OA16260A - Inhibitors of influenza viruses replication. - Google Patents
Inhibitors of influenza viruses replication. Download PDFInfo
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- OA16260A OA16260A OA1201100485 OA16260A OA 16260 A OA16260 A OA 16260A OA 1201100485 OA1201100485 OA 1201100485 OA 16260 A OA16260 A OA 16260A
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Abstract
Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A compound is represented by Structural Formula (IA) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
Description
INHIBITORS OF INFLUENZA VIRUSES REPLICATION
ATTORNEY DOCKET NO.: VPI/09-103 WO
RELATED APPICATIONS
This application daims priority to U.S. Provisional Application No. 61,187,713, filed on June 17, 2009, and to U.S. Provisional Application No. 61/287,781, filed on December 18, 2009. The entire teachings of these applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
Influenza spreads around the world in seasonal épidémies, resulting in the deaths of hundreds of thousands annually - millions in pandémie years. For example, three influenza pandémies occurred in the 20th century and killed tens of millions of people, with each of these pandémies being caused by the appearance of a new strain of the virus in humans. Often, these new strains resuit from the spread of an existing influenza virus to humans from other animal species.
Influenza is primarily transmitted from person to person via large virus-laden droplets that are generated when infected persons cough or sneeze; these large droplets can then settle on the mucosal surfaces of the upper respiratory tracts of susceptible individuals who are near (e.g. within about 6 feet) infected persons. Transmission might also occur through direct contact or indirect contact with respiratory sécrétions, such as touching surfaces contaminated with influenza virus and then touching the eyes, nose or mouth. Adults might be able to spread influenza to others from 1 day before getting symptoms to approximately 5 days after symptoms start. Young children and persons with weakened immune Systems might be infectious for 10 or more days after onset of symptoms.
Influenza viruses are RNA viruses of the family Orthomyxovindae, which comprises five généra: Influenza virus A, Influenza virus B, Influenza virus C, Isavirus and Thogoto virus. The Influenza virus A genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestîc poultry or give rise to human influenza pandémies. The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdîvided into different serotypes based on the antibody response to these viruses. The serotypes that hâve been confirmed in humans, ordered by the number of known human pandémie deaths, are: H1N1 (which caused Spanish influenza in 1918), H2N2 (which caused Asian Influenza in 1957), H3N2 (which caused Hong Kong Flu in 1968), H5N1 (a pandémie threat in the 2007-08 influenza season), H7N7 (which has unusual zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N2 , H7N3 and H10N7. The Influenza virus B genus has one species, influenza B virus. Influenza B almost
-116260 exclusively infects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza mutâtes at a rate 2-3 times slower than type A and consequently is less genetically diverse, with only one influenza B serotype. As a resuit of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early âge. However, influenza B mutâtes enough that lasting immunity is not possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandémies of influenza B do not occur.
The Influenza virus C genus has one species, influenza C virus, which infects humans and pigs and can cause severe illness and local épidémies. However, influenza C is less common than the other types and usually seems to cause mild disease in children. Influenza A, B and C viruses are very similar in structure. The virus particle is 80-120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur. Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pièces of segmented negative-sense RNA. The Influenza A genome encodes 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1, PB1-F2 and PB2,
HA and NA are large glycoproteins on the outside of the viral particles. HA is a lectin that médiates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from înfected cells, by cleaving sugars that bind the mature viral particles. Thus, these proteins hâve been targets for antiviral drugs. Furthermore, they are antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes based on antibody responses to HA and NA, forming the basis of the H and N distinctions (vide supra) in, for example, H5N1.
Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandémie could cause hundreds of billions of dollars in direct and indirect costs. Preventative costs are also high. Governments worldwide hâve spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandémie, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.
Current treatment options for influenza include vaccination, and chemotherapy or chemoprophylaxis with anti-viral médications. Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as children and the elderly, or in people that hâve asthma, diabètes, or heart disease. However, it is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few spécifie influenza strains but cannot possibly include all the strains actively infecting people
-216260 in the world for that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal épidémies, occasionally, a new or overlooked strain becomes prominent during that time and infects people although they hâve been vaccinated (as by the H3N2 Fujian flu in the 2003-2004 influenza season). It is also possible to get infected just before vaccination and g et sick with the very strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective,
Further, the effectiveness of these influenza vaccines is variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time, and different strains become dominant. Also, because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase of influenza vRNA makes a single nucléotide insertion error roughly every 10 thousand nucléotides, which is the approximate length ofthe influenza vRNA. Hence, nearly every newly-manufactured influenza virus is a mutant—antigenic drift. The séparation of the genome into eight separate segments of vRNA allows mixing or réassortiment of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allows the virus to Infect new host specîes and quickly overcome protective immunity.
Antiviral drugs can also be used to treat influenza, with neuraminidase inhibitors being particularly effective, but viruses can develop résistance to the standard antiviral drugs. Thus, there is still a need for drugs for treating influenza infections, such as for drugs with expanded treatment window, and/or reduced sensitivity to viral titer.
SUMMARY OF THE INVENTION
The présent invention generally relates to methods of treating influenza, to methods of inhibiting the réplication of influenza viruses, to methods of reducing the amount of influenza viruses, to compounds and compositions that can be employed for such methods.
In one aspect, the présent invention is directed to a method of inhibiting the réplication of influenza viruses in a biological sample or in a patient. In one embodiment, the method comprises administering to said biological sample or patient an effective amount of a cornpound represented by Structural Formula (IA):
-316260
or a pharmaceutically acceptable sait thereof, wherein:
Z1 is -R·, -F, -Cf, -CN, -OR*, -CO2R*, -NO2, or -CON(R*)2;
Z2 is -R*, -OR*, -CO2R*, -NR*2, or -CON(R*)2;
Z3 is -H, -OH, halogen (e.g., -Cl or -Br), -NH2; -ΝΗζΟ,-Ο,, alkyl); -N(C1-C4 alkyl)2, -O(C-i-C4 alkyl), or Ο,-Ce alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(Ci-C4 alkyl);
R1 is -H or CrCe alkyl;
R2 is -H; -F; -NH2; -NH(Ci-C4 alkyl); -N(CrC4 alkyl)2; -C=N-OH; cyclopropyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -OCH3, and -CH3; or Ci-C4 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(C1-C4 alkyl); and R3 is -H, -Cl, -F, -OH, -O(CrC4 alkyl), -NH2, -NH(C,-C 4 alkyl), -N(CrC4 alkyl)2, -Br, -CN, or C,-C4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C4-C4 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(CrC4 alkyl), and Ci-C4 alkoxy;
R4 is:
K- wherein ring T is a C3-C10 non-aromatic carbocycle optionally substituted with one or more instances of JA, or a 3-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB, or ring T and R9 optionally form a non-aromatic C5-C1Q membered carbocycle optionally substituted with one or more instances of JA or 5-10 membered non-aromatic heterocycle optionally substituted with one or more instances of J6 ;
-416260
wherein ring J is a 3-10 membered nonaromatic heterocycle optionally substituted with one or more instances of JB; or
wherein ring D is a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; and each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q’lIR6; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 4-8 membered ring (e,g„ spiro ring or fused ring) that is optionally substituted with one or more instances of JE1;
Q1 is independently a bond, ΟΟΠ, USO, ONR'D, 00(0)0, -C(=NR)-, -C(=NR)NR-,
-NRC(=NR)NR-, 0CO20, 000(0)0, □CiOJNR'O, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, □NRC(O)O, nNRC(O)NR’ûl, 0NRCO20, -0C(0)NRO, -S(0)-,
OSOZOO -SOzNR-, ONRSOzOD or-NRSO2NR'-, -P(O)(OR)O-, -0P(0)(0Ra)0-P(0)20-, -CO2SO2-, or -(CR6R7)p0Y10;
Y1 is independently a bond, OOO, OSO, ONR’O, 00(0)0, -C(=NR)-, -C(=NR)NR-,
-NRC(=NR)NR-„ OCOjO, 000(0)0, nC(O)NR’O, -C(0)NRC(0)0000-NRC(0)NRC(0)0-, 0NRC(O)0, ONRC(0)NRO, ONRC020, □OC(O)NRO, -S(0)-, DSOzOO -SO2NR’-, ONRSO2OO -NRS02NR’-, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(O)2O-, or -CO2SO2-,
R5 is: î) -H; ii) a C^Cs aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-Cio non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1; or
Rs, together with Q1, optionally forms a 4-8 membered, non-aromatic ring optionally substituted with one or more instances of JE1 ; and
R6 and R7 are each independently ΊΗ or Ci-Ce alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, CpCe haloalkoxy, CrC6 aminoalkoxy, CrCe cyanoalkoxy, Ci-C6hydroxyalkoxy and C2-C6alkoxyalkoxy, or optionally R6 and R7, together with the carbon atom to which they are attached, form aûcyclopropane ring optionally substituted with one or more instances of methyl;
-516260
R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, C,-Ce alkyl, CrC6 haloalkyl, Ο,-Ο6 cyanoalkyl, C2-C6 alkoxyalkyl, 0,-06 aminoalkyl, Ci-C6 hydroxyalkyl,
C,-C6 carboxyalkyl, Ο,-Οβ alkoxy, C,-C6 haloalkoxy, CrC6aminoalkoxy, CrCe cyanoalkoxy, CrC6 hydroxyalkoxy and Ο2-Οδ alkoxyalkoxy;
R13 and R14 are each independently DH, halogen, or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C,-C6 alkoxy, Ο,-Ο6 haloalkoxy, Ci-Ceaminoalkoxy, CrCe cyanoalkoxy, C,-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted with one or more instances of methyl; R and R’ are each independently ΊΗ or Ο,-Ο6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, C,-C6 haloalkoxy, Ο,-Ο6 aminoalkoxy, C^Ce cyanoalkoxy, C,-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy; or optionally R’, together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1;
R* is independently: i) -H; ii) a CrC6 alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C3-Ca non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 membered heteroaryl, -O(Ci-C6 alkyl), and -CfO^CrCs-alkyl); wherein each of said alkyl groups in -O(Ci-Ce alkyl), and -C(O)(CrC6-alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C,-C4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and 0,-04 alkoxy; and wherein each of said carbocycle, heterocycle, phenyl, and heteroaryl is independently and optionally substituted with one or more instances of JE1; or iii) a C3-C8 non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is independently and optionally substituted with one or more instances of JE1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, □ORb, OSRb, -S(O)Ra, 0SO2Ra, 0NRbRc, DC(O)Rb, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, □C(O)ORb, □OC(0)Rb, 0NRC(O)Rb, □C(O)NRbRc, □NRC(O)NRbRc, 01^0(0)0^, OOCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),0-SO2NRcRb. -NRSO2Rb, -NRSO2NRcRb, -P(O)(ORa)2, -OP(O)(ORa)2, -P(O)2ORa and -CO2SO2Rb, or optionally, two JC1 and two JD1, respectively, together with the atom(s) to which they are attached,
-616260 independently form a 4-8-membered ring that is optionally substituted with one or more instances of JE1;
each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, CrCe alkyl, -O(CrC6 alkyl), and -C(O)(Ci-C6alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(CrC4 alkyl)2, -OCO(Ci-C4 alkyl), -00(0,-^ alkyl), -CO2H, -CO2(C1-C4 alkyl), and CrC4 alkoxy; and
Ra is independently: i) a CrC6 aliphatiç group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -O(Ci-C6 alkyl), -C(O)(Ci-C6-alkyl), C3-C0 nonaromatic carbocycle, 4-8 membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and 6-10 membered carbocyclic aryl group; wherein each of said alkyl groups for the substituents of the C!-C6 aliphatiç group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(C,-C4 alkyl)21 -000(0,-0, alkyl), -00(0,-0, alkyl), -CO2H, -CO2(Ci-C4 alkyl), and 0,-04 alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl and carbocyclic aryl groups for the substituents of the 0,-06 aliphatiç group represented by Ra is optionally and independently substituted with one or more instances of JE1;
ii) a C3-C8 non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is optionally and independently substituted with one or more instances of JE1; or iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclic aryl group, each of which is optionally and independently substituted with one or more instances of JE1; and
Rb and Rc are each independently Ra or -H; or optionally, Rb and Rc, together with the nitrogen atom(s) to which they are attached, each independently form a 5-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1;
p is independently 1, 2, 3 or 4;
t is 0, 1 or 2; j is 1 or 2; and z is 1 or 2.
In another embodiment, the method comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I):
-716260
or a pharmaceutically acceptable sait thereof, wherein:
R1 is -H;
R2 is -H, -CH3, -NH2, -NH(CrC4 alkyl), or -N(C,-C4 alkyl)2;
R4 îs: i) a C3-C10 non-aromatic carbocycle optionally substituted with one or more instances of JA; ii) a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB; or iii) a Ci-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of Jc; a C3-C3 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JA; and a 5-10 membered heteroaryl group, or a 4-10 membered non-aromatic heterocycle, each optionally and independently substituted with one or more instances of JB; each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q1OR5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instanced of JE1;
Jc is independently selected from the group consisting of halogen, cyano, oxo, □OR5, -SR5, DNR'R5, nCtOiR5, nCO2R5, □OC(O)RS, aCiOJNR’R5, C(O)NRC(O)OR6, -NRC(O)NRC(O)OR5, DNRC(O)RS, □NRC(O)NR’R5, DNRCO2R5, □OC(O)NR’R5, -S(O)R5, □SO2R5î2.-SO2NR'R5, □NRS02R50 and -NRSO2NR’R£; Q1 is independently a bond, ΠΟ3, Π5Π, ONRO, nC(O)O, -C(=NR)-, C1CO2O, □OC(O)H, nC(O)NR'n,-C(O)NRC(O)O-, -NRC(O)NRC(O)O-, nNRC(O)n, □ NRC(O)NR'n, ΠΝΗΟΟζΟ, -OC(O)NRO, -S(O)-, OSO2ün -SO2NR’-, DNRSO2an or -NRSO2NR’-, or -(CR6R7)paY1D;
Y1 is independently a bond, 003, OSO, DNR’n, 00(0)0, -C(=NR)-, αθΟ2Π, □OC(O)n, nC(O)NR’n, -C(0)NRC(O)ODCin-NRC(0)NRC(O)O-, ONRC^n, □ NRC(O)NR’D, nNRCO2C, □OC(O)NR’Q, -S(O)-, 0SO200 -SO2NR’-, aNRSO^a or -NRSO2NR’-;
R5 is: i) -H; ii) a CrC6 aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one
-816260 or more instances of JD1. Optionally, R5, together with Q1, optionally forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of
each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, nORb, QSRb, -S(O)Ra, OSO2Ra, DNRbRc, nC(O)Rb, QCfOiOR6, □OC(O)Rb, aNRC(O)Rb, nC(O)NRbRc, nNRC(O)NRbRc, ONRCfOlOR11, □OCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(0)NR(ORb),D-SO2NRcRb, -NRSO2Rb, -NRSO2NRcRb, and -P(O)(ORa)2-, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached; and each of Z1, Z2, R3, R6, R7, R, R’, R*, JE1, Ra, Rb, Rc and p is independently as described above for Structural Formula (IA).
In another embodiment, the présent invention is directed to a method of reducing the amount of influenza viruses in a biological sample or in a patient. The method comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I) or Structural Formula (IA), each and independently as described above.
In yet another embodiment, the présent invention is directed to a method of treating or preventing influenza in a patient, comprising administering to said patient an effective amount of a compound represented by Structural Formula (I) or Structural Formula (IA), each and independently as described above.
In yet another embodiment, the présent invention is directed to a compound represented by Structural Formula (IA) or a pharmaceutically acceptable sait thereof: or a pharmaceutically acceptable sait thereof, wherein:
R1 is -H, Ci-C6 alkyl, -S(O)2-R, or -C(O)OR; or alternatively R1 is -H or CrCB alkyl;
R4 is:
O r^k ^·ο
R11 R12
or ; wherein:
.9.
ring A is a C3-Ci0 non-aromatic carbocycle optionally further substituted with one or more instances of JA, or heterocyle optionally further substituted with one or more instances of JB;
rings B and C are each independently a 4-10 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-10 membered, non-aromatic heterocycle optionally substituted with one or more instances of JD1; or ring A and Re optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each carbocycle is optionally further substituted with one or more instances of JA, and wherein each heteroocycle is optionally further substituted with one or more instances of JB; and Q2is independently a bond, ΊΟΟ, DSn, □NRD, 00(0)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, OCO20, 000(0)0, OC(0)NRO, -C(O)NRC(O)O-, NRC(O)NRC(O)O- nNRC(O)0, 0NRC(O)NR0, 0NRCO20, 0OC(O)NR0, -S(O)-, OS0200 0N(R)SO2n, 0SO2N(R)-, -NRSO2NR-, -P(O)(OR)O-, -OP(0)(ORa)O-, -P(O)2O-, -CO2SO2-, or -(CReR7)pOY1O;
Q3 is independently a bond, 00(0)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, iCO2O, -C(O)NR0, OSO2O.-SO2N(R)-, -C(O)NRC(O)O- or -(CRBR7)p0Y100
R” is independently: i) a CrCe-alkyl optionally substituted with one or more substituents selected independently from the group consisting of halogen, cyano, hydroxyl, 0NH2, ΠΝΗίΟ,-Οβ alkyl), ONfCrCs alkyl)2, C-i-Cealkoxy, CrC6 haloalkoxy, C-i-C6 aminoalkoxy, Ci-C0cyanoalkoxy, CrC8 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or ii) a C3-Cs carbocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, each optionally and independently being substituted with one ore more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, nitro, !NH2, 0NH(Ci-C6 alkyl), ΟΝίΟ,-Οβ alkyl)2, CrC6 alkyl, C;-C6 haloalkyl, CrC6 cyanoalkyl, Ci-C6-hydroxyalkyl, C2-C6-alkoxyalkyl, CrCe-aminoalkyl, Ci-Csalkoxy, Ci-C6 haloalkoxy, CrCsaminoalkoxy, Ci-C6cyanoalkoxy, CrCehydroxyalkoxy, and C2-Ce alkoxyalkoxy;
each of Z1, Z2, Z3, Q1, Q2, Q3, Y1, R2, R3, R5, R6, R7, R®, R9, R10, R11, R1Z, R13, R14, R, R', R*, JA, JB, JC1, JD1, JE1, Ra, Rb, Rc and p is independently as described above for Structural Formula (IA) for the method of inhibiting the réplication of influenza viruses;
n and m are each independently 0 or 1 when rings A and B are 3-6-membered; or n and m are each independently 0, 1 or 2 when rings A and B are 7-10-membered; k is 0, 1 or 2;
-1016260 x and y are each independently 0, 1 or 2;
z is 1 or 2; and provided that if Y1 is a bond, then R5 is neither-H nor a CrC6 aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither-H nor a
Ci-C6 aliphatic group.
In yet another embodiment, the présent invention is directed to a compound represented by Structural Formula (I) or a pharmaceutically acceptable sait thereof, wherein: the values of the variables of Structural Formula (I) are as described below:
R1 îs -H, Ci-C6 alkyl, -S(O)2-R, or-C(0)OR”; or alternatively R1 is -H or CrC6 alkyl.
R4 is:
o
R11 R12 ring A is a C3-Ce non-aromatic carbocycle optionally further substituted with one or more instances of JA, or heterocycle optionally further substituedd with one or more instances of JB;
rings B and C are each independently a 4-8 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-8 membered, non-aromatic heterocycle optionally substituted with one or more instances of JD1;
R is independently: i) a Ci-Ce-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, aNH2, nNHfC-i-Ce alkyl), αΝ^-ΰβ alkyl)2, CrC6alkoxy, CrC6 haloalkoxy, Ci-C6aminoalkoxy, CrCecyanoalkoxy, CrC6 hydroxyalkoxy and C2-C5alkoxyalkoxy; or ii) a C3-C6 carbocyclic group, 5-6 membered heteroaryl group, or phenyl group, each optionally and independently being substituted with one ore more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, nitro, DNH2, DNH(Ci-Ce alkyl), UN(Ci-C6 alkyl)2, C-i-Ce alkyl, Ci-Ce haloalkyl, Ci-Cg cyanoalkyl, Ci-C6-hydroxyalkyl, C2-C6-alkoxyalkyl, CrC6-aminoalkyl, Ci-C6alkoxy, C-i-C6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-C6cyanoalkoxy, Ci-Ce-hydroxyalkoxy, and C2-C6alkoxyalkoxy;
-1116260 each of Z1, Z2, Q1, Q2, Q3, Y1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R’2, R13, R14, R, Rr,
R*, JC1, JD1, JE1, Ra, Rb, Rc and p is independently as described above for Structural
Formula (I) for the method of inhibiting the réplication of influenza viruses;
n and m are each independently 0 or 1 when rings A and B are 4-6-membered; or n and m are each independently 0, 1 or 2 when rings A and B are 7-8 membered;
k is 0, 1 or 2;
x and y are each independently 0, 1 or 2;
z is 1 or 2;
provided that if Y1 is a bond, then R5 is neither -H nor an unsubstituted Ci-C6 aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither -H nor a Ci-C6 aliphatic group.
In yet another embodiment, the présent invention is directed to a pharmaceutical composition comprising a compound represented by Structural Formula (I) or Structura!
Formula (IA), or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein the values of the variable of Structural Formulae (I) and (IA) are each and independently as described above for the compounds of the invention.
The présent invention also provides use of a compound described herein for inhibiting the réplication of influenza viruses in a biological sample or patient, for reducing the amount of influenza viruses in a biological sample or patient, or for treating influenza in a patient. Also provided herein is use of a compound described herein for the manufacture of a médicament for treating influenza in a patient, for reducing the amount of influenza viruses in a biological sample or in a patient, or for inhibiting the réplication of influenza viruses in a biological sample or patient.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing percentages of survîal of Balb/c mice (4-5 weeks of âge) over time for a prophylaxis study in which an initial dose of Compound 514 (100 mg/kg) or vehicle only (0.5% Methylcellulose/0.5% Tween 80) were administered 2 hours prior to infection by oral gavage (10 mL/kg) and continued twice daily for 5 days.
FIG. 2 is a graph showing percentages of survîal of Balb/c mice (4-5 weeks of âge) over time for a therapeutic treatment study in which Compound 588 (200 mg/kg) or vehicle only were administered by oral gavage 24 hours post infection and continued twice daily for 10 days.
FIGs.3-8 are tables showing some spécifie compounds of the invention.
DETAILED DECRIPTION OF THE INVENTION
-1216260
Uses of Disclosed Compounds
One aspect of the présent invention is generally related to the use of the compounds described herein or pharmaceutically acceptable salts, or pharmaceutically acceptable compositions comprising such a compound or a pharmaceutically acceptable sait thereof, for inhibiting the réplication of influenza viruses in a biologieal sample or in a patient, for reducing the amount of influenza viruses (reducing viral titer) in a biologieal sample or in a patient, and for treating influenza in a patient.
In one embodiment, the présent invention is generally related to the use of compounds represented by Structural Formula (I) or Structural Formula (IA), or pharmaceutically acceptable salts thereof for any of the uses specified above:
A first set of variables of Structural Formulae (I) and (IA) is independently as follows: Z1 is -R*, -F, -Cl, -CN, -OR*, -CO2R*, -NO2, or -CON(R*)2. Specifically, Z1 is -H, Ci-C6 alkyl, -0(0,-06 alkyl), -F, -Cl, -CN, -CO2H, -CO2(CrC6 alkyl), -CONH2, -CONH(Ci-C6 alkyl), or -CON(Ci-C6 alkyl)2, wherein each of said alkyl groups (e.g., represented by C,-C6 alkyl, -O(C-i-Ce alkyl), -CO2(Ci-Ce alkyl), -CONH(C1-C6 alkyl), and -CON(CrC5 alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C1-C4 alkyl)2, -000(0,-04 alkyl), -CO(C,-C4 alkyl), -CO2H, -002(0ι-04 alkyl), and C,-C4 alkoxy. Specifically, Z1 is -H, -F, -Cl, 0,C4 haloalkyl (e.g., -CF3), C,-C4 alkyl, -CH2NH2, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -O(C,-C4 alkyl), or -CN. Specifically, Z1 is -H, -F, -Cl, -CF3, C,-C4 alkyl, or -CN. Specifically, Z1 is -H, -F, -Cl, -CF3, -CH3, or-CN. Specifically, Z1 is H, -F, or -CN. Specifically, Z1 is -H or -F.
Z2 is -R*, -OR*, -CO2R*, -NR‘21 or -CON(R*)2. Specifically, Z2 is -H, C,-C6 alkyl, -O(C,-C6 alkyl), -NH2, -NH(C,-C6 alkyl), or -N(C,-C6 alkyl)2, wherein each of said alkyl groups (e.g., represented by C,-C6 alkyl, -O(C,-C6 alkyl), -NH(C,-C6 alkyl), and -N(C,-C6 alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C-|-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and C4-C4 alkoxy. Specifically, Z2 is -H, Ci-C6 alkyl,
-1316260
| or -O(CrC6 alkyl), wherein each of the alkyl groups is optionally and independently substituted. Specifically, Z2 is -H, or an optionally substituted CrC8 alkyl. Z3 in Structural Formula (IA) is -H, -OH, halogen, -NH2; -NH(C-i-C4 alkyl); -N(CrC4 alkyl)2i -O(C!-C4 alkyl), or Ci-C6 alkyl that is optionally substituted with one or more | |
| 5 | substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(004 alkyl). Specifically, Z3 is -H, -0(0(^ alkyl), or CrC6 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl). Specifically, Z3 is -H or CrC6 alkyl optionally substituted with one or more |
| ΙΟ | substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(CrC4 alkyl). Specifically, Z3 is -H. R1 is -H or Cvb alkyl. Specifically, R1 is -H. R2 is -H; -F; -NH2; -NH(CrC4 alkyl): -N(C!-C4 alkyl)2; -C=N-OH; cyclopropyl that is optionally substituted with one or more substituents independently selected from the |
| 15 | group consisting of halogen, cyano, hydroxy, -OCH3, and -CH3; or CrC4 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(0,-^ alkyl). Specifically, R2 is -H, -CH3, -NH2, -NH(CrC4 alkyl), or -N(CrC4 alkyl)2. Specifically, R2 is -H, -F, CH3, -CH2OH, or -NH2. Specifically, R2 is -H or -CH3. |
| 20 | R3 is -H, -Cl, -F, -OH, -O(CrC4 alkyl), -NHZ, -NH(CrC 4 alkyl), -N(CrC4alkyl)2, -Br, -CN, or CrC4aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -0C0(CrC4 alkyl), -CO(C-|-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), and CrC4 alkoxy. Specifically, R3 is -H, -Cl, -F, - |
| 25 | CF3, -OCH3, -NH2, -NH(Ci-C 4alkyl), -N(CrC4alkyl)2, -Br, -O(CrC4 alkyl), -CN, CrC4haloalkyl, -OH, or-C π-C4 aliphatic. Specifically, R3 is -H, -Cl, -F, -CF3, OCH3, -NH2, -NH(CrC 4alkyl), -N(CrC4 alkyl)2, -Br, -O(CrC4 alkyl), -CHCH(CH3), -CHCH2, -CN, -CH2CF3] -CH2F, -CHF2i -OH, or -CrC4 alkyl. Specifically, R3 is -H, -Cl, -F, -Br, -CN, -CF3, -O(CrC4 alkyl), -OH, -NH2, -NHfCvC, alkyl), or-N(CrC4 |
| 30 | alkyl)2 Specifically, R3 is -H, -F, -Cl, -CF3, -NHZ, -NH(CH3), or-N(CH3)2. Specifically, R3 is -H, -Cl, or -F. Specifically, R3 is -Cl. Specifically, R3 is -H, -CI, F, -Br, -CN, -CF3, -CH3, -C2H5, -O(CrC4 alkyl), -OH, -NH2, -NH(C1-C4 alkyl), or N(CrC4 alkyl)2 Specifically, R3 is -H, -F, -Cl, -CF3, -CH3, -C2HS -NH2, -NH(CH3), or -N(CH3)2. Specifically, R3 is -F or-Cl. |
| 35 | R4 is: i) a C3-Ci0 non-aromatic carbocycle optionally substituted with one or more instances of JA; ii) a Ci-CB aliphatic group (e.g., CrC6alkyl or C2-C6alkenyl group) optionally substituted with one or more substituents independently selected from the group consisting of Jc; a C3-C8 non-aromatic carbocycle, or a 6-10 membered |
-1416260 carbocyclic aryl group, each optionally and independently substituted with one or more instances of JA; and a 5-10 membered heteroaryl group, or a 4-10 membered non-aromatic heterocycle, each optionally and independently substituted with one or more instances of JB; or iii) a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB Specifically, R4 is i) an optionally substituted C3-C-i0 carbocyclic ring; ii) a CrC6 aliphatic group (e.g., CrC6 alkyl or C2C6 alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted C3-Ca non aromatic carbocycle, and an optionally substituted 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle. Specifically, the CrCe aliphatic group represented by R4 is substituted with OOR5, -SR5, HNR'R5, nC(O)R5, aCO2R5, aOCfCOR5, DCtOJNR’R5, -C(O)NRC(O)OR5, -NRC(O)NRC(O)OR5, DNRC(O)R5, □NRC(O)NR’R5, l1NRCO2R5, nOC(0)NR’R5, -SOR5, -SO2Rs, nSO2NR’R5nnDN(R)SO2R5, -NRSO2NR'R5, an optionally substituted C3-C0 non-aromatic carbocycle, and an optionally substituted
4-10 membered non-aromatic heterocycle. More specifically, R4 is:
wherein ring T (including rings A, B and C described below) is a C3-C10 non-aromatic carbocycle optionally substituted with one or more instances of JA, or a 3-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB, or ring T and R9 optionally form a non-aromatic C5-C1Q membered carbocycle optionally substituted with one or more instances of JA or 5-10 membered
non-aromatic heterocycle optionally substituted with one or more instances of JB ;
wherein ring J is a 3-10 membered nonaromatic heterocycle optionally substituted with one or more instances of JB; or
wherein ring D is a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1. More specifically, R4 is:
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R5 is: i) -H; ii) a CrCB aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C10 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1. Specifically, R5 is: i) -H; ii) a CrC6 aliphatic group (e.g., Cr Ce alkyl or C2-C6 alkenyl group) optionally substituted with one or more instances of JC1; iii) a C3-C0 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1. Optionally, R5, together with each of Q1, Q2 and Q3, optionally and independently forms a 4-8 membered, non-aromatic ring optionally substituted with one or more instances of JE1. It is understood that the non-aromatic ring formed with R5 and Q1 can employ a portion of Q1. In some embodiments, R5, together with Q2 and R8, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1.
