.
- I-XI, 1-XIa 5 I-XIb, I-XIc, Ha 3 Hb, He, Hd, or He X is an alkyl substituted with one or more halos.
- X is a trifluoromethyl group.
- X is selected from the X substituents of compounds 1330-2128, and 2600-3348.
- X is selected from the group consisting of:
- X is selected from the group consisting of
- Ri is selected from the Ri substituents of compounds 1330- 2128, and 2600-3348.
- Ri is selected from the group consisting of
- the present invention includes compounds of Formula (I-XII)
- -an indole optionally substituted on the nitrogen with an SO 2 R x group
- -a CO to Cs aryl optionally substituted with one or more of the following: -an alkoxy,
- -an amino optionally substituted with one or more of the following: -SCbR x group, or
- Rab is a 5 or 6 membered heterocycle group, -a -NR 0 CORp group, where R p is: -a Ci to C 6 alkyl,
- Ci to Cg alkyl groups are optionally and independently substituted with one or more C 6 to C 8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Cj to C 6 alkyl or C 6 to C 8 aryl groups, and where R 0 is: -a hydrogen,
- Ci to C 6 alkyl optionally substituted with one or more of the following: -a hydroxyl,
- Ci to Ci2 alkyl optionally substituted with one or more groups independently selected from the following:
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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 REFERENCE 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. PCTΛJS2005/024881 , 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 IRES, (2) the 3'-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV IRES 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 y 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 IRES 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
W
domains II and III consist of multiple stems, loops, and bulges and are important for ERES 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 HId 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 4OS 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 40S ribosomal subunit and eIF3 to bind directly to the RNA. Subdomain HId of the HCV IRES harbors the binding site for the 4OS ribosomal subunit and the only initiation factors required for translation initiation are eIF2, eϊF3, and eIF4E (15, 58, 94, 100, 120, 124).
The polypyrimidine track-binding protein (PTB) and La autoantigen are noncanorήcal translation initiation factors that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53). PTB5 a 57-kDa protein involved in RNA splicing, is also necessary for efficient IRES- mediated translation initiation of picornavirus mRNA, and some cellular mRNAs (10, 11, 36, 53, 59, 89, 92). The La autoantigen, a 52 kDa double-stranded RNA unwinding protein, also increases the activity of polio virus 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 NS5A, 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 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 -stimulated 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 a more effective means of treating patients afflicted with HCV. Specifically, a need exists for novel antiviral drugs 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.
DETAILED DESCRIPTION OF THE INVENTION
A. Compounds of the Invention
In another embodiment, the present invention includes a compound of Formula (I)
(D
wherein:
X is:
-hydrogen;
-a cyano group;
-a nitro group;
-a formyl group;
-a -COOH group;
-a CORx group, wherein Rx is a Ci to CO alkyl;
HC\\
^""""amino optionally substituted with one or -a more Ci to Ce alkyl groups •
-a halo;
-an alkyl optionally substituted with one or more halo;
-an alkyne optionally substituted with a Ci to C6 alkyl optionally substituted with one or more independently selected halo or cyano groups; -an oxime;
-SO2Rx;
-SO2NH2;
-SO2NH(Rx);
-SO2N(Rx)2; -an amino optionally substituted with one or more Ci to Cg alkyl groups or Ci to C§ alkylcarbonyl groups;
-an amide group optionally substituted with one or more independently selected Ci to C& alkyl group;
-a 5 or 6 membered heterocycle; -a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Cβ alkyl groups optionally substituted with one or more halos;
-a Ce to C8 aryl group optionally substituted with one or more of the following:
-Ci to C6 alkyl optionally substituted with, one or more halos,
-halo, or
-cyano; Y is:
-a hydrogen; -a haloalkyl; -a halo; -a benzofuran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene;
-a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to Ce alkyls; -a naphthalene;
-an indole, optionally substituted on the nitrogen with a Ci to Ce alkyl or an -SO2Rx group;
where Rb is a hydrogen or a Ci to Cβ alkyl, and n is 0 or 1 ;
where Rc is a hydrogen, a -CONHRx, where Rx is a Ci to C6 alkyl, or an -SOaRx, where Rx is a C1 to C6 alkyl; or
where Rd is a Ci to Ce alkyl or a C6 to Cg aryl; -a -NHCORe group, where Re is: -a Ci to C6 alkyl;
-a C6 to Cs aryl optionally substituted with: -a Ci to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or
-a halo;
-a -NHCOORx group, where Rx is a Ci to C6 alkyl;
-a -NRgRh group, where Rg is a C] to C6 alkyl or a hydrogen and Rh is a hydrogen, Ci to C6 alkyl, or C6 to Cs aryl, the Ci to C6 alkyl or C6 to C8 aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with one or more of the following: -a Ci to C6 alkyl, optionally substituted with one or more halos or a C6 to CR aryl, -a C6 to Cs aryl, optionally substituted with -COORx, where Rx is a Ci to C6 alkyl, -an amino group, or -a substituent from Group A;
-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 halos,
-a 5 or 6 membered heterocycle, optionally substituted with:
-a Ci to C6 alkyl, or -a hydroxy,
-a C& to Cs aryl, optionally substituted with one or more substituents independently selected from Group A,
-a a 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from Group A, -an amino optionally substituted with one or more Cj to Cg alkyls,
-a -NRiSO2Rx group, where Rx is a Ci to Ce alkyl 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 C1 to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Cj to C6 alkyls, and Rj is:
-a hydrogen, -a Ci to C6 alkyl,
- a -CORx group, where Rx is a Ci to Ce alkyl, -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,
-a Ci 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 halo, -a hydroxy, -OC(O)NHRx, -OC(O)N(RX)2, -OC(O)NH(ORx),
-OC(O)NRx(ORx),
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -COORx group, where Rx is a Ci to Ce alkyl, -a -CORn, group, where R1n is: -an amino optionally substituted with one or more Ci to Ce alkyls, where the Cj 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 alkyls, -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 Cg to C8 aryl optionally substituted with:
-an alkyl,
-one or more halos, -a nitro group, or -one or more alkoxys, -a -NR0CORp group, where Rp is:
-a Ci to CO alkyl optionally substituted with: -a halo, -an alkoxy, or -a Ce to Cg aryl, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to
Ce alkyl or Ce to Cg aryl groups, -a Ce to C8 aryl, optionally substituted with a halo,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyls,
-a hydrogen,
and where R0 is:
-a hydrogen,
-a C1 to C6 alkyl,
-a -CORx group, where Rx is a Ci to C6 alkyl,
-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 Ce to C8 aryl optionally substituted with:
-a Ci to Cβ alkyl optionally and independently substituted with one or more Ce to C8 aryl, halo and/or C1 to Cg alkoxy groups, -a Ci to C6 alkoxy, -a Ci to Cή haloalkoxy, -a -ORS group, where Rs is a CO to C8 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 halo,
-a hydroxyl, -an alkoxy, -an alkylene,
-a 5 or 6 membered heterocycle optionally substituted with one or more halo, Ci to C6 alkyl, Ct to C6 haloalkyl, Ci to C6 alkoxy, Ci to C6 haloalkoxy,
-a 5 or 6 membered heteroaryl optionally substituted with one or more halo, Ci to C6 alkyl, Ci to C6 haloalkyl, Ci to C6 alkoxy, Ci to C6 haloalkoxy, -a C6 to Cs aryl optionally substituted with with one or more halo, Cj to
Ce alkyl, Ci to C6 haloalkyl, Ci to Ce alkoxy, Ci to Ce haloalkoxy, or -a -COORx group, where Rx is as defined above, -a C2 to C6 alkylene group, -a Ci to Ce alkoxy group, -a 5 or 6 membered heterocycle group optionally substituted with with one or more halo, Ci to Ce alkyl, Ci to Ce haloalkyl, Cj to Ce alkoxy., Ci to C6 haloalkoxy,
-a -COORx group, where Rx is as defined above, COORn group, where R11 is: -a Ci to Ci2 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to Cs aryl optionally substituted with one or more halo, Ci to C6 alkyl, Ci to C6 haloalkyl, Ci to C6 alkoxy, Ci to C6 haloalkoxy, -an alkylene, -an alkoxy,
-an alkyne,
-an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to Ce alkyl, -halo, or -a 5 or 6 membered heterocycle,
-a 5 or 6 membered heteroaryl, - a C2 to C6 alkylene,
-a C6 to Cg aryl, optionally substituted with: -an alkoxy,
-a halo, or -a C1 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 -NRvSO2Rw group, where Rv is:
-a hydrogen,
-a -CORx, where Rx is as defined above, or -a Ci to CO alkyl, optionally substituted with:
-a halo, -a -CORx group, where Rx is as defined above,
-a -OCORx group, where Rx is as defined above, -a hydroxyl, or -an alkoxy, and where Rw is: -a C) to C6 alkyl optionally substituted with:
-a halo, -a haloalkyl, -a Cg to Cg aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halo, -a 5 or 6 membered heterocycle, or
-a 5 or 6 membered heteroaryl optionally substituted with one or more of the following: -halo,
-a Ci to C6 alkyl, -Ci to C6 haloalkyl, -C] to Cg alkoxy, - Ci to Ce haloalkoxy,
-a 5 or 6 membered heterocycle, or
where Ry is a hydrogen, Ci to Ce alkyl optionally substituted with a Ci to Ce alkoxy, Ci to Ce haloalkyl, Ce to Cs aryl, 5 or 6 membered heteroaryl, or 5 or 6 membered heterocycle, where the Ce to Cg aryl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocycle are each optionally and independently substituted with one or more halo, Ci to C6 alkyl, Cj to C6 alkoxy, Ci to Cg haloalkyl,
Ci to CO haloalkoxy,
-a 'O , where Ry is as described above and R2 is hydrogen or a Ci to
CO alkyl optionally substituted with a Ce to C8 aryl,
where Ry is as described above, -a -SRx group, where Rx is as defined above,
-a -Sθ2Raa group, where R33 is:
-a Ci to C6 alkyl,
-an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy, a 5 or 6 membered heterocycle, a 5 or 6 membered heteroaryl, or a -COORx group, where Rx is as defined above, -a 5 or 6 membered heteroaryl,
-a 5 or 6 heterocycle optionally substituted with hydroxy, a Ci to Ce alkoxy, or a a Ci to Ce alkyl, where the alkyl is optionally substituted with one or more hydroxy, -a Ce to Cs aryl, or
-a -NHRbb group, where Rbb is:
-a -CC=S)NH2 group, or
-a -PO(ORx)2, 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, -an hydroxy,
-a halo,
-a Ci to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Ce alkyls, -a -NHPORxRx, where Rx is as defined above, -a -NReeCONRffRff group, where R03 is a hydrogen or a Ci to C6 alkyl, optionally substituted with a halo, 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 RM1 is: -a hydrogen,
-a Ci to CO alkyl optionally substituted with: -an alkoxy,
-a halo, or
-an amino optionally substituted with one or more Ci to Cβ alkyls,
-an amino optionally substituted with one or more C) to C6 alkyls, where the alkyls are optionally substituted with a halo,
-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 C] to C6 alkyls, -a -NR«Sθ2Rx 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 Ci to Ce alkyl optionally substituted with: -an alkoxy, -one or more halos, - a 5 or 6 membered heterocycle, or
-a Cβ to C8 aryl;
-a 5 or 6 membered heterocycle; -a C2 to Ce alkylene;
-a CO to Cg aryl optionally substituted with an alkoxy or one or more Cj to C6 alkyls; -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halo or an alkoxy;
-a hydrogen; -a hydroxy; -a halo; -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 halos,
-a C6 to C8 aryl optionally substituted with one or more halo, Ci to C6 alkyl, Ci to C6 alkoxy, Ci to C6 haloalkyl, Cj to Cg haloalkoxy, Cj to Ce hydroxy, and/or SOΪRX groups,
-a 5 or 6 membered heterocycle optionally substituted with one or more halo, Cj to Cg alkyl, C1 to C6 alkoxy, Ci to Ce haloalkyl, Ci to C6 haloalkoxy, Ci to C6 hydroxy, and/or SO2Rx groups,
-a 5 or 6 membered heteroaryl optionally substituted with one or more halo, Ci to Ce alkyl, Ci to C6 alkoxy, Ci to C6 haloalkyl, Ci to C6 haloalkoxy, C1 to C6 hydroxy, and/or SC^R* groups,
-an amino optionally substituted with a heterocycle; -a C6 to Cg aryl optionally substituted with an alkoxy; -a -CORx group, where Rx is as defined above; -a C1 to C6 alkyl optionally substituted with one or more dialkyl-amino, a Cg to Cg aryl, a 5 or 6 membered heteroaryl, and/or a 5 or 6 membered heterocycle, where each of the C6 to Cg aryl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocycle is optionally substituted with one or more halo, Ci to C6 alkyl, C1 to C6 alkoxy, Ci to C6 haloalkyl, Cj to C6 haloalkoxy, Ci to C6 hydroxy, and/or SO2Rx groups; or
Ri joins together with R2 to form:
R2 is:
-a nitro group; -a hydrogen; -a halo;
-a hydroxy group; -a Ci to Ce alkyl group, optionally substituted with one or more of the following:
-halos, -5 or 6 membered heterocycle group, optionally substituted with one or more halo, Ci to
CO alkyl, Ci to Cβ alkoxy, Ci to Ce haloalkyl, Ci to Ce haloalkoxy, Ci to Ce hydroxy, and/or SO2Rx groups,
-5 or 6 membered heteroaryl group, is optionally substituted with one or more halo, Ci to CO alkyl, Ci to Ce alkoxy, Ci to C6 haloalkyl, Ci to Ce haloalkoxy, Ci to Cg hydroxy, and/or SO2Rx groups,
-Cδ to C8 aryl group, is optionally substituted with one or more halo, Ci to Cδ alkyl, Ci to C6 alkoxy, Ci to Ce haloalkyl, Ci to CO haloalkoxy, Ci to Ce hydroxy, and/or SO2Rx groups, -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an amino group optionally substituted with one or more C] to Ce alkyl groups;
-an alkoxy group optionally substituted with one or more groups independently selected from the following: -halos,
-hydroxy group, -an alkoxy group optionally substituted with an alkoxy group,
-an -OCORx group, where Rx is as defined above,
-an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or
- an amino optionally substituted with one or more alkyl groups; -a dialkyl-amino optionally substituted with an alkoxy, -a 4 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C6 alkyl group, the Ci to Ce alkyl group optionally substituted with one or more independently selected Ci to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more independently selected halo, Ci to CO alkyl, Ci to CO alkoxy, Cj to CO haloalkyl, Ci to C6 haloalkoxy, Ci to Ce hydroxy, and/or SO2Rx groups, or -a C6 to Cg aryl group optionally substituted with one or more independently selected halo, Ci to C6 alkyl, Ci to C6 alkoxy, Ci to C6 haloalkyl, Ci to C6 haloalkoxy, Ci to C6 hydroxy, and/or SO2Rx groups; -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to Cg aryl groups; - a -COOH group;
-a -COORx group, where Rx is as defined above;
-a haloalkyl;
-a -C(O)NB^ optionally substituted with one or more of the following:
-Ci to C6 alkyl groups optionally substituted with one or more independently selected halo, Ci to C6 alkoxy, Cj to C6 hydroxy, a 5 or 6 membered heterocycle and/or a 5 or 6 membered heteroaryl, -hydroxy groups, or -C6 to Cs aryl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Ci to C6 alkyl,
-SO2RX,
-C(O)-C6 to C8 aryl, -C(O)ORx; or -hydroxy, -a 5 or 6 membered heteroaryl optionally substituted with one or more independently selected halo, Ci to C6 alkyl, Ci to C6 alkoxy, Ci to C6 haloalkyl, Ci to C6 haloalkoxy, Ci to C6 hydroxy, and/or SO2Rx groups;
-a -OCORx group, where Rx is as defined above; -a -NHCORjj group, where RJJ is:
-an alkyl, -a C6 to C8 aryl, -an alkoxy, or
-an amino optionally substituted with one or more Ci to Cg alkyls; -an -ORkk group, where Rkk is
-a C6 to C8 aryl optionally substituted with one or more independently selected halo, Ci to Ce alkyl, Ci to Ce alkoxy, Ci to CO haloalkyl, Ci to Ce haloalkoxy, Ci to CO hydroxy, and/or SO2Rx groups,
-a 5 to 6 membered heteroaryl, optionally substituted with a halo, Ci to Ce alkyl, Ci to Ce alkoxy, Ci to C$ haloalkyl, Ci to Ce haloalkoxy, Cj to Ce hydroxy, and/or SC^Rx groups,
-a 5 to 6 membered heterocycle, optionally substituted with a C] to Ce alkyl, optionally substituted with a Cg to Cs aryl group, or -an Si(Rx)3;
-a -NHSOaRx group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CEfeOCORx, and Rx is as defined above;
Group A is
-a halo,
-Ci to C6 alkyl,
-Ci to Ce alkoxy, -Ci to C6 haloalkyl,
-Ci to Ce haloalkoxy,
-a -NR0CORp group, where Rp is:
-a Ci to C6 alkyl optionally substituted with:
-a halo, -an alkoxy, or
-a C6 to C8 aryl,
-a 5 or 6 membered heterocycle, optionally substituted with one or more C) to Ce alkyl or CO to C8 aryl groups, -a Ce to Cs aryl, optionally substituted with a halo,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyls, -a hydrogen,
and where R0 is:
-a hydrogen,
-a Ci to Ce alkyl,
-a -CORx group, where Rx is a Ci to Ce alkyl,
-a haloalkyl, or
-a haloalkoxy, -a -NRqCONRqRr group, where R<, 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 Ce alkyl optionally and independently substituted with one or more Ce to C8 aryl, halo and/or Ci to CO alkoxy groups,
-a Ci to Cβ alkoxy,
-a Ci to C6 haloalkoxy,
-a -OR8 group, where Rs is a C6 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 halo,
-a hydroxyl,
-an alkoxy,
-an alkylene, -a 5 or 6 merabered heterocycle optionally substituted with one or more halo, Ci to C6 alkyl, Ci to C6 haloalkyl, Ci to C6 alkoxy, Ci to C6 haloalkoxy,
-a 5 or 6 membered heteroaryl optionally substituted with one or more halo, Ci to C6 alkyl, Ci to C6 haloalkyl, Ci to C6 alkoxy, Ci to C6 haloalkoxy,
-a C6 to Cg aryl optionally substituted with with one or more halo, C1 to
C6 alkyl, Cj to C6 haloalkyl, Ci to C6 alkoxy, Ci to C6 haloalkoxy, or
-a -COORx group, where Rx is as defined above, -a C2 to C6 alkylene group, -a Ci to C6 alkoxy group,
-a 5 or 6 membered heterocycle group optionally substituted with with one or more halo, Ci to C6 alkyl, Ci to C6 haloalkyl, Ci to C6 alkoxy, Ci to C6 haloalkoxy,
-a -COORx group, where Rx is as defined above, -a -NRtCOORu group, where Ru is:
-a C] to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to Cs aryl optionally substituted with one or more halo, Ci to C6 alkyl, Ci to C6 haloalkyl, Ci to C6 alkoxy, Ci to C6 haloalkoxy, -an alkylene,
-an alkoxy,
-an alkyne,
-an alkoxy group optionally substituted with one or more alkoxy groups,
-an amino optionally substituted with one or more C] to C6 alkyl,
-halo, or
-a 5 or 6 merabered heterocycle, -a 5 or 6 membered heteroaryl, - a C2 to Cδ alkylene, -a Cβ to Cg aryl, optionally substituted with:
-an alkoxy, -a halo, or -a Ci 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 -NRvSO2Rw group, where Rv is: -a hydrogen,
-a -CORx, where Rx is as defined above, or -a Ci to C6 alkyl, optionally substituted with: -a halo,
-a -CORx group, where Rx is as defined above, -a -OCORx group, where Rx is as defined above, -a hydroxyl, or -an alkoxy, and where Rw is:
-a Ci to Ce alkyl optionally substituted with: -a halo, -a haloalkyl, -a Cβ to Cs aryl, or -a 5 or 6 membered heterocycle,
-a C2 to C6 alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halo, -a 5 or 6 membered heterocycle, or
-a 5 or 6 membered heteroaryl optionally substituted with one or more of the following:
-halo,
-a C, to C6 alkyl,
-Ci to C6 haloalkyl,
-Ci to C6 alkoxy,
- Ci to Ce haloalkoxy,
-a 5 or 6 membered heterocycle, or
-a -SO2R38 group, where Raa is: -a Ci to C6 alkyl, -an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy, a 5 or 6 membered heterocycle, a 5 or 6 membered heteroaryl, or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl,
-a 5 or 6 heterocycle optionally substituted with hydroxy, a Ci to Ce alkoxy, or a a Ci to Ce alkyl, where the alkyl is optionally substituted with one or more hydroxy, -a -NHRbb group, where Rt* is: -a -C(=S)NH2 group, or
-a -PO(ORx)2, where Rx is as defined above; -a -CORn, group, where Rm is:
-an amino optionally substituted with one or more Ci to Ce alkyls, 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 alkyls, -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 C8 aryl optionally substituted with: -an alkyl,
-one or more halos, -a nitro group, or
-one or more alkoxys; and
L is a direct bond, Cj to Q2 alkylene, C2 to C12 alkenylene or C2 to Ci2 alkynylene, wherein one or more — CH2 — group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with — O — , — S — , — SO2 — and/or — NRmm — , and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s), halos, and/or hydroxy(s), where Rmm is hydrogen or Ci to Ce alkyl; or a pharmaceutical salt thereof. hi a further embodiment, the present invention includes compounds of Formula I, with the proviso that at least one of Y, Z, Rt and R2 is selected from the following: Y is:
-a benzothiazole substituted with an amino group optionally substituted with one or more Cj to CO alkyls;
-an indole substituted on the nitrogen with an -SC^Rx group; -a Ce to Cs aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following: -SO2Rx, or
-Ci to Cβ alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRx, -OC(O)N(RX)2,
-OC(O)NH(ORx), -OC(O)NRx(ORx), -OC(O)N(ORX)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is:
-an amino group optionally substituted with one or more Ci to Ce alkyl groups where the Ci to Cδ alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, or
-a 5 or 6 membered heterocycle, substituted with one or more Ci to C6 alkyl or Cδ to C8 aryl groups, -a -NRqCONRqRr group, where Rr is:
-a Ci to C6 alkyl substituted with one or more of the following: -a hydroxyl,
-an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a Ce to Cs aryl substituted with a halo, -a C2 to Ce alkylene group,
-a Ci to Ce alkoxy group, or -a 5 or 6 membered heterocycle group, -a -NRtCOORu group, where R11 is:
-a Ci to C12 alkyl, substituted with one or more of the following: -an alkoxy group substituted with one or more alkoxy groups,
-an amino optionally substituted with one or more Ci to Cβ alkyl, or -a 5 or 6 membered heteroaryl,
-a C2 to CO alkylene, or
Z is:
-a Ci to Cg alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; or
Ri is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle; R2 is:
-a Ci to Cδ alkyl group, substituted with one or more of the following: -5 or 6 membered heterocycle groups, or
-amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following:
-a hydroxy group,
-an alkoxy group optionally substituted with an alkoxy group,
-an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups; -a 7 membered heterocycle group;
-a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Cj to
Ce alkyl groups substituted with Ci to Ce alkoxy, or
-a 5 or 6 membered heteroaryl group substituted with one or more Ci to Ce alkyl groups;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to Cg aryl groups;
-a -COOH group;
-an amide group substituted with one or more Ci to CO alkyl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-Ci to C6 alkyl, -SO2Rx,
-C(O)-C6 to C8 aryl, or -C(O)ORx groups; -an -ORkk group, where R^k is:
-a 5 to 6 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a C6 to C8 aryl group, or
-an -Si(Rx)3; or a pharmaceutically acceptable salt thereof.
In another embodiment, a compound of Formula I is included, with the proviso that at least one of X, Y, Z, Ri, and R2 is selected from the following: X is:
-a -COOH group;
_a
to C6 alkoxy-
-a halo;
-an alkyl optionally substituted with one or more halo; -an alkyne optionally substituted with a Cj to Ce alkyl optionally substituted with one or more halo or cyano groups;
-an oxime;
-SO2Rx;
-SO2NH2; -SO2NH(Rx);
-SO2N(Rx)2;
-an amino optionally substituted with one or more Cj to Ce alkyl groups or C(O)- Ci to Cβ alkyl groups;
-an amide group optionally substituted with one or more independently selected Ci to C6 alkyl group;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl substituted with one or more Ci to Cs alkyl groups substituted with one or more halos; or
-a Ce to Cs aryl group substituted with one or more of the following: -Ci to Ce alkyl optionally substituted with one or more halos,
-halo, or -cyano;
Y is:
-a benzothiazole substituted with an amino group optionally substituted with one or more Cj to C6 alkyls;
-an indole substituted on the nitrogen with an SO2Rx group; -a Ce to Cs aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following: -SO2Rx, or
-Ci to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRx,
-OC(O)NH(ORx), -OC(O)NRx(ORx),
-OC(O)N(ORX)2,
-OC(O)Rat>, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is:
-an amino group optionally substituted with one or more Ci to Cβ alkyl groups where the C] to Ce alkyl groups are optionally and independently substituted with one or more Ce to C8 aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Ci to C$ alkyl or Cδ to Cs aryl groups, -a -NRqCONRqRr group, where Rr is: -a Ci to Ce alkyl substituted with one or more of the following:
-a hydroxyl, -an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a Cg to C8 aryl substituted with a halo,
-a Cj to Cg alkylene group, -a Ci to Ce alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORu group, where R1, is: -a Ci to Cu alkyl, substituted with one or more groups independently selected from the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to C$ alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to Ce alkylene, or
Z is:
-a Ci to Ce alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; Ri is: -a Ci to Ce alkyl substituted with:
-an amide optionally substituted with a Ci to C6 alkyl, or -a 5 or 6 membered heteroaryl; -a Ci to C6 alkoxy substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a Ci to Cβ alkyl,
-a 5 or 6 membered heterocycle substituted with a Ci to Ce alkyl, or
-a 5 or 6 membered heteroaryl; -an (O)-5 or 6 membered heterocycle; -an (O)-5 or 6 membered heteroaryl; -an -SO2RX group optionally substituted with the following:
-a 5 or 6 membered heterocycle,
-a C6 to Cg aryl,
-a 5 or 6 membered heteroaryl; or -alkylthio optionally substituted with the following: -a 5 or 6 membered heterocycle,
-a Ce to Cg aryl,
-a 5 or 6 membered heteroaryl; or
R2 is:
~a Ci to Cή alkyl group, substituted with one or more of the following: -5 or 6 membered heterocycle groups,
-5 or 6 membered heteroaryl groups,
-Cδ to Cg aryl groups,
-an amide optionally substituted with a Ci to C6 alkyl, or
-amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
-an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
-an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group;
-an alkylthio group optionally substituted with a C6 to C8 aryl group;
-an alkylthio group optionally substituted with a C] to C6 alkyl group; -an SO2R* group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyl groups;
-an SO2RX group optionally substituted with a 5 or 6 membered heterocycle group; -an SO2R.X group optionally substituted with a CO to Cg aryl group; -an SC^Rx group optionally substituted with a Ci to C6 alkyl group; -an S(O)Rx group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)Rx group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)Rx group optionally substituted with a Ce to Cs aryl group; -an S(O)Rx group optionally substituted with a Ci to C6 alkyl group; -an alkoxy group substituted with an alkoxy group,
-an amino group substituted with one or more 5 or 6 membered heteroaryl, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups; -an amide optionally substituted with a Ci to C6 alkyl, -S-5 or 6 membered heterocycle,
-S-5 or 6 membered heteroaryl optionally substituted with a Ci to Ce alkyl, -S-Ci to C6 alkyl,
-S-C6 to C8 aryl,
-sulfinyl-5 or 6 membered heterocycle, -sulfinyl-5 or 6 membered heteroaryl, -sulfinyl-Ci to C6 alkyl, -sulfϊnyl-Cό to C8 aryl,
-sulfonyl-5 or 6 membered heterocycle,
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ci to C(, alkyl, -sulfonyl- Ci to Ce alkyl, -sulfonyl- C6 to C8 aryl, -a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Ci to Cβ alkyl groups substituted with Ci to Ce alkoxy, or
-a 5 or 6 membered heteroaryl group substituted with one or more Ci to C6 alkyl groups -a C6 to C8 aryl group;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -C(O)- C6 to C8 aryl; -a -COOH group; -an amide group substituted with one or more C] to C6 alkyl groups optionally substituted with one or more Ci to Cg alkoxy; -a 5 or 6 membered heterocycle, substituted with one or more of the following:
-hydroxy,
-C] to C6 alkyl, -SO2Rx groups,
-C(O)-C6 to C8 aryl, or
-C(O)ORx groups; -an -ORkk group, where Rkk is:
-a Ce to C8 aryl, -a 5 to 6 membered heterocycle, optionally substituted with a Ci to C6 alkyl, optionally substituted with a Cβ to Cg aryl group, or
-an -Si(Rx)3;
-an (O)-5 or 6 membered heterocycle; or
-an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Cj to Ce alkyl groups; or a pharmaceutically acceptable salt thereof.
In another embodiment the present invention includes compounds of Formula I, with the proviso that with the proviso that at least one of Y, Z, and R2 is selected from the following: Y is: -a benzothiazole substituted with an amino group optionally substituted with one or more Ci to C6 alkyls;
-an indole substituted on the nitrogen with an -SO2Rx group; -a Ce to C8 aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following: -SO2Rx, or
-Ci to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRx, -OC(O)N(RX)2,
-OC(O)NH(ORx),
-OC(O)NRx(ORx), -OC(O)N(ORx)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is: -an amino group optionally substituted with one or more Cj to C6 alkyl groups where the C) to Cή alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, substituted with one or more Ci to Ce alkyl or Ce to Cg aryl groups, -a -NRqCONRqRr group, where R1- is:
-a Ci to Ce alkyl substituted with one or more of the following: -a hydroxyl, -an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or
-a Cδ to Cs aryl substituted with a halo, -a C_ to C& alkylene group, -a Ci to Ce alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORu group, where Ru is:
-a Ci to Ci2 alkyl, substituted with one or more groups independently selected from the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to C6 alkyl, or -a 5 or 6 membered heteroaryl,
-a C2 to Ce alkylene,
Z is:
-a Ci to Ce alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; R2 is:
-a C1 to CO alkyl group, substituted with one or more of the following: -5 or 6 membered heterocycle groups,
-amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following:
-hydroxy group,
-an alkoxy group optionally substituted with an alkoxy group,
-an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups; -a 7 membered heterocycle group; -a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Ci to C6 alkyl groups substituted with Ci to Ce alkoxy, or
-a 5 or 6 membered heteroaryl group substituted with one or more Ci to Cg alkyl groups; -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more Cg to Cs aryl groups;
-a -COOH group;
-an amide group substituted with one or more Ci to Ce alkyl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Ci to C6 alkyl,
-SO2Rx group, -C(O)-C6 to C8 aryl, or -C(O)ORx groups; -an -ORkk group, where Rkk is: -a 5 to 6 membered heterocycle, optionally substituted with a Ci to C6 alkyl, optionally substituted with a C$ to Cs aryl group, or -an -Si(Rx)3; or a pharmaceutically acceptable salt thereof.
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 Ci to Cn, or Ci to C8 or Ci to C6 alkyl groups.
As used herein, "alkylene" generally refers to straight, branched or cyclic alkene radicals having one or more carbon-carbon double bonds, such as C2 to Q alkylene groups including 3-proρenyl.
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, fiuorenyl, 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 heteroatom(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, furazan, 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 compound of the present invention, 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 another embodiment, the present invention includes compounds of Formula (I-X)
(I-X) wherein: X is:
-a cyano group;
Y is:
-a hydrogen; -a haloalkyl; -a halo; -an amino optionally substituted with one or more Ci to Ce alkyls; -a benzofuran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene; -a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to Cg alkyls; -a naphthalene; -an indole, optionally substituted on the nitrogen with a Ci to Cg alkyl or an -SOaRx group;
, where Rb is a hydrogen or a Cj to Ce alkyl, and n is 0 or 1 ;
, where R0 is a hydrogen, a -CONHRx, where Rx is a Ci to Ce alkyl, or an -Sθ2Rx, where Rx is a Ci to C6 alkyl; or
where Ra is a Ci to C6 alkyl or a C6 to Cg aryl; -a -NHCORe group, where R6 is: -a C1 to C6 alkyl;
-a C6 to Cg aryl optionally substituted with: -a Ci to C6 alkyl,
-an alkoxy, -a cyano group, -a nitro group, or -a halo; -a -NHCOORx group, where Rx is a Cj to C6 alkyl; -a -CH2O-Rf group, where Rf is a C6 to C8 aryl;
-a -NRgRh group, where R8 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 C] to C6 alkyl, optionally substituted with a C6 to C8 aryl,
-a C6 to Cg aryl, optionally substituted with -COORx, where Rx is a Ci to C6 alkyl, 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 halos,
-a 5 or 6 membered heterocycle, optionally substituted with: -a C i to C6 alkyl, or -a hydroxy, -an amino optionally substituted with one or more Ci to C6 alkyls,
-a -NRiSO2Rx group, where Rx is a Ci to Ce alkyl 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 Rk is: -a Ci to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Q to Cg alkyls, and Rj is:
-a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is a Cj to Ce alkyl, -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 of the following:
-SO2(Rx), or
-Ci to C6 alkyl, the Cj to Ce alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -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 halo, -a hydroxy,
-OC(O)NHRx, -OC(O)N(RX)2, -OC(O)NH(ORx), -OC(O)NRx(ORx),
-OC(O)N(ORX)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -COORx group, where Rx is a Ci to Ce alkyl, -a -CORm group, where Rm is: -an amino optionally substituted with one or more Ci to C6 alkyls, 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 CO alkyls, or -an alkoxy,
-a 3 to 7 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a dialkyl-amino, or -a -NHRn group, where Rn is:
-a -CH2CONH2, or -a Ca to Cs aryl optionally substituted with:
-an alkyl,
-one or more halos, -a nitro group, or -one or more alkoxys, -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with: -a halo, -an alkoxy, or -a Cg to C8 aryl, -an amino group optionally substituted with one or more Ci to Cg alkyl groups where the Ci to Ce alkyl groups are optionally and independently substituted with one or more C6 to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Cj to Ce alkyl or Cβ to Cg aryl groups, -a Ce to C8 aryl, optionally substituted with a halo,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyls,
-a hydrogen,
and where R0 is:
-a hydrogen,
-a C1 to C6 alkyl,
-a -CORx group, where Rx is a Ci to CO alkyl,
-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 CO to Cs aryl optionally substituted with:
-a Ci to C6 alkyl, -a haloalkyl,
-a -OR3 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 halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle,
-a 5 or 6 membered heteroaryl, -a C6 to Cg aryl optionally substituted with a halo, or -a -COORx group, where Rx is as defined above, -a C2 to C6 alkylene group, -a Ci to Cδ alkoxy group,
-a 5 or 6 membered heterocycle group, or -a -COORx group, where Rx is as defined above, -a -NR1COORu group, where Ru is:
-a Ci to Ci2 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C8 aryl optionally substituted with halo, Ci to C6 alkyl, or alkoxy,
-an alkylene, -an alkoxy, -an alkyne,
-an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to C6 alkyl, -halo,
-a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl,
-a C2 to Cδ alkylene,
-a Ce to Cs aryl, optionally substituted with: -an alkoxy, -a halo, 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 -NRvSO2Rw group, where Rv is: -a hydrogen,
-a -CORx, where Rx is as defined above, or -a Ci to Cg alkyl, optionally substituted with:
-a halo,
-a -CORx group, where Rx is as defined above,
-a -OCORx group, where Rx is as defined above,
-a hydroxyl, or
-an alkoxy, and where Rw is:
-a C] to Ce alkyl optionally substituted with:
-a halo,
-a halo alkyl,
-a CO to Cs aryl, or
-a 5 or 6 membered heterocycle, -a C2 to Ce alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halo, -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 CO alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
where R2 is hydrogen or a Ci to Cs alkyl, optionally substituted with a Ce to Cs aryl,
-a -SRx group, where Rx is as defined above,
-a -SOaRa3 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, or
-a 5 or 6 membered heteroaryl, -a Ce to Cg aryl, or -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or
-a -PO(ORX)2, where Rx is as defined above; or -a * ■■ ■■' Rcc group, where R00 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 halo,
-a Ci to CO alkyl, optionally substituted with a cyano group, . -an amino optionally substituted with one or more Ci to Ce alkyls,
-a -NHPORXRX, where Rx is as defined above,
-a -NReeCONRffRff group, where R∞ is a hydrogen or a Ci to Cβ alkyl. optionally substituted with a halo, and Rn- 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 Ce alkyl optionally substituted with: -an alkoxy, -a halo, or
-an amino optionally substituted with one or more Ci to Ce alkyls,
-an amino optionally substituted with one or more Ci to Cg alkyls, where the alkyls are optionally substituted with a halo,
-a 5 or 6 membered heterocycle, or
-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 Cβ alkyls, or -a -NR11SOaRx group, where Rx is as defined above, and Ru 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 hydrogen;
-a Ci to C6 alkyl optionally substituted with: -an alkoxy, -one or more halos, -a 5 or 6 membered heterocycle, or
-a C6 to Cg aryl;
-a 5 or 6 membered heterocycle; -a C2 to Ca alkylene;
-a CO to Cg aryl optionally substituted with an alkoxy or one or more C] to Ce alkyls; -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halo or an. alkoxy;
-a hydrogen; -a hydroxy; -a halo; -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 halos, -a Cβ to Cs aryl,
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with a heterocycle;
-a Ce to Ce aryl optionally substituted with an alkoxy; -a -CORx group, where Rx is as defined above; or
-a Cj 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 halo;
-a hydroxy group;
-a C) to C6 alkyl group, optionally substituted with one or more of the following: -halos,
-5 or 6 membered heterocycle groups, or
-amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
-an amino group;
-an alkoxy group optionally substituted with one or more groups independently selected from the following: -halos, -a hydroxy group,
-an alkoxy group optionally substituted with an alkoxy group, -an -OCORx group, where Rx is as defined above, or
-an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups; -a dialkyl-amino optionally substituted with an alkoxy, -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to Cβ alkyl group, the Ci to Ce alkyl group optionally substituted with one or more independently selected Ci to Ce alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to C6 alkyl groups, or -a Cβ to Cg aryl group; -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more Cg to C8 aryl groups;
-a -COOH group;
-a -COORx group, where Rx is as defined above; -a haloalkyl; -an amide group optionally substituted with one or more of the following: -Ci to C6 alkyl groups, -hydroxy groups, or -C6 to Cg aryl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-Ci to C6 alkyl,
-SO2RX,
-C(O)-C6 to C8 aryl, or
-C(O)ORx groups; -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 alkyls; -an -ORkk group, where R^ is:
-a 5 to 6 membered heteroaryl,
-a 5 to 6 membered heterocycle, optionally substituted with a C] to Ce alkyl, optionally substituted with a Cg to Cg aryl group, or
-an Si(Rx)3; or
-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; or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention includes compounds of Formula (I-Xa)
wherein
X is:
-a cyano group;
Y is:
-a hydrogen; -a haloalkyl;
-a halo;
-an amino optionally substituted with one or more Ci to Cβ alkyls;
-a benzofuran;
-a benzothiophene; -a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to Ce alkyls;
-a naphthalene; -an indole, optionally substituted on the nitrogen with a Cj to C$ aUcyl or an -SC^R*;
, 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 a Ci to Ce alkyl, or an -SO2Rx, where Rx is a Ci to CO alkyl; or
where Rd is a Ci to C6 alkyl or a C6 to Cs aryl; -a -NHCORe group, where Re is: -a C] to C6 alkyl;
-a C6 to Cg aryl optionally substituted with: -a Ci to Ce alkyl,
-an alkoxy, -a cyano group, -a nitro group, or -a halo; -a -NHCOORx group, where Rx is a C] to C6 alkyl; -a -CH2O-Rf group, where Rr is a C6 to C8 aryl;
-a -NRgRh group, where Rg is a Ci to Ce alkyl or a hydrogen and Rh is a C6 to Cs aryl optionally substituted with an alkoxy; -a Ci to Ce alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
-a Ci to C6 alkyl, optionally substituted with a C6 to C8 aryl,
-a C6 to C8 aryl, optionally substituted with -COORx, where Rx is a Cj to C6 alkyl, 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 CO to Cg aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy,
-one or more halos,
-a 5 or 6 membered heterocycle, optionally substituted with: -a Ci to C6 alkyl, or -a hydroxy, -an amino optionally substituted with one or more Ci to C6 alkyls,
-a -NRiSO2Rx group, where Rx is a Ci to C6 alkyl 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 -NRjCORk group, where Rk is: -a Ci to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Ci to Ce alkyls, and Rj is:
-a hydrogen, -a C1 to C6 alkyl,
-a -CORx group, where Rx is a Ci to C6 alkyl, -a haloalkyl, or
-a haloalkoxy, -a -N=N+=N" group, or
-a -COR], where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more of the following:
-SO2(Rx), or
-Ci to C6 alkyl, the Ci to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -a nitro group, -a Ci to C6 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 halo, -a hydroxy,
-OC(O)NHRx, -OC(O)N(RX)2, -OC(O)NH(ORx), -OC(O)NRx(ORx),
-OC(O)N(ORX)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -COORx group, where Rx is a Ci to C6 alkyl, -a -CORm group, where Rm is: -an amino optionally substituted with one or more Ci to Ce alkyls, 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 C^ alkyls, or -an alkoxy,
-a 3 to 7 membered heterocycle, optionally substituted with a Ct to C6 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 halos, -a nitro group, or -one or more alkoxys, -a -NR0CORp group, where Rp is:
-a Ci to CO alkyl optionally substituted with: -a halo, -an alkoxy, or -a Cβ to Cg aryl, -an amino group optionally substituted with one or more Ci to Cf, alkyl groups where the Cj to C& alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to Ce alkyl or Ce to Cs aryl groups, -a Ce to Cs aryl, optionally substituted with a halo,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyls,
-a hydrogen,
and where R0 is:
-a hydrogen,
-a Ci to C6 alkyl,
-a -CORx group, where Rx is a Ci to Ce alkyl,
-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 Ce to Cs aryl optionally substituted with:
-a Ci to C6 alkyl, -a haloalkyl,
-a -OR5 group, where R3 is a Cβ to C8 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 halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle,
-a 5 or 6 membered heteroaryl, -a C6 to C8 aryl optionally substituted with a halo, or -a -COORx group, where Rx is as defined above, -a C2 to Cβ alkylene group, -a Ci to CO alkoxy group,
-a 5 or 6 membered heterocycle group, or -a -COORx group, where Rx is as defined above, -a -NRtCOORu group, where R11 is:
-a Ci to C12 alkyl, optionally substituted with one or more of the following: -a Cδ to Cs aryl optionally substituted with halo, Ci to Ce alkyl, or alkoxy,
-an alkylene, -an alkoxy, -an alkyne, -an alkoxy group optionally substituted with one or more alkoxy groups,
-an amino optionally substituted with one or more Ci to Ce alkyl, -halo,
-a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene,
-a Ce to Cs aryl, optionally substituted with: -an alkoxy, -a halo, or -a C) 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 -NRvSO2Rw group, where Rv is: -a hydrogen, -a -CORx, where Rx is as defined above, or
-a Ci to Cβ alkyl, optionally substituted with:
-a halo,
-a -CORx group, where Rx is as defined above,
-a -OCORx group, where Rx is as defined above,
-a hydroxyl, or
-an alkoxy, and where Rw is:
-a Ci to Ce alkyl optionally substituted with:
-a halo,
-a haloalkyl,
-a C6 to Cs aryl, or
-a 5 or 6 membered heterocycle, -a C2 to Cβ alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halo, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 atkyl,
-a 5 or 6 membered heterocycle, or
optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to Ce alkyl or hydrogen,
where Rx is hydrogen or a Ci to CO alkyl, optionally substituted with a CO to C8 aryl,
-a -SRx group, where Rx is as defined above,
-an -SO2Raa 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, or
-a 5 or 6 membered heteroaryl, -a Ce to Cs aryl, or -a -NHRbb group, where Rbb is:
-a -C(3S)NH2 group, or -a -PO(ORx)2, where Rx is as defined above; or = 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 halo,
-a Ci to Ce alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to C^ alkyls, -a -NHPORxRx, where Rx is as defined above,
-a -NReeCONRffRff group, where R00 is a hydrogen or a Ci to Ce alkyl, optionally substituted with a halo, and Rn- 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 C] to Cβ alkyl optionally substituted with:
-an alkoxy, -a halo, or
-an amino optionally substituted with one or more Ci to Ce alkyls,
-an amino optionally substituted with one or more C] to Ce alkyls, where the alkyls are optionally substituted with a halo, -a 5 or 6 membered heterocycle, or
-a 5 or 6 membered heteroaryl,
-a hydrogen, -a C1 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 C6 alkyls, or
-a -NRiiSdRx group, where Rx is as defined above, and RU 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 hydrogen;
-a C1 to CO alkyl optionally substituted with: -an alkoxy,
-one or more halos, -a 5 or 6 membered heterocycle, or -a Ce to Cs aryl; -a 5 or 6 membered heterocycle;
-a C2 to Ce alkylene;
-a C6 to Cs aryl optionally substituted with an alkoxy or one or more Cj to C6 alkyls;
-a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halo or an alkoxy; Ri is:
-a hydrogen; -a hydroxy; -a halo; -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 halos,
-a C6 to C8 aryl,
-a 5 or 6 membered heterocycle, or
-an amino optionally substituted with 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; or
-a Ci to C6 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 halo;
-a hydroxy group;
-a CJ to C6 alkyl group, optionally substituted with one or more of the following: -halos,
-5 or 6 membered heterocycle groups, or
-amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an amino group; -an alkoxy group optionally substituted with one or more of the following: -halos,
-a hydroxy group,
-an alkoxy group optionally substituted with an alkoxy group, -an -OCORx group, where Rx is as defined above, -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups; -a dialkyl-amino optionally substituted with an alkoxy,
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C& alkyl group, the Ci to Cβ alkyl group optionally substituted with one or more independently selected Ci to Ce alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to C6 alkyl groups, or
-a Ce to Cg aryl group;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C$ to C8 aryl groups;
-a -COOH group; -a -COORx group, where Rx is as defined above; -a haloalkyl;
-an amide group optionally substituted with one or more of the following: -Ci to Ce alkyl groups, -hydroxy groups, or
-C6 to C8 aryl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-Ci to C6 alkyl,
-SO2Rx groups, -C(O)-C6 to C8 aryl, or
-C(O)ORx groups; -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 C6 alkyls; -an -ORkic group, where Rkk is:
-a 5 to 6 membered heteroaryl,
-a 5 to 6 membered heterocycle, optionally substituted with a C] to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
-an -Si(Rx)3;
-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; with the proviso that at least one of Y5 Z, Ri and R2 is selected from the following:
Y is: -a benzothiazole substituted with an amino group optionally substituted with one or more Ci to
C6 alkyls;
-an indole substituted on the nitrogen with an -SO2Rx group;
-a C6 to C8 aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following: -SO2Rx, or
-Ci to C(, alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRx, -OC(O)N(RX)2> -OC(O)NH(ORx), -OC(O)NRx(ORx),
-OC(O)N(ORX)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is:
-an amino group optionally substituted with one or more Ci to Ce alkyl groups where the Ci to C6 alkyl groups are optionally and independently substituted with one or more C6 to Cs aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Ci to Ce alkyl or Ce to Cg aryl groups, -a -NRqCONRqRr group, where Rr is: -a Ci to Ce alkyl substituted with one or more of the following:
-a hydroxyl, -an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a CO to Cs aryl substituted with a halo,
-a C∑ to Ce alkylene group, -a Ci to Cδ alkoxy group, or -a 5 or 6 membered heterocycle group, -a -NRtCOORn group, where Ru is: -a Ci to C12 alkyl, substituted with one or more of the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Cj to Ce alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to C$ alkylene, or
Z is:
-a Ci to C6 alkyl substituted with a 5 or 6 membered heterocycle, or
-a 5 or 6 membered heterocycle; or
Ri is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle;
R2 is:
-a Ci to C6 alkyl group, substituted with one or more of the following: -5 or 6 membered heterocycle groups, or
-amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
-an alkoxy group substituted with one or more groups independently selected from the following:
-a hydroxy group,
-an alkoxy group optionally substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups; -a 7 membered heterocycle group;
-a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Cj to Cg alkyl groups substituted with Ci to Q alkoxy, or
-a 5 or 6 membered heteroaryl group substituted with one or more Ci to Cg alkyl groups;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to Cg aryl groups;
-a -COOH group;
-an amide group substituted with one or more Ci to C6 alkyl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Cj to C6 alkyl, -SO2Rx,
-C(O)-C6 to C8 aryl, or -C(O)ORx groups;
-an -ORkk group, where Rkk is:
-a 5 to 6 membered heterocycle, optionally substituted with a C) to C6alkyl, optionally substituted with a Ce to C$ aryl group, or -an -Si(Rx)3; or a pharmaceutically acceptable salt thereof.
In some embodiments, R is selected from the R substituents of compounds 1330-2128 and 2600-3348.
In some embodiments of the invention, compounds are provided wherein R is selected from the following non-limiting substituents:
In other embodiments of the invention, R is hydrogen.
In some embodiments of the invention, Ri is selected from the following non-limiting substituents:
In some embodiments of the invention, R2 is selected from the following non-limiting substituents:
In some embodiments, R3 is selected from the R3 substituents of compounds 1330- 2128, and 2600-3348.
In some embodiments of the invention, compounds are provided wherein R3 is selected from the following non-limiting subsituents:
In other embodiments of the invention, compounds are provided wherein R3 is hydrogen.