Specifically, R5 is independently i) -H; ii) a C<|-C6-alkyl or C2-C6-alkenyl group optionally substituted with one or more instances of JC1; iii) a C3-C0 non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of J01. Specifically, R5 is independently i) -H; ii) a CrC6-alkyl or C2-C6-alkenyl group optionally and independently substituted with one or more instances of JC1; or iii) a 48 membered non-aromatic heterocycle optionally substituted with one or more
-1616260 instances of JD1. Specifically, R5 is independently i) -H; or ii) a Ci-Ce-alkyl or C2-Cealkenyl group optionally and independently substituted with one or more instances of
JC1.
Re and R7 are each independently ΠΗ or Ci-C6 alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-C6alkoxy, C-,-C6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-C6 cyanoalkoxy, Ο,-Οβ hydroxyalkoxy, and C2-Cs alkoxyalkoxy, or optionally Rsand R7, together with the carbon atom to which they are attached, form aOcyclopropane ring optionally substituted with one or more instances of methyl. Alternative^, R6 and R7 are each independently OH or C1-C4 alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, 7NH2, DNHiCrCe alkyl), ΠΝΙΟ,-Οβ alkyl)2, -C(O)OH, -(CO)O(CrC6 alkyl), -OC(O)(Ci-C6 alkyl), Ci-C6alkoxy, Ci-C6 haloalkoxy, Ci-C6 aminoalkoxy, CrCe cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy, or optionally R6 and R7, together with the carbon atom to which they are attached, form ancyclopropane ring optionally substituted with one or more instances of methyl. Specifically, R6 and R7 are each independently -H or -CH3, or, together with the carbon atoms to which they are attached, they form a cyclopropane ring.
Each R8 is independently -H, halogen, cyano, hydroxy, amino, carboxy, CrC6 alkyl, CrC6 haloalkyl, CrC6 cyanoalkyl, C2-C6 alkoxyalkyl, CrC6 aminoalkyl, CrC6 hydroxyalkyl, Ci-C6alkoxy, Ci-C6 haloalkoxy, Ci-C6 aminoalkoxy, CrC6 cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or R8, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1.
Each R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, CrC6 alkyl, Ci-C6 haloalkyl, CpCg cyanoalkyl, C2-Ç6 alkoxyalkyl, Ci-C6 aminoalkyl, CrC6 hydroxyalkyl, CrCB carboxyalkyl, Ci-Cealkoxy, Ci-C6 haloalkoxy, CrC6 aminoalkoxy, C-i-Ce cyanoalkoxy, C-|-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or R8, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1. Specifically, each R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, CrC6 alkyl, C-i-Cg haloalkyl, C^Cb cyanoalkyl, C2-C6 alkoxyalkyl, CrC6 aminoalkyl, Ci-Ce hydroxyalkyl, CrCealkoxy, Ci-C6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-C6 cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or R®, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1.
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Optionally, R9 and ring T form a non-aromatic C5-Ci0 membered carbocycle optionally substituted with one or more instances of JA or 5-10 membered nonaromatic heterocycle optionally substituted with one or more instances of JB . Specifically, each R0 is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, Cr C4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C-|-C4alkyl), DNH2, □ΝΗ^Π^ alkyl), or ΠΝ(Ο-|Π04 alkyl)2; and each R9 is independently -H or CrC4 alkyl, more specifically, -H, -CH3, or-CH2CH3.
R10 is independently -H; or a CrC6 alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-CÊalkoxy, CrCB haloalkoxy, C!-C6 aminoalkoxy, CrC6cyanoalkoxy, C,-C6 hydroxyalkoxy, C2-C6 alkoxyalkoxy, C3-Ca non-aromatic carbocycle, phenyl, a 4-8 membered non-aromatic heterocycle, and a 5-6 membered heteroaryl group; wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl group for the substituents of the Ci-Ce alkyl group represented by R10 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, CrCs alkyl, Ci-C6 haloalkyl, CrC6 cyanoalkyl, C2-C6 alkoxyalkyl, C^Ce aminoalkyl, CrC6 hydroxyalkyl, CpCealkoxy, CrC6 haloalkoxy, Crûs aminoalkoxy, Ci-C6cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy. Specifically, R10 is independently -H, CrC6 alkyl, C-i-Ce haloalkyl, C:Ce-alkoxyalkyl, CrCe hydroxyalkyl, Ct-Ce aminoalkyl, or CrC6 cyanoalkyl. Specifically, R10 is -H or CrCe-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C-|-C4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and CrC4 alkoxy. Specifically, R10 is -H or CpCe-alkyl.
R11, R12, R13 and R14 are each independently ΠΗ, halogen, or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, CrC6 alkoxy, Ci-C6 haloalkoxy, Ci-C6 aminoalkoxy, CrC6 cyanoalkoxy, C-i-C6 hydroxyalkoxy, and C2-Ce alkoxyalkoxy; or optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring; optionally substituted with one or more instances of methyl. Specifically, R11 and R12 are each independently -H or CrC4 alkyl; and R13 and R14 are each independently -H or Ci-C4 alkyl, or together with the carbon atoms to which they are attached, they form a cyclopropane ring. Specifically, R11 and R12 are each independently -H or -CH3; and R13 and R14 are each independently -H, -CH3, or -CH2CH3, or together with the carbon atoms to which they are attached, they form a cyclopropane ring.
-1816260
Optionally R11 and ring A form a bridged ring optionally further substituted with one or more instances of JA.
Ring A is a C3-C10 non-aromatic carbocycle optionally further substituted with one or more instances of JA, or 3-10 membered non-aromatic heterocycle optionally further substituted with one or more instances of JB Specifically, ring A is an optionally substituted C3-C0 non-aromatic carbocyclic or heterocyclic ring. Specifically, Ring A is a C3-C0 non-aromatic carbocycle optionally further substituted with one or more instances of JA. Specifically, Ring A is a non-aromatic, 4-7 or 5-7 membered, carbocyclic ring optionally further substituted with one or more instances of JA A spécifie example of Ring A is an optionally substituted, cyclohexyl or cyclopentyl ring.
Optionally, ring A and Rs form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, ring A and R11 optionally form a non-aromatic, 510 membered, bridged carbocycle or heterocycle, wherein each carbocycle is optionally further substituted with one or more instances of JA, and wherein each heteroocycle is optionally further substituted with one or more instances of JB. In some embodiments, the bridged rings are each independently 6-10 membered.
optionally further substituted with one or more instances of JA, and ring G5 is a 5-10 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB; R21, R22, R23, R24, and R25 are each independently OH, halogen, -OH, CrC6 alkoxy, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, CrC6 haloalkoxy, CrC6aminoalkoxy, CrC6 cyanoalkoxy, C^Ce hydroxyalkoxy, and Cî-C6alkoxyalkoxy; X is -O-, -S-, or -NR9-; R9 is -H or Cri-Cg alkyl
-1916260 optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-Ce alkoxy, Ci-C6 haloalkoxy,
Ci-C6aminoalkoxy, C-|-C6cyanoalkoxy, CrCe hydroxyalkoxy, and C2-C6 alkoxyalkoxy; q is 0, or 2; x is 0, 1 or 2; r is 1 or 2, An additional example of the bridged rings includes an adamantyl ring.
Ring B is a 4-10 membered, non-aromatic, heterocyclic ring that is optionally further substituted with one or more instances of JB. Specifically, ring B is 4-8 membered. Specifically, ring B is 4-7 or 5-7 membered. Spécifie examples of Ring B include:
wherein each of rings B1-B9 is optionally substituted.
Ring C is a 4-10 membered, non-aromatic, heterocyclic ring that is optionally further substituted with one or more instances of JB. Specifically, ring C is 4-8 membered. Specifically, ring C is 4-7 or 5-7 membered. Spécifie examples of Ring C include:
wherein each of rings C1-C5 is optionally and independently substituted.
Ring D is a 4-10 membered, non-aromatic, heterocyclic ring that is optionally substituted with one or more substituents instances of JD1. Specifically, ring D is 4-8 membered. Specifically, ring D is 4-7 or 5-7 membered. Spécifie examples of ring D include:
wherein each of rings D1-D7 is optionally substituted.
Specifically, each of Rings A -D is independently and optionally substituted 4-8 or 47 membered ring.
-2016260
Each Q1 is îndependently a bond, 000, OSO, lJNR’O, 00(0)21, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, 00020, 000(0)0, DC(O)NR’O, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, DNRC(0)0, 0NRC(O)NR’n, ONRCOjO, -OC(O)NRO, -S(0)-, □S0200 -SO2NR’-, DNRS0200 or-NRSO2NR’-, -P(O)(OR)O-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CR6R7)POY1O, Specifically, each Q1 is îndependently a bond, 003, lOSO, ONR’O, 00(0)0, -C(=NR)-, 0C020, 000(0)0, 0C(O)NRO, C(0)NRC(0)0-, -NRC(O)NRC(O)O-, ONRC(0)0, □NRC(O)NR’O, ONRCO2O, □OC(O)NRO, -S(0)-, 0S0200 ONRSOzO, -SO2NR’-, NRSO2NR'-, or -(CR6R7)POY1O. Specifically, each Q1 is îndependently a bond, 000, OSO, ONR'O, 00(0)0, OC020, 000(0)0, OC(0)NR’0, -C(O)NHC(O)O-, -C(0)N(CH3)C(0)0, NHC(O)NHC(O)O-, -N(CH3)C(O)NHC(O)O-, 0NHC(O)0, -N(CH3)C(O)-, -NHC(O)NR’n, -N(CH3)C(O)NR,O000NHCO20,0N(CH3)CO20) 00C(O)NR’0, -S(0)-, 0S0200 ONHS02OOOON(CH3)S020, -SOzNR’-, or-(CR6R7)p0Y10. Each Q2 is îndependently a bond, Π0Π, OSO, ONRO, 00(0)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, 00020, 000(0)0, 0C(O)NR0, -C(0)NRC(0)0-, -NRC(O)NRC(O)O-, 0NRC(O)0, ONRCtOJNRa, 0NRCO20, 000(0)NRO, -S(0)-, □S0200 ON(R)S020, □S02N(R)-, -NRSOsNR-, -P(O)(OR)O-, -0P(0)(0Ra)0-, -P(O)2O-, -CO2SO2-, or -(CR6R7)pOY1. Specifically each Q2 is îndependently a bond, OOO, OSO, ONR’O, 00(0)0, -C(=NR)-, OC020, 000(0)0, OC(0)NR'0,C(0)NRC(0)0- -NRC(0)NRC(0)0-, 0NRC(O)0, ONRC(O)NR'n, 0NRCO20, □OCÎOJNR’O, -S(0)-, OSOzOO 0NRSO20, -SO2NR’-, NRSO2NR’-, or(CRSR7)POY1O, Specifically, each Q2 is îndependently ΠΟΟ, ONR'O, 00(0)0, □ C020, OCîOÏNR’lI, 0NRC(O)lI, ONRCÎOÎNRU ONRCOaO, OOCiOJNR’O, NRS02l), -SOzNR’-, or-(CReR7)pOY1n. Specifically, each Q2 is îndependently 0C020, 00(0)NRO, ONRC(O)O, 0NRC(O)NR’0, ONRCOzO, OOCtOJNR’O, NRSO20, or -(CReR7)pOY1O, Specifically, each Q2 is îndependently ONR’O, 0C(O)NR’0, ONRC(O)O, -SO2NR’-, □NRC(O)NR’0, ONRCOzOmOOCONR’n, or -(CReR7)pOY1O. Specifically, each Q2 is îndependently 0C(O)NR’0, 0NRC(O)3,
1NRC(O)NR’D, ONRCOzOOOOOCONR’O, or -(CR6R7)POY1O, Specifically, each Q2 is îndependently 000, ONR’O, 00(0)0, 00020, OC(O)NR’O, 0ΝΗ0(Ο)0, □N(CH3)C(0)0, ONHCÎOÎNRO, ON(CH3)C(0)NROOOONHC020, ΟΝ(ΟΗ3)ΟΟ2Ο, □ 00(0)NR'0, -NHSO2O, -N(CH3)S02Onn-S02NR’-, or-(CR6R7)pOY1O. Specifically, each Q2 is îndependently OC020, 0C(O)NR’0, 0NHC(O)0, 0N(CH3)C(O)00nnNHC(O)NRO, □N(CH3)C(0)NR’nDODNHC020, 0N(CH3)CO20, aOC(O)NRO, -NHSO20.0i0-N(CH3)SO2000-SO2NH-, -SO2N(CH3)or-(CReR7)pOY1O. Specifically, each Q2 is îndependently ONR'O, OCÎOÏNR’O, ONHC(O)O, nN(CH3)C(0)0, 0NHC(O)NR’0, nN(CH3)C(O)NRO, -NHC020,0-N(CH3)C02000 OOCONR’O, or-(CR6R7)pOY10. Specifically, each Q2
-2116260 is independently DCtOJNR’O, □NHC(O)aiDOaN(CH3)C(O)a, ONHC(O)NR'O, -N(CH3)C(O)NR’-, -NHCO20,a-N(CH3)CO20a OOCONR'OOOor-(CR6R7)pOY10. Each Q3 is independently a bond, 00(0)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, 0CO2a, -C(0)NRO, nS020.-SO2N(R)-, -C(O)NRC(O)O- or -(CR6R7)POY1-, Specifically, each Q3 is independently is a bond, 00(0)0, -C(=NR)-, OCO2O, C(O)NR’O, □SO2-.“SO2NR’-,0-C(O)NRC(O)0- or-iCR^pOY'nnn Specifically, each Q3 is independently 00(0)0, 00020, -C(O)NR’O, 0SO20, -SO2NR'-, -C(O)NRC(O)O-, or-(CR5R7)pOY1oa Specifically, each Q3 is independently 00(0)0, 0CO20, -C(O)NH0, -C(O)N(CH3)-, 0S02-,-SO2NH-,0 -SO2N(CH3)-, -C(O)NHC(O)O-, -C(O)N(CH3)C(O)O-, or -(CR6R7)pOY1OOOSpecifically, each Q3 is independently 00(0)0, 0CO20, OC^NRO, -C(O)NHC(O)O-, or -(CR6R7)pOY1OOO Specifically, each Q3 is independently 0C(0)0, 0C020, □C(O)NR’0, or -(CR6R7)POY1OOO
Optionally, Q2 and Q3, together with Rs, each and independently can form a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1. It is understood that the non-aromatic ring formed with R5 and Q2can employ a portion of Q2. It is also understood that the non-aromatic ring formed with R5 and Q3 can employ a portion of Q3.
Each Y1 is independently a bond, Ξ10ΣΙ, OSO, ONRO, OC(0)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, ΠΟΟΖΊ, 000(0)0, 0C(0)NR0, -C(O)NRC(O)O-, NRC(O)NRC(O)O-, ONRC(O)O, 0NRC(0)NR0, ONRCOzO, OOCfOJNRD, -S(O)-, □S0200 0N(R)SO20, □SO2N(R)-j -NRS02NR-, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(0)20-, or -CO2SO2-. Specifically each Y1 is independently a bond, OOO, OSO, ONR’O, 00(0)0, -C(=NR)-, 0CO20, 000(0)0, 0C(O)NRO, 0NRC(O)0, 0NRC(O)NR’0, 0NRC020, 000(0)NR’0, -S(0)-, 0SO200 -SO2NR'-, 0NRSO200 NRSO2NR’-, -NRC(O)NRC(O)O- or-C(0)NRC(0)00. Specifically, each Y1 is independently a bond, -O-, ONR’O, 0C(O)NR’0, 0NRC(0)0, 0NRC(0)NR’0, 0NRCO20, OOC(O)NR’O, -NRC(0)NHC(0)0-, or-C(O)NHC(O)OO. Specifically, each Y1 is independently a bond, 000, OSO, ONR’O, 00(0)0, 0CO20, 000(0)0, □C(O)NR’O, ONHC(O)O, 0N(CH3)C(O)0, ONHC(O)NR’lI, □N(CH3)C(0)NR,0, -NHCOs-, -N(CH3)C02-OOOOC(0)NRO, -S(0)-, -S020, ONHSOaO, QN(CH3)SO2O, -SO2NH-, SO2N(CH3)-, -NHSOsNH-, -N(CH3)SO2NH-, -N(CH3)SO2N(CH3)-, -C(O)NHC(O)O-, -C(O)N(CH3)C(O)O-, 0O-NHC(O)NHC(O)0-, or -Ν(ΟΗ3)0(0)ΝΗΟ(0)0- Specifically, each Y1 is independently a bond, -O-, ONR’O, 0C(O)NR’0, 0NHC(O)0, □N(CH3)C(0)OOOONHC(0)NRO1
ON(CH3)C(0)NROODONHC020, ON(CH3)CO2O, 000(0)NR’0, -C(0)NHC(0)00, or -NHC(O)NHC(O)O-.
-2216260
Each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q10R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 4-8 membered ring (e.g., spiro ring or fused ring) that is optionally substituted with one or more instances of JE1. Specifically each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q1DR5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instanced of JE1. The 5-7-membered ring formed with JA or JB can be aromatic or non-aromatic. The 5-7-membered ring formed with JA or JB can optionally be fused to the ring to which they are attached. In some embodiments, the 5-7membered ring can optionally be a spiro ring formed by two geminal JA and two geminal JB, respectively.
Jc is independently selected from the group consisting of halogen, cyano, oxo, □ OR5, -SR5, HNR’R5, OC(O)R6, HCOîR5, □OCfOJR5, nC(O)NR'R6, C(O)NRC(O)OR5, -NRC(O)NRC(O)OR5, aNRC(O)Rs, nNRC(O)NR'R5, nNRCO2R5, □OC(O)NR’R5, -S(O)R5, □SOzRsn -SOzNR’Rs, aNRSO2R5a -NRSO2NR'R5, and -P(O)(ORa)2- Specifically, Jc is independently selected from the group consisting of □OR5, -SR5, DNR’R5, aC(O)R5, DCO2R5, DOC(O)R5, □C(O)NR’R5, C(O)NRC(O)OR5, -NRC(O)NRC(O)OR5, □ NRCiOJR5, □NRC(O)NR’R5, ONRCO2R5, □ OC(O)NR'R5, -S(O)R5, □ S02R50 -SO2NR’R5, ONRSO2R5a and -NRSOjNR'R5, Specifically, Jc is selected from the group consisting of halogen, cyano, oxo, 3OR5, nNR'R5, □ C(O)R5, nCO2R5, 0OC(O)R5, nC(O)NR’R5, -C(O)NRC(O)OR5, 7NRC(O)RS, l!NRC(O)NR’R5, ONRCOîR5, and -OC(O)NR’RS. Specifically, Jc is selected from the group consisting of halogen, cyano, oxo, aOR5, ONR’R5, 00(0^5. □CO2R5, nOC(O)Rs, nC(O)NR’Rs, and 0NRC(O)R5. Specifically, Jc is selected from the group consisting of halogen, cyano, oxo, OOR5, nNR'R5, QCiOJNR'R5, and □ NRC(O)R5. Specifically, Jc is selected from the group consisting of DOR5, INR’R5, nC(O)NR'R5, and ONRC(O)R5.
Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, nORb, DSRb, -S(O)Ra, DSO2Ra, nNRbRc, nC(O)Rb, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, nC(O)ORb, nOC(O)Rb, ONRC(O)Rb, □ C(O)NRbRc, nNRC(O)NRbRc, □NRC(O)0Rb, TlOCONRhR0, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),n-SO2NRcRb, -NRSO2Rb, -NRSO2NRcRb, -P(O)(ORa)2, -OP(O)(ORa)2-, -P(O)z(ORa), and -CO2SOzRb, or optionally, two JC1 and two JD1, respectively, together with the atom(s) to which they are attached, independently form a 4-8-membered ring that is optionally substituted with one or more instances of JE1. Specifically, each of JC1 and JD1 is independently selected
-2316260 from the group consisting of halogen, cyano, oxo, Ra, nORb, OSRb, -S(O)Ra, □ SO2Ra, nNRbRc, nC(O)Rb, nC(O)ORb, □OC(O)Rb, DNRC(O)Rb, nCfOJNRhR0, □ NRC(O)NRbRc, L)NRC(O)ORb, LlOCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(0)NR(ORb),D-SO2NRcRb, -NRSO2Rb, and -NRSO2NRcRb Optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are l L attached. It is understood that sélections of values of each JC1 and JD1are those that resuit in the formation of stable or chemically feasible compounds. For example, suitable values of each JC1 and JD1 on a carbon atom independently include halogen, cyano, oxo, Ra, □ORb, nSRb, -S(O)Ra, aSC^R3, ONRbRc, □C(O)Rb, nC(O)ORb, □OC(O)Rb, ONRbC(O)Rb, LlC(O)NRbRc, nNRC(O)NRbRc, ONRCfOiORh, □OCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb), -SO2NRcRb, -NRSO2Rb, and -NRSO2NRcRb; and suitable values of JD1 on a nitrogen atom include Ra, ÔSO2RaLld-SO2N(R)Rb, DC(O)Rb, nC(O)ORb, □C(O)NRbRc, -C(O)NRCO2Rb, and -C(O)NR(ORb). Spécifie examples of each JC1 and JD1 on a carbon atom independently include halogen, cyano, oxo, Ra, LlORb, nSRb, -S(O)Ra, 0SO2Ra,
1NHRC, 'C(O)Rb, nC(O)ORb, nOC(O)Rb, nNHC(O)Rb, □CfOJNHR0, ' iNHC(O)NHRc, nNHC(O)ORb and nOCONHRc, □N(CK3)R°, ON(CH3)C(O)Rb, □C(O)N(CH3)RC, [2N(CH3)C(O)NHRc, nN(CH3)C(O)ORb, DOCONfCH^R0, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -NHC(O)NHC(O)ORb, -N(CH3)C(O)NHC(O)0Rb, -C(O)NH(ORb)-, C(O)N(CH3)(ORb), -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb. Spécifie examples of each JD1 on a nitrogen atom independently include Ra, □SO2Ra, □C(O)Rb, aC(O)ORb, nC(O)NHRc, □C(O)N(CH3)Rc, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -C(O)NH(ORb)-, and -C(O)N(CH3)(ORb). More spécifie examples of each JC1 and JD1 on a carbon atom independently include halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4 alkyl), ΠΝΗ2ι □ ΝΗ(Ο,ΠΟ4 alkyl), αΝ(Ο,αθ4 alkyl)2, -C(O)(C,-C4 alkyl), -00(0)(0,C4 alkyl), -0(0)0(0,-04 alkyl), C3-Ce cycloalkyl, and -CO2H, wherein each of said alkyl groups (e.g., represented by Ci-C4 alkyl, -0(0,-04 alkyl), 0NH2, □ ΝΗ(0,Π04 alkyl), □N(C10C4 alkyl)21 -0(0)(0,-04 alkyl), -00(0)(0,-C4 alkyl), -0(0)0(0,-C4 alkyl), and C3-C6 cycloalkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -0(0)(0,-04 alkyl), -0C0(C,-C4 alkyl), -CO2H, -C02(C,-C4!alkyl), and Ci-C4 alkoxy. More spécifie examples of each JD1 on a nitrogen atom independently include halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -C(O)(Ci-C4 alkyl), -0(0)0(0,-C4 alkyl), and C3-C6 cyclo(alkyl), wherein each of said alkyl groups is optionally and independently
-2416260 substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, alkyl), -N(CrC4 alkyl)2,
-0(0)(0,-04 alkyl), -OCO(Ci-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), and 0,-0« alkoxy. Each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C-i-CB alkyl, -0(0,-06 alkyl), and -0(0)(0,-06alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(0ι-04 alkyl), -Ν(Οι-Ο4 alkyl)2, -000(0ι-04 alkyl), -00(0,-04 alkyl), -CO2H, -C02(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, 0,-06 alkyl, -O(C,-C6 alkyl), -CtOXCrCs-alkyl), -NH2, -NH(C,-C6 alkyl), -N(Ci-C6 alky1)2, -C(O)NH2, -C(O)NH(C,-C6 alkyl), -C(O)N(C,-Ce alkyl)2t -0(0)(0,Ce-alkyl), -C(O)O(C,-Ce alkyl), -OC(O)(C,-C6 alkyl), -NHC(O)(C,-Ce alkyl), -N(C,-C6 alkyl)C(O)(C,-C6 alkyl), and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -002(0,-04 alkyl), and C,-C4 alkoxy. It is understood that sélections of suitable JE1 are those that resuit in the formation of stable or chemically feasible compounds. For example, suitable substituents on a carbon atom independently include halogen, cyano, hydroxy, oxo, C,-C6 alkyl, -O(C,-C6 alkyl), -C(O)(C,-C6-alkyl), -NH2, -NH(C,-Ce alkyl), -N(C,-CS alkyl)2, -C(O)NH2, -C(O)NH(CrC6 alkyl), -C(O)N(C,-C6 alkyl)2, -C(O)(C,-C6-alkyl), -C(O)O(C,-C6 alkyl), -OC(O)(C,-C6 alkyl), -NHC(O)(C,-C6 alkyl), -N(C,-CB alkyl)C(O)(C,-C6 alkyl), and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C4-C4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and CrC4 alkoxy. For example, suitable substituents on a nitrogen atom independently include CrC6 alkyl, -C(O)NH(CrC6 alkyl), -C(0)N(CrC6 alkyl)?, -C(O)(CrCB-alkyl), and -C(O)O(C-i-C6 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(Cr C4 alkyl)?, -OCO(CrC4 alkyl), -00(Ο04 alkyl), -CO2H, -CO2(CrC4 alkyl), and C,-C4 alkoxy.
R and R' are each independently ΠΗ or C;-C6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, (fo-Ce alkoxy, CrC6 haloalkoxy, Ci-CBaminoalkoxy, CrCecyanoalkoxy, CrCehydroxyalkoxy, and C2-Ce
-2516260 alkoxyalkoxy. Specifically, R and R' are each independently DH or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C6 alkyl), -N(CrC6 alkyl)2, -0(0)0(0-,-06 alkyl), -OC(O)(C,-C6 alkyl), -CO2H, 0·,-06 haloalkoxy, C,-C6 aminoalkoxy, Ci-Cecyanoalkoxy, C,-C6hydroxyalkoxy, and C,-C6alkoxyalkoxy. Specifically, R and R' are each independently DH or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C,-Ce alkyl), -N(C,-Ce alkyl)2, and -O(C,-C6 alkyl). Specifically, R and R’ are each independently ΠΗ or C,-C6alkyl (e.g., -CH3 or -CH2CH3).
Optionally R’, together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered, non-aromatic, heterocyclic ring optionally substituted with one or more instances of JD1. Specifically, the non-aromatic heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC6alkyl, C2-C6 alkenyl, -NH2, -NH(C,C6 alkyl), -N(Ci-Cb alkyl)2, -0(C,.C6 alkyl), -C(O)NHZ, -C(O)NH(Ci-C6 alkyl), C(0)N(C,-Ce alkyl)2, -C(O)(C,-C6-alkyl), -OC(O)(CrC6 alkyl), -NHC(O)(C,-C6 alkyl), -N(C,-Ce alkyl)C(O)(C,-C5 alkyl), and -CO2Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -0(0)(0,-0, alkylO, -CO2H, -CO2(Ci-C4 alkyl), and C,-C4 alkoxy. Specifically, the non-aromatic heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C,-C4 alkyl, -O(Ci-C4 alkylnnonNH2, ΟΝΗίΟ,ΊΟ, alkyl), ΟΝίΟ,ΠΟ, alkyl)z, -000(0,-0, alkyl), -0(0)(0,C4 alkyl□, -CO2H, and -CO2(C,-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C,-C, alkyl), -N(C,-C, alkyl)2, -000(0,-0, alkyl), -C02H, -COZ(C,-C4 alkyl), and Ci-C, alkoxy.
Each R* is independently: I) -H; ii) a C,-C6 alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C3-Ce non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 membered heteroaryl, -O(C,-C6 alkyl), and -C(O)(C,-C6-alkyl); wherein each of said alkyl groups (e.g., represented by -0(C,-C6 alkyl), and -C(O)(Ci-Cs-alkyl)) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C,-C, alkyl), -N(C,-C, alkyl)2, -OCO(C,-C4 alkyl),
-2616260
-CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; and wherein each of said C3-Ce non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl is independently and optionally substituted with one or more instances of JE1; or iii) a C3-Ca non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is independently and optionally substituted with one or more instances of JE1. Specifically, each R* independently is: i) -H; ii) C-i-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C,-C4 alkoxy, Ο,-Ο4 haloalkoxy, C-i-C^aminoalkoxy, C,-C4 cyanoalkoxy, C,-C4 hydroxyalkoxy, and C2-C4 alkoxyalkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C,-C4 alkyl, Ci-C4 haloalkyl, CrC4 cyanoalkyl, C2-C4 alkoxyalkyl, C,-C4 aminoalkyl, Ci-C4 hydroxyalkyl, C,-C4 alkoxy, CrC4 haloalkoxy, C,-C4 aminoalkoxy, C,-C4 cyanoalkoxy, C,-C4 hydroxyalkoxy, and C2-C4 alkoxyalkoxy. Specifically, each R* is i) -H, ii) CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2i -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(CrC4 alkyl), and Ci-C4 alkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alky))2, -OCO(CrC4 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(CrC4 alkyl), C,-C4 alkoxy, and CrCe alkyl, wherein each alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(0ι-04 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -002(0,-04 alkyl), and C,-C4 alkoxy.