In another embodiment, the present invention includes a compound of Formula (I-XI)
(I-XI) wherein: X is:
-hydrogen;
-a cyano group;
-a nitro group;
-a formyl group; -a -COOH group;
-a CORx group, wherein Rx is a Ci to Ce alkyl;
to C6 alkoxy-
-a halo;
-an alkyl optionally substituted with one or more halo;
-an alkyne optionally substituted with a Ci to Cg alkyl optionally substituted with one or more independently selected halo or cyano groups; -an oxime; -SO2Rx; -SO2NH2; -SO2NH(Rx); -SO2N(Rx)2;
-an amino optionally substituted with one or more Ci to Ce alkyl groups or C(O)- Ci to Ce alkyl groups;
-an amide group optionally substituted with one or more independently selected Ci to Ce alkyl group;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyl groups optionally substituted with one or more halos; or
-a Ce to Cs aryl group optionally substituted with one or more of the following:
-Ci to C6 alkyl optionally substituted with one or more halos,
-halo, or
-cyano; Y is:
-a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to Ce alkyls;
-an indole, optionally substituted on the nitrogen with an -SO2Rx group; or -a Ce to Cg aryl, optionally substituted with one or more of the following: -halo;
-a Ci to C6 alkyl;
-an alkoxy,
-an amino optionally substituted with one or more of the following:
-SO2Rx, -Ci to C6 alkyl, the Ci to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, or -PO2Rx, -OC(O)NHRx,
-OC(O)N(Rx)2,
-OC(O)NH(ORx), -OC(O)NRx(ORx), -OC(O)N(ORX)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl,
-an amino group optionally substituted with one or more Ci to Ce alkyl groups where the Ci to C6 alkyl groups are optionally and independently substituted with one or more Cβ to Cs aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to
Ca alkyl or Ce to C8 aryl groups, and where R0 is:
-a hydrogen, or -a Ci to C6 alkyl, -a -NRqCONRqRr group, where Rq is a hydrogen, and where Rr is:
-a C] to Ce alkyl optionally substituted with one or more of the following: -halo, -hydroxyl, -an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a Ce to C8 aryl optionally substituted with a halo, -a C2 to C6 alkylene group optionally substituted with one or more halo, -a Ci to Ce alkoxy group, or
-a 5 or 6 membered heterocycle group, -a -NRtCOORu group, where R11 is:
-a Ci to Ci2 alkyl, optionally substituted with one or more groups independently selected from the following: -a C6 to C8 aryl optionally substituted with halo,
-an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C] to C6 alkyl, -halo, or -a 5 or 6 membered heteroaryl,
-a C2 to Ce alkylene, or
-a Ce to C8 aryl, optionally substituted with halo, and Rt is:
-a hydrogen; -a -NHRbb group, where Rt* is:
-a -C(=S)NH2 group, or
-a -PO(ORX)2, where Rx is as defined above; -a -NRVSO2RW group, where Rv is a hydrogen, and where Rw is a Ci to Cg alkyl,
Z is:
-a Ci to C<s alkyl optionally substituted with a 5 or 6 membered heterocycle, or
-a 5 or 6 membered heterocycle;
R is a hydrogen; Ri is:
-a hydrogen;
-a Ci to Ce alkyl optionally substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a Ci to Ce alkyl, -a 5 or 6 membered heterocycle optionally substituted with a Ci to Ce alkyl,
-a 5 or 6 membered heteroaryl, or -a Ce to Cg aryl; -a Ci to C6 alkoxy optionally substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a Ci to Ce alkyl,
-a 5 or 6 membered heterocycle optionally substituted with a Ci to Cβ alkyl,
-a 5 or 6 membered heteroaryl, or
-a C6 to C8 aryl;
-an (O)-5 or 6 niembered heterocycle; -an (O)-5 or 6 membered heteroaryl; -an -SO2Rx group optionally substituted with the following:
-a 5 or 6 membered heterocycle,
-a C6 to C8 aryl,
-a 5 or 6 membered heteroaryl; or -alkylthio optionally substituted with the following: -a 5 or 6 membered heterocycle,
-a Ce to C8 aryl,
-a 5 or 6 membered heteroaryl;
R2 is:
-a Ci to Ce alkyl group, optionally substituted with one or more of the following: -5 or 6 membered heterocycle groups,
-5 or 6 membered heteroaryl groups, -C6 to Cs aryl groups,
-an amide optionally substituted with a Ci to Ce alkyl, or
-amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
-an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
-an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group; -an alkylthio group optionally substituted with a C6 to C8 aryl group; -an alkylthio group optionally substituted with a Ci to Cβ alkyl group;
-an SO2Rx group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyl groups;
-an SO2Rx group optionally substituted with a 5 or 6 membered heterocycle group; -an SO2Rx group optionally substituted with a Ce to Cs aryl group; -an SO2Rx group optionally substituted with a Ci to Ce alkyl group;
-an S(O)Rx group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)Rx group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)Rx group optionally substituted with a Ce to C8 aryl group; -an S(O)Rx group optionally substituted with a Ci to C6 alkyl group;
-an alkoxy group optionally substituted with one or more groups independently selected from the following: -halo,
-hydroxy group, -an alkoxy group optionally substituted with an alkoxy group,
-an amino group optionally substituted with one or more 5 or 6 mernbered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-5 or 6 membered heterocycle, or -amino optionally substituted with one or more alkyl groups,
-an amide optionally substituted with a Ci to C6 alkyl, -S-5 or 6 membered heterocycle,
-S-5 or 6 membered heteroaryl optionally substituted with a Ci to C6 alkyl, -S-Ci to C6 alkyl, -S-C6 to C8 aryl,
-sulfinyl-5 or 6 membered heterocycle, -sulfinyl-5 or 6 membered heteroaryl, -suIfϊnyl-Ci to C6 alkyl, -sulfinyl-Cβ to Cs aryl, -sulfonyl-5 or 6 membered heterocycle,
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ci to C6 alkyl, -sulfonyl- Ci to Ce alkyl, -sulfonyl- C6 to Cs aryl,
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C6 alkyl group, the Cj to C6 alkyl group optionally substituted with one or more independently selected Ci to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to Ce alkyl groups, -a C6 to Cs aryl group; -a C6 to C8 aryl group;
-an (O)-5 or 6 membered heterocycle;
-an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Cj to C6 alkyl groups;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more Ce to Cg aryl groups;
-a -C(O)S or 6 membered heteroaryl; -a -C(O)- C6 to C8 aryl; -a -COOH group;
-an amide group optionally substituted with one or more Ci to C6 alkyl groups optionally substituted with one or more Ci to CO alkoxy;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-hydroxy, -Ci to C6 alkyl,
-SO2Rx,
-C(O)-C6 to C8 aryl, or
-C(O)ORx groups; -an -ORkk group, where Rkk is: -a C6 to C8 aryl,
-a 5 to 6 membered heteroaryl,
-a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a Cg to C8 aryl group, or
-an -Si(Rx)3; and R3 is a hydrogen; or a pharmaceutically acceptable salt thereof.
In a further embodiment of the present invention, compounds of the present invention include compounds of Formula (I-XIa)
X is:
-hydrogen; -a cyano group; -a nitro group; -a formyl group; -a -COOH group;
-a CORx group, wherein Rx is a Ci to C6 alkyl; CH
_a "Ci to C6 alkoxy;
-a halo; -an alkyl optionally substituted with one or more halo;
-an alkyne optionally substituted with a Ci to C6 alkyl optionally substituted with one or more halo or cyano groups;
-an oxime;
-SO2Rx; -SO2NH2;
-SO2NH(Rx);
-SO2N(Rx)2;
-an amino optionally substituted with one or more Cj to C6 alkyl groups or C(O)- Ci to Cg alkyl groups; -an amide group optionally substituted with one or more independently selected Cj to Cg alkyl group;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyl groups optionally substituted with one or more halos; or -a Ce to C8 aryl group optionally substituted with one or more of the following: -Ci to Ce alkyl optionally substituted with one or more halos, -halo, or -cyano;
Y is:
-a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to Ce alkyls;
-an indole, optionally substituted on the nitrogen with a -SO2Rx group; -a CO to Cg aryl, optionally substituted with one or more of the following: -halo;
-a C1 to C6 alkyl;
-an alkoxy,
-an amino optionally substituted with one or more
-SO2Rx groups, -Ci to Cδ alkyl, the C] to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, or -PO2Rx groups, -OC(O)NHRx, -OC(O)N(RX)2, -OC(O)NH(ORx),
-OC(O)NRx(ORx), -OC(O)N(ORX)2,
-OC(O)Ra05 wherein R30 is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is: -a Ci to C6 alkyl,
-an amino group optionally substituted with one or more Ci to Ce alkyl groups where the Ci to Ce alkyl groups are optionally and independently substituted with one or more CO to C8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to Ce alkyl or Cβ to Cg aryl groups, and where R0 is:
-a hydrogen, -a Ci to C6 alkyl,
-a -NRqCONRqRr group, where Rq is a hydrogen, and where Rr is:
-a Ci to Ce alkyl optionally substituted with one or more of the following: -halo, -hydroxyl, -an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a Cg to C8 aryl optionally substituted with a halo, -a C2 to Ce atkylene group optionally substituted with one or more halo, -a C i to CO alkoxy group, or
-a 5 or 6 membered heterocycle group, -a -NRtCOORu group, where R11 is:
-a Ci to Cu alkyl, optionally substituted with one or more groups independently selected from the following: -a Ce to Ci aryl optionally substituted with halo,
-an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to Q alkyl, -halo, or
-a 5 or 6 membered heteroaryl, • -a C2 to Ce alkylene,
-a C6 to Cs aryl, optionally substituted with halo, and R1 is a hydrogen; -a -NHRbb group, where Rbb is: -a -C(=S)NH2 group, or -a -PO(ORx)2, where Rx is as defined above;
-a -NRvSO2Rw group, where Rv is a hydrogen, and where Rw is a Ci to Ce alkyl,
Z is: -a CJ to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
R is a hydrogen;
Ri is:
-a hydrogen;
-a Ci to Q alkyl optionally substituted with: -an amino optionally substituted with a heterocycle,
-an amide optionally substituted with a Cj to C6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a Ci to Cδ alkyl, -a 5 or 6 membered heteroaryl, or -a Ce to C8 aryl; -a C] to C(, alkoxy optionally substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a Ci to C6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a Ci to Ce alkyl, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl;
-an (O)-5 or 6 membered heterocycle;
-an (O)-5 or 6 membered heteroaryl;
-an -SO2RX group optionally substituted with the following:
-a 5 or 6 membered heterocycle, -a C6 to C8 aryl,
-a 5 or 6 membered heteroaryl; or -alkylthio optionally substituted with the following: -a 5 or 6 membered heterocycle, -a Cs to C8 aryl, -a 5 or 6 membered heteroaryl;
R2 Is:
-a Ct to C(, alkyl group, optionally substituted with one or more of the following:
-5 or 6 membered heterocycle groups,
-5 or 6 membered heteroaryl groups, -Cδ to Cg aryl groups,
-an amide optionally substituted with a Cj to Ce alkyl, or
-amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
-an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
-an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group; -an alkylthio group optionally substituted with a C6 to Cs aryl group; -an alkylthio group optionally substituted with a Cj to C6 alkyl group;
-an SO2Rx group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyl groups;
-an SO2Rx group optionally substituted with a 5 or 6 membered heterocycle group; -an SO2Rx group optionally substituted with a C6 to Cg aryl group; -an SO2Rx group optionally substituted with a Ci to Cg alkyl group;
-an S(O)Rx group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)Rx group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)Rx group optionally substituted with a Cg to Cs aryl group; -an S(O)Rx group optionally substituted with a Ci to CO alkyl group; -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halo,
-hydroxy group,
-an alkoxy group optionally substituted with an alkoxy group, -an amino group optionally substituted with one or more 5 or 6 membered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups, -an amide optionally substituted with a Ci to C6 alkyl,
-S-5 or 6 membered heterocycle,
-S-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl, -S-Ci to C6 alkyl, -S-C6 to C8 aryl, -sulfinyl-5 or 6 membered heterocycle,
-sulfinyl-5 or 6 membered heteroaryl, -sulfinyl-Ci to C6 alkyl, -sulfinyl-Cδ to Cg aryl, -sulfonyl-5 or 6 membered heterocycle,
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ci to Cg alkyl,
-sulfonyl- C| to CO alkyl,
-sulfonyl- C6 to C8 aryl,
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to Ce alkyl group, the Ci to C6 alkyl group optionally substituted with one or more independently selected Ci to C6 alkoxy group,
-a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to Ce alkyl groups,
-a CO to C8 aryl group; -a C6 to Cs aryl group;
-an (O)-5 or 6 membered heterocycle;
-an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Ci to Cg alkyl groups;
-a -C(O)S or 6 membered heterocycle optionally substituted with one or more Ce to Cg aryl groups;
-a -C(O)S or 6 membered heteroaryl; -a -C(O)-C6 to C8 aryl; -a -COOH group;
-an amide group optionally substituted with one or more of the following: -Ci to CO alkyl groups optionally substituted with one or more C] to C6 alkoxy,
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-hydroxy,
-Ci to C6 alkyl,
-SO2Rx, -C(O)-C6 to C8 aryl, or
-C(O)ORx groups; -an -ORkk group, where Rkk is:
-a C6 to C8 aryl,
-a 5 to 6 membered heteroaryl, -a 5 to 6 membered heterocycle, optionally substituted with a Ci to C$ alkyl, optionally substituted with a C6 to C8 aryl group, or
-an -Si(Rx)3; and
R3 is a hydrogen; with the proviso that at least one of X, Y, Z, Ri, and R2 is selected from the following:
X is:
-a -COOH group;
CH
N. amino optionally substituted with one or more C^ to Cβ alkyl _a groups ; -a halo;
-an alkyl optionally substituted with one or more halo;
-an alkyne optionally substituted with a Ci to Ce alkyl optionally substituted with one or more halo or cyano groups;
-an oxime; -SO2Rx;
-SO2NH2;
-SO2NH(Rx);
-SO2N(Rx)2;
-an amino optionally substituted with one or more Ci to Ce alkyl groups or C(O)- Ci to Ce alkyl groups;
-an amide group optionally substituted with one or more independently selected Ci to Ce alkyl group;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl substituted with one or more Ci to CO alkyl groups substituted with one or more halos; or
-a Cg to C8 aryl group substituted with one or more of the following: -Ci to C6 alkyl optionally substituted with one or more halos, -halo, or -cyano; Y is:
-a benzothiazole substituted with an amino group optionally substituted with one or more Ci to
CO alkyls;
-an indole substituted on the nitrogen with an SO2Rx group;
-a C(, to C8 aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following: -SO2Rx, or
-Ci to Ce alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRx, -OC(O)N(RX)2,
-OC(O)NH(ORx), -OC(O)NRx(ORx), -OC(O)N(ORx)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is:
-an amino group optionally substituted with one or more Ci to Ce alkyl groups where the Ci to C6 alkyl groups are optionally and independently substituted with one or more Ce to Ce aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Ci to Ce alkyl or Ce to C8 aryl groups,
-a -NRqCONRqRr group, where Rr is:
-a Ci to CO alkyl substituted with one or more of the following: -a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle,
-a 5 or 6 membered heteroaryl, or -a Ce to Cg aryl substituted with a halo, -a C2 to Cβ alkylene group, -a Ci to Ce alkoxy group, -a 5 or 6 membered heterocycle group,
-a -NRtCOORu group, where Ru is:
-a Ci to Ci2 alkyl, substituted with one or more groups independently selected from the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to Ce alkyl, or
-a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, or
Z is:
-a Ci to Ce alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
-a Ci to Cδ alkyl substituted with: -an amide optionally substituted with a Cj to Ce alkyl, or -a 5 or 6 membered heteroaryl; -a Ci to Ce alkoxy substituted with: -an amino optionally substituted with a heterocycle,
-an amide optionally substituted with a Ci to Ce alkyl,
-a 5 or 6 membered heterocycle substituted with a Ci to C6 alkyl, or
-a 5 or 6 membered heteroaryl; -an (O)-5 or 6 membered heterocycle; -an (O)-5 or 6 membered heteroaryl;
-an -SO2Rx group optionally substituted with the following:
-a 5 or 6 membered heterocycle,
-a C6 to C8 aryl,
-a 5 or 6 membered heteroaryl; or -alkylthio optionally substituted with the following:
-a 5 or 6 membered heterocycle,
-a Ce to Cs aryl,
-a 5 or 6 membered heteroaryl; or
R2 is: —a Ci to Cδ alkyl group, substituted with one or more of the following: -5 or 6 membered heterocycle groups, -5 or 6 membered heteroaryl groups, -Ce to Cg aryl groups, -an amide optionally substituted with a Ci to C6 alkyl, or
-amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
-an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group; -an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group; -an alkylthio group optionally substituted with a Cδ to Ce aryl group; -an alkylthio group optionally substituted with a C] to CO alkyl group; -an SOaRx group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyl groups; -an SO2Rx group optionally substituted with a 5 or 6 membered heterocycle group; -an SOaRx group optionally substituted with a Ce to Cg aryl group; -an SOaRx group optionally substituted with a Ci to C$ alkyl group; -an S(O)Rx group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)Rx group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)Rx group optionally substituted with a Ce to C% aryl group; -an S(O)Rx group optionally substituted with a Ci to CO alkyl group; -an alkoxy group substituted with an alkoxy group,
-an amino group substituted with one or more 5 or 6 membered heteroaryl, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups; -an amide optionally substituted with a Ci to Ce alkyl, -S-5 or 6 membered heterocycle, -S-5 or 6 membered heteroaryl optionally substituted with a Ci to Ce alkyl,
-S-Ci to C6 alkyl, -S-C6 to C8 aryl,
-sulfinyl-5 or 6 membered heterocycle, -sulfinyl-5 or 6 membered heteroaryl, -sulfinyl-C] to C6 alkyl,
-sulfinyl-Cό to C$ aryl, -sulfonyl-5 or 6 membered heterocycle,
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Cj to Cg alkyl, -sulfonyl- Ci to Ce alkyl,
-sulfonyl- C6 to C8 aryl,
-a 5 to 7 rnembered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Ci to
C6 alkyl groups substituted with Ci to C6 alkoxy, or -a 5 or 6 membered heteroaryl group substituted with one or more Ci to C6 alkyl groups
-a C6 to C8 aryl group;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to Cg aryl groups;
-a -C(O)- C6 to C8 aryl; -a -COOH group;
-an amide group substituted with one or more Ci to Ce alkyl groups optionally substituted with one or more Ci to Ce alkoxy;
-a 5 or 6 membered heterocycle, substituted with one or more of the following:
-hydroxy, -Ci to C6 alkyl,
-SO2Rx groups,
-C(O)-C6 to C8 aryl, or
-C(O)ORx groups; -an -ORkk group, where Rkk is: -a C6 to C8 aryl,
-a 5 to 6 membered heterocycle, optionally substituted with a Ci to C6 alkyl, optionally substituted with a C6 to Cs aryl group, or
-an -Si(Rx)3;
-an (O)-5 or 6 membered heterocycle; or -an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Ci to C6 alkyl groups; or a pharmaceutically acceptable salt thereof.
In another embodiment, Formula I-XIb, a compound is provided wherein all substituents except X are as stated for Formula I-XI, and X is an electron withdrawing group. In a further embodiment, Formula I-XIc, a compound is provided wherein all substituents except X are as stated for Formula I-XIa, and X is an electron withdrawing group. As an example, an electron withdrawing group includes any electronegative element, which may be attached to or adjacent to an aromatic ring. By way of non-limiting example, an electron withdrawing group can include a cyano group, an alkynyl group, a nitro group, an oxime, a
halo, a halosubstituted alkyl, a carbonyl group, a sulfonyl group, and a heterooycle. In an embodiment of the present invention, X is a cyano group. In another embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, Hc, Hd, or lie, X is a halo. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, Hc, lid, or He, X is a fluorine, chlorine, bromine or iodine. In an embodiment of I, I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, Hc, Hd, or He, X is a fluorine, bromine or iodine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, lie, Hd, or lie, X is a fluorine or chlorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, Hb, Hc, Hd, or He, X is a fluorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I- XIc, Ha, Hb, Hc, Hd, or He, X is a chlorine. In an embodiment of Formulas I, I-XI, I-XIa, I- XIb, I-XIc, Ha, Hb3 He, Hd, or He, X is bromine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, Hb, Hc, lid, or He, X is iodine. In a further embodiment of Formulas I, I-XI, 1-XIa5 I-XIb, I-XIc, Ha3 Hb, He, Hd, or He, X is an alkyl substituted with one or more halos. hi another embodiment, X is a trifluoromethyl group.
In some embodiments, X is selected from the X substituents of compounds 1330-2128, and 2600-3348.
In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, Hb, He, Hd, or He, X is selected from the group consisting of:
In other non-limiting examples of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, lie, or lie, X is selected from the group consisting of
In some embodiments, Ri is selected from the Ri substituents of compounds 1330- 2128, and 2600-3348.
In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, Hc, Hd, or He, Ri is selected from the group consisting of
In another embodiment, the present invention includes compounds of Formula (I-XII)
(I-XII) wherein: X is: -a cyano group;
Y is:
-a beπzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to C6 alkyls;
-an indole, optionally substituted on the nitrogen with an SO2Rx group; -a CO to Cs aryl, optionally substituted with one or more of the following: -an alkoxy,
-an amino optionally substituted with one or more of the following: -SCbRx group, or
-Ci to C6 alkyl, the Q to Cg alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group,
-OC(O)NHRx, -OC(O)N(Rx)2, -OC(O)NH(ORx), -OC(O)NRx(ORx), -OC(O)N(ORX)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is: -a Ci to C6 alkyl,
-an amino group optionally substituted with one or more Ci to Cg alkyl groups where the Ci to Cg alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Cj to C6 alkyl or C6 to C8 aryl groups, and where R0 is: -a hydrogen,
-a Ci to C6 alkyl,
-a -NRqCONRqR1- group, where Rq is a hydrogen, and where Rr is:
-a Ci to C6 alkyl optionally substituted with one or more of the following: -a hydroxyl,
-an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to Cg aryl optionally substituted with a halo,
-a C2 to C6 alkylene group, -a Ci to Ce alkoxy group, -a 5 or 6 membered heterocycle group, -a -NR1COORu group, where Ru is:
-a Ci to Ci2 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to Cg aryl optionally substituted with halo,
-an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C) to Cg alkyl, -halo, or
-a 5 or 6 membered heteroaryl, -a C2 to Ce alkylene,
-a C6 to Cs aryl, optionally substituted with halo,
-a hydrogen;
-a -NHRbb group, where Rt* is: -a -C(=S)NH2 group, or -a -PO(ORx)2, where Rx is as defined above; -a -NRvSO2Rw group, where Rv is a hydrogen, and where Rw is a Ci to C& alkyl,
Z is:
-a C] to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; R is a hydrogen; Ri is a hydrogen;
R2 is:
-a Ci to Cβ alkyl group, optionally substituted with one or more of the following: -5 or 6 membered heterocycle groups,
-amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
-an alkoxy group optionally substituted with one or more groups independently selected from the following: -halo,
-hydroxy group, -an alkoxy group optionally substituted with an alkoxy group,
-an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to Ce alkyl group, the C] to Ce alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more C] to Cg alkyl groups, -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -COOH group; -an amide group optionally substituted with one or more -Ci to Ce alkyl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Ci to C6 alkyl, -SO2Rx,
-C(O)-C6 to C8 aryl, or -C(O)ORx groups;
-an -ORkk group, where Rkk is:
-a 5 to 6 membered heterocycle, optionally substituted with a Cj to Ce alkyl, optionally substituted with a C6 to C8 aryl group, or -an -Si(Rx)3;
R3 is a hydrogen; or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention includes compound of Formula (I-XIIa)
(I-XIIa) wherein:
X is:
-a cyano group; Y is: -a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to CO alkyls;
-an indole, optionally substituted on the nitrogen with an SO2Rx group; -a Cg to Cs aryl, optionally substituted with one or more of the following:
-an alkoxy, -an amino optionally substituted with one or more of the following:
-SO2Rx, or
-Ci to Cδ alkyl, the Ci to Ce alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRx, -OC(O)N(Rx)2,
-OC(O)NH(ORx), -OC(O)NRx(ORx), -OC(O)N(ORX)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is:
-a Ci to C6 alkyl,
-an amino group optionally substituted with one or more Cj to Ce alkyl groups where the Ci to Cβ alkyl groups are optionally and independently substituted with one or more C6 to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to Cδ alkyl or Ce to C8 aryl groups, and where R0 is:
-a hydrogen, -a Ci to C6 alkyl,
-a -NRqCONRqRn group, where Rq is a hydrogen, and where Rr is:
-a Ci to CO alkyl optionally substituted with one or more of the following: -a hydroxyl, -an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or
-a Ce to Cs aryl optionally substituted with a halo, -a C2 to C(, alkylene group, -a Ci to Cg alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORu group, where R11 is:
-a Ci to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a Ce to Cs aryl optionally substituted with halo,
-an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to Ce alkyl,
-halo, or
-a 5 or 6 membered heteroaryl, -a C2 to Ce alkylene,
-a Ce to C8 aryl, optionally substituted with halo, and Rt is:
-a hydrogen;
-a -NHRbb group, where Rbb is: -a -C(=S)NH2 group, or -a -PO(ORx)2, where Rx is as defined above;
-a -NRVSO2RW group, where Rv is a hydrogen, and where Rw is a Ci to C6 alkyl,
Z is:
-a C) to Ce alkyl optionally substituted with: a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; R is a hydrogen; Ri is a hydrogen; R2 is:
-a Ci to Ce alkyl group, optionally substituted with one or more of the following: -5 or 6 membered heterocycle groups,
-amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halo,
-hydroxy group,
-an alkoxy group optionally substituted with an alkoxy group, -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups; -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C6 alkyl group, the Ci to Ce alkyl
group optionally substituted with one or more independently selected Cj to Q alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more Cj to CO alkyl groups, -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more Ce to Cs aryl groups;
-a -COOH group;
-an amide group optionally substituted with one or more C\ to Cs alkyl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Ci to C6 alkyl,
-SO2Rx,
-C(O)-C6 to C8 aryl, or -C(O)ORx groups; -an -ORkk group, where R^ is: -a 5 to 6 membered heterocycle, optionally substituted with a Cj to Ce alkyl, optionally substituted with a C6 to Cg aryl group, or -an -Si(Rx)3; R3 is a hydrogen; with the proviso that at least one of Y, Z, and R2 is selected from the following: Y is:
-a benzothiazole substituted with an amino group optionally substituted with one or more Ci to C6 alkyls;
-an indole substituted on the nitrogen with an -SO2Rx group; -a Ce to Cg aryl substituted with one or more of the following: -an amino optionally substituted with one or more of the following:
-SO2Rx, or
-Ci to Ce alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRx, -OC(O)N(Rx)2, -OC(O)NH(ORx),
-OC(O)NRx(ORx), -OC(O)N(ORx)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is:
-an amino group optionally substituted with one or more C] to Ce alkyl groups where the Ci to C6 alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, substituted with one or more C| to Ce alkyl or Cg to Cs aryl groups,
-a -IsIRqCONRqRr group, where Rr is:
-a Ci to CO alkyl substituted with one or more of the following: -a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle,
-a 5 or 6 membered heteroaryl, or -a Ce to Cs aryl substituted with a halo, -a C2 to Ce alkylene group, -a Ci to Ca alkoxy group, -a 5 or 6 membered heterocycle group,
-a -NRtCOORu group, where Ru is:
-a C] to Ci2 alkyl, substituted with one or more groups independently selected from the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to Cβ alkyl, or
-a 5 or 6 membered heteroaryl, -a C2 to Cή alkylene,
Z is: -a Ci to C6 alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; R2 is: -a Ci to Cδ alkyl group, substituted with one or more of the following:
-5 or 6 membered heterocycle groups, -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
-an alkoxy group substituted with one or more groups independently selected from the following:
-hydroxy group,
-an alkoxy group optionally substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or
-an amino optionally substituted with one or more alkyl groups; -a 7 membered heterocycle group;
-a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected C] to Cδ alkyl groups substituted with Ci to C6 alkoxy, or -a 5 or 6 membered heteroaryl group substituted with one or more Ci to C6 alkyl groups;
-a -C(O)-S or 6 membered heterocycle optionally substituted with one or more CO to Cs aryl groups;
-a -COOH group;
-an amide group substituted with one or more Ci to Ce alkyl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Ci to C6 alkyl, -SO2Rx group, -C(O)-C6 to C8 aryl, or -C(O)ORx groups; -an -ORick group, where Rkk is:
-a 5 to 6 membered heterocycle, optionally substituted with a Ci to C6 alkyl, optionally substituted with a Ce to Cs aryl group, or -an -Si(Rx)3; or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention includes compounds of Formulas I, I-X,
I-XI, 1-XII3 1-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, Da, lib, lie, Hd, or lie, wherein Y is a C6 to C8 aryl, optionally substituted with one or more of the following: -a -NRqCONRqRr group, where Rq is a hydrogen, and where Rr is:
-a Ci to C& alkyl optionally substituted with one or more of the following: -a hydroxyl, -an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or
-a Ce to Cs aryl optionally substituted with a halo, -a C2 to Cβ alkylene group, -a Ci to Ce alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORu group, where Ru is:
-a Ci to Ci 2 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C(, to Cg aryl optionally substituted with halo,
-an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to C$ alkyl,
-halo, or
-a 5 or 6 membered heteroaryl, -a C2 to Cs alkylene,
-a C6 to Cg aryl, optionally substituted with halo, and R, is:
-a hydrogen; -a -NHRbb group, where Ra, is:
-a -C(=S)NH2 group, or -a -PO(ORx)2, where Rx is as defined above; or
-a -NRvSθ2Rw group, where Rv is a hydrogen, and where Rw is a Ci to Ce alkyl.
In another embodiment, the present invention includes compounds wherein Y is a CO to C& aryl, optionally substituted with:
-a -NRqCONRqRr group, where Rq is a hydrogen, and where Rr is:
-a Ci to CO alkyl optionally substituted with one or more of the following: -a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle,
-a 5 or 6 membered heteroaryl, or
-a C6 to Cg aryl optionally substituted with a halo, -a C2 to Cβ alkylene group, -a Ci to C(, alkoxy group, or -a 5 or 6 membered heterocycle group.
In a further embodiment, the present invention includes compounds wherein Y is a - NRtCOOR11 group, where Ru is:
-a Ci to Ci2 alkyl, optionally substituted with one or more groups independently selected from the following:
-a Cg to Ce aryl optionally substituted with halo,
-an alkoxy group optionally substituted with one or more alkoxy groups,
-an amino optionally substituted with one or more Ci to C6 alkyl,
-halo, or
-a 5 or 6 membered heteroaryl, -a C2 to Ce alkylene,
-a Ce to Cg aryl, optionally substituted with halo, and Rt is:
-a hydrogen.
In yet another embodiment, the present invention includes compounds of the following:
1. A compound of formula Ha
or a pharmaceutically acceptable salt thereof, wherein: X is:
-cyano;
-nitro;
-formyl;
-COOH;
-CORx, wherein Rx is Ci to C6 alkyl; -CH=N-(C1 to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more d to C6 alkyls); -halo; -alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with Ci to Ce alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos; -oximyl; -SO2Rx; -SO2NH2;
-SO2NH(Rx);
-SO2N(RX)2;
-amino optionally substituted with one or more Ci to Ce alkyls and/or -C(O)-Cj to Cg alkyls; -amido optionally substituted with one or more independently selected Ci to C6 alkyls;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl optionally substituted with one or more Cj to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -Cή to Cg aryl optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more halos; -halo; and -cyano; Y is: -benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more Cj to Cg alkyls; -indolyl optionally substituted on the nitrogen with -SO2Rx; -C<5 to Cg aryl optionally substituted with one or more substituents independently selected from: -halos;
-Ci to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from: -one or more halos; and
-5 or 6 membered heterocyclo; -hydroxy; -amino optionally substituted with one or more substituents independently selected from: -SO2Rx;
-C] to Ce alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls; and -PO2Rx; -OC(O)NHRx; -OC(O)N(RX)2;
-OC(O)NH(ORx); -OC(O)NRx(ORx); -OC(O)N(ORX)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo; -NRoCORp, wherein Rp is:
-Ci to C6 alkyl;
-amino optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally and independently substituted with one or more C& to Cs aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more Ci to Ce alkyls and/or C6 to Cg aryls; and wherein R0 is: -hydrogen; or -Ci to CO alkyl; -NRqCONRqR1, wherein Rq is hydrogen; and wherein Rr is:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from: -halo; -hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Cs to Cg aryl optionally substituted with one or more halos;
-C2 to C6 alkenyl optionally substituted with one or more halos; -Ci to C6 alkoxy; or -5 or 6 membered heterocyclo; -SO2Ra33 wherein Raa is: -5 or 6 heterocyclo optionally substituted with hydroxy;
-C] to Ce alkoxy; or -Ci to C6 alkyl; -CORm, wherein Rm is:
-amino optionally substituted with one or more Ci to Cg alkyls, wherein the Ci to Ce alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo optionally substituted with Ci to Cδ alkyl, which alkyl is optionally substituted with dialkyl-amino; -NRtCOORu, wherein R1 is hydrogen, and wherein R11 is: -Ci to C] 2 alkyl optionally substituted with one or more substituents independently selected from: -C6 to Cg aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to Ce alkyls;
-halo;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo; -C2 to CO alkenyl; or -Cδ to Cg aryl optionally substituted with halo;
-NHRbb, wherein Rbb is: -C(=S)NH2; or -PO(ORX)2;
-NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is: -Ci to C6 alkyl; or
-alkyl- or dialkyl-amino optionally substituted with halo;
Z is:
-Ci to Cδ alkyl optionally substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;
R is hydrogen;
-hydrogen;
-5 or 6 membered heterocyclo; -Cj to CO alkyl optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with heterocyclo; -amido optionally substituted with Ci to Ce alkyl;
-5 or 6 membered heterocyclo optionally substituted with Ci to Ce alkyl; -5 or 6 membered heteroaryl; and
-C6 to C8 aryi;
-Ci to Cf, alkoxy optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with heterocyclo; -amido optionally substituted with Ci to Cg alkyl;
-5 or 6 membered heterocyclo optionally substituted with Ci to Ce alkyl; -5 or 6 membered heteroaryl; and -C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl;
-SO2Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; -C6 to Cg aryl; and -5 or 6 membered heteroaryl; or
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; -Cg to C8 aryl; and -5 or 6 membered heteroaryl; R2 is: -Ci to Ce alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; -C6 to C8 aryl; -amido optionally substituted with Ci to Ce alkyl; and
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
-alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo; -alkylthio optionally substituted with C6 to Cg aryl; -alkylthio optionally substituted with Ci to Ce alkyl;
-SO2Rx optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more Ci to C^ alkyls;
-SO2Rx optionally substituted with 5 or 6 membered heterocyclo; -SO2Rx optionally substituted with Ce to Cs aryl; -SO2Rx optionally substituted with Ci to Ce, alkyl; -S(O)Rx optionally substituted with 5 or 6 membered heteroaryl; -S(O)Rx optionally substituted with 5 or 6 membered heterocyclo;
-S(O)Rx optionally substituted with Ce to C§ aryl; -S(O)Rx optionally substituted with Ci to Ce alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-halo; -hydroxy;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls; -amido optionally substituted with Cj to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl; -S-Ci to C6 alkyl; -S-C6 to C8 aryl; -sulfinyl-5 or 6 membered heterocyclo;
-sulfϊnyl-5 or 6 membered heteroaryl; -sulfinyl-Ci to C6 alkyl; -sulfinyl-Cβ to C8 aryl; -sulfonyl-5 or 6 membered heterocyclo; -sulfonyl-5 or 6 membered heteroaryl optionally substituted with C] to C6 alkyl;
-sulfonyl-Ci to C6 alkyl; -sulfonyl-Q to C8 aryl; -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and Ci to C6 alkyl, which alkyl is optionally substituted with one or more Ci to C6 alkoxys;
-5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyls; and -C6 to C8 aryl; -C6 to C8 aryl; -(O)S or 6 membered heteroaryl optionally substituted with one or more independently selected Cj to C6 alkyls; -C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls; -C(O)-C6 to C8 aryl;
-COOH;
-C(O)NH2 optionally substituted with one or more substituents independently selected from:
-Ci to Cβ alkyl optionally substituted with one or more substituents independently selected from halo. Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -atnido optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more Ci to Cg alkoxys;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to C6 alkyl; and
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy; -C1 to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl; and -C(O)ORx; or -ORkk> wherein Rkk is: -C6 to C8 aryl;
-5 or 6 membered heterocyclo optionally substituted with Ci to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkyl, Cj to C6 alkoxy, and Ci to C6 haloalkyl;
-SO2Rx; or -Si(R3O3; and R3 is hydrogen; with the proviso that at least one of X, Y, Z, Ri, and R2 is selected from the following: X is:
-COOH;
-CH=N-(C1 to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more Ci to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with Ci to C6 alkyl, which aUcyl is optionally substituted with one or more halos and/or cyanos; -oximyl; -SO2Rx;
-SO2NH2; -SO2NH(Rx); -SO2N(Rx),;
-amino optionally substituted with one or more Ci to Ce alkyls and/or -C(O)-Cj to Ce alkyls;
-amido optionally substituted with one or more independently selected Ci to Cf, alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more Cj to Cf, alkyls, which alkyls are substituted with one or more halos; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more halos; -halo; and -cyano; Y is: -benzothiazolyl substituted with amino, which amino is optionally substituted with one or more Ci to Cf, alkyls;
-indolyl substituted on the nitrogen with SO2Rx; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from:
-SO2Rx, and
-Ci to Ce alkyl substituted with one or more 5 or 6 membered heteroaryls; -OC(O)NHRx; -OC(O)N(RX)2;
-OC(O)NH(ORx);
-OC(O)NRx(ORx);
-OC(O)N(ORX)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo;
-NR0CORp, wherein Rp is:
-amino optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally and independently substituted with one or more Ce to C8 aryls and/or alkoxys, or -5 or 6 membered heterocyclo substituted with one or more Ci to Ce alkyls and/or C(, to C8 aryls, -NRqCONRqRr, wherein Rr is:
-CJ to Ce alkyl substituted with one or more substituents independently selected from: -hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Cδ to C8 aryl substituted with one or more halos; -C2 to C6 alkenyl;
-Ci to Ce alkoxy; or -5 or 6 membered heterocyclo; -NRtCOORu, wherein R11 is:
-Cj to Ci 2 alkyl substituted with one or more substituents independently selected from:
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more Ci to Ce alkyls; and
-5 or 6 membered heteroaryl; or -Gz to Ce alkenyl; and
Z is:
-Ci to Ce alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo; R1 is:
-Ci to Ce alkyl substituted with:
-amido optionally substituted with Ci to C6 alkyl; and/or -5 or 6 membered heteroaryl; -Ci to Q alkoxy substituted with:
-amino optionally substituted with heterocyclo; -amido optionally substituted with Ci to C6 alkyl;
-5 or 6 membered heterocyclo substituted with Ci to C6 alkyl; and/or -5 or 6 membered heteroaryl; -(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl; -SO2Rx optionally substituted with:
-5 or 6 membered heterocyclo; -Ce to Cg aryl; and/or -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with: -5 or 6 membered heterocyclo;
-Cβ to Cg aryl; and/or -5 or 6 membered heteroaryl; R2 is:
-Ci to C(, alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; -C6 to C8 aryl;
-amido optionally substituted with Cj to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys; -alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo; -alkylthio optionally substituted with Ce to C8 aryl;
-alkylthio optionally substituted with Ci to Ce alkyl; -SO2Rx optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more Ci to Ce alkyls; -SO2Rx optionally substituted with 5 or 6 membered heterocyclo;
-SO2Rx optionally substituted with Cg to Cg aryl; -SO2R.X optionally substituted with Ci to Ce alkyl; -S(O)Rx optionally substituted with 5 or 6 membered heteroaryl; -S(O)Rx optionally substituted with 5 or 6 membered heterocyclo; -S(O)Rx optionally substituted with CO to C8 aryl;
-S(O)Rx optionally substituted with Ci to C6 alkyl; -alkoxy substituted with: -alkoxy;
-amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclos; and -amino optionally substituted with one or more alkyls; -amido optionally substituted with Ci to CO alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl; -S-C, to C6 alkyl; -S-C6 to C8 aryl; -sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl; -sulfinyl-Ci to C6 alkyl; -sulfϊnyl-Cβ to Cs aryl; -sulfonyl-5 or 6 membered heterocyclo; -sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl;
-sulfonyl-Ci to C6 alkyl; -sulfonyl-C6 to Cg aryl; -5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and Ci to C6 alkyl, which alkyl is substituted with one or more Ci to C6 alkoxys;
-5 or 6 membered heteroaryl substituted with one or more Ci to C6 alkyls; or -C6 to C8 aryl;
-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
-C(O)-C6 to C8 aryl;
-COOH;
-amido substituted with one or more Ci to C6 alkyls optionally substituted with one or more Ci to Cβalkoxys; -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-Ci to C6 alkyl;
-SO2Rx; -C(O)-C6 to C8 aryl; and
-C(O)ORx; -ORkkj wherein Rkk is:
-C6 to C8 aryl;
-5 or 6 membered heterocyclo optionally substituted with Ci to C6 alkyl and/or Ce to Cs aryl; or
-(O)S or 6 membered heterocyclo optionally substituted with one or more independently selected Ci to C6 alkyls; or
-(O)-S or 6 membered heteroaryl optionally substituted with one or more independently selected Ci to C6 alkyls.
2. The compound of embodiment 1 , wherein: X is:
-COOH;
-CH=N-(Ci to C6 alkoxy); -CH=N-(amino optionally substituted with one or more C| to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos; -alkynyl optionally substituted with Ci to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos; -oximyl;
-SO2Rx; -SO2NH2; -SO2NH(Rx); -SO2N(RX)2;
-amino optionally substituted with one or more Ci to Ce alkyls and/or -C(O)-Cj to C6 alkyls;
-amido optionally substituted with one or more independently selected Ci to C6 alkyls; -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl substituted with one or more Ci to Cg alkyls, which alkyls are substituted with one or more halos; or -CO to C8 aryl substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more halos;
-halo; and -cyano.
3. The compound of embodiment 2, wherein X is cyano, halo, or alkyl substituted with one or more halos.
4. The compound of embodiment 3, wherein X is cyano.
5. The compound of embodiment 3, wherein X is fluoro, bromo, chloro, or iodo. 6. The compound of embodiment 3, wherein X is trifluoromethyl.
7. The compound of embodiment 1, wherein:
Y is Cβ to Cg aryl substituted with one or more of the following:
-amino optionally substituted with one or more substituents independently selected from: -SO2Rx; and
-Ci to Ce alkyl substituted with one or more 5 or 6 membered heteroaryls; -OC(O)NHRx; -OC(O)N(RX)2; -OC(O)NH(ORx); -OC(O)NRx(ORx);
-OC(O)N(ORX)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo; -NR0CORp, wherein Rp is:
-amino optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally and independently substituted with one or more Ce to Cs aryls and/or alkoxys; or -5 or 6 membered heterocyclo substituted with one or more Ci to C6 alkyls and/or Ce to C8 aryls;
-NRqCONRqR1, wherein Rr is:
-Ci to C6 alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Ce to C8 aryl substituted with halo; -Cj to Ce alkenyl; -Ci to C6 alkoxy; or
-5 or 6 membered heterocyclo; -NRtCOORu, wherein R11 is:
-C) to Ci2 alkyl substituted with one or more substituents independently selected from the following: -alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more Ci to CO alkyls; and -5 or 6 membered heteroaryl;
-C2 to Cs alkenyl, or
8. The compound of embodiment 7, wherein Cδ to Cs aryl is phenyl.
9. The compound of embodiment 8, wherein phenyl has at least one substituent at the para position.
10. The compound of embodiment 1, wherein Z is:
-Ci to Cg alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo.
11. The compound of embodiment 1 , wherein Z is Ci to Ce alkyl.
12. The compound of embodiment 11 , wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.
13. The compound of embodiment 1 , wherein:
Ri is:
-C) to Ce alkyl substituted with:
-amido optionally substituted with C] to CO alkyl; and/or -5 or 6 membered heteroaryl; -Ci to Ce alkoxy substituted with:
-amino optionally substituted with heterocyclo; -amido optionally substituted with Ci to C6 alkyl; -5 or 6 membered heterocyclo substituted with Ci to C& alkyl; and/or -5 or 6 membered heteroaryl; -(O)-5 or 6 membered heterocyclo;
-(O)-5 or 6 membered heteroaryl; -SO2R.X optionally substituted with:
-5 or 6 membered heterocyclo; -Ce to Cg aryl; and/or -5 or 6 membered heteroaryl; or
-alkylthio optionally substituted with: -5 or 6 membered heterocyclo; -C6 to C8 aryl; and/or -5 or 6 membered heteroaryl. 14. The compound of embodiment 1, wherein: R2 is:
-Ci to C(, alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; -C6 to C8 aryl;
-amido optionally substituted with Ci to Ce alkyl; and
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys; -alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo; -alkylthio optionally substituted with Ce to C8 aryl; -alkylthio optionally substituted with Ci to Ce alkyl;
-SO2Rx optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more Ci to C6 alkyls; -SO2Rx optionally substituted with 5 or 6 membered heterocyclo; -SO2Rx optionally substituted with C6 to C8 aryl; -SO2RX optionally substituted with Cj to C6 alkyl;
-S(O)Rx optionally substituted with 5 or 6 membered heteroaryl; -S(O)Rx optionally substituted with 5 or 6 membered heterocyclo; -S(O)Rx optionally substituted with C6 to Cg aryl; -S(O)Rx optionally substituted with Ci to Cg alkyl; -alkoxy substituted with:
-alkoxy;
-amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo s; and -amino optionally substituted with one or more alkyls; -amido optionally substituted with Ci to C6 alkyl; -S-5 or 6 membered heterocyclo; -S-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl;
-S-Ci to C6 alkyl; -S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo; -sulfinyl-5 or 6 membered heteroaryl; -sulfϊnyl-Ci to C6 alkyl;
-sulfinyl-C6 to C8 aryl; -sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl; -sulfonyl-Ci to C6 alkyl; -sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and Cj to C6 alkyl, which alkyl is substituted with Ci to C6 alkoxy; -5 or 6 membered heteroaryl substituted with one or more Cj to C6 alkyls; or
-Ce to Cg aryl; -C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
-C(O)-C6 to C8 aryl; -COOH;
-amido substituted with one or more Ci to CO alkyls optionally substituted with one or more Ci to Ce alkoxys; -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from: -hydroxy;
-Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl; and ' -C(O)ORx; -ORkk, wherein Rkk is:
-C6 to C8 aryl; -5 or 6 membered heterocyclo optionally substituted with Ci to Ce alkyl and/or
C6 to C8 aryl; or -Si(Rx)3; -(O)-5 or 6 membered heterocyclo; or
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Ci to C6 alkyls.
15. The compound of embodiment 1, wherein: X is: -cyano;
-halo; or
-alkynyl optionally substituted with Ci to C6 alkyl; Y is:
-Ce to C8 aryl substituted with one or more substituents independently selected from: -halo;
-hydroxy;
-alkoxy optionally substituted with: -one or more halos; or -5 or 6 membered heterocyclo;
-Ci to C6 alkyl;
-amino optionally substituted with one or more substituents independently selected from: -SO2Rx; and -Ci to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls; -OC(O)NHRx; -NR0CORp, wherein Rp is: -Ci to Ce alkyl; or -amino optionally substituted with one or more Ci to Cβ alkyls; and wherein R0 is hydrogen; -NRqCONRqRr, wherein Rq is hydrogen, and wherein R1- is:
-Ci to Cβ alkyl optionally substituted with one or more halos; or -Ce to Cs aryl optionally substituted with halo; -Sθ2Raa, wherein Raa is:
-5 or 6 heterocyclo optionally substituted with hydroxy; -Ci to C$ alkoxy; or -Ci to C6 alkyl; -CORm, wherein Rn, is: -amino optionally substituted with one or more Ci to Ce alkyls, wherein the Ci to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo optionally substituted with Ci to Cβ alkyl, which alkyl is optionally substituted with dialkyl-amino; -NRtCOORu, wherein Ri is hydrogen, and wherein Ru is:
-Ci to Cu alkyl optionally substituted with one or more substituents independently selected from: -CO to Cs aryl optionally substituted with one or more halos and/or haloalkyls; -halo; and
-5 or 6 membered heteroaryl; -C6 to C8 aryl optionally substituted with halo; or -5 or 6 membered heterocyclo; -NHRbb, wherein Rbb is:
-CO=S)NH2; or
-po(ORx)2;
-NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is: -Ci to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo; or
Z is:
-Ci to Ce alkyl; or -5 or 6 membered heterocyclo; R is hydrogen; Ri is:
-hydrogen;
-Ci to Ce alkoxy substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl; or -5 or 6 membered heterocyclo; R2 is: -alkoxy substituted with one or more substituents independently selected from:
-halo; -hydroxy;
-alko'xy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl; -amido optionally substituted with Ci to Ce alkyl;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl;
-S-Ci to C6 alkyl; -sulfinyl-Ci to Ce alkyl; -sulfonyl-C| to C6 alkyl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and Ci to C6 alkyl, which alkyl is optionally substituted with one or more independently selected C| to C6 alkoxys; and -5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyls; -SChRx optionally substituted with C i to C6 alkyl;
-S(O)Rx optionally substituted with Ci to C6 alkyl; -(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Ci to Ce alkyls;
-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to Cs aryls;
-C(O)-C6 to C8 aryl;
-COOH;
-C(O)NHb optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C$ alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl; and;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -one or more halos; -Ci to C6 alkyl; and -SO2Rx;
-amido optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more Ci to Ce alkoxys; or -ORkk, wherein Rkk is:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C[ to C$ alkyl, Ci to Cβ alkoxy, and Ci to Cβ haloalkyl; or
-5 or 6 membered heterocyclo optionally substituted with Ci to Cg alkyl, which alkyl is optionally substituted with Ce to C8 aryl; and
R.3 is hydrogen.
16. The compound of embodiment 15, wherein: X is:
-cyano; or -halo;
Y is:
-phenyl substituted with one or more substituents independently selected from: -halo; and
-NRtCOORu, wherein Rt is hydrogen, and wherein Ru is: -Ci to Ci 2 alkyl optionally substituted with one or more substituents independently selected from:
-Ce to C8 aryl optionally substituted with one or more halos; -halo; and
-5 or 6 membered heteroaryl; -C$ to Cs aryl optionally substituted with halo; or
-5 or 6 membered heterocyclo; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is:
-alkoxy substituted with one or more substituents independently selected from: -halo; and
-alkoxy optionally substituted with alkoxy; -(O)-5 or 6 membered heterocyclo; -amido optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more Ci to Ce alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -one or more halos;
-C1 to C6 alkyl; and -SO2Rx; and R-3 is hydrogen.
17. The compound of embodiment 15, wherein: X is cyano;
Y is Ce to Ce aryl substituted with one or more substituents independently selected from
NRtCOORu, wherein is hydrogen, and wherein Ru is Ci to Cj2 alkyl optionally substituted with one or more Cg to C8 aryls; Z is 5 or 6 membered heterocyclo; R is hydrogen; Ri is hydrogen; R2 is alkoxy; and R3 is hydrogen.
18. The compound of embodiment 15, wherein: X is cyano;
Y is Cg to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with Ci to Ce alkyl;
-NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is Cj to Ce alkyl; -CORm, wherein Rm is: -amino optionally substituted with one or more Ci to C6 alkyls, wherein the Ci to Ce alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or
-3 to 7 membered heterocyclo; and -NR1COORu, wherein Rt is hydrogen, and wherein Ru is: -Ci to Ci 2 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more haloalkyls; and -halo; or
-5 or 6 membered heterocyclo; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is alkoxy substituted with alkoxy; and
R3 is hydrogen.
19. The compound of embodiment 15, wherein: X is cyano;
Y is Ca to C8 aryl substituted with one or more substituents independently selected from: -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to C alkyl optionally substituted with one or more halos; and
-NRvSθ2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is amido optionally substituted with one or more Ci to C6 alkyls, which alkyls are substituted with one or more Ci to Cβ alkoxys; and R3 is hydrogen.
20. The compound of embodiment 15, wherein: X is cyano;
Y is Ce to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more Cj to Ce alkyls;
-NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to Q2 alkyl optionally substituted with one or more halos; -NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to Ce alkyl; and
Z is Ci to C6 alkyl; R is hydrogen; Rt is hydrogen; R2 is alkoxy substituted with sulfonyl-Ci to C6 alkyl; and R3 is hydrogen.
21. The compound of embodiment 15, wherein Y is Ce to Cg aryl substituted with one or more substituents independently selected from NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to C)2 alkyl optionally substituted with one or more halos.
22. The compound of embodiment 15, wherein: X is cyano;
Y is Ce to Cg aryl substituted with one or more substituents independently selected from:
-Ci to Ce alkyl; -amino optionally substituted with one or more Ci to Cg alkyls;
-NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is Ci to Ce alkyl; -NR4COORu, wherein Rt is hydrogen, and wherein Ru is Ci to Cn alkyl; -NRvSO2Rw, wherein Rv is hydrogen and wherein Rw is:
-Ci to C6 alkyl; or -alkyl- or dialkyl-amino;
Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is ORkk, wherein R^ is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Ci to C6 alkoxy, and C] to
Cβ haloalkyl; and R3 is hydrogen.
23. The compound of embodiment 22, wherein: X is cyano; Y is Ce to Cs aryl substituted with one or more substituents independently selected from: -NR1COORu, wherein Rt is hydrogen, and wherein Ru is Cj to C12 alkyl; and -NRvSθ2Rw, wherein Rv is hydrogen, and wherein Rw is: -Ci to C6 alkyl; or -alkyl- or dialkyl-amino; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Cj to C6 alkoxy, and Ci to C6 haloalkyl; and
R3 is hydrogen.
24. The compound of embodiment 22, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more Ci to C6 haloalkyls.
25. The compound of embodiment 22, wherein R2 is ORkk, wherein R^ is 5 or 6 membered heteroaryl substituted with one or more C] to Ce alkyls;
26. The compound of embodiment 1, wherein: X is cyano; Y is C(, to Cs aryl substituted with one or more substituents independently selected from: -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to Ci2 alkyl; and -NRySO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is C(O)-5 or 6 membered heterocyclo; and R3 is hydrogen.
27. The compound of embodiment 1, wherein: X is halo; Y is C6 to Cs aryl substituted with one or more substituents independently selected from: -amino;
-NRqCONRqRr, wherein Rq is hydrogen, and wherein Rn is Ci to Ce alkyl; and -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl; Z is C, to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is alkoxy; and R3 is hydrogen.
28 The compound of embodiment 15 wherein: X is cyano;
Y is C6 to Cg aryl substituted with one or more substituents independently selected from: -halo;
-NRqCONRqRn, wherein Rq is hydrogen, and wherein Rr is Ci to Ce alkyl; -NRtCOORu, wherein Rt is hydrogen, and wherein R11 is C) to C]2 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to Cs aryl optionally substituted with one or more halos; and -halo; -NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is:
-Ci to C6 alkyl; or
-alkyl- or dialkyl-amino optionally substituted with halo; and
Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is 5 or 6 membered heterocyclo; and R3 is hydrogen.
29. The compound of embodiment 28, wherein Y is C6 to Cs aryl substituted with NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to Ce alkyl.
30. The compound of embodiment 28 wherein Y is Ce to Cg aryl substituted with
31. The compound of embodiment 15, wherein: X is cyano; Y is Ce to Cs aryl substituted with one or more substituents independently selected from: -halo;
-amino optionally substituted with one or more Ci to Cs alkyls; -OC(O)NHRx;
-NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is Cj to Cg alkyl; -NR1COORU, wherein R1 is hydrogen, and wherein Ru is Ci to C12 alkyl optionally substituted with one or more substituents independently selected from:
-Ce to C8 aryl optionally substituted with one or more halos and/or haloalkyls; and -halo; -NHRbb, wherein R1* is -C(=S)NH2;
-NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is:
-C1 to C6 alkyl; or
-alkyl- or dialkyl-amino optionally substituted with halo; and
Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is (O)-5 or 6 membered heterocyclo; and R3 is hydrogen.
32. The compound of embodiment 31 , wherein Y is Ce, to Cg aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein R0 is C] to C12 alkyl optionally substituted with one or more substituents independently selected from Cβ to Cg aryl optionally substituted with one or more halos and/or haloalkyls.
33. The compound of embodiment 15, wherein: X is cyano; Y is C6 to Ce aryl substituted with one or more substituents independently selected from
NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl substituted with one or more halos; Z is Ci to C6 alkyl; R is hydrogen; Ri is
-hydrogen;
-(O)-5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo; R2 is: -alkoxy substituted with one or more substituents independently selected from:
-halo; -alkoxy;
-sulfonyl-Ci to C6 alkyl; -5 to 7 membered heterocyclo; -5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl; -5 or 6 membered heteroaryl; -5 or 6 membered heterocyclo; or -ORkk, wherein Rkk is 5 or 6 membered heteroaryl optionally substituted with one or more C] to C6 alkoxys; and R.3 is hydrogen.
34. The compound of embodiment 33, wherein Ri is hydrogen, and R2 is alkoxy substituted with one or more halos. 35. The compound of embodiment 33, wherein Ri is hydrogen; and R2 is alkoxy substituted with one or more alkoxys.
36. The compound of embodiment 15, wherein: X is cyano;
Y is Ce to Cs aryl substituted with one or more substituents independently selected from: -NRqCONRqRr, wherein Rq is hydrogen; and wherein Rr is C6 to C8 aryl substituted with halo; and
-NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl substituted with Cβ to Cg aryl, which aryl is substituted with one or more halos and/or haloalkyls; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is:
-alkoxy substituted with one or more substituents independently selected from:
-alkoxy; and -5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo; or -(O)-5 or 6 membered heteroaryl; and R3 is hydrogen.
37. The compound of embodiment 36, wherein Y is Cg to Cg aryl substituted with NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is Cδ to Cg aryl substituted with halo.
38. The compound of embodiment 36, wherein Y is C6 to Cs aryl substituted with one or more substituents independently selected from NRtCOORu, wherein Rt is hydrogen, and
wherein Ru is Ci to C 12 alkyl substituted with C6 to Cg aryl, which aryl is substituted with one or more halos and/or haloalkyls.
39. A compound of formula lib
or a pharmaceutically acceptable salt thereof, wherein: X is cyano;
Y is Ce to Cg aryl substituted with one or more substituents independently selected from: -C1 to C6 alkyl;
-amino substituted with C1 to Ce alkyl -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Q to C^ alkyl optionally substituted with one or more halos;
-NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Cj to Ce alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is:
-alkoxy substituted with one or more halos; -5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to C6 alkyl; and -NO2:
-C(O)-3 to 7 membered heterocyclo or -C(O)-5 membered heterocyclo; and -ORkk, wherein Rkk is: -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from cyano, and Ci to C6 alkyl; or -5 or 6 membered heterocyclo optionally substituted with one or more =O; and R3 is hydrogen.
40. The compound of embodiment 39, wherein: X is a cyano group;
Y is Ce to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to
Ci2 alkyl substituted with one or more halos; Z is Ci to C6 alkyl; R is a hydrogen, Ri is a hydrogen;
R2 is alkoxy substituted with one or more halos; and R3 is a hydrogen. 41. The compound of embodiment 40, wherein the C6 to Cs aryl is phenyl.
42. The compound of embodiment 41, wherein the phenyl is substituted at the para position.
43. The compound of embodiment 41, wherein R11 is Ci to Ci2 alkyl substituted with fluoro.
44. The compound of embodiment 39, wherein: X is cyano;
Y is Ce to Cs aryl substituted with one or more substituents independently selected from:
-Ci to C6 alkyl;
-amino substituted with Ci to Ce alkyl; and
-NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with cyano; and R3 is hydrogen. 45. The compound of embodiment 44, wherein Y is Ce to Cs aryl para substituted with NRvSO2Rw5 wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl.
46. The compound of embodiment 44, wherein Y is C6 to Cs aryl para substituted with Ci to C6 alkyl and NRVSO2RW9 wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl.
47. The compound of embodiment 44, wherein Y is C6 to Cs aryl para substituted with amino substituted with Ci to C6 alkyl.
48. The compound of embodiment 44, wherein R2 is ORkk, wherein R^ is 5 or 6 membered heteroaryl substituted with cyano at the ortho position.
49. The compound of embodiment 39, wherein: X is cyano;
Y is Ce to C8 aryl substituted with one or more substituents independently selected from:
-NRtCOORu, wherein Rt is hydrogen, and wherein R11 is Cj to C 12 alkyl; and -NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to Ce alkyl;
Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with Ci to Ce alkyl; and R3 is hydrogen.
50. The compound of embodiment 49, wherein the C6 to Cg aryl is phenyl.
51. The compound of embodiment 50, wherein Y is phenyl substituted at the para position with NRvSOoRw, wherein Rv is hydrogen, and wherein Rw is Ci to Cβ alkyl.
52. The compound of embodiment 50, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein R1 is hydrogen, and wherein Ru is Ci to Cn alkyl.
53. The compound of embodiment 39, wherein: X is cyano;
Y is C6 to Cs aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to
Cn alkyl substituted with one or more halos; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is ORkk, wherein R^ is 5 or 6 membered heteroaryl; and R3 is hydrogen. 54. The compound of embodiment 53, wherein the Ce to Cg aryl is phenyl.
55. The compound of embodiment.54, wherein the phenyl is substituted at the para position.
56. The compound of embodiment 55, wherein Ru is Ci to C12 alkyl substituted with fluoro.
57. The compound of embodiment 39, wherein: X is cyano;
Y is Ce to Cg aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein R1, is Cj to
C12 alkyl optionally substituted with one or more halos;
Z is C1 to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is 5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl; and R3 is hydrogen.
58. The compound of embodiment 57, wherein the C6 to Cg aryl is phenyl.
59. The compound of embodiment 58, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C] to C12 alkyl.
60. The compound of embodiment 58, wherein Y is phenyl substituted at the para position with NR1COORu, wherein Rt is hydrogen, and wherein R11 is Ci to Ci 2 alkyl substituted with one or more halos.
61. The compound of embodiment 60, wherein R11 is Ci to C)2 alkyl substituted with fluoro.
62. The compound of embodiment 39, wherein: X is cyano; Y is Ce to Cs aryl substituted with NRtCOORU5 wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl;
Z is Ci to C6 alkyl;
R is hydrogen;
Ri is hydrogen; R2 is ORkk, wherein Rkk is 5 or 6 membered heterocyclo; and
R3 is hydrogen.
63. The compound of embodiment 62, wherein the C6 to C8 aryl is phenyl.
64. The compound of embodiment 63, wherein the phenyl is substituted at the para position. 65. The compound of embodiment 39, wherein:
X is cyano;
Y is CQ to Cs aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl;
Z is Ci to C6 alkyl; R is hydrogen;
Ri is hydrogen;
R2 is 5 or 6 membered heterocyclo; and
R.3 is hydrogen.
66. The compound of embodiment 65, wherein the Ce to Cg aryl is phenyl.
67. The compound of embodiment 66, wherein the phenyl is substituted at the para position. 68. The compound of embodiment 39, wherein: X is cyano;
Y is C6 to Cs aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Cj to
C12 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is 5 or 6 membered heteroaryl substituted with NO2; and R3 is hydrogen.
69. The compound of embodiment 68, wherein the C6 to Cs aryl is phenyl. 70. The compound of embodiment 69, wherein the phenyl is substituted at the para position.
71. The compound of embodiment 39, wherein: X is cyano;
Y is C6 to Cs aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Cj to C12 alkyl;
Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is -C(O)-3 to 7 membered heterocyclo or -C(O)-5 membered heterocyclo; and R3 is hydrogen.
72. The compound of embodiment 71, wherein the C6 to C§ aryl is phenyl.
73. The compound of embodiment 72, wherein the phenyl is substituted at the para position.
74. The compound of embodiment 39, wherein: X is cyano;
Y is Ce to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Cj to
C12 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is ORick, wherein Rkk is -5 or 6 membered heterocycle substituted with one or more =O; and R3 is hydrogen.
75. The compound of embodiment 74, wherein the Ce to Cg aryl is phenyl.
76. The compound of embodiment 75, wherein the phenyl is substituted at the para position.
77. A compound of formula Hc
or a pharmaceutically acceptable salt thereof, wherein: X is cyano; Y is C6 to C8 aryl substituted with one or more substituents independently selected from: -NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is Ci to Ce alkyl; -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Cj to C12 alkyl optionally substituted with one or more substituents independently selected from: -Cβ to Cg aryl optionally substituted with one or more halos; -halo; and
-5 or 6 membered heteroaryl; and
-NRvSθ2RWj wherein Rv is hydrogen, and wherein Rw is C) to Cg alkyl; Z is:
-Ci to Ce alkyl; or -5 or 6 membered heterocyclo;
R is hydrogen;
-Ci to Ce alkoxy substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -5 or 6 membered heteroaryl; -(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl; or
-5 or 6 membered heterocyclo; R2 is hydrogen; and R3 is hydrogen; with the proviso that when Ri is Ci to Ce alkoxy substituted with a 5 or 6 membered heterocyclo or when Ri is a 5 or 6 membered heterocyclo, Y is a Ce to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
Ci to C12 alkyl substituted with one or more halos; or aryl substituted with one or more halos.
78. The compound of embodiment 77, wherein: Y is Ce to C8 aryl substituted with NRtCOORu., wherein R, is hydrogen, and wherein Ru is Cj to
Ci2 alkyl;
Z is Ci to C6 alkyl; and Ri is Ci to C6 alkoxy substituted with 5 or 6 membered heteroaryl.
79. The compound of embodiment 77, wherein Ri is Ci to Cβ alkoxy substituted with 5 or 6 membered heteroaryl.
80. The compound of embodiment 77, wherein R] is (O)-5 or 6 membered heterocyclo.
81. The compound of embodiment 77, wherein Ri is (O)-5 or 6 membered heteroaryl.
82. The compound of embodiment 77, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, or cyclopentyl. 83. A compound of formula Hd
or a pharmaceutically acceptable salt thereof, wherein: X is hydrogen;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NR^CONRqRr, wherein Rq is hydrogen, and wherein Rr is C1 to C6 alkyl; and -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to Ci2 alkyl optionally substituted with one or more halos; Z is C1 to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is ORkk, wherein Rkk is:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo; or
-5 or 6 membered heteroaryl optionally substituted with one or more independently selected halos; and R3 is hydrogen.
84. The compound of embodiment 83, wherein: X is hydrogen;
Y is Ce to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to
C]2 alkyl substituted with one or more halos; Z is C1 to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl; and R3 is hydrogen. 85. The compound of embodiment 84, wherein the Ce to Cg aryl is phenyl.
86. The compound of embodiment 84, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Cj to C12 alkyl substituted with fluoro.
87. The compound of embodiment 84, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.
88. The compound of embodiment 83, wherein R2 is (0)-5 or 6 membered heterocyclo.
89. A compound of formula He
or a pharmaceutically acceptable salt thereof, wherein: X is:
-hydrogen; -cyano;
-nitro; -formyl; -COOH;
-CORx, wherein Rx is Ci to C6 alkyl; -CH=N-(C1 to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more Cj to C6 alkyls); -halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with Ci to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl; -SO2Rx; -SO2NH2; -SO2NH(Rx); -SO2N(RX)2;
-amino optionally substituted with one or more independently selected Ci to C6 alkyls and/or -C(O)-Ci to C6 alkyls;
-amido optionally substituted with one or more independently selected Ci to C6 alkyls; -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-Ci to C6 alkyl optionally substituted with one or more halos;
-halo; and
-cyano;
Y is: -benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more Cj to Ce alkyls; -indolyl optionally substituted on the nitrogen with -SO2Rx; -Ce to Cg aryl optionally substituted with one or more substituents independently selected from: -halo;
-Ci to C6 alkyl;
-alkoxy, optionally substituted with one or more substituents independently selected from: -halo; -5 or 6 membered heterocyclo;
-C(O)NH2 optionally substituted with C6 to C8 alkyl; -C(O)NH-(Ci to C6)-alkyl; -hydroxy; -haloalkyl; -cyano;
-nitro; -COOH; -N=CHN(Rx)2;
-amino optionally substituted with one or more substituents independently selected from:
-SO2Rx; -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to C8 aryl optionally substituted with halo;
-5 or 6 metnbered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-Ci to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
-C(, to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl; -alkoxy; and -halo; and -PO2Rx; -OC(O)NHRx wherein Rx is optionally substituted with vinyl;
-OC(O)N(Ru)2, wherein Ru is alkyl or C6 to Cs aryl, which alkyl or aryl is optionally substituted with dialkylamino; -OC(O)NH(ORuu), wherein Ruu is -C6 to Cg aryl optionally substituted with dialkylamino; -OC(O)NRx(ORx);
-OC(O)N(ORX)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl; -NR0C(O)Rp, wherein Rp is:
-C] to C6 alkyl;
-amino optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from Cs to Cs aryl and alkoxy; or -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from Ci to C6 alkyl and Ce to Cs aryl; and wherein R0 is: -hydrogen; or
-Ci to C6 alkyl; -NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from: - halo;
-hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Ce to Cg aryl optionally substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos; -Ci to C6 alkoxy; -5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -SChRaaj wherein Raa is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy;
-Ci to C6 alkoxy; and -Ci to C6 alkyl;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -alkoxy; -hydroxy;
-halo; -CORm, wherein Rm is:
-amino optionally substituted with one or more Cj to C6 alkyls, which alkyls are optionally substituted with 5 or 6 membered heterocyclo or C6 to Cs aryl, which heterocyclo or aryl is optionally substituted one or more substituents independently selected from halo and alkoxy; -heterocyclo optionally substituted with hydroxy;
-3 to 7 membered heterocyclo optionally substituted with Ct to Ce alkyl, which alkyl is optionally substituted with dialkyl-amino; -NRiCOORu, wherein Rt is hydrogen, and wherein Ru is:
-Ci to CJ2 alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cg aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to Ce alkyls; -halo;
-SO2RwJ -SO2Rx;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo; -C2 to C6 alkenyl;
-Ce to Cg aryl optionally substituted with halo;
-4 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: =O; -SO2RW;
-CORP; and
-(CO)O-(Ci to C4 alkyl)-O-(C, to C4 alkyl); -NHRbb, wherein Rbb is:
-C(=S)NH2; -C(=S)NHRX;
-C(=S)NRXRX; -C(=N-CN)NHRx; or -PO(ORX)2; -N(CONHRW)2;
-N(SO2RW)2; -NRvSO2Rw3 wherein Rv is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo; and wherein Rw is:
-Ci to CO alkyi optionally substituted with Ce to Cs aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-Ce to Cs aryl;
-Cδ to Cg heteroaryl; or
-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to CO allcoxy, alkoxycarbonyl, (CO)O-(Ci to Cβ) alkyl), hydroxy, cyano, 5 or 6
10 membered heterocyclo, and 5 or 6 membered heteroaryl;
-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -halo;
-Ci to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from: -halo; -5 or 6 membered heterocyclo; and
-C(O)NH2 optionally substituted with C6 to C8 alkyl; -hydroxy; -haloalkyl; -cyano; -nitro;
-COOH;
-amino optionally substituted with one or more substituents independently selected from: -SO2Rx; -6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -Ce to Cg aryl optionally substituted with halo;
- Cs to Cβ heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and
-Ci to C7 alkyl optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls; -Cβ to Cg aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -alkoxy; and -halo; -NR0CORp, wherein Rp is:
-Ci to C6 alkyl;
-amino optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more Ci to Ce alkyls and/or Ce to C8 aryls; and wherein R0 is: -hydrogen; or -Ci to C6 alkyl; -NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is:
-Ci to CO alkyl optionally substituted with one or more substituents independently selected from: - halo; -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -C6 to Cs aryl optionally substituted with halo; -C2 to Ce alkenyl optionally substituted with one or more halos; -Ci to C6 alkoxy;
-5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
-Ci to Cu alkyl optionally substituted with one or more substituents independently selected from: -Ce to Cg aryl optionally substituted with one or more halos and/or haloalkyls; -alkoxy optionally substituted with one or more alkoxys;
-amino optionally substituted with one or more Cj to Ce alkyls; -halo; -SC^Rw; -SO2Rx; -5 or 6 membered heteroaryl; and
-5 or 6 membered heterocyclo; and -NRySChRw5 wherein Rv is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo; and wherein Rw is: -Ci to Ce alkyl optionally substituted with Cβ to C% aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl; -C6 to C8 aryl; -C6 to Cs heteroaryl; -amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
Z is:
-Ci to Cβ alkyl optionally substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;
R is hydrogen;
R, is:
-hydrogen;
-a 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy; -Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl; -CORp; and
-C(O)ORx; or
-5 or 6 membered heteroaryl optionally substituted with one or more independently selected from:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; -heterocyclo;
-nitro; -hydroxy; -COOH; -CO2 Rx; -CORx;
-C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to C6 alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -Ci to Cβ alkyl optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys; -amido optionally substituted with Ci to C& alkyl; -5 or 6 membered heterocyclo optionally substituted with Ci to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl;
-SO2 Rx;
-C2 to C6 alkenyl optionally substituted with -SO2 Rx; -Ci to Cβ alkoxy optionally substituted with one or more substituents independently selected from: -halo; -hydroxy; -cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl; -amino optionally substituted with heterocyclo; -amido optionally substituted with C1 to C6 alkyl; -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and Ci to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -Ci to C6 alkoxy; and -C6 to C8 alryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl; and -4 to 7 membered heterocyclo; -alkoxy; and
-C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy; -Ci to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C] to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy; -halo; -alkylthio; -haloalkyl; -cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -heterocyclo;
-nitro; -hydroxy; -COOH; -CO2Rx; -CORx;
-C(O)NH2 optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and
-amido optionally substituted with one or more or more substituents independently selected from halo, C] to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Ci to Cs alkoxys;
-C(O)NH2 optionally substituted with one or more C] to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -Ce to Cs aryl; -5 or 6 membered heteroaryl; and
-C1 to Cδ alky farther optionally substituted with one or more substituted with hydroxys;
-SO2R.X optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo;
-Ce to C8 aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo;
-Cβ to Cs aryl; and -5 or 6 membered heteroaryl; -Ce to C8 aryl;
-C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl;
-COOH; or -ORfck, wherein R^ is:
-Cβ to Cg aryl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkyl, Ci to Ce alkoxy, and Ci to Ce haloalkyl;
R2 is:
-Cj to Ce alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl;
-C6 to Cg aryl;
-amido optionally substituted with Ci to C^ alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and
"SO2 Rx;
-C2 to Ce alkenyl optionally substituted with SO2Rx;
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl; -5 or 6 membered heterocyclo; -C6 to Cg aryl; and -C, to C6 alkyl; -SOaRx optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyls;
-5 or 6 membered heterocyclo; -C6 to C8 aryl; and
-Ci to C6 alkyl;
-S(O)Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl; -5 or 6 membered heterocyclo;
-C6 to Cg aryl; and -Ci to C6 alkyl; -alkoxy optionally substituted with one or more substituents independently selected from: -halo;
-hydroxy; -cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from -SO2-C1 to C4 alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls; -amido optionally substituted with Ci to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl; -S-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from:
-Cg to Ce aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to Cs heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from: -C6 to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfinyl-Cδ to Cs aryl; -sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C] to Ce alkyl; -sulfonyl-Ci to C& alkyl optionally substituted with one or more substituents independently selected from:
-C^ to Ce aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfonyl-Ce to Cs aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =0, heterocyclo, and
Ci to Ce alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -Ci to Cδ alkoxy; and -C6 to C8 aryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -Ci to Cβ alkyl optionally substituted with one or more alkoxys; -4 to 7 membered heterocyclo; and -alkoxy; and
-C6 to C8 aryl; -C6 to C8 aryl; -(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy;
=O;
-Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; or
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-CJ to Cg alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl;
-cyano; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C] to Cβ alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently
selected from halo, C] to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more substituents independently selected from halo, Cj to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Ci to C6 alkoxys; -C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -C6 to Cg aryl; -5 or 6 membered heteroaryl; and
-Ci to Ce alkyl optionally substituted with one or more hydroxys; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl; -COOH; -C(O)NH2 optionally substituted with one or more Cj to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more Ci to Cβ alkyls, which alkyls are optionally substituted with one or more Ci to Ce alkoxys;
-amino optionally substituted with one or more substituents independently selected from:
-SO2Rx;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -Cβ to Cs aryl optionally substituted with halo; -C5 to Ce heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; -C] to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-Ce to Cs aryl optionally substituted with one or more substituents independently selected from allcyl, halo and haloalkyl;
-alkoxy; and -halo; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ca alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio;
-haloalkyl; -cyano; -amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and
5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy; -COOH;
-CO2Rx; -CORx; -C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered
heterocyclo, 5 or 6 membered heteroaryl, and Ci to Q alkyl, which alkyl is optionally substituted with one or more Cj to Q alkoxys; -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy;
=O;
-Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; -ORkic, wherein Rj* is:
-Ce to Cg aryl optionally substituted with one or more substituents independently selected from halo, C] to C$ alkyl, Ci to Ce alkoxy, and Cj to Ce haloalkyl;
-5 to 6 membered heterocyclo optionally substituted with Ci to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or -5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, C1 to Cg alkoxy, and Cj to Cβ haloalkyl;
-SO2Rx; or -Si(Rx)3;
-OC(O)NHRx wherein Rx is optionally substituted with -Ce to Cg aryl; -OC(O)N(RX)2; or
R3 is hydrogen; or nitro; with the proviso that at least one of X, Y, Z, Ri, R2 and R3 is selected from the following:
X is:
-CH=N-(Ci to C5 alkoxy); -CH=N-(amino optionally substituted with one or more C] to C6 alkyls);
-halo;
-alkyl optionally substituted with one. or more halos;
-alkynyl optionally substituted with C| to CO alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos; -oximyl;
-SO2Rx; -SO2NH2; -SO2NH(Rx); -SO2N(Rx)2; -amino optionally substituted with one or more independently selected Ci to Cg alkyls and/or -C(O)-Ci to C6 alkyls;
-amido optionally substituted with one or more independently selected Ci to Ce alkyls; -5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more Ci to Cδ alkyls, which alkyls are optionally substituted with one or more halos; or
-Cs to C8 aryl substituted with one or more substituents independently selected from: -Ci to Ce alkyl optionally substituted with one or more halos; -halo; and -cyano; Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more Ci to Ce alkyls;
-indolyl substituted on the nitrogen with -SO2Rx;
-C6 to Cs aryl substituted with one or more substituents independently selected from: -alkoxy substituted with one or more substituents independently selected from:
-C(O)NH2 optionally substituted with C6 to C8 alkyl; and -C(O)NH-(C, to C6)-alkyl; -haloalkyl; -cyano; -COOH;
-N=CHN(RX)2;
-amino substituted with one or more substituents independently selected from: -SO2Rx;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, • cyano, alkoxy, haloalkoxy and CO to Cg aryl optionally substituted with halo; -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-Ci to C7 alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
-Ce to Cg aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl; -alkoxy; and -halo; and
-PO2Rx;
-OC(O)NHRx wherein Rx is optionally substituted with vinyl; -OC(O)N(Ru)2, wherein Ru is alkyl or Ce to Cs aryl, which alkyl or aryl is optionally substituted with dialkylamino; -OC(O)NH(OR1111), wherein Ruu is -C6 to C8 aryl optionally substituted with dialkylamino; -OC(O)NRx(ORx); -OC(O)N(ORX)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl; -NR0C(O)Rp, wherein Rp is:
-amino optionally substituted with one or more Cj to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C8 aryl and alkoxy; or -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from Ci to C6 alkyl and C6 to C8 aryl;
-NR^CONRqRr, wherein Rr is:
-Ci to Ce alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Cβ to C8 aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos; -Ci to C6 alkoxy;
-5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -SO2Raa, wherein R33 is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-Ci to C6 alkoxy; and -Ci to C6 alkyl;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -alkoxy; -hydroxy; -halo; -CORm, wherein Rn, is:
-amino substituted with one or more Ci to Ce alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or C6 to C8 aryl, which heterocyclo is substituted with one or more halos and/or
alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys; -heterocyclo substituted with hydroxy; -NRtCOOR115 wherein R11 is: -Ci to C] 2 alkyl substituted with one or more substituents independently selected from: -Cβ to Cs aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to Ce alkyls;
-SO2RW; -SO2Rx; and
-5 or 6 membered heteroaryl; -C2 to Cg alkenyl; -4 to 7 membered heterocyclo substituted with one or more substituents independently selected from:
=o;
-SO2RW; -CORP; and -(CO)O-(Ci to C4 alkyl)-O-(Ci to C4 alkyl);
-4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: =O;
-so2Rw; -CORP; and
-(CO)O-(Ci to C4 alkyl)-O-(Ci to C4 alkyl); -NHRbb, wherein Rbb is: -C(=S)NHRX; -C(=S)NRXRX; or -C(=N-CN)NHRX;
-N(CONHRW)2; -NH(SORw); -N(SO2RW)2; -NRvSO2Rw5 wherein Rv is alkyl substituted with 4 or 7 membered heterocyclo;
or wherein Rw is:
-Ci to Ce alkyl substituted with Ce to Cg aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl; -amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, alkoxycarbonyl, (CO)O-(C) to Ce) alkyl), hydroxy, cyaπo, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -halo; -Ci to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from: -halo;
-5 or 6 membered heterocyclo; and -C(O)NH2 optionally substituted with C6 to Cg alkyl;
-hydroxy; -haloalkyl; -cyano; -nitro; -COOH;
-amino optionally substituted with one or more substituents independently selected from: -SO2Rx;
-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to Cs aryl optionally substituted with halo;
- C5 to Ce heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and
-Ci to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls; -Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo; -NRoCORp, wherein Rp is:
-amino optionally substituted with one or more C] to Cg alkyls, which alkyls are optionally and independently substituted with one or more Ce to C8 aryls and/or alkoxys; or
-5 or 6 membered heterocyclo optionally substituted with one or more Ci to Ce alkyls and/or C6 to C8 aryls;
-NRqCONRqRr, wherein Rr is:
-Ci to C6 alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Cβ to Cg aryl substituted with halo;
-C2 to CO alkenyl optionally substituted with one or more halos; -Ci to Cβ alkoxy;
-5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -NR1COORu, wherein R11 is:
-Cj to C12 alkyl substituted with one or more substituents independently selected from:
-Ce to Cg aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to Ce alkyls; -SO2RW;
-SO2Rx; and
-5 or 6 membered heteroaryl; -NRvSθ2Rw, wherein Rv is alkyl substituted with 4 to 7 membered heterocyclo; or wherein Rw is: -Ci to Ce alkyl substituted with Ce to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl; -Ce to C8 aryl;
-amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
Z is:
-Ci to Ce alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;
Ri is:
-a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl; -CORp; and -C(O)ORx; or
-5 or 6 membered heteroaryl substituted with one or more independently selected from: -Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; -alkoxy;
-halo; -alkyltbio; -haloalkyl; -cyano; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; -heterocyclo; -nitro;
-hydroxy; -COOH; -CO2 Rx; -CORx; -C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Cj to Ce alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -Ci to Cβ alkyl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
-amido optionally substituted with Ci to CO alkyl; -5 or 6 membered heterocyclo substituted with Ci to Cg alkyl;
-5 or 6 membered heteroaryl; and
-C6 to C8 aryl;
-SO2 Rx;
-C2 to Ce alkenyl optionally substituted with -SO2Rx; -Ci to Cβ alkoxy substituted with one or more substituents independently selected from:
-hydroxy; -cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl; -amino optionally substituted with heterocyclo;
-amido optionally substituted with C 1 to Cg alkyl; -5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and Ci to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkoxy; and -C6 to C8 alryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl; and
-4 to 7 membered heterocyclo; and -alkoxy;
-(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy; -Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; or
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Q; alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl;
-cyano; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Cj to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx;
.CORx;
-C(O)NH2 optionally substituted with one or more substituents independently selected from:
-Ci to Cβ alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce, alkoxy, hydroxy, 5 or
6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to
Cβ alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -C(O)NH2 optionally substituted with one or more Cj to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -Ce to C8 aryl; -5 or 6 membered heteroaryl; and
-Ci to Cδ alky further optionally substituted with one or more substituted with hydroxys; optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo;
-Ce to Cg aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo;
-Ce to C8 aryl; and -5 or 6 membered heteroaryl; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to Cg aryl; -COOH;
-ORkk, wherein Rj* is:
-CO to C8 aryl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Ci to Ce alkoxy, and Ci to Ce haloalkyl; R2 is:
-Ci to Cδ alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; -C$ to Cg aryl;
-amido optionally substituted with Ci to Ce alkyl; and
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and -SO2 Rx;
-C2 to CO alkenyl optionally substituted with SOiRx;
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl; -5 or 6 membered heterocyclo;
-Cg to Cs aryl; and -Ci to C6 alkyl; -SO2Rx optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more Cj to Ce alky Is;
-5 or 6 membered heterocyclo; -Ce to Cg aryl; and -C1 to C6 alkyl; -S(O)Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl; -5 or 6 membered heterocyclo; -Cg to Cg aryl; and -Ci to C6 alkyl;
-alkoxy substituted with one or inore substituents independently selected from: -halo; -hydroxy; -cyano; -alkoxy optionally substituted with alkoxy;
-amino substituted with one or more substituents independently selected from - SO2-Ci to C4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and
-amino optionally substituted with one or more alkyls; -amido substituted with Ci to Ce alkyl; -S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl; -S-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo; -sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-Ci to Cg alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfmyl-Ce to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl;
-sulfonyl-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from: -Ce to Cg aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfonyl-Cή to Cs aryl; -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, heterocyclo, and Ci to Cβ alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -Ci to Ce alkoxy; and
-C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -C1 to C6 alkyl optionally substituted with one or more alkoxys; -4 to 7 membered heterocyclo; and
-alkoxy; and -Cδ to Cs aryl; -C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy; =O;
-Ci to C6 alkyl; -SO2Rx; -C(O)-C6 to C8 aryl;
-C(O)ORx; or -(O)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from: -Ci to Cg alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio;
-haloalkyl; -cyano; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy;
-COOH; -CO2Rx; -CORx;
-C(O)NH2 optionally substituted with one or more Cj to Cg alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Cj to C6 alJcoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Cj to C^ alkoxys; -C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -C6 to C8 aryl; -5 or 6 membered heteroaryl; and
-Ci to Cg alkyl optionally substituted with one or more hydroxys; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl; -COOH; -C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido substituted with one or more Ci to Ca alkyls, which alkyls are optionally substituted with one or more Ci to Cg alkoxys;
-amino substituted with one or more substituents independently selected from: -SO2Rx; -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -Ce to C8 aryl optionally substituted with halo;
-C5 to Ce heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; -C1 to C7 alkyl optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -alkoxy; and
-halo; membered heteroaryl substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl;
-cyano;
-amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently
selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Cj to C6 alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy; =O;
-Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl; -CORp; and -C(O)ORx;
-ORick, wherein Rkic is:
-Cδ to C8 aryl optionally substituted with one or more substituents independently selected from halo, C] to Ce alkyl, Cj to Ce alkoxy, and Ci to C6 haloalkyl; -5 to 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with Ce to Cg aryl; or -5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Ci to Ce alkyl, Cj to Ce alkoxy, and Ci to Ce haloalkyl; -SO2Rx; or
-Si(R*)3;
-OC(O)NHRx wherein Rx is optionally substituted with -Cg to Cs aryl; -OC(O)N(RX)2; or
R3 is nitro.
90. The compound of embodiment 89, wherein: X is:
-CH=N-(C, to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C] to Ce alkyls); -halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos; -oximyl; -SO2Rx;
-SO2NH2; -SO2NH(Rx); -SO2N(RX)2;
-amino optionally substituted with one or more independently selected Ci to C6 alkyls and/or -C(O)-Ci to C6 alkyls;
-amido optionally substituted with one or more independently selected Ci to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to Cs aryl substituted with one or more substituents independently selected from:
-Ci to C6 alkyl optionally substituted with one or more halos; -halo; and -cyano.
91. The compound of embodiment 89, wherein: Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more Ci to C6 alkyls;
-indolyl substituted on the nitrogen with -SO2Rx; or
-C6 to C8 aryl substituted with one or more substituents independently selected from: -alkoxy substituted with one or more substituents independently selected from:
-C(O)NH2 optionally substituted with C6 to C8 alkyl; and -C(O)NH-(C, to Gø-alkyl; -haloalkyl;
-cyano; -COOH; -N=CHN(RX)2;
-amino substituted with one or more substituents independently selected from: -SO2Rx;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and Ce to Cg aryl optionally substituted with halo; -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-Ci to C7 alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
-Ce to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl; -alkoxy; and -halo; and
-PO2Rx;
-OC(O)NHRx wherein Rx is optionally substituted with vinyl; -OC(O)N(Ru)2, wherein Ru is alkyl or Cβ to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino; -OC(O)NH(ORuu), wherein Ruu is -C6 to C8 aryl optionally substituted with dialkylamino; -OC(O)NRx(ORx); -OC(O)N(ORX)2;
-OC(O)Rab, wherein Rab is 5 or 6 niembered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
-NR0C(O)Rp, wherein Rp is: -amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from Ce to C8 aryl and alkoxy; or -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from Cj to Cβ alkyl and Ce to C8 aryl; -NRqCONRqRr, wherein Rr is:
-Ci to CO alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy; -5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to Cg alkenyl optionally substituted with one or more halos; -Ci to Ce alkoxy; -5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -Sθ2Raa, wherein Raa is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy;
-Ci to Ce alkoxy; and -Ci to C6 alkyl; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-alkoxy; -hydroxy; -halo; -CORm, wherein Rra is:
-amino substituted with one or more Ci to C6 alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or C^ to Cg aryl, which heterocyclo is substituted with one or more halos and/or alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys;
-heterocyclo substituted with hydroxy; -NRtCOORu, wherein R11 is:
-Ci to Cu alkyl substituted with one or more substituents independently selected from: -Cβ to Cg aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to Ce alkyls; -SO2RW; -SO2Rx; and
-5 or 6 membered heteroaryl; -C2 to Ce alkenyl; -4 to 7 membered heterocyclo substituted with one or more substituents independently selected from: =O;
-so2Rw; -CORP; and
-(CO)O-(C, to C4 alkyl)-O-(Ci to C4 alkyl);
-4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
=O;
-so2Rw;
-CORP; and
-(CO)O-(C, to C4 alkyl)-O-(Ci to C4 alkyl); -NΗRbb, wherein Rbb is:
-C(=S)NHRX; -C(=S)NRXRX; or -C(=N-CN)NHRX; -N(CONHRw)2;
-NH(SORW); -N(SO2RW)2:
-NRvSO2Rw, wherein Rv is alkyl substituted with 4 or 7 membered heterocyclo; or wherein Rw is:
-Ci to Ce alkyl substituted with Ce to Cg aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl; -amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, alkoxycarbonyl, (CO)O-(C1 to Cβ) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -halo;
-Ci to C6 alkyl; -alkoxy optionally substituted with one or more substituents independently selected from: -halo;
-5 or 6 membered heterocyclo; and -C(O)NH2 optionally substituted with C6 to C8 alkyl; -hydroxy;
-haloalkyl; -cyano; -nitro; -COOH; -amino optionally substituted with one or more substituents independently selected from: -SO2Rx; -6 to 8 memebered aryl optionally substituted with one or more
. substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -Ce to Cs aryl optionally substituted with halo; - C5 to Cg heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and -Ci to C7 alkyl optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls; -Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo; -NR0CORp, wherein Rp is:
-amino optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally and independently substituted with one or more Ce to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more C) to Ce alkyls and/or Ce to Cg aryls; -NRqCONRqRr, wherein Rr is: -Ci to C6 alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and
-Ce to Cs aryl substituted with halo;
-C2 to Cg alkenyl optionally substituted with one or more halos; -Ci to Ce alkoxy; -5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-NR1COORU, wherein R11 is:
-Ci to C12 alkyl substituted with one or more substituents independently selected from:
-Cg to Cs aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to Ce alkyls; -SO2RW; -SO2Rx; and -5 or 6 membered heteroaryl; and
-NRvSO2Rw1 wherein Rv is alkyl substituted with 4 to 7 membered heterocyclo; or wherein Rw is:
-Ci to CO alkyl substituted with Cβ to Cg aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-C6 to C8 aryl;
-amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, Ci to C& alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
92. The compound of embodiment 89, wherein: Z is:
-Cj to Ce alkyl substituted with 5 or 6 membered heterocyclo; or
-5 or 6 membered heterocyclo.
93. The compound of embodiment 89, wherein: Ri is:
-a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy; -C, to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl; -CORp1. and
-C(O)ORx; or
-5 or 6 membered heteroaryl substituted with one or more independently selected from: -Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Cj to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-alkoxy; -halo; -alkylthio; -haloalkyl; -cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; -heterocyclo;
-nitro; -hydroxy; -COOH; -CO2 Rx; .CORx;
-C(O)NH2 optionally substituted with one or more Cj to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more C] to C6 alkoxys; -Ci to Ce alkyl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
-amido optionally substituted with Ci to Cs alkyl; -5 or 6 membered heterocyclo substituted with Ci to C6 alkyl;
-5 or 6 membered heteroaryl; and
-C6 to C8 aryl;
-SO2 Rx;
-C2 to Cs alkenyl optionally substituted with -SC>2RX; -C] to Cβ alkoxy substituted with one or more substituents independently selected from;
-hydroxy; -cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl; -amino optionally substituted with heterocyclo;
-amido optionally substituted with Ci to Ce alkyl; -5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and Ci to Ce alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Ci to Cβ alkoxy; and -C6 to C8 alryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkyl; and -4 to 7 membered heterocyclo; and -alkoxy;
-(O)-S or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy; -C] to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; or
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl;
-cyano; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx;
.CORx;
-C(O)NH2 optionally substituted with one or more substituents independently selected from:
-Ci to Ce aikyl optionally substituted with one or more substituents independently selected from halo, Ci to Cg alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or
6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to C& alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys;
-C(O)NH2 optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -C6 to C8 aryl;
-5 or 6 membered heteroaryl; and
-C] to C6 alky further optionally substituted with one or more substituted with hydroxys;
-SO2Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; -CO to Cs aryl; and -5 or 6 membered heteroaryl; or
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; -CO to C8 aryl; and -5 or 6 membered heteroaryl; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl;
-COOH; or -ORkk, wherein Rkk is:
-Ce to C8 aryl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Ci to Ce alkoxy, and Ci to Ce haloalkyl.
94. The compound of embodiment 89, wherein: R2 is:
-Ci to C6 alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; -C6 to C8 aryl; -amido optionally substituted with Cj to Cβ alkyl; and
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and
-SO2 Rx; -C2 to CQ alkenyl optionally substituted with SO2Rx;
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo; -C6 to C8 aryl; and
-Ci to C6 alkyl; -SO2Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyls;
-5 or 6 membered heterocyclo;
-C^ to C8 aryl; and
-C1 to C6 alkyl;
-S(O)Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo;
-Ce to C8 aryl; and
-Ci to C6 alkyl;
-alkoxy substituted with one or more substituents independently selected from: -halo; -hydroxy; -cyano; -alkoxy optionally substituted with alkoxy;
-amino substituted with one or more substituents independently selected from - SO2-C1 to C4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls;
-amido substituted with C) to C6 alkyl; -S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl; -S-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to Cg heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from: -CO to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfinyl-Cβ to Cs aryl; -sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl; -sulfonyl-Ci to Cβ alkyl optionally substituted with one or more substituents independently selected from:
-C6 to Ce aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfonyl-Cβ to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =0, heterocyclo, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -Ci to C6 alkoxy; and
-C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -Ci to Ce alkyl optionally substituted with one or more alkoxys; -4 to 7 membered heterocyclo; and
-alkoxy; and -Cg to C8 aryl; -C6 to Cg aryl;
-(O)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy; =O;
-Ci to C6 alkyl;
-SO2Rx; 1 -C(O)-C6 to C8 aryl;
-C(O)ORx; or -(O)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from: -Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo;
-alkylthio; -haloalkyl; -cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy;
-COOH; -CO2Rx; -CORx;
-C(O)NH2 optionally substituted with one or more Ci to Cg alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to C6 alkyl, which alkyl is optionally substituted with one or more Ci to C6 alkoxys; -C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -C6 to C8 aryl; -5 or 6 membered heteroaryl; and
-Ci to Ce alkyl optionally substituted with one or more hydroxys; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl; -COOH; -C(O)NH2 optionally substituted with one or more Cj to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more C) to Ce alkoxys; -amino substituted with one or more substituents independently selected from:
-SO2Rx; -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;
-C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; -Ci to C7 alkyl optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -alkoxy; and
-halo;
-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl;
-cyano;
-ammo optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from
halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy;
-COOH; -CO2Rx; .CORx;
-C(O)NH2 optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy; =O;
-C1 to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx;
-ORick, wherein Rkk is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Ci to C6 alkoxy, and Ci to C6 haloalkyl; -5 to 6 membered heterocyclo optionally substituted with Ci to C6 alkyl, which alkyl is optionally substituted with C6 to Cs aryl; or -5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Cj to C6 alkoxy, and Ci to Ce haloalkyl;
-SO2Rx; or
-Si(Rx)3;
-OC(O)NHRx wherein Rx is optionally substituted with -C6 to Cg aryi; -OC(O)N(RX)2; or
95. The compound of embodiment 89, wherein R3 is nitro.
96. The compound of embodiment 89, wherein: X is cyano or hydrogen;
Y is: -Cg to Cg aryl optionally substituted with one or more substituents independently selected from: -halo;
-C1 to C6 alkyl;
-amino optionally substituted with one or more substituents independently selected from:
-SO2Rx; -5 or 6 membered heteroaryl optionally substituted with one or more alkyl;
-Ci to C7 alkyl; -NR1COORu, wherein Rt is hydrogen, and wherein R11 is Cj to Cj2 alkyl;
-NRySOaRw5 wherein Rv is hydrogen, and wherein Rw is Ci to CΘ alkyl or amino optionally substituted withalkyl;
Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano; and R3 is hydrogen.
97. The compound of embodiment 96, wherein the C6 to C8 aryl is phenyl.
98. The compound of embodiment 97,wherein:
X is cyano; Y is phenyl para substituted with NRVSO2RW, wherein Rv is hydrogen, and wherein Rw is Cj to Ce alkyl; and R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
99. The compound of embodiment 97, wherein: X is cyano; v Y is phenyl substituted with Cj to C6 alkyl and NRVSO2RW, wherein Rv is hydrogen, and wherein Rw is Ci to C$ alkyl; and R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
100. The compound of embodiment 97, wherein: X is cyano; Y is phenyl substituted with halo and NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to Ce alkyl; and R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
101. The compound of embodiment 97, wherein: X is hydrogen; Y is phenyl is para substituted with -NRtCOORU5 wherein Rt is hydrogen, and wherein Ru is Ci to C]2 alkyl;
Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl; and R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
102. The compound of embodiment 89, wherein: X is cyano;
Y is:
-Cg to Cg aryl optionally substituted with one or more substituents independently selected from:
-NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to Ci2 alkyl optionally substituted with one or more halo; or
-NRVSO2RW, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is -(O)-S or 6 membered heterocyclo substituted with one or more =O; and R3 is hydrogen.
103. A compound which is selected from the compound range: 1330-2128 and 2600-3348. 104. The compound of embodiment 103 selected from:
2879 2892
2888
2895 2922
2907
2976 2978 2925
3002 3192 3194
3245
3239 3247
105. A composition comprising the compound of embodiment 1 and one or more pharmaceutically acceptable excipient(s).
106. A composition comprising the compound of embodiment 39 and one or more pharmaceutically acceptable excipient(s).
107. A composition comprising the compound of embodiment 77 and one or more pharmaceutically acceptable excipient(s).
108. A composition comprising the compound of embodiment 83 and one or more pharmaceutically acceptable excipient(s). 109. A composition comprising the compound of embodiment 89 and one or more pharmaceutically acceptable excipient(s).
110. A method for treating Hepatitis C viral infection in a subj ect in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 1.
111. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 39.
112. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 77. 113. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 83.
114. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 89.
115. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 1.
116. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 39.
117. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 77.
118. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more comρound(s) according to embodiment 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 83.
119. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 89.
In yet another embodiment, the present invention includes compounds of Formulas I, I- X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, T-XIc, Ha, lib, lie, Hd, or He, wherein Y is a - NR1COORu group and R11 is a Ci to Cβ alkyl. In an embodiment, compounds are provided wherein Y is a -NRtCOOR11 group and Ru is a Ci to C6 alkyl in the para position. In another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XH, I-Xa, I- XIa, I-XIIa, I-XIb, I-XIc, Ha, lib, Hc3 Hd3 or He, wherein Y is a -NR,COORU group and Ru is a branched Ci to C6 alkyl. In an embodiment of Formulas I, I-X, I-XI, I-Xπ, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, Ha, lib, Hc, πd, or lie, Y is a -NRtCOORu group and R11 is a branched C1 to C6 alkyl in the para position. Ih another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XΩa, I-XIb, I-XIc, Ha, Hb, He, πd, or He, wherein Y is a -NRtCOOR11 group and R0 is an isopropyl. hi another embodiment, the present invention includes compounds of I-X, I-XI, I-XH, I-Xa, I-XIa, I-Xπa, I-XIb, I-XIc, Ha, Hb, πc, Hd, or He, wherein Y is a -NR1COOR11 group and Ru is a methyl cyclopropyl. In another embodiment, the present invention includes compounds of I-X, I-XI, I-XH, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, πa, lib, He, Hd, or He, wherein Y is a -NRtCOOR1, group and R11 is an ethyl cyclopropyl.
In another embodiment, the present invention includes compounds of I-X, I-XI, I-XII, I- Xa, I-XIa, I-XHa, I-XIb, I-XIc, πa, lib, Hc5 Hd, or πe, wherein Y is a -NRVSO2RW group, Rv is a hydrogen, and where Rw is a Ci to Ce alkyl. hi a further embodiment, the present invention includes compounds wherein Y is a -NRvSO2Rw group and Rw is a propyl group.
In an embodiment of the present invention, compounds are provided wherein Y is a Ce to Cs aryl that is substituted. In an embodiment of the present invention, compounds are provided wherein Y is a phenyl that is substituted. In an embodiment of the present invention, compounds are provided wherein Y is a Ce to Cg aryl that has one, two, three, or four substituents. In another embodiment of the compounds of the present invention, Y is a Cg to C8 aryl that has one, two, or three substituents. In another embodiment, Y is a C6 to C8 aryl that has one or two substituents. hi a further embodiment, Y is a Ce to C8 aryl that has three substituents. In a further embodiment, Y is a C6 to C8 aryl that has two substituents. hi a further embodiment, Y is a Cβ to Cg aryl that has one substituent.
In another embodiment of the present invention, compounds are provided wherein Y is a Ce to Cs aryl with at least one substituent in the ortho, meta, or para position. In a further embodiment, Y is a C6 to Cs aryl with at least one substituent in the meta or para position. In yet another embodiment, Y is a C6 to Cg aryl with a substituent in the para position. In. an embodiment of the present invention, compounds are provided wherein Y is a Ce to Cs aryl, optionally substituted with one of the following in the para position: -an alkoxy, -an amino optionally substituted with one or more of the following:
-SO2Rx groups, or -C1 to Ce alkyl, the C i to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRx, -OC(O)N(RX)2, -OC(O)NH(ORx), -OC(O)NRx(ORx),
-OC(O)N(ORx)2,
-OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NR0CORp group, where Rp is:
-a Ci to C6 alkyl, -an amino group optionally substituted with one or more C1 to C6 alkyl groups where the Ci to C6 alkyl groups are optionally and independently substituted with one or more C6 to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to Cδ alkyl or Ce to Cg aryl groups, and where R0 is:
-a hydrogen, -a Ci to C6 alkyl,
-a -NRqCONRqRr group, where Rq is a hydrogen, and where Rr is: -a Ci to Ce alkyl optionally substituted with one or more of the following:
-a hydroxyl, -an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or
-a Cβ to Cg aryl optionally substituted with a halo, -a C2 to Ce alkylene group, -a Ci to Ce alkoxy group, -a 5 or 6 membered heterocycle group, -a -NR1COORu group, where Ru is;
-a Ci to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C8 aryl optionally substituted with halo,
-an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to Ce alkyl,
-halo, or
-a 5 or 6 membered heteroaryl, -a C2 to CO alkylene,
-a Ce to Cs aryl, optionally substituted with halo, and Rt is:
-a hydrogen;
-a -NHRbb group, where Ry3 is: -a -C(=S)NH2 group, or -a -PO(ORχ)2, where Rx is as defined above; -a -NRvSO2Rw group, where Rv is a hydrogen, and where Rw is a Ci to Ce alkyl,
In some embodiments, Y is selected from the Y substituents of compounds 1330-2128, and 2600-3348. In other embodiments of the present invention, compounds are provided wherein Y is selected from the group consisting of the following substituents:
In other non-limiting embodiments of the present invention, compounds are provided wherein Y is selected from the group consisting of
In an embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, Ha5 lib, Uc, Hd, or He, wherein Z is a 5 or 6 membered heterocycle. In another embodiment of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, 1-XIc3 Ha, lib, lie, Hd, or He, Z is a 5 membered heterocycle. In a further embodiment of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, Ha, Hb, Hc, IH5 or He, Z is a 6 membered heterocycle. In another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-Xπ, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, πa, lib, Hc, Hd, or He, wherein Z is a Ci to Ce alkyl optionally substituted with a 5 or 6 membered heterocycle. In another embodiment, the present invention includes compounds wherein Z is a Ci to Cβ alkyl. In another embodiment, the present invention includes compounds wherein Z is a Ci alkyl. In another embodiment, the present invention includes compounds wherein Z is a C2 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C3 alkyl. hi another embodiment, the present invention includes compounds wherein Z is a C4 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C5 alkyl. In another embodiment, the present invention includes compounds wherein Z is a Ce alkyl. In another embodiment, the present invention includes compounds wherein Z is a straight chain Ci to Ce alkyl. hi another embodiment, the present invention includes compounds wherein Z is a cyclic Ci to C$ alkyl. In another embodiment, the present invention includes compounds wherein Z is a Cj to C6 alkyl that is a combination of straight and cyclic. In yet another embodiment, the present invention includes compounds wherein Z is selected from the group consisting of cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl, cyclopentyl, and isopropyl. La a further embodiment, the present invention includes compounds wherein Z is cyclobutyl, cyclopropyl or ethyl. In a further embodiment, the present invention includes compounds wherein Z is cyclobutyl, cyclopropyl, or cylcopropyl methyl. In an embodiment, the present invention includes compounds wherein Z is cyclobutyl or cyclopropyl. In an embodiment of the present invention, a compound is provided wherein Z is cyclobutyl.
In some embodiments, Z is selected from the Z substituents of compounds 1330-2128, and 2600-3348. In a non-limiting embodiment of the compounds of the present invention, Z is selected from the group consisting of
In another non-limiting embodiment of the present invention, compounds are provided wherein Z is selected from the following:
In some embodiments, the Z substituent is a hydrogen. In other embodiments, Z is a Ci to C6 alkyl optionally substituted with a five membered heterocycle. In other embodiments, Z is a C] to Ce alkyl optionally substituted with a six membered heterocycle. In an embodiment of the present invention, compounds are provided wherein R2 is an alkoxy group. In an embodiment, the present invention provides compounds wherein R2 is a methoxy or an ethoxy group. In an embodiment of the compounds of the present invention, R2 is a methoxy group. In an embodiment of the compounds of the present invention, R2 is an ethoxy group. In an embodiment, the present invention provides compounds wherein R2 is an alkoxy group optionally substituted with one or more groups independently selected from the following:
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected Ci to Cβ alkyl, alkoxy, or hydroxy groups, or
-a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to Ce alkyl groups. In an embodiment, the present invention provides compounds wherein R2 is an alkoxy group substituted with an imidazole, a triazole, a thiazole. In another embodiment, R2 is an alkoxy group substituted with a hydroxy group and an imidazole, a triazole, or a thiazole.