Each Ra is independently: i) a C,-C6 aliphatiç group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -O(C,-C6 alkyl), -CfOXC-i-Ce-alkyl), C3Ca non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and 6-10 membered carbocyclic aryl group; wherein each of said alkyl groups for the substituents of the C,-CB aliphatiç group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), and C,-C4 alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl and carbocyclic aryl groups for the substituents of the C,-C6 aliphatiç group represented by Ra is optionally and independently
-2716260 substituted with one or more instances of JE1; ii) a C3-Ce non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is optionally and independently substituted with one or more instances of JE1; iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclic aryl group, each of which is optionally and independently substituted with one or more instances of JE1.
Alternative^, each R3 is independently: i) a C,-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC6 alkyl), -N(C,-C6 alkyl)2, -C(O)O(CrC6-alkyl), -OCCOJfCrCe-alkyl), -CO2H, -C(O)NH21 -C(O)NH(C,-C6 alkyl), -C(O)N(C,-Cs alkyl)2, -NHC(O)(C,-C6 alkyl), -N(Ci-C6 alkyl)C(O)(C,-C6 alkyl), -O(C,-C6 alkyl), -C(O)(Ci-C6-alkyl), C3-Ce non-aromatic carbocycle, 6-10 membered carbocyclic aryl, 4-8 membered non-aromatic heterocycle, and 5-10 membered heteroaryl; wherein each of said alkyl groups for the substituents of the C,-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -002(0,-04 alkyl), and C,-C4 alkoxy; and wherein each of said carbocycle, phenyl, non-aromatic heterocycle, and heteroaryl groups for the substituents of the C-|-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6 alkyl, -NH2, -NH(C,-Ce alkyl), -N(CrC6 alkyl)21 -C(O)O(C,-C6-alkyl), -OC(O)(C,-C6-alkyl), -CO2H, C(O)NH2, -C(O)NH(C,-C6 alkyl), -C(O)N(C,-C6 alkyl)2, -NHC(O)(C,-C6 alkyl), -N(Cr C6 alkyl)C(O)(C,-C6 alkyl), -0(C,-C6 alkyl), and -C(O)(C,-Ce-a)kyl), each said alkyl groups being optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and C,-C4 alkoxy; ii) a C3-C0 non-aromatic carbocyclic group, or a 4-8 membered, non-aromatic heterocyclic group, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6 alkyl, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -CiOJOiCrCe-alkyl), -OC(O)(C,-C6-alkyl), -CO2H, -C(O)NH21 -C(O)NH(C,-C6 alkyl), -C(0)N(C,-C5 alkyl)2, -NHC(O)(C,-C6 alkyl), -N(C,-C6 alkyl)C(O)(C,-C6 alkyl), -O(C,-C6 alkyl), and -C(O)(Ci-C6-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH21 -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; or iii) a 5-10 membered
-2816260 heteroaryl group or a 6-10 membered carbocyclic aryl group, each of which is optionally and independently substituted with one or more instances of halogen, cyano, hydroxy, oxo, Ο,-Ο6 alkyl, -NH2> -ΝΗ(Ο,-Οβ alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-C6-alkyl), -OC(O)(C,-C6-alkyl), -CO2H, -C(O)NHZ, -C(O)NH(C,-C6 alkyl), -C(O)N(C,-C6 alkyl)21 -NHC(O)(C,-C6 alkyl), -N(C,-C6 alkyl)C(OXC,-C6 alkyl), -O(C,C6 alkyl), and -CiOXC-i-Ce-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(Οι-Ο4 alkyl), -N(CiC« alkyl)2, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy,
Specifically, Ra is independently: i) a C,-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen; cyano; hydroxy; oxo; -NH2; -NH(C,-CS alkyl); -N(C,-C6 alkyl)2; -0(0)0(0,C6-alkyl); -OCiOXCrCe-alkyl); -CO2H; -O(C,-C6 alkyl); -C(O)(C,-C6-alkyl); and a C3C7 non-aromatic carbocyclic group, phenyl group, 4-7 membered non-aromatic heterocyclic group, or 5-6 membered heteroaryl group, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C6 alkyl, -NH2, NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -C(O)O(C,-C6-alkyl), -OC(O)(C,-C6-alkyl), -CO2H, -O(C,-C6 alkyl), and -C(O)(C,-C6-alkyl); ii) a C3-C7 non-aromatic carbocyclic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C6 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(C,-CS alkyl)21 -0(0)0(0,-C6-alkyf), -OC(O)(CrCe-alkyl), -CO2H, -O(C,-C6 alkyl), and -C(O)(C,-C6-alkyl); iii) a 4-7 membered, non-aromatic heterocyclic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6 alkyl, -NH2, -NH(C,-Ce alkyl), -Ν(Ο,-ΟΘ alkyl)2, -C(O)O(C,-C6-alkyl), -00(0)(0,-C6-alkyl), -CO2H, -0(CrC6 alkyl), and -C(O)(C,-C6-alkyl); iv) a 5-6 membered heteroaryl group or a phenyl group, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C6 alkyl, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)21 -0(0)0(0,-06alkyl), -OC(O)(C,-C6-alkyl), -CO2H, -O(C,-C6 alkyl), and -C(O)(C,-C6-alkyl). Each of the alkyl groups referred to in the values of Ra, including substituents thereof, independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -N(CrC4 alkyl)z, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and 0,-04 alkoxy.
-2916260
Specifically, the optionally substituted Ci-C6 aliphatic group represented by Ra is an optionally substituted CrC6 alkyl group.
Rb and Rc are each independently Ra or -H; or optionally, Rb and Rc, together wrth the nitrogen atom(s) to which they are attached (e.g., represented by uNRbRc, □ C(O)NRbRc, □NRC(O)NRbRc, or DOCONRhR0), each independently form a nonaromatic, 5-7 membered, heterocyclic ring that is optionally substituted with one or more instances of JE1. Suitable spécifie substituents for the heterocyclic ring formed with Rb and Rc independently include halogen, cyano, hydroxy, oxo, amino, carboxy, amido, CrCe alkyl, CrC6 haloalkyl, CrC6 cyanoalkyl, C2-C6'alkoxyalkyl, C,-C6 aminoalkyl, Ci-C6 hydroxyalkyl, C,-C6 alkoxy, C-i-C6 haloalkoxy, C-i-Ceaminoalkoxy, CrCecyanoalkoxy, CrC6 hydroxyalkoxy, C2-C6alkoxyalkoxy, and -C(O)(C,-C6-alkyl). Spécifie suitable substituents for the heterocyclic ring formed with Rb and Rc independently include halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,C4 alkyl)2, C,-C4 alkyl, CrC4 haloalkyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, C,.C4 alkoxy, C,-C4 haloalkoxy, CrC4 hydroxyalkoxy, C2-C4 alkoxyalkoxy, -CO2(Ci-C4 alkyl), -00(0)(0,-^alkyl), and -CO2H.
It is understood that sélections of suitable substituents for the heterocyclic ring formed with Rb and Rc are those that resuit in the formation of stable or chemically feasible compounds. For example, suitable substituents on a carbon atom independently include halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(0,-06 alkyl), -Ν(0,C6 alkyl)2, CrC6 alkyl, CrC6 haloalkyl, C,-C6 hydroxyalkyl, C2-C0 alkoxyalkyl, C,'C6 aminoalkyl, Ci-Ce cyanoalkyl, Ci-C6 alkoxy, C-t-C6 haloalkoxy, 0,-Ce-aminoalkoxy, Ci-Ce-cyanoalkoxy, C^-Ce-hydroxyalkoxy, C2-C6-alkoxyalkoxy, -C(O)(Ci-C6-alkyl), C(O)O(C,-C6-alkyl), -OCiOXCrCe-alkyl), -CO2H, -C(0)NH2, -C(0)NH(CrC6 alkyl), C(O)N(CrC6 alkyl)2, -ΝΗΟ(Ο)(Ο,-Ο0 alkyl), and -N(CrC6 alkyl)C(O)(CrC6 alkyl). In another example, suitable substituents on a carbon atom independently include halogen, cyano, hydroxy, oxo, -NH2, -NHfCrC^ alkyl), -N(Ci-C4 alkyl)2, CrC4 alkyl, C-i-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, C,.C4 alkoxy, C1-C4 haloalkoxy, C2-C4 hydroxyalkoxy, C2-C4 alkoxyalkoxy, -C0(CrC4 alkyl), -CO2(C1-C4 alkyl), and -CO2H. For example, suitable substituents on a nitrogen atom independently include C,-C6 alkyl, C,-C6 haloalkyl, C,-Ce hydroxyalkyl, C2-C6 alkoxyalkyl, C,-Ce aminoalkyl, C,-C6 cyanoalkyl, -C(O)(Ci-Ce-alkyl), -0(0)0(0,-06alkyl), -00(0)(0,-C6-alkyl), -CO2H, -C(O)NH2> -C(O)NH(C,-Ce alkyl), and -C(O)N(C,-C6 alkyl)2. In another example, suitable substituents on a nitrogen atom independently include C,-C4 alkyl, C,-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, C,.C4 alkoxy, C,-C4 haloalkoxy, C2-C4 hydroxyalkoxy, -CO(C,-C4 alkyl), CO2(Ci-C4 alkyl), and -CO2H.
Each Rd is independently -H, 0,-06 alkyl or -C(0)(CrC6 alkyl), wherein each of said alkyl
-3016260 moiety is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2> -OCO(CrC4 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, each Rd is independently -H, or C,-Cs alkyl optionally substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -000(0,-04 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and 0,-04 alkoxy.
p is independently 1, 2, 3 or 4. Specifically, p is independently 1 or 2.
k, n and m are each independently 0, 1 or 2. Alternative^, when rings A and B are 3-6-membered, n and m are each independently 0 or 1; and k is independently 0, 1 or 2; and when rings A and B are 7-8-membered, n and m, are each independently 0, 1 or 2; and k is independently 0, 1 or 2.
x and y are each independently 0, 1 or 2.
z is 1 or 2.
A second set of variables of Structural Formulae (I) and (IA) is as follows:
R2 is -H or-CH3.
R3 is -H, -Cl, -F, -Br, -CN, -CF3, -0(0,-04 alkyl), -OH, -NH2, -NH(C,-C4 alkyl), or -N{C,-C4 alkyl)2.
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
A third set of variables of Structural Formulae (I) and (IA) is as follows:
R2 is -H or —CH3.
R4 is i) an optionally substituted C3-C,o carbocyclîc ring; ii) a C,-C6 aliphatic group (e.g., C,-C6 alkyl or C2-C6 alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted, C3-C8 non-aromatic carbocycle, and an optionally substituted, 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle.
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
A fourth set of variables of Structural Formulae (I) and (IA) is as follows:
R2 is -H or —CH3.
R3 is -H, -Cl, -F, -Br, -CN, -CF3, -O(C,-C4 alkyl), -OH, -NH21 -NH(C,-C4 alkyl), or -N(C,-C4 alkyl)2
R4 is selected from formulae A-D depicted above.
The remaining variables of Structural Formulae (I) and (IA), including spécifie values,
-3116260 are each and independently as described above for the first set of variables of
Structural Formulae (I) and (IA).
A fifth set of variables of Structural Formulae (I) and (IA) is as follows:
R2 is -H or -CH3.
R3 is -H, -F, -Cl, -CF3, -NH2, -NHMe or -NMe2.
R4 is i) an optionally substituted C3-Ci0 carbocyclic ring; ii) a CrC6 aliphatic group (e.g., C-i-Ce alkyl or C2-C6 alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted, C3-C8 non-aromatic carbocycle, and an optionally substituted, 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle.
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
A sixth set of variables of Structural Formulae (I) and (IA) is as follows:
R2 is -H or -CH3.
R3 is -H, -F, -Cl, -CF3, -NH2, -NH(CH3), or -N(CH3)2.
R4 is selected from formulae A-D depicted above.
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, are each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
A seventh set of variables of Structural Formulae (I) and (IA) is as follows:
R2 is -H or-CH3.
R3 is-H,-F, or -Cl.
R4 is i) an optionally substituted C3-C10 carbocyclic ring; ii) a C^Ce aliphatic group (e.g., CrCg alkyl or C2-C6 alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted, C3-C8 non-aromatic carbocycle, and an optionally substituted, 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle.
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
An eighth set of variables of Structural Formula I is as follows:
R2 is -H or —CH3.
R3 is -H,-F, or -Cl.
R4 is selected from formulae A-D depicted above.
-3216260
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
A ninth set of variables of Structural Formulae (I) and (IA) is as follows:
R2 is -H.
R3 is -H or -Cl.
R4 is i) an optionally substituted C3-C10 carbocyclic ring; ii) a CrCe aliphatic group (e.g., CtC6 alkyl or C2-C6 alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted, C3-CB non-aromatic carbocycle, and an optionally substituted, 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle.
Values of the remaining variables of Structural Formulae (1) and (IA), including spécifie values, and provisos are each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
A tenth set of variables of Structural Formulae (I) and (IA) is as follows:
R2 is -H.
R3 is-H or-Cl.
R4 is selected from formulae A-D depicted above.
Values of the remaining variables of Structural Formulae (1) and (IA), including spécifie values, and provisos are each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
An eleventh set of variables of Structural Formulae (I) and (IA) is as follows:
Each of R2, R3 and R4 is independently as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth set of variables of Structural Formulae (I) and (IA).
Z1 is -H, CrC6 alkyl, -O(CrC6 alkyl), -F, -Cl, -CN, -CO2H, -CO2(Ci-C6 alkyl), -CONHï. -CONH(Ci-Ce alkyl), or -CON(Ci-C6 alkyl)2; and Z2 is -H, C^Ce alkyl, -O(Ci-C6 alkyl), -NH2, -NH(Ci-Ce alkyl), or -N(CrCB alkyl)2; wherein each of said alkyl groups (e.g., represented by C3-C6 alkyl, -O(Ci-C6 alkyl), -CO2(Ci-C6 alkyl), -NH(Cr C6 alkyl), and -N(Ci-C6 alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(CrC4 alkyl)2, -OCO(Ci-C4 alkyl), -COICtCî alkyl), -CO2H, -CO2(CrC4 alkyl), and CrC4 alkoxy.
Values of the remaining variables of Structural Formulae (1) and (IA), including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
A twelfth set of variables of Structural Formulae (1) and (IA) is as follows:
-3316260
Each of R2, R3 and R4 is independently as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth set of variables of Structural Formulae (I) and (IA).
Z1 is -H, -F, -Cl, CrC4 haloalkyl (e.g, -CF3), CrC4 alkyl, -O(CrC4 alkyl), or-CN. Z2 is -H, CrC6 alkyl, -O(C1-C6 alkyl), -NH2, -NH(CrC6 alkyl), or -N(CrCe alkyl)2; wherein each of said alkyl groups (e.g., represented by CrC6 alkyl, -OfCrCg alkyl), -NH(CrCe alkyl), and -N(CrC6 alky1)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(0·|-04 alkyl), -N(CrC4 alkyl)2, -OCO(C1-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(CrC4 alkyl), and C,-C4 alkoxy.
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (1) and (IA).
A thirteenth set of variables of Structural Formulae (I) and (IA) is as follows:
Each of R2, R3 and R4 is independently as described in the first set, second set, third set, fourth set, fifth set, sixth set, seventh set, eighth set, ninth set, or tenth set, of variables of Structural Formulae (I) and (IA).
Z1 is -H, -F, -Cl, CrC4 haloalkyl (e.g, -CF3), Ci-C4 alkyl, -O(CrC4 alkyl), or -CN.
Z2 is -H or a CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C4-C4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -COiCrC-, alkyl), -CO2H, -CO2(C1-C4 alkyl), and C4-C4 alkoxy.
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
A fourteenth set of variables of Structural Formulae (I) and (IA) is as follows:
Each of R2, R3 and R4 is independently as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth set of variables of Structural Formulae (I) and (IA).
Z1 is -H, -F, -Cl, -CF3, -CH3, or -CN.
Z2 is -H or a CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(C4-C4 alkyl)Z1 -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(C-i-C4 alkyl), and Ci-C4 alkoxy.
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
In a fifteenth set of variables of Structural Formulae (I) and (IA), values of the the variables,
-3416260 except R*, R and R’, of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as described above in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, orfourteenth set of variables of Structural Formulae (I) and (IA); and, where applicable:
each R* independently is: i) -H; ii) CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -N(CrC4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -002(0,-04 alkyl), and 0,-04 alkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -Ν(0-|-04 alkyl)Z1 -000(0,-04 alkyl), -00(0,-04 alkyl), -C02H, -002(0,-04 alkyl), 0,-04 alkoxy, and C,-C6 alkyl, wherein each alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Cr C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; and
R and R‘ are each independently ΠΗ or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-Ce alkyl), -N(C,-C6 alkyl)2, and -0(Ci-Cs alkyl); or optionally R’, together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered, non-aromatic, heterocyclic ring optionally substituted with one or more instances of JD1.
A sixteenth set of variables of Structural Formulae (I) and (IA) is as follows:
Each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, and Q10R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1, and fused to the ring to which they are attached,
Q1 is independently a bond, 000, OSO, ONR’O, 00(0)13, DC02D, 000(0)0, OC(0)NR'OI, —C(O)NRC(O)O-,-NRC(0)NRC(0)0-, 0NRC(O)0, ONRC(O)NR'n, 0NRCO20, -OC(O)NRO, -S(0)-, OSOzOO -SOjNR’-, ONRSOzOO or -NRSOîNR’-, or -(CR6R7)p0Y10,
Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, OORb, 0SRb, -S(O)Ra, 0SO2Ra, □ NRbRc, DC(0)Rb, 0C(0)0Rb, DOC(O)Rb, ONRC(0)Rb, 0C(O)NRbRc, DNRC(0)NRbRc, 0NRC(O)ORb, □ OCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),0-SO2NRcRb, -NRSO2Rb, and -NRSO2NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-3516260 membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
Values of the remaining variables of Structural Formulae (I) and (IA), including spécifie values, and provisos are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, orfourteenth set of variables of Structural Formulae (I) and (IA).
A seventeenth set of variables of Structural Formulae (1) and (IA) is as follows:
R1 is -H.
R2 is -H, -CH3, -CH2OH, or -NH2. Alternative^ R2 is -H or -CH2OH.
R3 is -H, DF, EJCI, alkyl, or Cm haloalkyl. Alternative^, R3 is -H, DF, or CCI.
Z1 is -H, -F, or -Cl.
Z2 is -H or C^Cs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -OfCrCi alkyl).
Z3 is -H or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(CrC4 alkyl).
The remaining variables are as decribed above in any set of variables for Structural Formulae (IA) and (!) as applicable.
An eighteenth set of variables of Structural Formulae (I) and (IA) is as follows:
R1 is -H.
R2 is -H or-CH2OH.
R3 is -H, DF, or CICI. Alternative^ R3 is -F or -Cl.
Z1 is -H,-F, or-Cl.
Z2 and Z3 are -H.
The remaining variables are each and independently as decribed above in any set of variables for Structural Formulae (IA) and (1).
A nineteenth set of variables of Structural Formulae (I) and (IA) is as follows: R5 is: i) -H; ii) an optionally substituted C^Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), CrC4 alkoxy, -NRCO(CrC4 alkyl), -CONR(CrC4
-3616260 alkyl), -NRCO2(CrC4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1; and wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O(Ci-C4 alkyl), ΠΝΗ2, □NH^DC, alkyl), DNÎC^Cî alkyl)2, -0(0)(^C4 alkyl), -OC(O)(Ci-C4 alkyl), -0(0)0(0^-04 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -C0(C,-C4 alkyl), -CO2H, -00^0^04 alkyl), and CrC4 alkoxy.
R1, R2, R3, Z1, Z2, and Z3 are each independently as described in the seventeenth or eighteenth set of variables above.
The remaining variables are each and independently as decribed above in any set of variables for Structural Formulae (IA) and (I).
In some embodiments, the variables of Structural Formulae (IA) and (I) are each and independently as described above in any set of variables, provided that: R4 is:
n and m are each independently 0 or 1 when rings A and B are 3-6-membered; or n and m are each independently 0, 1 or 2 when rings A and B are 7-10-membered; and provided that if Y1 is a bond, then R5 is neither -H nor a Ch-Ce aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither -H nor a CrCe aliphatic group.
In another embodiment, the présent invention is directed to the use of compounds represented by any one of the Structural Formulae 11, III, IV, and V, depicted below, or pharmaceutically acceptable salts thereof, for any of the uses described above:
The first set of variables of Structural Formulae II - V is as follows:
Z1 is -H, -F, -Cl. C1-C4 haloalkyl (e.g, -CF3), C1-C4 alkyl, -O(CrC4 alkyl), or-CN. Z2 is -H, CrCg alkyl, -O(CrCe alkyl), -NH2, -NH(C4-CS alkyl), or -N(CrCs alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(C1-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and CrC4 alkoxy.
R3 is -H, -Cl, -F, -Br, -CN, -CFa, -O(Ci-C4 alkyl), -OH, -NH2, -NH(CrC4 alkyl), or -N(CrC4 a1kyl)2 Specifically, R3 is -H, -F, -Cl, -CF3, -NH2, -NH(CH3), or -N(CH3)2. Specifically, R3 is -H, -Cl, or-F. Specifically, R3 is -Cl.
Each R and R' are independently -H or CrC 6alkyl.
Définitions of rings A-D of formulae ll-V, including spécifie variables, are each and independently as described above for the first set of variables of Structura) Formulae (I) and (IA), wherein each of rings A-D is independently an optionally substituted, 4-7 membered ring.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
A second set of variables of Structural Formulae 11, III, IV and V is as follows:
Z1 is -H, -F, -Cl, -CF3, -CH31 or -CN.
Z2 is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -C02(CrC4 alkyl), and C1-C4 alkoxy.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae ll-V.
A third set of variables of Structural Formulae II, III, IV and V is as follows:
Z1 is-H.-F or-CN.
-3816260
Z2 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo,
-NHZ, -NH(C,-C4 alkyl), -N(CrC4 alkyl)2, -OCO(C1-C4 alkyl), -CO(CrC4 alkyl), -CO2H,
-CO2(C,-C4 alkyl), and Ci-C4 alkoxy.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae ll-V.
A fourth set of variables of Structural Formulae II, III, IV and V is as follows:
Z1 is-H, -F or-CN.
Z2 is -H or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(0,-Ο4 alkyl), -N(CrC4 alkyl)2, -000(0,-04 alkyl), -00(0Ί-04 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and CrC4 alkoxy.
R3 is-H, -Cl or-F.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae ll-V.
A fifth set of variables of Structural Formulae II, III, IV and V is as follows:
Z1 is -H, -F or-CN.
Z2 is -H or Ci~C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -000(0ι-04 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and C,-C4 alkoxy.
R3 is -H, -Cl, -F, -CF3,-NH21 -NH(CH3), or -N(CH3)2.
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each Re is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, CrC4 haloalkyl, 0,-04 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(Ci-C4 alkyl), αΝΗ2, ΠΝΗ(01004 alkyl), or □Ν(0,Π04 alkyl)2.
Each R9 is independently -H or-CH3.
R11 and R12 are each independently -H or -CH3.
R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae ll-V.
A sixth set of variables of Structural Formulae II, III, IV and V is as follows:
Z1 is-H,-F or-CN.
-3916260
Z2 is -H or an optionally substituted CrC6 alkyl.
R3 is -H, -Cl or-F.
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each R® is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, CrC4 haloalkyl, C-i-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C1-C4 alkyl), ΟΝΗ2, ΠΝΗ(Ο1ΟΟ4 alkyl) or CN^üCî alkyl)2.
Each R9 is independently -H or -CH3.
R11 and R12 are each independently -H or -CH3.
R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Values of the remainîng variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae ll-V.
In a seventh set of variables of Structural Formulae ll-V, values for variables, except Re, R7, R6, R9, R11, R1z, R13, and R14, of Structural Formulae ll-V, including spécifie values, are each and independently as described above for the first, second, third, orfourth set of variables of Structural Formulae ll-V; and
R6 and R7 are each independently -H or -Ci-C4 alkyl, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each R® is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, CrC4 haloalkyl, CrCi hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C1-C4 alkyl), CNH2, l1NH(C1CC4 alkyl) or □N(CiOC4 alkyl)2.
Each R9 is independently -H or-CrC4 alkyl.
R11 and R12 are each independently -H or -CrC4 alkyl.
R13 and R14 are each independently -H or -CrC4 alkyl, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
In an eighth set of variables of Structural Formulae ll-V, values for variables of Structural Formulae ll-V, including spécifie values, are each and independently as described above for the first set of variables of Structural Formulae ll-V.
It is provided that when Q2-R® is -OR5 or -NR’R5, ring A is further substituted with one or more instances of JA other than -H.
It is provided that if Q3 is -C(O)-, then R5 is a substituted CrC6 aliphatic group (e.g., Cf-Ce alkyl group or C2-Cs alkenyl group); an optionally substituted C3-CB nonaromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroaryl group. In one embodiment, the Cr C6 aliphatic group is substituted with one or more instances of JC1, wherein JC1 is
-4016260 independently selected from: an optionally substituted, C3-Ca non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclîc aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; □OR1’; DSRb; -S(O)Ra; nSOzRa; □NRbRc; nC(O)Rb; □C(O)ORb; nOC(O)Rb; HNRC(O)Rb; OC(O)NRbRc; □NRC(O)NRbRc; □NRC(O)ORb; nOCONRbRc; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -SO2NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
In a ninth set of variables of Structural Formulae ll-V, values for variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A tenth set of variables of Structural Formulae ll-V is as follows:
Each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, andQ1OR5; or optionally two JA and two J0, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1, and fused to the ring to which they are attached.
Q1 is independently a bond, ΠΟΠ, OSn, üNRJ, 2IC(O)0, nCO2 i, 000(0)71, □C(O)NRn,-C(O)NRC(O)O-, -NRC(O)NRC(O)O-, □NRC(O)0, ONRC(O)NRri, nNRCO2O, □OCÎOJNRlI, -S(O)-, nSO20n nN(R)SO2O, 0S02N(R)-, -nrso2nr-, or -(CR6R7)pOY1OD
Q2is independently a bond, 000, DSO, ONRH, 00(0)0, nCO2n, 000(0)0, 0C(O)NR!7l, -C(O)NRC(O)O-, -NRC(0)NRC(0)0-, DNRC(0)0, nNRC(O)NR0, ONRCOzO, OOC(O)NRn, -S(0)-, “SO/IO ON(R)S020, 0SO2N(R)-, -NRSO2NR-, or -(CR6R7)pOY1 0.
Q3 is independently a bond, 00(0)0, 0 0020, -C(O)NR0, ,OS020.-S02N(R)-, -C(O)NRC(O)O- or -(CR6R7)POY1OO
R5 is: i) -H; ii) a 0,-06 aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-CB non-aromatic carbocycle, or 6-10 membered carbocyclîc aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of J01.
Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, 0ORb, nSRb, -S(O)Ra, USOsR3, ONR^, nC(O)Rb, □C(O)ORb, □OC(O)Rb, nNRC(O)Rb, DC(O)NRbRc, DNRC(O)NRbRc, □NRC(O)ORb,
-4116260 □ OCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),7-SO2NRcRb,
-NRSO2Rb, and -NRSO2NRcRb, or optionally, two JC1 and two J01, respectively, together with the atoms to which they are attached, independently form a 5-7membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
Ring A is a C3-C8 non-aromatic carbocycle optionally and independently further substituted with one or more instances of JA.
Values of the remaining variables of Structura) Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth set of variables of Structural Formulae ll-V.
In another embodiment, the présent invention is directed to the use of compounds represented by the Structural Formula below XI(A) or X1(B), or a pharmaceutically acceptable sait thereof, for any of the uses described above.
H or h
XI(A) XI(B)
A first set of variables of Structural formulae XI(A) and XI(B) is as follows: Ring A is a 5-7 membered, non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ch-Ce alkyl, C2-C6 alkenyl, -NH2, -NH(Cr C6 alkyl), -N^-Cb alkyl)2, -0(0,.^ alkyl), -C(O)NH2, -C(O)NH(CrC6 alkyl), C(O)N(CrC6 alkyl)2, -CiOMCrCs-alkyl), -OC(O)(Ci-C6 alkyl), -NHC(O)(CrC6 alkyl), -N(CrC6 alkyl)C(O)(Ci-C6 alkyl), and -CO2Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(CrC4 alky1)2> -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and CrC4 alkoxy. Specifically, ring A is a 5-7 membered, nonaromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(CrC4 alkyl3naoNH2, αΝΗ(0ιΠ04 alkyl), ΟΝ(ΟιΠΟ4 alkyl)2, -C(O)(Ci-C4 alkyln, -00(0)(0^04 alkyla, -CO2H, and -CO2(Ci-C4 alkyl), wherein
-4216260 each of said alkyl groups is optionally and indepednently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and CrC4 alkoxy. Specifically, ring A is a 5-7 membered carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C2 alkyl), -NH(CrC2 alkyl)2, CrC2 alkyl, C^-C^ haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, CrC2 alkoxy, Ci-C2 hydroxyalkoxy, CrC2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(C.|-C4 alkyl).
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each R8 is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, Ci-C4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C-|—C4 alkyl), aNH2] aNH(C5aC4 alkyl), or nN(CiDC4 alkyl)2.
Each R9 is independently -H or -CH3.
R11 and R12 are each independently -H or -CH3.
R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each R and R' are independently -H or CrC6 alkyl.
Values of the remaining variables of Structural formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A second set of variables for Structural formulae Xl(A) and XI(B) is as follows:
Values of Ring A, R, R’, Re, R7, R8, R3, R11, R12, R13 and R14, including spécifie values, are each and independently as described above in the first set of variables of Structural formulae Xl(A) and XI(B).
Variable x is 0 or 1 and variable n is 0 or 1.
Values of the remaining other variables of Structural formulae X1(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A third set of variables for Structural formulae XI(A) and XI(B) is as follows:
Values of Ring A, R, R’, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, are each and independently as described above in the second set of variables of Structura) formulae XI(A) and XI(B).Q
Q2 is -Ο-,Π-NR'-, CO TX02·!, □C(O)NR,n, nnRC(O)7, □□RC(O)NRΊ lRCO2n, lOCONR’n ni-NRSO-nD.:i-SO2NR'-,Oor-(CR6R7)p7Y1n. Specifically, Q2 is DÛ.D, ΠΝΗΟ, -N(CH3)-. nC(O)n, 0CO2a, l!C(O)NHCI, □C(O)N(CH3)U, □NHC(O)n, ON(CH3)C(O)l], ÜNHCÎOJNR’O, □N(CH3)C(O)NR’n,
-4316260 □NHCO2O, □N(CH3)CO2Q, nOC(O)NR'D, -NHSO2O, -N(CH3)SO2aaa-SO2NH-,
-S02N(CH3)-nnor -(CR6R7)paY’a.