In an embodiment, the present invention provides compounds wherein R2 is an -ORyc group, where Rkk is a 5 to 6 membered heterocycle, optionally substituted with a Cj to C6 alkyl, optionally substituted with a Ce to Cs aryl group.
In an embodiment of the present invention, compounds are provided wherein R2 is a Ci to C6 alkyl group, optionally substituted with one or more 5 or 6 membered heterocycle groups. In a further embodiment of the present invention, compounds are provided wherein R2 is a - C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups.
In some embodiments, R2 is selected from the R2 substituents of compounds 1330- 2128, and 2600-3348.
In an embodiment of the present invention, compounds are provided wherein R2 is selected from the group consisting of the following substituents:
In another embodiment, compounds of the present invention are provided wherein R2 is selected from the group consisting of the following substituents:
In an embodiment of the present invention, Z is a Ci to Ce alkyl group, Y is a - NRtCOORu group, where Ru is-a Ci to Cn alkyl and Rt is -a hydrogen, and R2 is: -an alkoxy group optionally substituted with one or more groups independently selected from the following:
-an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more 5 or 6 membered heterocycle, -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to Q5 alkyl group, the Ci to Ce alkyl group optionally substituted with one or more independently selected Ci to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to Ce alkyl groups,
-an -ORkk group> where R& is a 5 to 6 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a Cβ to Cs aryl group.
In another embodiment of the present invention, Z is a Ci to Ce alkyl group, Y is a - NRtCOORu group, where R11 is-a Ci to C12 alkyl and Rt is -a hydrogen, and R2 is: -an alkoxy group optionally substituted with one or more groups independently selected from the following: -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C^ alkyl group, the Ci to Ce alkyl group optionally substituted with one or more independently selected C] to Ce alkoxy group,
-a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to Qe alkyl groups,
-an -ORkic group, where Rkk is a 5 to 6 membered heterocycle, optionally substituted with a Cj to Cβ alkyl, optionally substituted with a Cg to Cg aryl group.
In another embodiment of the present invention, Z is a Ci to Ce alkyl group, Y is a - NRtCOORu group, where Ru is-a Ci to C12 alkyl and Rt is -a hydrogen, and R2 is: -an alkoxy group optionally substituted with one or more groups independently selected from the following:
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to Ce alkyl group, the Ci to C& alkyl group optionally substituted with one or more independently selected Ci to C6 alkoxy group,
-a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to C(, alkyl groups.
In another embodiment of the present invention, Z is a Ci to Ce alkyl group, Y is a - NRtCOORu group, where Ru is-a Cj to Cj2 alkyl and Rt is -a hydrogen, and R2 is: -an alkoxy group optionally substituted with one or more groups independently selected from the following:
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to Ce alkyl group, the Ci to C$ alkyl group optionally substituted with one or more independently selected C1 to Cg alkoxy group.
In another embodiment of the present invention, Z is a Ci to Cβ alkyl group, Y is a - NRtCOORu group, where R« is-a Ci to Ci2 alkyl and R1 is -a hydrogen, and R2 is: -an alkoxy group optionally substituted with one or more groups independently selected from the following:
Exemplary compounds include the following:
2780 2781 2782
2783 2784 2785
2786 2787 2788
2789 2790 2791
2792 2793 2794
Exemplary compounds include the following:
B. Preparation of Compounds of the Invention
Indole compounds of the present invention can be obtained via standard, well-known synthetic methodology. Many of the indole starting materials can be prepared 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 II can be prepared as shown in Scheme A below:
Treatment of nitromethane with base followed by reaction with an activated carboxylic acid, e.g., an imidazolide, such as compound Al gives compounds of type A2. Treatment of compounds of type A2 with an amine of structure A3 gives the compound A4. Reaction of compound A4 with quinine in the presence of acid, e.g., acetic acid gives the hydroxyindoles of structure II.
HOAc
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. π. 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-nitroindole 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 -300C to +5O0C. 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 KsPO4, 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 IV.
HI. Scheme C
R9-L (C3) R9-L (C3)
Compounds of formula I, 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 R9 containing a suitable leaving group L (E5) 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 VII.
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
Compounds of formula H, represented by structure DC can be prepared as shown in Scheme H.
Lαdole-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 tbionyl 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
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, CH3CN 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 IS that can then be cyanated as above to give compounds of formula X.
IX. Scheme I
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 Rp containing a suitable leaving group L (K6) as described in 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 Rg containing a suitable leaving group L (K6) as described previously, affords, the compound XII.
An alternative use of intermediate K.4 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 (K.6) 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 XIII. Alternatively, cyanation of K9 with chlorosulfonyl isocyanate gives Kl 1, which can be reacted with a reactive functional group R9 containing a suitable leaving group L (K6) as described in previously, affords the compound XIII.
XI. Scheme K
Compounds of formula L, represented by structure XIV 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 chlorosuccinimide. 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 XTV. The reaction can be conducted in a suitable solvent, e.g., THF, CH2Cl2 or DMF, within a temperature range of 00C 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.
XEL 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 diazonπun 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 O0C to 1200C. 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
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., dimethylformamide dimethyl acetal, optionally in the presence of a suitable solvent, e.g., DMF or dioxane, at a temperature range from ambient to 15O0C 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 hydro genation, 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 1000C. The compound N4 can then be reacted with a reactive functional group R9 containing a suitable leaving group L (N5) 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 with 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
Compounds of formula I, represented by structure XVTI can be prepared as shown in Scheme O. Compounds of structure Ol can be converted to 2-iodo- or bromoύidoles O2.
Typically, a strong base, such as n-butyllitbium 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 O2. Reaction of 2-iodo- or bromoindoles O2 with a boronic acid (commonly referred to as a Suzuki reaction) or trialkyl stannane (commonly referred to as a Stille reaction) can give the compounds of structure XVH. 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 phosphine ligand. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dunethoxy ethane or dioxane at a temperature range of ambient to 15O0C. 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- trialkylstannane 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.
XVI. Scheme P
\ Compounds of the present invention, represented by structure XIX 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 trialkyl 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 (triphenylphosphήie) palladium (0), bis (triphenylphosphine) palladium (II) dicbloride 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 Rg 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 XIX.
XVII. Scheme Q
Compounds of formula I, represented by structure XX can be prepared as shown in Scheme R.
Compounds of structure Rl 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 -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 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 (II) dichloride or palladium acetate with added phosphine
ligand. Reaction with R6 with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure XX. XViπ. 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 1500C. XX. Scheme T
T1 XXII
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., CH2Cl2, ether, THF, methanol or solvent combinations.
XXI. Scheme U
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 -780C 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 XXIV. Alternatively, 2-iodo or bromoindoles of structure V4, prepared from compounds Vl as described previously, can be reacted wititi
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 15O0C. XXII. Scheme V
V4 XXIV
Compounds of formula I, represented by structure XXV-XXVIII can be prepared as shown in Scheme W.
2-Iodo- or bromoindoles 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 15O0C. Reaction with XXV with a reactive functional group Rg 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 R9 containing a suitable leaving group L as described above can give compounds of structure XXVIIL
XXHI. Scheme W
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 XXIX. 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 carried out in a suitable non- reactive solvent including CHZCI25 carbon disulfide or dichloroethane and is typically conducted within a temperature range of -200C to 8O0C. XXTV. Scheme X
Compounds of formula I3 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- (l,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 130°C.
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 hydroxylamine 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 TA 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 XXXI.
XXVI. Scheme Z
XXXl Z4
Compounds of the present invention, represented by structure XXXII can be prepared as described in scheme AA below.
Ketoindoles of type AAl can be converted to oximes of structure AA2 by heating the ketoindoles with hydroxylamine (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-butyllitbium or tert-butyllithium) followed by reaction with DMF can give compounds of formula XXXII.
XXVII. Scheme AA
Compounds of formula I, represented by structure XXXIII can be prepared as shown in Scheme AB.
3-Ketoindoles of structure ABl 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 foπnamide, acetamide and propionamide. Examples would include dimethlfoπnamide 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 hydroxylamine (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. XXViπ. Scheme AB
AB1 AB3 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 1500C to give compounds of structure XXXTV.
XXIX. Scheme AC
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 ammonia. 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 thioamides 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 thioamides 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.
XXXI. Scheme AE
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 XXXVIII.
Treatment of compounds AF3 with thioamides of type AF5 in a suitable solvent at temperatures above ambient and up to 1500C with or without added base can give thiazoles of structure XXXIX.
XXXII. Scheme AF
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 (H) 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 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 described above to form compounds of structure XL. XXXiπ. Scheme AG
PcP Pd0 R12-B(OH)2 R12-L
(AG3) (AG6)
Compounds of the present invention, represented by structure XLI can be prepared as described 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.
XXXIV. Scheme AH
Compounds of formula I, 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 XLHI with a base followed by reaction with a reactive functional group Rg containing a suitable leaving group L can give the compounds of formula XLIV. XXXVI. 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 Ri 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 R115 containing a suitable leaving group L similarly can give compounds of structure XLVII.
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.
XXXVH. 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 hydroxyamtdines of structure AL3 can give O-acylhydroxyamidines AL4. Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxylamine. 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 XLDC.
XXXVπi. Scheme AL
Compounds of formula I, represented by structure L can be prepared as shown in Scheme AM.
3-Cyanoindoles of structure AMI can be converted to tetrazoles of structure AM2 by treatment with, e.g., sodium azide. Heating a mixture of AM2 and the reagent AM3 can give the 3-(l,2,4-oxadiazolyl)indole compound L. The reagent AM3 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 AM2 and AM3 at a temperature range of 30° to 1300C.
XXXIX. Scheme AM
AM1 AM2
Compounds of formula I, represented by structure LI can be prepared as shown in
Scheme AN.
3-Cyanoindoles of structure ANl can be treated with hydroxylamine to give hydroxyamidine compounds of formula AN2. Reaction of hydroxyamidines of structure AN2 with compounds of structure AN3 can give O-acylhydroxyamidines AN4. Compounds AN3 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodϋmide or diisopropyl carbodiimide. Heating compounds of structure AN4 . 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 LI.
XL. Scheme AN
AN1 AN2
LI AN4
Compounds of the present invention, represented by structure Lu can be prepared as described in scheme AO below.
Ketoindoles of type AQl can be converted to oximes of structure AO2 by heating the ketoindoles with hydroxylamine (free base or acid salt) in a suitable solvent. Bis-deprotonation of compounds of type AO2 with a strong organic base (e.g., n-butyllithium or sec-butyllitbium or tert-butyllithium) followed by reaction with DMF can give compounds of formula LH.
XLI. Scheme AO
Compounds of formula I, represented by structure LIII can be prepared as shown in Scheme AP.
3-Ketoindoles of structure API can be homologated to vinylogous amides of structure AP3 by reaction with dialkyl amide dialkyl acetals AP2. The dialkyl amides can include e.g., lower alkyl amides such as formamide, acetamide and propionamide. Examples would include dimethlformamide dimethyl acetal and dimethyl acetamide dimethyl acetal. The reaction can be conducted by reacting API and AP2 with or without additional solvent at a temperature from ambient to 15O0C. Treatment of AP3 with hydroxylamine (free base or acid salt) in a suitable solvent can give compounds of structure LEtL The reaction is typically conducted within a temperature range from ambient to 1200C.
XLH. Scheme AP
Compounds of formula I, represented by structure LIV can be prepared as shown in Scheme AQ.
Vinylogous amides of structure AQl (as prepared above) can be treated with hydrazines AQ2 in a suitable organic solvent (DMF, alcohol or acetic acid) at temperatures ranging from ambient temperature to 1500C to give compounds of structure LIV.
XLΠI. Scheme AQ
Compounds of the present invention, represented by structure LV can be prepared as described in scheme AR below.
Indole-3-carboxaldehydes of structure ARl (as prepared in Scheme F) can be reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC, AR2) in the presence of a base to give compounds of structure LV. 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.
XLIV. Scheme AR
Compounds of formula I, represented by structures LVI and LVII can be prepared as shown in Scheme AS .
3-Indolecarboxylic acids of structure ASl (from Scheme F) can be converted to amides of structure AS2. Compounds of structure AS 1 can be activated by any of the standard methods. For example, the acid ASl can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of ammonia. 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 AS2 can be reacted with substituted aldehydes or ketones (AS3) 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 LVI.
The indole-3-carboxamides of structure AS2 can also be converted to thioamides of structure AS4 by treating the primary amides with Lawesson's reagent or phosphorous pentasulfide at or above ambient temperature in a suitable organic solvent. The resulting thioamides AS4 can be reacted with substituted aldehydes or ketones containing a suitable leaving group L (AS3), in a suitable solvent at temperatures above ambient and up to 15O0C. The reaction can be performed with or without added base to afford thiazoles of structure LVII.
XLV. Scheme AS
LVII
Compounds of the present invention, represented by structure LVIII and LIX can be prepared as described in scheme AT below.
3-Ketoindoles of structure ATI can be halogenated (e.g., brominated) to give compounds of structure AT3. Suitable bromuiating agents can include but are not limited to phenyltrimethylammonium tribromide (AT2), N-bromosuccinirαide or bromine and can be carried out in a variety of organic solvents.
Treatment of compounds AT3 with amides of type AT4 in a suitable solvent at temperatures above ambient and up to 2000C with or without added base can give oxazoles of structure LVEII.
Treatment of compounds AT3 with thioamides of type AT5 in a suitable solvent at temperatures above ambient and up to 15O0C with or without added base can give thiazoles of structure LEX.
XLVI. Scheme AT
LVlIl LlX
Compounds of the present invention, represented by structure LX can be prepared as described in scheme AU below.
Indole-3-carboxylic acids of structure AUl can be activated to give compounds of structure AU2. Compounds of structure AU2 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 AU2 with hydroxyamidines of structure
AU3 can give O-acylhydroxyamidines AU4. Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxylamine. Heating compounds of structure AU4 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 LX. XLVII. Scheme AU
(AU4) LX
Compounds of formula I, represented by structure LXI can be prepared as shown in Scheme AV.
Reaction of 3-iodo- or bromoindoles AVl with a boronic acid AV2 (commonly referred to as a Suzuki reaction) can give the compounds of structure LXI. 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 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 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 AVl can be converted to the indole-3 -boronic acid derivative AV3 by reacting the 3-haloindole AVl with a strong organic base (alkyllithium or Grignard reagent) and reacting the resultant anion with a trialkylborate reagent AV4. Compounds of type AV3 can be reacted with aryl and heteroaryl bromides and iodides AV6 under similar conditions to those described above to form compounds of structure LXI.
XLVIII.
Pd° Pd0
R12-B(OH)2 R12-L (AV2) (AV6)
LXl
Compounds of formula I, represented by structure LXII, can be prepared as shown in Scheme AW.
Compounds of formula AWl can be reacted with a protecting group, e.g., di-tert-butyl dicarbonate, to form the boc-protected indole, in the presence of a suitable base and solvent at ambient temperature to give compounds of structure AW2. Treatment of compounds of structure AW2 with base in a polar aprotic solvent at temperatures from -78° C to ambient temperature, followed by addition of a trialkyl borate would yield compounds of type AW3 upon hydrolytic workup. Reaction of reactive aryl halides or triflates (of the type AW4) with compounds of formula AW3 at or around ambient temperature, in a suitable solvent system containing base and catalytic amounts of palladium catalyst, can give compounds of formula AW5. Removal of the protecting group in compounds of structure AW5, e.g., acid treatment to remove the Boc group would yield compounds of structure AW6. Compounds of type AW6 can be alkylated at the indole nitrogen to give compounds of structure LXII. The alkylation can be carried out in the presence of a suitable alkylating agent and base in a polar solvent at temperatures ranging from ambient temperature to 150 ° C to yield compounds of formula LXII.
XLIX. Scheme AW
Compounds of formula I5 represented by structure LXIII, can be prepared as shown in Scheme AX.
Compounds of formula AXl can be fluorinated at the 3-position with an electrophilic fluorinating agent, e.g., N-fluorocollidine tetrafluoroborate, in a suitable non-polar solvent at temperatures ranging from -78° C to 100 ° C to yield compounds of structure LXIII.
L. Scheme AX
Compounds of formula I. represented by structure LIV, can be prepared as shown in
Scheme AY.
Compounds of formula AYl can be chlorinated at the 3-position with an electrophilic chlorinating agent, e.g., N-cWoiOSUccinimide or chlorine, in a suitable solvent at temperatures ranging from -78° C to 100 ° C to yield products of structure LXIV. IX Scheme AY
Compounds of formula I, represented by structure LXV, can be prepared as shown in scheme AZ.
Compounds of formula AZl can be brominated at the 3-position with an electrophilic brominating agent, e.g., N-bromosuccinimide or bromine) in a suitable solvent at temperatures ranging from -78° C to 100 ° C to yield products of structure LXV.
LII. Scheme AZ
Compounds of formula I, represented by structure LXVI, can be prepared as shown in Scheme BA.
Compounds of formula BAl can be iodinated at the 3-position with an electrophilic iodinating agent, e.g., N-iodosuccmimide, (bis-trifluoroacetoxy)iodobenzeneJ or ICl, in a suitable solvent at temperatures ranging from -78° C to 1000C to yield products of structure LXVI.
LUl. Scheme BA
Compounds of formula I, represented by structure LXVII can be prepared as shown in Scheme BB.
3-Iodo- or bromoindoles of structure BB I can be reacted with acetylenes BB2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type LXVII. 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 BBl with an acetylene compound BB2 in the presence of a source of palladium, a copper co-catalyst and an amine and carrying out the reaction at a temperature range of ambient to 1500C.
LIV. Scheme BB
LXVIl
Compounds of formula I, represented by structure LXVIII, can be prepared as shown in Scheme BC.
Compounds of formula BCl can react with a mixture of POCI3 and DMF at temperatures ranging from ambient to 14O0C to yield 3-carboxaldehydes of structure LXVIII after hydrolysis of the intermediate imminium salt with aqueous NaOH.
LV. Scheme BC
LXVIII
Compounds of formula I, represented by structure LXIX, can be prepared as shown in Scheme BD.
Carboxaldehydes of formula BDl can be treated with, a fluormating reagent, e.g., (diethylammonium sulfur trifluoride) in a suitable solvent at temperatures ranging from 0° C to 8O0C to yield compounds of formula LXIX.
LVI. Scheme BD
Compounds of formula I, represented by structure LXX, can be prepared as shown in Scheme BE.
Carboxaldehydes of formula BEl can react with hydroxylamines of structure BE2 in the presence of a suitable polar solvent system and base at temperatures ranging from ambient tol 000C to yield compounds of formula LXX.
LVII. Scheme BE
Compounds of formula I, represented by structure LXXI, can be prepared as shown in Scheme BF.
Carboxaldehydes of formula BFl can react with hydrazines of structure BF2, in the presence of a suitable solvent and base at temperatures ranging from ambient to 100° C to yield compounds of formula LXXI. LVIIL Scheme BF
Compounds of formula I5 represented by structure LXXII, can be prepared as shown in Scheme BG.
Indolecarboxaldehydes of formula BGl can be oxidized to carboxylic acids of formula LXXIL using reagents known to those skilled in the art, e.g., KMnO4 or chromic acid. The oxidation can usually be carried out in aqueous or mixed-aqueous/organic solvent systems and carried out at ambient or elevated temperature.
LIX. Scheme BG
BG1 LXXII
Compounds of formula I5 represented by structure LXXIII, can be prepared as shown in Scheme BH.
Carboxylic acids of formula BHl can be converted to amides by treatment of the carboxylic acid with a suitable activating reagent (thionyl chloride, oxalyl chloride or carbonyldiimidazole) and then treated with amines of formula BH2 to give compounds of formula LXXIII.
LX. Scheme BH
Compounds of formula I, represented by structure LXXTV, can be prepared as shown in Scheme BL
Carboxylic acids of formula BIl can be converted to hydrazides and N-allcoxyamides by treatment of the carboxylic acid with a suitable activating reagent (thionyl chloride, oxalyl chloride or carbonyldiimidazole) and then treating the activated carboxylic acids with hydrazines and alkoxylamines of formula BI2 to give compounds of formula LXXTV.
LXI. Scheme BI
BH LXXlV
Compounds of formula I, represented by structure LXXV, can be prepared as shown in Scheme BJ.
Carboxaldehydes of formula BJl can be treated with the appropriate alkyllithium or Grignard reagent of formula BJ2 at temperatures between -78° C to ambient temperature in a suitable aprotic solvent to produce secondary alcohols of formula LXXV. An alternative reduction of the carboxaldehydes with an appropriate hydride reducing agent at -780C to ambient temperatures can produce primary alcohols of formula LXXV.
LXII. Scheme BJ
Compounds of formula I5 represented by structure LXXVI, can be prepared as shown in Scheme BK.
Compounds of structure BKl can be sulfonated at the 3-position with sulfur trioxide or some similar sulfuric acid equivalent to produce compounds of formula BK2. Compounds of formula BK2 can be treated with reagents such as, but not limited to, POCI3 at temperatures from 50° C to 100 ° C to convert them into sulfonyl chlorides of formula BK3. Alternatively, treatment of compounds of structure BKl with reagents such as chlorosulfonic acid can directly afford compounds of structure BK3. Compounds BK3 can react with amines of formula BK4 at ambient temperature in the presence of a suitable base and solvent to produce sulfonamides of formula LXXVI.
LXπi. Scheme BK
LXXVI
Compounds of formula I, represented by structure LXXVII5 can be prepared as shown in Scheme BL.
Iodides or bromides of structure BLl can be transformed into 3-thioalkyl indoles using an appropriate copper catalyst, e.g., CuI, and a suitable thiol or disulfide. The reaction can generally be carried out at temperatures between ambient and 150 ° C to yield compounds of structure BL2. Compounds of structure BL2 can be oxidized to sulfones of formula LXXVII, using oxidizing agents such as, but not limited to, m-CPBA in chloroform at ambient or elevated temperatures.
LXIV. Scheme BL
[O]
LXXVII
Compounds of formula I, represented by structure LXXVIII3 can be prepared as shown in Scheme BM.
Iodides or bromides of structure BMl can be transformed into 3-thioalkyl indoles using an appropriate copper catalyst, e.g., CuI, and a suitable thiol or disulfide. The reaction can generally be carried out at temperatures between ambient and 150 ° C to yield compounds of structure BM2. Compounds of structure BM2 can be selectively oxidized to sulfoxides of formula LXXVIII, using oxidizing agents such as, but not limited to, sodium periodate in methanol at ambient temperature.
LXV. Scheme BM
LXXVlIl
Compounds of formula I, represented by structure LXXIX, can be prepared as shown in Scheme BN.
Compounds of structure BNl can be converted to ketones of formula LXXIX via a Friedel-Crafts reaction using an acid chloride of formula BN2. The reaction can typically be carried out in a non-polar solvent such as dichloromethane or CS2 in the presence of a suitable Lewis acid, e.g., AICI3 or FeCl3 and carried out in a temperature range of 0° C to 100 ° C.
LXVI. Scheme BN
BN1 LXXIX
Compounds of formula I, represented by structure LXXX, can be prepared as shown in Scheme BO.
Compounds of structure BOl can be selectively nitrated at the 3 -position using stoichiometric amounts of nitric acid under mild reaction conditions to produce compounds of formula LXXX. These conditions may include, but are not limited to, the use of nitric acid in acetic anhydride at a temperature range of -400C to room temperature.
LXVII. Scheme BO
BO1 LXXX
Compounds of formula I, represented by structure LXXXI, can be prepared in several ways, as shown in Scheme BP.
3-Nitroindoles of structure BPl can be reduced to 3-aminoindoles of structure BP2 using any number of standard conditions familiar to chemist skilled in the art, such as hydrogenation or iron reduction. Compounds of formula BP2 can be further elaborated by mono- or di-alkylation of the amino group, using the appropriate alkylating agent, solvent, and base at temperatures ranging from ambient to 150° C to yield compounds of formula LXXXI.
Alternatively, 3-haloindoles of structure BP3 can undergo Buchwald coupling with mono- or di-alkylamines of formula BP4 in the presence of copper or palladium catalysts, using conditions familiar to chemists skilled in the art, to produce compounds of formula LXXXI.
LXVIH. Scheme BP
R12L base
Compounds of formula I, represented by structure LXXXII, can be prepared as shown in BQ.
3-Aminoindoles of structure BQl can be reacted with acyl halides or anhydrides of formula BQ2 in the presence of a suitable base and solvent at ambient temperature to yield amides of structure LXXXII.
LXIX. Scheme BQ
LXXXII
Compounds of formula I, represented by structure LXXXIII, can be prepared as shown in Scheme BR.
3-Aminoindoles of structure BRl can react with cbloroformates or carbonates or dicarbonates of formula BR2 in the presence of a suitable base and solvent at ambient or elevated temperature to yield carbamates of structure LXXXIII. Alternative conditions involve
the synthesis of a reactive carbamoyl intermediate of compounds BRl, e.g., by treatment of the amine BRl with p-nitrophenyl chlorofoπnate or phosgene, followed by reaction of the activated carbamoyl intermediate with alcohols of formula BR3 at temperatures ranging from ambient to 1000C in a suitable solvent to form carbamates of formula LXXXIII. LXX. Scheme BR
(BR3)
Compounds of formula I, represented by structure LXXXTV, can be prepared as shown in Scheme BS.
3-Aminoindoles of structure BS 1 can react with isocyanates of formula BS2 in the presence of a suitable base and solvent at ambient or elevated temperature to yield ureas of structure LXXXIV. Alternative conditions involve the synthesis of a reactive carbamoyl intermediate of compounds BSl, e.g., by treatment of the amine BSl with p-nitrophenyl chloroformate or phosgene, followed by reaction of the activated carbamoyl intermediate with amines of formula BS3 at ambient temperature to form ureas of structure LXXXIV. LXXI. Scheme BS
<BS3>
Compounds of formula I, represented by structure LXXXV, can be prepared as shown in Scheme BT.
3-Aminoindoles of structure BTl can be reacted with sulfonyl chlorides of formula BT2 in the presence of a suitable base and solvent and reacted at temperatures in the range of -2O0C to 50° C to yield sulfonamides of structure LXXXV.
LXXII. Scheme BT
LXXXV
Compounds of formula I, represented by structure LXXXVI can be prepared as shown in Scheme BU.
3-Iodo- or bromoindoles of structure BUl can be reacted with alkenes BU2 in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of structure LXXXVL 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.
LXXπi. Scheme BU
LXXXVI
Compounds of formula I5 represented by structure LXXXVII can be prepared as shown in Scheme BV.
Hydrazines of structure BVl can react with 3,3,3-trifluoropropanal to form hydrazone intermediates. Heating the hydrazone intermediates in a suitable solvent and at temperatures from ambient to 150° C can form indoles of formula BV2. Typically, a Lewis acid catalyst is used, e.g., AlCb, TiCL> or ZnCLj. Compounds of formula BV2 can be reacted with a protecting group, e.g., di-terf-butyl dicarbonate, to prepare the Boc derivative BV3. Treatment of compounds of structure BV3 with a strong base, e.g., lithium diisopropyl amide, in an aprotic solvent, e.g., THF or DME at temperatures from -78° C to ambient temperature, followed by
addition of a trialkyl borate can yield compounds BV4 upon hydrolytic workup. Reaction of compounds BV4 with reactive aryl halides or triflates, e.g., BV5 at temperatures in the range of -2O0C to 1000C, in a suitable solvent system containing base and sub-stoichiometric amounts of a palladium catalyst, can give compounds of formula BV6. Proteolytic cleavage of the Boc group of compounds of type BV6 can give compounds of structure BV7. The indole BV7 can be alkylated in the presence of a suitable alkylating agent and base in a suitable solvent at temperatures ranging from 0° C to 150 ° C to yield indoles of formula LXXXVII. LXXW. Scheme BV
Compounds of formula I, represented by structure LXXXVIII can be prepared as shown in Scheme BW.
Compounds of structure BWl are commercially available, or can be prepared by well- known methodology, e.g., from the hydrolysis of substituted phenylacetonitriles. BWl can then be activated, e.g., using peptide coupling reagents, or converted to an acid halide, and then reacted with amines (B W2) to provide substituted acetamides BW3. Compounds of type BW3 can undergo cyclization in the presence of a base, such as potassium carbonate or sodium hydride, and a catalyst, such as CuI or CuBr to form compounds of structure BW4. Reduction of compounds BW4 with a reducing agent, such as DIBALH or lithium aluminum hydride can furnish indoles of type BW5. Compounds of type BW5 can then be cyanated with a reagent such as chlorosulfonyl isocyanate (BW6) to afford compounds of type BW7. Treatment of
compounds BW7 with a base, e.g., lithium diisopropyl amide in a solvent such as THF or DME and a trialkyl borate can give a 2-indolylboronic acid intermediate. Reaction of the 2- indolylboronic acid intermediate with a group L-R12 in the presence of a palladium catalyst can afford compounds of structure LXXXVIII. LXXV. Scheme BW
BW7 LXXXVIII
Compounds of formula I, represented by structure LXXXIX can be prepared as shown in Scheme BX.
Indoles BXl can be cyanated with an appropriate cyanating agent, e.g., cblorosulfonyl isocyanate (BX2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH3CN or dioxane, and carrying out the reaction at or above ambient temperature to afford compounds of structure BX3. Treatment of BX3 with a reactive functional group Z containing a suitable leaving group L (BX4) can give compounds of structure BX5. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate. The reaction between BX3 and BX4 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 . to afford compounds of formula BX5.
Compounds of structure BX5 can be converted to indolyl-2-boronic acids BX6. Typically, a strong base, such as lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed 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. Quenching with a trialkylborate derivative can give the indolyl-2- boronic acid BX6. Reaction of the indolyl-2-boronic acid BX6 with an aryl or heteroaryl halide BX7 (commonly referred to as a Suzuki reaction) can give the compounds of structure
BX8. 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 1,1'- bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C in the presence of a base. 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.
Compounds BX8 can be de-methylated to give compounds of structure BX9. Suitable de-methylating reagents can include, but are not limited to boron tribromide, boron trichloride or iodotrimethylsilane in a variety of organic solvents, such as methylene chloride. Indoles of structure BX9 can be alkylated with an electrophile, L(CH2)nOP (BXlO), to give compounds of structure BXl 1. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate. N can be equal 2,3 or 4. P can represent any acid-labile protecting group, such as tert-butyldimethylsilyl, triethylsilyl or tetrahydropyranyl. The reaction can be conducted in a suitable solvent, e.g., THF5 CH2Cl2 or DMF, within a temperature range of 20° C to 100° C. A base, e.g., an inorganic base, such as potassium or cesium carbonate or an organic base, such as a trialkylamine can be used to remove the acid formed in the reaction. Compounds BXl 1 can be deprotected to give compounds of structure BX12. Suitable deprotecting reagents can include, but are not limited to any mild organic acid, such as para-toluenesulfonic acid or pyridinium para-toluenesulfonate or an inorganic acid, such as acetic or hydrochloric acid in a variety of organic solvents, such as methylene chloride, THF or methanol.
Oxidation of compounds BX12 to carboxylic acids with structure BXl 3 can be accomplished with various oxidating reagents such as potassium permanganate or pyridinium dichromate. Compounds of type BX13 can then be activated and treated with amines of type BX 14 to form compounds of structure LXXXIX. Activation of the carboxylic acid can be carried out by any of the standard methods. For example, the acid BXl 3 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine BX 14, 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 BX14.
LXXVI. Scheme BX
BX1 BX3 BX5
demethylation
oxidation
Compounds of the present invention represented by structure XC and XCI can be prepared by the methodology depicted in Scheme BY below, wherein p is an integer between 2 and 6.
A compound of formula BYl is treated with a reagent of structure BY2, wherein L and L' represent leaving groups (halogen, arylsulfonate, etc.) and can be the same or different. If different, the more reactive of the two will be displaced by the phenol oxygen atom to give compound BY3. Conditions for this reaction include solvents such as, but not limited to, acetonitrile, acetone, 2-butanone or dimethylformamide; bases such as sodium carbonate, potassium carbonate, cesium carbonate, tertiary amine bases or sodium hydride; and reaction temperatures from ambient to the reflux temperature of the chosen solvent. The remaining leaving group in this molecule may be displaced by a reagent of formula RiβSH (BY4), wherein Ri 8 may be alkyl, aryl or heteroaryl to give compounds of structure XC. The conditions for this reaction may be similar but not necessarily the same as used for the transformation of BYl to BY3.
Oxides of the resulting sulfide group in compound XC may be prepared, utilizing oxidizing reagents, such as m-chloroperbenzoic acid, potassium permanganate, potassium peroxymonosulfate or dimethyldioxirane, in stoichiometries chosen to optimize the particular oxidation state, using solvents such as dichloromethane, ethanol, methanol or acetone, and at temperatures ranging from -300C to 12O0C to afford compounds of structure XCI.
LXXVH. Scheme BY
BY1 BY3
R-18-SH (BY4)
Compounds of this invention represented by structure XCII can be prepared by the methodology depicted in Scheme BZ below, wherein p is 1-6:
A compound of formula BZl is treated with a reagent of structure BZ2, wherein L and L' represent leaving groups (halogen, arylsulfonate, etc.) and can be the same or different. The resulting compounds of formula BZ3 may be alkylated by an amine of formula RigRiθNH to prepare compounds of formula XCII. Conditions for this alkylation reaction may include solvents such as ethanol, tetrahydrofuran or dimethylformamide. The presence of a basic reagent, such as pyridine, diisopropylethylamine or potassium carbonate, may be utilized.
LXXVm. Scheme BZ
BZ1 BZ3
Compounds of this invention represented by structure XCIII can be prepared by the methodology depicted in Scheme CA below.
A phenol compound, CAl, can be reacted with an alkylating agent C A3, which can be derived from a compound of structure CA2. Compounds of structure CA2, wherein Rj 9 taken together with the hydroxyl-bearing carbon atom to which Ri 9 is attached, represent a 4-7 membered ring. Such atoms may be all carbon, but may also include up to two heteroatoms, chosen from N, O, S or SO2. A reagent of the formula CA2 may be purchased from commercial sources or be prepared by means familiar to those skilled in the art of organic synthesis and is then converted to compounds of structure CA3, wherein L represents a leaving group. Compound CA3 is then used in an alkylation reaction with the phenol compound CAl, employing the usual alkylation reaction conditions discussed above, to give the compound of formula XCIII.
LXXIX. Scheme CA
Compounds of this invention represented by structure XCIV and XCV can be prepared by the methodology depicted in Scheme CB below.
Compounds of structure CBl can be prepared starting from bromo-substituted indoles using the methodology discussed elsewhere in this invention (introduction of the Z group, installation of the cyano group at C-3 of the indole ring, and cross-coupling of the indole with an aryl reagent to give the corresponding 2-aryl group). Alternatively, the bromide may be introduced at a later stage by bromination of the indole ring, employing brominating reagents such as bromine, N-bromosuccinimide or HOBr. The bromide compound can be then subjected to a metal-halogen exchange reaction to generate an organometallic compound CB2, which is not isolated but taken on directly to the next reaction, wherein M is a metal atom such as magnesium or lithium. Organomagnesium reagents may be prepared from aryl bromides by treating with magnesium metal in refluxing ether-like solvents, or treatment with other organomagnesium reagents such as isopropyl magnesium chloride. Organolithium reagents may be prepared from aryl bromides by treating with lithium metal in refluxing solvents, or by treatment with other organolithium reagents such as sec- or tert-butyllithium. The metallated indole may then be treated in situ with a thionating reagent to afford compounds such as XCIV or CB3. If the group Ri8-(CH2)P- is relatively simple, it may prove convenient to employ a reagent of the structure Ri8-(CH2)P-S-S-(CH2)P-Ri8, which will give sulfide compound XCIV directly. Otherwise, it may be more efficient to react compound CB2 with a reagent such as atomic sulfur (S8), which will afford a thiol compound CB3. The thiol group may be alkylated with a reagent of structure CB4, where L represents a suitable leaving group. Typical alkylation conditions known to those skilled in the art can be employed.
Oxides of the resulting sulfide group in compound XCV can be prepared using oxidizing reagents, such as w-chloroperbenzoic acid, potassium permanganate, potassium peroxymonosulfate or dimethyldioxirane in stoichiometries chosen to optimize the particular oxidation state desired, in solvents such as dichloromethane, ethanol, methanol or acetone, and at temperatures ranging from -30°C to 1200C.
LXXX. Scheme CB
XCV
Compounds of this invention represented by structures XCVI and XCVII can be prepared by the methodology depicted in Scheme CC below.
A compound of formula CCl may be nitrated at the indole C-5 position with reagents such as concentrated nitric acid optionally with solvents such as acetic acid or sulfuric acid. The resulting nitro group in compound CC2 may be reduced to the amino compounds of structure CC3 with the use of reducing reagents such as hydrogen (with a catalyst such as palladium on carbon), tin dichloride (in the presence of HCl), sodium thiosulfate (in the presence of ammonia) or iron powder. The amino and Jhydroxyl groups of compound CC3 may be used to construct a ring; for example, cyclocondensation of CC3 with a reagent CC4, such as phosgene, carbonyldiimidazole or trichloromethyl chloroformate in the presence of a basic reagent to afford compounds of structure CC5. Alternatively, reacting compounds of structure CC3 with compounds of structure CC6 in the presence of a base gives compounds of structure CC7. Compounds CC5 and CC7 can be alkylated with groups of structure L-R21 to give compounds XCVI and XCVII.
LXXXI. Scheme CC
Compounds of this invention represented by structures CXVIII, XCIX and C can be prepared by the methodology depicted in Scheme CD, below.
Commercially available 5,6-dihydroxyindole maybe protected on the phenol groups with group P to give compound CDl. Suitable protecting groups include e.g., tert- butyldimethylsilyl, benzyl, or tetrahydropyranyl, and their synthesis and subsequent removal are well known to those skilled in the art. Functionalization of the indole nitrogen to give compound CD2, followed by cyanation of CD2 to give CD3, and aryl cross-coupling of CD3 to give CD4 have been discussed elsewhere in this invention. The protecting groups on the phenol oxygen atoms may then be removed, and the oxygens used in various cyclocondensation reactions. For example, reaction with a reagent of structure CD6 in the presence of a suitable base can afford the dioxanyl-fϊised ring system of compound XCIX.
Treatment of CD5 with phosgene or a phosgene equivalent (CD7) can give compounds of structure XCVIIL Condensation of CD5 with ketones of formula CD8 or ketal derivatives of the ketone CD8 can afford the cyclic ketal compounds of structure C. LXXXII. Scheme CD
Compounds of formula I, represented by structure CI can be prepared by the methodology depicted in Scheme CE below.
Treatment of CEl with a reactive heteroaryl 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., a trialkylamine, can afford the compound of structure CI. The leaving group L can be a halide, particularly choro, bromo or iodo. Ri 8 can be an alkyl, aryl or heteroaryl group.
LXXXIII. Scheme CE
Compounds of formula I, represented by structure CII can be prepared by the methodology depicted in Scheme CF below.
Treatment of CFl with the compound CF2 containing leaving groups L arid 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 CF3. L and L' independently represent a leaving group, including but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates, and p is an integer between 1 and 6. The reactive heterocycle or heteroaryl compound CF4 can be reacted with the compound CF3 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, diisopropylamine, to afford the compound of structure CII. Alternatively, the compound CFl can be treated with a reactive compound CF5 containing a suitable leaving group L as described above to afford the compound of structure CII.
LXXXIV. Scheme CF
CF1 CF3
Compounds of formula I, represented by structure CHI can be prepared by the methodology depicted in Scheme CG below:
Indoles CGl can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (CG2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH3CN or dioxane, carrying out the reaction at a temperature between -200C and 800C to afford compounds of structure CG3. The compounds CG3 can then be reacted with a reactive functional group Z containing a suitable leaving group L (CG4) as described previously to afford the compound CG6. Alternatively, compound CGl can be reacted with a reactive functional group Z containing a suitable leaving group L to give compounds of structure CG5, which can then be cyanated as above to give compounds of formula CG6,
Compounds of structure CG6 can be converted to indolyl-2-boronic acid CG7. Typically, a strong base, such as lithium diisopropylamide or lithium orpotassium hexamethyldisilazide is employed in a suitable unreactive solvent, e.g., ether or THF5 or solvent mixtures containing them. The reaction is typically carried out in the range of —78° C to ambient temperature. Quenching with a trialkylborate derivative can give the indolyl-2- boronic acid CG7. Reaction of indolyl-2-boronic acid CG7 with aryl or heteroaryl halide CG8 (commonly referred to as a Suzuki reaction) can give the compounds of structure CG9. 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 l,l'-bis(diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150 ° C in the presence of a base. 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. Indole-carboxylic esters CG9 can be converted to indole-carboxylic acids CGl 0 by treatment of compounds of structure CG9 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 CGlO can then be activated and treated with amines of type CGl 1 to form compounds of structure CIII. Activation of the carboxylic acid can be carried out by any of the standard methods. For example, the acid CGlO can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine CGl 1 , 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 with amines CGl 1. LXXXV. Scheme CG
cm
Compounds of formula I, represented by structure CIV can be prepared as shown in Scheme CH.
Compounds of formula CHl can be reduced at the 6-ester group to give 6- hydroxymethyl indoles CH2. The reduction reaction can be carried out using a hydride regent such as lithium borohydride, in an ethereal solvent such as THF, ethyl ether or DME at temperatures ranging from ambient to reflux to give the alcohol CH2. The benzylic alcohol group in CH2 can be converted to a leaving group L (halogen, aryl sulfonate or alkyl sulfonate) by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide,
methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform. The leaving group L in compounds of formula CH3 can be displaced by a reagent of formula Ri8H to afford compounds of formula CIV, wherein Ri8 maybe a heterocycle or a heteroaryl compound. Conditions for this reaction include solvents such as but not limited to acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranging from ambient to reflux. LXXXVI. Scheme CH
Compounds of formula I, represented by structure CV can be prepared as shown in Scheme CI
Compounds of formula CIl in which V represents bromide or iodide, can undergo reaction with alkyl vinyl ethers such as ethyl vinyl ether in the presence of palladium catalysts such as but not limited to palladium acetate, palladium (tetrakis)triphenylphosphine, in solvents such as but not limited to dimethyl formamide or dimethoxyethane to give the addition products of formula CI2. Vinyl ethers of formula CI2 can be hydrolyzed to aldehydes of formula CD using aqueous acids, such as but not limited to, hydrochloric acid, sulfuric acid or acetic acid. Compounds of formula CB can be reduced to the alcohol using hydrides such as lithium borohydride or sodium borohydride, in solvents such as methanol or tetrahydrofuran to give primary alcohols CI4.
The alcohol group in CI4 can be converted to a leaving group L (halogen or aryl sulfonate or alkyl sulfonate) by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent
such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform. The leaving group L in compounds of formula CI5 can be displaced by a reagent of formula Ri sH to afford compounds of formula CV, wherein Ri8 maybe a heterocycle or a heteroaryl group. Conditions for this reaction include using solvents such as but not limited to acetonitrile, tetrahydrofuran, dunethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranging from ambient to reflux. LXXXVπ. Scheme CI
Compounds of formula I, represented by structure CVI can be prepared as shown in
Scheme CJ.
Compounds of formula CJl in which V represents iodine or bromine, can undergo reaction with acrylic esters in the presence of palladium catalysts such as palladium acetate, palladium (tetrakis)triphenylphosphine or palladium (bis)-triphenylphosphinedichloride, and ligands such as triphenylphosphine or tri-ortho-tolylphosphine, in solvents such as but not limited to, dimethyl formamide, dimethoxyethane or toluene to give compounds of structure CJ2. Hydrogenation of compounds of type CJ2 can give products of type CJ3 by addition of hydrogen in the presence of a catalyst such a palladium or platinum in a solvent such as, but not limited to, methanol, ethanol or acetic acid at pressures ranging from 1-5 atmospheres. Reduction of the ester group hi compounds CJ3 can be accomplished using hydride reagents such as lithium borohydride to give the alcohols CJ4. Conversion of the alcohol in CJ4 to a
leaving group L (halogen or aryl sulfonate or alkyl sulfonate) can be accomplished by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform. The leaving group L in compounds of formula CJ5 can be displaced by a reagent of formula Ri8H to afford compounds of formula CVI, wherein Ri8 maybe a heterocycle or a heteroaryl group. Conditions for this reaction include solvents such, as but not limited to, acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranging from ambient to reflux. LXXXVIII. Scheme CJ
CJI
activation
CVI
Compounds of formula I, represented by structure CVII can be prepared as shown in Scheme CK.
Compounds of formula CKl (in which L is a leaving group such as chloride, bromide, iodide or sulfonate and n is 0 or 1) can undergo reaction with triphenylphosphine in a solvent such as but not limited to tetrahydrofuran, toluene or dichloromethane; at a temperature ranging from ambient or to reflux to give the phosphonium salt CK2. Phosphonium salt CK2 can be converted to olefin compounds of type CK3 by treatment with a base such as butyllithium, sodium hydride, sodium amide or potassium *-butoxide in a solvent such as tetrahydrofuran, ethyl ether or DME followed by addition of an aldehyde Ri 8CHO (in which Ri8 is an aryl,
heterocycle or heteroaryl) at temperatures ranging from ambient to reflux. Hydrogenation of compounds of type CK3 can be accomplished in the presence of a catalyst such a palladium or platinum in a solvent such as but not limited to methanol, ethanol or acetic acid at pressures ranging from ambient to 100° C under a hydrogen atmosphere to give compounds of formula CVII.
LXXXIX. Scheme CK
CK1 CK2
Compounds of formula I, represented by structure CVIII can be prepared as shown in Scheme CL.
Compounds of formula CLl (in which L represents iodide, bromide or chloride or methanesulfoxiate) can undergo reaction with boronic acids of structure RisB(OH)2 (in which Ri 8 is an aryl or heteroaryl) in the presence of palladium catalysts such as palladium acetate, palladium tetrakis triphenylphospbine or palladium dichloride; and ligands such as triphenylphosphine or tri-ortho-tolylphosphine in solvents such as but not limited to acetone, dimethyl formamide or toluene at temperatures from ambient to reflux to give the addition product CVπi.
XC. Scheme CL
CVIII
Compounds of formula I, represented by structure CDC can be prepared as shown in Scheme CM.
Compounds of formula CMl (in which L represents iodide, bromide or chloride or methanesulfonate) can undergo reaction with metal sulfinates (in which Ri8 is an alkyl, aryl or heteroaryl) in solvents such as but not limited to acetone, dimethylformamide or toluene at temperatures from ambient to reflux to give the addition product CDC.
XCI. Scheme CM
CM1 CIX
Compounds of formula I, represented by structure CX can be prepared as shown in Scheme CN.
Compounds of formula CLl (in which R17, defined above, is 1-3 substituents placed on the indole ring) when treated with a base such as potassium hydride, sodium hydride or the like, and then an alkyl lithium such as f erf-butyl lithium form a carbanion that reacts with disulfide Ri8SS Ri8 (in which Ri8 is an alkyl, aryl or heteroaryl) in solvents such as but not limited to THF, diethyl ether, or toluene at temperatures from ~78°C to ambient to provide intermediate. Cyanation (CN3), alkylation of the indole nitrogen (CN4) and metal coupling to form product CX are described above. XCII. Scheme CN
CN4 CX
Compounds of formula I, represented by structure CXI, can be prepared as shown in Scheme CO.
Compounds of formula COl (in which Ri7, 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 formula CO2. 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 CO3 which is subsequently cyclized to form compounds of structure CO4 employing palladium (II) acetate as catalyst, a phosphine ligand and a base 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 0 0C to reflux provides intermediate CO5. The subsequent steps leading to product CXI are described above. XCπi. Scheme CO
CO1 CO2 CO3
CO4 CO5 CO6
CO7 CXI
Compounds of formula I5 represented by structure CXII can be prepared as shown in Scheme CP. Compounds of formula CPl was elaborated using conditions as described above provide CP3 which can be subsequently hydrogenated using a metal such as palladium on carbon and a
source of hydrogen such as hydrogen gas or ammonium formate to provide the aniline intermediate CP4. Bis-alkylation using CP5 where X can be CH2, S, SO, SO2, O, C=O, etc. and n = 0 to 3, with two leaving groups (L), as described above, and an appropriate base such as triethylamine or potassium hydroxide in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux will provide intermediate CP6. Employing conditions described above then provides product CXII. XCIV. Scheme CP
Compounds of formula I, represented by structure CXIII, can be prepared as shown in
Scheme CQ.
Compounds of formula CQl can be elaborated using conditions described above to provide product CXIII.
XCV. Scheme CQ
CQ1 CQ2 CQ3
CXlIl
Compounds of formula I, represented by structure CXTV, can be prepared as shown in
Scheme CR.
Compounds of formula CRl can be elaborated using conditions described above to provide intermediate CR4. Treatment of indole CR4 with a halogen source, such as halogen substituted succinimides, in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux provide halogen substituted product CXIV. 5 XCVI. Scheme CR
halogenation
Compounds of formula I, represented by structure CXV, can be prepared as shown in Scheme CS.
10 Compounds of formula CSl 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 tetrahydrofuran, dichloromethane or toluene at temperatures from ambient to reflux to provide intermediate CS2. CS2 can either be directly reacted with palladium (0) and a Ri 2 substituted trialkyl tin compound in the presence of cesium fluoride and copper (T) iodide in solvents such as but not limited to
15 tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux to provide product CXV 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 and then a second palladium coupling with palladium (0),
20. cesium fluoride and an appropriate R12L compound in solvents such as but not limited to tetrahydrofuran, dimethoxy ethane or toluene at temperatures from ambient to reflux to provide CXV.
XCVII. Scheme CS
H0 R4 base Tf0 R4 Pd (ll) (RnO)2B >R4
CS1 CS2 CS3
CXV
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 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. 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. In 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 flavivirus 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 and/or translation in a subject in need thereof, 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.
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 marmosets and tarmarins. 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., ED50 (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, ED50/LD5C). Li 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.lg 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, age, weight, and gender of the
subject, diet, time and frequency of administration, drug combinations), reaction sensitivities, 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, amidatioπ, esterification 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 fβ) 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 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.
A pharmaceutical composition of the present invention 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; a glucosidase inhibitor; protease inhibitors; polyermase inhibitors; p7 inhibitors; entry inhibitors, including fusion inhibitors such as Fuzeon™ (Trimeris); helicase inhibitors; a Toll-like receptor agonist, a caspase inhibitor, anti-fibrotics; drugs that target IMPDH (inosine monophosphate dehydrogenase inhibitors), such as Merimepadib™ (Vertex Pharmaceuticals Inc.); synthetic thymosin alpha 1 (ZADAXESf™, SciClone Pharmaceuticals Inc.); a glycosidase inhibitor; therapeutic viral vaccines, such as those produced by Chiron and Immunogenics; and immunomodulators, such as histamine.
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 exist 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, hydroxyalkylnαethylcellulose, 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 croscarmellose 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 period. For example, a time delay material 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 nonaqueous 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 in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, 5 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 chain, aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a 0 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-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin. 5 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-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol 0 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. 5 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 0 in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils maybe 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, palatabiliry, decrease adverse reactions, etc.), for example by esterification, 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 cyclodextrin 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; a glucosidase inhibitor, protease inhibitors, polymerase inhibitors, helicase inhibitors, a Toll-like receptor agonist, a caspase inhibitor and a glycosidase inhibitor. 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 or in vivo or both in vitro and 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-δ-methoxy-l/f-indole-S-carbonitrile (compound 5).
Step A: A solution of 6-methoxyindole (10.0 g, 68.0 mtnol) in DMF (120 mL) is cooled to 00C 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 6-me&oxy-lH-indole-3-carbonitrile as a light brown solid. Step B: To a solution of 6-methoxy~l/7-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 ό-ethoxy-l-ethyl-lH-indole-S-carbonitrile (compound 9).
Δ
Step A: To a solution of l-eώyl-ό-methoxy-lH-indole-θ-carbonitrile (2.85 g, 14.2 mmol), prepared by example IA, step B, in CH2Cl2 (40 mL) is added a IM solution of BBr3 in CH2Cl2 (28.5 mL, 28.5 mmol) at 00C. 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 CH2CI2 (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-emyl-lH-mdole-3-carboriitrile as a yellow solid.
Step B: To a solution 6-hydoxy-l-ethyl-lH-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodomethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with Η2O and extracted with EtOAc (3X). The combined organic phases are dried and concentrated. Flash chromatography (CH2CI2) gives 94 mg (100%) of 6-ethoxy-l-ethyl-li/- indole-3-carbonitrile as a white wax.
Li 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]dioxolo[4,5-f]indole-7- carbonitrile (compound 44).
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-ls2-diamine (14 mg, 0.096 mmol) is added to 5H-[l,3]dioxolo[4,5-f]indole-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 CH2CI2 (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-methoxyphenyl)-5H-[l,3]dioxolo[4,5-fJindoIe-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)-lHr-indole-3-carbonitrile (compound 13).