Values of the remaining variables of Structural formulae Xl(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A fourth set of variables for Structural formulae XI(A) and XI(B) is as follows:
Values of Ring A, Q2, R, R’, R6, R7, R8, R9, R11, R1Z, R13, R14, x and n, including spécifie values, are each and independently as described above in the third set of variables of Structural formulae XI(A) and X1(B).□
R5 is independently i) -H; ii) a CrCe-aliphatic group (e.g., Ci-C6-alkyl or C2-C6alkenyl group) optionally substituted with one or more instances of JC1; iii) a C3-CB non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of J01.
Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, DORb, DSRb, -S(O)Ra-, û!SO2Ra, nNHRc, □C(O)Rb, □CiOJOR0, □OC(O)Rb, □NHC(O)Rb, 0C(O)NHRc, DNHC(O)NHRC, DNHC(O)ORb, DOCONHR0, -NHC(0)NHC(0)ORb, aNfCHaïR, nN(CH3)C(O)Rb, nC(O)N(CH3)Rc, nN(CH3)C(O)NHRc, nN(CH3)C(O)0Rb, nOCON(CH3)Rc, -C(O)NHCO2Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(O)NHC(O)ORb, -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb.
Values of the remaining variables of Structural formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A fifth set of variables for structure Structural formulae Xl(A) and XI(B) is as follows;
Values of Q2, R, R’, R5, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, are each and independently as described above in the fourth set of variables of Structural formulae XI(A) and ΧΙ(Β).Π
Ring A is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -O(CrC4 alkylLinonNH2, DNHîC^Cî alkyl), □N(C1aC4 alkyl)2, -C(O)(CrC4 alkylD, -CO2H, and -CO2(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -NH2, -NH(C1-C4 alkyl), -N(C4-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(C4-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), and CrC4 alkoxy.
-4416260
Values of the remaining variables of Structural formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (l) and (IA).
A sixth set of variables for Structural formulae XI(A) and XI(B) is as follows:
Values of Q2, R, R’, R5, Re, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, are each and independently as described above in the fifth set of variables of Structural formulae XI(A) and ΧΙ(Β),Π
The group -[(C)0-iR13R14]-ringA-Q2-R5 is independently selected from one of the depicted below:
wherein each of rings A1-A27 is independently and optionally further substituted with one or more substituents. Suitable substituents are as described above for ring A in the first set of variables of Structural formulae XI(A) and XI(B).a
Values of the remaining variables of Structural formulae XI(A) and XI(B)T including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A seventh set of variables of Structural formulae XI(A) and Xl(B) is as follows:
Values of the group -[CR13R14]x-ringA-Q2-R5, Q2, R, R’, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, are each and independently as described
-4516260 above in the sixth set of variables of Structural formulae XI(A) and XI(B).n Each R6 is independently: i) -H; ii) a Ci-CB-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(0,-0,alkyl), DNH2, αΝΗ(0,Π0, alkyl), □ N(C,aC, alkyl)2, -C(O)(C,-C, alkyl), -00(0)(0,-0, alkyl), -0(0)0(0,-0, alkyl), -C02H, C3-Ce non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl; or iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C^C, alkyl, -O(Ci-C, alkyl), ΠΝΗ2, aNH(C,nC, alkyl), !N(CriC, alkyl)2, -C(O)(C,-C, alkyl), -OC(O)(C,-C, alkyl), -0(0)0(0,-0, alkyl), and -CO2H; wherein each of said alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH21 -NH(Ci-C4 alkyl), -N(C,-C, alkyl)2, -000(0,-0, alkyl), -00(0,-0, alkyl), -CO2H, -CO2(C,-C4 alkyl), and 0,-C, alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the C,-C6-a)iphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(C,-C4 alkyl), -N(Ci-C, alkyl)2, -OCO(Ci-C, alkyl), -CO(C,-C, alkyl), -CO2H, -C02(C,-C, alkyl), and C,-C, alkoxy.
Values of the remaining variables of Structura) formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
An eighth set of variables of Structural formulae XI(A) and XI(B) is as follows:
Values of Q2, R, R’, R5, Rs, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, are each and independently as described above in the seventh set of variables of Structural formulae XI(A) and XI(B). □ The group -[(C)0.iR13R14]-ringA-Q2-R5 is independently selected from one of the depicted below
-4616260
Wo,1 \ R5 >0'
O , wherein each of rings A6, A8, A11, A14 and A15 is optionally and independently further substituted.
Rs independently is halogen, cyano, hydroxy, 0,-04 alkyl, C,-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(0^0^ alkyl), □NH(C1nC4 alkyl), or □Ν(0,α04 alkyl)2.
Values of the remaining variables of Structural formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A ninth set of variables of Structural formulae Xl(A) and XI(B) is as follows:
Values of the group -[CR13R14]-ringA-Q2-R5, Q2, R, R’, R6, R7, Re, R9, R11, R12, R13, R14, x and n, including spécifie values, are each and independently as described above in the eighth set of variables of Structural formulae XI(A) and XI(B).n R5 is: i) -H; ii) an optionally substituted C,-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle. Each of said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(Ο,-Ο4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), Ci-C4 alkoxy, optionally substituted, C3-C7 non-aromatic carbocycle, and optionally substituted, 47 membered non-aromatic heterocycle. Each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Ci-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -0(C,-C4alkyl), lINH2, ΠΝΗ(0,Π04 alkyl), C]N(C1aC4 alkyl)2, -C(O)(C,-C4 alkyl), -00(0)(0,-04 alkyl), -0(0)0(0,-04 alkyl), and -CO2H, wherein each of said alkyl groups (e.g., represented by 0,-04 alkyl, -0(0ι~04 alkyl), □NH(C1DC4 alkyl), ΠΝ(0,004 alkyl)2l -0(0)(0,-04 alkyl), -00(0)(0,-04 alkyl), and -0(0)0(0,-04 alkyl)) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -Ν(0,-04 alkyl)2, -0C0(Ci-C4 alkyl), -00(0ι-04 alkyl), -C02H, -002(0,-04 alkyl), and C1-C4 alkoxy.
-4716260
Values of the remaining variables of Structural formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A tenth set of variables of Structural formulae XI(A) and XJ(B) is as follows:
Values of Q2, R, R’, R5, R6, R7, Re, R9, R11, R1Z, R13, R14, x and n, including spécifie values, are each and independently as described above in the seventh set of variables of Structural formulae Xl(A) and XI(B).D
The group -[(C)0-iR13R14l-ringA-Q2-R5 is independently selected from one of the depicted below:
wherein each of rings A1-A4, A7-A20, A22, A23, A25 and A27 is independently and optionally further substituted. Suitable substituents are as described above for ring A in the first set of variables of Structural formulae XI(A) and Xl(B).n
Values of the remaining variables of Structural formulae XI(A) and XI(B), including 15 spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
An eleventh set of variables of Structural formulae XI(A) and XI(B) is as follows:
4816260
Values of Q2, R, R', R5, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, are each and independently as described above in the seventh set of variables of Structural formulae XI(A) and Xl(B).D
The group -[(C)0.1R13R14]-ringA-Q2-R6 is independently selected from one of the depicted below:
ORj wherein each of rings A5-A7, A21, A24 and A26 is independently and optionally further substituted. Suitable substituents are as described above for ring A in the first set of variables of Structure Formulae XI(A) and XI(B).U
Values of the remaining variables of Structural formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
In a twelfth set of variables of Structural formulae XI(A) and XI(B), values of the variables for Structural formulae Xl(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
In a thirteenth set of variables of Structura) Formulae XI(A) and XI(B), values of the variables for Structural Formulae XI(A) and XI(B), including spécifie values, are each and independently as described above in the sixteenth set of variables of Structural Formulae (I) and (IA), or in the tenth set of variables of Structural Formulae ll-V.
In another embodiment, the présent invention is directed to the use of compounds represented by Structural Formula below XII(A) or XII(B), or a pharmaceutically acceptable sait thereof, for any of the uses described above:
Cf
or (XIIA) (XII B),
A first set of variables of Structural Formulae XII(A) and XII(B) is as follows:
-4916260
Ring B is a 4-7 membered, non-aromatic, heterocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C^Ce alkyl, C2-C6alkenyl, -NH2, -NHiCr C6 alkyl), -ΝίΟ,-Οε alkyl)2, -O(C,.C6 alkyl), -C(O)NHZl -CfOJNHiCrCe alkyl), C(O)N(CrC6 alkyl)2l -CfOXCrCe-alkyl), -OC(O)(CrC6 alkyl), -NHCiOXCrCe alkyl), -NfCpCe alkyljCfOXCrCg alkyl), and -CO2Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NHfCrCi alkyl), -NfC^ alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(CrC4 alkyl), and C;-C4 alkoxy. Specifically, Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -O(CrC4 alkyloannNH2, □NH(C1OC4 alkyl), alkyl)2, -0(0)(^-04 alkyla, -CO2H, and -002(0Ί-04 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(C1-C4 alkyl)2, -OCO(Ci-C4 alkyl), -COfCr^ alkyl), -CO2H, -CO2(Ci-C4 alkyl), and 0Ί-04 alkoxy. Specifically, Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Cr C2 alkyl), -NH(Ci-C2 alkyl)2, CrC2 alkyl, C^Cs haloalkyl, C-|-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, CrC2 alkoxy, CrC2 hydroxyalkoxy, C,-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(C-i-C4 alkyl).
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
R9 is -H or-CH3.
R11 and R12 are each independently -H or -CH3.
R13 and R14 are each independently -H or-CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each R and R’ are independently -H or C-[-C6 alkyl.
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A second set of variables of Structural Formulae XII(A) and XII(B) is as follows: Values of Ring B, R, R', R6, R7, R9, R11, R12, R13 and R14, including spécifie values, are each and independently as described above in the first set of variables of Structura! Formulae Xll(A) and XII(B).
Variable y = 0 or 1.
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including
-5016260 spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A third set of variables of Structural Formulae XII(A) and XII(B) is as follows:
Values of Ring B, R, R', R6, R7, R9, R11, R12, R13 and R14 and y, including spécifie values, are each and independently as described above in the second set of variables of Structural Formulae XII(A) and XII(B).
Q3 is independently OC(O)D, aCO20, aC(O)NH3, □C(O)N(CH3)a, -C(O)NHC(O)O, -C(O)N(CH3)C(O)O-, -S02-, -SO2NH-, -SO2N(CH3)-, ot-(CR6R7)p-Y1-.
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A fourth set of variables of Structural Formulae XII(A) and XII(B) is as follows:
Values of Ring B, Q3, R, R’, R6, R7, R9, R11, R12, R13 and R14 and y, including spécifie values, are each and independently as described above in the third set of variables of Structural Formulae XII(A) and XII(B).
R5 is independently i) -H; ii) CrC8-aliphatic group (e.g., Ci-Ce-alkyl or C2-C6-alkenyl group) optionally substituted with one or more instances of JC1; iii) a C3-C0 nonaromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1.
Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, □OR”, nSRb, OSORa, OSO2Ra, FlNHRc, 0C(O)Rb, nC(O)ORb, nOC(O)Rb, □NHC(O)Rb, □C(O)NHRC, nNHCfOjNHR0, nNHC(O)ORb, nOCONHRc,
-NHC(O)NHC(O)ORb, aN(CH3)Rc, □NiCHaJCfOjRh, □C(O)N(CH3)RC, □N(CH3)C(O)NHRc, aN{CH3)C(O)ORb, □OCON(CH3)Rc, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(O)NHC(O)ORb, -NHSO2Rb, -SO2NHRb, -SOzN(CH3)Rb, and -N(CH3)SO2Rb.
Values of the remaining variables of Structural Formulae XII(A) and Xll(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structura) Formulae (I) and (IA).
A fifth set of variables of Structural Formulae XII(A) and XII(B) is as follows:
Values of Ring B, Q3, R, R’, R5, R6, R7, R9, R11, R12, R13, R14, and y, including spécifie values, are each and independently as described above in the fourth set of variables of Structural Formulae XII(A) and XII(B).
Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl,
-5116260
-O(Ci-C4 alkylaaonNHj, □NH(C1DC4 alkyl), □N(C1DC4 alkyl)?, -C(O)(CrC4 alkyln, -CO2H, and -CO2(C1-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(CrC4 alkyl), -NtC,alkyl)?, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A sixth set of variables of Structural Formulae Xll(A) and XII(B) is as follows:
Values of Q3, R, R’, Rs, R6, R7, R9, R11, R12, R13, R14, and y, including spécifie values, are each and independently as described above in the fifth set of variables of Structural Formulae XII(A) and XII(B).
Ring B is independently selected from one of the structures depicted below:
wherein each of rings B1-B9 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4 alkylaannNH2, □NH(C1nC4 alkyl), DN^DC, alkyl)?, -C(O)(C,C4 alkyl21, -CO2H and -CO2(C,-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, each of rings B1 to B9 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C2 alkyl), -NH(C,-C2 alkyl)2, C,-C2 alkyl, CrC2 haloalkyl, CrC2 hydroxyalkyl, C2-C4 alkoxyalkyl, C;-C2 alkoxy, CpC? hydroxyalkoxy, CrC2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(C1-C4 alkyl).
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A seventh set of variables of Structural Formulae XII(A) and XII(B) îs as follows:
-5216260
Values of ring B, Q3, R, R', R5, R6, R7, R9, R11, R12, R13, R14, and y, including spécifie values, are each and independently as described above in the sixth set of variables of Structural Formulae XII(A) and XII(B).
Each Rs is independently: i) -H; ii) a Ci-C6-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(C,-C4alkyl), CNH2, alkyl), nN(C1üC4 alkyl)2, -0(0)(0,-04 alkyl), -OC(O)(C,-C4 alkyl), -0(0)0(0,-0, alkyl), -CO2H, C3-Ce non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl; or iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -0(0,-04alkyl), □NH2, ΠΝΗ(0,Π04 alkyl), □N(C,nC4 alkyl)2l -0(0)(0,-0, alkyl), -OC(O)(C,-C4 alkyl), -C(O)O(C,-C4 alkyl), and -CO2H; wherein each of said alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, □NH2, 0ΝΗ(0,Ί04 alkyl), 0^0,004 alkyl)2, -OCO(C,-C4 alkyl), -C0(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the C,-Cs-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, ΠΝΗ2, □NH(C1DC4 alkyl), nN(CiDC4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2K, -COsfCrC, alkyl), and alkoxy.
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (1 A).
An eighth set of variables of Structural Formulae Xll(A) and XII(B) is as follows:
Values of Q3, R, R’, R5, R6, R7, R9, R11, R1Z, R13 and R14 and y, including spécifie values, are each and independently as described above in the seventh set of variables of Structural Formulae XII(A) and XII(B).
The group (ring B)-Q3-R5 is
-5316260 wherein ring B2 is optionally and independently further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C,-C2 alkyl), -NH(C,-CZ alkyl)2, CrC2 alkyl, CrC2 haloalkyl, CrC2 hydroxyalkyl, C2-C4 alkoxyalkyl, CrC2 alkoxy, C,-C2 hydroxyalkoxy, C,-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(C,-C4 alkyl).
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A ninth set of variables of Structural Formulae XII(A) and XII(B) is as follows:
Values of the group (ring B)-Q3-R5, Q3, R, R’, R6, R7, R9, R11, R12, R13, R14, and y, including spécifie values, are each and independently as described above in the eighth set of variables of Structural Formulae XII(A) and XII(B).
R5 is: i) -H; ii) an optionally substituted C,-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle, wherein said alkyl group represented by R6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, ΠΝΗ2, ΠΝΗ(0ιΠ04 alkyl), □N(C,nC4 alkyl)2, -000(0,-0, alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), C,-C4 alkoxy, optionally substituted, C3-C7 non-aromatic carbocycle, and optionally substituted, 4-7 membered non-aromatic heterocycle. Each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Ci-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4 alkyl), ΠΝΗ2, nNH(C,aC, alkyl), nN(C,aC4 alkyl)2, -0(0)(0,-0, alkyl), -00(0)(0,-0, alkyl), -0(0)0(0,-0, alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, DNH2, ΠΝΗ(0,004 alkyl), □N(C,DC4 alkyl)2, -000(0,-0, alkyl), -00(0,-0, alkyl), -CO2K, -002(0,-04 alkyl), and 0,-0, alkoxy. Values of the remaining variables of Structural Formulae Xll(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
In a tenth set of variables of Structural Formulae XII(A) and XII(B), values of the variables for Structural Formulae XII(A) and XII(B), including spécifie values, are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
In an eleventh set of variables of Structural Formulae XII(A) and XII(B), values of the variables for Structural Formulae XII(A) and XII(B), including spécifie values, are each and
-5416260 independently as described above in the sixteenth set of variables of Structural Formulae (I) and (IA), or in the tenth set of variables of Structural Formulae ll-V.
In another embodiment, the présent invention is generally directed to the use of compounds represented by Structural Formula below XIII, or a pharmaceutically acceptable sait thereof, for any of the uses described above.
(XIII).
A first set of variables of Structural Formula XIII is as follows:
Ring C is a 5-7 membered, non-aromatic, heterocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C,-CBalkyl, C2-CB alkenyl, -NH2, -NH(CrC6 alkyl), -N(Ci-Cb alkyl)2, -O(CVC6 alkyl), -C(O)NH2, -C(O)NH(Ci-C6 alkyl), C(O)N(CrC6 alkyl)2, -C(O)(CrC6-alkyl), -00(0)(0,-06 alkyl), -NHC(O)(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(O)(CrCe alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo,
C1-C4 alkyl, ίΝΗ2, nNH(CiDC4 alkyl), □ N(C10C4 alkyl)2, -000(0,-04 alkyl), -00(0,C4 alkyl), -CO2H, -C02(CrC4 alkyl), and C,-C4 alkoxy. Specifically, ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C,-C4 alkyl, -0(0ι-04 alkynnnONHj, ΠΝΗ(Ο,αθ4 alkyl), ΠΝ(Ο,ΠΟ4 alkyl)2, -0(0)(0,-04 alkylD, -CO2H, and -002(0-ι-04 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, ΠΝΗ2, □ NH(C1nC4 alkyl), nN(C,QC4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H,
-CO2(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(C,-C2 alkyl), -NH(Ci-C2 alky()2, C,-C2 alkyl, C-|-C2 haloalkyl, C,-C2 hydroxyalkyl, C2-C4 alkoxyaîkyl, C,-C2 alkoxy, C130 C2 hydroxyalkoxy, C,-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(C,-C4 alkyl).
-5516260
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
R9is-H or-CH3.
R11 and R12 are each independently -H or-CH3.
Each R and R’ are independently -H or Ci-C6 alkyl.
Values of the remaining variables of Structural Formula XIII, including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A second set of variables of Structural Formula XIII is as follows:
Values of Ring C, R, R’, Rs, R7, R9, R11 and R12, including spécifie values, are each and independently as described above în the first set of variables of Structural Formula XIII.
R10 is -H or Cn-Ce-alkyl.
Values of the remaining variables of Structural Formula XIII, including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
A third set of variables of Structural Formula XIII is as follows:
Values of R, R’, R6, R7, R9, R10, R11 and R12, including spécifie values, are each and independently as described above in the first set of variables of Structure Formula 20 XIII. □
Ring C is a 5-7 membered, non-aromatic, heterocyclic group optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C,-C4 alkyl, -0(0,-04 alkyllmnNH2, □NH(C,aC4 alkyl), □ΙψΟ,ΟΟ, alkyl)2, -C(O)(C,-C4 alkyln, -CO2H and-CO2(Ci-C4 25 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, aNH2, nNH(C,DC4 alkyl), □N(C,nC4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
Values of the remaining variables of Structural Formula XIII, including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (1) and (IA).
A fourth set of variables of Structural Formula XIII is as follows:
Values of R, R’, R6, R7, R9, R10, R11 and R12, including spécifie values, are each and 35 independently as described above in the second set of variables of Structure
Formula XIII.□
Ring C is independently selected from:
-5616260
wherein each of rings C1-C5 îs optionally and independently substituted. Suitable substituents are as described above for ring C in the first set of variables of Structural Formula XIV.
Values of the remaining variables of Structural Formula XIII, including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA),
In a fifth set of variables of Structural Formula XIII, values of the variables for Structural Formula XIII, including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).
In another embodiment, the présent invention is generally directed to the use of compounds represented by Structural Formula below XIV, or a pharmaceutically acceptable sait thereof for any of the uses described above.
(XIV).
A first set of variables of Structural Formula XIV is as follows:
Ring D is 4-7 membered, non-aromatic, heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrCe alkyl, C2-C6 alkenyl, -NH2, -NH(CrC6 alkyl), NiCrCs alkyl)z, -0(0,.^ alkyl), -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(CrC6 alkyl)2, -C(O)(C1-C6-alkyl), -OC(O)(C,-C6 alkyl), -NHC(O)(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)(C1-C6 alkyl), and -CO2Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, ClNHz, alkyl), □N(C10C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Cr
C4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and CrC4 alkoxy. Specifically, ring D is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CVC4 alkyl, -0((^-04 alkylDÜLl JNH2, □NH(C12C4 alkyl), ΠΝ(Ο1ΠΟ4 alkyl)2, -C(O)(Ci-C4 alkyl!, -CO2H
-5716260 and -002(0-1-04 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, EJNI-^, □ΝΗ(0,α04 alkyl), □N(C1aC4 alkyl)2, -000(0,-04 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and Ci-C4 alkoxy, Specifically, ring D is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C2 alkyl), -NH(C,-CZ alkyl)2, Ci-C2 alkyl, C,-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and CO2(Ci-C4 alkyl),
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
R13 and R14 are each independently -H or -CH3) or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each of R and R’ are independently -H or C,-C6 alkyl.
Values of the remaining variables of Structural Formula XIV, including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (!) and (IA).
A second set of variables of Structural Formula XIV is as follows:
Values for Ring D, R, R', R6, R7, R13 and R14, including spécifie values, are each and independently as described above in the first set of variables of Structural Formula XIV,
Value z is 1.
Values of the remaining variables of Structural Formula XIV, including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA),
A third set of variables of Structural Formula IV is as follows:
Values for z, R, R’, R6, R7, R13 and R14, including spécifie values, are each and independently as described above in the second set of variables of Structural Formula XIV. Ring D is independently selected from the group consisting of
-5816260 wherein each of rings D1-D7 is optionally and independently substituted. Suitable substituents are as described above for ring D in the first set of variables of Structural
Formula XIV.
Each Rd is independently -H, C-rC6 alkyl or - C(O)(CrC6 alkyl), wherein each of said alkyl moiety is optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, Cî-C4 alkyl, ΠΝΗΖ, ΠΝΗ^ΠΟί alkyl), ΠΝ(Ο,ΠΟ4 alkyl)21 -000(0,-04 alkyl), -CO(Ci-C4 alkyl), -CO2H, -ΟΟ2(Ο,-Ο4 alkyl), and C,-C4 alkoxy. Specifically, each Rd is independently -H or Ο,-Οθ alkyl optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, C,-C4 alkyl, ΠΝΗζ, □ΝΗ(0,004 alkyl), ΠΝ(0,Π04 alkyl)2> -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. Values of the remaining variables of Structural Formula XIV, including spécifie values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).
ln a fourth set of variables of Structural Formula XIV, values of the variables for Structural Formula XIV, including spécifie values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA), ln another embodiment, the compounds of Structural Formulae l-IV and XI-XIV, and pharmaceutically acceptable salts thereof, are independently as described above; and provided that, where applicable, if Y1 is a bond, then R5 is neither -H, nor an unsubstituted C,-C6 aliphatic group. Specifically, if Y1 is a bond, then Rs is a substituted 0,C6 aliphatic group; an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; and an optionally substituted, 5-10 membered heteroary group. Specifically, the Ci-C6 aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-Ca non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; nORb; aSRb; -S(O)Ra; DSO2Ra; nNRbRc; □C(O)Rb; □C(0)ORb; 0OC(O)Rb; □NRC(O)Rb; □C(O)NRbRc; ONRCiOJNRhR0; aNRC(O)ORb; □OCONRbRc; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(0)NR(0Rb); -SO2NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
ln yet another embodiment, the compounds of Structural Formulae IA-IV and XI-XIV, and pharmaceutically acceptable salts thereof, are independently as described above; and provided that, where applicable, if Q2 is a bond, then R6 is neither-H nor a CrC6 aliphatic
-5916260 group; and provided that if Q3 is a bond, then R6 is neither -H nor a CrC6 aliphatic group. Specifically, if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-Ce non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group. Specifically, if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocycle; or an optionally substituted, 4-8 membered non-aromatic heterocycle.
In yet another embodiment, the compounds are represented by Structural Structural Formula (I), or pharmaceutically acceptable salts thereof, wheren each variables of the formulae are independently as described above; and wherein:
R4 is:
more instances of JA.
Rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1.
Each of rings G1 and G2 is independently a 5-10 membered non-aromatic bridged carbocycle optionally substituted with one or more instances of JA.
Q2is independently bond, 300, OSO, 3NR0, 00(0)3, -C(=NR)-, OC020, □ 00(0)0, 0C(O)NR0, -C(0)NRC(O)0-, -NRC(O)NRC(O)O-, ONRC(0)0, □ NRC(O)NRO, nNRC020, □OCiOJNRD, -S(0)-, nS02n0 nN(R)SO2O, OSOaNR’-, -NRSO2NR’-, or-(CReR7)paY10.
R5 is: i) -H; ii) an optionally substituted 0,-06 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted nonaromatic heterocycle. The alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C1-C4 alkyl), -00(0,-0., alkyl), -CO2H, -002(0,-04 alkyl), Ci-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; wherein each of said carbocycles and heterocycles represented by Rs, and referred to for the substituents of the 0,-0Β
-6016260 alkyl group represented by Rs is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -0(0,-04 alkyl), ΠΝΗ2, αΝΗ(Οιαθ4 alkyl), □ N(C,0C4 alkyl)2, -C(O)(C,-C4 alkyl), -OC(O)(C,-C4 alkyl), -0(0)0(0,-04 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(CrC4 alkyl)21 -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
Each of Re and R9 is independently -H, halogen, cyano, hydroxy, C,-C4 alkyl, C,-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C,-C4 alkyl), ONHZ, 0NH(C,QC4 alkyl), or nN(C,ElC4 alkyl)2.
R11, R12, R13 and R14 are each independently OH, halogen, or C,-Cs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C,-C6 alkoxy, C,-C6 haloalkoxy, Ci-C6aminoalkoxy, C,-CBcyanoalkoxy, Ci-CB hydroxyalkoxy, and C2-CB alkoxyalkoxy; or optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl.
R21, R22, R23 and R24 are each independently ΠΗ, halogen, -OH, or C,-CB alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, 0,-06 alkoxy, C,-Ce haloalkoxy, Ci-C6aminoalkoxy, C,-C6cyanoalkoxy, C,-CB hydroxyalkoxy, and Cz-C6 alkoxyalkoxy.
p and q are each independently 0, 1 or 2.
x is 0, 1 or 2.
r is 1 or 2.
Values of the remairimg variables of Structural formula I, including spécifie values, and provisos are each and independently as described above in any one of the first through fifteenth sets of variables of Structural Formula I.
In yet another embodiment, the compounds represented by Structural Formula (I) or pharmaceutically acceptable salts thereof are independently as described above in the preceding paragraph; and ring F is selected from any one of rings F1-F6:
each of rings F1-F6 optionally and independently substituted; and each Rr is independently OH or CrCBalkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of
-6116260 halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, Ci-C6 haloalkoxy, CrC6 aminoalkoxy, CrC6 cyanoalkoxy, Ci-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy.
In yet another embodiment, the compounds represented by Structural Formula (XIA) or (XIB), or pharmaceutically acceptable salts thereof are as described above; and the group -[C(R13R14)]x-ringA-Q2-R5 is independently:
O r ; wherein:
each of rings A14 and A28 is optionally and independently further substituted; and values of the remaining variables of Structural Formulae (XIA) and (XIB), including spécifie values, and provisos are each and independently as described above in any one of the first through eleventh sets of variables of Structural Formulae (XIA) and (XIB).
In yet another embodiment, the compounds represented by Structural Formula (XIA) or (XIB), or pharmaceutically acceptable salts thereof are independently as described above in the preceding paragraph; and R6 is an optionally substituted Ci-C6 alkyl group; an optionally substituted, C3-C7 non-aromatic carbocycle; or an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle. Specifically, R5 is an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle.
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein:
Ring E is a C4-Ci0 non-aromatic carbocycle optionally further substituted with one or more instances of JA.
Rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1. Spécifie examples of ring F includes:
o
Additional example includes
Each of rings F1-F7 optionally and independently substituted, Exemplary substituents for ring F (including rings F1-F7) include halogen, cyano, hydroxy, C,-C4 alkoxy, and CrC4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(CrC4 alkyl).
Rf is independently OH or CrC6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C,-Ce alkoxy, CrC6 haloalkoxy, C,-C6 aminoalkoxy, Ci-Cs cyanoalkoxy, CrCe hydroxyalkoxy and C2-C6 alkoxyalkoxy, R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, Cj-Ce alkyl, Ο,-Οβ haloalkyl, Ci-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C-|-C6 aminoalkyl, Ci-C6 hydroxyalkyl,
CrCe carboxyalkyl, C^Cs alkoxy, C-pCe haloalkoxy, CrC6 aminoalkoxy, C^-Cg cyanoalkoxy, hydroxyalkoxy, or C2-Ce alkoxyalkoxy.
R11, R12, R13 and R14 are each independently DH, halogen, or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, CrC6 haloalkoxy, C-i-Ce aminoalkoxy, C^Cbcyanoalkoxy, CrC6 hydroxyalkoxy, and C2-Ce alkoxyalkoxy, > (
Optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl. s is 0, 1 or 2.
x is 0, 1 or 2.
The remaining variables are each and independently as described above in any one of the sets of variables for Structural Formulae (IA) and (I).
In yet another embodiment, the compounds are represented by Structural Formula (I) or (IA), or pharmaceutically acceptable salts thereof, wherein:
Ring E is a C4-Cs non-aromatic carbocycle optionally further substituted with one or more instances of JA.
R9 is independently-H, halogen, cyano, hydroxy, CtC4 alkyl, CrC4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(Ci-C4 alkyl), ΠΝΗ2, ONH(CiDC4 alkyl), or □Ν(Ο,ΠΟ4 alkyl)2.
The other varibales are each and independently as described in the preceeding paragraph.
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein:
-6316260
Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JA.
Eing G5 is a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JB.
Xis -O-, -S-, or -NR9-.
R8 and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Cr C6 alkyl, Ci-C6 haloalkyl, CrC6 cyanoalkyl, C2-C6 alkoxyalkyl, Ci-C6 aminoalkyl, C,C6 hydroxyalkyl, Ο,-Οβ carboxyalkyl, C,-C6 alkoxy, Ο,-Ce haloalkoxy, C,-Ce aminoalkoxy, CrCe cyanoalkoxy, CrC6 hydroxyalkoxy, or C2-C6 alkoxyalkoxy.
R13 and R14 are each independently ΠΗ, halogen, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C,-C6alkoxy, C-|-C6 haloalkoxy, Ci-C6 aminoalkoxy, CvCecyanoalkoxy, Ο,-Ce hydroxyalkoxy, and C2-C6 alkoxyalkoxy.
Optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl.
RZ1, Rzz, R23, R24, and R25 are each independently ΠΗ, halogen, -OH, C^Cs alkoxy, or C-i-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C^Ce alkoxy, CrC6 haloalkoxy, CrC6 aminoalkoxy, CrCscyanoalkoxy, Cr Cs hydroxyalkoxy, and C2-C6 alkoxyalkoxy. Specifically, R21, Rzz, R23, R24, and R25 are each independently QH, halogen, -OH, Ci-C6alkoxy, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ο,-Οβ alkyl, -NH2, -NH(C,-CS alkyl), -N/Ch-Ce alkyl)2, -OiCvCe alkyl), -C(O)NHZ, -0(0)1^(0,-0,5 alkyl), -C(O)N(C,-C6 alkyl)2,
-6416260
-CfOXCKCs-alkyl), -OC(O)(CrC6 alkyl), -NHC(O)(CrC6 alkyl), -N(CrC6 alkyl)C(O)(CrC6 alkyl).
R9 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, CrC6alkoxy, C,-C6 haloalkoxy, Cj-Ceaminoalkoxy, Ci-C6 cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-C6alkoxyalkoxy.
q is 0, 1 or 2; x is 0, 1 or 2; and r is 1 or 2.
The remaining variables are each and independently as described above in any set of variables for Structural Formulae (IA) and (I).
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), pharmaceutically acceptable salts thereof, wherein:
wherein rings G1 and G2 are each and independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JA.
Each of Re and R9 is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, CrC4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C1-C4 alkyl), ΠΝΗ2, □NH(C1OC4 alkyl), or ΠΝ(Ο-[ΠΟ4 alkyl)2.
R21, R22, R23, and R24 are each independently DH, halogen, -OH, or C^Cs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6alkoxy, Ο,-Cb haloalkoxy, Ci-C6aminoalkoxy, C-|-C6 cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.
Q2is independently a bond, ΠΟΊ, OSn, INRO, ΊΟ(Ο)Π, -C(=NR)-, Π0Ο2Ί,
ΊΟΟ(Ο)“Ι, i3C(O)NRG, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, ONRC(O)3, 1NRC(O)NRG, nNRCO2n, OOC(0)NRG, -S(O)-, nSO2no nN(R)SO20, □SOZNR‘-, -NRSOZNR’-, or -(CR6R7)pnY1G. Alternatively Q2is independently □Οϋ,ΠΠ0Οζα, □OC(O).l, nC(O)NRO, 0NRC(O)n, LlNRC(O)NRn, aNRCOzO, 0OC(O)NRa, -CO2SO2-, -P(O)20-, or -(CR6R7)paY1a. Alternatively Q2is independently ΠΟΠ or ico2n.
In some embodiments, rings E and G (including G1-G5) are optionally and independently further substituted with one or more instances of JA (for carbocycle) or JB (for heterocycle), wherein each of JA and J8 is independently selected from the group consisting of halogen,
-6516260 cyano, oxo, -NCO, and Q1-Rs, and wherein:
Q1 is independently a bond, DO3, nSD, DNRü, aC(O)D, -C(=NR)-, DCC^O, □OC(O)lJ, nC(O)NRD, -C(O)NRC(O)O-, -NRC(O)NRC(0)0-, □NRCfOjn, □ NRC(O)NRD, □ NRCOZO, nOC(O)NRD, -S(O)-, DSO^D □N(R)SO2D, aSO2NR’-, -NRSOZNR’-, or -(CR6R7)püY1Lin and Y1 is independently a bond, ΠΟΟ, DSü, □ NRO, 00(0)0, -C(=NR)-, 0CO2O, 0OC(O)D, OC(O)NR’-, -C(0)NRC(0)0000-NRC(0)NRC(0)0-, 0NRC(O)0, ONRC(O)NR’O, ONRCO2O, OOC(O)NR’O, -S(O)-, 0SO200 -SO2NR‘-, DNRSO200 or -NRSOZNR’-.
Alternatively: Q1 is independently a bond, OOO, OSO, lINRl!, 00(0)0, OC020, 000(0)0, 0C(O)NR0, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, ONRC(0)0, 0NRC(O)NR0, DNRCO20, OOC(0)NRO, -S(0)-, OS0200 QN(R)S020, OSO2NR’-, -NRSO2NR'-, or -(CR6R7)pOY1O; and Y1 is independently OOO, OCOzO, 000(0)0, □C(O)NRD, DNRC(O)O, DNRC(0)NRO, ONRCOïO, or 0OC(O)NR0.
In yet another embodiment, Q1 and Y1 are each independently as described above in the preceeding paragraph, and:
R5 is independently i) -H; ii) a CrCe-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-Ce non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, aORb, nSR6, -S(O)Ra, DSC^R3, DNHR0, OC(O)Rb, aC(O)ORb, 30C(0)Rb, ONHC(O)Rb, OC(O)NHRC, ONHC(0)NHRC, nNHC(O)ORb, nOCONHRc, -NHC(0)NHC(0)ORb, lN(CH3)Rc. 0N(CH3)C(O)Rb, nC(O)N(CH3)Rc. nN(CH3)C(O)NHRc, nN(CH3)C(O)ORb, □OCON(CH3)RC, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(O)NHC(O)ORb, -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb.
In some spécifie embodiments, the compounds are represented by Structural Formula (IA) or (I), wherein:
R1 is -H.
r2 is -H, -CH3, -CH20H, or -NHZ. Specifically, R2 is -H, or -CHZOH.
R3 is -H, DF, DCI, CM alkyl, or C-m haloalkyl. Alternative^, R3 is -H, OF, or DCI.
Z1 is-H, -F, or-Cl.
Z2 is -H or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(Ci-C4 alkyl).
-6616260
Z3 is -H or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and
-0(0,-04 alkyl).
R5 is: i) -H; ii) an optionally substituted C,-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -C0(C,-C4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), C1-C4 alkoxy, -NRC0(C,-C4 alkyl), -CONR(C,-C4 alkyl), -NRCO2(C,-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1; and wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(0,-04alkyl), αΝΗ2, 0NH(C,aC4 alkyl), ΟΝίΟ,αΟί alkyl)2, -0(0)(0,C4 alkyl), -OC(O)(Ci-C4 alkyl), -C(O)O(C,-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -000(0,-04 alkyl), -CO(C,-C4 alkyl), -C02H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
The remaining variables, including R4 that includes a spiro ring represented by rings E and F, or a bridged ring represented by rings G1-G5, are each and independently as described in any one of the preceeing four embodiments.
In yet another embodiment, the compounds are presented by Structural Formula (IA) or (I), wherein values of the variabels are each and independently as described in the preceeding embodiment, except:
Z2 is -H; .,
Z3 is -H;
R5 is independently: i) -H or ii) a C,-C6-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4 alkyl), ΠΝΗ2, □NH(C,nC4 alkyl), □ N(C,nC4 alkyl)21 -C(O)(C,-C4 alkyl), -0C(O)(C,-C4 alkyl), -C(O)O(C,-C4 alkyl), -6716260
-CO2H, C3-C0 non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl;
wherein each of said alkyl groups referred to in the substituents of the CrCe-alkyl group represented by R5 is îndependently and optionally substituted with one or more substituents îndependently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2l -NHiCrCi alkyl), -N(CrC4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(CrC4 alkyl), and Ci-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the CrCs-alkyl group represented by R5 is îndependently and optionally substituted with one or more substituents îndependently selected from the group consisting of halogen, cyano, hydroxy, oxo, C-|-C4 alkyl, -NH2, -ΝΗ(0γ04 alkyl), -Ν(θ!-Ο4 alkyl)z, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and Ci-C4 alkoxy.
In yet another embodiment, each of rings E, G1-G5 is îndependently and optionally substituted with onr or more substituents selected from the group consisting of halogen, cyano, hydroxy, C,-C6 alkyl, -NH2, -NH(C,-C6 alkyl), -N(C,-Ce alkyl)2, -O(C,.C6 alkyl), -C(O)NH2, -C(O)NH(C,-C6 alkyl), -C(O)N(C,-C6 alkyl)2, -C(O)(C,-C6-alkyl), -OC(O)(C,-Ce alkyl), -NHC(0)(C,-C6 alkyl), -N(C,-C6 alkyl)C(O)(C,-C6 alkyl), and -CO2Rb; wherein each of said alkyl groups is optionally and îndependently substituted with one or more substituents îndependently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -CO2(C,-C4 alkyl), and Ci-C4 alkoxy. Specifically, each of rings E, G1-G5 is îndependently and optionally substituted with onr or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -C0(Ci-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, and CrC4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -O(C!-C4 alkyl).
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein:
Ring A is a non-aromatic, 5-10 membered, bridged carbocylce or heterocycle, or ring A and Re optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic,
-6816260
5-10 membered, bridged carbocycle or heterocycle, wherein each of said carbocycle is independently and optionally substituted with one or more instances of JA and wherein each carbocycle is independently and optionally substituted with one or more instances of JB.
R1 is -H.
R2 is -H, -CH3, -CH2OH, or -NH2. Specifically, R2 is -H, or -CH2OH.
R3 is -H, DF, CICI, Cn alkyl (e.g., -CH3 or-C2H6), orC-M haloalkyl (e.g., -CF3). Alternative^, R3 is -H, OF, or DCI.
Z1 is -H,-F, or -Cl.
Z2 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(CrC4 alkyl).
Z3 is -H or C-|-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(Ci-C4 alkyl).
Q2 is independently 303, 30020, 000(0)0, □C(0)NR’0, -C(O)NRC(O)O-, □ NRC(0)3, nNRC(O)NR’n, 3NRCO23, -OC(O)NR’D, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(O)2O-, -CO2SO2-, or -(CReR7)p3Y13.
Y1 is D03, nC020, 300(0)0, 0C(O)NRO, -C(0)NRC(O)O-,0NRC(O)O, 0NRC(O)NRO, ONRCOjO, -00(0)NR’0, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(0)20-, or -CO2SO2-.
R5 is: i) -H; ii) an optionally substituted 0Ί-06 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, -002(0,-04 alkyl), C,-C4 alkoxy, -NRCO(Ci-C4 alkyl), -CONR(C,-C4 alkyl), -NRCO2(Ci-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1;
wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo,
-6916260
C,-C4 alkyl, -0(0,-04 alkyl), aNH2] □NH(C,DC4 alkyl), ΠΝ(0,Π04 alkyl)2, -0(0)(0,C4 alkyl), -OC(O)(C,-C4 alkyl), -C(O)O(C,-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy,
Each of R8 and R9 is independently -H, halogen, cyano, hydroxy, C,-C4 alkyl, C,-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C,-C4alkyl), □NH2, □NH(C,0C4 alkyl), or □N(C,DC4 alkyl)2.
R11, R12, R13, and R14 are each independently OH, halogen, or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and C,-Ce alkoxy.
Each of JA and J8 is independently selected from the group consisting of halogen, cyano, hydroxy, CrC6 alkyl, -NH2, -NH(Ci-C6 alkyl), -NfCrCg alkyl)2, -0(0,.06 alkyl), -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -0(0)Ν(0,-06 alkyl)2, -CfOJfCrCe-alkyl), 0C(O)(C,-C6 alkyl), -NHC(O)(CrC6 alkyl), -Ν(Ο,-Ο6 alkyl)C(O)(CrCe alkyl), and -CO2Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -00(0,-04 alkyl), -CO2H, -ΟΟ2(Ο,-Ο4 alkyl), and C,-C4 alkoxy. n is 0 or 1.
x is 0 or 1.
The remaining variables are each and independently as described above in any set of variables for Structural Formulae (IA) and (I).
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein:
carbocycle optionally further substituted with one or more instances of JA, and ring
-7016260
G5 is a 5-10 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB.
X is-O-,-S-, or-NR9-. ,
R21, R22, R23, R24, and R25 are each independently DH, halogen, -OH, CrCealkoxy, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, CrC6 alkyl, -NH21 NH(CrC6 alkyl), -N(CrC6 alkyl)2, -Ο(0νΟ6 alkyl), -C(O)NH21 -0(Ο)ΝΗ(0ν06 alkyl), C(O)N(Ci-C6 alkyl)2, -CfOXCrCe-alkyl), -00(0)(0,-06 alkyl), -NHC(0)(C,-C6 alkyl), -N(C,-C6 alkyl)C(O)(C,-Ce alkyl).
R9 is -H or C-i-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, CrC6 alkoxy, C,-C6 haloalkoxy, C,-C6aminoalkoxy, C,-C6 cyanoalkoxy, C,-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.
q is 0,1 or 2.
r is 1 or 2.
The remaining variables are each and independently as described above in the preceeding paragraph.
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein the variables are each and independently as described above in the preceeding paragraph except those described below:
R1 is -H.
R2 is -H.
R3 is -H, FIF, CCI, C,.4 alkyl, or C,.4 haloalkyl. Altematively, R3 is -H, OF, or ΠΟΙ.
Z1 is -H, -F, or-Cl.
Z2 is -H.
Z3 is -H.
X is -O-,
R6 is -H, an optionally substituted C,-C6 alkyl, or optionally substituted phenyl.
Each R8 is independently -H, halogen, hydroxy, Ci-C4 alkyl, Ci-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or -O(C,-C4alkyl).
Each of R9, R13, and R14is independently -H or C,-C4 alkyl.
R21, R22, R23, R24, and R25 are each independently ΊΗ, halogen, -OH, Ci-C6 alkoxy, or C,-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C,-C6alkyl, and -O(C,.C6 alkyl). Specifically R21, R22, R23, R24, and R25 are each independently -H, C,.e alkyl, or Ci_6 haloalkyl.
-7116260
Each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NHZ, NH(CrCe alkyl), -NtCrCg alkyl)2, -0(0;Ό6 alkyl), C;-C4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and CrC4 alkoxy.
In yet another embodiment, the compounds are represented by any one of Structural Formulae l-V (hereinafter reference to Structural Formulae l-IV includes Structural Formulae I, IA, II, III, IV, V, and VI) and XI(A)-XIV (hereinafter reference to Structural Formulae XI(A)XIV includes Structural Formulae ΧΙΑ, XIB, XIIA, XIIB, XIII, and XIV), wherein values ofthe variables therein are independently as described above in any embodiments except that R3 is Ct-e alkyl, such as methyl or ethyl.
In yet another embodiment, the compounds are represented by any one of Structural Formulae l-V and XI(A)-XIV, wherein values ofthe variables therein are independently as described above in any embodiments described above, except that x is 0.
In yet another embodiment, the compounds are represented by any one of Structural Formulae I, IA, II, VI, Xl(A), and XI(B), wherein values of the variables therein are independently as described above in any embodiments described above, except that ring A is bridged.
In yet another embodiment, the compounds are represented by any one of Structural Formulae I, IA, II, VI, XI(A), and XI(B), wherein values of the variables therein are independently as described above in any embodiments described above, except that Q2is independently-C(=NR)-,-C(=NR)NR-, -NRC(=NR)NR-, DCOzO, nOC(O)îl, DCÎOÎNRO, -C(O)NRC(O)O-, —NRC(O)NRC(O)O-, nNRC(O)n, DNRC(O)NRn, nNRCO2D, HOC(O)NRD, -S(O)-, nso2nn nNiRJSOzLl, r]SO2N(R)-, -NRSO2NR-, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(O)2O-, -CO2SO2-, or -(CR6R7)pnY1nn or alternative^, Q2is independently LlCO2n, nOC(O)D, nC(O)NRCI, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, □NRC(O)0, aNRC(O)NRn, DNRCO2O, OOC(O)NRO, -S(O)-, nSO2nQ □N(R)SOza, □SOzN(R)-, -NRSO2NR-, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(O)2O-, -CO2SO2-, or -(CR6R7)pDY1annn
In yet another embodiment, the compounds are represented by any one of Structural Formulae l-V and Xl(A)-XIV, wherein values of the variables therein are independently as described above in any embodiments described above, provided that when Q2 is -O- or -NR-, then ring A is further substituted with JA other than -H; and provided that if Q3 is C(O)-, then Rs is a substituted Ci-C6 aliphatic group; an optionally substituted C3-Ce nonaromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group. In a spécifie embodiment, when Q2 is -O- or -NR-, then ring A is further substituted with JA other than -H at the geminal position to -Q2R5.
-7216260
In yet another embodîment, the présent invention is directed to the use of any compound selected from the compounds depicted in FIGs. 3, 4, 5, 6, 7, and 8, or a pharmaceutically acceptable sait thereof, for any of the uses described above.
In some embodiments, the compounds are represented by any one of Structural Formulae IV and XI(A)-XIV, and the variables are each independently as depicted in the compounds of FIGs. 1-8.
In yet another embodîment, the présent invention is directed to the use of a compound described in any one of the embodiments, including various sets of variables, for Structural Formulae l-V and XI(A)-XIV described above, or a pharmaceutically acceptable sait thereof, for any of the uses described above, provided that when R3 is -Cl, Z1 is -F, and Zz is -H, then R4 is not 2-NHz-cyclohexyl.
In yet another embodîment, the compounds described herein or pharmaceutically acceptable salts thereof can be used to reduce viral titre in a biological sample (e.g. an infected cell culture) or in humans (e.g. lung viral titre in a patient).
The terms influenza virus mediated condition”, “influenza infection”, or Influenza”, as used herein, are used interchangeable to mean the disease caused by an infection with an influenza virus.
Influenza is an infectious disease that affects birds and mammals caused by influenza viruses. Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five généra: Influenzavîrus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. Influenzavirus A genus has one species, influenza A virus which can be subdivided into different serotypes based on the antibody response to these viruses: H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2 , H7N3 and H10N7. Influenzavirus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. Influenzavirus C genus has one species, Influenzavirus C virus, which infects humans and pigs and can cause severe illness and local épidémies. However, Influenzavirus C is less common than the other types and usually seems to cause mild disease in children.
In some embodiments of the invention, influenza or influenza viruses are associated with Influenzavirus A or B. In some embodiments of the invention, influenza or influenza viruses are associated with Influenzavirus A. In some spécifie embodiments of the invention, Influenzavirus A is H1N1, H2N2, H3N2 orH5N1.
In humans, common symptoms of influenza are chills, fever, pharyngitis, muscle pains, severe headache, coughing, weakness, and general discomfort. In more serious cases, influenza causes pneumonia, which can be fatal, particularly in young children and the elderly. Although it is often confused with the common cold, influenza is a much more severe disease and is caused by a different type of virus. Influenza can produce nausea and vomiting, especially in children, but these symptoms are more characteristic of the
-7316260 unrelated gastroenteritis, which is sometimes called stomach flu or 24-hour flu. Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body températures ranging from 38-39 °C (approxîmately 100-103 °F). Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worse in their backs and legs. Symptoms of influenza may include: body aches, especially joints and throat, extreme coldness and fever, fatigue, Headache, irritated watering eyes, reddened eyes, skin (especially face), mouth, throat and nose, abdominal pain (in children with influenza B). Symptoms of influenza are non-specific, overlapping with many pathogens (“influenza-like illness). Usually, laboratory data is needed in orderto confirm the diagnosis.
The terms, “disease”, disorder, and condition may be used interchangeably here to refer to an influenza virus mediated medical or pathological condition.
As used herein, the terms “subject and patient are used interchangeably. The terms subject” and patient refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), specifically a “mammal” including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more specifically a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human.
The term biological sample, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
As used herein, multiplicity of infection or “MOI is the ratio of infectious agents (e.g. phage or virus) to infection targets (e.g. cell). For example, when referring to a group of cells inoculated with infectious virus particles, the multiplicity of infection or MOI is the ratio defined by the number of infectious virus particles deposited in a well divided by the number of target cells présent in that well.
As used herein the term inhibition of the réplication of influenza viruses” includes both the réduction in the amount of virus réplication (e.g. the réduction by at least 10 %) and the complété arrest of virus réplication (i.e., 100% réduction in the amount of virus réplication). In some embodiments, the réplication of influenza viruses are inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.
Influenza virus réplication can be measured by any suîtable method known in the art. For example, influenza viral titre in a biological sample (e.g. an infected cell culture) or in humans (e.g. lung viral titre in a patient) can be measured. More specifically, for cell based assays, in each case cells are cultured in vitro, virus is added to the culture in the presence or absence of a test agent, and after a suîtable length of time a virus-dependent endpoint is
-7416260 evaluated. Fortypical assays, the Madin-Darby canine kidney cells (MDCK) and the standard tissue culture adapted influenza strain, A/Puerto Rico/8/34 can be used. A first type of cell assay that can be used in the invention dépends on death of the infected target cells, a process called cytopathic effect (CPE), where virus infection causes exhaustion of the cell resources and eventual lysis of the cell. In the first type of cell assay, a low fraction of cells in the wells of a microtiter plate are infected (typically 1/10 to 1/1000), the virus is allowed to go through several rounds of réplication over 48-72 hours, then the amount of cell death is measured using a decrease in cellular ATP content compared to uninfected controls. A second type of cell assay that can be employed in the invention dépends on the multiplication of virus-specific RNA molécules in the infected cells, with RNA levels being directly measured using the branched-chain DNA hybridization method (bDNA). In the second type of cell assay, a low number of cells are initially infected in wells of a microtiter plate, the virus is allowed to replicate in the infected cells and spread to additional rounds of cells, then the cells are lysed and viral RNA content is measured. This assay is stopped early, usually after 18-36 hours, while ail the target cells are still viable. Viral RNA is quantitated by hybridization to spécifie oligonucleotide probes fixed to wells of an assay plate, then amplification of the signal by hybridization with additional probes linked to a reporter enzyme.
As used herein a “viral titer (or titre)” is a measure of virus concentration. Titer testing can employ serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only évaluâtes as positive or négative. The titer corresponds to the highest dilution factor that still yields a positive reading; for example, positive readings in the first 8 serial twofold dilutions translate into a titer of 1:256. A spécifie example is viral titer. To détermine the titer, several dilutions will be prepared, such as 10'1, 10'2, 10'3,...,10 e. The lowest concentration of virus that still infects cells is the viral titer.
As used herein, the terms treat”, “treatment and “treating refer to both therapeutic and prophylactic treatments. For example, therapeutic treatments includes the réduction or amelioration of the progression, severity and/or duration of influenza viruses mediated conditions, or the amelioration of one or more symptoms (specifically, one or more discernible symptoms) of influenza viruses mediated conditions, resulting from the administration of one or more thérapies (e.g., one or more therapeutic agents such as a compound or composition of the invention). In spécifie embodiments, the therapeutic treatment includes the amelioration of at least one measurable physical parameter of an influenza virus mediated condition. In other embodiments the therapeutic treatment includes the inhibition of the progression of an influenza virus mediated condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the therapeutic treatment includes the réduction or stabilization of influenza viruses mediated infections.
-7516260
Antiviral drugs can be used in the community setting to treat people who already hâve influenza to reduce the severity of symptoms and reduce the number of days that they are sick.
The term chemotherapy refers to the use of médications, e.g. small molécule drugs (rather than “vaccines) for treating a disorder or disease.
The terms “prophylaxis” or “prophylactic use and “prophylactic treatment as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. As used herein, the terms prevent, prévention” and “preventing refer to the réduction in the risk of acquiring or developing a given condition, or the réduction or inhibition of the récurrence or said condition in a subject who is not ill, but who has been or may be near a person with the disease. The term chemoprophylaxis refers to the use of médications, e.g. small molécule drugs (rather than “vaccines) for the prévention of a disorder or disease.
As used herein, prophylactic use includes the use in situations in which an outbreak has been detected, to prevent contagion or spread of the infection in places where a lot of people that are at high risk of serious influenza complications live in close contact with each other (e.g. in a hospital ward, daycare center, prison, nursing home, etc). It also includes the use among populations who require protection from the influenza but who either do not get protection after vaccination (e.g. due to weak immunse system), or when the vaccine is unavailable to them, or when they cannot get the vaccine because of side effects. It also includes use during the two weeks following vaccination, since during that time the vaccine is still ineffective. Prophylactic use may also include treating a person who is not ill with the influenza or not considered at high risk for complications, in order to reduce the chances of getting infected with the influenza and passing it on to a high-risk person in close contact with him (for instance, healthcare workers, nursing home workers, etc).
According to the US CDC, an influenza “outbreak is defined as a sudden increase of acute febrile respiratory illness (AFRI) occurring within a 48 to 72 hour period, in a group of people who are in close proximity to each other (e.g. in the same area of an assisted living facility, in the same household, etc) over the normal background rate or when any subject in the population being analyzed tests positive for influenza. One case of confirmed influenza by any testing method is considered an outbreak.
A cluster is defined as a group of three or more cases of AFRI occurring within a 48 to 72 hour period, in a group of people who are in close proximity to each other (e.g. in the same area of an assisted living facility, in the same household, etc).
As used herein, the index case, “primary case” or patient zéro” is the initial patient in the population sample of an epidemiological investigation. When used in general to refer to such patients in epidemiological investigations, the term is not capitalized. When the term is used to refer to a spécifie person in place of that person's name within a report on a spécifie
-7616260 investigation, the term is capitalized as Patient Zéro. Often scientists search for the index case to détermine how the disease spread and what réservoir holds the disease in between outbreaks. Note that the index case is the first patient that indicates the existence of an outbreak. Earlier cases may be found and are labeled primary, secondary, tertîary, etc. In one embodiment, the methods of the invention are a preventative or “pre-emptive measure to a patient, specifically a human, having a prédisposition to complications resulting from infection by an influenza virus. The term “pre-emptive as used herein as for example in pre-emptive use, “pre-emptively”, etc, is the prophylactic use in situations in which an “index case or an outbreak has been confirmed, in order to prevent the spread of infection in the rest of the community or population group.
In another embodiment, the methods of the invention are applied as a pre-emptive measure to members of a community or population group, specifically humans, in order to prevent the spread of infection.
As used herein, an “effective amount” refers to an amount sufficient to elicit the desired biological response. In the présent invention the desired biological response is to inhibit the réplication of influenza virus, to reduce the amount of influenza viruses or to reduce or ameliorate the severity, duration, progression, or onset of a influenza virus infection, prevent the advancement of an influenza viruses infection, prevent the récurrence, development, onset or progression of a symptom associated with an influenza virus infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy used against influenza infections. The précisé amount of compound administered to a subject will dépend on the mode of administration, the type and severity of the infection and on the characteristics of the subject, such as generahhealth, âge, sex, body weight and tolérance to drugs. The skilled artisan will be able to détermine appropriate dosages depending on these and other factors. When co-administered with other anti viral agents, e.g., when coadministered with an anti-influenza médication, an “effective amount” of the second agent will dépend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed. For example, compounds described herein can be administered to a subject in a dosage range from between approximately 0.01 to 100 mg/kg body weight/day for therapeutic or prophylactic treatment.
Generally, dosage regimens can be selected in accordance with a variety of factors including the disorder being treated and the severity of the disorder; the activity of the spécifie compound employed; the spécifie composition employed; the âge, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excrétion of the spécifie compound employed; the rénal and hepatic function of
-7716260 the subject; and the particular compound or sait thereof employed, the duration of the treatment; drugs used in combination or coincidental with the spécifie compound employed, and like factors well known in the medical arts, The skilled artisan can readily détermine and prescribe the effective amount of the compounds described herein required to treat, to prevent, inhîbit (fully or partially) or arrest the progress of the disease. Dosages of the compounds described herein can range from between about 0,01 to about 100 mg/kg body weight/day, about 0,01 to about 50 mg/kg body weight/day, about 0.1 to about 50 mg/kg body weight/day, or about 1 to about 25 mg/kg body weight/day, It is understood that the total amount per day can be administered in a single dose or can be administered in multiple dosing, such as twice a day (e.g., every 12 hours), tree times a day (e.g., every 8 hours), or four times a day (e.g., every 6 hours).
For therapeutic treatment, the compounds described herein can be administered to a patient within, for example, 48 hours (or within 40 hours, or less than 2 days, or less than 1.5 days, or within 24 hours) of onset of symptoms (e.g., nasal congestion, sore throat, cough, aches, fatigue, headaches, and chîlls/sweats). The therapeutic treatment can last for any suitable duration, for example, for 5 days, 7 days, 10 days, 14 days, etc. For prophylactic treatment during a community outbreak, the compounds described herein can be administered to a patient within, for example, 2 days of onset of symptoms in the index case, and can be continued for any suitable duration, for example, for 7 days, 10 days, 14 days, 20 days, 28 days, 35 days, 42 days, etc.
Various types of administration methods can be employed in the invention, and are described in detail below under the section entitled Administration Methods.