DMF, 1100C
To a solution of l-ethyl-δ-hydroxy-li-T-indole-S-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 mg, 0.40 mmol). The mixture is heated at 1100C 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 NaCI, dried and concentrated. The product is isolated by chromatography (EtOAcZCH2Cl2, 1-3%) over silica gel to afford 76 mg (96%) of the title compound, l-ethyl-6-(pyrazin-2-yloxy)-lH"-indole- 3-carbonitrile, as an off-white solid.
Example IE: Preparation of S-cyano-l-ethyl-lH-indole-ό-carboxylic acid phenylamide (compound 15).
Step A: A solution of methyl S-cyano-l-ethyl-lH-indole-ό-carboxylate (1.6Og, 7.02 mmol), prepared by the method described in example IA from methyl lH-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-δ-carboxylic acid as a white solid.
Step B: A suspension of S-cyano-l-ethyl-lH-indole-δ-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 became 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 H2O and extracted with EtOAc (2X). The combined organic phases are washed with saturated NaCl and then dried and concentrated to . afford the product. Chromatography (EtOAcZCH2Cl2, 2/98) over silica gel gives 44 mg (51 %) of S-cyano-l-ethyl-lH-indole-ό-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-cyaαo-l-ethyl-lH-indole-ό-carboxylic acid (0.60 g, 2.80 rαmol) from Example IE5 step A, int-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 H2O, the organic phase is back-extracted with EtOAc and the organic layers are combined and washed sequentially with additional H2O3 saturated NaHCθ3 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 (3-cyano-l-eώyl-l/y-indol-6-yl)-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- carbonitrile via Suzuki route (compound 55).
reflux
Step A: A 2M solution of lithium diisopropyl amide in THF/hexanes (Acres) (3.9 mL, 7.8 mmol) is diluted with THF (5 mL) in a flame-dried flask. After cooling the reaction to — 300C5 a solution of l-ethyl-β-methoxy-lH-indole-S-carbonitrile (1.30 g, 6.5 mmol) in THF (10 mL) is added dropwise during 10 min, maintaining the temperature at — 300C. 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 JCe-H2O and extracted with EtOAc (2X). The
combined organic phases are washed with IM sodium thiosulfate and saturated NaCl and then concentrated to a brown solid. Chromatography (CϊkCVhexanes, 1/1) over silica gel gives 1.31 g (62%) of l-ethyl-2-iodo-6-methoxy-lH'-indole-3-carbonitrile as an off-white solid.
Step B: A mixture of l-ethyl-2-iodo-6-methoxy-li/-mdole-3-carbonitrile (1.25 g, 3.83 mmol), 4-(4,4,5,5-tetramethyl)-l53-2-dioxaboralanyl-2-yl-aniline (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 then 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-aminophenyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile 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.
To a solution of (i-Pr)2NH (1.35 mL, 9.65 mmol) in THF (30 mL) cooled to -78°C 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 min. The solution is cooled to — 78°C and solution of l-butyl-6-methoxy-lH-indole-3-carbonitrile, prepared as in example IA (2.0 g, 8.77 mmol) in TΗF (10 mL) is added dropwise. This solution is stirred for 15 min at -78°C, 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.
PPh3
THF
Δ
A nitrogen-purged flask fitted with a septum and a nitrogen needle is charged with dry THF (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 00C. 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 THF solution of 6-methoxy- l-propyl-lH-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 ZnCl2 (0.5 M solution in THF, 27.0 mL, 13.5 mmol) is slowly added. A precipitate is observed at this point, which maybe 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 THF 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/Nb 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-lH-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 -78°C for 10 minutes, and then at 00C for 20 minutes. The solution is re-cooled to -78°C. 1 -ethyl-β-methoxy-lH-indole-S-carbonitrile (5.0 g, 25 mmol), prepared as in example IA, is taken up in TΗF (30 mL) and added dropwise to the LDA mixture over 15 minutes. The reaction is stirred at -78°C for 10 minutes, and at 00C for 30 minutes. Once again, the reaction mixture is cooled to -78°C. Tributyltin iodide (10 mL, 35 mmol) is added dropwise. This is stirred at -78°C for 15 minutes, and then at 00C for 30 minutes. The reaction mixture is absorbed onto silica gel and concentrated. Purification by chromatography (CΗ2CI2) yields l-ethyl-6-methoxy-2-tributylstannanyl-lHr-indole-3- carbonitrile (12.05 g, 98%).
Step B: l-Ethyl-e-methoxy^-tributylstannanyl-lH-indole-S-carbonitrile (1.0 g, 2.05 mmol), prepared in step A, is combined with 3-iodophenol (474 mg, 2.15 mmol), Pd(PPh3)2C-2
(67 mg, 0.102 mmol), CuI (75 mg, 0.39 mmol) and THF (4.0 mL). This mixture is heated at 650C overnight. The reaction mixture is diluted in EtOAc3 and is filtered through celite. The filtrate is concentrated and the residue is purified by silica gel chromatography (4: 1, CH2Cl2ZEtOAc) to yield crude product. Ether trituration yields l-ethyl-2-(3-hydroxy-phenyl)- ό-methoxy-lH-indole-S-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/f-indol-2-yl)-phenyl]-amide via Heck route (compound 519).
Step A: A solution of 6-difiuoromethoxy-l -ethyl- IH-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 DMA (5 ml) is heated to 1350C 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 chromatography on silica gel (25 g) using EtOAc/Hexanes (10-20%) as eluent to afford 298.2 mg (37.1% yield) of ethanesulfonic acid [4-(6-difluoromethoxy-l-ethyl-lH-iodo-2-yl)-phenyl]- amide, compound 516, as a light brown solid.
Step B: Following the procedure IA, step A, ethanesulfonic acid [4-(6- difiuoromethoxy-l-ethyI-lH-iodo-2-yl)-phenyl]-amide is converted to ethanesulfonic acid [4- (3-cyano-6-difluoromethoxy-l-ethyl-lH-indol-2-yl)-phenyl]-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-liy-iiαdole-
3-carbonitrile (compound 67).
DMF Et3N
8O0C
A mixture of l-ethyl-2-iodo-6-meΛoxy-lH-mdole-3-carbomtrile (150 mg, 0.46 mmol), prepared as described in example IGa, step A, 4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triρhenylphosphine) palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol) is added to a sealable tube and alternatively 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-liϊ'- 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-emyl-3-(5-emyl-[l,2,4]oxadiazol~3-yl)-6-methoxy-lH"- indole (compound 28).
Step A: A solution of l-ethyl-δ-methoxy-lH-indole-S-carbonitrile (1.00 g, 5.00 mmol) in MeOH (10 mL) is treated with a 50% aqueous solution of hydroxylamine (0.38 mL, 6.25 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 CΗ2CI2 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-6-methoxy-lH-indole-3-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 CH2Cl2 (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/CEbCla, 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).
Δ
Step A: A mixture of l-ethyl-ό-methoxy-lH-indole-S-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 NaHCO3 and extracted with EtOAc. The organic layer is then washed with additional NaHCO3 (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-6-methoxy-3-(lH-tetrazol-5-yl)-li;?'-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 2 Ih. 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 (EtOAc/CH2Cl2, 5-10%) to afford 30 mg (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-difluoromethoxy-l-(4-methoxyphenyl)-2-methyl- liif-indole-3-carboxylate (compound 49).
Freon-22 (HCF2Cl) gas is bubbled into a solution of ethyl 5-hydroxy-l-(4- memoxyphenyl)-2-methyl-lH-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 0°C. 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 Na2SO-}. 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-H-indole (50 mg, 0.2 mmol), prepared by the method of example 1C, is dissolved in 1 mL of CH2Cl2 at 00C. Et2AlCl (300μL, IM in hexanes, 0.3 mmol) is then added. After stirring at 00C for 30 min, a solution of acetyl chloride (22 μL, 0.3 mmol) in 1 mL OfCH2Cl2 is added dropwise. This is stirred at 00C for a further 90 min. The reaction mixture is quenched with H2O and is extracted with CH2CI2 and concentrated in vacuo. Purification by column chromatography on silica gel EtOAc/CHaCb (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-ethyI-3-isoxazol-3-yl-6-methoxy-l-H-indole (compound
57).
Δ
Step A: A mixture of l-(l-ethyl-6-methoxy-l-iy-indole-3-yl)ethanone (200 mg, 0.92 mmol), prepared from l-ethyl-6-methoxy-l/f-indole by the procedure described in example IL5 hydroxylamine hydrochloride (128 mg, 1.84 mmol), NaOAc (151 mg, 1.84 mmol) and EtOH (7mL) is heated at 850C 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 EtOAc/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 TΗF (900 μL) at 00C. 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 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 Η20, 1 mL of THF, and 100 μL of concentrated H2SO4. This mixture is heated at 75°C 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-S-isoxazol-S-yl-ό-methoxy-l-H-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-memoxy-lH-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from 1- ethyl-6-methoxy-lH-indole by the procedure described in example IL5 is heated with 1.5 mLof dimethylformamide dimethylacetal and 100 μL of pyrrolidine at 1100C overnight. The dimethylformamide dimethylacetal is then concentrated in vacuo. The residue is redissolved in 1.25 mL of EtOH and 250 μL OfH2O, and is treated with hydroxylamine hydrochloride (66 mg, 0.95 mmol) and heated at 8O0C 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-ethyl-3-isoxazol-5-yl-6-methoxy-lH-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-ethyI-6-methoxy-3-(2H-pyrazol-3-yl)-lH-indole (compound 59).
l-(l-Ethyl-6-methoxy-li?-indol-3-yl)-ethanone (100 mg, 0.46 mmol), prepared from 1- ethyl-6-methoxy-lH-indole by the procedure described in example IL, is heated with 1.5 mL of dimethylfoπnamide dimethyl acetal and 100 μL pyrrolidine at 110°C 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 NaHCC>3. The organic phase is dried and concentrated and the product purified by silica gel chromatography (EtOAc/Hex, 1/1) to give 59 mg of l-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)- lff-indole (54%) as a colorless semisolid. Trituration in Et2O 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/CH2Cl2) yields l-ethyl-3-formyl-lH-indole-6-carboxylic acid methyl ester (985 mg, 96%) as a white solid.
Step B: l-Ethyl-S-formyl-lH-indole-β-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 800C overnight. The reaction mixture is then partitioned between EfeO 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-ethyl-3-oxazol-5-yl-lH-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).
Step A: l-EΛyl-3-formyl-lH-:indole-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 OfKMnO4 (655 mg, 4.15 mmol) in H2O (31 mL) is added. The reaction mixture is stirred at room temperature for 90 minutes. Another addition OfKlMnO4 (108 mg) 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 1 -ethyl- lH-indole-Sjό-dicarboxylic acid 6- methyl ester (696 mg, 79%) as a light orange solid.
Step B: l-Ethyl-lH-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg, 2.43 mmol) is suspended in a solution OfCH2Cl2 (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-lH-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 (EtOAcZCH2Cl2 5-10%). The product containing fractions are combined and concentrated and the solid is triturated with hexanes to yield methyl l-ethyl-S-oxazol^-yl-lH"- indole-6-carboxylate (75 mg, 46%) as a yellow solid.
Example IR: Preparation of l-ethyl-6-methoxy-3-thiazol-2-yl-lH-indole (compound
73).
DMF
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 POCh (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-ό-methoxy-lH-indole-S-carbaldehyde (849 mg, 81%) as a yellow solid.
Step B: l-Ethyl-δ-methoxy-lH-mdole-S-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 of KMnθ4 (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-ό-methoxy-lH-indole-S-carboxylic acid (365 mg, 56%) as a yellow solid.
Step C: l-Ethyl-β-methoxy-lH-indole-S-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-ethyl-6-methoxy-lH-indole-3-carboxaraide (134 mg, 54%) as a white solid.
Step D: l-Ethyl-6-mefooxy-lH-mdole-3-carboxaπύde (120 mg, 0.55 mmol), Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) are heated at 900C for 90 min. The reaction mixture is concentrated and purified by silica gel chromatography
(EtOAc/CΗ2Cl2, 1/9) to yield l-ethyl-6-methoxy-lH-indole-3-thiocarboxamide as a yellow solid (92 mg, 71%).
Step E: l-Ethyl-6-methoxy-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 800C for 16h. More bromoacetaldehyde dimethyl acetal (250μL is added. This is heated at 80°C 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-liϊ-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-β-methoxy^-phenoxymethyl-lH-indole-S- carbonitrile (compound 99).
CISO2NCO DMF
Step A: To a suspension OfLiAlH4 (7.6 g, 0.2 mol) in dioxane (100 mL) is added dropwise a solution of methyl 6-memoxy-liy-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 Na2SO4 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-lH-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 NaHCO3 is added to it until it becomes basic. The aqueous phase is extracted with CH2Cb and then evaporated. The residue is purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 81% of ό-methoxy^-methyl-lff-indole-S-carbonitrile. Step C: To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) is added a solution of 6- ' me&oxy-2-meώyl-l#-mdole-3-carbonitrile (1.3 g, 7.0 mmol) in DMF (S mL) followed by - ethyl iodide (1.2 mL, 2 eq.) at 00C. After stirring for Ih, the mixture is poured into ice water and the mixture is 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 92% of 1- ethyl-6-memoxy-2-methyl-lH-mdole-3-carbomtrile.
Step D: To a solution of l-ethyl-β-methoxy^-methyl-lH-indole-S-carbonitrile (1.38 g, 6.45 mmol) in benzene (130 mL) is added benzoyl peroxide (226 mg) and NBS (1.21g,
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-li7-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 2Oh3 the mixture is poured into ice water and extracted with CH2Cl2. 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-6-methoxy-2-phenoxymethyl-lH-indole-3-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-fIuoro-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 oϊChem. 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 NBaSO4, filtered and partially evaporated to give a precipitate, which is collected by filtration. Further evaporation and filtration gives a second crop. The two crops are combined and dried under vacuum to give 2-amino-l-ethyl-6-nitro- li/-indole-3-carbonitrile (7.90 g, 52%) as an orange powder.
Step B: A solution of 2-amino-6-nitro-lH-indole-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 CO2 evolution ceased. The mixture is extracted with EtOAc (2 X 100 mL), and the extracts are washed with saturated brine, combined, dried over MgSO4, 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/f-indole-3 -carbonitrile, compound 5, as a yellow solid (232 mg, 51%).
Example IU: Preparation of N-(3-cyano-l-ethyl-6-nitro-lH-mdol-2-yl)acetamide (compound 25).
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- lH-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-lH-mdole-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-ammo-l-ethyl-6-nitro-lif- 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 Et2θ, collected by filtration and dried under vacuum to afford JV-(3-cyano-l - etiiyl-6-nitro-lH-indoI-2-yl)-acetamide (100 mg, 71%), compound 25, as an off-white powder. Using this procedure and substituting the appropriate acid chlorides or chlorofoπnates gives the following compounds: Compounds 23, 26, 35, 36, 203, 204, 214, 215, 216.
Example IV: Preparation of N-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 rain 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), triphenylphosphine (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 reaction mixture is degassed again. To the reaction is added palladium (II) acetate (23.4mg, 0.104 mmol)5 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 MgSO4 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-ρhenyl-5-nitroindole (40.0 mg, 2.1 mmol) in DMF (0.75 mL). The reaction mixture is stirred for 20 min at 00C 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).
In 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 CH2Cl2. Another silica column (3/2, ether/hexanes) is needed to fully purify the product, [3-cyano-l-(4-methoxy- phenyl)-lH-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid.
Example IX: Preparation of N-[4-(3-cyano-l-ethyl-6-memoxy-lH-mdol-2-ylethynyl)- ρhenyl]-methanesulfonamide (compound 130).
2-(4-Asωnophenyl6thynyl)-l-ethyl-6-mefhoxy-lH-indole-3-carboiiitrile (50 mg, 0.16 mmol), prepared as described by the method of Example 1Η, is dissolved in pyridine (550 μL) at room temperature. Methanesulfonyl chloride (17 μL, 0.21 mmol) is added dropwise. This i 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-liy-indol-2-ylethynyl)-phenyl]-methanesulfonamide (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)-ρhenyl]- methanesulfonamide (compound 129).
rt
A solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-li?-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example IGa, step B in THF (3 mL) is cooled to 00C and treated with triethylamine (6.04 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 H2O and saturated NaCl5 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-yI)-phenyl]-m.ethanesulfonamide as a tan solid.
Using essentially the same procedure as above and substituting the appropriate aminophenylindole 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, 44O5448, 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-lH-indol-2-ylethynyl)- phenyl]-acetamide (compound 138).
2-(4-Aminophenylethynyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (95 mg, 0.29 mmol), prepared as described in Example 1Η, is dissolved in TΗF (1.4 mL). Triethylamine (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, ClfeCla/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 0cC. 2-(4-Aminophenylethynyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as in example 1Η, is taken up in TΗF (1.2 mL) and added to the formic acetic anhydride mixture. This is stirred at 00C for 30 minutes. The reaction mixture is then partitioned between H2O and EtOAc. The EtOAc layer is washed with
saturated NaHCCh, followed by saturated brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CHbQs/EtOAc) yields N-[4-(3-cyano-l-ethyl- 6-methoxy-l#-mdol-2-ylemynyl)-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-lJ:f-indol-2-yl)- phenylj-acetamide (compound 128).
A solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-lJcf-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example IGa, step B in THF (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 EfeO 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-indol-2-yl)- phenyl] acetamide as a tan solid.
Using essentially the same procedure as above and substituting appropriate amiuophenyl 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, S99, 900, 901, 913, 914, 915, 916, 983.
Example IAB: Preparation of l-[3-(3-cyano-l-ethyl-6-methoxy-lHr-indol-2- ylethynyl)phenyl]-3 -ethyl urea (compound 220).
EtNCO pyridine
2-(3-AnainophenylethynyI)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example IH, 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, CHaCla/EtOAc), followed by trituration with hexanes/acetone (1/1), yields l-[3-(3-cyano-l- ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-3-ethyl urea (44 mg, 36%) as a white solid.
Example IAC: Preparation of l-(2-chloroethyl)-3-[4-(3-cyano-l-ethyl-6-methoxy-lH- indol-2-ylethynyl)-phenyl] urea (compound 156).
2-(4-Ajninophenylethynyl)-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-δ-methoxy-l/f-indol^-ylethynyO-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-liϊ- indol-2-ylethynyl)-phenyl]methyl amide (compound 157).
N-[4-(3 -cyano- 1 -ethyl-6-methoxy- 1 H-indol-2-ylethynyl)phenyl j 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 H2O and then brine. The organic layer is dried and concentrated. Purification by silica chromatography (95/5, CH2Cl2/EtOAc) yields a light tan solid. Trituration gives ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-ρhenyl]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-(moφholine-4-carbonyl)- phenyl]-lH-indole-3-carbonitrile (compound 245).
Step A: Methyl 4-(3-cyano-l-ethyl-5-methoxy-l/-T-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 800C 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-lH-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 occurs. This reaction mixture is pipetted dropwise into a vigorously stirring solution of morpholine (1.0 mL) in CH2Ck (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-lH"-indol-2-ylethynyl)-phenyl] amide (compound 194).
Cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yletb.ynyl)- phenyl]-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).
1 -(2-Chloroethyl)-3 -[4-(3 -cyano- 1 -ethyl-6-methoxy- lH-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%,
EtOAc/CH2Cl2) yields l-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-l-yl)-phenylethyαyl]-lH;- 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 1AΗ: Preparation of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2- ylethynyl)-phenyl]-dimethylphosphinic amide (compound 227).
2-(3-Aminophenylethynyl)-l-ethyl-6-methoxy-lH/-i«dole-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 TKDF (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-lϋf- indol-2-ylethynyl)-ρhenyl]-dimethylphosphinic amide (65 mg, 52%), compound 227, as a pure white solid. The silica column is then flushed with 9/1 CH2Cl2MeOH to yield 9 mg of N-[4- (3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-bis-(dimethylphosphinic) amide as a by-product.
Example IAI: Preparation of l-ethyl-6-methoxy-3-[5-(4-methoxyphenyl)-isoxazol-3- yl]-lif-mdole (compound 116).
Step A: A mixture of l-ethyl-δ-methoxy-lH-indole-S-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 (EtO Ac/hexanes, 10-20%) gives 16 mg (24%) of 1 -emyl-6-methoxy-3-[5-(4-methoxy- phenyl)-isoxazol-3-yl]-lH-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).
A biphasic mixture of 2-(4-amino-phenyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile
(70 mg, 0.24 mmol), prepared as described in example IGa step B, and ethyl chlorofoπnate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at O0C 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-lH-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, 581, 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, 117911801186, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1211, 1222, 1232, 1233, 1300, 1302.
Example IAK: Preparation ofl-ethyl-5-ttøophen-3-yl-lH-indole-3-carbomtrile (compound 141).
DME
A tube is charged with a mixture of S-bromo-l-emyl-lH-indole-θ-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 900C for 19h. After cooling, the crude reaction mixture is diluted with saturated NaHCO3 and extracted with EtOAc (2X). The combined organic phases are washed with saturated NaCl and dried and concentrated. Flash chromatography over silica gel (CEfeCk/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-lH-indol-2-yl)- phenyl]-N-methyl methanesulfonamide (compound 180).
A solution of N-[4-(3 -cyano- 1 -ethyl-6-methoxy- 1 H-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 (EtOAc/CH2Cl2, 0-1%) gives 60 mg (45%) ofN-[4-(3-cyano-l-ethyl-6-methoxy-lH-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)- phenyl]-methanesulfonamide (compound 189).
A solution of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] methanesulfonamide (85 mg, 0.23 mmol) in CH2Cl2 (2 mL) is cooled to -50C. A solution of boron tribromide (1.15 mL, 1.15 mmol, IM solution in CH2Cl2) is added and the reaction mixture is allowed to warm to 100C 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 (EtOAcZCH2Cl2, 5-10%) gives 18 mg (22%) of N-[4-(3-cyano-l-ethyl-6-hydroxy-lH'-indol-2-yl)-phenyl] 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-l/-T-indol-2-yl)- [l,2,4]oxadiazol-3-yl]benzoate (compound 226).
2. Δ
Step A: To a mixture of β-methoxy-l/f-indole-S-carbonitrile (5.88 g, 40 mmol), prepared as described in the previous examples, and (BoC)2O (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 Na2SO-I. The crude product is chromatographed over silica gel (hexanes/EtOAc, 7/1) to furnish the desired intermediate, 3- cyano-6-methoxyindole-l-carboxylic acid fert-butyl 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, 10.0 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-tert-butyl ester (2.40 g, 73%).
Step C: To a solution of 3-cyano-6-methoxyindole-l,2-dicarboxylic acid 1-tert-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, CH2Cl2ZEtOAc, 8/2) to furnish the intermediate, 3-cyano-6-methoxy-2-[3-(3- memoxycarbonylphenylHl^Joxadiazol-S-yll-mdole-l-carboxylic acid tert-hutyl 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 tibe desired product, methyl 3-[5-(3-cyano-6-methoxy-lH-indol-2-yl-)[l,2,4]oxadiazol- 3-yl]benzoate5 compound 226 (350 mg, 62%).
Example IAO: Preparation of l-ethyl-2-(4-methanesulfonylphenyl)-6-methoxy-l//- indole-3-carbonitrile (compound 265).
A solution of l-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-lH-mdole-3-carbonitrile (0.12 g, 0.37 mmol) in CH2Cl2 (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 NaHCC*3 and extracted twice with EtOAc. The organic phases are washed with NaHCO3 (2X) and saturated NaCl and dried and concentrated to a dark semi-solid. The crude product is purified by flash chromatography (EtOAc/CH2C12, 0-3%) through a 5 gram silica cartridge topped with 1 gram of basic alumina to give 72 mg (55%) of 1 -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-morpholin-4-yl-ethoxy)-lH- indol-2-yl]-phenyl} methanesulfonamide (compound 478).
A solution of N-{4-[6-(2-chloroethoxy)-3-cyano-l-ethyl-l/f-indol-2-yl]-phenyl} methanesulfonamide (90 mg, 0.21 mmol), morpholine (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-moipholin-4-yl-ethoxy)-lH-indol-2-yl]-phenyl} 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- e&yl-6~methoxy-lH-indol-2-yl)-phenyr] 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-lH-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-morpholin-4-yl-ethanesulfonic acid [4-(3- cyano-l-ethyl-6-methoxy-lHr-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-morpholin-4-yl-ethanesulfonic acid ^-(S-cyano-l-ethyl-ό-methoxy-lH- indol~2-yl)-phenyl] 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-lif-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-(l,l-dioxo-lλ6-isothiazolidin-2-yl)phenyl]-l-ethyl- 6-methoxy-lH/-indole-3-carbonitrile (compound 84).
Step A: A solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile, 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 pΗ 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-lH-indol- 2-yl)-phenyl] amide as a brown foam which is used directly in the next step. Step B: A solution of 3 -chloropropane-1 -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 K2COj and heated at 700C 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 example IB step A, 2-[4-(l,l-dioxo-lλ6- isothiazolidin-2-yl)phenyl]-l-ethyl-6-methoxy-lH-indole-3-carbonitrile is treated with IM BBrβ solution in CH2Cl2 at —15°C for 1.5h and then poured into ice-water and filtered and dried to afford 2-[4-(l,l-dioxo-lλ6-isothiazolidin-2-yl)phenyl]-l-ethyl-6-hydroxy-li7-indole-3- carbonitrile in nearly quantitative yield.
Step B: Following the procedure in examplelB step B, 2-[4-(l,l-dioxo-l λ6- isothiazolidin-2-yl)phenyl]- 1 -ethyl-6-hydroxy- 1 H-indole-3-carbonitrile, K2CO3, 2-iodopropane and methyl ethyl ketone are heated at reflux to give, after flash chromatography (EtOAc/CΗ2Cl2, 0-2%), 61% of 2-[4-(l,l-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-efliyl- 6-(2-morpholin-4-yl-ethoxy)-lH-indole-3-carbonitrile (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, O.lδmmol), 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-chloroethyl) morpholine hydrochloride and 135 mg OfK2COs 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-(l,l-dioxo-lλ6-isothiazolidin-2-yl)-phenyl]-l-ethyl-6-(2-morpholin-4- yl-ethoxy)-lH-indole-3-carbonitrile is obtained by flash chromatography (MeOH/CKfeCla, 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-l/f-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-lH- indol-2-yl)-phenyl]-ureido}-3-phenyl-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 TΗF (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 (elutirig 2/1 ethyl acetate/hexane on silica gel 60) to afford 2-[4- (2,5-dioxo-imidazolidin-l-yl)-phenyl]-6-ethoxy-l-ethyl-lH-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-lH"-indole-3-carbonitrile (compound 776).
A solution of 2-(4-aminophenyl)-6-ethoxy-l -ethyl- lH-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 ΛT,Λ/"-Dimethyl-2-[4-(3 , 4-dimethyl-2,5-dioxo- imidazolidin-l-yl)-phenyl]-6-ethoxy-l-ethyl-lHr-indole-3-carboxamide (compound 780) and
iV;N-Dimetiiyl-6-ethoxy-l-ethyl-2-[4-(3-methyl-2,5-dioxo-imidazolidin-l-yl)-phenyl]-lH- indole-3-carboxamide (compound 781).
Step A. A solution of ethyl {3-[4-(3-cyaαo-6-ethoxy-l-ethyl-lH-indol-2-yl)-phenyl]- 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]-lHr-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)-methanesυlfonatnide (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-ethyi-6- methoxy-lH-indol-2-yi)-phenyl] 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,
Step B: A mixture of N-(2-acetoxyethyl)-N-[4-(3-cyano-l-ethyl-6-methoxy-liy-indol-2- yl)-phenyl] methanesulfonamide (compound 815, 164 mg, 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-lH:-indol-2-yl)-phenyl]-JV:-(2-hydroxyethyl) methanesulfonamide, compound 828 (137 mg, 0.331 mmol, 92%).
Example IAZ: Preparation of l-etiιyl-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 πimol), bromoethyl methyl ether (26 μL, 0.28 mmol), and DMF (450 μL). This is stirred at room temperature for 1 hour, and then at 75°C for 3 hours. The reaction mixture is then partitioned between H2O 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)- phenyl]-lH-indole-3-carbonitrile (compound 261).
Step A: l-Ethyl-6-methoxy-2-[4-(2-hydroxyethoxy)-phenyl]-lJH-indole-3-carboriitrile (450 mg, 1.34 mmol), prepared as in example IAZ, is combined with PPb.3 (878 mg, 3.35 mmol) in CH2Cl2 (32 mL) 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 NaHCO3. The organic layer is dried and concentrated, and purified by silica gel chromatography (CH2Cl2) 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-lH-indole-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 CΗ2CI2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (6/4, acetone/hexanes) yields l-ethyl-6-methoxy-2- [4-(2-moφholin-4-yl-ethoxy)-phenyl]-l/-r-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-β-methoxy-lH-indol-2-yl)- phenoxy]-ethyl} methanesulfonamide (compound 268).
H2, PctfC
Step A: 2-[4-(2-Bromoethoxy)phenyl]-l -ethyl-δ-methoxy-lH-indole-S-carbonitrile (258 mg, 0.65 mmol), prepared in example IBA, step A, is combined with NaN^ (144 mg, 2.2 mmol), and MeOH (3.2 mL). This is heated overnight at 750C. The reaction mixture is then partitioned between CH2CI2 and EfeO. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2CI2) yields 2-[4-(2-azidoethoxy)phenyl]-l- ethyl-6-methoxy-lH-indole-3-carbonitrile (187 mg, 80%), compound 266 as a white solid.
Step B: 2-[4-(2-Azidoethoxy)phenyl]-l-ethyl-6-methoxy-lH-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%, MeOHZCH2Ck) yields 2-[4- (2-aminoethoxy)phenyl]-l-ethyl-6-methoxy-liϊ"-indole-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 CH2Cl2ZEtOAc) yields N-{2-
[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)phenoxy]ettiyl} 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-Aminoethoxy)ρhenyl]- 1 -ethyl-6-methoxy- lH-indole-3 -carborάtrile (30 mg, 0.09 mmol), prepared as in example IBB3 step B5 is dissolved in TΗF (400 μL), and EtaN (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 Η2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (EtOAc) yields N-{2-[4-(3-cyano-l-ethyl-6-methoxy-l/f-indol-2-yl)phenoxy]ethyl} acetamide (33 mg, 97%) as a white solid.
Example IBD: Preparation of l-{2-[4-(3-cyano-l -ethyl-6-methoxy- lH-indol-2-yl)- phenoxy]ethyl} -3 -ethyl-urea (Compound 279).
2-[4-(2-Aminoethoxy)phenyl]-l-ethyl-6-methoxy-liϊ-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example IBB5 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-memoxy-li7-indol-2-yl)- phenoxy]ethyl}formamide (compound 280).
Acetic anhydride (700 μL) and 98% formic acid (280 μL) are heated at 65°C for Ih. This is cooled to 00C. 2-[4-(2-Aminoethoxy)phenyl]-l-ethyl-6-methoxy-lH-indole-3- carbonitrile (30 mg, 0.09 tnmol), prepared as in example IBB, is taken up in THF (400 μL), and added to the mixed anhydride. This is stirred at 00C for 45 minutes. The mixture is then portioned between EtOAc and aqueous NaHCO3. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CHada/acetone) yields N-{2-[4-(3-cyano-l- ethyl-6-methoxy-lH-indol-2-yl)ρhenoxy]-ethyl} formamide (28 mg, 86%) as a white solid.
Example IBF: Preparation of l-ethyl-2-{4-[2-(3-hydroxypyrrolidm-l-yl)-2-oxo- ethoxy]phenyl}-6-methoxy-lH-indole-3-carbonitrile (compound 285).
Step A: l-Ethyl-2-(4-hydroxyphen.yl)-6-methoxy-lH-indole-3-carbonitrile (559 mg, 1.91 mmol), is used to prepare [4-(3-cyano-l -ethyl-6-methoxy-lH"-indol-2-yl)-phenoxy]-acetic acid tert-bvtyl ester (780 mg, 100%) utilizing essentially the same procedure as example IAZ.
Step B: [4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy] -acetic acid terf-butyl ester (745 mg, 1.83 mmol) is stirred in 20% TFA in CH2Cl2 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 CH2Cl2 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-l/f-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 ramol) is added. This is stirred at room temperature for 30 minutes. The resulting solution is then pipetted into a stirring solution of S~3-hydroxypyrrolidine (150 μL) and CH2Cl2 (3.0 mL). The mixture is washed with aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (3/2 CH2Cl2/acetone) yields l-ethyl-2- {4-[2-(3-hyό^oxy-pyiτolidm-l-yl)-2-oxo-e1hoxy]-phenyl}-6-methoxy-l/-r-indole-3-carbonitrile (40 mg, 79%), compound 285 as a white solid.
Example IBG: Preparation of l-ethyl-6-methoxy-2-(2-oxo-253-dihydro-benzooxazol-5- yl)-liy-indole-3-carbonitrile (Compound 332).
Step A: l-Ethyl-2-(4-hydroxy-3-nitrophenyl)-6-methoxy-lH-indole-3-carbonitrile (369 mg, 1.1 mmol), prepared as in example IGd, 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-methoxy-liy-indole-3-carbonitrile (307 mg, 91%), compound 322, as a white solid. Step B: 2-(3-Aτnino-4-hydroxyphenyl)-l-ethyl-6-methoxy-l/ir-indole-3-carbonitrile
(100 mg, 0.33 mmol), prepared as in step A, is combined with CDI (83 mg, 0.51 mmol), and THF (1.1 mL). This is heated at 65°C 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-(2-oxo-2,3-dihydro- benzooxazol-S-y^-lH-indole-S-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)-lH-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-lH-mdole-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 H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CHfeCWEtOAc) 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 H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2CbZEtOAc) yields l-ethyl-6-methoxy-2-(3-oxo-3,4- dihydro-2/-'-benzo[l,4]oxazin-6-yl)-lH-indole-3-carbonitrile (45 mg, 90%) as a white solid.
Example IBI: Preparation of l-ethyl-6-methoxy-2-(2-oxo-233-dihydro-benzooxazol-6- yl)-lH"-indole-3-carbonitrile (Compound 340).
Step A: -^-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-3/f- benzooxazol-2-one (369 mg, 37%) as a white solid.
Step C: 6-Iodo-3i^-benzooxazol-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/f-indole-3-carbonitrile, compound 340 (75 mg, 55%), utilizing essentially the same procedure as in example IGd.
Example IBJ: Preparation of l-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,-dihydro-2/ϊ- benzo[l,4]oxazin-6-yl)-lH/-indole-3-carbonitrile (compound 339).
1 -Ethyl-6~methoxy-2-(3-oxo-3 ,4-dihydro-2H-benzo[ 1 ,4]oxazin-6-yl)- l/Z-indole-S- 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 stirred 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,- dihydro-2H-benzo[l,4]oxazin-6-yl)-lH'-indole-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-lH/-indole-3- carbonitrile (compound 499).
l-Ethyl-2-iodo-6-methoxy-lH-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example IGa, Step A5 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 CΗ2CI2 and H2O. The organic layer is washed with aqueous NaHCCb, and then is dried and concentrated. Purification by silica gel chromatography (6/4, CHaCVhexanes), followed by ether trituration, yields l-ethyi-2-iodo-6-methoxy-5-nitro-liϊ- indole-3-carbonitrile (16 mg, 29%) as a yellow solid.
Example IBL: Preparation of r-ethanesulfonyl-l-ethyl-6-methoxy-2',3'-dihydro-
(compound 753).
Step A: 6-Nitroindoline (3.0 g, 18.3 mnαol) is dissolved in THF (45 mL) and Et3N (3.4 mL, 24.4 mmol) at O0C. Acetyl chloride (1.5 mLs 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.sii. 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-aminoindoline (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 900C 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,l/7-[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,lH'-[2,6']biindolyl-3-carbonitrile (30 mg, 0.095 mmol) is used to prepare l'-Ethanesulfonyl-l-Ethyl-6-methoxy-2',3'-dihydro-lH,lJftf - [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-ρhenyl)-lH'- indole-3-carbonitrile (compound 844).
DCE
l-Ethyl-6-methoxy-2-(4-nitrophenyl)-liy-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 CH2Cl2ZEtOAc) yields 5-acetyl-l-ethyl-6-methoxy-2-(4-nitro-phenyl)-lH-indole-3-carbonitrile (33 mg, 29%) as an orange solid.
Example IBN: Preparation of l-ethyl-6-methoxy-5-morpliolin-4-yImethyl-2-(4-nitro- phenyl)-li/-indole-3-carbonitrile (compound 845).
Step A: l-Ethyl-6-methoxy-2-(4-nitrophenyl)-lH-mdole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example IGc, is combined with 1,3,5-trioxane (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 CH2Cl2 and H2O. The organic layer is washed with aqueous NaHCO3, and is subsequently dried and concentrated. The crude material is carried through to the next step.
Step B: Crude 6-bromomethyl-l-ethyl-6-methoxy-2-(4-nitro-phenyl)-lH-indole-3- carbonitrile (0.3 mmol) is heated with morpholine (150 μL, 1.75 mmol) and DCE (1.0 mL) at 900C 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/CH2Cl2), followed by trituration with 1/1 hexane/acetone yields l-ethyl-6-methoxy-5- morpholin-4-yhnethyl-2-(4-nitrophenyl)-lH'-indole-3-carbonitrile (57 mg, 44% overall yield) as a yellow solid.
Example 1 BO: 2-[4-( 1 , 1 -dioxidoisothiazolidin-2-yl)phenyl]- 1 -cyclopropylmethyl-6- methoxy-l/7-indole-3-carbonitrile (compound 716).
Step A: To a solution of 6-methoxyindole (5.88 g, 40.0 mmol) and di-ferf-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 HCl, water and brine and dried over anhydrous
The solvent is evaporated and the residue is chromatographed (silica gel, EtOAc/hexanes, 1/7) to provide tert-butyl ό-methoxy-lH-indole- 1-carboxyϊate (8.48 g, 86%). Step B: The above Boc-indole (3.08 g, 12.5 ramol) 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 O0C 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-mehoxymdole-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 2hr 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 N52 X 15 mL), water (2 X 50 mL) and brine (20 mL) consecutively and dried over anhydrous Na2SO4. 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 g, 100%).
Step D: To a mixture of l-Boc-6-mehoxyindole-2-borom"c acid prepared in step B above (0.36 g, 1.25 mmol), 2-(4-iodoρhenyl)isothiazolidine- 1,1 -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 /EtOAc, 9/1) to furnish 1- Boc-2-[4-(l,l- dioxidoisottaazohdin-2-yl)phenylJ-6-methoxy-lH-indole (0.43 g, 98%). The following compound is made similarly: Compound 768
Step E: 1- Boc-2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-li7-indole (1.63 g, 3.7 mmol) 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 NaHCθ3 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%).
At 00C, l-H-2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (0.95 g, 2.8 mmol) is dissolved in DMF (10 mL) and treated with chlorosulfonyl isocyanate (0.36 mL, 4.2 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)ρhenyl]-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 l-H-2-[4-(l,l-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-cyclopropylmethylindole-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,r-dioxo-lλ6-isothiazolidin-2-yl)-6-methoxy-3- oxazol-5-yl-l -propyl- lH-indole (compound 805).
Step A: 2-[4-(l,r-Dioxo-lλ6-isothiazolidm-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-
isoMazolidin-2-yl)-6-methoxy-l-propyl-lH-indole (608 mg, 60%), utilizing essentially the same procedure as example IA, Step B.
Step B: 2-[4-(l,r-Dioxo-R6-isothiazolidin-2-yl)-6-methoxy-l-propyl-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 IBQ: 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 0.5hr after the addition, followed by the addition of hexachloroethane and the mixture is then brought to room temperature slowly and stirred for 0.5hr. 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, dichlorometiαane/hexanes, 3 /2) to provide 2-chloro-l-ethyl-6-(trifluoromethyl)-lϋ-r-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) and N-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-eώyl-6-trifluoromethyl-lH-indol-2-yl)-piρerazine-l-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- l.H-indol-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester (0.26 g, 6.1 mmol) is treated with TFA (5 roL) in dichloromethane (5 mL) for lhr at room temperature. After the removal of the volatiles, the residue is treated with saturated NaHCO3 and the precipitate is collected via filtration, washed with water thoroughly and dried in air to furnish essentially pure l-ethyl-2-piperazui-l-yl-6-(trifluoromethyl)-lH'- indole-3-carbonitrile (0.20 g, 100%).
Step D: To a solution of l-ethyl-2-piperazin-l-yl-6-(trifluoromethyl)-liy-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 (dichloromethane/ethyl acetate, 9/1) to provide 2-[4-(cyclopropylsulfonyl)piperazin-l-yl]-l- ethyl-6-(trifluoromethyl)-lH"-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-lH-indol-6- yl]-amide (compound 835).
TFAJDCM
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, Λf'-dimeώylcyclohexane-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-lΛr-indol-6-yl]-carbaπiic acid tert-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- emoxyphenyl)-l-ethyl-lH-mdole-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-cyanσ-2-(4-ethoxy-phenyl)- l-emyl-l.H-indol-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-l//-indol-6-yl]- carbamic acid ethyl ester (compound 838)
EtOCOCl pyridine
6-Amino-2-(4-ethoxyphenyl)-l -ethyl- l.H-indole-3-carbonitrile (31 mg, 0.1 mmol), compound 833, prepared in example IBR3 step B is treated with ethyl chlorofoπnate (16 mg, 0.15 mmol) in pyridine (LO mL) at room temperature overnight to furnish, after purification using column chromatography, [3-cyano-2-(4-ethoxyphenyl)-l-ethyl-l/f-indol-6-yl]-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-carbonitrile (31 mg, 0.1 mmol) is treated with ethyl isocyanate (14 mg, 0.2 mmol) in dichloromethane (1.0 mL) at 400C
overnight. The precipitate is collected via filtration, washed with dichloromethane and 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-chloroethyl)-3-[4-(3-cyano-l-ethyl-6-methoxy-lH- indol-2-yl)-phenyl]-urea (compound 442).
To a solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-liy-indole-3-carbomtrile (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-lH-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, 101O5 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, 11731197,1190, 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]-lH-indoIe-3-carbonitrile (compound 771).
To a solution of l-(2-chloroethyl)-3-[4-(3-cyano-l-ethyl-6-meihoxy-lH-hidol-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 MgSO-t, 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 I- ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-l -yl)-phenyl]-lH*-indole-3-carbonitrile (56 mg, 62%). 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]-lH-indole~3-carbonitrile (compound 638).
To a solution of [4-(3-cyano- 1 -ethyl-6-isopropoxy- li?-indol-2-yl)-phenyl]-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-eftyl-6-(3-pyrrolidin-l-yl-proρoxy)-lH- indol-2-yl]-ρhenyl}-carbamic acid ethyl ester (compound 530).
Step A: To a solution of [3-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]- carbamic acid ethyl ester (1.65 g, 4.37 mmol) in DCM (20 mL) is added 1 M BBr3 in DCM (13.12 mL) over a period of 20 min. The reaction mixture is stirred further Ih 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-liy-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-chloroproane (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-pyrrolidin-l-yl-propoxy)-lH'-indol-2- yl]-phenyl} -carbamic acid ethyl ester (50 mg, 0.12 mmol) in CH3CN (2 mL) is added DIEA (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 l-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-li-T-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- lH-indol-2-yl)-phenyl]-thiourea (90% yield) as a light yellow solid.
Step B: A suspension of l-benzoyl-3-[3-(3-cyano-l-ethyl-6-methoxy-lH"-indol-2-yl)- phenylj-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 500C 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-indol-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]-lH-indole-3-carbonitrile (Compound 458)
A solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-lH-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)- phenyl]-phosρhoramidate (compound 772).
A solution of 2-(4-aminophenyl)-6-ethoxy- 1 -ethyl- lH-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- li7-mdol-2-yl)-phenyl]-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-lλ6- [l,2,5]thiadiazolidin-2-yl)-phenyl]-lH-indole-3-carbonitrile (compound 726).
Step A: To a solution of 2-(4-ammophenyl)-l-ethyl-6-memoxy-lH/-indole-3- carbonitrile (202 mg, 0.693 mmol) in pyridine (2.0 mL) 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 X 2 mL), water (2 X2 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 -¥-(2-chloro-ethyl)-iV-[4-(3-cyano-l-ethyl-6-methoxy-lH'-indol-2-yl)phenyl] sulfamide, compound 724, as a tan solid (75% yield).
In similar fashion the following compounds are prepared: Compounds 540, 541, 542, 574, 576, 704. Step B: To a solution of JV-(2-chloro-ethyl)-N5-[4-(3-cyano-l-ethyl-6-methoxy-li7- 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-(l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-2-yl)phenyl]-l-ethyl-6-methoxy-lH-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-l5l-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: Compound 727, 1110.
Example ICC: Preparation of [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-2- fluorophenylj-carbamic acid propyl ester (compound 877).
A biphasic mixture of 2-(4-ammo-3-fiuorophenyl)-l -ethyl-6-methoxy-l//-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-ethyl-6-methoxy-liy-indol-2- yl)-2-fluorophenyl]-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-amino-3-methylphenyl)-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. In similar fashion, utilizing 2-(4-amino-3 -methylphenyl)- 1 -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- l/f-indole-3 -carbonitrile, the following compounds are prepared: Compound: 966, 961.
Example CD: Preparation of cyclopropanecarboxylic acid {4-[3-cyano-l-ethyl-6-(2~ imidazol-l-yl-ethoxy)-lH-indol-2-yl]-phenyl}-amide (compound 1183).
Step A: To a solution of compound 2-(4-aminophenyl)-6-ethoxy-l -ethyl- lif-indole-3- carbonitrile (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 Na2SO4, 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)- phenyfj-amide.
Step B: To a solution of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-l -ethyl- IH- 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 becomes basic. The crude solid is collected by filtration to give 91% of cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-hydroxy-l-fiT- 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- lJFf-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 Na2SQ*, filtered and
concentrated to yield 81% of the crude cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3- cyano- 1 -ethyl- lH-indol-2-yl]-phenyl}-amJde.
Step D: To a solution of cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3-cyano- l-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, 1394, 1395, 1413, 1414.
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 J-BuONO (8.01 mL, 67.5 mmol) and CuCl2 (7.26 g, 54 mmol) in acetonitrile (50 mL), at 610C 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 rotovap 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 Na2SO4, 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 (hen stirred at 45°C overnight and poured into ice-water (700 mL), and extracted with dichloromethane (3 x 100 mL). The organics are dried over anhydrous Na2SO4 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 with Na2CO3 (2 M, 2 x 50 mL), water (2 x 50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The crude product, obtained after the removal of the solvent, is chromatographed (silica gel, DCM/ Hexanes, 1/1) to provide 6-trifiuoromethoxyindole (5.70 g, 63% based on 2-rdtro-4- trifluoromethoxyaniline).
Step B: To a solution of 6-trifluoromethoxyindole (2.68 g, 13.3 mmol) in dry DMF (10 mL) at O0C, 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 500C 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-trifluoromethoxyindole-3-carbonitrile (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 -78°C 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-aniinopheiiyl)-l-ethyl-6-trifluoromethoxyindole-3-carboriitxile (1.99 g, 72%).
Step D: To a solution of the compound obtained in step C (31 mg, 0.1 mmol) in dry pyridine (1.0 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)phenyl] 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)ρhenyl]-l-ethyl-6- (trifluoromethoxy)indole-3-carbonitrile (compound 903).
2N HCI - RT O 0C - RT
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 400C 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 Na2SO4. 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 inL, 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-6-trifluoromehoxyindole-2-boronic acid prepared above (0.74 g, 2.1 mrnol), 2-(4-iodophenyl)isothiazolidine- 1,1 -dioxide (0.76 g, 2.4 mmol), and
PdCl2(dρpf) (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- dioxidoisothiazoltdin-2-yl)phenyl]-6-trifluoromethoxyindole. Step D: At 00C, 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)phenyl]-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 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-trifluoromethoxy-l-ethylindόle-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-cyaπo-l-cyclopropyl-6-methoxyindol-2- yl)phenyl]carbamic acid isopropyl ester (compound 1234). - -NNHHHHNN- K2CO3/CUI/ O
toluene/110 °C/48h
Step A: To a suspension of 2-bromo-4-methoxyphenylacetic acid (24.5 g, 100 mmol) in DCM (100 mL), while stirring, is added DMF (~10 mL) until all the solid disappeared, 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) andiViN'-dimethylcyclohexanediamine (1.42 g, 1.57 mL, 10.0 mmol) in toluene (150 mL) is stirred at 1100C under N2 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 chromatographed (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 00C, is added DIBAL-H (1.0 M in DCM, 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 Na2SO4. 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-cyclopropyl-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-β- 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 (10 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-cycloprdpyl-6-methoxyindol-2-yl)phenyl]carbamic acid isopropyl ester (66 tag, 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)-ρhenyl]- liϊ-indole-3-carbonitrile (compound 938).
Utilizing the procedure described in Example IGb, substituting l-allyl-6-methoxy-liy- indole-3-carbonitrile (92.3 mg, 0.43 mmol) and l-(4-iodophenyl)-pyrrolidin-2-one gives 99.0 mg (61.3% yield) of compounds 938.
Example 1 CI: Preparation of 6-cyclopropoxy-2-[4-( 1 , 1 -dioxo- 1 λδ-isothiazolidin-2-yl)- phenyl]-l-ethyl-li7-indole-3-carbonitrile (compound 1046)
Step A: To a solution of 6-hydoxy-l-e&yl-lH-mdole-3-carbomtrile (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 rag, 3.29 mmol). The resulting mixture is stirred at 8O0C 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 is continued at 8O0C overnight. The mixture is partitioned between EtOAc (30 mL) and IN HCl (20 mL). The organic phase is washed with saturated NaHCθ3, 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-δ-vinyloxy-lH-indole-S-carbonitrile as a white solid.
Step B: Via a syringe, diethyl zinc is added to a mixture of l-ethyl-6-vinyloxy-liϊ'- indole-3-carbonitrile (288.1 mg, 1.36 mmol), 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 arnrnonium 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 β-cyclopropoxy-l-ethyl-lH-indole-S-carbonitrile as a yellow solid.
Step C: 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 C, above, compound 1047 is also prepared.
Example CJ: Propane- 1 -sulfonic acid [4-(3-cyano-6-difluoromethoxy-l-ethyl-lΗ- indoel-2-yl)-phenyl]-amide (compound 928).
4. K2CO3 (3M, aq.) PdCl2dppf
Step A: A solution of ό-difluoromethoxy-l-ethyl-lH-indole-S-carbonitrile (316.3 mg, 1.34 mmol) and triisopropyl borate (402.9 mg, 2.14 mmol) in THF (15 mL) is cooled to -78°C and treated with LDA (1.5 M mono-THF 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 (2M52.01 mL, 6.02 mmol) and PdCl∑dppf (51.3 mg, 0.07 mmol) are added in sequence. The mixture is degassed by three successive cycles of vacuum
pumping/N2 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-lH-indol-2-yl)-phenyl]- carbamic acid methyl ester (compound 1130).
A solution of 2-(4-aminophenyl)-6-difluoromethoxy-l-ethyl-lH-indole-3-carbonitrile (200 mg, 0.611 mmol) and methyl chloroformate (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-cyano-6-difluoromethoxy-l-ethyl-lH'-indol-2-yl)-phenyl]-3- propyl-urea (Compound 893).
A solution of 2-(4-aminophenyl)-6-difluoromedioxy-l-ethyl-lH'-indole-3-carbonitrile (200 mg, 0.611 mmol) 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 morpholuie-4-carboxylic acid [4-(3-cyano-l-cyclobutyl- 6-ethoxy-lH-indol-2-yl)-phenyl]-amide (compound 1166).
DMF
Step A: 6-E&oxy-liWndole-3-carbonitrile (2.8 g, 15 mmol), prepared as shown in example IA, step A, is combined with Cs2Cθ3 (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 800C 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/CHiCb, 50-100%) yields 1- cyclobutyl-6-ethoxy-ljf/-indole-3-carbonitrile (3.00 g, 83%) as a white solid.
Step B: Following essentially the procedure in example IGb, l-cyclobutyl-6-ethoxy- l/f-indole-3-carbonitrile (3.0 g, 12.4 mmol) is converted via Suzuki coupling to yield 2-(4- aminopheny^-l-cyclobutyl-ό-ethoxy-lH-indole-S-carbonitrile (2.60 g, 68%) as an off-white solid.
Step C: 2-(4-aminophenyl)-l-cyclobutyl-6-ethoxy-lH-indole-3-carbonitrile (40 mg, 0.12 mmol), 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), CH2Cl2 (400 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 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 (QHfeGb/EtOAc, 7/3) yields morpholine-4-carboxylic acid [4-(3-cyano-l- cyclobutyl-6-ethoxy-lH-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 rac-[4-(3-cyano-l-cyclobutyl-6-ethoxy-lHr-indol-2-yl)- phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1147).