Combination Therapy
An effective amount can be achieved in the method or pharmaceutical composition of the invention employing a compound of any one of Structural Formulae l-V (e.g., Structural Formulae I, IA, II, III, IV and V) and XI(A)-XIV (e.g., Structural Formulae ΧΙΑ, XIB, XIIA, XIIB, XIII, and XIV) or a pharmaceutically acceptable sait or solvaté (e.g., hydrate) thereof alone or in combination with an additional suitable therapeutic agent, for example, an antiviral agent or a vaccine. When “combination therapy” is employed, an effective amount can be achieved using a first amount of a compound of any one of Structural Formulae l-V and XI(A)-X1V, or a pharmaceutically acceptable sait or solvaté (e.g., hydrate) thereof, and a second amount of an additional suitable therapeutic agent (e.g. an antiviral agent or vaccine).
In another embodiment of this invention, the compound of any one of Structural Formulae IV and XI(A)-XIV, and the additional therapeutic agent, are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In another embodiment, the compound of any one of Structural Formulae l-V and
-7816260
XI{A)-XlV, and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose), ln yet another embodiment, the compound of any one of Structural Formulae l-V and XI(A)-XIV can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, the compound of any one of Structural Formulae l-V and Xl(A)-XIV can be administered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer-therapeutic agent is administered in an effective amount.
As used herein, the terms “in combination or “co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not restrict the order in which thérapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject. Coadministration encompasses administration of the first and second amounts of the compounds of the coadministration in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. ln addition, such coadministration also encompasses use of each compound in a sequential manner in either order.
ln one embodiment, the présent invention is directed to methods of combination therapy for inhibiting Flu viruses réplication in biological samples or patients, or for treating or preventing Influenza virus infections in patients using the compounds or pharmaceutical compositions of the invention of any one of Structural Formulae l-V and XI(A)-XIV. Accordingly, pharmaceutical compositions of the invention also include those comprising an inhibitor of Flu virus réplication of this invention in combination with an anti-viral compound exhibiting a nti-Influenza virus activity.
Methods of use of the compounds and compositions of the invention also include combination of chemotherapy with a compound or composition of any one of Structural Formulae l-V and XI(A)-XIV or with a combination of a compound or composition of this invention with another anti-viral agent and vaccination with a Flu vaccine.
When co-administration involves the separate administration of the first amount of a compound of any of Structural Formulae l-V and XI(A)-XIV and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to hâve the desired therapeutic effect. For example, the period of time between each administration which can resuit in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, a compound of any one of Structural Formulae l-V and XI(A)-XIV and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16
-7916260 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.
More, specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the invention) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subséquent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent) to a subject.
It is understood that the method of co-administration of a first amount of a compound of any one of Structural Formulae l-V and XI(A)-XIV and a second amount of an addîtional therapeutic agent can resuit in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additîve effect that would resuit from separate administration of the first amount of the compound of any one of Structural Formulae l-V and XI(A)-XIV and the second amount of the addîtional therapeutic agent.
As used herein, the terrn synergistic” refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which îs more effective than the additîve effects of the thérapies. A synergistic effect of a combination of thérapies (e.g., a combination of prophylactic or therapeutic agents) can permit the use of lower dosages of one or more of the thérapies and/or less frequent administration of said thérapies to a subject. The ability to utilîze lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently can reduce the toxicity associated with the administration of said therapy to a subject wîthout reducing the efficacy of said therapy in the prévention, management or treatment of a disorder. In addition, a synergistic effect can resuit in improved efficacy of agents in the prévention, management or treatment of a disorder. Finally, a synergistic effect of a combination of thérapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone. When the combination therapy using compounds of the présent invention of any one of Structural Formulae l-V and XI(A)-XIV is in combination with a Flu vaccine, both therapeutic agents can be administered so that the period of time between each administration can be longer (e.g. days, weeks or months).
The presence of a synergistic effect can be determined using suitable methods for assessing drug interaction. Suitable methods include, for example, the Sigmoid-Emax équation (Holford, N.H.G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 (1981)), the équation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol.
-8016260
114: 313-326 (1926)) and the median-effect équation (Chou, T.C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each équation referred to above can be applied with experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the équations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
Spécifie examples that can be co-administered with a compound described herein include neuraminidase inhibitors, such as oseltamivir (Tamiflu®) and Zanamivir (Rlenza®), viral ion channel (M2 protein) blockers, such as amantadine (Symmetrel®) and rimantadine (Flumadine®), and antiviral drugs described in WO 2003/015798, including T-705 under development by Toyama Chemical of Japan. (See alsoRuruta et al., Antiviral Reasearch, 82: 95-102 (2009), “T-705 (flavipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections.”) In some embodiments, the compounds described herein can be co-administerd with a traditional influenza vaccine.
Compounds of the Invention
Another aspect of the présent invention is generally related to compounds. In one embodiment, the présent invention is generally related to compounds represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof:
A first subset of variables of Structural Formulae (I) and (IA) for the compounds of the invention is as follows:
R1 is -H, CrC6 alkyl, -S(O)3-R” or-C(0)OR”. Specifically, R1 is -H or S(O)2-R”. Specifically, R1 is -H or -S(O)2-(phenyl), wherein the phenyl is optionally substituted with one or more selected from the group consisting of CrC6 alkyl and CpCe haloalkyl. More specifically, the phenyl is optionally substituted with one or more selected from the group consisting of -CH3 and -CF3 (e.g., at its para position). Specifically, R1 is -H or Ci.6 alkyl. Specifically, R1 is -H.
R4 is:
-8116260
R” îs independently: i) a CpCe-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, ΠΝΗ21 □NHtCi-Ce alkyl), lJNÎCtCb alkyl)2, C^Cg alkoxy, Ci-CB haloalkoxy, CrC6 aminoalkoxy, Ci-C6 cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-Ce alkoxyalkoxy; or ii) a C3-C6 carbocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, each optionally and independently being substituted with one ore more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, nitro, l)NH2, nNH(CrCe alkyl), ONiC^Ce alkyl)2, C-|-Cs alkyl, Ci-C6 haloalkyl, CrCe cyanoalkyl, CrCe hydroxyalkyl, C2-C6 alkoxyalkyl, CrC6 aminoalkyl, CrCe alkoxy, CrCe haloalkoxy, Ci-C6 aminoalkoxy, CrCB cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-CB alkoxyalkoxy, Specifically, R” is independently an optionally substituted, 5-6 membered heteroaryl group, or an optionally substituted phenyl group. Specifically, R” is independently a phenyl group optionally substituted with one or more substituents independently selected from the group consisting of Ci-CB alkyl and ΟΓΟ6 haloalkyl.
Values of Z1, Z2, Z3, Q1, Q2, Q3, Y1, rings A-D, R*, R, R’, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R3, Rb, Rc, Rd, JA, JB, JC1, JD1 and JE1, including spécifie values and substituents therefor, are each and independently as described above in the first set of variables of Structural Formulae (IA) and (I) for the methods of the invention. Value p is independently 1,2, 3 or 4. Specifically, p is independently 1 or 2.
When rings A and B are 3-6-membered, n and m are each independently 0 or 1; and k is independently 0, 1 or 2. Alternative^, when rings A and B are 7-10-membered, n and m, are each independently 0, 1 or 2, and k is independently 0, 1 or 2. Values x and y are each independently 0, 1 or 2.
Value z is 1 or 2.
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It is provided that if Y1 is a bond, then R6 is neither -H, nor an unsubstituted CrC6 aliphatic group. Specifically, if Y1 is a bond, then R5 is a substituted C^Ce aliphatic group; an optionally substituted C3-Ce non-aromatic carbocycle; an optionally substituted 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group. Specifically, the CrC6 aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-Ce non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; riORb; DSR6; -S(O)Ra; nSO2Ra; □NRbRc; QC(O)Rb; □C(O)ORb; HOC(O)Rb; nNRC(O)Rb; nC(O)NRbRc; 0NRC(O)NRbRc; DNRC(O)ORb;
□ OCONRbRc; -C(O)NRCO2Rb; -NRC(0)NRCOzRb; -C(O)NR(ORb); -SOzN(R)Rb; -NRSO2Rb; and -NRSO2NRRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
It is provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-C0 non-aromatic carbocycle; an optionally substituted 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group. Specifically, if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-Ce non-aromatic carbocycle; or an optionally substituted, 4-8 membered non-aromatic heterocycle.
Alternatively, it is provided that if rings A and B each and independently 5- or 6membered, R1 and R2 are both -H, R3 is -Cl, Z2 is -H, and Z1 îs -F, then Q2-R5 and Q3-R5, respectively, are not -H; and it is provided that the ring B-Q3-R5 moiety is not
A/-methyl-3-pyrrolidinyl ( ).
A second subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention is as follows:
R2 is-H or-CH3.
R3 is -H, -Cl, -F, -Br, -CN, -CF3, -O(CrC4 alkyl), -OH, -NHZ, -NH(C,-C4 alkyl), or -N(CrC4 alkyl)2
R4 is selected from formulae A-D depicted above.
Values of the remaining variables of Structural Formulae (IA) and (I), including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
-8316260
A third subset of variables of Structural Formula I for the compounds of the invention is as follows:
R2 is -H or -CH3.
R3 is -H, -F, -Cl, -CF3, -NH21 -NH(CH3), or -N(CH3)2.
R4 is selected from formulae A-D depicted above.
Values of the remaining variables of Structural Formulae (IA) and (I), including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
A fourth subset of variables of Structural Formulae (IA) and (l)for the compounds of the invention is as follows:
R2 is -H or -CH3.
R3is-H,-F, or -Cl.
R4 is selected from formulae A-D depicted above.
Values of the remaining variables of Structural Formulae (IA) and (I), including spécifie values, are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
A fifth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention is as follows:
R2 is -H.
R3 is -H or-Cl.
R4 is selected from formulae A-D depicted above.
Values of the remaining variables of Structural Formulae (IA) and (I), including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
A sixth subset of variables of Structural Formulae (IA) and (l)for the compounds of the invention is as follows:
Each of R2, R3 and R4 is independently as described in the first subset, second subset, third subset, fourth subset, or fifth subset, of variables of Structural Formulae (IA) and (I).
Z1 is -H, CrC6 alkyl, -O(CrC6 alkyl), -F, -Cl, -CN, -CO2H, -CO2(CrC6 alkyl), -CONH2. -CONH(Ci-Ce alkyl), or -CON^-Ce alkyl)2; and Z2 is -H, CrCe alkyl, -O(CrCe alkyl), -NH2, -NH(C-|-C6 alkyl), or -NiC^Ce alkyl)2; wherein each of said alkyl groups (e.g., represented by CrC6 alkyl, -OfC^Ce alkyl), -CO2(C1-CS alkyl), -NH(CiCe alkyl), and -N(Cf-Ce alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, αΝΗ2, □ NH(C10C4 alkyl), □N(C4CC4 alkyl)2, -OCO(C-i-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and CrC4 alkoxy.
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Values of the remaining variables of Structural Formulae (IA) and (I), including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
A seventh subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention is as follows:
Each of R2, R3 and R4 is independently as described in the first subset, second subset, third subset, fourth subset, or fifth subset, of variables of Structural Formulae (IA) and (I).
Z1 is -H, -F, -Cl, -CF3, CrC4 alkyl, -O(Ci-C4 alkyl), or -CN; and Z2 is -H, CrC6 alkyl, -O(C!-Ce alkyl), -NH2, -NH(C-i-C6 alkyl), or -NfC^Ce alkyl)2, wherein each of said alkyl groups (e.g., represented by CrC6 alkyl, -O(CrC6 alkyl), -NH(Ci-C6 alkyl), and -NfCrCe alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, ΠΝΗ2, □NH(CiDC4 alkyl), l]NÎC-|OC4 alkyl)2, -OCO(CrC4 alkyl), -COiCrC-i alkyl), -CO2H, -CO2(CrC4 alkyl), and C-|-C4 alkoxy.
Values of the remaining variables of Structural Formulae (IA) and (I), including spécifie values, and provisos are each and independently as described above for the first subset of variables.
An eighth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention îs as follows:
Each of R2, R3 and R4 is independently as described in the first subset, second subset, third subset, fourth subset, or fifth subset, of variables of Structural Formulae (IA) and (I).
Z1 is -H, -F, -Cl, C,-C4 haloalkyl (e.g, -CF3), C,-C4 alkyl, -O(C,-C4 alkyl), or-CN.
Z2 is -H or a CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, ONH2, nNH(CiCC4 alkyl), □N(C1DC4 alkyl)2, -OCO(CrC4 alkyl), -CO(Cr C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and CrC4 alkoxy.
Values of the remaining variables of Structural Formulae (IA) and (I), including spécifie values, and provios are each and independently as described above for the first subset of variables.
A ninth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention is as follows:
Each of R2, R3 and R4 is independently as described in the first subset, second subset, third subset, fourth subset, or fifth subset, of variables of Structural Formulae (IA) and (1).
Z1 is -H, -F, -Cl, -CF3, -CH3, or -CN.
Z2 is -H or a CrC6 alkyl optionally substituted with one or more substituents
-8516260 independently selected from the group consisting of halogen, cyano, hydroxy, oxo,
C1-C4 alkyl, ΠΝΗΖ1 □NH(C13C4 alkyl), □N(C1OC4 alkyl)2, -OCO(CrC4 alkyl), -CO(Cr
C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and CrC4 alkoxy.
Values of the remaining variables of Structural Formulae (IA) and (I), including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
In a tenth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention, the variables of Structural Formulae (IA) and (I), including spécifie values, are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth subset of variables of Structural Formulae (IA) and (I); and where applicable:
each R* independently is: i) -H; ii) CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, ONHZ, □NH(C1nC4 alkyl), □N(C1DC4 alkyl)2, -OCO(CrC4 alkyl), -00(0,-04 alkyl), -CO2H, -002(0,-04 alkyl), and C,-C4 alkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, DNH^ ΠΝΗ(0,Π04 alkyl), αΝ(0,004 alkyl)2, -000(0,-04 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), 0,-04 alkoxy, and 0,-06 alkyl, wherein each alkyl is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, ΠΝΗ2, 0ΝΗ(0,Π04 alkyl), ΊΝ(0,Π04 a1kyl)z, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -COZH, -CO2(Ci-C4 alkyl), and CrC4 alkoxy; and
R and R’ are each independently DH or C,-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C,-C6 alkyl), -N(C-|-Ce alkyl)2, and -0(0,-06 alkyl); or optionally R’, together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered, non-aromatic, heterocyclic ring optionally substituted with one or more instances of JD1; and
R” is independently a phenyl group optionally substituted with one or more substituents independently selected from the group consisting of C,-Ce alkyl and C,C6 haloalkyl.
In an eleventh subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention, the variables of Structural Formulae (IA) and (I), including spécifie values, are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth subset of variables of Structural Formulae (IA) and (I); and where applicable:
-8616260 provided that if Y1 is a bond, then R5 is a substituted CrC6 aliphatic group; an optionally substituted C3-Cs non-aromatic carbocycle; an optionally substituted 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group;
and provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-Ca non-aromatic carbocycle; an optionally substituted 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group. In a twlefth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention , the variables of Structural Formulae (IA) and (1), including spécifie values, are each and independently as described above for the eleventh subset of variables of Structural Formulae (IA) and (I); and the CrCg aliphatic group represented by R5, when Y1 is a bond, is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; OORb; OSRb; -S(O)Ra; OSO2Ra; ONRbRc; 0C(O)Rb; 0C(O)ORb; 0OC(O)Rb; ONRC(O)Rb; 3C(0)NRbRc; 0NRC(O)NRbRc; ONRC(O)ORb; OOCONRbRc; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -SO2NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JG1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
A thirteenth subset of variables of Structural Formulae (IA) and (I) is as follows:
Each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, and Q1QR5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1, and fused to the ring to which they are attached.
Q1 is independently a bond, DOO, DSO, ONR’O, 00(0)0, OCO2O, DOC(O)O, 0C(O)NR’D, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, 0NRC(O)0, ONRC(O)NR'O, ONRCOZO, -OC(O)NR’D, -S(O)-, OSO2OO -SO2NR’-, 0NRSO2D0 or-NRSO2NR’-, or -(CR6R7)pOY1n.
Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, OORb, 0SRb, -S(O)Ra, OSO2Ra, DNRbRc, DC(O)Rb, OC(O)ORb, □ OC(O)Rb, QNRC(O)Rb, OC(O)NRbRc, DNRC(O)NRbRc, 0NRC(O)ORb, □OCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),D-SO2NRcRb, -NRSO2Rb, and -NRSO2NRcRb, or optionally, two JC1 and two JD1, respectively,
-8716260 together with the atoms to which they are attached, independently form a 5-7membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
Values of the remaining variables of Structural Formulae (IA) and (I), including spécifie values, and provisos are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth subset of variables of Structural Formulae (IA) and (I).
ln a fourteenth subset of variables of Structural Formulae (IA) and (I), values of the variables are independently as described above in the seventeenth set of variables of Structural Formulae (IA) and (I).
ln a fifteenth subset of variables of Structural Formulae (IA) and (I), values of the variables are independently as described above in the eighteenth set of variables of Structural Formulae (IA) and (I).
ln a sixteenth subset of variables of Structural Formulae (IA) and (I), values of the variables are independently as described above in the nineteenth set of variables of Structural Formulae (IA) and (1).
In some embodiments, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein R1 is -H or Ci.e alkyl, and wherein values of the remaining variables are independently as described above in any one of the subsets of variables of Structural Formulae (IA) and (I).
ln another embodiment, the présent invention is generally related to compounds represented by Structural Formula VI, or pharmaceutically acceptable salts thereof.
A first subset of variables of Structural Formula VI for the compounds of this invention is as follows:
Z1 is -H, C,-C6 alkyl, -0(0,-06 alkyl), -F, -Cl, -CN, -CO2H, -002(0,-0β alkyl), -CONH2i -CONH(C,-Cb alkyl), or -CON(C,-C6 alkyl)2, wherein each of said alkyl groups (e.g., representd by Ci-Ce alkyl, -O(C-i-Ce alkyl), -002(0,-06 alkyl), -CONH(C,-C6 alkyl), and -0ΟΝ(0,-06 alkyl)2) is optionally and independently substituted with one or more substîtuents independently selected from the group consîsting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(C,-C6 alkyl), -8816260
N(Ci-C6 alkyl)2, -OCO(Ci-C4 alkyl), -00(0,-04 alkyl), -CO2H, -002(0,-04 alkyl), and
CrC4 alkoxy.
Z2 is -H, CrC6 alkyl, -O(C,-C6 alkyl), -NH2, -ΝΗ(Ο,-Ο6 alkyl), or -N(C,-C6 alkyl)2, wherein each of said alkyl groups (e.g., represented by CrC6 alkyl, -O(C,-CS alkyl), -NH(Ci-C6 alkyl), and -Ν(0,-06 alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, 0,-04 alkyl, -NH2, -NH(C,-C6 alkyl), -Ν(Οι-Ο6 alkyl)2, -000(0,-04 alkyl), -0Ο(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. Values of the remaining variables of Structural Formula VI, including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
A second subset of variables of Structural Formula VI for the compounds of this invention is as follows:
Z1 is -H, C,-Ce alkyl, -O(C,-Ce alkyl), -F, -Cl, -CN, -C02H, -CO2(C,-C6 alkyl), -CONH2, -CONH(C,-C6 alkyl), or -CON(C,-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NHZ, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, ·002(0,-04 alkyl), and C,-C4 alkoxy.
Z2 is -H, C,-C6 alkyl, -O(C,-C6 alkyl), -NHZ, -NH(C,-C6 alkyl), or -N(C,-C6 alkyl)2; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, 0,-04 alkyl, -NH2, -ΝΗ(0,-06 alkyl), -N(C,-C6 alkyl)2, -000(0ι-04 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
R3 is -H, -Cl, -F, -Br, -CN, -CF3, -O(C,-C4 alkyl), -OH, -NHZ, -NH(C,-C4 alkyl), or -N(C,-C4 alkyl)2.
Values of the remaining variables of Structural Formula VI, including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
A third subset of variables of Structural Formula VI for the compounds of this invention is as follows:
Z1 is -H, C,-C6 alkyl, -0(C,-C6 alkyl), -F, -Cl, -CN, -CO2H, -CO2(C,-C6 alkyl), -CONH2. -C0NH(C,-C5 alkyl), or -CON(Ci-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(CrC6 alkyl), -Ν(0,-06 alkyl)z, -OCO(C,-C4 alkyl), -00(0,-0, alkyl), -C02H, -002(0ι-04 alkyl), and C,-C4 alkoxy.
Z2 is -H, C,-C6 alkyl, -0(C,-C6 alkyl), -NH2, -NH(CrC6 alkyl), or -N(C,-C6 alkyl)2;
-891 wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -NH2, -NH(C,-CS alkyl), -Ν^Ο,-Οβ alkyl)2, -OCO(CrC4 alkyl), -00(0,-(^ alkyl), -CO2H, -CO2(Ci-C4 alkyl), and C,-C4 alkoxy.
R3 is -H, DF, DCI, DCF3, ΠΝΗ2, □NH(CH3), or ONiCH^. Specifically, R3 is -H, -Cl, or-F. Specifically, R3 is Cl.
Values ofthe remaining variables of Structural Formula VI, including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
In a fourth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
In a fifth subset of variables of Structural Formula VI for the compounds ofthis invention, values ofthe variables for Structural Formula VI, including spécifie values, and provisos are each and independently as described above in the first, second, third, or fourth subset of variables of Structural Formulae (IA) and (I); and where applicable:
provided that if Q2-R5 is -OR5 or-NR'R5, then ring A is further substituted with one or more instances of JA other than -H; and provided that if Q3 is -C(O)-, then R5 is a substituted CrC6 aliphatic group; an optionally substituted C3-C0 non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclîc aryl group; optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group.
In a sixth subset of variables of Structural Formula VI for the compounds of this invention, values ofthe variables for Structural Formula VI, including spécifie values, and provisos are each and independently as described above in the fifth subset; and the C^Ce aliphatic group represented by R5, when Q3 is -C(O)-, is substituted with one or more instances of JC1, wherein JC1 is independently selected from; an optionally substituted, C3-Ce non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclîc aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; DOR6; aSRb; -S(O)Ra; aSO2Ra; aNRbRc; 0C(O)Rb; iC(O)ORb; riOC(O)Rb; DNRC(O)Rb; nC(O)NRbRc; □NRC(O)NRbRc; □NRC(O)ORb; nOCONRbRc; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -SO2NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
In a seventh subset of variables of Structural Formula VI for the compounds of this
-9016260 invention, values of the variables for Structural Formula VI, including spécifie values, and provisos are each and independently as described above in the first, second, third, or fourth subset of variables of Structural Formulae (IA) and (I); and where applicable:
provided that if Y1 is a bond, then R5 is a substituted CpCe aliphatic group; an optionally substituted C3-Ca non-aromatic carbocycle; an optionally substituted 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group; and provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-Ce non-aromatic carbocycle; an optionally substituted 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.
In an eighth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including spécifie values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae (IA) and (I); and the CrC6 aliphatic group represented by R5, when Y1 is a bond, is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-Ce non-aromatic carbocycle; an optionally substituted, 610-membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; □ORb; nSRb; -S(O)Ra; aSOzRa; □NRbRc; nC(O)Rb; DC(O)ORb; nOC(O)Rb; □NRC(O)Rb; DC(O)NRbRc; aNRC(O)NRbRc; □NRCÎOJOR'3; □OCONRhR0; -C(O)NRCOzRb; -NRC(O)NRCOzRb; -C(O)NR(ORb); -SOzNRcRb; -NRSOzRb; and -NRSOzNRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
In a ninth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including spécifie values, and provisos are each and independently as described above in the first, second, third, or fourth subset of variables of Structural Formulae (IA) and (l); and where applicable:
provided that if Q2-R5 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H;
provided that if Q3 is -C(O)-, then R5 is a substituted Ci-C6 aliphatic group; an optionally substituted C3-Ca non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group;
-9116260 provided that if Y1 is a bond, then R5 is a substituted C^Ce aliphatic group; an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group;
and provided that if Qz and Q3 are each and independently a bond, then Rs is an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group. In a tenth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including spécifie values, and provisos are each and independently as described above in the ninth subset of variables of Structural Formulae (IA) and (I); and when Q3 is -C(O)-, or Y1 is a bond, the Ci-C6 aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-Ce non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; DORb; HSRb; -S(O)Ra; nSO2Ra; 0NRbRc; nC(O)Rb; □CtOiOR1’;
□ OC(O)Rb; nNRC(O)Rb; □CiOJNRhR'; □NRC(O)NRbRc; QNRC(O)ORb; □OCONRbRc; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -SO2NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
in an eleventh subset of variables of Structural Formula VI, values of the variables for Structural Formula VI, including spécifie values, are each and independently as described above in the thirteenth subset of variables of Structural Formulae (IA) and (I).
In another embodiment, the présent invention is generally related to compounds represented by any one of Structural Formulae II, III, IV and V, or pharmaceutically acceptable salts thereof:
1)1
H (H) (III)
-9216260
(IV)
A first subset of variables of Structural Formulae 11, III, IV and V for the compounds of the invention is as follows:
Each Q2is independently 300, DSD, ONRO, nC(0)D, α0Ο2α, nOC(O)D, nC(O)NRO, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, aNRC(O)a, □NRC(O)NR'n, nNRCO2n, nOC(O)NR’D, -S(O)-, HSO2nn nN(R)SO2D, -SO2NR’-, -NRSO2NR'-, or -(CR^pnY’n.
Each Q3 is independently 00(0)0, 0C020, -C(0)NR'0, OSO2n .-SO2NR’-, -C(O)NRC(O)O-, or -(CR6R7)paY1aO
Z1 is -H, -F, -Cl, Ci-C4 haloalkyl (e.g., -CF3), CrC4 alkyl, -O(CrC4 alkyl), or-CN. Z2 is -H, CrCe alkyl, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), or -N(Ci-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -NH2, -NHfCrCe alkyl), -NfCrCe alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -002(0!-04 alkyl), and CrC4 alkoxy. R3 is -H, -Cl, -F, -Br, -CN, -CF3, -O(CrC4 alkyl), -OH, -NH2, -NH(CrC4 alkyl) or -N(CrC4 alkyl)2. Specifically, R3 is -H, -F. -Cl, -CF3, -NH2, -NH(CH3), or-N(CH3)2. Specifically, R3 is -H, -Cl, or -F. Specifically, R3 îs -Cl.
Each R and R’ is independently -H or CrC 6alkyl.
Définitions of rings A-D of formulae ll-V, including spécifie variables, are each and independently as described above for the first set of variables of Structural Formulae (IA) and (I), wherein each of rings A-D is independently an optionally substituted, 4-7 membered ring.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
A second subset of variables of Structural Formulae II, lll, IV and V for the compounds of the invention is as follows:
Z1 is-H, -F, -Cl, -CF3, -CH3, or-CN.
Z2 is -H or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo,
-9316260
Ci-C4 alkyl, -NH2, -NH(CrC6 alkyl), -N(CrC6 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and CrC4 alkoxy.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values and provisos are each and independently as described above for the first subset of variables of Structural Formulae H-V.
A third subset of variables of Structural Formulae ΙΕ, III, IV and V for the compounds of the invention is as follows:
Z1 is-H, -F, or-CN.
Z2 is -H or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -NH2, -NH(CrC6 alkyl), -N(Ci-Ce alkyl)2, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae ll-V.
A fourth subset of variables of Structural Formulae II, III, IV and V for the compounds of the invention is as follows:
Z1 is-H,-F, or-CN.
Z2 is -H or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
R3 is -H, -Cl or -F.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae ll-V.
A fifth subset of variables of Structural Formulae II, III, IV and V for the compounds of the invention is as follows:
Z1 is -H,-F or-CN.
Z2 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -OCO(C,-C4 alkyl), -00(0Γ04 alkyl), -CO2H, -CO^C^ alkyl), and ΟνΟ4 alkoxy.
R3 is -H, -Cl, -F, -CF3]-NH2, -NH(CH3), -N(CH3)2.
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
-9416260
Each R® is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, 0,-04 haloalkyl,
C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(0,-04 alkyl), 3NH2] □ NH(C1DC4 alkyl) or □ N(C,nC4 alkyl)2.
Each R9 is independently -H or -CH3.
R11 and R12 are each independently -H or -CH3.
R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae ll-V.
A sixth subset of variables of Structural Formulae II, III, IV and V for the compounds of the invention is as follows:
Z1 is-H, -For-CN.
Z2 is -H or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(C,-C6 alkyl), -N(C,-CB alkyl)Z1 -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
R3 is -H, -Cl or -F.
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each R0 is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, C,-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(Ci-C4 alkyl), üNH2, □NH(C,0C4 alkyl), or nN(C,nC4 alkyl)2.
Each R9 is independently -H or-CH3.
R11 and R12 are each independently -H or -CH3.
R13 and R14 are each independently -H or-CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae ll-V.
In a seventh subset of variables of Structural Formulae ll-V for the compounds of the invention, values for variables, except for Rs, R7, Ra, R9, R11, R12, R13 and R14, of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above in the first, second, third, or fourth subset of variables of Structural Formulae (IA) and (I).
R6 and R7 are each independently -H or -CrC4 alkyl, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
-9516260
Each Re is îndependently -H, halogen, cyano, hydroxy, C!-C4 alkyl, CrC4 haloalkyl,
CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(0!-04alkyl), aNH2, 0191-1((^üC4 alkyl) or □N(C-|dC4 alkyl)2.
Each R9 is îndependently -H or-CrC4 alkyl.
R11 and R12 are each îndependently -H or -CrC4 alkyl.
R13 and R14 are each îndependently -H or -CrC4 alkyl, or together with the carbon atoms to which they are attached they form a cyclopropane ring
In an eighth subset of variables of Structural Formulae ll-V for the compounds of the invention, values for variables of Structural Formulae ll-V, including spécifie values, and provisos are each and îndependently as described above in the first subset of variables of Structural Formulae (IA) and (I).
In a ninth subset of variables of Structural Formulae ll-V for the compounds of the invention, values for variables of Structural Formulae ll-V, including spécifie values, are each and îndependently as described above for the first, second, third, fourth, fifth, sixth, seventh, or eighth subset of variables of Structural Formulae ll-V; and where applicable:
provided that if Q2-R6 is -OR5 or -NR'R5, then ring A is further substituted with one or more instances of JA other than -H; and provided that if Q3 is -C(O)-, then R5 is a substituted C^Ce aliphatic group; an optionally substituted C3-Ca non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group.
In a tenth subset of variables of Structural Formulae ll-V for the compounds of the invention, values for variables of Structural Formulae ll-V, including spécifie values, are each and îndependently as described above for the ninth subset of variables of Structural Formulae IIV; and where applicable:
when Q3 is -C(O)-, the C^-Ce aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is îndependently selected from: an optionally substituted, C3-C8 non-aromatic carbocycle; an optionally substituted, 610-membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; 3ORb; nSRb; -S(O)Ra; nSO2Ra; nNRbRc; □C(O)Rb; 3C(O)ORb; aOC(O)Rb; 3NRC(0)Rb; 0C(O)NRbRc; 3NRC(0)NRbRc; nNRC(O)ORb; □OCONRbRc; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -SO2NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectîvely, together with the atoms to which they are attached, îndependently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
In an eleventh subset of variables of Structural Formulae ll-V for the compounds of the
-9616260 invention, values for variables of Structural Formulae ll-V, including spécifie values, are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, oreighth subset of variables of Structural Formulae ll-V; and where applicable: provided that if Y1 is a bond, then R5 is a substituted Ο,-Ce aliphatiç group; an optionally substituted C3-Ce non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group, and provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-C0 non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.
In a twlefth subset of variables of Structural Formulae ll-V for the compounds of the invention, values for variables of Structural Formulae ll-V, including spécifie values, are each and independently as described above for the eleventh subset of variables of Structural Formulae ll-V; and where applicable:
when Y1 is a bond, the Ο,-Οβ aliphatiç group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-C0 non-aromatic carbocycle; an optionally substituted, 610-membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; 7lORb; 3SRb; -S(O)Ra; nSO2Ra; FiNRbRc; aC(O)Rb; nC(O)ORb; nOC(O)Rb;
□ NRC(O)Rb; □C(O)NRbRc; nNRC(O)NRbRc; DNRCXOiOR15; nOCONRbRc; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -SO2NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
In a thirteenth subset of variables of Structural Formulae ll-V for the compounds of the invention, values for variables of Structural Formulae ll-V, including spécifie values, are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, or eighth subset of variables of Structural Formulae ll-V; and where applicable: provided that if Q2-R5 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H;
provided that if Q3 is -C(O)-, then R5 is a substituted Ch-Ce aliphatiç group; an optionally substituted C3-Ce non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group.
-9716260 provided that if Y1 is a bond, then R5 is a substituted CrC6 aliphatic group; an optionally substituted C3-Ce non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group;
and i F provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.
In a fourteenth subset of variables of Structural Formulae ll-V for the compounds of the invention, values for variables of Structural Formulae ll-V, including spécifie values, are each and independently as described above for the thirteenth subset of variables of Structural Formulae ll-V; and where applicable:
when Q3 is -C(O)-, or Y1 is a bond, the CrCe aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; □ORb; OSRb; -S(O)Ra; OSO2Ra; ONRbRc; OC(O)Rb; OC(O)ORb; □OC(O)Rb; nNRC(O)Rb; 0C(O)NRbRc; nNRC(O)NRbRc; 0NRC(O)ORb; nOCONRbRb; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -SOzNRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
A fifteenth subset of variables of Structural Formulae ll-V is as follows:
Each of JA and J8 is independently selected from the group consisting of halogen, cyano, oxo, and Q1OR5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1, and fused to the ring to which they are attached.
Q1 is independently a bond, OOO, OSO, ONRO, OC(0)0, OC020, 000(0)0, □ C(O)NRO, -C( O) N RC (O) O-, -NRC(O)NRC(O)O-, ONRC(O)O, 0NRC(O)NR0, HNRCOsO, 0OC(O)NR0, -S(O)-, OSO2OO ON(R)SO2O, 0SO2N(R)-, -NRSO2NR-, or-(CR6R7)pOY1OO
Q2is independently a bond, 000, OSO, ONRO, OC(O)O, OCOzO, DOC(O)O, □C(O)NRO, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, 0NRC(O)0, ONRC(O)NRO,
-9816260 □NRCO2O, nOC(0)NRO,-S(O)-, lISC^ÊI nN(R)SO2O, □SO2N(R)-, -NRSO2NR-, or -(CRsR7)p0Y1n.
Q3 is independently a bond, Π0(Ο)Π, 0CO20, -C(O)NR0, 0SO20.-SO2N(R)-,
-C(O)NRC(O)O- or -(CReR7)p0Y100
R5 is: i) -H; ii) a CrC6 alîphatic group optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromaticcarbocycle, or 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-8 membered non-aromatîc heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1.
Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, DORb, DSRb, -S(O)Ra, ElSO2Ra, QNRbRc, □CfOJR6, □C(O)ORb, □OC(O)Rb, DNRC(O)Rb, aC(O)NRbRc, □NRC(O)NRbRc, 0NRC(0)ORb, □OCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),D-S02NRcRb, -NRSO2Rb, and -NRSO2NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
Ring A is a C3-Ca non-aromatic carbocycle optionally and independently further substituted with one or more instances of JA.
Values of the remaining variables of Structural Formulae ll-V, including spécifie values, and provisos are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, orfourteenth subset of variables of Structural Formulae ll-V.
In another embodiment, the présent invention is generally related to compounds of Structural Formula XI(A) or X1(B), or pharmaceutically acceptable salts thereof.
A first subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:
-9916260
Each Q2is independently DOO, OSO, ONRO, OC(O)D, Π0Ο2α, 000(0)0, □C(0)NR'0, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, □NRCtOjO, □NRC(O)NR’ü, □NRCO2a, DOC(O)NR’a, aS02OD □N(R)SO2n, -SO2NR’-, or -(CR6R7)pDY1D. Ring A is a 5-7 membered, non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrCealkyl, C2-C6alkenyl, -NH2, -NH(CiC6 alkyl), -NtCrCe alkyl)z, -O(Ci.C6 alkyl), -C(O)NHZ1 -C(O)NH(CrC6 alkyl), C(O)N(Ci-Ce alkyl)2, -0(0)(^-C6-alkyl), -00(0)(0,-06 alkyl), -NHC(O)(C,-Ce alkyl), -N(Ci-Ce alkyl)C(O)(C,-C6 alkyl), and -CO2Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(C,-Ce alkyl), -N(C,-C6 alkyl)2, -OCO(C,-C4 alkyl), -C0(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, ring A is a 5-7 membered, non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(Cn-C4 alkylDQDaNH2, nNH(C,aC4 alkyl), □N(CilIC4 alkyl)2, -C(O)(C,-C4 alkylo, -CO2H, and -CO2(C,-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -000(Ογ04 alkyl), -C0(CrC4 alkyl), -COZH, -CO^CrC^ alkyl), and CrC4 alkoxy. Specifically, ring A is a 5-7 membered carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(0γ02 alkyl), -NH(C1-C2 alkyl)2, Ci-C2 alkyl, C4-C2 haloalkyl, 0;-02 hydroxyalkyl, C2-C4 alkoxyalkyl, CrC2 alkoxy, Ci-C2 hydroxyalkoxy, CrC2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(C-|-C4 alkyl).
Re and R7 are each independently -H or -CH3] or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each R® is independently -H, halogen, cyano, hydroxy, C;-C4 alkyl, C-i-C4 haloalkyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(0^04 alkyl), aNH2, □NH(C1üC4 alkyl), or □NîC^DCî alkyl)2.
Each R9 is independently -H or-CH3.
R11 and R12 are each independently -H or -CH3.
R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each R and R’ is independently -H or alkyl.
Provided that if Q2-R5 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H.
-10016260
Values of the remaîning variables of Structural Formulae XI(A) and X1(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A second subset of variables of Structural Formulae Xl(A) and XI(B) for the compounds of the invention is as follows:
Values of Ring A, Q2, R, R’, R5, R6, R7, R8, R9, R11, R12, R13 and R14, including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae XI(A) and Xl(B).
Variable x is 0 or 1 and variable n is 0 or 1.
Values of the remaîning variables of Structural Formulae XI(A) or XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae XI(A) and XI(B).
A third subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:
Values of Ring A, R, R’, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, and provisos are each and independently as described above in the second subset of variables of Structural Formulae XI(A) and XI(B).D
Q2 is -Ο-,Π-NR’-, -CO-nnnCChO, nC(O)NRO, nnRC(O)D, aORC(0)NR-, □ FlRCOzn, nOCONR’anü -NRSOcjnnn-S02NR’-,Dor-(CR6R7)pnY1n. Specifically, Q2 is ΠΟΟ, ΠΝΗΊ, -N(CH3)-, 00(0)0, 000,0, OC(O)NHO, □C(O)N(CH3)O, 0NHC(O)0, DN(CH3)C(0)0, 0NHC(O)NR'D, ON(CH3)C(O)NR’O, □ NHCO2O, 0N(CH3)CO20, 0OC(O)NR’0, -NHSOjO, -N(CH3)SO2000 -so2nh-, -SO2N(CH3)-, or-(CR6R7)pOY1O.
Values of the remaîning variables of Structural Formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A fourth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:
Values of Ring A, Q2, R, R’, Rs, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, and provisos are each and independently as described above in the third subset of variables of Structural Formulae Xl(A) and Xl(B)0
R5 is independently i) -H; ii) a CrC6 aliphatic group (e.g., C-i-Ce-alkyl or C2-C6 alkenyl group) optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1.
-10116260
Each JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, QORb, aSRb, -S(O)Ra-, nSO2Ra, DNHR6, □C(O)Rb, nC(O)ORb, □OC(O)Rb, nNHCfOlRh, □CiOJNHR'; nNHC(O)NHRc, nNHC(O)ORb, COCONHR', -NHC(O)NHC(O)ORb, □N(CH3)RC, □N(CH3)C(O)Rb, □C(O)N(CH3)Rc, □ N(CH3)C(O)NHRc, 0N(CH3)C(O)ORb, □OCON(CH3)RC, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(O)NHC(O)ORb, -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb.
Values of the remaining variables of Structural Formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A fifth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:
Values of Q2, R, R’, R5, R6, R7, RB, R9, R11, R12, R13, R14, x and n, including spécifie values, and provisos are each and independently as described above in the fourth subset of variables of Structural Formulae XI(A) and XI(B).D
Ring A is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4 alkyl □□□□NHj, nNH(C,nC4 alkyl), alkyl)2, -0(0)(0,-04 alkyln,
-CO2H, and -CO2(C,-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of h halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2i -NH(Ci-C6 alkyl), -N(C,-C6 alkyl)2, -000(0,-04 alkyl), -CO(C,-C4 alkyl), -COZH, -002(0,-04 alkyl), and Ο,-Ο4 alkoxy.
It is provided that if Q2-R5 is -OR6 or -NR'R6, then ring A is further substituted with one or more instances of JA other than -H.
Values of the remaining variables of Structural Formulae Xl(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A sîxth subset of variables of Structural Formulae Xl(A) and XI(B) for the compounds of the invention is as follows:
Values of Q2, R, R’, Rs, R6, R7, Ra, R9, R11, R12, R13, R14, x and n, including spécifie values, and provisos are each and independently as described above in the fifth subset of variables of Structural Formulae XI(A) and XI(B). □
The group -[(C)0_,R13R14]-ringA-Q2-R5 is independently selected from one of the depicted below
-10216260
wherein each of rings A1-A27 is independently and optionally further substituted with one or more substituents. Specifically, rings A5, A6, A21, A24, and A26 are each independently further substituted with one or more instances of substituents other than -H. Suitable substituents are as described above for ring A in the first subset of variables of Structural Formulae XI(A) and XI(B).D
Values of the remaining variables of Structural Formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A seventh subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:
Values ofthe group-[CR13R14]x-ringA-Q2-Rs, ring A, Q2, R, R’, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, and provisos are each and independently as described above in the sixth subset of variables of Structural
Formulae XI(A) and XI(B).a
Each R5 is independently: i) -H; ii) a Ci-C6-aliphatic group optionally substituted with one or more substituents independently selected from the group consîsting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -0(0,-04 alkyl), DNH2, □ NH(CiOC4 alkyl), □ Ν(0,Ί04 alkyl)21 -C(O)(C,-C4 alkyl), -OC(O)(Ci-C4 alkyl), -0(0)0(0,-04 alkyl),
-10316260
-COîH, C3-Cs non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl; or iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(Ci-C4 alkyl), ONH^ □NH(C1nC4 alkyl), □N(CiDC4 alkyl)2, -C(O)(C,-C4 alkyl), -OC(O)(C,-C4 alkyl), -C(O)O(C,-C4 alkyl), and -CO2H; wherein each of said alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by Rs is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, 0NH2, □NH(C,nC4 alkyl), nN(C,DC4 alkyl)2) -OCO(C,-C4 alkyl), -00(0,-04 alkyl), -CO2H, -002(0,-04 alkyl), and CrC4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the Ci-C6-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, ΠΝΗ2, nNH(C,nC4 alkyl), ΠΝ(0,Π04 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -002Η, -002(0,-04 alkyl), and C,-C4 alkoxy.
Values of the remaining variables of Structural Formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I),
An eighth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:
Values of Q2, R, R’, R5, R6, R7, Rs, Ra, R11, R12, R13, R14, x and n, including spécifie values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae XI(A) and XI(B).O
The group -[(C)0.iR13R1',]-ringA-Q2-R5 is independently selected from one of the depicted below
independently further substituted. Suitable substituents are as described above for ring A in the first subset of variables of Structural Formulae XI(A) and XI(B).ü
-10416260
Each R8 independently is halogen, cyano, hydroxy, CrC4 alkyl, C,-C4 haloalkyl, Cp
C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C4—C4 alkyl), □NH2, □ΝΗίΟ,ΠίΙ, alkyl) or □ N(C,3C4 alkyl)?.
Values of the remaining variables of Structural Formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A ninth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:
Values of the group HCR13R14]x-ringA-Q2-R5, ring A, Q2, R, R’, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, and provisos are each and independently as described above in the eighth subset of variables of Structural Formulae Xl(A) and ΧΙ(Β).Π
Each R5 is independently: i) -H; ii) an optionally substituted C,-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle, wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, □NH2, üNH(C,nC4 alkyl), nN(C,OC4 alkyl}?, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C-|-C4 alkyl), C,-C4 alkoxy, optionally substituted, C3-C7 non-aromatic carbocycle, and optionally substituted, 4-7 membered non-aromatic heterocycle.
Each of said carbocycles and heterocycles represented by R6, and referred to for the substituents of the CrC6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(C1-C4 alkyl), DNH2, nNH(C,nC4 alkyl), □N(C1nC4 alkyl)?, -C(O)(C,-C4 alkyl), -OC(O)(C,-C4 alkyl), -0(0)0(0,-04 alkyl) and -CO2K, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, DN^, 0NH(C1aC4 alkyl), □ N(C10C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -002(0,-04 alkyl), and Ci-C4 alkoxy.
Values of the remaining variables of Structural Formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (i).
A tenth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:
Values of Q2, R, R’, R5, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including spécifie values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae XI(A) and XI(B).D
-10516260
The group -[(C)Q.iR13R14]-ringA-Qz-R5 is independently selected from one of the depicted below:
wherein each of rings A1 -A4, A7-A20, A22, A23, A25 and A27 is independently and optionally further substituted. Suitable substituents are as described above for ring A in the first subset of variables of Structural Formulae XI(A) and XI(B)D
Values of the remaining variables of Structural Formulae Xl(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
An eleventh subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:
Values of Qz, R, R', R5, R6, R7, R6, R9, R11, R1Z, R13, R14, x, and n, including spécifie values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae XI(A) and XI(B).D
The group -[(C)0.iR13R14]-ringA-Qz-R5 is independently selected from one of the depicted below:
-10616260
R8 fjlH
H
R5 wherein each of rings A5-A7, A21, A24 and A26 is independently and optionally further substituted. Suitable substituents are as described above for ring A in the first subset of variables of Structura) Formulae Xl(A) and XI(B).n
Each R0 independently is halogen, cyano, hydroxy, CrC4 alkyl, CrC4 haloalkyl, Cr C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(C!-C4alkyl), ΠΝΗ2, alkyl), or lN(Ci ~iC4 alkyl)2.
Values of the remaining variables of Structural Formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
In a twelfth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention, values of the variables for Structural Formulae Xl(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
In a thirteenth subset of variables of Structural Formulae XI(A) and XI(B)for the compounds of the invention, values of the variables for Structural Formulae X!(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subset of variables of Structural Formulae Xl(A) and XI(B); and where applicable:
provided that if Y1 is a bond, then R5 is a substituted Ci-C6 aliphatic group; an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group;
and provided that if Q2 is a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.
In a fourteenth subset of variables of Structural Formulae Xl(A) and Xl(B) for the compounds of the invention, values of the variables for Structural Formulae XI(A) and XI(B), including spécifie values, and provisos are each and independently as described above in the thirteenth subset of variables of Structural Formulae XI(A) and XI(B); and where
-10716260 applicable:
when Y1 is a bond, the CrC6 aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-Ca non-aromatic carbocycle; an optionally substituted, 610-membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; □ORb; nSRb; -S(O)Ra; DSOzRa; ONR^0; DC(O)Rb; nC(O)ORb; DOC(O)Rb;
□ NRC(O)Rb; nC(O)NRbRc; aNRC(O)NRbRc; nNRC(O)ORb; dOCONRbRc; -C(O)NRCOzRb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -SO2NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
In a fifteenth subset of variables of Structural Formulae XI(A) and XI{B), values of the variables for Structural Formulae XI(A) and Xl(B), including spécifie values, are each and independently as described above in the thirteenth subset of variables of Structural Formulae (IA) and (I), in the eleventh subset of variables of Structural Formula (VI), or in the fifteenth subset of variables of Structural Formulae (ll)-(V).
In another embodiment, the présent invention generally relates to compounds of Structural Formula XII(A) or XII(B), or pharmaceutically acceptable salts thereof.
(XIIA) (XI1B),
A first subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:
Each Q3 is independently üC(O)n, nCO2O, -C(O)NR’n, 71SOzn, -SO2NR’-, -C(O)NRC(O)O-, or -(CR6R7)pDY1aa
Ring B is a 4-7 membered, non-aromatic, heterocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C-i-C6 alkyl, C2-C6 alkenyl, -NH2, -NH(Cr C6 alkyl), -N(CrC6 alkyl)2, -O(Ci.C6 alkyl), -C(O)NHZ, -C(O)NH(CrCB alkyl), C(O)N(CrC6 a!kyl)Z] -CtOXCrCe-alkyl), -OC(O)(CrCB alkyl), -NHC(O)(CrC6 alkyl), -NiC^Cs alkyl)C(O)(CrC6 alkyl), and -COzRb; wherein each of said alkyl and alkenyl
-10816260 groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -NH2, -NHiCrCe alkyl), -N(Ci-C6 alkyl)2, -000(0,-04 alkyl), -C0(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(Ci-C4 alkylnrmNH2, □ΝΗ(Ο,ΠΟ4 alkyl), □N(C10C4 alkyl)2, -C(O)(C,-C4 alkylO, -CO2H, and -CO2(C,-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, CrC2 haloalkyl, CrC2 hydroxyalkyl, C2-C4 alkoxyalkyl, CrC2 alkoxy, CrC2 hydroxyalkoxy, CrC2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(Ci-C4 alkyl).
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
R9 is -H or-CH3.
R11 and R12 are each independently -H or -CH3.
R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
Each R and R’ is independently -H or C^Ce alkyl.
Provided that if Q3 is -C(0)-, then R5 is a substituted CrC6 aliphatic group; an optionally substituted C3-C0 non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group. Specifically, the Ci-C6 aliphatic group is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-C0 nonaromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; DORb; aSRb; -S(0)Ra;
lSO2Ra; nNRbRc; nC(O)Rb; 3C(O)ORb; □OC(O)Rb; HNRC(O)Rb; aC(O)NRbRc; 3NRC(0)NRbRc; 3NRC(O)ORb; □OCONRbRc; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -SO2NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached,
-10916260 independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
Values of the remaining variables of Structural Formulae Xll(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A second subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:
Values of Ring B, Q3, R, R’, R6, R7, R9, R11, R12, R13, and R14, including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae XII(A) and XII(B).
Variable y = 0 or 1,
Values of the remaining variables of Structural Formulae Xll(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A third subset of variables of Structural Formulae XII(A) and Xll(B) is as follows: Values of Ring B, R, R’, Re, R7, R9, R11, R12, R13, R14 and y, including spécifie values, and provisos are each and independently as described above in the second subset of variables of Structural Formulae Xll(A) and XII(B).
Q3 is independently 00(0)71, OCOzO, 0C(O)NH0, 0C(O)N(CH3)D, -C(O)NHC(O)O-, -C(O)N(CH3)C(O)O-.-SO2-, -SO2NH-, -SO2N(CH3)-, or -(CReR7)pY1-.
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A fourth subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:
Values of Ring B, Q3, R, R’, R6, R7, R9, R11, R12, R13, R14, and y, including spécifie values, and provisos are each and independently as described above in the third subset of variables of Structural Formulae XII(A) and XII(B).
R5 is independently i) -H; ii) a CpCe aliphatic group (e.g., CrC5-alkyl or C2-C6alkenyl group) optionally substituted with one or more instances of JC1; iii) a C3-Ce non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of J01 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1.
Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, nORb, RSRb, -S(O)Ra, nSO2Ra, ClNHRc, nC(O)Rb, OC(O)ORb,
-11016260 □ OC(O)Rb, □ NHC(O)Rb, □C(O)NHRC, □ NHC(O)NHRC, DNHC(O)ORb, nOCONHR0, -NHC(O)NHC(O)ORb, □ NiCHsJR0, □ N(CH3)C(O)Rb, nC(O)N(CH3)Rc, □ N(CH3)C(O)NHRc, □ N(CH3)C(O)ORb, □OCON(CH3)RC, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(O)NHC(O)ORb, -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb
Values of the remaining variables of Structural Formulae XII(A) and Xll(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A fifth subset of variables of Structural Formulae XII(A) and XII(B)for the compounds of the invention is as follows:
Values of Q3, R, R’, R5, R6, R7, R9, R11, R12, R13, R14, and y, including spécifie values, and provisos are each and independently as described above in the fourth subset of variables of Structural Formulae XII(A) and XII(B)
Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -O(C,-C4 alkylûiaaoNHz, nNH(C,QC4 alkyl), ON(C,nC4 alkyl)2, -0(0)(0,-04 alkyll, -CO2H, and -002(0,-04 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-CS alkyl), -N(C,Ce alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -002(0,-04 alkyl), and C,-C4 alkoxy.
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A sixth subset of variables of Structural Formulae Xll(A) and XII(B) for the compounds of the invention is as follows:
Values of Q3, R, R’, R5, R6, R7, R9, R11, R12, R13, R14, and y, including spécifie values, and provisos are each and independently as described above in the fifth subset of variables of Structural Formulae XII(A) and XII(B).
Ring B is independently selected from one of the structures depicted below:
-ni16260 wherein each of rings B1, B2 and B4-B9 is optionally and independently substituted.
Suitable substituents are independently as described above for ring B in the first subset of variables of Structural Formulae (IA) and (I).
Values ofthe remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (l).
A seventh subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:
Values ofthe ring B, Q3, R, R’, R6, R7, Ra, R11, R1Z, R13, R14, and y, including spécifie values, and provisos are each and independently as described above in the sixth subset of variables of Structura! Formulae XII(A) and XII(B).
Each R5 is independently; i) -H; ii) a Ci-Ce-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -0(0^0, alkyl), DN^, ΠΝΗ(0,α04 alkyl),
ΟΝίΟ,ΠΟ, alkyl)2, -0(0)(0,-04 alkyl), -OC(O)(C,-C, alkyl), -0(0)0(0,-04 alkyl),
-CO2H, C3-Cb non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl; or iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4alkyl), aNH2, □NH(C,nC4 alkyl), □N(C,üC4 alkyl)2, -C(O)(C,-C4 alkyl), -00(0)(0,-0, alkyl), -0(0)0(0,-0, alkyl), and -C02H; wherein each of said alkyl groups for the substituents ofthe aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by Rs is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, □ NH2, □ΝΗίΟ,αΟ, alkyl), ΠΝίΟ,ΠΟ, alkyl)2, -0C0(C,-C4 alkyl), -00(0,-0, alkyl), -C02H, -CO2(Ci-C4 alkyl), and 0,-C, alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the C,-C6-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, 0,-0, alkyl, αΝΗ2, 0ΝΗ(0,α04 alkyl), LlN(CinC4 alkyl)2, -0C0(C,-C, alkyl), -C0(C,-C4 alkyl), -C02H, -CO2(C,-C4 alkyl), and CrC4 alkoxy.
Values ofthe remaining variables of Structural Formulae XII(A) and Xll(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (l).
An eighth subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:
-11216260
Values of Q3, R, R’, R5, Re, R7, R9, R11, R12, R13, R14, and y, including spécifie values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae XII(A) and XII(B).
The group -[C(R13R14)lx-ringB-Q2-Rs:
N
Q3
wherein ring B2 is optionally and independently further substituted with one or more substituents independently selected from the group consisting of with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2) -NH(C,-C2 alkyl), -NH(C,-CZ alkyl)2, CrC2 alkyl, CrC2 haloalkyl, CrC2 hydroxyalkyl, C2-C4 alkoxyalkyl, C,-C2 alkoxy, Ci-Cz hydroxyalkoxy, C,-Cz haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -COz(CrC4 alkyl).
Values of the remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A ninth subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:
Values of ring B, Q3, R, R’, R6, R7, R9, R11, R12, R13, R14, and y, including spécifie values, and provisos are each and independently as described above in the eighth subset of variables of Structural Formulae XII(A) and XII(B).
Each R5 is independently: i) -H; ii) an optionally substituted C-|-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle, wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, 1NHZ, ΊΝΗ(Ο,ΠΟ4 alkyl), ΠΝ(0,α04 alkyl)2, -OCO(CrC4 alkyl), -00(0,-0, alkyl), -CO2H, -CO2(CrC4 alkyl), C,-C4 alkoxy, optionally substituted, C3-C7 non-aromatic carbocycle, and optionally substituted, 4-7 membered non-aromatic heterocycle.
Each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the C,-Ce alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4 alkyl), ΠΝΗ2, □ NH(C,aC4 alkyl), Ε1Ν(0ιΠ04 alkyl)2, -0(0)(0,-0, alkyl), -00(0)(0,-0, alkyl), -C(O)O(Ci-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, ElNI-b, □ΝΗίΟ-,ΠΟ, alkyl),
-11316260 □N(CiDC4 alkyl)2, -000(0,-04 alkyl), -00(0,-04 alkyl), -C02H, -CO2(Ci-C4 alkyl), and C,-C4 alkoxy.
Values ofthe remaining variables of Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and îndependently as described above in the first subset of variables of Structural Formulae (IA) and (I).
In a tenth set of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention, values of the variables for Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and îndependently as described above in the first subset of variables of Structural Formulae (IA) and (I).
In an eleventh subset of variables of Structural Formulae XII(A) and XII(B)for the compounds ofthe invention, values ofthe variables for Structural Formulae Xll(A) and XII(B), including spécifie values, and provisos are each and îndependently as described above in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subset of variables of Structural Formulae XII(A) and XII(B); and where applicable: provided that if Y1 is a bond, then RE is a substituted C,-C6 aliphatic group; an optionally substituted C3-Ce non-aromatic carbocycle; an optionally substituted, 6-10membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group; and provided that if Q3 is a bond, then R5 is an optionally substituted C3-CB non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.
In a twelfth subset of variables of Structural Formulae XII(A) and XII(B)for the compounds of the invention, values ofthe variables for Structural Formulae XII(A) and XII(B), including spécifie values, and provisos are each and îndependently as described above in the eleventh subset of variables of Structural Formulae XIJ(A) and XII(B); and where applicable: when Y1 is a bond, the C,-Ce aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is îndependently selected from: an optionally substituted, C3-Cs non-aromatic carbocycle; an optionally substituted, 610-membered carbocyclic aryl group; an optionally substituted, 4-8 membered nonaromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; □ORb; aSRb; -S(O)Ra; nSO2Ra; 3NRbRc; □C(O)Rb; 3C(O)ORb; nOC(O)Rb;
□ NRC(O)Rb; □CfOJNRhR0; 0NRC(O)NRbRc; nNRC(O)ORb; DOCONRbRc; -C(O)NRCO2Rb; -NRC(O)NRCO2Rb; -C(O)NR(ORb); -S02NRcRb; -NRSO2Rb; and -NRSO2NRcRb; or optionally two JC1 and two JD1, respectîvely, together with the atoms to which they are attached, îndependently form a 5-7-membered ring that is
-11416260 optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
In a thirteenth subset of variables of Structural Formulae XII(A) and XII(B), values of the variables for Structural Formulae XII(A) and XII(B), including spécifie values, are each and independently as described above in the thirteenth subset of variables of Structural Formulae (IA) and (I), in the eleventh subset of variables of Structural Formula VI, or in the fifteenth subset of variables of Structural Formulae ll-V.
In another embodiment, the présent invention generally relates to compounds of Structural Formula XIII, or pharmaceutically acceptable salts thereof:
(XIII).