2-(4-Aniinophenyl)-l-cyclobutyl-6-ethoxy-lH-mdole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example ICM, step B, is 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 75°C 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 rac- [4-(3-cyano-l -cyclobutyl-6-ethoxy-lH-indol-2-yl)-ρhenyl]-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, 1268, 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-lH-indole-3-carbonitrile (600 mg, 1.81 mmol), prepared as in example ICM, step B, is suspended in CH2CI2 (18 mL), and Et3N (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 NaHCOϊ solution. The organic layer is dried and concentrated to yield iV-[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: iV-[4-(3-Cyano-l -cyclobutyl-6-ethoxy-lH-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-[4-(3 -cyano- 1 -cyclobutyl-θ-ethoxy- 1 H-indol-2-yl)-phenyl]-N-el.iyl- 2,2,2 -trifluoro-acetamide and hydrolyzed l-cyclobutyl-6-ethoxy-2-(4-ethylamino-phenyl)-l/-r- 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 H2O and is extracted into CH2Cl2. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2CI2) yields pure l-cyclobutyl-6- ethoxy-2-(4-ethylaminophenyl)-lH-indole-3-carbonitrile (343 mg, 53% over two steps) as a white solid. l-Cyclobutyl-2-(4-diethylamino-phenyl)-6-ethoxy-lH"-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-emoxy-2-(4-emylaminophenyl)-liif-indole-3-carboriitrile (35 mg, 0.10 mrαol), prepared as in example ICO, step C, is dissolved in pyridine (300 μL). Cyclopentyl chlorofoπnate (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-β-ethoxy-lif-indol^-y^-phenyy-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)-lH-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1255).
Step A: To a solution ^-(S-cyano-l-cyclobutyl-δ-methoxy-lH-indol^-y^-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 [4-(3-cyano-l-cyclobutyl -6- hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (650 mg, 71%).
Step B: To a solution of [4-(3-cyano-l-cyclobutyl -ό-hydroxy-l/f-indol^-ylj-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-li-T-indol-2- . yl] -phenyl} -carbamic acid isopropyl ester (37 mg, 0.08 mmol) in CH3CN (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)-liy-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, 1427, 1430.
Example ICR: Preparation of {4-[3-cyano-l-cyclobutyl-6-(2-[l,2,4]triazol-l-yl- ethoxy)-l/7-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1276).
Step A: To a solution of [4-(3-cyano-l-cyclobutyl -6-hydroxy-lH-indol-2-yl)-phenyl]- carbamic acid isopropyl ester (390 mg, 1.0 mmol) in CKfeCN (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 CΗ3CN (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)-liϊ-indol-2- yl]-phenyl} -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, 1434, 1435.
Example ICS: Preparation of {4-[3-cyano-l-cycIobutyI-6-(2-[l,2,4]triazol-l-yl- ethoxy)-lH"-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (compound 1329).
Step A: To a solution 2-(4-ammophenyl)-l-cyclobutyl-6-hydroxy-lH-indole~3- carbσnitrile (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-indoI-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (996 mg, 80%).
Step B: To a solution of ^-(S-cyano-l-cyclobutyl-β-hydroxy-lΗ-indol^-yO-phenyl]- carbamic acid 1-cyclopropyl-ethyl ester (1.5 g, 3.61 mmol) in CΗ3CN (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 CΗ3CN (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)-lH-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)-lH-indol-2-yl]-phenyl}-3-isopropyl-urea (compound 1314).
Step A: To a solution of l-[4-(3-cyano-l-cyclobutyl-6-methoxy-l/7-indol-2-yl)- phenyl]-3-isopropyl-urea (2.21 g, 5.49 mmol in CH2CI2 (30 mL) is added a IM solution of BBr3 in CH2CI2 (16.5 mL, 16.5 mmol) at 00C. The mixture is allowed to warm to room temperature and kept for Ih. The reaction mixture is then poured onto ice and aqeous IM NaHCθ3 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-ό-hydroxy-lH-'indol^-ylJ-phenyy-S-isopropyl-urea, as a tan solid.
Step B: To a solution of l-^-Q-cyano-l-cyclobutyl-β-hydroxy-lH-indol^-yty-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 8O0C, 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 OfH2O, 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 1 - {4-[6-(3-chloropropoxy)- S-cyano-l-cyclobutyl-l/T-indol^-ylJ-phenylJ-S-isopropyl-urea as a tan powder.
Step C: To a solution of 1- {4-[6-(3-chloropropoxy)-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 6O0C, 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 mL of 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- propoxy)-lH-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 1 -ethyl- l'-methanesulfonyl-ό-methoxy- IH, I1H- [2,51]biindolyl-3-carbonitrile (compound 1330).
. A solution of l-ethyl-6-methoxy-lH,l'H-[2J5']biindolyl-3-carbonitrile (70 mg, 0.22 mmol), prepared as described in Example IGb, in pyridine (2 mL) is treated with methanesulfonyl chloride (0.034 mL, 0.44 mmol) and stirred overnight. The reaction mixture is then diluted with H^O 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 (30-80%) to afford 70 mg (81%) of 1 -ethyl- r-methanesulfonyl-6- methoxy-lH,l'H-[2,5']biindolyl-3-carbonitrile as a tan solid.
Using the same procedure as above and substituting the appropriate ethanesulfonyl chloride gives the following compound: Compound 1331.
Example ICV: Preparation of 3-cyano-l-emyl-2-[4-(ρropane-l-sulfonylamino)- phenyl]-lH-indole-6-carboxylic acid diethylamide (compound 1360).
Step A: 3-Cyano- 1 -ethyl-2-[4-(propane- 1 -sulfonylamino)-phenyl]- lH-indole-6- carboxylic acid methyl ester (1.25g, 3.04 mmol), prepared by the method described in example IY from methyl 2-(4-aminophenyl)-3-cyano-l-ethyl-lH-indole-6-carboxylate, is treated with 0.5N KOH (30 mL, 15.2 mmol) and heated at reflux for 2.5h. After cooling to room temperature, the aqueous phase is acidified with 3N HCl to pH 2 and the resultant precipitate is filtered, washed with water (2X) and dried until constant weight to afford 1.15 g (96%) of 3- cyano-l-ethyl-2-[4-(propane-l-sulfonylamino)-phenyl]-liϊ-indole-6-carboxylic acid as a white solid.
Step B: To a sample of PS-HOBt resin (2.84g, 1.02 mmol/g loading) is added a solution of DMAP in DCM (0.045M, 39 mL) followed by a solution of 3-cyano-l-ethyl-2-[4-(propane- l-sulfonylaminoj-phenylj-l/f-indole-θ-carboxylic acid in DMF (0.38M, 7.5 mL). This mixture is stirred for 15 min., then a solution of diisopropylcarbodiimide in DCM (1.65M5 7.9 mL) is added and the reaction mixture is stirred for 18h at room temperature. The resin is filtered and washed with DMF (3X50 mL), DCM (3X50 mL) and THF (3X50 mL) and then dried under vacuum for 4h to afford 4.1 g of active ester resin. The loading of this resin is determined by combining a small aliquot of the active ester resin with benzyl amine in CDCl3 directly in NMR tube, shaking the resultant mixture at room temperature overnight, and then comparing the integration of protons of unreacted benzyl amine with the protons of resultant amide.
Step C: The above active ester resin (400 mg, 0.551 mmol/g loading), DIEA (0.036 mL, 0.22 mmol) and THF (3 mL) are combined and diethylamine (0.03 mL, 0.15 mmol) is added to the mixture. The tube is sealed and the reaction mixture is shaken overnight. The resin is
filtered, washed with THF (2X5 mL), DCM (2X5 mL) and the combined organic fractions are concentrated. The crude product is purified by preparative HPLC to afford 50 mg (71% yield) of 3-cyano-l-ethyl-2-[4-(propane-l-sulfonylamino)-phenyl]-lH-indole-6-carboxylic acid diethylamide.
The following compounds are prepared utilizing the above procedure with substitution of the appropriate amine: Compounds 1361, 1362, 1363, 1364.
Example ICW: Preparation of isopropyl-methyl-carbamic acid4-(3-cyano-l-ethyl-6- methoxy-lif-indol-2-yl)-phenyl ester (compound 1349).
Step A: To a solution of l-ethyl-ό-methoxy-l/f-indole-S-carbonitrile (2.5 g, 12.5 rnmol) in 21 mL of THF is added LDA (23 mL, 22.5 mmol) at -78°C. After warming to 00C and stirring for 10 min, the mixture is re-cooled to -780C and B(O-1Pr)3 (4.35mL, 18.8 mmol) is added. After the addition, the reaction is allowed to warm to room temperature and stirred for about Ih. 4-iodophenol (2.89 g, 13.1 mmol), PdCl2(dppf) (510 mg, 0.625 mmol), aqueous K2CO3 (25 mL, 50 mmol) and DMF (42 mL) is added and the reaction mixture is stirred at room temperature overnight. The organic solvent is evaporated under reduced pressure. The residue is washed with water and the mixture is filtered. The filtrate is concentrated to afford crude solid which is purified via column chromatography on silica gel using EtOAc/petrolum ether (1/5 to 2/1) as eluant to yield 73% of l-ethyl-2-(4-hydroxyphenyl)-6-methoxy-lH-indole- 3-carbonitrile.
Step B: To a solution of l-ethyl-2-(4-hydroxyphenyl)-6-methoxy-lH-indole-3- carbonitrile (58 mg, 0.2 mmol) in 4 mL OfEt3N and CH2Gb (1/1) is added p-nitrophenyl chloroformate (100 mg, 0.5 mmol) at room temperature. After the mixture is stirred for about Ih, N-isopropyhnethylamine (0.062 mL, 0.6 mmol) is added. The mixture is stirred for 3h and then water and ethyl acetate are added to the reaction mixture. The organic layer is separated, washed with aqueous HCl (IN) and brine, dried over anhydrous Na2SQ*, and filtered and
concentrated- The crude solid is purified by preparative HPLC to afford 70% of isopropyl- methyl-carbamic acid 4-(3-cyano-l-ethyl-6-methoxy-lH'-indol-2-yl)-phenyl ester.
The following compounds are prepared utilizing the above procedure with substitution of the appropriate amines: Compounds 1348, 1350, 1351,1385.
Example ICX: Preparation of N-{4-[3-cyano-6-difluoromethoxy-l-(tetrahydro-furan-2- ylmethyl)-lΗ-idole-2-yl]-phenyl}-methanesulfonamide (compound 1334).
aq.) PdCI2dppf
Step A: Utilizing the procedure described in Example IA (Step B) substituting iodo ethane with 2-bromomethyl tetrahydrofuran affords 6-difluromethoxy-l-(tetrahydrofuran-2- ylmethyl)-lH-indole-3-carbonitrile.
Step B: A solution of 6~difluoromethoxy-l-e&yl-liϊ-mdole-3-carbomtrile (516.2 mg,
1.77 mmol) and tri-isopropyl borate (532.7 mg, 2.83 mmol) in THF (15 mL) is cooled to -78°C and treated with LDA (1.5 M mono-THF in cyclohexane, 1.43 ml, 2.04 mmol). After the addition, the acetone/dry ice bath is exchanged for 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 (390.2 mg,
1.78 mmol) in DMF (8 mL), K2CO3 (2M, 2.7 ml, 5.31 mmol) and PdChdppf (67.4 mg, 0.09 mmol) are added in sequence. The mixture is degassed by three successive cycles of vacuum pumping/TSt purging and is stirred overnight (ca. 16h), after which it 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, 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 367.5 mg (55.0% yield) of 2-(4-aminophenyl)-6-difluoromethoxy-l-(tetrahydrofuran-2- ylmethyl)- lH-indole-3-carbonitrile as a white solid.
Step C: Utilizing the same procedure described in Example IY gives the title compound, N- {4-[3-cyano-6-difluoromethoxy- 1 -(tetrahydro-furan-2-ylmethyl)- 1 H-idole-2-yl]- phenyl}-methanesulfonamide (compound 1334).
The following compounds are made using essentially the same procedure and substituting other sulfonyl chlorides: Compounds 1335, 1336.
Example ICY: Preparation of l-cyclobutyl-6-ethoxy-2-[4-(2-oxo-[l,3]oxazinan-3-yl)- phenyl]-l//-indole-3-carbonitrile (compound 1346).
Step A: To a suspension of 2-(4-ammophenyl)-l-cyclobutyl-6-ethoxy-lHr-indole-3- carbonitrile (50.0 mg, 0.15 mmol), K2CO3 (2N5 0.45 mL, 0.45 mmol) and 5 mL of ethyl acetate is added 3-chloropropylchlorofromate (35.6 mg, 0.23 mmol). The resulting mixture is stirred at room temperature until complete consumption of the starting material as determined by TLC. The phases are separated and the organic phase is washed by saturated NaCl, dried over MgSO4 and concentrated. The residual oil is crystallized from diethyl ether/ hexanes to afford [4-(3-cyano-l-cyclobutyl-6-ethoxy-l/f-indole-2-yl)-phenyl]-carbamic acid 3-chloro-propyl ester as a white solid.
Step B: To a solution of ^-(S-cyano-l-cyclobutyl-δ-ethoxy-liϊ-indole^-yO-phenyl]- carbamic acid 3-chloro-ρropyl ester in 5 mL of DMF is added anhydrous K2CO3. The resulting mixture is stirred at 8O0C until complete consumption of the starting material is determined by TLC. After cooling, 10 mL of water is added to the reaction mixture to afford a solid precipitation which is collected by filtration, followed by washing with ether. The desired 1- cyclobutyl-6-ethoxy-2-[4-(2-oxo-[ 1 ,3]oxazinan-3 -yl)-phenyl]- lH-indole-3-carbonitrile is obtained as a white powder (76.2 mg, 91.8% yield).
Example ICZ: Preparation of {4-[3-cyano-l-cyclobutyl-6-(2-meihoxy-ethoxy)-liyr- indole-2-yl]-phenyl}-carbamic acid ethyl ester (compound 1397).
C
4. K2CO3 (3M, aq.) PdCI2dppf
Step A: Utilizing the same procedure described in Example ICW (Step B) gives 2-(A- aminophenyl)- 1 -cyclobutyl-ό-methoxy- lH-indole-3-carbonitrile.
Step B: Utilizing the procedure described in Example IB (Step A) gives 2-(4- aminophenyl)-l -cyclobutyl-β-hydoxy-lH-indole-S-carbonitrile.
Step C: To a suspension of 2-(4-ammophenyl)-l-cyclobutyl-6-hydoxy-lH-indole-3- carbonitrile (519.2 mg, 1.71 mmol), K2CO3, 10 mL of methyl ethyl ketone, and 2 mL of DMF is added 2-bromoethyl methyl ether. The resulting mixture is stirred at 85°C for 8h. The mixture is concentrated and the residue is partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase is extracted with additional ethyl acetate (20 mL). The combined organic phases are washed with saturated NaCl, dried over MgSO4, and then the solution is concentrated and the product is washed with diethyl ether to afford 505.0 mg (81.7% yield) of 2-(4-aminophenyl)-l-cyclobutyl-6-(2-methoxy-ethoxy)-lΗ-indole-3-carbonitrile as a yellow solid.
Step D: Utilizing the same procedure described in Example IAJ gives the desired title compound, {4-[3-cyano-l-cyclobutyl-6-(2-methoxy-ethoxy)— lH-indole-2-yl]-phenyl}- carbamic acid ethyl ester (compound 1397) as a white solid.
Ih similar fashion, following steps A to D above, the following compounds are prepared: Compounds 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1398, 1399, 1400, 1401, 1402, 1407, 1431.
In similar fashion, substituting the procedure described in example IBU for step D above, gives the following urea derivatives: Compounds 1403, 1404, 1405, 1406, 1412.
Example IDA: Preparation of [4-(3-cyano-l-cyclobutyl-6-(2-methoxyethoxy)-lH- indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1423).
To a solution of 2-(4-aminophenyl)-l-cyclobutyl-6-(2-methoxy-ethoxy)-lH-indόle-3- • carbom'trile (76.0 mg, 0.21 mmol), pyridine (36.5 mg, 0.46 mmol) in 10 mL of 1,1 dichloroethane is added 4-nitrophenyl chloroformate (93.2 mg, 0.46 mmol). The resulting mixture is stirred at room temperature for 2h. Then α-methylcyclopropane methanol (54.3 mg, 0.63 mmol) is added. The reaction mixture is heated to 700C for 5h. After cooling, the reaction is partitioned between ethyl acetate (10 mL) and saturated K2CO3 (10 mL). The organic phase is washed with additional saturated K2CO3 (2 x 10 mL), water, and saturated NaCl. The colorless solution is dried over MgSO4, filtered and evaporated. The remaining solid is washed with diethyl ether to yield the title compound, of [4-(3-cyano-l-cyclobutyl-6- (2-methoxyethoxy)-lH:-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1423) as a white solid.
Example IDB: Preparation of 4-[3-cyano-2-(4-ethoxyphenyl)-l-ethylindol-6- yl]piperazine-l-carboxylic acid tert-bntyl ester (compound 1337).
Pd2(CIbS)3ZBlNAP
Naθ''Bu/toIuene
80 0C
Step A: 6-Bromo-2-(4-ethoxyphenyl)-l-ethyl-indole-3-carbonitrile (0.37 g, 1.0 mmol), prepared from 6-bromoindole using the procedure described in example IGb, is mixed with NaO 'T3u (0.13 g, 1.4 mmol), Pd2(dba)3 (0.009 g, 0.01 mmol), BINAP (0.019 g, 0.03 mmol), I-
Boc-piperazine (0.22 g, 1.2 mmol) and dry toluene (3.0 mL). The mixture is stirred at 8O0C for 6h. After cooling, the solvent is replaced with dichloromethaαe and chromatographed (silica gel, DCM/EtOAc, 9.5/0.5) to provide 4-[3-cyano-2-(4-ethoxyphenyl)-l-ethylindol-6- yl]piperazine-l-carboxylic acid (erf-butyl ester (0.41 g, 86%).
Compound 1338 is prepared in the same fashion as described above.
Example IDC: Preparation of {N-{4-[3-cyano-l-ethyl-6-(4-methylpiperazin-l-yl)- indol-2-yl]phenyl}propionamide (compound 1341).
F/-780 C
pyridine
Step A: ό-chloro-l-ethylindole-S-carbonitrile (1.02 g, 5.0 mmol), prepared from 6- chloroindole using the procedures described in example IA, is mixed with K3PO4 (1.48 g, 7.0 mmol), Pd2(dba)3 (0.11 g, 0.12 mmol), biphenyl-2-yldicyclohexylphosphane (0.17 g, 0.48 mmol), 1-methylpiperazine (0.60 g, 0.67 mL 6.0 mmol) and dry DME (10.0 mL). The mixture is stirred at 1000C overnight. After cooling, the solvent is replaced with dichloromethane and chromatographed (silica gel, DCM, then EtOAc, finally DCM/MeOH, 9/1) to provide 1-ethyl- 6-(4-methylpiperazin- 1 -yl)indole-3-carbonitrile (0.96 g, 72%).
Step B: To a solution of l-ethyl-6-(4-methylpiperazin-l-yl)indole-3-carbonitrile (0.81 g, 3.0 mmol) obtained above and triisopropylborate (0.81 g, 0.99 mL, 4.50 mmol) in dry THF (5 mL) at -78°C is added LDA (2.5 mL, 1.5 M, 3.75 mmol). The mixture is stirred at -78°C for 15 min after the addition, then slowly brought to room temperature and stirred for an additional 30 min. The reaction is then cooled to -78°C followed by the addition of 4- iodoaniline (0.78 g, 3.6 mmol), PdCl2(dppf) (0.11 g, 0.15 mmol), DMF (10 mL) and K2CO3 (4.5 mL, 2.0 M, 9.0 mmol). The mixture is brought to room temperature slowly and stirred overnight and then poured into ice-water (200 mL). The precipitate is collected and washed with water, chromatographed (silica gel, EtOAc/DCM/Et3N, 6/4/0.02) to furnish 2-(4- aminophenyl)-l-ethyl-6-(4-methylpiperazin-l-yl)indole-3-carbonitrile (0.90 g, 83%).
Step C: To a solution of the compound obtained in step B (54 mg, 0.15 mmol) in dry pyridine (1.5 mL) is added propionyl chloride (26 μL, 0.30 mmol). The mixture is stirred at room temperature overnight and the solvent is removed in vacuo. The residue is dissolved with DCM (5 mL) and washed with water (2 x 4 mL) and chromatographed (silica gel, MeOH/DCM, 0.5/9.5) to provide product, {N-{4-[3-cyano-l-ethyl-6-(4-methylpiperazin-l- yl)indol-2-yl]phenyl}propionamide (45 mg, 73%).
Compounds 1339 and 1340 are prepared by utilizing the above procedure using ethyl chloroformate and cyclopropane carbonylchloride.
Example IDD: Preparation of {4-[3-cyano-l-cyclopropyl-6-(2-methoxyethoxy)indol-2- yl]phenyl} carbamic acid 1-cyclopropylethyl ester (compound 1436).
Step A: To a solution of 2-(4-aminophenyl)-l-cyclopropyl-6-methoxyindole-3- carbonitrile (2.02 g, 6.7 mmol), prepared in example ICG, step E, in dry DCM (30 mL), at — 3O0C, is added boron tribromide (8.35 g, 3.15 mL, 33.3 mmol). The mixture is stirred at -300C — 15°C for 1.5h and then brought to ambient temperature and stirred for 15 mm. The mixture is poured into saturated NaHCU3 and ice and stirred for Ih. The volatiles are removed on a rotovap and the precipitate is collected via filtration and washed with water and then dried under a stream of N2 to provide 2-(4-aminophenyl)-l-cyclopropyl-6-hydroxyindole-3- carbonitrile in quantitative yield. Step B: The intermediate obtained above (0.29 g, 1.0 mmol) is mixed with CS2CO3
(0.98 g, 3.0 mmol), 2-methoxyethyl bromide (0.21 g, 0.14 mL, 1.5 mmol) and acetonitrile (5 mL) and the mixture is stirred at 85°C overnight. The solvent is removed in vacuum and the
residue is treated with DCM and chromatographed (silica gel, DCM/EtOAc, 9/1) to provide 2- (4-aminophenyl)-l-cyclopropyl-6-(2-methoxyethoxy)indole-3-carbonitrile (0.16 g, 46%).
Step C: A mixture of 2-(4-aminophenyl)-l-cyclopropyl-6-(2-memoxyemoxy)indole-3- carbonitrile (35 mg, 0.1 mmol), 4-nitrophenylchloroformate (50 mg, 0.25 mmol) in pyridine (2.0 mL) is stirred at 35°C for 2h, followed by the addition of 1-cyclopropylethanol (98 μL, 1.0 mmol). The mixture is then stirred at 600C overnight and diluted with water (10 mL) and DCM (5 mL). The organic is washed with water (3 x 5 mL), HCl (2N, 3 x 5 mL), saturated NaHCO3 (3 x 5 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the title compound, {4-[3-cyano- 1 -cyclopropyl-6-(2-methoxyethoxy)indol-2-yl] phenyl} carbamic acid 1 -cyclopropylethyl ester (22 mg, 48%).
Compounds 1437, 1438 and 1439 are prepared by utilizing the above chemistry.
Example IDE: Preparation of {4-[3-cyano-l-cyclopropyl-6-(tetrahydrofuran-2-yloxy)- 2-yl]-phenyl} carbamic acid 1-cyclopropylethyl ester (compound 1444).
Acetonitrile/ 80 °C
h pyridine/60 °C/3 h
Step A: 2-(4-aminophenyl)-l-cyclopropyl-6-hydroxyindole-3-carbonitrile (0.29 g, 1.0 mmol), prepared in example IDD, step A, is mixed with K2CO3 (0.35 g, 2.5 mmol), toluene-4- sulfonic acid tetrahydrofuran-2-yl ester (0.36 g, 1.5 mmol) and acetonitrile (5 mL) and the mixture is stirred at 8O0C overnight. The solvent is removed in vacuum and the residue is treated with DCM and chromatographed (silica gel, DCM/EtOAc, 9/1) to provide 2-(4- aminophenyl)-l-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indole-3-carbonitrile (0.27 g, 75%).
Step B: A mixture of 2-(4-aminophenyl)-l-cyclopropyl-6-(tetrahydrofuran-2- yloxy)mdole-3~carbonitrile (36 mg, 0.1 mmol), 4-m'trophenylchloroformate (50 mg, 0.25 mmol) in pyridine (2.0 mL) is stirred at 35°C for 2h, followed by the addition of 1- cyclopropylethanol (98 μL, 1.0 mmol). The mixture is then stirred at 6O0C overnight and diluted with water (10 mL) and DCM (5 mL). The organic is washed with water (3 x 5 mL),
HCl (2N, 3 x 5 mL), saturated NaHCO3 (3 x 5 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the title compound, {4-[3-cyano-l-cyclopropyl-6- (tetrahydrofuran-2-yloxy)indol-2-yl]ph.enyl}carbamic acid 1-cyclopropylethyl ester (32 mg,
In similar fashion, the following compounds are prepared following the procedure described above: Compounds 1445, 1446, 1447, 1448, 1449, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461.
Example IDF: Preparation of 4-Methyl-piperidine-l-carboxylic acid {4-[3-cyano-l- cyclobutyl-6-(2-methoxy-ethoxy)-lH-indol-2-yl]-phenyl}-amide (compound 1377).
Step A: To a solution 2-(4-aminophenyl)-l-cyclobutyl-6-(2-methoxyethoxy)-l/f- indole-3-carbonitrile (530 mg, 1.58 mmol) in EtOAc (10 mL) is added 2M aqueous K2CO3 (556 uL, 5.9 mmol) and 4-methoxyphenyl chlorofoimate over a period of 5 min. The reaction mixture is stirred further for 3h at room temperature. The reaction mixture is diluted with EtOAc (20 mL) and then washed with water (5 mL). The solvents are removed under reduced pressure and the residue is dissolved in EtOAc and then triturated with hexane. The precipitate is collected by filtration and washed with 50% EtOAc/hexane and dried in vacuo to afford {4- [3-cyano-l -cyclobutyl-6-(2-methoxy-ethoxy)-liϊ-indol-2-yl]-phenyl}-carbainic acid 4- methoxy-phenyl ester (761 mg, 98%). Step B: To a solution of {4-[3-cyano-l-cyclobutyl-6-(2-methoxy-ethoxy)-l/-'-indol-2- yl]-phenyl}-carbamic acid 4-methoxy-phenyl ester (40 mg, 0.082 mmol) in DCM (4 mL) is added 4-methylpiperidine (0.16 mmole) and the reaction is stirred for 18h at reflux temperature. The solvent is removed under reduced pressure. The residue is dissolved in EtOAc and then triturated with hexane. The precipitate is collected by filtration and washed with 50% EtOAc/hexane and dried in vacuo to afford 4-methyl-piperidine-l-carboxylic acid
{4-[3-cyano-l-cyclobutyl-6-(2-methoxyethoxy)-lH-indol-2-yl]-phenyl} -amide, compound 1377, (26 mg, 68%).
The following compounds are made in similar fashion following steps A and B, above: Compounds 1378, 1379, 1380, 1381, 1382, 1383, 1384.
Example IDG: Preparation of {4-[3-Cyano-l-cyclobutyl-6-(2-hydroxy-3-[l,2,4]triazol- l-yl-propoxy)-lH-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1420).
Step A: To a solution of [4-(3-cyano-l-cyciobutyl -6-hydroxy-l/f-indol-2-yl)-phenyI)- carbamic acid isopropyl ester (1.0 g, 2.57 mmol) in DMF (10 mL) is added K2CO3 (710 mg, 5.13 mmole) and epibromohydrin (436 uL, 5.13 mmole) and the reaction is stirred for 42h at ambient temperature. 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 960 mg, 84% of the desired product.
Step B: To a solution of ^-(S-cyano-l-cyclobutyl-β-oxiranylmethoxy-lH-indol-l-yl)- phenyl]-carbamic acid isopropyl ester (40 mg, 0.09 mmole) in DMF (1 mL) is added the sodium salt of 1 ,2,4-triazole (30 mg). The resulting mixture is stirred at 6O0C 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 1/1 ethyl acetate/hexane and dried in vacuo to afford {4-[3-cyano-l-cyclobutyl-6-(2-hydroxy-3-[l>2,4]triazol-l-yl-propoxy)-lH- indol-2-yl] -phenyl} -carbamic acid isopropyl ester, compound 1420, (29 mg, 63%).
The following compounds are made in similar fashion following steps A and B, above: Compounds 1418, 1419.
Following the chemistry described above the urea derivative, compound 1421 is prepared similarly.
Example IDH: Preparation of {4-[3-cyano-l-cyclobutyl-6-(3,4-dihydroxy-butoxy)-lJy- indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1429).
Step A: To a solution of [4-(3-cyano-l-cyclobutyl -6-hydroxy-lH-indol-2-yl)-phenyl]- carbamic acid isopropyl ester (100 mg, 0.26 mmol) in DMF (3 roL) is added K2CO3 (43.2 mg, 0.312 mmole) and 4-nitrobenzenesulfonic acid 2-(2,2-dimethyl-[l,3]dioxolan-4-yl)-ethyl ester (129 mg, 0.39 mmole) and the reaction is stirred for 18h at ambient temperature. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with EtOAc/hexane and dried in vacuo to afford 96 mg, 84% of the desired product, (4-{3- cyano-1 -cyclobutyl-6-[2-(2,2-dimethyl-[ 1 ,3]dioxolan-4-yl)-ethoxy]- lH-indol-2-yl} -phenyl)- carbamic acid isopropyl ester, compound 1428.
Step B: To a solution of (4-{3-cyano-l-cyclobutyl-6-[2-(2,2-dimethyl-[l,3]dioxolan-4- yl)-emoxy]-127~indol-2-yl}-phenyl)-carbamic acid isopropyl ester (70 mg, 0.135 mmole) in DCM (2 mL) is added TFA (10 uL). The resulting mixture is stirred at ambient temperature for 2h. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-l-cyclobutyl-6-(3,4- dihydroxy-butoxy)-l/f-indol-2-yl]-phenyl} -carbamic acid isopropyl ester, compound 1429, 45 mg, (70%).
W
Example IDI: Preparation of l-[4-(3-cyano-l-cyclobutyl-6-ethoxy-lH'-indol-2-yl)- phenyl]-3-(2-hydroxy-ethyl)-urea (compound 1408).
2-(4-Aminophenyl)-l-cyclobutyl-6-ethoxy-lH-indole-3-carbonitrile (40 mg, 0.12 mmol), prepared as in example ICM, step B, is combined with 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), CΗ2CI2 (400 μL), and pyridine (25 μL, 0.31 mmol). This suspension is stirred at room temperature for 1 hour. Ethanolamine (42 μL, 0.70 mmol) is added. After stirring at room temperature for an additional 30 min, the reaction mixture is diluted in CH2CI2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer is dried and concentrated. Purification by silica gel chromatography (CEkCVAcetone, 7/3) yields l-[4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-3-(2-hydroxy-ethyl)- urea (40 mg, 80%) as a white solid.
The following compounds are prepared in a similar fashion, using the appropriate amine and aniline coupling partner: Compounds 1375, 1390, 1391, 1392, 1396, 1409, 1440, and 1441.
Example IDJ: Preparation of [4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)- phenyl]- carbamic acid 2-(2-methoxyethoxy)-ethyl ester (compound 1424).
2-(4-Aminophenyl)-l-cyclobutyl-6-ethoxy-lH"-indole-3-carbonitrile (40 mg, 0.12 mmol), prepared as in example ICM, step B, is combined with 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), DCE (0.4 mL), and pyridine (25 μL, 0.31 mmol). This suspension is stirred at room temperature for Ih. 2-(2-methoxyethoxy)ethanol (150 μL, 1.25 mmol) is added. This mixture is heated at 800C overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields [4- (3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-carbamic acid 2-(2-methoxy-ethoxy)- ethyl ester (51 mg, 89%) as a white solid. The following compounds are prepared in a similar fashion, using the appropriate alcohol: Compoundsl416, 1426, 1432.
Example IDK: Preparation of l-[4-(3-cyano-l-cyclobutyl-6-ethoxy-liy-indol-2-yl)- phenyl]-3-cyclopenyl-l-ethyl-urea (compound 1425).
1 -Cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-lH-indole-3-carbonitrile, prepared in example ICO, step C, (35 mg, 0.10 mmol) is dissolved in pyridine (300 μL). Cyclopentyl isocyanate (130 μL, 1.08 mmol) is added. The reaction mixture is heated at 1100C for 2h. The reaction mixture is then partitioned between aqueous HCl and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography using hexanes/EtOAc (6/4) followed by a second chromatography using CHiCVEtOAc (95/5) is required to remove the dicyclopentyl urea impurity, affording pure l-^-P-cyano-l-cyclobutyl-δ-emoxy-lH'-indol^- yl)-phenyl] -3 -cyclopenyl-1 -ethyl-urea (39 mg, 82%) as an off-white solid.
Example IDL: Preparation of l-cyclobutyl-6-ethoxy-2-[4-(2-pyridin-2-yl-ethylamino)- phenyl]-lϋf-indole-3-carbonitrile (compound 1433).
2-(4-Aminophenyl)-l -cyclobutyl-β-ethoxy-lH-indole-S-carbonitrile (40 mg, 0.12 mmol), prepared as in example ICM, step B, is combined with 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), DCE (0.4 mL), and pyridine (25 μL, 0.31 mmol). This suspension is stirred at room temperature for Ih. 2-(2-methoxyethoxy)ethanol (150 μL, 1.25 mmol) is added. This mixture is heated at 75°C overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2ZEtO Ac, 4/1), followed by trituration with hexanes/acetone (2/1) yields 1 -cyclobutyl-6-ethoxy-2-[4-(2- pyridin-2-yl-ethylamino)-phenyl]-lH-indole-3-carbonitrile (23 mg, 42%) as a white solid.
Example IDM: Preparation of 2-(2-Diethylaminobenzothiazol-6-yl)-l-ethyl-6- methoxy-lH-indole-3-carbonitrile (compound 1343).
Step A: tert-butyl 6-methoxy-lJΪ-indole-l-carboxylate, from example IBO, (2.5Og, 8.6 mmol) is dissolved in anhydrous dimethoxyethane (21.5 mL). To the solution is added 2- chloro-6-iodobenzothiazole (2.42g, 8.2 mmol), cesium fluoride (2.53 g, 16.7 mmol) and PdCl2(PPh3)2 (0.23 g, 0.33 mmol). The reaction mixture is heated at reflux. After 17h the reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (4 x 20 mL). The extract is washed with saturated aqueous NaHCC>3 (20 mL), dried over MgSO4 and concentrated under vacuum to give /erf-butyl 2-(2-chlorobenzothiazol- 6-yl)-6-methoxy-indole-l-carboxylate (2.95g, 83%) as a hard foam.
Step B: The above Boc indole (2.87g, 6.9 mmol) is dissolved in anhydrous CH2Cl2 (13 mL). To the solution is added trifluoroacetic acid (3.0 mL, 38.9 mmol) at room temperature. The reaction mixture is stirred at room temperature for 17h. Water (20 mL) is added and the mixture is extracted with CH2Cl2 (3 x 10 mL). The extract is washed with water (1 x 15 mL), saturated aqueous NaHCO3 (20 mL), dried over MgSO4 and concentrated using a rotary evaporator to give the crude product. The product is purified by silica gel chromatography (1- 50% ethyl acetate/hexane) to give 2-chloro-6-(-methoxy-lH-indol-2-yl)-benzothiazole (0.4Og, 18%). Step C: The above indole is dissolved in anhydrous DMF (3.0 mL) and cooled in an ice bath. Chlorosulfonyl isocyanate (0.12 mL, 1.4 mol) is added and the mixture stirred for 2h in an ice bath. Water (15 mL) is added and the mixture stirred at room temperature for 30
minutes. The precipitate is filtered, washed with water and dried to give 2-(2- chlorobenzothiazol-6-yl)-6-methoxy-lH'- indole-3-carbonitrile (0.39 g, 95%).
Step D: The above indole (373 mg, 1.1 mmol) is dissolved in anhydrous DMF (2.2 mL) and stirred at room temperature as iodoethane (0.2Og, 1.3 mmol) and potassium carbonate (0.3 Ig, 2.2 mmol) are added. The mixture is stirred at 500C for 22h. The mixture is diluted with water (15 mL) and stirred at room temperature for 15 minutes. The solid is filtered, washed with water and dried to give 2-(2-chlorobenzothiazol-6-yl)-l-ethyl-6-methoxy-lH'- indole-3-carbonitrile (0.39g, 96%).
Step E: The above indole (46mg, 0.13 mmol) is dissolved in 15% water/isopropyl alcohol (1.5 mL). Diethyl amine (25 mg, 0.34 mmol) is added followed by sodium bicarbonate (43 mg, 0.51 mmol). The reaction mixture is heated at reflux for 21 hours. The reaction mixture is cooled to room temperature, and diluted with water (5 mL). The precipitate is filtered, washed with water and dried to give 2-(2-diethylaminobenzothiazol-6-yl)-l-ethyl-6- methoxy-lH"- indole-3-carbonitrile (40 mg, 79%).
Example IDN: Preparation of Ethanesulfonic acid [4-(3-cyano-6-diethylaminomethyl- l-ethyl-liy-indol-2-yl)-phenyl]-amide (compound 1352).
DMF / H2O
Step A: A solution of methyl 3-cyano-l-ethyl-lH'-indole-6-carboxylate (4.1 Ig, 18.0 mmol), prepared by the method described in example IA from methyl lH-indole-6- carboxylate, in anhydrous TKF (36 mL) is cooled in a dry ice/ether bath. Lithium diisopropylamide (1.5 M solution in cyclohexane, 14.4 mL, 21.6 mmol) is added at a rate to keep the reaction temperature below -600C. After the addition, the reaction mixture is stirred at
-600C for 30 minutes. Trimethylborate (3.1 mL, 27.8 mmoϊ) is added to the reaction and the mixture is stirred at -60°C for 30 minutes. The reaction mixture is allowed to warm to room temperature and DMF (60 mL), 4-iodoaniline (4.0Og3 18.3 mmol), PdCl2(dppf) (735 mg, 0.90 mmol) and aqueous K2CO3 (2M, 36 mL) are added. The mixture is stirred at 400C for 17h. The mixture is cooled to room temperature and concentrated to remove THF. Water is added to a volume of 500 mL and the mixture is extracted with ethyl acetate (3 x 50 mL). The extract is washed with water (3 x 50 mL), dried over MgSO4 and concentrated to give the product as a semi-solid. The product is crystallized from ethyl acetate to give methyl 2-(4-aminophenyl)-3- cyano-l~ethyl~lH-mdole-6-carboxylate (2.53g, 44%) as a tan solid. Step B: The indole product from above (1.26g, 3.95mmol) is dissolved in anhydrous pyridine (6 mL). To the solution is added ethanesulfonyl chloride (0.63g, 4.90 mmol). The mixture is heated to 500C for 17 hours. The reaction mixture is cooled to room temperature and water (30 mL) is added. The mixture is extracted with ethyl acetate (3 x 5 mL). The extract is washed with 10% aqueous hydrochloric acid (5 mL), water (2 x 10 mL), dried over MgSO4 and concentrated using a rotary evaporator to give 3-cyano-2-(4-ethanesulfonylamino- phenyl)-l-ethyl-li7-indole-6-carboxylic acid methyl ester (1.47g, 90%).
Step C: The indole product from above (0.72g, 1.76 mmol) is suspended in anhydrous THF (3.3 mL). A solution of lithium borohydride (2.6 mL, 5.2 mmol, 2M in THF) is added at room temperature. The mixture is heated at reflux for 2Oh. The mixture is cooled to room temperature and water (4 mL) is added. The pH is adjusted to 4 by addition of 10% aqueous hydrochloric acid. The mixture is extracted with methylene chloride (4 x 2 mL). The extract is washed with water (2. 2 mL), dried over MgSO4 and concentrated to give ethanesulfonic acid[4-(3-cyano-l-ethyl-6-hydroxymethyl-l/f-indol-2-yl)-phenyl]-amide (595 mg, 88%) as a tan solid. Step D: The indole product from above (471 mg, 1.23 mmol) is suspended in anhydrous methylene chloride (6 mL). Thionyl chloride (0.135 mL, 1.85 mmol) is added and the mixture stirred at room temperature for 2h. The mixture is concentrated on a rotary evaporator to give ethanesulfonic acid [4-(6-chloromethyl-3-cyano-l -ethyl-lH-indol-2-yl)-phenyl]-amide (493mg, 99%). Step E: The indole product from above (50 mg, 0.124 mmol) is dissolved in anhydrous acetonitrile (1.0 mL). piethylamine (28.1 mg.0.38 mmol) is added and the mixture is heated at 8O0C for 17 hours. The mixture is cooled to room temperature, concentrated on a rotary evaporator and purified by silica gel chromatography (0-10% MeOΗ/CΗaQb) to give
ethanesulfonic acid ^-(S-cyano-β-diethylaminomethyl- 1 -ethyl-l/f-indol-2-yl)-phenyl]-arnide (33.6mg, 62%).
Example IDO: {4-[3-Cyano-l-cyclobutyl-6-(2-methanesulfonyl-ethoxy)-lH-indol-2- yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (compound 2695)
Step A: To a solution of 2-(4-aminophenyl)-l-cyclobutyl-6-hydroxy-lH-indole-3- carbonitrile (3.43 g, 11.3 mmol) in CH3CN (8 mL) was added Cs2CO3 (4.30 g, 73.2 mmol) and 2-cbloroethyl-/7-tosylate (2.39 mL, 13.2 mmol) and the reaction mixture was stirred for 18h at 400C in a sealed tube. An aqueous workup was performed in 0.5M HCl (500 mL) and the mixture extracted with. EtOAc (2 X 500 mL). Organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified over silica gel column in 10% EtOAc/CH2Cl2. Solvent was removed to provide 4.06 g (98% yield) of 2-(4-Amino-phenyl)-6- (2-chloro-ethoxy)-l-cyclobutyl-lH-indole-3-carbonitrile, as a white solid.
Step B: 2-(4-Amino-phenyl)-6-(2-chloro-ethoxy)-l-cyclobutyl-lH-indole-3- carbonitrile (800 mg, 2.19 mmol) was dissolved in phosgene in toluene (2M5 10 mL,
5.00mmol) and stirred for 2h at 800C in a sealed tube. Solvent was removed and the white solid obtained was suspended in 1 ml of DCE. To this solution was added (R)-I- cyclopropylethanol (400 uL, 5.28 mmol) and DMAP (268 mg, 2.19 mmol). Solution was stirred in a sealed tube for 16h at room temperature. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2 X 100 mL). The organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether to
generate 800 mg (77% yield) of {4-[6-(2-Chloro-ethoxy)-3-cyano-l-cyclobutyl-lH-indol-2-yl]- phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, as a white solid.
Step C: To a solution of {4-[6-(2-Chloro-ethoxy)-3-cyano-l-cyclobutyl-lH-indol-2-yl]- phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (800 mg, 1.67 mmol) in 1:4 DMF/CH3CN (8 mL) is added sodium iodide (2.50 g, 16.7 mmol). The resulting mixture was refluxed overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2 X 100 mL). Organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether and used without further purification. To 4 mL of a DMF solution containing the iodoethyl intermediate (0.56 mmol) was added the sodium methane sulfinate (113 mg, 1.11 mmol), and the reaction was stirred at room temperature overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2 X 100 mL). The organic layers were combined, dried over MgSO4 and concentrated. The mixture was purified over silica gel column (CH2CI2) to provide 100 mg (35% yield) of {4-[3-Cyano-l-cyclobutyl-6-(2-methanesulfonyl-ethoxy)-lH-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester, as an off-white powder.
Example IDP: Preparation of [4-(l-cyclopropylmethyl-6-ethoxy-3-iodo-lH'-indol-2-yl)- phenyl]-carbamic acid isopropyl ester (compound 2634).
Step A: To a solution 6-Ethoxy-l-i7-indole (5.0 g, 31 mmol) in CH3CN (31 mL) was added di-tert-butyldicarbonate (7.2 g, 33 mmol) and DMAP (480 mg, 3.9 mmol). The mixture was stirred overnight at room temperature, concentrated and the residue purified by silica gel chromatography (1:1 GH^Ck/hexane) provided 6-ethoxy-indole-l-carboxylic acid tenf-butyl ester (7.67 g, 95%) as a tan oil.
Step B: A solution of 6-ethoxy-indole-l-carboxylic acid tert-bvtyl ester (8 g, 30 mmol) and B(OiPr)3 (12 mL, 52 mmol) in THF (48 mL) was cooled to 0° C and LDA (1.5 M in THF- cyclohexane, 30 mL, 45 mmol) was added dropwise. The reaction mixture was stirred at 0° C for 20 minutes, and then at room temperature for 30 minutes. HCl (7.5 mL, 6 M) was added and the mixture concentrated to roughly 30 mL of solution. This concentrate was acidified with aqueous HCl to pH 1-2. The solids were filtered, washed with H2O, and dried at 50° C at reduced pressure for 30 minutes. The product, 2-(6-ethoxy-indole-l-*ert-butoxy-carbonyl- indole)-boronic acid trihydrate (10.32 g, 96%) was isolated as a white solid.
Step C; To a mixture of 2-(6-emoxy-mdole-l~ή?r^butoxy-carbonyl-ώdole)-boronic acid trihydrate (5.1 g, 14.2 mmol), I-iodo-4-nitrobenzene (3.6 g, 14.4 mmol), Pd(dppf)Cl2- CH2Cl2 (205 mg, 0.25 mmol) and DMF (45 niL) was added aq. K2CO3 (2M5 20 mL, 40 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O and was extracted with EtOAc. The EtOAc layer was washed with H2O5 and then with brine. The organic layer was dried, concentrated and purified by silica gel chromatography (1:1 CH2Cl2/hexane), followed by trituration with 1:1 hexane/ether to provide 6-ethoxy-2-(4-nitro- phenyl)-indole-l-carboxylic acid tert-butyl ester (3.63 g, 67%) as a yellow solid.
Step D: To a solution of 6-ethoxy-2-(4-nitro-phenyl)-indole-l-carboxylic acid tert-butyl ester (8.1 g, 21.2 mmol) in CH2Cl2 (8 mL) was added TFA (8 mL). This mixture was stirred at room temperature for 2h and concentrated. The residue was diluted in EtOAc and washed with sataq. NaHCO3. The organic layer was concentrated and purified by silica gel chromatography (7:3 CH2Cl2/hexane, followed by 100% CH2Cl2) to provide 6-ethoxy-2-(4-nitro-phenyl)-liT- indole (4.5 g, 68%) as an orange-red solid. Step E: 6-Ethoxy-2-(4-nitro-phenyl)-lH-indole (4.5 g, 16 mmol), Cs2CO3 (7.8 g, 24 mmol), DMF (23 mL), and bromomethylcyclopropane (1.8 mL, 18 mmol) were stirred at 80° C in a sealed tube for 16 hours. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried and concentrated. Purification by silica gel chromatography (1:1 CH2CVhexane) provided 1-cyclopropylmethyl- 6-ethoxy-2-(4-nitro-phenyi)-l /^-indole (4.73 g, 88%) as an orange solid.
Step F: To l-cyclopropylmethyl-6-ethoxy-2-(4-nitro-ρhenyl)-lH'-indole (800 mg, 2.38 mmol) in DMF (8.6 mL) at room temperature was added a solution of N-iodosuccinimide (585 mg, 2.6 mmol) in DMF (5.6 mL) dropwise. The reaction mixture was stirred at room temperature for 2h, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O, and then with sat. aq. NaHCOa and then dried and concentrated. The residue was triturated with hexane to provide l-cyclopropyhnethyl-6-ethoxy-3-iodo-2-(4-nitro-phenyl)-l/f- indole (1.061 g, 96%) as an orange solid.
Step G: A mixture of l-CyclopropyImethyl-6-ethoxy-3-iodo-2-(4-nitro-phenyl)-liϊ- indole (990 mg, 2.14 mmol), iron powder (690 mg, 11.8 mmol), NH4Cl (690 mg, 12.9 mmol), ethanol (22 mL), and H2O (8 mL) were heated at 80 ° C for 90 minutes. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The organic layer was dried, concentrated and purified by silica gel chromatography (CH2Cl2). Product containing fractions were used immediately in the next reaction. The compound in CHaCl2 (80 mL) was treated with pyridine (15 mL) and isopropylchlorofortnate (IM in toluene, 2.5 mL, 2.5 mmol) and stirred at room
temperature for 15 minutes. The reaction mixture was concentrated and extracted with a mixture of EtOAc and aq. HCl. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CHbCk/hexane, 1:1 to 3:1) to provide [4-( 1 -cyclopropylmethyl-β-ethoxy-S-iodo- lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (644 mg, 58%) as a white solid.
Example IDQ: Preparation of [4-(l-Cyclopropylmemyl-6-ethoxy-3-fluoro-lH-indol-2- yl)-phenyl]-carbamic acid isopropyl ester (compound 2640).
iPrOCOCI, Pyridine, rt
Step A: To l-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-lH"-indole (600 mg, 1.79 mmol) in CH2CI2 (4 mL) was added l-fluoro-2,4,6-trimethyl pyridinium tetrafluoroborate (418 mg, 1.85 mmol). The reaction mixture was stirred at room temperature for 3 days and then diluted in CH2CI2 and washed with aq. NaHCθ3. The organic layer was dried, concentrated and purified by silica gel chromatography (1:1 CH-Ck/hexane) to provide l-cyclopropylmethyl-6- ethoxy-3-fluoro-2-(4-nitro-phenyl)-lH-indole (161 mg, 25%) as a yellow solid.
Step B: A mixture of l-cyclopropylmethyl-6-ethoxy-3-fluoro-2r(4-nitro-phenyl)-lH'- indole (161 mg, 0.45 mmol), iron powder (170 mg), NH4Cl (170 mg, 3.2 mmol), ethanol (4 mL) and H2O (1.5 mL) were heated at 80 ° C for 90 minutes. The reaction mixture was diluted with H2O and was extracted with CH2CI2. The organic layer was dried and concentrated to provide 4-(l-cyclopropyhiiemyl-6-ethoxy-3-fiuoro-lH-indol-2-yl)-ρhenylamine (122 mg, 83%) as a white solid.
Step C: A mixture of 4-(l-cyclopropylmethyl-6-ethoxy-3-fluoro-lH-indol-2-yl)-phenyl amine (30 mg, 0.093 mmol), pyridine (300 μL), and isopropylchloro formate (1 M in toluene,
110 μL, 0.11 mmol) was stirred at room temperature for 90 minutes. The residue was extracted with a mixture of EtOAc and aqueous HCl. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2CI2 / Hex, 1:1) to provide [4-(l-cyclopropyhnethyl-6-ethoxy-3-fiuoro-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (35 mg, 92%) as a white solid.
Example IDR: Preparation of [4-(3-cyclopropylethynyl-l-cyclopropyhnethyl-6-ethoxy- l/f-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (compound 2635).
[4-(l-Cyclopropyhnethyl-6-ethoxy-3-iodo-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (lOOmg, 0.19 mmol), cyclopropylacetylene (50 μL, 70% in toluene, 0.4 mmol), Pd(PPlVs)2Cl2 (6.7 mg, 0.0096 mmol), CuI (5 mg, 0.026 mmol), triethylamine (600 μL), and DMF (600 μL) was stirred at room temperature for 5h. Additional Pd(PPhS)2Cl2 (5 mg), and cyclopropylacetylene (30 μL) was then added and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed with H2O and aq. HCl. The organic layer was dried, concentrated and purified by silica gel chromatography (3:1 CH2Cl2/hexane), followed by a second chromatography (7:3 hexane/ether) to provide [4-(3-cyclopropylethynyl- l-cyclopropylmethyl-6-ethoxy-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (2.1 mg, 24%) as a white solid.
Example IDS: Preparation of [4-(3-bromo-l-cyclopropylme&yl-6-ethoxy-lH-indol-2- yl)-phenyl]-carbamic acid isopropyl ester (compound 2691).
Step A: To l-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-lH-indole (200 mg, 0.6 παmol) in DMF (2.5 mL) was added a solution of N-bromosuccinimide (107 mg, 0.6 mmol) in DMF (1.5 mL) dropwise. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted in H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (1:1 CHaC^/hexane) to provide 3-bromo-l-cyclopropylmethyi-6-ethoxy-2-(4- nitro-phenyl)-l.H-indole (219 mg, 88%) as a yellow solid.
Step B: Following Example IDP step B, 3-bromo-l-cyclopropyhnethyl-6-ethoxy-2-(4- nitro-phenyl)-lH-indole (205 mg, 0.5 mmol) was reduced to provide 4-(3-bromo-l- cyclopropymiemyl-6-emoxy-lH-mdol-2-yl)-phenylaniine (164 mg, 85%) as yellowish solid. Step C: Following Example IDP step C, 4-(3-bromo-l-cyclopropylmethyl-6-ethoxy- l/7-indol-2-yl)-phenylamine (30 mg, 0.078 mmol) was carbamoylated to provide [4-(3-bromo- l-cyclopropyhnethyl-6-ethoxy-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (25 mg, 68%) as a white solid.
Example IDT: Preparation of [4-(3-chloro-l-cyclopropylmethyl-6-methoxy-lH-indol- 2-yl)-phenyl]-carbaπric acid isopropyl ester (compound 2804).
Step A: 2-(6-Mefhoxy-indole-l-tert-butoxy-carbonyl-indole)-boronic acid (14g, 48 mmol) was combined withN-(4-iodophenyl)-isoρropylcarbamate (15.25 g, 50 mmol), Pd(dppf)Cl2 (678 rog, 0.92 mmol), aq. K2CO3 (2M566 mL, 132 mmol), and DMF (150 mL). The reaction mixture was stirred overnight at room temperature then diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2CI2), followed by trituration with 2:1 hexane/ether to provide 2-(4-isopropoxycarbonylamino-pheπyl)-6-methoxy-indole-l- carboxylic acid tert-butyl ester (15.6 g, 76%) as a gray solid.
Step B: A mixture of 2-(4-Isopropoxycarbonylamino-phenyl)-6-methoxy-indole-l- carboxylic acid ter/-butyl ester (17.4 g, 41 mmol), CH2Cl2 (50 mL), and TFA (50 mL) was stirred at room temperature for Ih. The reaction mixture was concentrated, diluted in CH2CI2, and washed with sat. aq. NaHCθ3. The organic layer was dried, concentrated, and triturated with ether to provide [4-(6-methoxy-lΛT-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (11.4 g, 86%) as a grayish solid.
Step C: To [4-(6-Methoxy-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (11.3 g, 34.9 mmol) in DMF (50 mL) was added a solution of N-chlorosuccinimide (5 g, 37.4 mmol) dropwise over 20 minutes and the mixture stirred at room temperature for Ih. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with
H2O and brine and then dried, concentrated and triturated with ether to provide [4-(3-chloro-6- Methoxy-l/if-mdol-2-yl)-phenyl]-carbamic acid isopropyl ester (10.65 g, 85%) as a tan solid. Step D: A mixture of ^-(S-Chloro-o-Methoxy-lH-indol^-yO-phenyll-carbamic acid isopropyl ester (50 mg, 0.14 mmol), CS2CO3 (95 mg, 0.29 tαmol), bromomethylcyclopropane (18 μL, 0.18 mmol), and DMF (200 μL) was stirred at 60° C for 4h. The reaction mixture was then stirred at room temperature for Ih, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (7:3 CH2Cl2/hexane) to provide [4-(3-chloro-l-cyclopropylmethyl-6~ methoxy-lΛT-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (19 mg, 33%) as a white solid.
Example IDU: Preparation of (R)-[4-(3-cyano-l-cyclobutyl-6- methanesulfonylmethoxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 2988).
Step A: [4-(3-Cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (1.6 g, 4 mmol) was combined with CS2CO3 (2.6 g, 8 mmol), methyl chloromethyl sulfide (410 μL, 5 mmol), and DMF (16 mL). The reaction mixture was stirred overnight at room temperature, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2Cl2) to provide [4-(3-cyano-l-cyclobutyl-6-methanesulfanyhnethoxy-liϊ- indol-2-yl)-pϊienyl]-carbamic acid tert-butyl ester (1.72 g, 93%) as an off-white solid.
Step B: To ^-(S-Cyano-l-cyclobutyl-o-methanesulfanylmethoxy-lH-indol^-yl)- phenyl]-carbamic acid tert-butyi ester (1.35 g, 2.9 mmol) in CHCl3 (20 mL) was added 3- Chloroperoxybenzoic acid (1.5 g, 8.7 mmol) in one portion. After 10 minutes the reaction mixture was washed with dilute NaHCCh solution, dried, concentrated and purified by silica gel chromatography (95:5 CH2Cl2ZEtOAc) to yield [4-(3-cyano-l-cycIobutyl-6- methanesulfonyhnethoxy-lH-indol-2-yl)-phenyl]-carbamic acid tert-bntyl ester (1.11 g, 77%) as an off-white solid.
Step C: To ^-(S-Cyano-l-cyclobutyl-ό-methanesulfonyknetb.oxy-lH'-indol^-yl)- phenyl]-carbamic acid tert-butyl ester (1.21 g, 2.47 mmol) in CΗ2CI2 (6 mL) was added TFA (2 mL) and stirred at room temperature for Ih. The reaction mixture was diluted in CH2 CI2, washed with aq. NaHCO3, dried and concentrated. Trituration with acetone (5 mL) provided 2- (4-ammo-phenyl)-l-cyclobutyl-6-memansulfonymiethoxy-lH-indole-3-carbojiitrile (891 mg, 91 %) as a light pink solid.
Step D: 2-(4-Amino-phenyl)-l-cyclobutyl-6-methansulfonyknethoxy-lHr-indole-3- carbonitrile (100 mg, 0.25 mmol) was combined withp-nitrophenyl chloroformate (120 mg, 0.6 mmol), DCE (1 mL), and pyridine (60 μL, 0.75 mmol) and stirred at room temperature for Ih. To this mixture was added (R)-1-Cyclopropylethanol (90 μL, 0.92 mmoi) and then heated at 8O0C for 2h. The reaction mixture was diluted with CH2CI2 and washed with dilute aqueous . NaOH solution. The organic layer was dried, concentrated and purified by silica gel chromatography (95:5 CH2Cl2ZEtOAc) to provide (R)-[4-(3-cyano-l-cyclobutyl-6- methanesulfonyhnethoxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (105 mg, 83%) as a white solid.
Example IDV: Preparation of [4-(3-cyano-l-cyclobutyl-6-moφholm-4-yl-lH-indol-2- yl)-phenyl]-carbamic acid isopropyl ester (compound 2800).
Step A: To a solution of 6-nitroindole (16.2 g, 100 mmol) in DMF (60 mL) at 00C was added chlorosulfonylisocyanate (10.9 mL, 125.0 mmol). The mixture was then stirred at room temperature overnight, poured into ice- water (1.0 L) and stirred for 3 h. The precipitate was filtered, washed with water and dried in air to provide 3-cyano-6-nitroindole (17.63 g, 94%). Step B: A mixture of 3-cyano-6-nitroindole (3.74 g, 20.0 mmol), cyclobutylbromide (2.27 mL, 24.0 mmol), Cs2CO3 (13.04 g, 40.0 mmol) in DMF (20 mL) was stirred at 900C in a sealed tube for 3 days. After cooling, the mixture was poured into ice-water (200 mL) and the precipitate was filtered, washed with water and transferred to a Paar hydrogenator. The hydrogenation was carried out with 5% Pd/C (1.0 g), in MeOH (50 mL) and EtOAc (50 mL) at 60 psi of H2 for 24h. The mixture was filtered through Celite, washed with MeOH and concentrated to dryness to provide 6-amino-l-cyclobutyl-3-cyanoindole (3.13 g, 74%). Step C: A mixture of 6-amino-l-cyclobutyl-3-cyanoindole (4.60 g, 21.8 mmol), bromoethylether (6.07 g, 26.16 mmol), DIEA (10.79 mL, 65.4 mmol) in DMF (100 mL) was stirred at 900C overnight and then poured into ice-water (1.0 L). The precipitate was filtered, washed with water, and purified on silica gel (CHaCWEtOAc, 9:1) to provide l-cyclobutyl-6- morpholin-4-yl-lH-indole-3-carbonitrile (5.24 g, 85%). Step D: To a solution of l-cyclobutyl-6-moφholin-4-yl-lH-mdole-3-carbomtrile (1.20 g, 4.27 mmol), triisopropylborate (1.28 mL, 5.55 mmol) in THF (15 mL) at-78°C was added
LDA (1.5M mono THF in cyclohexane, 3.27 mL, 4.91 nxmol) with stirring. The mixture was stirred at -78°C for 10 minutes and at room temperature for 30 min followed by the addition of 4-iodoaniline (1.03 g, 4.70 mmol) and PdCl2 (dppf) (0.16 g, 0.2 mmol). The reaction system was cooled to -780C, flushed with nitrogen followed by the addition of DMF (30 mL) and aq. K2CO3 (2.0M, 6.4 mL, 12.8 mmol). The cooling bath was removed and the mixture was stirred overnight and poured into ice water (500 mL). The precipitate was filtered, washed with water, dried in air and purified on silica gel (CH2Cl2ZEtOAc, 9:1) to give 2-(4-amino-phenyl)-l- cyclobutyl-6-moφholin-4-yl-lH-indole-3-carbonitrile (1.49 g, 94%).
Step E: A solution of 2-(4-ammo-phenyl)-l-cyclobutyl-6-moφholin-4-yl-lH-indole-3- carbonitrile (0.112 g, 0.3 mmol), pyridine (1.0 mL) in CH2CI2 (2.0 mL) was treated with isopropylchloroformate (1.0 M in toluene, 0.6 mL, 0.6 mmol). The mixture was stirred at room temperature for 5h and diluted with CH2CI2 (5 mL). The organic layer was separated, washed with HCl (1.0 N, 3 X 2 mL), water (5 mL x 2) and brine (5 mL), and purified on silica gel (CH2Cl2ZEtOAc, 9:1) to provide [4-(3-cyano-l-cyclobutyl-6-morpholin-4-yl-lH-indol-2-yl)- phenyl]-carbamic acid isopropyl ester (0.12 g, 87%).
Example IDW: Preparation of {4-[3-cynao-l-cyclobutyl-6- (tetrahydro-pyran-4-yloxy)- /H-indole-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 2616).
(2M),
Step A: A mixture of 6-hydroxyindole (1.47 g, 6.93 mmol), toluene-4-sulfonic acid tetrahydro-pyran-4-yl ester (2.65 g, 10.42 mmol), K2CO3 (2.87 g, 20.77 mmol) and DMF (15 ml) was stirred at 800C overnight. After cooling, the reaction mixture was poured into ice- water (60 ml) to afford precipitate, which was collected by filtration, washed with water and
ether/hexanes (1:1). The solid was dried under vacuum to obtain the product (1.76 g, 86%) as a brown solid.
Step B: A solution of l-cyclobutyl-6-(tetrahydro-pyran-4-yloxy)-lH-indole-3- carbonitrile (1.68 g, 5.68 mmol) and triisopropyl borate (1.39g, 7.38 mmol) in THF (15 mL) was cooled to -78°C whereupon LDA (1.5 M in THF-cyclohexane, 4.73 mL, 7.10 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature and continued stirring for 30 minutes. The reaction mixture was cooled to -780C. 4-iodoaniline (1.31 g, 5.96 mmol) in DMF (10 mL), K2CO3 (2 M, 8.5 mL, 17.0 mmol), and PdCl2dppf (208 mg, 0.29 mmol) were added to it in sequence. The mixture was de-gassed, back-filled with N2 and then stirred at room temperature for 3h. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous phase was washed with more EtOAc (40 mL). The combined organic phase was washed with water (2 X 30 mL), brine and dried over Mg2SO4, concentrated and purified on silica gel (EtOAc /hexanes, 10% to 50 %) to afford the product (1.81 g, 83%) as a brown solid. Step C: To a mixture of 2-(4-amino-phenyl)-l-cyclobutyl-6-(tetrahydro-pyran-4-yloxy)-
2H-indole-3-carbonitrile (897.8 mg, 2.32 mmol), K2CO3 (7 mL), and ethyl acetate (7 mL) was added iPrOCOCl (6.9 mL, 1 M in toluene, 6.96 mmol). The resulting mixture was stirred at room temperature overnight. The organic layer was washed with brine, dried over Mg2SO.*, concentrated and purified on silica gel (EtOAc /hexanes, 10% to 30 %) to provide the product (1.01 g, 92 %) as white solid.
Example IDX: Preparation of ^-(B-cynao-l-cyclobutyl-δ-ethylsulfanyl-i^f-indole^- yl)-phenyl} - carbamic acid 1- cyclopropyl-ethyl ester (compound 2720).
Step A: To a mixture of potassium hydride (30 % wt. in mineral oil, 2.71 g, 20.2 mmol) and THF (30 mL) was added a solution of 6-bromoindole (3.98 g, 20.3 mmol) in THF (10 mL) at 00C. After 15 minutes the solution was cooled to -78°C, and tert-butyllithium (1.5 M in pentane, 27.07 mL, 40.60 mmol) was added via syringe. The mixture was stirred at -78°C for 10 min then ethyl disulfide (4.97 g, 40.6 mmol) in THF (10 mL) was added. The reaction mixture was allowed to warm to room temperature, poured into ice-sataq. NH4Cl (150 mL), and then extracted with EtOAc (150 mL). The organic phase was washed with water (150 mL), brine (150 mL), dried over Mg2SO4, concentrated, and purified on silica gel (EtOAc /hexane 5% to 15%), to provide 6-ethylsulfanyl-lH-indole (2.75 g, 77%) as a clear liquid. Step B: To a mixture of 6-ethylsulfanyl-lH-indole (2.75 g, 15.54 mmol) in DMF (20 mL) was added chlorbsulfonyl isocyante dropwise at -300C. The temperature was raised to O0C after addition and stirred for 30 minutes. The mixture was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over Mg2SO4, concentrated and purified on silica gel (CH2Cl2) to provide 6-emylsulfanyl~7H'-mdole-3-carbonitrile (3.25 g, 84%) as a white solid.
Step C: A mixture of β-ethylsulfanyl-lΗ-indole-S-carbonitrile (2.13 g, 10.5 mmol) Cs2CO3 (6.9 g, 21 mmol), cyclobutyl bromide (1.78 g, 13.2 mmol) and DMF (20 mL) was heated to 85°C overnight and, after cooling, partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over Mg2SO4, concentrated and purified on silica gel (EtOAc /hexane 5% to 30%) to provide l-cyclobutyl-6-e&ylsulfanyl-7H'-indole-3- carbonitrile (2.58 g, 96%) as a light-yellow oil.
Step D: To a solution of l-cyclobutyl-δ-ethylsulfanyl-iH-indole-S-carbonitrile (2.58 g, 10.08 mmol), triisopropyl borate (2.47 g, 13.13 mmol) in TΗF (25 mL) was slowly added LDA (1.5 M in TΗF-cyclohexane, 9.41 mL, 14.1 mmol). The reaction mixture was allowed to warm to room temperature and continued stirring for 30 minutes. The reaction mixture was then cooled to -78°C and 4-iodoaniline (2.42 g, 11.09 mmol) in DMF (10 mL), K2CO3 (15.5 mL, 31.00 mmol), and PdCfedppf (368.0 mg, 0.50 mmol) were added. The mixture was degassed, back-filled with N2, stirred at room temperature for 3h and then partitioned between EtOAc (40 mL) and water (40 mL). The aqueous phase was washed with more ethyl acetate (30 mL) and the combined organics were washed with water (2 X 40 mL), brine, dried over Mg2SO4, and then concentrated. A precipitate was collected by filtration, washed with water and ether afford 1.45 g of product. The filtrate was condensed and purified on silica gel (EtOAc /hexane 5% to40) to afford a further 1.65 g of 2-(4-amino-phenyl)-l-cyclobutyl-6-ethylsulfanyl-/H/-indole- 3-carbonitrile (3.1O g, 89%) as a solid.
Step E: To 2-(4-amino-phenyl)-l-cyclobutyl-6-ethylsulfanyl-iH-indole-3-carbonitrile (230.0 mg, 0.66 mmol) was combined withjσ-nitrophenyl chloroformate (266 mg, 1.32 mmol), DCE (3.0 mL), and pyridine (104.7 mg, 1.32 mmol) and stirred at room temperature for 2h. (R)-1-Cyclopropylethanol (115.0, 1.34 mmol) was added and mixture was heated at 8O0C for 2h. The reaction mixture was diluted with EtOAc and washed with sat. aq. K2CO3 (2 X 15 mL), water, and brine. The organic layer was dried, concentrated and purified on silica gel (EtOAc /hexane 10%),) to provide (R^-O-cyano-l-cyclobutyl-β-ethylsulfanyl-lH-indol^- yl)-phenyl]-carbamic acid l-cyclopropyl-ethyl ester (209 mg, 69%) as a white solid.
Example IDY: Preparation of {4-[l -cyclobutyl-6-(pyrimidin-2-yloxy)- lH-indole-2-yl]- phenyl}-carbamic acid 2,2,2-trifluoro-l-methyl-ethyl ester (compound 2888).
Step A: To a solution of 6-methoxyindole (18.32 g, 124.0 mmol), di-(ter/- butyl)dicarbonate (35.3 g, 162.2 mmol) in CH2Cl2 (120 mL) was added DMAP (200 mg, 1.64 mmol) at 00C. The resulting mixture was stirred at room temperature for 16h, concentrated and partitioned between EtOAc and water. The organic layer was washed with water, brine, dried, concentrated and purified on silica gel (EtOAc /hexane 5%) to provide 6-methoxy-indole-l- carboxylic acid /-butyl ester (30.4 g, 99%) as a solid.
Step B: To a solution of 6-methoxy-indole-l -carboxylic acid tert-butyl ester (14.33 g, 57.90 mmol) triisopropyl borate (15.25 g, 81.06 mmol) in THF (80 mL) at -78°C was added
LDA slowly. The resulting mixture was stirred at room temperature for Ih, concentrated to half of its original volume, poured into ice-water (100 mL) and acidified with IN HCl. A precipitate was collected by filtration, washed with water and hexanes to provide 2-Boronic acid 6- methoxy-indole-1-carboxylic acid f-butyl ester (14.2 g, 85% yield) as a brown solid. Step C: To a solution of indole 2-boronic acid from Step B (5.98 g, 20.5 mmol) and 1- iodo-4-nitrobenzene (5.37 g, 21.6 mmol) in DMF (60 mL) was added aq. K2CO3 (2M, 30.8 mL, 61.6 mmol) dropwise at 00C and then PdCkdppf (375.4 mg, 0.51 mmol). The mixture was degassed by three successive cycles of vacuum pumping / N2 backfilling, then stirred at room temperature for 5h and partitioned between EtOAc and water. The organic layer was washed with water, brine, dried and concentrated. The residue was suspended in hexanes and a precipitate collected by filtration and washed with hexanes to afford the product (7.20 g, 95 %) as a red solid.
Step Dt To a solution of 6-methoxy-2- (4-nitro-phenyi)-uαdole-l-carboxylic acid tert- butyl ester (7.20 g, 19.55 mmol) in CH2Cl2 (50 mL) was added TFA (22 mL) dropwise at 00C. The resulting mixture was stirred at room temperature for 3h, concentrated and suspended in ether to afford a solid, which was collected by filtration, washed with ether to provide 2.43 g of a red solid as the first crop product. The filtrate was condensed, and the residue was purified on silica gel (EtOAc /hexane 5% to 20%), to provide 1.55 g of a second crop of 6-methoxy-2-(4- nitro-phenyl)-l/ϊ-indole (combined: 3.98 g, 76% yield) as a red solid. ' Step E: A mixture of 6-methoxy-2-(4-nitro-phenyl)-l/f-indole (2.12 g, 7.90 mmol),
Cs2CO3 (5.15 g, 15.80 mmol), cyclobutyl bromide (1.28 g, 9.48 mmol) and DMF (20 mL) was heated at 85°C for 2 days. After cooling, the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water, brine, dried, concentrated and purified on silica gel (EtOAc /hexane 5% to 20 to provide the product (0.96 g, 37%) as a yellow solid. Step F: A mixture of l-cyclobutyl-6-methoxy-2-(4-nitro-phenyl)-lH-indole (0.83 g,
2.60 mmol), iron powder (0.84 mg, 15.0 mmol), ammonium chloride (0.96 g, 18.0 mmol), and EtOΗ/water (25 mL/8 mL) was stirred at 800C for Ih and concentrated. The residue was suspended in DMF (20 mL) and MeOΗ/CIfcCl. (1 : 1 , 20 mL). The mixture was passed through a Celite pad, washed with MeOΗ/CΗ2Cl2 (1:1), concentrated and water was added to afford a precipitate which was collected by filtration and washed with water. The solid was dissolved in CH2CI2, dried over MgSO4, concentrated and purified on silica gel (EtOAc /hexane 20%) to provide 4-(l-cyclobutyl-6-methoxy-liy-indole-2-yl)-phenylamine (0.57 mg, 75%) as a white solid.
Step G: To a solution of 4-(l-cyclobutyl-6-methoxy-lHr-indole-2-yl)-phenylamine (518.5 mg, 1.77 mmol) in CH2Cl2 (15 mL) was added borontribromide (1.33 g, 5.31 mmol) at " 3O0C. The resulting mixture was stirred at O0C for 2h, poured into ice-water, neutralized with aq KHCO3 and then extracted with EtOAc. The aqueous phase was washed with more EtOAc and the combined organics were washed with water, brine, dried, concentrated and purified on silica gel (EtOAc /hexane 20%) to afford the product (480 mg, 98%) as a white solid.
Step H: A mixture of 2-(4-ammo-ρhenyl)-l-cyclobutyl-l/7-indole-6-ol (480 mg, 1.72 mmol), Cs2CO3 (1.12 g, 3.45 mmol), 2-chloropyridine (296 mg, 2.60 mmol) and DMF (3 mL) was stirred at 500C overnight. After cooling, the mixture was partitioned between EtOAc and water. The aqueous phase was washed with more ethyl acetate and the combined organics were washed with water, brine, dried, concentrated and purified on silica gel (EtOAc /hexane 25%) to afford the product the product (567 mg, 92% yield) as a white sold.
Step 1: Prepared as in Example IDX, step E.
Example IDZ: Preparation of {4-[3-cyano-l-cyclobutyl-6-(l,l-dioxo-hexahydro-lλ6- thiopyran-4-yloxy)-lH-indol-2-yl]-phenyl} -carbamic acid isopropyl ester (compound 3182).
Step A: To tetrahydrothiopyran-4-one in CH3CN (50 mL) and H2O (35 mL) at 0° C was added in portions over 1 hour a mixture of oxone (70.5 g, 115 mmol) and NaHCO3 (29.9 g, 356 mmol). The reaction mixture was then, stirred at room temperature for Ih, diluted in CH3CN (250 mL) and filtered. The filtrate was concentrated, suspended in acetone and filtered. 1,1- Dioxo-tetrahydrothiopyran-4-one (6.3 g, quantitative yield) was obtained as a white solid. Step B: To l,l-dioxo-tetrahydrothiopyran-4-one (6.3 g, 36 mmol) in H2O (55 mL) was added, in portions, sodium borohydride (720 mg, 18.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then the pH was adjusted to 4 with aq. HCl. The reaction mixture was concentrated and suspended in acetone and filtered. The filtrate was concentrated and triturated with ether/hexane to provide l,l-dioxo-tetrahydrotbiopyran-4-ol (5.63 g, 90%) as a white solid.
Step C: l,l-Dioxo-tetrahydrothiopyran-4-ol (1.0 g, 6.6 mmol), pyridine (10 mL), and tosyl chloride (1.6 g, 8.4 mmol) were combined and stirred at room temperature overnight. The reaction mixture was concentrated, diluted in EtOAc and washed with aqueous HCl and brine. The organic layer was dried, concentrated and triturated with hexane to yield O-tosyH,l- dioxo-tetrahydrothiopyran-4-ol (1.073 g, 53%) as a white solid.
Step D: [4-(3-Cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (90 mg, 0.23 mmol) was combined with CS2CO3 (156 mg, 0.48 mmol), DMF (0.9 mL), and 0-tosyl-l,l-dioxo-tetrahydrothiopyran.-4-ol (96 mg, 0.32 mmol). The reaction mixture was heated overnight at 80° C, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (95:5 CHaCl2ZEtOAc) to provide 4-[3-cyano-l-cyclobutyl-6-(l,l- dioxo-hexahydro-lλ6-lhiopyran-4-yloxy)-li/-indol-2-yl]-phenyl}-carbamxc acid isopropyl ester (66 mg, 56 %) as a white solid.
Example IEA: Preparation of 1 -cyclobutyl-2-[4-(4-methyl-thiazol-2-ylamino)-phenyl]-
6-(pyrimidin-2-yloxy)-lH- indole-3-carbonitrile (compound 3180).
Step A: Prepared as in Example IEA, step H.
Step B: 1. A solution of 6-pyrimidin-indole aniline (2.25 g, 5.90 mmol) prepared in Step A, Fmoc-NCS (1.74 g, 6.19 mmol) and CH2Cl2 (15 mL) was stirred at room temperature for 2h, concentrated and washed with ethyl ether to afford Fmoc-indole-urea used without further purification. To the above solid was added CH2Cl2 (30 mL) and piperidine (5 mL). The resulting mixture was stirred at room temperature for 14h, concentrated, washed with ether, dried and concentrated to afford the product (2.5 g, 96%) as a light-brown solid.
Step D: To a mixture of indole thiourea obtained in step C (150 mg, 0.34 mmol), DIPEA (88 mg, 0.68 mmol), isopropanol (3.5 mL) and DMSO (2.0 mL) was added 1-chloro- propan-2-one (92.5 mg, 47.6 mmol). The resulting mixture was stirred at 700C for 2 days. After cooling, the reaction mixture was partitioned between EtOAc and water and the organic layer was washed with water, brine, dried over MgSO4, and purified on silica gel (EtOAc /hexane 25%) the product (102 mg, 63% yield) as a brown solid.
Example IEB. Preparation of l-cyclobutyl-2-[4-(2,5-dimethyl-2H'-pyrazol-3-ylamino)- phenyl]-6-(pyrimidin-2-yloxy)-lH-indole-3-carbonitrile (compound 3285).
Step A: A mixture of 2,5-dimethyl-2H-pyrazol-3-ylamine (2.53 g, 22.8 mrnol), acetic anhydride (2.67 g, 26.2 mmol) and acetic acid (1OmL) was stirred at 500C for 3h. After cooling, the mixture was treated with sat. aq. NaΗCθ3 to afford a precipitate, which was collected by filtration, washed with water and hexanes, and dried to provide the product (3.43 g, quant.) as a white solid.
Step B: To N-(2,5-dimethyl-2H-pyrazol-3-yl)-acetamide (2.01 g, 13.1 mmol), 1,4- dϋodobenzene (5.20 g, 15.8 mmol), K3PO4 (5.57 g, 26.2 mmol), CuI (125 mg, 0.66 mmol), and dioxane (50 mL), was added N,N-dimethyl-cyclohexane-l ,2-diamine. The mixture was degassed by three successive cycles of vacuum pumping / N2 backfilling, then stirred at reflux for 14h. After cooling, the mixture was partitioned between EtOAc and water and the organic
layer was washed with water, brine, dried over Mg2SO4, concentrated and purified on silica gel (EtOAc /CH2Cl220%) to afford the product (4.91 g, 69%) as a white solid.
Step C. Prepared N-[4-cycno-l-cyclobutyl-6-hydroxy-lH-indole-yl)-phenyl]-N-(2,5- dimethyl-2H-pyrazol-3-yl)-acetamide (2.12 g, 86% yield) as in Example IEI5 Step D. Step D. A mixture of N-[4-cycno-l-cyclobutyl-6-hydroxy-lH-indole-yl)-phenyl]-N-
(2,5-dimethyl-2H-pyrazol-3-yl)-acetamide (1.54 g, 3.50 mmol) and HCl (6N, 6 mL) was stirred at 800C for 15h. After cooling, the reaction mixture was partitioned between EtOAc and water and organic layer was washed with sat. aq. NaΗCθ3, water, brine, dried over MgSO4, and concentrated. The residual solid was washed with ether to afford the product (1.27 g, 92% yield) as a brown solid.
Step E: l-cyclobuiyl-2-[4-(255-dimethyl-2H-pyrazol-3-ylamino)-phenyl]-6-(pyrimidin- 2-yloxy)-l/f-indole-3-carbonitrile (PS102656) was prepared as in Example 3, step Η.
Example 1 EC {4-[3-Cyano- 1 -cyclobutyl-6-(2-methanesulfonyl-viiiyloxy)- 1 Η-indol-2- yl]-phenyl}-carbamic acid tert-butyl ester (compound 3301).
To a solution of the indole triflate (1.07 g, 2.00 mmol) in DMF (2 mL) was added methyl vinyl sulfone (432 mg, 3.99 mmol), bis(triphenylphosphiQe)palladium(π)chloride (72 mg, 0.103 mmol) and Et3N (0.84 mL, 6.03 mmol). The mixture was purged with nitrogen and heated at 90°C for 2Oh then additional methyl vinyl sulfone (106 mg, 1 mmol) and bis(triphenylphosphine)palladium (72 mg, 0.10 mmol) were added. The mixture was heated for 2Oh at 900C then cooled to room temperature. Water (14 mL) was added and the solid was filtered, washed with water, dried and purified on silica gel (EtOAc /1:1 CHfeCfe-hexanes 0- 10%) to give the product (250 mg, 26%) as a tan solid.
Example IED: Preparation of (i?)-{4-[3-cyano-l-cyclopropyl-6-(pyrimidin-2-yloxy)- lH-iαdol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester (compound 3321)
Step A: To a solution of l-cyclobutyl-δ-hydroxy-lH-indole-S-carbonitrile (4.24 g, 20 mmol) in THF (60.0 mL) at "780C was added LDA (30.7 mL, 46.0 mmol) and iodine (7.62 g, 30.0 mmol). The mixture was stirred at ~78°C for 10 min, warmed to room temperature and stirred for 3 h. The reaction mixture was poured into ice-water (500 mL) and the precipitate was filtered and washed with water and CH2Cl2. After drying in air the crude iodide obtained (3.99 g) was taken up in DMF (25 mL) and Cs2CO3 (9.78 g, 30.0 mmol) and 2- chloropyrimidine (2.18 g, 19.0 mmol) were added to this solution. The mixture was stirred at 700C for 30 min, poured into ice water (200 mL) and the precipitate was collected on a filter, washed with water and purified on silica gel (QHtCl2ZEtOAc5 9.75:0.25) to provide 1- cyclobutyl-2-iodo-6-(pyrirnidin-2-yloxy)-lH-indole-3-carbonitrilβ (1.52 g, 47%).
Step B: The iodide obtained in Step A (0.83 g, 2.0 mmol), 5-(4,4,5,5-eetramethyl- [l,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (0.48 g, 2.2 mmol), PdCI2(dppf) (0.07 g, 0.1 mmol) were mixed with DMF (10.0 mL), followed by the addition of aq. K2CO3 (2.0 M5 3.0 mL, 6.0 mmol). The mixture was stirred at 8O0C overnight and poured into ice-water (100 mL). The precipitate was filtered, washed with water and purified on silica gel (CH2Cl2ZEtOAcZMeOH, 5:5:0.2) to furnish 2-(6-amino-pyridin-3-yl)-l-cyclobutyl-6- (pyrimidin-2-yloxy)-lH-indole-3-carbonitrile (0.61 g, 80%).
Step C: A mixture of 2-(6-ammo-pyridm-3-yl)-l-cyclobutyl-6-(pyrimidin-2-yloxy)-lH- indole-3-carbonitrile (115 tng, 0.3 mmol), 4-nitrophenylcbloroformate (91 mg, 0.45 mmol) in pyridine (1.0 mL) was stirred at 3O0C for 2h, followed by the addition of (R)-I- cyclopropylethanol (150 μL, 1.5 mmol). The mixture was stirred at 8O0C overnight and diluted
with water (10 mL) and CH2Cl2 (5 mL). The organic layer was washed with water (3 x 5 mL), HCl (2N, 3 x 5 mL), sat. aq. NaHCO3 (3 x 5 mL) and and purified on silica gel (CH2Cl2ZEtOAc, 1 :9) to provide (R)- {4-[3-cyano- 1 -cyclopropyl-6-(pyrimidin-2-yloxy)-lH- indol-2~yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester (25 mg, 17%).
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 HepG 2 (hepatoblastoma) cell line (termed HepGmono-4) or a Huh7 cell line (termed Huhmono 7), or a Hela-cell 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 bits may specifically act on HCV ERES-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 IKES and cap-dependent translation is considered to be desirable. Using these cell-based cap-dependent translation assays, compounds are identified that show IC50 values that are at least 5-fold greater in the cap-dependent translation assays than in the HCV IRES translation assay.
Western blotting assays are used to further demonstrate that compounds selectively inhibit HCV IRES-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 Laminin 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 compounds of the present invention are tested in this manner.
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 are tested in this manner.
Example 4: Evaluation of the selectivity for HCV IRES-drrven translation using cellular IKES-mediated translation assays
A number of human mRNAs 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 IRES are different from those of cellular IRESs, an important test for selectivity is to determine whether the selected compounds are active against cellular IRESs. The VEGF IRES has poor initiation activity in in vitro assays, but demonstrates substantial activity in cell-based translation assays (18, 45). For example, some of the compounds of the present invention are tested
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 mat 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 are selected for further evaluation.
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 recently been described and have been widely used to assess the efficacy of anti-HCV inhibitors (8, 70, 104).
Interferon (IFN) α 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 identified and assays for testing the HCV IRES inhibitors are established. 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 replicon by quantitating the Flue reporter signal. Replicon- containing cells are cultured with the compounds of the invention for 2 days or for 3 days. Interferon (IFN) α is used as a positive control. For example, some compounds of the present invention are tested in this manner.
In the following table (Table IA),
* = replicon or HCV-PV IC50 > 2uM ** - replicon or HCV-PV IC50 between 0.5 uM and 2 uM *** = replicon or HCV-PV IC50 < 0.5 uM
Replicon IC50 values are determined by firefly luciferase signal. HCV-PV IC50 values are determined by viral RNA reduction.
Table IA
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) (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 cis-acύng 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, 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 in cytopathic effect, plaque assay, and/or viral RNA production (see e.g., Tables IA and IB).
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 pPVIRESmono, 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 pPVIRESmono 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, HeIa cells 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 IRESs, then the compounds are useful for treating viral infection by any virus containing an ERES.
TABLE 2
Example 9: In 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 pHCVTRESmono 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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Claims
1. A compound of formula Ha
or a pharmaceutically acceptable salt thereof, wherein: X is:
-cyano;
-nitro;
-formyl;
-COOH;
-CORx, wherein Rx is Ci to Cβ alkyl;
-CH=N-(C, to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C1 to Cg alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with Cj to Cg alkyl, which alkyl is optionally substituted with one or more independently selected halos or cyanos;
-oximyl;
-SO2Rx;
-SO2NH2;
-SO2NH(Rx);
-SO2N(RX)2;
-amino optionally substituted with one or more Ci to Ce alkyls and/or -C(O)-Ci to C6 alkyls;
-amido optionally substituted with one or more independently selected Cj to Ce alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce- alkyls, which alkyls are optionally substituted with one or more halos; or
-Cβ to Cs aryl optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more halos; -halo; and -cyano; Y is:
-benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more Ci to Ce alkyls; -indolyl optionally substituted on the nitrogen with -Sθ2Rx; -Cβ to Cg aryl optionally substituted with one or more substituents independently selected from: -halos;
-Ci to C6 alkyl; -alkoxy optionally substituted with one or more substituents independently selected from:
-one or more halos; and
-5 or 6 membered heterocyclo; -hydroxy; -amino optionally substituted with one or more substituents independently selected from:
-SO2Rx;
-Ci to CO alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls; and
-PO2Rx; -OC(O)NHRx; -OC(O)N(RX)2; -OC(O)NH(ORx); -OC(O)NRx(ORx); -OC(O)N(ORX)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo; -NR0CORp, wherein Rp is:
-Ci to C6 alkyl;
-amino optionally substituted with one or more Cj to C$ alkyls, which alkyls are optionally and independently substituted with one or more Ce to Cg aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more Cj to C6 alkyls and/or Q to C8 aryls; and wherein R0 is: -hydrogen; or -Ci to C6 alkyl;
-NRqCONRqRr, wherein Rq is hydrogen; , and wherein Rr is:
-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from: -halo; -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and
-Ce to Cs aryl optionally substituted with one or more halos; -C2 to Cs alkenyl optionally substituted with one or more halos; -Ci to Ce alkoxy; or -5 or 6 membered heterocyclo; -SC«2Raa> wherein R83 is:
-5 or 6 heterocyclo optionally substituted with hydroxy; -Ci to Ce alkoxy; or -Ci to Ce alkyl; -CORm5 wherein R1n is:
-amino optionally substituted with one or more Ci to C6 alkyls, wherein the Ci to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo optionally substituted with Ci to Cβ alkyl, which alkyl is optionally substituted with dialkyl-amino; -NR4COORu, wherein R1 is hydrogen, and wherein R1, is:
-Cj to Ci2 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys; -amino optionally substituted with one or more Q to C6 alkyls; -halo;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo; -C2 to Ce alkenyl; or
-C6 to Cs aryl optionally substituted with halo; -NHRbb, wherein Rbb is: -C(=S)NH2; or -PO(ORX)2;
-NRvSθ2Rw, wherein Rv is hydrogen, and wherein Rw is: -Ci to C6 alkyl; or
-alkyl- or dialkyl-amino optionally substituted with halo;
Z is:
-Ci to Cs alkyl optionally substituted with 5 or 6 membered heterocyclo; or
-5 or 6 membered heterocyclo; R is hydrogen; R1 is:
-hydrogen;
-5 or 6 membered heterocyclo;
-Ci to CO alkyl optionally substituted with one or more substituents independently selected from: -amino optionally substituted with heterocyclo;
-amido optionally substituted with Ci to C6 alkyl;
-5 or 6 membered heterocyclo optionally substituted with Ci to C6 alkyl;
-5 or 6 membered heteroaryl; and
-C6 to C8 aryl; -Ci to Ce alkoxy optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with Ci to C6 alkyl;
-5 or 6 membered heterocyclo optionally substituted with Ci to C6 alkyl;
-5 or 6 membered heteroaryl; and
-C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl;
-SO2RX optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and
-5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and
-5 or 6 membered heteroaryl; R2 is:
-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C8 aryl;
-amido optionally substituted with Ci to C6 alkyl; and
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
-alkylthio optionally substituted with.5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo; -alkylthio optionally substituted with C6 to Cs aryl; -alkylthio optionally substituted with Ci to Q alkyl; -SO2Rx optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more Ci to CO alkyls; -SCbRx optionally substituted with 5 or 6 membered heterocyclo; -SO2Rx optionally substituted with C$ to Cs aryl; -SO2RX optionally substituted with Ci to Cβ alkyl; -S(O)Rx optionally substituted with 5 or 6 membered heteroaryl; -S(O)Rx optionally substituted with 5 or 6 membered heterocyclo; -S(O)Rx optionally substituted with C6 to Cs aryl; -S(O)Rx optionally substituted with Ci to C6 alkyl; -alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and
-amino optionally substituted with one or more alkyls;
-amido optionally substituted with Ci to Ce alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl;
-S-Ci to C6 alkyl;
-S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-Ci to C6 alkyl;
-sulfinyl-Cβ to Cg aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to C& alkyl;
-sulfonyl-Ci to Cs alkyl;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and Ci to Ce aϊkyl, which alkyl is optionally substituted with one or more Ci to C6 alkoxys;
-5 or 6 membered heteroaryl optionally substituted with one or more Ci to CO alkyls; and
-Ct to Cs aryl; -C6 to C8 aryl; -(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Ci to Cg alkyls; -C(O)-S or 6 membered heterocyclo optionally substituted with one or more Ce to Cg aryls;
-C(O)-C6 to C8 aryl; -COOH; -C(O)NBk optionally substituted with one or more substituents independently selected from:
-Ci to Cg alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Cs alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more Cj to C6 alkyls, which alkyls are optionally substituted with one or more Cj to C6 alkoxys; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to C6 alkyl; and -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-Ci to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl; and
-C(O)ORx; or
-ORfck, wherein Rkk is: -C6 to C8 aryl; -5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with Ce to Cg aryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1 to Ce alkyl, Ci to C6 alkoxy, and Ci to C6 haloalkyl; -SO2Rx; or -Si(Rx)3; and R3 is hydrogen; with the proviso that at least one of X, Y5 Z, R], and R2 is selected from the following: X is:
-COOH;
-CH=N-(Ci to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more Ci to Ce alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with Ci to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos; -oximyl; -SO2Rx; -SO2NH2; -SO2NH(Rx); -SO2N(Rx);,; -amino optionally substituted with one or more Ci to Ce alkyls and/or -C(O)-Ci to Ce alkyls;
-amido optionally substituted with one or more independently selected Ci to Cs alkyls; -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl substituted with one or more Cj to Ce alkyls, which alkyls are substituted with one or more halos; or -C6 to Cs aryl substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more halos;
-halo; and
-cyano;
Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more Ci to CO alkyls;
-indolyl substituted on the nitrogen with SO2Rx; or
-C6 to Cs aryl substituted with one or more substituents independently selected from: -amino optionally substituted with one or more substituents independently selected from: -SO2Rx, and
-Ci to Ce alkyl substituted with one or more 5 or 6 membered heteroaryls; -OC(O)NHRx; -OC(O)N(RX)2; -OC(O)NH(ORx); -OC(O)NRx(ORx); -OC(O)N(ORX)2;
-OC(O)R3I,, wherein Rab is 5 or 6 membered heterocyclo; -NRoCORp, wherein Rp is:
-amino optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally and independently substituted with one or more Ce to Cg aryls and/or alkoxys, or -5 or 6 membered heterocyclo substituted with one or more Cj to C6 alkyls and/or Cg to Cs aryls, -NRqCONRqRr, wherein Rr is:
-Ci to Cg alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Ce to Cg aryl substituted with one or more halos; -Q2 to C6 alkenyl; -Ci to Cg alkoxy; or -5 or 6 membered heterocyclo; -NRtCOORu, wherein Ru is:
-Ci to Ci2 alkyl substituted with one or more substituents independently selected from:
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more Ci to C6 alkyls; and
-5 or 6 membered heteroaryl; or -C2 to C$ alkenyl; and
Z is:
-Ci to Cg alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo; Ri is:
-Cj to Cg alkyl substituted with:
-amido optionally substituted with Ci to C6 alkyl; and/or
-5 or 6 membered heteroaryl; -Ci to Ce alkoxy substituted with:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with Q to Ce alkyl;
-5 or 6 membered heterocyclo substituted with Ci to Ce alkyl; and/or
-5 or 6 membered heteroaryl; -(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl; -SO2Rx optionally substituted with:
-5 or 6 membered heterocyclo;
-Ce to Cs aryl; and/or
-5 or 6 membered heteroaryl; or -alkylthio optionally substituted with:
-5 or 6 membered heterocyclo;
-Ce to C8 aryl; and/or
-5 or 6 membered heteroaryl; R2 is:
-Ci to C6 alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; -CO to Cs aryl;
-amido optionally substituted with Cj to Cs alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys; -alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo; -alkylthio optionally substituted with C6 to C8 aryl; -alkylthio optionally substituted with Ci to Ce alkyl; -SC<2Rχ optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more Ci to Ce alkyls; -SO2Rx optionally substituted with 5 or 6 membered heterocyclo; -SO2Rx optionally substituted with Ce to Cg aryl; -Sθ2Rx optionally substituted with Ci to Ce alkyl; -S(O)Rx optionally substituted with 5 or 6 membered heteroaryl; -S(O)Rx optionally substituted with 5 or 6 membered heterocyclo; -S(O)Rx optionally substituted with Ce to C8 aryl; -S(O)Rx optionally substituted with Ci to C6 alkyl; -alkoxy substituted with: -alkoxy;
-amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclos; and -amino optionally substituted with one or more alkyls; -amido optionally substituted with Ci to Ce alkyl; -S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to Cβ alkyl; -S-Ci to C6 alkyl;
-S-C6 to C8 aryl;
-sulfϊnyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-suIfinyl-Cj to C6 alkyl;
-sulfinyl-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl;
-sulfonyl-C] to Ce alkyl;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and Ci to Cg alkyl, which alkyl is substituted with one or more Ci to Ce alkoxys;
-5 or 6 membered heteroaryl substituted with one or more Ci to Cg alkyls; or
-C6 to C8 aryl; -C(O)-5 or 6 membered heterocyclo optionally substituted with one or more Ce to Cs aryls;
-C(O)-C6 to C8 aryl; -COOH; -amido substituted with one or more Ci to C6 alkyls optionally substituted with one or more Ci to Cg alkoxys; -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-Ci to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl; and
-C(O)ORx; -ORkk, wherein R^ is:
-C6 to C8 aryl;
-5 or 6 membered heterocyclo optionally substituted with Ci to C6 alkyl and/or C6 to C8 aryl; or
-Si(Rx)3; -(O)-5 or 6 membered heterocyclo optionally substituted with one or more independently selected Ci to C6 alkyls; or
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Ci to Ce alkyls.
2. The compound of claim 1, wherein: X is:
-COOH;
-CH=N-(Ci to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more Ci to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with Ci to Cg alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos; -oximyl; -SO2Rx; -SO2NH2; -SO2NH(Rx); -SO2N(RX)2;
-amino optionally substituted with one or more Ci to Ce alkyls and/or -C(O)-Ci to Ce alkyls;
-amido optionally substituted with one or more independently selected Ci to Ce alkyls; -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl substituted with one or more Ci to Ce alkyls, which alkyls are substituted with one or more halos; or -Ce to Cg aryl substituted with one or more substituents independently selected from:
-Ci to C& alkyl optionally substituted with one or more halos;
-halo; and
-cyano.
3. The compound of claim 2, wherein X is cyano, halo, or alkyl substituted with one or more halos.
4. The compound of claim 3, wherein X is cyano.
5. The compound of claim 3, wherein X is fluoro, bromσ, chloro, or iodo.
6. The compound of claim 3, wherein X is trifluoromethyl.
7. The compound of claim 1, wherein:
Y is Cβ to Cg aryl substituted with one or more of the following:
-amino optionally substituted with one or more substituents independently selected from:
-SO2Rx; and
-C1 to Ce alkyl substituted with one or more 5 or 6 membered heteroaryls; -OC(O)NHRx; -OC(O)N(RX)2; -OC(O)NH(ORx); -OC(O)NRx(ORx); -OC(O)N(ORX)2;
-OC(O)Rab, wherein R5* is 5 or 6 membered heterocyclo; -NR0CORp, wherein Rp is:
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to Cs aryls and/or alkoxys; or -5 or 6 membered heterocyclo substituted with one or more Cj to Ce alkyls and/or C6 to C8 aryls; -NRqCONRqRr, wherein R1. is:
-Ci to Ce alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Cβ to Cg aryl substituted with halo; -C2 to Ce alkenyl; -Ci to Ce alkoxy; or -5 or 6 membered heterocyclo; -NRtCOOR11, wherein R11 is:
-Ci to Ci 2 alkyl substituted with one or more substituents independently selected from the following:
-alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to C^ alkyls; and -5 or 6 membered heteroaryl;
-C2 to Ce alkenyl, or
8. The compound of claim 7, wherein Cβ to Cg aryl is phenyl.
9. The compound of claim 8, wherein phenyl has at least one substituent at the para position.
10. The compound of claim 1 , wherein Z is:
-Ci to Ce alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo.
11. The compound of claim 1, wherein Z is Q to C& alkyl.
12. The compound of claim 11, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.
13. The compound of claim 1 , wherein: Ri is:
-Ci to Ce alkyl substituted with:
-amido optionally substituted with Ci to C$ alkyl; and/or
-5 or 6 membered heteroaryl; -Ci to Ce alkoxy substituted with:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with Ci to Ce alkyl;
-5 or 6 membered heterocyclo substituted with Cj to Q alkyl; and/or
-5 or 6 membered heteroaryl; -(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl; -SChRx optionally substituted with:
-5 or 6 membered heterocyclo;
-Ce to Cg aryl; and/or
-5 or 6 membered heteroaryl; or -alkylthio optionally substituted with:
-5 or 6 membered heterocyclo;
-Ce to C8 aryl; and/or
-5 or 6 membered heteroaryl.
14. The compound of claim 1, wherein: R2 is:
-Ci to Ce alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; -C6 to C8 aryl;
-amido optionally substituted with Ci to Cβ alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys; -alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo; -alkylthio optionally substituted with CO to C8 aryl; -alkylthio optionally substituted with Ci to C6 alkyl; -SO2Rx optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more Cj to C6 alkyls; -SO2Rx optionally substituted with 5 or 6 membered heterocyclo; -SO2Rx optionally substituted with Ce to C8 aryl; -SO2Rx optionally substituted with Ci to Ce alkyl; -S(O)Rx optionally substituted with 5 or 6 membered heteroaryl; -S(O)Rx optionally substituted with 5 or 6 membered heterocyclo; -S(O)Rx optionally substituted with Ce to C8 aryl; -S(O)Rx optionally substituted with Ci to C6 alkyl; -alkoxy substituted with: -alkoxy;
-amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclos; and -amino optionally substituted with one or more alkyls;
-amido optionally substituted with Ci to C6 alkyl;
-S-5 or 6 membered heterocyelo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl;
-S-Ci to C6 alkyl;
-S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfϊnyl-5 or 6 membered heteroaryl;
-sulfinyl-Ci to Ce alkyl;
-sulfinyl-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to Cg alkyl;
-sulfonyl-Ci to C6 alkyl;
-sulfonyl-Cδ to Cg aryl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and Ci to C6 alkyl, which alkyl is substituted with Ci to Ce alkoxy;
-5 or 6 membered heteroaryl substituted with one or more Cj to C6 alkyls; or
-C6 to Cg aryl; -C(O)-5 or 6 membered heterocyclo optionally substituted with one or more Ce to Cs aryls;
-C(O)-C6 to C8 aryl; -COOH; -amido substituted with one or more Ci to CO alkyls optionally substituted with one or more Ci to C6 alkoxys; -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-Ci to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl; and
-C(O)ORx; -ORfck, wherein Rkk is:
-C6 to C8 aryl;
-5 or 6 membered heterocyclo optionally substituted with Ci to Ce alkyl and/or C6 to Cg aryl; or
-Si(Rx)3;
-(O)-5 or 6 membered heterocyclo; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Ci to C$ alkyls.
15. The compound of claim 1 , wherein: X is:
-cyano; -halo; or
-alkynyl optionally substituted with Ci to Ce alkyl; Y is:
-Ce to Cs aryl substituted with one or more substituents independently selected from: -halo; -hydroxy;
-alkoxy optionally substituted with: -one or more halos; or -5 or 6 membered heterocyclo; -Ci to C6 alkyl;
-amino optionally substituted with one or more substituents independently selected from: -SO2Rx; and -Ci to Ce alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls; -OC(O)NHRx; -NR0CORp, wherein Rp is: -Ci to Ce alkyl; or
-amino optionally substituted with one or more Ci to C$ alkyls; and wherein R0 is hydrogen; -NRqCONRqRr, wherein Rq is hydrogen, and wherein Ry is:
-Ci to Ce alkyl optionally substituted with one or more halos; or -Ce to Cg aryl optionally substituted with halo; -Sθ2Raa, wherein R31, is:
-5 or 6 heterocyclo optionally substituted with hydroxy;
-Ci to C6 alkoxy; or -Ci to C6 alkyl; -CORn,, wherein Rm is:
-amino optionally substituted with one or more Ci to C6 alkyls, wherein the Ci to Cβ alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo optionally substituted with Ci to Ce alkyl, which alkyl is optionally substituted with dialkyl-amino; -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
-Ci to Ci2 alkyl optionally substituted with one or more substituents independently selected from: -Cβ to Cg aryl optionally substituted with one or more halos and/or haloalkyls; -halo; and
-5 or 6 membered heteroaryl; -C6 to Cs aryl optionally substituted with halo; or -5 or 6 membered heterocyclo; -NHRbb, wherein Rbt, is: -C(=S)NH2; or -PO(ORX)2;
-NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is: -Ci to C6 alkyl; or
-alkyl- or dialkyl-amino optionally substituted with halo; or
Z is:
-Ci to C6 alkyl; or
-5 or 6 membered heterocyclo; R is hydrogen; Ri is:
-hydrogen;
-Ci to CO alkoxy substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -5 or 6 membered heteroaryl; -(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl; or -5 or 6 membered heterocyclo; R2 is:
-alkoxy substituted with one or more substituents independently selected from: -halo; -hydroxy;
-alkoxy optionally substituted with alkoxy; -amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl; -amido optionally substituted with Ci to C6 alkyl;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to Cβ alkyl; -S-Ci to C6 alkyl; -sulfinyl-Ci to C6 alkyl; -sulfonyl-Cj to Ce alkyl; -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and Ci to Ce alkyl, which alkyl is optionally substituted with one or more independently selected Ci to C6 alkoxys; and -5 or 6 membered heteroaryl optionally substituted with one or more C1 to Cβ alkyls;
-SOiRx optionally substituted with C] to Ce alkyl; -S(O)Rx optionally substituted with C, to C6 alkyl; -(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Ci to Cβ alkyls; -C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C$ aryls; -C(O)-C6 to C8 aryl;
-COOH;
-C(O)NH2 optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Cj to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl; and;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -one or more halos; -Ci to C6 alkyl; and -SO2Rx; -amido optionally substituted with one or more Ci to C$ alkyls, which alkyls are optionally substituted with one or more Ci to Ce alkoxys; or -ORkk, wherein Rkk is:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Ci to C6 alkoxy, and Ci to C6 haloalkyl; or -5 or 6 membered heterocyclo optionally substituted with Ci to C6 alkyl, which alkyl is optionally substituted with C6 to Cs aryl; and R3 is hydrogen.
16. The compound of claim 15, wherein: X is:
-cyano; or -halo; Y is:
-phenyl substituted with one or more substituents independently selected from: -halo; and -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
-CJ to Ci 2 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to Cg aryl optionally substituted with one or more halos;
-halo; and
-5 or 6 membered heteroaryl; -Cβ to Cs aiyl optionally substituted with halo; or -5 or 6 membered heterocyclo; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is:
-alkoxy substituted with one or more substituents independently selected from: -halo; and
-alkoxy optionally substituted with alkoxy; -(O)-5 or 6 membered heterocyclo; -amido optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more Ci to Ce alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -one or more halos; -Ci to C6 alkyl; and -SO2Rx; and R3 is hydrogen.
17. The compound of claim 15, wherein: X is cyano;
Y is C6 to Cg aryl substituted with one or more substituents independently selected from
NRtCOORu, wherein is hydrogen, and wherein Ru is Ci to C12 alkyl optionally substituted with one or more Cg to C8 aryls; Z is 5 or 6 membered heterocyclo; R is hydrogen; Ri is hydrogen; R2 is alkoxy; and R3 is hydrogen.
18. The compound of claim 15, wherein: X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with Cj to C6 alkyl;
-NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is Ci to C6 alkyl; -CORm, wherein Rn, is:
-amino optionally substituted with one or more Ci to C6 alkyls, wherein the Cj to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or
-3 to 7 membered heterocyolo; and -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
-Ci to Ci2 alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cg aryl optionally substituted with one or more haloalkyls; and -halo; or
-5 or 6 membered heterocyclo; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is alkoxy substituted with alkoxy; and R3 is hydrogen.
19. The compound of claim 15, wherein: X is cyano;
Y is Ce to Cs aryl substituted with one or more substituents independently selected from:
-NRtCOORu3 wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl optionally substituted with one or more halos; and
-NRVSO2RW, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is amido optionally substituted with one or more Ci to C6 alkyls, which alkyls are substituted with one or more Cj to C6 alkoxys; and R3 is hydrogen.
20. The compound of claim 15, wherein: X is cyano;
Y is Cβ to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more Ci to C6 alkyls;
-NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl optionally substituted with one or more halos;
-NRVSO2RW, wherein Rv is hydrogen, and wherein Rw is Ci to Ce alkyl; and
Z is Ci to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is alkoxy substituted with sulfonyl-Ci to C6 alkyl; and
R3 is hydrogen.
21. The compound of claim 15, wherein Y is Ce to Cg aryl substituted with one or more substituents independently selected from NR4COORU, wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl optionally substituted with one or more halos.
22. The compound of claim 15, wherein: X is cyano;
Y is Cg to C8 aryl substituted with one or more substituents independently selected from:
-Ci to C6 alkyl;
-amino optionally substituted with one or more Ci to Cg alkyls;
-NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is Ci to Ce alkyl;
-NRtCOORu5 wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl;
-NRvSO2Rw, wherein Rv is hydrogen and wherein Rw is: -Ci to C6 alkyl; or -alkyl- or dialkyl-amino; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is ORjdc, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Cj to Ce alkoxy, and C1 to
C6 haloalkyl; and R3 is hydrogen.
23. The compound of claim 22, wherein: X is cyano;
Y is C6 to Cg aryl substituted with one or more substituents independently selected from:
-NR1COORu, wherein R1 is hydrogen, and wherein R11 is C1 to C12 alkyl; and
-NRvSθ2Rw, wherein Rv is hydrogen, and wherein Rw is: -C1 to C6 alkyl; or -alkyl- or dialkyl-amino; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Ci to C6 alkoxy, and Ci to
Ce haloalkyl; and R3 is hydrogen.
24. The compound of claim 22, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more Ci to C6 haloalkyls.
25. The compound of claim 22, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more Ci to C6 alkyls.
26. The compound of claim 1, wherein: X is cyano;
Y is C6 to Cs aryl substituted with one or more substituents independently selected from:
-NR4COORu, wherein R, is hydrogen, and wherein Ru is Cj to Ci2 alkyl; and -NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl;
Z is Ci to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is C(O)-5 or 6 membered heterocyclo; and
R3 is hydrogen.
27. The compound of claim 1, wherein: X is halo;
Y is C6 to Cg aryl substituted with one or more substituents independently selected from:
-amino;
-NRqCONRqR1, wherein Rq is hydrogen, and wherein Rr is Ci to C6 alkyl; and
-NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C] to C12 alkyl; Z is C1 to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is alkoxy; and R3 is hydrogen.
28 The compound of claim 15 wherein: X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from: -halo;
-NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is d to Ce alkyl; -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl optionally substituted with one or more substituents independently selected from: -Ce to Cs aryl optionally substituted with one or more halos; and -halo;
-NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is: -C1 to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo; and
Z is Ci to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is 5 or 6 membered heterocyclo; and
R3 is hydrogen.
29. The compound of claim 28, wherein Y is Cg to C8 aryl substituted with NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to Ce alkyl.
30. The compound of claim 28 wherein Y is Ca to C8 aryl substituted with
31. The compound of claim 15, wherein: X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from: -halo;
-amino optionally substituted with one or more Ci to Ce alkyls; -OC(O)NHRx;
-NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is Cj to Ce alkyl; -NR1COORu, wherein Rt is hydrogen, and wherein Ru is Ci to C^ alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cg aryl optionally substituted with one or more halos and/or haloalkyls; and -halo;
-NHRbb, wherein RN, is -C(=S)NH2; -NRvSO2Rw5 wherein Rv is hydrogen, and wherein Rw is: -Ci to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo; and
Z is Ci to C6 alkyl;
R is hydrogen;
R] is hydrogen;
R2 is (O)-5 or 6 membered heterocyclo; and
R3 is hydrogen.
32. The compound of claim 31 , wherein Y is Cβ to Cs aryl substituted with NRtCOORu, wherein R1 is hydrogen, and wherein Ru is Ci to C]2 alkyl optionally substituted with one or
more substituents independently selected from C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls.
33. The compound of claim 15, wherein: X is cyano;
Y is Q to Cg aryl substituted with one or more substituents independently selected from
NRtCOORU:J wherein Rt is hydrogen, and wherein R11 is Ci to Ci2 alkyl substituted with one or more halos; Z is Ci to C6 alkyl; R is hydrogen; Ri is
-hydrogen;
-(O)-5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo; R2 is:
-alkoxy substituted with one or more substituents independently selected from: -halo; -alkoxy;
-sulfonyl-Ci to C6 alkyl; -5 to 7 membered heterocyclo; -5 or 6 membered heteroaryl; -(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl; -5 or 6 membered heteroaryl; -5 or 6 membered heterocyclo; or -ORkk, wherein Rkk is 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkoxys; and R3 is hydrogen.
34. The compound of claim 33, wherein Ri is hydrogen, and R2 is alkoxy substituted with one or more halos.
35. The compound of claim 33, wherein Ri is hydrogen; and R2 is alkoxy substituted with one or more alkoxys.
36. The compound of claim 15, wherein: X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NRqCONRqRr, wherein Rq is hydrogen; and wherein Rr is C6 to C8 aryl substituted with halo; and
-NRtCOORu, wherein Rt is hydrogen, and wherein R11 is Ci to C12 alkyl substituted with Ce to C8 aryl, which aryl is substituted with one or more halos and/or haloalkyls; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is:
-alkoxy substituted with one or more substituents independently selected from: -alkoxy; and
-5 or 6 membered heteroaryl; -(O)-5 or 6 membered heterocyclo; or -(O)-5 or 6 membered heteroaryl; and R3 is hydrogen.
37. The compound of claim 36, wherein Y is Ce to Cs aryl substituted with NRqCONRqRr, wherein Rq is hydrogen, and wherein R1- is C$ to Cg aryl substituted with halo.
38. The compound of claim 36, wherein Y is C6 to Cg aryl substituted with one or more substituents independently selected from NRtCOOR11, wherein R, is hydrogen, and wherein R11 is Ci to C 12 alkyl substituted with Ce to Cs aryl, which aryl is substituted with one or more halos and/or haloalkyls.
39. A compound of formula lib
or a pharmaceutically acceptable salt thereof, wherein: X is cyano;
Y is Ce to C8 aryl substituted with one or more substituents independently selected from: -Ci to C6 alkyl;
-amino substituted with Ci to CO alkyl
-NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more halos;
-NRVSO2RW) wherein Rv is hydrogen, and wherein Rw is C1 to Ce alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is:
-alkoxy substituted with one or more halos; -5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -C1 to C6 alkyl; and
"NO2;
-C(O)-3 to 7 membered heterocyclo or -C(O)-5 membered heterocyclo; and -ORkk, wherein Rtk is:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from cyano, and Ci to Ce alkyl; or -5 or 6 membered heterocyclo optionally substituted with one or more =O; and Rj is hydrogen.
40. The compound of claim 39, wherein: X is a cyano group;
Y is C6 to C8 aryl substituted with NRtCOORu, wherein R1 is hydrogen, and wherein Ru is C] to
Ci2 alkyl substituted with one or more halos; Z is Ci to C6 alkyl; R is a hydrogen, R] is a hydrogen;
R2 is alkoxy substituted with one or more halos; and R3 is a hydrogen.
41. The compound of claim 40, wherein the Ce to C8 aryl is phenyl.
42. The compound of claim 41 , wherein the phenyl is substituted at the para position.
43. The compound of claim 41, wherein Ru is Ci to C12 alkyl substituted with fluoro.
44. The compound of claim 39, wherein: X is cyano;
Y is Cβ to Cs aryl substituted with one or more substituents independently selected from:
-Ci to C6 alkyl;
-amino substituted with C] to C6 alkyl; and
-NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with cyano; and Rj is hydrogen.
45. The compound of claim 44, wherein Y is C6 to Cs aryl para substituted with NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl.
46. The compound of claim 44, wherein Y is C6 to Cs aryl para substituted with Ci to C6 alkyl and NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C] to C6 alkyl.
47. The compound of claim 44, wherein Y is C6 to Cs aryl para substituted with amino substituted with Ci to C6 alkyl.
48. The compound of claim 44, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with cyano at the ortho position.
49. The compound of claim 39, wherein: X is cyano;
Y is C6 to Cg aryl substituted with one or more substituents independently selected from:
-NRtCOORu, wherein R1 is hydrogen, and wherein R11 is Ci to C12 alkyl; and -NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl;
Z is Ci to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with Cj to C6 alkyl; and
R3 is hydrogen.
50. The compound of claim 49, wherein the C6 to Cs aryl is phenyl.
51. The compound of claim 50, wherein Y is phenyl substituted at the para position with NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl.
52. The compound of claim 50, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein R11 is Ci to C12 alkyl.
53. The compound of claim 39, wherein: X is cyano;
Y is Ce to Cs aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to
C12 alkyl substituted with one or more halos; Z is C1 to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl; and R3 is hydrogen.
54. The compound of claim 53, wherein the C6 to Cg aryl is phenyl.
55. The compound of claim 54, wherein the phenyl is substituted at the para position.
56. The compound of claim 55, wherein Ru is Ci to C12 alkyl substituted with fluoro.
57. The compound of claim 39, wherein: X is cyano;
Y is C6 to Cg aryl substituted with NR4COORu, wherein R4 is hydrogen, and wherein Ru is Cj to
C12 alkyl optionally substituted with one or more halos; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is 5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl; and R3 is hydrogen.
58. The compound of claim 57, wherein the C6 to Cs aryl is phenyl.
59. The compound of claim 58, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to Cn alkyl.
60. The compound of claim 58, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to C12 alkyl substituted with one or more halos.
61. The compound of claim 60, wherein R0 is Ci to Cn alkyl substituted with fluoro.
62. The compound of claim 39, wherein: X is cyano;
Y is Ce to Cg aryl substituted with NRtCOORu, wherein R, is hydrogen, and wherein Ru is Ci to
C12 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is ORfck, wherein R\& is 5 or 6 membered heterocyclo; and R3 is hydrogen.
63. The compound of claim 62, wherein the Ce to C8 aryl is phenyl.
64. The compound of claim 63, wherein the phenyl is substituted at the para position.
65. The compound of claim 39, wherein: X is cyano;
Y is CO to Cs aryl substituted with NRtCOORU5 wherein R4 is hydrogen, and wherein Ru is Ci to
C12 alkyl; Z is C1 to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is 5 or 6 membered heterocyclo; and R3 is hydrogen.
66. The compound of claim 65, wherein the Ce to Cs aryl is phenyl.
67. The compound of claim 66, wherein the phenyl is substituted at the para position.
68. The compound of claim 39, wherein: X is cyano;
Y is Cg to Cg aryl substituted with NR1COORu, wherein R1 is hydrogen, and wherein Ru is C1 to
C]2 alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is 5 or 6 membered heteroaryl substituted with NO2; and R3 is hydrogen.
69. The compound of claim 68, wherein the Ce to Cg aryl is phenyl.
70. The compound of claim 69, wherein the phenyl is substituted at the para position.
71. The compound of claim 39, wherein: X is cyano;
Y is Ce to Cn aryl substituted with NRtCOORU) wherein Rt is hydrogen, and wherein R0 is Ci to
C12 alkyl; Z is C1 to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is -C(O)-3 to 7 membered heterocyclo or -C(O)-5 membered heterocyclo; and R3 is hydrogen.
72. The compound of claim 71 , wherein the Ce to Cs aryl is phenyl.
73. The compound of claim 72, wherein the phenyl is substituted at the para position.
74. The compound of claim 39, wherein: X is cyano;
Y is Cg to Cg aryl substituted with NRtCOOR11, wherein R4 is hydrogen, and wherein Ru is Ci to
C12 alkyl; Z is C1 to C6 alkyl; R is hydrogen; R] is hydrogen;
R2 is ORkk, wherein Rkk is -5 or 6 membered heterocycle substituted with one or more =O; and R3 is hydrogen.
75. The compound of claim 74, wherein the C6 to C8 aryl is phenyl.
76. The compound of claim 75, wherein the phenyl is substituted at the para position.
77. A compound of formula lie
or a pharmaceutically acceptable salt thereof, wherein:
X is cyano;
Y is Cg to C8 aryl substituted with one or more substituents independently selected from:
-NRqCONRqRr, wherein R<, is hydrogen, and wherein Rr is Ci to Ce alkyl; -NRtCOORu, wherein Rt is hydrogen, and wherein R11 is Ci to C]2 alkyl optionally substituted with one or more substituents independently selected from: -Ce to Cg aryl optionally substituted with one or more halos; -halo; and
-5 or 6 membered heteroaryl; and
-NRvSθ2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to Ce alkyl; Z is:
-Ci to C6 alkyl; or -5 or 6 membered heterocyclo; R is hydrogen; Ri is:
-Ci to Ce alkoxy substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -5 or 6 membered heteroaryl; -(O)-5 or 6 membered heterocyclo; -(O)-5 or 6 membered heteroaryl; or -5 or 6 membered heterocyclo; R2 is hydrogen; and R3 is hydrogen; with the proviso that when Ri is Ci to Ce alkoxy substituted with a 5 or 6 membered heterocyclo or when Ri is a 5 or 6 membered heterocyclo, Y is a Ce to Cs aryl substituted with NR1COORu, wherein Rt is hydrogen, and wherein R11 is:
Ci to C12 alkyl substituted with one or more halos; or aryl substituted with one or more halos.
78. The compound of claim 77, wherein:
Y is Ce to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein R11 is Ci to
C12 alkyl;
Z is Ci to C6 alkyl; and Ri is Ci to Ce alkoxy substituted with 5 or 6 membered heteroaryl.
79. The compound of claim 77, wherein Ri is Ci to Ce alkoxy substituted with 5 or 6 membered heteroaryl.
80. The compound of claim 77, wherein Rj is (O)-5 or 6 membered heterocyclo.
81. The compound of claim 77, wherein Ri is (O)-5 or 6 membered heteroaryl.
82. The compound of claim 77, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, or cyclopentyl.
83. A compound of formula Hd
or a pharmaceutically acceptable salt thereof, wherein: X is hydrogen;
Y is Ce to C8 aryl substituted with one or more substituents independently selected from:
-NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is Ci to C6 alkyl; and
-NRtCOORu, wherein Rt is hydrogen, and wherein Ru is Ci to Cn alkyl optionally substituted with one or more halos; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen; R2 is ORkk, wherein Rkk is:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo; or
-5 or 6 membered heteroaryl optionally substituted with one or more independently selected halos; and Ri is hydrogen.
84. The compound of claim 83, wherein: X is hydrogen;
Y is Ce to Cg aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein R11 is Ci to
Cu alkyl substituted with one or more halos;
Z is C1 to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is ORkk, wherein R^k is 5 or 6 membered heteroaryl; and
R3 is hydrogen.
85. The compound of claim 84, wherein the Ce to Cz aryl is phenyl.
86. The compound of claim 84, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein R11 is Ci to Cn alkyl substituted with fluoro.
87. The compound of claim 84, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.
88. The compound of claim 83, wherein R2 is (O)-5 or 6 membered heterocyclo.
89. A compound of formula lie
or a pharmaceutically acceptable salt thereof, wherein:
X is:
-hydrogen;
-cyano;
-nitro;
-formyl;
-COOH;
-CORx, wherein Rx is Ci to Ce alkyl;
-CH=N-(C, to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more Ci to Ce alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with cyano or Ci to C6 alkyl, which alkyl is optionally substituted with one or more halos; -oximyl; -SO2Rx; -SO2NH2; -SO2NH(Rx); -SO2N(Rx)2; -amino optionally substituted with one or more independently selected Ci to Ce alkyls and/or -C(O)-Ci to C6 alkyls;
-amido optionally substituted with one or more independently selected Ci to Ce alkyls; -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more halos; or -Ce to C8 aryl optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more halos; -halo; and -cyano; Y is:
-benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more Ci to C6 alkyls; -indolyl optionally substituted on the nitrogen with -SO2RX; -Cδ to Cs aryl optionally substituted with one or more substituents independently selected from: -halo;
-Ci to C6 alkyl;
-alkoxy, optionally substituted with one or more substituents independently selected from: -halo;
-5 or 6 membered heterocyclo; -C(O)NH2 optionally substituted with Ce to C8 alkyl; -C(O)NH-(Ci to C6)-alkyl; -hydroxy; -haloalkyl;
-cyano; -nitro; -COOH; -N=CHN(Rx)2;
-amino optionally substituted with one or more substituents independently selected from: -SO2Rx; -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and Cβ to C8 aryl optionally substituted with halo;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-Ci to C7 alkyl optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl; -Ce to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl; -alkoxy; and -halo; and -PO2Rx;
-OC(O)NHRx wherein Rx is optionally substituted with vinyl; -OC(O)N(Ru)2, wherein R1, is alkyl or C$ to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino; -OC(O)NH(ORuu), wherein Ruu is -Ce to Cg aryl optionally substituted with dialkylamino; -OC(O)NRx(ORx);
-OC(O)N(ORX)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
-NR0C(O)Rp, wherein Rp is: -Ci to C6 alkyl;
-amino optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from Ce to Cs aryl and alkoxy; or -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from Ci to Ce alkyl and Ce to C8 aryl; and wherein R0 is: -hydrogen; or -Ci to C6 alkyl; -NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is:
-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from: - halo; -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Ce to Cs aryl optionally substituted with halo; -C2 to Ce alkenyl optionally substituted with one or more halos; -Ci to Ce alkoxy; -5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -Sθ2R_a, wherein Ra3 is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy;
-Ci to Ce alkoxy; and -Ci to C6 alkyl;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-alkoxy;
-hydroxy;
-halo; -CORm, wherein Rn, is:
-amino optionally substituted with, one or more Cj to C6 alkyls, which alkyls are optionally substituted with 5 or 6 membered heterocyclo or Ce to C8 aryl, which heterocyclo or aryl is optionally substituted one or more substituents independently selected from halo and alkoxy; -heterocyclo optionally substituted with hydroxy; -3 to 7 membered heterocyclo optionally substituted with Ci to Ce alkyl, which alkyl is optionally substituted with dialkyl-amino; -NRtCOORu, wherein R1 is hydrogen, and wherein R11 is:
-Ci to Ci2 alkyl optionally substituted with one or more substituents independently selected from:
-Cβ to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys;
-amino optionally substituted with one or more Cj to Ce alkyls;
-halo;
-SO2Rw; -SO2Rx;
-5 or 6 membered heteroaryl; and
-5 or 6 membered heterocyclo; -C2 to Ce alkenyl;
-Ce to C8 aryl optionally substituted with halo; -4 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
=O;
-SO2RW;
-CORp; and
-(CO)O-(Ci to C4 alkyl)-O-(Ci to C4 alky]); -NHRbb, wherein Rbb is: -C(=S)NH2; -C(=S)NHRX; -CC=S)NRxRx; -C(=N-CN)NHRx; or -PO(ORX)2; -N(CONHRW)2; -NH(SORw); -N(SO2RW)2; -NRvSO2Rw, wherein Rv is hydrogen or alkyl optionally substituted with 4 to 7 • membered heterocyclo; and wherein Rw is:
-Ci to Ce alkyl optionally substituted with Ce to Cs aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl; -C6 to C8 aryl; -Cs to Cs heteroaryl; or -amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C& alkoxy, alkoxycarbonyl, (CO)O-(Ci to Q) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -halo;
-Ci to C6 alkyl; -alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo; and
-C(O)NH2 optionally substituted with C6 to C8 aJJcyl; -hydroxy; -haloalkyl; -cyano;
-nitro; -COOH;
-amino optionally substituted with one or more substituents independently selected from: -SO2Rx;
-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -Ce to Cs aryl optionally substituted with halo;
- Cs to Cβ heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and
-C1 to C7 alkyl optionally substituted with one or more substituents independendy selected from: -5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls; -Cs to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -alkoxy; and -halo;
-NR0CORp, wherein Rp is: -C] to C6 alkyl;
-amino optionally substituted with one or more Ci to Cs alkyls, which alkyls are optionally and independently substituted with one or more C& to Cg aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more Ci to Ce alkyls and/or Cβ to C8 aryls; and wherein R0 is: -hydrogen; or -Ci to C6 alkyl;
-NRςCONRqRr, wherein R<, is hydrogen, and wherein Rr is:
-Ci to Cβ alkyl optionally substituted with one or more substituents independently selected from: - halo; -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Q to C8 aryl optionally substituted with halo; -C2 to Ce alkenyl optionally substituted with one or more halos; -Ci to Cβ alkoxy; -5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
-Ci to Ci 2 alkyl optionally substituted with one or more substituents independently selected from: -Ce to Cg aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to Ce alkyls; -halo; -SO2RW; -SO2Rx;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo; and -NRvSθ2Rw, wherein Rv is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo; and wherein Rw is:
-Ci to Ce alkyl optionally substituted with C6 to C8 aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl; -C6 to C8 aryl; -Ce to Cg heteroaryl;
-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, alkoxycarbonyl, hydroxy, cyano. 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
Z is:
-Ci to C6 alkyl optionally substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;
R is hydrogen; Ri is:
-hydrogen;
-a 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-Ci to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; or -5 or 6 membered heteroaryl optionally substituted with, one or more independently selected from:
-Cj to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C i to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2 Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to C6 alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys;
-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from: -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys; -amido optionally substituted with Ci to Ce alkyl; -5 or 6 membered heterocyclo optionally substituted with C] to Cg alkyl; -5 or 6 membered heteroaryl; and -C6 to Cg aryl;
-SO2 Rx;
-C2 to C6 alkenyl optionally substituted with -SO2 Rx;
-Ci to Ce alkoxy optionally substituted with one or more substituents independently selected from: -halo; -hydroxy; -cyano;
-alkoxy optionally substituted with alkoxy; -amino optionally substituted with one or more independently selected from 5 or
6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and
-amino optionally substituted with one or more alkyl; -amino optionally substituted with heterocyclo; -amido optionally substituted with Ci to Ce alkyl; -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and Cj to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkoxy; and
-Cβto Cg alryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to CO alkyl; and
-4 to 7 membered heterocyclo; -alkoxy; and -C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy; -Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl; -CORp; and -C(O)ORx; or
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl; -cyano; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx; -CORx; -C(O)NH2 optionally substituted with one or more substituents independently selected from:
-Ci to Cg alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C& alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Cβ alkyl, which alkyl is optionally substituted with one or more Ci to C6 alkoxys; -C(O)NH2 optionally substituted with one or more Ci to Cs alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -Ce to C8 aryl;
-5 or 6 membered heteroaryl; and
-Ci to Cg alky further optionally substituted with one or more substituted with hydroxys;
-SOaRx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; -Ce to Cs aryl; and -5 or 6 membered heteroaryl; or
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; -Ce to C8 aryl; and -5 or 6 membered heteroaryl;
-Cg to Cg aryl optionally substituted with one or more substituents independently selected from: -Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx; -CORx; -C(O)NEb optionally substituted with one or more Ci to Cβ alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to C6 alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl; -COOH; or -ORkk, wherein Rkk is:
-Ce to C8 aryl optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Cj to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Cg alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and
-amido optionally substituted with one or more substituents independently selected from halo, Cj to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Cg alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys;
R2 is:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; -C6 to C8 aryl;
-amido optionally substituted with Ci to Ce alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and
-SO2 Rx;
-C2 to Cf, alkenyl optionally substituted with Sθ2Rx;
-alkylthio optionally substituted with one or more sύbstituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo;
-Ce to Cs aryl; and
-Ci to C6 alkyl; -SO2Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyls;
-5 or 6 membered heterocyclo;
-Cβ to Cs aryl; and
-C1 to C6 alkyl; -S(O)Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and
-Ci to C6 alkyl; -alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from -SO2-C1 to C4 alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and
-amino optionally substituted with one or more alkyls;
-amido optionally substituted with Ci to Ce alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl;
-S-C] to Ce alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-C5 to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo; -sulfinyl-5 or 6 membered heteroaryl; -sulfinyl-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cg aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -suljfinyl-Cβ to Cg aryl; -sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl; -sulfonyl-C] to Cβ alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-C5 to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfonyl-Cβ to C8 aryl; -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =0, heterocyclo, and
Ci to Ce alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Ci to Cβ alkoxy; and
-Cβ to C8 aryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to C6 alkyl optionally substituted with one or more alkoxys;
-4 to 7 membered heterocyclo; and -alkoxy; and
-C6 to C8 aryl; -C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C& alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Ci to Cg alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and
-amido optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to C6 alkyl, which alkyl is optionally substituted with one or more Ci to C6 alkoxys; -(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
=O;
-Ci to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl;
-CORp; and
-C(O)ORx; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and
-amido optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Cj to Ce alkoxys;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -C6 to C8 aryl;
-5 or 6 membered heteroaryl; and
-Ci to C6 alkyl optionally substituted with one or more hydroxys; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl; -COOH; -C(O)NH2 optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more Ci to C6 alkoxys;
-amino optionally substituted with one or more substituents independently selected from:
-SO2Rx;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyi, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyi, cyano, alkoxy, haloalkoxy and -C6 to Cg aryl optionally substituted with halo; -Cs to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyi; -Ci to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyi; -C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyi; -alkoxy; and -halo;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C] to Cg alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-mtro;
-hydroxy;
-COOH;
-CO2Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Cj to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Cg alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Ci to Cβ alkoxys; -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
=O;
-C1 to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl; -CORp1 and -C(O)ORx; -ORick, wherein R1& is:
-C6 to Cs aryl optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl; -cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Cg alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and
-amido optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to C6 alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys;
-5 to 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with Cβ to Cg aryl; or
-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1 to Ce alkyl, Ci to Ce alkoxy, and Ci to Ce haloalkyl;
-SO2Rx; or
-Si(Rx)3;
-OC(O)NHRx wherein Rx is optionally substituted with -Ce to Cs aryl; -OC(O)N(RX)2; or
with the proviso that at least one of X, Y, Z, Ri , R2 and R3 is selected from the following: X is:
-CH=N-(Ci to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more Ci to Ce alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with Ci to CO alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SO2Rx;
-SO2NH2;
-SO2NH(Rx);
-SO2N(RX)2;
-amino optionally substituted with one or more independently selected Ci to CQ alkyls and/or -C(O)-Ci to C6 alkyls;
-amido optionally substituted with one or more independently selected Ci to Ce alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with, one or more C] to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -Ce to C8 aryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more halos;
-halo; and
-cyano;
Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more Q to Ce alkyls;
-indolyl substituted on the nitrogen with -SO2Rx;
-Ce to C8 aryl substituted with one or more substituents independently selected from: -alkoxy substituted with one or more substituents independently selected from: -C(O)NH2 optionally substituted with C6 to C8 alkyl; and -C(O)NH-(Ci to C6)-alkyl; -haloalkyl; -cyano; -COOH; -N=CHN(RX)2;
-amino substituted with one or more substituents independently selected from: -SO2Rx; -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and Cβ to C8 aryl optionally substituted with halo;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-C1 to C7 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl., halo, and haloalkyl; -C$ to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl; -alkoxy; and -halo; and -PO2Rx;
-OC(O)NHRx wherein Rx is optionally substituted with vinyl; -OC(O)N(Ru)2, wherein Rn is alkyl or CU to Cg aryl, which alkyl or aryl is optionally substituted with dialkylamino; -OC(O)NH(ORuu), wherein Ruu is -Cs to C8 aryl optionally substituted with dialkylamino; -OC(O)NRx(ORx); -OC(O)N(ORX)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl; -NR0C(O)Rp, wherein Rp is:
-amino optionally substituted with one or more C1 to Cg alkyls, which alkyls are optionally substituted with one or more substituents independently selected from Ce to Cg aryl and alkoxy; or -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from Ci to Ce alkyl and Ce to Cs aryl; -NRqCONRqRr, wherein Rr is:
-C) to Cή alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Ce to C8 aryl substituted with halo; -C2 to CO alkenyl optionally substituted with one or more halos;
-Ci to Ce alkoxy; -5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -SO2Ra85 wherein Raa is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy;
-Ci to Ce alkoxy; and -Ci to C6 alkyl; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -alkoxy; -hydroxy; -halo; -CORm, wherein Rn, is:
-amino substituted with one or more C1 to C6 alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or Ce to Cs aryl, which heterocyclo is substituted with one or more halos and/or alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys; -heterocyclo substituted with hydroxy; -NRtCOORu, wherein Ru is:
-Ci to Ci 2 alkyl substituted with one or more substituents independently selected from: -Ce to Cs aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys; -amino optionally substituted with, one or more Ci to Ce alkyls; -SO2RW; -SO2Rx; and
-5 or 6 membered heteroaryl; -C2 to Ce alkenyl;
-4 to 7 membered heterocyclo substituted with one or more substituents independently selected from: =O;
-SO2Rw;
-CORP; and
-(CO)O-(C] to C4 alkyl)-O-(C1 to C4 alkyl);
-4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: =O; -so2Rw;
-CORP; and
-(CO)O-(Ci to C4 alkyl)-O-(Ci to C4 alkyl); -NHRbb, wherein Rω, is: -C(=S)NHRX; -C(=S)NRXRX; or -C(=N-CN)NHRX; -N(CONHRw)2;
-N(SO2Rw)2;
-NRvSO2Rw, wherein Rv is alkyl substituted with 4 or 7 membered heterocyclo; or wherein Rw is:
-Ci to C6 alkyl substituted with Ce to Cg aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, alkoxycarbonyl, (CO)O-(Ci to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -halo;
-Ci to C6 alkyl; -alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo; and
-C(O)NH2 optionally substituted with C6 to C8 alkyl; -hydroxy; -haloalkyl; -cyano; -nitro; -COOH; -amino optionally substituted with one or more substituents independently selected from:
-SO2Rx;
-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;
- Cs to Ce heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and
-Ci to C7 alkyl optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls; -Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -alkoxy; and -halo; -NR0CORp, wherein Rp is:
-amino optionally substituted with one or more Ci to Cβ alkyls, which alkyls are optionally and independently substituted with one or more C^ to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more Ci to CO alkyls and/or Ce to C8 aryls; -NRqCONRqRr, wherein Rr is:
-Ci to Ce alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Ce to Cs aryl substituted with halo; -C2 to C6 alkenyl optionally substituted with one or more halos;
-Ci to Ce alkoxy; -5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -NR1COORu, wherein Ru is:
-C] to C]2 alkyl substituted with one or more substituents independently selected from: -Ce to Cg aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to Ce alkyls;
-SO2Rx; and
-5 or 6 membered heteroaryl;
-NRvSθ2Rw* wherein Rv is alkyl substituted with 4 to 7 membered heterocyclo; or wherein Rw is:
-Cj to Ce alkyl substituted with Ce to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl; -C6 to C8 aryl;
-amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, C] to Cg alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
Z is:
-Ci to Ce alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;
Ri is:
-a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from: -hydroxy; -Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl; -CORp; and -C(O)ORx; or
-5 or 6 membered heteroaryl substituted with one or more independently selected from: -Ci to Cβ alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2 Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Ci to Cβ alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Ci to C6 alkoxys; -Ci to Ce alkyl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
-amido optionally substituted with Ci to Ce alkyl;
-5 or 6 membered heterocyclo substituted with Ci to C6 alkyl;
-5 or 6 membered heteroaryl; and
-C6 to C8 aryl;
-SO2 Rx;
-C2 to Ce alkenyl optionally substituted with -SO2Rx; -Ci to Ce alkoxy substituted with one or more substituents independently selected from:
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl;
-amino optionally substituted with heterocyclo;
-amido optionally substituted with Ci to C6 alkyl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and Ci to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkoxy; and
-C6 to C8 alryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl; and -4 to 7 membered heterocyclo; and
-alkoxy; -(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-Ci to Ce alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; or . -(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C6 aUcoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx; -CORx;
-C(O)NEb optionally substituted with one or more substituents independently selected from: -C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, Cj to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -C(O)NH2 optionally substituted with one or more Ci to Cs alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to CQ alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -Ce to Cs aryl;
-5 or 6 membered heteroaryl; and
-Ci to Cg alky further optionally substituted with one or more substituted with hydroxys;
-SO2Rx optionally substituted with one or more substituents independently selected from.:
-5 or 6 membered heterocyclo;
-Cβ to Cs aryl; and
-5 or 6 membered heteroaryl; or -alkylthio optionally substituted with, one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-Ce to Cs aryl; and
-5 or 6 membered heteroaryl; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl; -COOH; -ORfck, wherein Rtk is:
-Ce to Cs aryl optionally substituted with one or more substituents independently selected from halo, Ci to C^ alkyl, Cj to C$ alkoxy, and Ci to Cg haloalkyl;
R2 is:
-Ci to Ce alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-Ct to Cg aryl;
-amido optionally substituted with Ci to Cδ alkyl; and
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and
-SO2 Rx:
-C2 to Ce alkenyl optionally substituted with SO2RX; -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo;
-Ce to C8 aryl; and
-Ci to C6 alkyl;
-SO2Rx optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyls;
-5 or 6 membered heterocyclo; -Ce to C8 aryl; and -C, to C6 alkyl;
-S(O)Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl; -5 or 6 membered heterocyclo; -Cβ to C8 aryl; and -Ci to C6 alkyl;
-alkoxy substituted with one or more substituents independently selected from: -halo; -hydroxy; -cyano;
-alkoxy optionally substituted with alkoxy; -amino substituted with one or more substituents independently selected from -
SO2-C1 to C4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and
-amino optionally substituted with one or more alkyls; -amido substituted with Ci to C6 alkyl; -S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl; -S-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to Ce aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -S-C6 to C8 aryl; -sulfinyl-5 or 6 membered heterocyclo;
-sulfϊnyl-5 or 6 membered heteroaryl;
-sulfinyl-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-Cs to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfinyl-C6 to Cs aryl; -sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl; -sulfonyl-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-Cs to Cβ heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfonyl-Cβ to Cg aryl; -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =0, heterocyclo, and
Ci to Ce alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Ci to Cg alkoxy; and
-Cs to Ce aryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more alkoxys;
-4 to 7 membered heterocyclo; and
-alkoxy; and -C6 to C8 aryl; -C6 to Cg aryl;
-(O)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from: -hydroxy; =O;
-Ci to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; or -(O)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2Rx;
-CORx;
-C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Ci to Cg alkoxys;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -C6 to C8 aryl;
-5 or 6 membered heteroaryl; and
-Ci to C6 alkyl optionally substituted with one or more hydroxys; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl; -COOH; -C(O)NHk optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Cj to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more Cj to C6 alkoxys;
-amino substituted with one or more substituents independently selected from: -SO2Rx; -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C^ to C% aryl optionally substituted with halo; -Cs to Ce heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; -C] to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -C(S to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -alkoxy; and -halo;
-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2Rx;
.CORx;
-C(O)NH2 optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, Cj to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Ce alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
=O;
-Ci to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl; -CORp; and -C(O)ORx; -ORkk, wherein R^k is:
-Cβ to C8 aryl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkyl, Ci to Ce alkoxy, and Ci to C6 haloalkyl; -5 to 6 membered heterocyclo optionally substituted with Ci to CQ alkyl, which alkyl is optionally substituted with Cβ to Cs aryl; or -5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Ci to C6 alkoxy, and Ci to CO haloalkyl; -SO2Rx; or
-OC(O)NHRx wherein Rx is optionally substituted with -Ce to Cg aryl; -OC(O)N(RX)2; or
R3 is nitro.
90. The compound of claim 89, wherein: X is:
-CH=N-(C, to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more Ci to Ce alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with Ci to Ce alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SO2Rx;
-SO2NH2;
-SO2NH(Rx);
-amino optionally substituted with one or more independently selected Ci to C6 alkyls and/or -C(O)-Ci to C6 alkyls;
-amido optionally substituted with one or more independently selected Ci to Ce alkyls; -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl substituted with one or more Ci to Cg alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more halos;
-halo; and
-cyano.
91. The compound of claim 89, wherein: Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more Ci to C6 alkyls;
-indolyl substituted on the nitrogen with -SO2Rx; or
-Ce to Cs aryl substituted with one or more substituents independently selected from: -alkoxy substituted with one or more substituents independently selected from: -C(O)NH2 optionally substituted with Ce to Cg alkyl; and -C(O)NH-(Ci to C6)-alkyl; -haloalkyi; -cyano; -COOH; -N=CHN(Rx)2;
-amino substituted with one or more substituents independently selected from: -SO2Rx; -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyi, cyano, alkoxy, CORx and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyi, cyano, alkoxy, haloalkoxy and Ce to Cs aryl optionally substituted with halo;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-C] to C7 alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl; -C6 to Cg aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl; -alkoxy; and -halo; and -PO2Rx;
-OC(O)NHRx wherein Rx is optionally substituted with vinyl; -OC(O)N(RU)2, wherein Ru is alkyl or Ce to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino; -OC(O)NH(ORuu), wherein Ruu is -Ce to C8 aryl optionally substituted with dialkylamino; -OC(O)NRx(ORx); -OC(O)N(ORX)2;
-OC(O)Rat» wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl; -NR0C(O)Rp, wherein Rp is:
-amino optionally substituted with one or more Ci to CO alkyls, which alkyls are optionally substituted with one or more substituents independently selected from Ce to Cs aryl and alkoxy; or -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from Ci to Cg alkyl and Ce to Cg aryl; -NRqCONRqRr, wherein Rr is:
-Ci to Ce alkyl substituted with one or more substituents independently selected from: -hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Ce to C8 aryl substituted with halo;
-C2 to Cβ alkenyl optionally substituted with one or more halos; -Ci to C6 alkoxy; -5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -SO2Ra3, wherein R88 is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy;
-Ci to Ce alkoxy; and -Ci to C6 alkyl; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -alkoxy; -hydroxy; -halo; -CORm, wherein R1n is:
-amino substituted with one or more Ci to Ce alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or Cg to C8 aryl, which heterocyclo is substituted with one or more halos and/or alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys; -heterocyclo substituted with hydroxy; -NRtCOORu5 wherein R11 is:
-Ci to Ci2 alkyl substituted with one or more substituents independently selected from: -Ce to Cs aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to C^ alkyls;
-SO2RW;
-SO2Rx; and
-5 or 6 membered heteroaryl; -C2 to Ce alkenyl; -4 to 7 membered heterocyclo substituted with one or more substituents independently selected from:
=0;
-SO2Rw;
-CORP; and
-(CO)O-(Ci to C4 alkyl)-O-(C, to C4 alkyl);
-4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: =O;
-SO2Rw;
-(CO)O-(Cj to C4 alkyl)-O-(C! to C4 alkyl); -NHRbb, wherein R^, is: -C(=S)NHRX; -C(=S)NRXRX; or -C(=N-CN)NHRX; -N(CONHRw)2; -NH(SORw);
-N(SO2Rw)2;
-NRvSO2Rw, wherein Rv is alkyl substituted with 4 or 7 membered heterocyclo; or wherein Rw is:
-Ci to Cβ alkyl substituted with CQ to Cs aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, alkoxycarbonyl, (CO)O-(Ci to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
00923
-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: -halo;
-Ci to C6 alkyl; -alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo; and
-C(O)NH2 optionally substituted with C6 to C8 alkyl; -hydroxy; -haloalkyl; -cyano; -nitro;
-COOH;
-amino optionally substituted with one or more substituents independently selected from: -SO2Rx;
-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to Cs aryl optionally substituted with halo;
- Cs to Ce heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and
-Ci to C7 alkyl optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls; -Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -alkoxy; and -halo; -NR0CORp, wherein Rp is:
-amino optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally and independently substituted with one or more Cβ to Cg aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more Ci to Ce alkyls and/or C6 to Cs aryls; -NRqCONRqRr, wherein Rr is:
-Ci to Ce alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy;
-5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -Ce to C8 aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos; -Ci to Ce alkoxy; -5 or 6 membered heterocyclo; or
-5 to 6 membered heteroaryl optionally substituted with alkyl; -NR,COORU, wherein R11 is:
-Ci to Cj2 alkyl substituted with one or more substituents independently selected from: -Ce to C8 aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more Ci to C6 alkyls;
-SO2Rx; and
-5 or 6 membered heteroaryl; and
-NRVSO2RW, wherein Rv is alkyl substituted with 4 to 7 membered heterocyclo; or wherein Rw is:
-C1 to C6 alkyl substituted with C6 to Cg aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-C6 to C8 aryl;
-amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
92. The compound of claim 89, wherein Z is:
-Cj to Ce alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo.
93. The compound of claim 89, wherein: Ri is:
-a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-Ci to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl;
-CORp; and
-C(O)ORx; or
-5 or 6 membered heteroaryl substituted with one or more independently selected from:
-C1 to CO alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2 Rx;
.CORx;
-C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Cj to Ce alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -Ci to Ce alkyl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
-amido optionally substituted with Ci to Cg alkyl;
-5 or 6 membered heterocyclo substituted with Ci to Ce alkyl;
-5 or 6 membered heteroaryl; and
-C6 to C8 aryl;
"SO2 Rx;
-C2 to Q alkenyl optionally substituted with -SO2RX;
-Ci to Ce alkoxy substituted with one or more substituents independently selected from: -hydroxy; -cyano;
-alkoxy optionally substituted with alkoxy; -amino optionally substituted with one or more independently selected from 5 or
6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and
-amino optionally substituted with one or more alkyl; -amino optionally substituted with heterocyclo; -amido optionally substituted with Ci to C6 alkyl; -5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C] to C<s alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-C] to Ce alkoxy; and
-C6 to C8 alryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to Cή alkyl; and
-4 to 7 membered heterocyclo; and -alkoxy;
-(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy; -Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; or
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents . independently selected from: -Ci to Cβ alkyl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl; -cyano; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx; -CORx;
-C(O)NH2 optionally substituted with one or more substituents independently selected from: -Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one. or more or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to Cg alkyl, which alkyl is optionally substituted with one or more Ci to CO alkoxys; -C(O)NH2 optionally substituted with one or more Ci to Cβ alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more , substituents independently selected from:
-Q to Cg aryl;
-5 or 6 membered heteroaryl; and
-Ci to Ce alky further optionally substituted with one or more substituted with hydroxys;
-SO2Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-Cg to Ce aryl; and
-5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-Cβ to Cg aryl; and
-5 or 6 membered heteroaryl; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl; -COOH; or -ORkk, wherein R^ is:
-Cβ to C8 aryl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Ci to Ce alkoxy. and Ci to Cg haloalkyl.
94. The compound of claim 89, wherein:
R2 is:
-Ci to Ce alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; -Ce to C8 aryl;
-amido optionally substituted with Ci to C(, alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and
-SO2 Rx.,
-C2 to C6 alkenyl optionally substituted with SO2Rx; -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo;
-C6 to Cs aryl; and
-Ci to C6 alkyl; -SO2RX optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more Cj to Ce alkyls;
-5 or 6 membered heterocyclo;
-Ce to Cs aryl; and
-Ci to C6 alkyl; -S(O)Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo;
-C6 to Cg aryl; and
-Ci to C6 alkyl; -alkoxy substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino substituted with one or more substituents independently selected from - SO2-Ci to C4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls;
-amido substituted with Cj to C6 alkyl; •
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ci to C6 alkyl;
-S-Ci to Ce alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-Cs to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo; -sulfinyl-5 or 6 membered heteroaryl; -sulfinyl-Ci to C& alkyl optionally substituted with one or more substituents independently selected from:
-Ce to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-C5 to Ce heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfinyl-Cβ to Cg aryl; -sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Ci to Ce alkyl; -sulfonyl-Ci to C^ alkyl optionally substituted with one or more substituents independently selected from:
-Cβ to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and
-Cs to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; -sulfonyl-Cβ to Cg aryl; -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, heterocyclo, and
Ci to Q alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Ci to Cβ alkoxy; and
-C6 to C8 aryl; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ci to Ce alkyl optionally substituted with one or more alkoxys;
-4 to 7 menibered heterocyclo; and
-alkoxy; and -Ce to Cg aryl; -C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from: -hydroxy; =O;
-Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl; -CORp; and -C(O)ORx; or
-(O)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from: -Ci to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C] to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl; -cyano; -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx; -CORx;
-C(O)NH2 optionally substituted with one or more Q to C6 alkyls, which alkyls . are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered - heterocyclo, 5 or 6 membered heteroaryl, and Ci to C6 alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: -C6 to C8 aryl;
-5 or 6 membered heteroaryl; and
-Ci to Ce alkyl optionally substituted with one or more hydroxys; -C(O)-5 or 6 membered heteroaryl; -C(O)-C6 to C8 aryl; -COOH; -C(O)NH2 optionally substituted with one or more Ci to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido substituted with one or more C1 to Cg alkyls, which alkyls are optionally substituted with one or more Ci to Ce alkoxys;
-amino substituted with one or more substituents independently selected from: -SO2Rx; -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -Ce, to Cs aryl optionally substituted with halo; -C5 to Cg heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; -Ci to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-Ce to Cz aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and
-halo;
-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from: -Ci to Ce alkyl optionally substituted with one or more substituents independently selected from halo, Cj to Cg alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -alkoxy; -halo; -alkylthio; -haloalkyl; -cyano; -amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Cδ alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and
5 or 6 membered heteroaryl; -heterocyclo; -nitro; -hydroxy; -COOH; -CO2Rx; .CORx; -C(O)NH2 optionally substituted with one or more C1 to Ce alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; -amido optionally substituted with one or more substituents independently selected from halo, Ci to Ce alkoxy, hydroxy, 5 or 6 membered
heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more Ci to Ce alkoxys; -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy; =O;
-Ci to C6 alkyl; -SO2Rx;
-C(O)-C6 to C8 aryl;
-C(O)ORx; -ORkk, wherein Rkk is:
-Cg to Cg aryl optionally substituted with one or more substituents independently selected from halo, Ci to Cβ alkyl, Ci to Ce alkoxy, and Ci to Ce haloalkyl; -5 to 6 membered heterocyclo optionally substituted with Ci to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or -5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Cj to CQ alkyl, Ci to Ce alkoxy, and C] to Ce haloalkyl; -SO2Rx; or -Si(Rx)3;
-OC(O)NHRx wherein Rx is optionally substituted with -Ce to Cg aryl; -OC(O)N(Rx)2; or
95. The compound of claim 89, wherein R3 is nitro.
96. The compound of claim 89, wherein: X is cyano or hydrogen;
Y is:
-Cβ to Cg aryl optionally substituted with one or more substituents independently selected from: -halo;
-C1 to C6 alkyl; -amino optionally substituted with one or more substituents independently selected from:
-SO2Rx;
-5 or 6 membered heteroaryl optionally substituted with one or more alkyl;
-C5 to C7 alkyl;
-NRtCOORu, wherein R1 is hydrogen, and wherein Ru is Ci to C12 alkyl; -NRvSθ2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to Ce alkyl or amino optionally substituted withalkyl;
Z is Ci to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano; and
R3 is hydrogen.
97. The compound of claim 96, wherein the C6 to C$ aryl is phenyl.
98. The compound of claim 97,wherein: X is cyano;
Y is phenyl para substituted with NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to
C6 alkyl; and
R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
99. The compound of claim 97, wherein: X is cyano;
Y is phenyl substituted with Ci to Cβ alkyl and NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to C6 alkyl; and
R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
100. The compound of claim 97, wherein: X is cyano;
Y is phenyl substituted with halo and NRvSO≥Rw, wherein Rv is hydrogen, and wherein Rw is Ci to Cβ alkyl; and
R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
101. The compound of claim 97, wherein: X is hydrogen;
Y is phenyl is para substituted with -NRtCOORu, wherein R4 is hydrogen, and wherein R11 is Cj to C 12 alkyl;
Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl; and
R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
102. The compound of claim 89, wherein: X is cyano;
Y is:
-Ce to Cg aryl optionally substituted with one or more substituents independently selected from:
-NR1COORu, wherein Rt is hydrogen, and wherein Ru is C] to C)2 alkyl optionally substituted with one or more halo; or
-NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is Ci to Ce alkyl; Z is Ci to C6 alkyl; R is hydrogen; Ri is hydrogen;
R2 is -(O)-5 or 6 membered heterocyclo substituted with one or more =O; and R3 is hydrogen.
103. A compound which is selected from the compound range: 1330-2128 and 2600-3348.
104. The compound of claim 103 selected from:
105. A composition comprising the compound of claim 1 and one or more pharmaceutically acceptable excipient(s).
106. A composition comprising the compound of claim 39 and one or more pharmaceutically acceptable excipient(s).
107. A composition comprising the compound of claim 77 and one or more pharmaceutically acceptable excipient(s).
108. A composition comprising the compound of claim 83 and one or more pharmaceutically acceptable excipient(s).
109. A composition comprising the compound of claim 89 and one or more pharmaceutically acceptable excipient(s).
110. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 1.
111. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 39.
112. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 77 or a pharmaceutical composition comprising an effective amount of one of more compoιmd(s) according to claim 77.
113. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 83.
114. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 89.
115. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 1.
116. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 39.
117. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 77 or a pharmaceutical
composition comprising an effective amount of one of more compound(s) according to claim
77.
118. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 83.
119. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 89.
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 |
| US65343607A | 2007-01-13 | 2007-01-13 | |
| PCT/US2007/000923 WO2007084413A2 (en) | 2004-07-14 | 2007-01-16 | Methods for treating hepatitis c |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1984332A2 true EP1984332A2 (en) | 2008-10-29 |
Family
ID=56290903
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP07718004A Withdrawn EP1984332A2 (en) | 2006-01-13 | 2007-01-16 | Methods for treating hepatitis c |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1984332A2 (en) |
| CA (1) | CA2636905A1 (en) |
| MX (1) | MX2008009061A (en) |
-
2007
- 2007-01-16 CA CA002636905A patent/CA2636905A1/en not_active Abandoned
- 2007-01-16 MX MX2008009061A patent/MX2008009061A/en not_active Application Discontinuation
- 2007-01-16 EP EP07718004A patent/EP1984332A2/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2007084413A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2008009061A (en) | 2008-09-23 |
| CA2636905A1 (en) | 2007-07-26 |
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