A first subset of variables of Structural Formula XIII for the compounds of the invention is as follows:
Ring C is a 5-7 membered, non-aromatic, heterocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, CrC6alkyl, C2-C6 alkenyl, -NH2, -NH(C-i-C6 alkyl), -NiCrCe alkyl)2, -0(0,_06 alkyl); -C(O)NH2, -C(O)NH(CrC6 alkyl), C(O)N(CrCe alkyl)2, -CfOXCrCe-alkyl), -00(0)(0,-06 alkyl), -NHC(O)(C,-C6 alkyl), -N(Ci-C6 alkyl)C(O)(Ci-Ce alkyl), and -CO2Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and Ci-C4 alkoxy. Specifically, ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C,-C4 alkyl, -O(C,-C4 alkylkinnnNH2, LlNH(C,aC4 alkyl), aN(Ci0C4 alkyl)2, -C(O)(C,-C4 alkyln, -COZH and -CO2(C,-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH21 -NH(Ci-C6 alkyl), -N(C,-CS alkyl)2, -OCO(C,-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and CrC4 alkoxy. Specifically, ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NHfCrCj
-11516260 alkyl), -NH(CrC2 alkyl)21 C,-^ alkyl, CrC2 haloalkyl, CrC2 hydroxyalkyl, C2-C4 alkoxyalkyl, Cj-C2 alkoxy, CrC2 hydroxyalkoxy, C,-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(C!-C4 alkyl).
Rs and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
R9 is -H or-CK3.
R11 and R12 are each independently -H or -CH3.
Each R and R' is independently -H or CrC6 alkyl.
Values of the remaining variables of Structural Formula XIII, including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A second subset of variables of Structural Formula XIII for the compounds of the invention is as follows:
Values of Ring C, R, R’, R6, R7, R9, R11, and R12, including spécifie values, are each and independently as described above in the first subset of variables of Structural Formula XIII.
R10 is -H or Ci-C6-alkyl.
Values of the remaining variables of Structural Formula XIII, including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A third subset of variables of Structural Formula XIII for the compounds of the invention is as follows:
Values of R, R', R6, R7, R9, R10, R11, and R12, including spécifie values, are each and independently as described above in the second subset of variables of Structure Formula XIII. □
Ring C is a 5-7 membered, non-aromatic, heterocyclic group optionally further substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, CtC4 alkyl, -O(Ci-C4 alkylDDDONH2l □NH(C1DC4 alkyl), □NîCïEIC^ alkyl)2, -C(O)(CrC4 alkyld, -CO2H, and -CO2(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2> -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)21 -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), and CrC4 alkoxy.
Values of the remaining variables of Structural Formula XIII, including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A fourth subset of variables of Structural Formula XIII for the compounds of the invention is as follows:
-11616260
Values of R, R’, R6, R7, R9, R10, R11, and R12, including spécifie values, are each and independently as described above in the third subset of variables of Structure
Formula XIII.□
Ring C is independently selected from:
wherein each of rings C1-C5 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C,-C4 alkyl, -O(C,-C4 alkyloannNH2, ΠΝΗίΟ,Ο^ alkyl), alkyl)2, -0(0)(0,-04 alkyln, -CO2H, and -CO2(C,-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more independently substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -000(0,-04 alkyl), -CO(C,-C4 alkyl), -CO2H, -002(0,-04 alkyl), and C,-C4 alkoxy.
Specifically, each of rings C1-C5 is optionally and independently further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(C,-C2 alkyl), -NH(C,-C2 alkyl)2, C,-C2 alkyl, 0,C2 haloalkyl, C,-Ca hydroxyalkyl, C2-C4 alkoxyalkyl, C,-C2 alkoxy, C,-C2 hydroxyalkoxy, C,-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(C,-C4 alkyl).
Values of the remaining variables of Structural Formula XIII, including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
In a fifth set of variables of Structural Formula XIII for the compounds of the invention, values of the variables for Structural Formula XIII, including spécifie values, are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
In another embodiment, the présent invention generally relates to compounds represented by Structural Formula below XIV, or a pharmaceutically acceptable sait thereof:
-11716260 (XIV).
A first subset of variables of Structural Formula XIV for the compounds of the invention is as follows:
Ring D is 4-7 membered, non-aromatic; heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC6alkyl, C2-C6 alkenyl, -NH2, -NHfCrCe alkyl), N(CrC6 alkyl)2, -0(0,.06 alkyl), -C(O)NH21 -C(O)NH(C,-C6 alkyl), -C(O)N(C,-C6 alkyl)2, -C(O)(C,-C6-alkyl), -OC(O)(C,-C6 alkyl), -NHC(O)(C,-Ce alkyl), -N(C,-C6 alkyl)C(O)(Ci-Ce alkyl), and -COzRb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C1-C4 alkoxy. Specifically, ring D is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4 alkylnnOüNH2, 0NH(C,nC4 alkyl), □N(C,0C4 alkyl)2, -C(O)(C,-C4 alkylO, -CO2H and -CO2(C,-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-Ce alkyl), -NfCj-Ce alkyl)2, -OCO(Ci-C4 alkyl), -CO(C1-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), and Ci-C4 alkoxy. Specifically, ring D is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2> -NH(CiC2 alkyl), -NH(CrC2 alkyl)2, CrC2 alkyl, CrC2 haloalkyl, CtC2 hydroxyalkyl, C2-C4 alkoxyalkyl, C!-C2 alkoxy, C,-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(Ci-C4 alkyl).
R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring. Each of R and R’ is independently -H or C^-Cg alkyl.
Vlaues of the remaining variables of Structural Formula XIV, including spécifie values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
A second subset of variables of Structural Formula XIV for the compounds of the invention is as follows:
Values for Ring D, R, R', Rs, R7, R13, and R14, including spécifie values, are each and independently as described above in the first subset of variables of Structural Formula XIV.
-11816260
Variable z is 1.
All other variables of Structural Formula XIV, including spécifie values, and provisos are each and independently as described above for the first subset of variables of
Structural Formulae (IA) and (I).
A third subset of variables of Structural Formula IV for the compounds of the invention is as follows:
Values forz, R, R', R6, R7, R13, and R14, including spécifie values, are each and independently as described above in the second subset of variables of Structural Formula XIV,
Ring D is independently selected from the group consîsting of wherein each of rings D1-D7 is optionally and independently substituted one or more substituents independently selected from the group consîsting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(CrC4 alkylil Π71 üNHa, nNH(C10C4 alkyl), alkyl)21 -0(0)(0,C4 alkylFl, -CO2H and -CO2(C,-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consîsting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-Ce alkyl), -N(C,-Ce alkyl)21 -OCO(C,-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
Specifically, each of rings D1-D7 is optionally and independently further substituted with one or more substituents independently selected from the group consîsting of halogen, cyano, hydroxy, oxo, -NH21 —NH(Ci-C2 alkyl), -NH(C,-C2 alkyl)2, C,-C2 alkyl, C,-C2 haloalkyl, C,-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, CtC2 hydroxyalkoxy, C,-Cz haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -CO2(C,-C4 alkyl).
Each Rd is independently -H, C,-Ce alkyl or - C(O)(Ci-C6 alkyl), wherein each of said alkyl moiety is optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-Ce alkyl), -N(Ci-C0 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and Ci-C4 alkoxy. Specifically, each Rd is independently -H or CrC6 alkyl optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, -NH2, -NHfCrCe alkyl), -NfCrCe alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(CrC4 alkyl), and CrC4 alkoxy.
Vlaues of the remaining variables of Structural Formula XIV, including spécifie
-11916260 values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).
In a fourth subset of variables of Structural Formula XIV for the compounds of the invention, values of the variables for Structural Formula XIV, including spécifie values and provisos, are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).
In yet another embodiment, the compounds are represented by Structural Structural Formula (I), or pharmaceutically acceptable salts thereof, wheren each variables of the formulae are independently as described above; and wherein·.
R4 is:
Ring E is a C4-C8 non-aromatic carbocycle optionally further substituted with one or more instances of JA
Rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1.
Each of rings G1 and G2 is independently a 5-10 membered non-aromatic bridged carbocycle optionally substituted with one or more instances of JA.
Q!is independently bond, DOO, nSD.'aNRD, 00(0)0, -C(=NR)-, OCOzO, 000(0)0, 0C(O)NR0,-C(O)NRC(O)O-, -NRC(O)NRC(O)O-, nNRC(O)0, □ NRC(O)NRD, 0NRCO2O, 0OC(O)NR0, -S(0)-, OSOsOO nN(R)S020, 0SO3NR'-, -NRSO2NR'-, or -(CR6R7)POY1O.
R5 is: i) -H; ii) an optionally substituted 0,-06 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted nonaromatic heterocycle. The alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C!-C4 alkyl)?, -OCO(Ci-C4 alkyl), -C0(CrC4 alkyl), -CO2H, -002(0,-04 alkyl), C1-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the 0,-06 alkyl group represented by R5 is independently and optionally substituted with one or
-12016260 more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -0(^-04 alkyl), ΠΝΗ2, □NH(C1QC4 alkyl), □NfC^C, alkyl)2, -0(0)(0,-0, alkyl), -00(0)(0,-0, alkyl), -0(0)0(0,-0, alkyl) and -002Η, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -0C0(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -002(0,-04 alkyl), and 0,-04 alkoxy,
Each of R8 and R9 is independently -H, halogen, cyano, hydroxy, C,-C4 alkyl, C,-C4 haloalkyl, 0,-C, hydroxyalkyl, C2-C4 alkoxyalkyl, -0(0,-0, alkyl), ΠΝΗζ, ΠΝΗ(Ο,αθ, alkyl), or αΝίΟ,ΠΟ, alkyl)2,
R11, R12, R13 and R14 are each independently DH, halogen, or C,-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, C,-C6 haloalkoxy, 0,-06 aminoalkoxy, Ci-C6cyanoalkoxy, C,-Ce hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl,
R21, R22, R23 and R24 are each independently OH, halogen, -OH, or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CpCe alkoxy, CtCb haloalkoxy, CpCe aminoalkoxy, Ο,-Οβ cyanoalkoxy, ΟτΟθ hydroxyalkoxy, and C2-CB alkoxyalkoxy, p and q are each independently 0, 1 or 2.
x is 0, 1 or 2.
r is 1 or 2.
Values of the remaining variables of Structural formula I, including spécifie values, and provisos are each and independently as described above in any one of the first through fifteenth sets of variables of Structural Formula I.
In yet another embodiment, the compounds represented by Structural Formula (I) or pharmaceutically acceptable salts thereof are independently as described above in the preceding paragraph; and ring F is selected from any one of rings F1-F6:
o each of rings F1-F6 optionally and independently substituted; and each R* is independently DH or Ci-Ce alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of
-12116260 halogen, cyano, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, CrCe haloalkoxy, CrCB aminoalkoxy, CrCBcyanoalkoxy, CrC6 hydroxyalkoxy and C2-C6 alkoxyalkoxy.
In yet another embodiment, the compounds represented by Structural Formula (XIA) or (XIB), or pharmaceutically acceptable salts thereof are as described above; and the group -[C(R13R14)]x-ringA-Q2-R6 is independently:
0,1 H
O R ; wherein:
each of rings A14 and A28 is optionally and independently further substituted, and values of the remaining variables of Structural Formulae (XIA) and (XIB), including spécifie values, and provisos are each and independently as described above in any one of the first through eleventh sets of variables of Structural Formulae (XIA) and (XIB).
In yet another embodiment, the compounds represented by Structural Formula (XIA) or (XIB), or pharmaceutically acceptable salts thereof are independently as described above in the preceding paragraph; and R5 is an optionally substituted CrC8 alkyl group; an optionally substituted, C3-C7 non-aromatic carbocycle; or an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle. Specifically, R5 is an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle.
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein:
R4 is:
Ring E is a C4-Ci0 non-aromatic carbocycle optionally further substituted with one or more instances of JA.
Rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1. Spécifie examples of ring F includes:
O
-122-
r-N
J?>
Ύ,/'ο
Additional example includes G <. Each of rings F1-F7 optionally and independently substituted. Exemplary substituents for ring F (including rings F1-F7) include halogen, cyano, hydroxy, C,-C4 alkoxy, and C,-C4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -O(C;-C4 alkyl).
R* is independently DH or Ci-C6alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, CrC6 haloalkoxy, CrCs aminoaikoxy, CpCs cyanoalkoxy, Ci-C6 hydroxyalkoxy and C2-Ce alkoxyalkoxy.
R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, CrC6 alkyl, CrC6 haloalkyl, CrC6 cyanoalkyl, C2-C6 alkoxyalkyl, CpCe aminoalkyl, Ci-C6 hydroxyalkyl, CpCe carboxyalkyl, CrC6 alkoxy, CrC6 haloalkoxy, CrC6 aminoaikoxy, Ci-Ce cyanoalkoxy, C,-C6 hydroxyalkoxy, or C2-C6 alkoxyalkoxy.
R11, R12, R13 and R14 are each independently OH, halogen, or C-i-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C^-Ce alkoxy, C^-Ce haloalkoxy, CrC6 aminoaikoxy, CrC6 cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-Cs alkoxyalkoxy.
Optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl.
s is 0, 1 or 2.
x is 0, 1 or 2.
The remaining variables are each and independently as described above in any one of the sets of variables for Structural Formulae (IA) and (I).
In yet another embodiment, the compounds are represented by Structural Formula (I) or (IA), or pharmaceutically acceptable salts thereof, wherein:
Ring E is a C4-Ce non-aromatic carbocycle optionally further substituted with one or more instances of JA.
Ra is independently -H, halogen, cyano, hydroxy, C!-C4 alkyl, Ci-C4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C-,-C4 alkyl), ΠΝΗ2, ΊΝΗ(Ο4ΠΟ4 alkyl), or INîCtOCî alkyl)2.
The other varibales are each and independently as described in the preceeding paragraph.
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein:
-12316260
optionally further substituted with one or more instances of JA.
Eing G5 is a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JB.
X is-O-, -S-, or-NR9-.
R8 and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Cr C6 alkyl, Ο,-Οβ haloalkyl, Ο,-Οβ cyanoalkyl, C2-Ce alkoxyalkyl, Ο,-Οβ aminoalkyl, Cr C6 hydroxyalkyl, CrC6 carboxyalkyl, Ο,-Ce alkoxy, Ο,-Cb haloalkoxy, Ci-C6 aminoalkoxy, CpCe cyanoalkoxy, Ο,-Ce hydroxyalkoxy, or C2-C6 alkoxyalkoxy.
R13 and R14 are each independently OH, halogen, or Ο,-Οθ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, CrC6 haloalkoxy, CrC6 aminoalkoxy, CrC6cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-Cs alkoxyalkoxy.
Optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl.
R21, R22, R23, R24, and R25 are each independently CIH, halogen, -OH, CrC6 alkoxy, or Ci-CB alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, Ci-C6 haloalkoxy, CrC6 aminoalkoxy, Ο,-Οβcyanoalkoxy, Cr C6 hydroxyalkoxy, and Ο2-Οθ alkoxyalkoxy. Specifîcally, R21, R22, R23, R24, and R25 are each independently DH, halogen, -OH, CrC6 alkoxy, or C^Cb alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C6 alkyl, -NH2, -ΝΗ^,-Οβ alkyl), -N(C-|-C6 alkyl)2, -0(0^ alkyl), -C(O)NH2, -C(0)NH(CrC6 alkyl), -C^NÎCvCb alkyl)2,
-12416260
-CiOXCrCe-alkyl), -OC(O)(Ci-C6 alkyl), -NHC(O)(CrC6 alkyl), -N(CrC6 alkyl)C(O)(Ci-C6 alkyl).
R9 is -H or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-C6 alkoxy, C-i-C6 haloalkoxy, CrCeaminoalkoxy, CrC6 cyanoalkoxy, C^Cg hydroxyalkoxy, and C2-C6 alkoxyalkoxy.
q is 0, 1 or 2; x is 0, 1 or 2; and r is 1 or 2.
The remaining variables are each and independently as described above in any set of variables for Structural Formulae (IA) and (I).
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), pharmaceutically acceptable salts thereof, wherein:
wherein rings G1 and G2 are each and independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JA
Each of Re and R9 is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, C,-C4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O/C^C^ alkyl), üNH2, □NH(CiDC4 alkyl), or □N(C1üC4 alkyl)2.
R21, R22, R23, and R24 are each independently ΠΗ, halogen, -OH, or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6alkoxy, CrC6 haloalkoxy, CrCeaminoalkoxy, C^Cg cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.
Qzis independently a bond, ΠΟΊ, DSO, ONREI, nC(O)O, -C(=NR)-, DCOzO, □ OC(O)n, nC(O)NRn, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, □NRC(O)OI □ NRC(O)NR0, □NRCO23, OOC(O)NRD, -S(O)-, nS02DO nN(R)SO2U, aSOzNR'-, -NRSO2NR’-, or -(CR6R7)paY1a. Altematively Q2is independently OOa,anC02n, □OC(O)D, aC(O)NRn, ONRCCOJO, DNRC(O)NR0, nNRCO2a, □OC(O)NRn, -CO2SO2-, -P(O)2O-, or -(CR6R7)pOY1a. Altematively Qzis independently ΠΟΠ or □co2r.
In some embodiments, rings E and G (including G1-G5) are optionally and independently further substituted with one or more instances of JA (for carbocycle) or JB (for heterocycle), wherein each of JA and JB is independently selected from the group consisting of halogen,
-12516260 cyano, oxo, -NCO, and Q1-R5, and wherein:
Q1is îndependently a bond, DSO, DNRn, 00(0)0, -C(=NR)-, 000Ξ0, □ 00(0)0, DC(0)NRO, -C(0)NRC(0)0-, -NRC(O)NRC(O)O-, 0NRC(O)0r 3NRC(0)NR0, ONRCOzO, 0OC(O)NRD, -S(0)-, OSOzOD 0N(R)SO20, DSO2NR'-, -NRSO2NR'-, or-(CReR7)pOY1OD and Y1 is îndependently a bond, 000, OSO, ONR’O, 00(0)0, -C(=NR)-, OCOzO, 000(0)0, DC(O)NR'-, -C(0)NRC(0)0000-NRC(0)NRC(0)0-, UNRC(0)0, ONRC(O)NR’D, ONRC020, □OC(O)NR’D, -S(O)-, OS0200 -SO2NR’~, ONRSO2OO or-NRSO2NR’-.
Alternative^: Q1 is îndependently a bond, 000, OSO, DNRO, 00(0)0, 00020, 000(0)0, DC(O)NRn, -C(O)NRC(O)O-, -NRC(0)NRC(0)0-, 0NRC(O)0, □ NRC(0)NRO, 0NRCO20, 0OC(O)NR0, -S(0)-, 0SO200 ON(R)S020, OS02NR’-, -NRSO2NR'-, or -(CReR7)pOY1O; and Y1 is îndependently OOO, OC020, 000(0)0, □ C(O)NRO, 0NRC(O)3, □NRCiOJNRO, ONRCO2O, or 00C(O)NRO.
In yet another embodiment, Q1 and Y1 are each îndependently as described above in the preceeding paragraph, and:
R5 is îndependently i) -H; ii) a C^Ce-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1; and each of JC1 and JD1 is îndependently selected from the group consisting of halogen, cyano, oxo, Ra, □OR, nSRb, -S(O)Ra, OSO2Ra, nNHRc, FlC(O)Rb, nC(O)ORb, 30C(0)Rb, DNHCtOiR11, □C(O)NHRc, □NHC(O)NHRc, □NHC(O)ORb, QOCONHR0, -NHC(O)NHC(O)ORb, ClN(CH3)Rc, nN(CH3)C(O)Rb, □C(O)N(CH3)RC, □ N(CH3)C(O)NHRC, nN(CH3)C(O)ORb, nOCON(CH3)Rc, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(O)NHC(O)ORb, -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb.
In some spécifie embodiments, the compounds are represented by Structural Formula (IA) or (I), wherein:
R1 is -H.
R2 is -H, -CH3, -CH2OH, or -NH2. Specifically, R2 is -H, or -CH2OH.
R3 is -H, OF, 301, ClJt alkyl, or C14 haloalkyl. Alternative^, R3 is -H, OF, or OCI.
Z1 jS -H, —F, or-Cl.
Z2 is -H or CrCe alkyl optionally substituted with one or more substituents îndependently selected from the group consisting of halogen, cyano, hydroxy, and -O(C1-C4 alkyl).
-12616260
Z3 is -H or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and
-O(C,-C4 alkyl).
R5 is: i) -H; ii) an optionally substituted Ci-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), C,-C4 alkoxy, -ΝΡ0Ο(0,-04 alkyl), -CONR(CrC4 alkyl), -ΝΗ002(0,-04 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1; and wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C3-C4alkyl), αΝΗζ, ΠΝΗ(ΟιΠΟ4 alkyl), alkyl)2, -C(O)(CiC4 alkyl), -OC(O)(C,-C4 alkyl), -C(O)O(Ci-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and CrC4 alkoxy.
The remaining variables, including R4 that includes a spiro ring represented by rings E and F, or a bridged ring represented by rings G1-G5, are each and independently as described in any one of the preceeing four embodiments.
In yet another embodiment, the compounds are presented by Structural Formula (IA) or (I), wherein values of the variabels are each and independently as described in the preceeding embodiment, except:
Z2 is -H;
Z3 is -H;
R6 is independently: î) -H or ii) a Ci-C6-alkyI group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C1-C4 alkyl), ΠΝΗ2, □NH(C1DC4 alkyl), ΊΝ(0,ϊΐ04 alkyl)2, -0(0)(0,-04 alkyl), -00(0)(0,-0, alkyl), -C(O)O(C,-C4 alkyl),
-127E
-CO2H, C3-CB non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl;
wherein each of said alkyl groups referred to in the substituents of the CrC6-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NHiCpCi alkyl), -N(Ci-C4 alkyl)2, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, -002(0,-04 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the CrCe-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -0C0(Ci-C4 alkyl), -00(0,-04 alkyl), -CO2H, -002(0,-04 alkyl), and C1-C4 alkoxy.
In yet another embodiment, each of rings E, G1-G5 is independently and optionally substituted with onr or more substituents selected from the group consisting of halogen, cyano, hydroxy, 0,-06 alkyl, -NHZ, -NH(C,-C6 alkyl), -Ν(Ο,-Οβ alkyl)2, -0(0,.06 alkyl), -C(O)NHZ, -0(0)ΝΗ(0,-06 alkyl), -C(O)N(CrC6 alkyl)2, -CtOXCrCe-alkyl), -00(0)(0,-06 alkyl), -ΝΗ0(Ο)(0,-06 alkyl), -Ν(0,-06 alkyî)C(O)(Ci-C6 alkyl), and -C02Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, each of rings E, G1-G5 is independently and optionally substituted with onr or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)z, -OCO(Ci-C4 alkyl), -CO(Cj-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), C1-C4 alkoxy, and C1-C4alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(0^04 alkyl).
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein:
Ring A is a non-aromatic, 5-10 membered, bridged carbocylce or heterocycle, or ring A and Re optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic,
-12816260
5-10 membered, bridged carbocycle or heterocycle, wherein each of said carbocycle is independently and optionally substituted with one or more instances of JA and wherein each carbocycle is independently and optionally substituted with one or more instances of JB.
R1 is -H.
R2 is -H, -CH3, -CH2OH, or -NH2. Specifically, R2 is -H, or -CH2OH.
R3 is -H, DF, OCI, C1.4 alkyl (e.g., -CH3 or -C2HS), or C1Jt haloalkyl (e.g., -CF3). Alternative^, R3 is -H, OF, or OCI.
Z1 is -H, -F, or -Cl.
Z2 is -H or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(0,-0/, alkyl).
Z3 is -H or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(C,-C4 alkyl).
Q2 is independently ΠΟΟ, 0CO2O, 000(0)1, nC(O)NR'n, -C (O) N R 0(0) O-, □ NRC(O)O, □NRC(0)NR'a, 0NRCO2O, -OC(O)NR'O, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(O)ZO-, -CO2SOZ-, or -(CR6R7)POY1O.
Y1 is Π01, 0CO20, 100(0)0, 0C(0)NRO, -C (O) N RC (0)0-, ON RC (0)0, □ NRC(0)NR’0, □NRCO20, -OC(O)NR'O, -P(O)(OR)O-, -0P(0)(0Ra)0-, -P(0)20-, or -C02S02-.
R5 is: i) -H; ii) an optionally substituted C,-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH21 -NH(CrC4 alkyl), -N(C,-C4 alkyl)?, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), C,-C4 alkoxy, -NRCO(Ci-C4 alkyl), -0ΟΝΡ(0,-04 alkyl), -NRCO2(Ci-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1;
wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo,
-12916260
C,-C4 alkyl, -0(0,-04 alkyl), DNH^ αΝΗ(Ο,αθ4 alkyl), ΟΝ^,α^ alkyl)2, -C(O)(C,C4 alkyl), -OC(O)(C,-C4 alkyl), -C(O)O(C,-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy,
Each of R8 and R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C,-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C,—C4alkyl), QNH2, αΝΗ(0ιΠ04 alkyl), or DNiC-iQ^ alkyl)2.
R11, R12, R13, and R14 are each independently ΠΗ, halogen, or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and C,-C6 alkoxy.
Each of JA and JB is independently selected from the group consisting of halogen, cyano, hydroxy, C,-Cs alkyl, -NHZ, -NH(C,-C6 alkyl), -N(CrC6 alkyl)2, -0(0,.06 alkyl), -C(O)NH2, -C(O)NH(C,-C6 alkyl), -C(O)N(C,-C6 alkyl)2, -C(O)(Ci-C6-alkyl), OC(O)(C4-C6 alkyl), -NHC(O)(C,-C6 alkyl), -N(C,-C6 alkyl)C(O)(C,-C6 alkyl), and -CO2Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. n is 0 or 1.
x is 0 or 1.
The remaining variables are each and independently as described above in any set of variables for Structural Formulae (IA) and (I).
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein:
Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring
-13016260
G5 is a 5-10 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB.
X is -O-, -S-, or -NR9-.
R21, R22, R23, R24, and R25 are each independently DH, halogen, -OH, C,-C6 alkoxy, or C,-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, CrC6 alkyl, -NH2, NH(CrC6 alkyl), -N(C,-C6 alkyl)2, -0(0,.06 alkyl), -C(O)NH2, -C(O)NH(C,-Ce alkyl), C(O)N(C,-C6 alkyl)2, -CiOXCrCe-alkyl), -00(0)(0,-06 alkyl), -NHC(O)(C,-C6 alkyl), -N(C,-C6 alkyl)C(O)(C,-Cs alkyl).
R9 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, C,-C6alkoxy, C,-Ce haloalkoxy, C,-Ceaminoalkoxy, C,-C6 cyanoalkoxy, C,-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.
q is 0, 1 or 2.
r is 1 or 2.
The remaining variables are each and independently as described above in the preceeding paragraph.
In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein the variables are each and independently as described above in the preceeding paragraph except those described below:
R1 is -H.
R2 is -H.
R3 is -H, DF, ΠΟΙ, C,.4 alkyl, or C,^ haloalkyl. Alternative^, R3 is -H, DF, or OCI.
Z1 is-H, -F, or-Cl.
Z2 is -H.
Z3 is -H.
X is -0-.
R5 is -H, an optionally substituted C,-C6 alkyl, or optionally substituted phenyl.
Each Ra is independently -H, halogen, hydroxy, C,-C4 alkyl, C,-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or-O(C,-C4 alkyl).
Each of R9, R13, and R14is independently -H or C1-C4 alkyl.
R21, R22, R23, R24, and R26are each independently QH, halogen, -OH, C,-Cealkoxy, or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C-i-C6 alkyl, and -O(C,.Ce alkyl). Specifically R21, R22, R23, R24, and R25 are each independently -H, C,.6 alkyl, or Ci.e haloalkyl.
-13116260
Each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, NH(CrCs alkyl), -NfCrCe alkyl)2, -O(Ci.C6 alkyl), CrC4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and CrC4 alkoxy.
In yet another embodiment, the compounds are represented by any one of Structural Formulae l-VI (hereinafter reference to Structural Formulae l-VI includes Structural Formulae I, IA, II, III, IV, V, VI) and XI(A)-XIV (hereinafter reference to Structural Formulae XI(A)-XIV includes Structural Formulae ΧΙΑ, XIB, XIIA, XIIB, XIII, and XIV), wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, except that R3 is C^e alkyl, such as methyl or ethyl.
In yet another embodiment, the compounds are represented by any one of Structural Formulae l-VI and XI(A)-XIV, wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, except that x is 0. In yet another embodiment, the compounds are represented by any one of Structural Formulae I, IA, II, VI, XI(A), and XI(B), wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, except that ring A is bridged.
In yet another embodiment, the compounds are represented by any one of Structural Formulae I, IA, II, VI, XI(A), and XI(B), wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, except that Q2îs independently -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, nCO2TI, ΊΟΟ(0)Π, nC(O)NRn, -C( O) N RC (0)0-, -NRC(O)NRC(O)O-, □NRC(O)n, □NRCÎOJNRCJ, □ NRCO2a, nOC(O)NR0, -S(O)-, DSO2aa aNfRjSOza, nSOzN(R)-, -NRSOzNR-, -P(0)(OR)0-, -OP(O)(ORa)O-, -P(O)2O-, -CO2SO2-, or -(CR6R7)pDY1an or alternative^, Q2 is independently aCO2n, nOC(O)a, DCÎOJNRD, -C(O)NRC(O)O-, -NRC(0)NRC(O)O-, :NRC(O)n, nNRC(O)NRQ, nNRCO2n, nOC(O)NRn, -S(O)-, DSOzGn nN(R)SO2O, iSOzN(R)-, -NRSO2NR-, -P(O)(OR)O-, -0P(O)(0Ra)O-, -P(0)20-, -CO2SO2-, or
-(CR^pnY’nnnn
In yet another embodiment, the compounds are represented by any one of Structural Formulae l-VI and XI(A)-XIV, wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, provided that when Q2 is -O- or -NR-, then ring A is further substituted with JA other than -H; and provided that if Q3 is -C(O)-, then R5 is a substituted Ch-Ce aliphatic group; an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group. In a spécifie embodiment, when Q2 is -O- or -NR-, then ring A is further substituted with JA other than -H at the geminal position to -Q2R5.
-13216260
In yet another embodiment, the présent invention is directed to any one of the compounds depicted in FIGs. 3-5, or pharmaceutically acceptable salts thereof.
In yet another embodiment, the présent invention is directed to any one of the compounds depicted in FIG. 6, or pharmaceutically acceptable salts thereof. In yet another embodiment, the présent invention is directed to any one of the compounds depicted in FIG.
7, or pharmaceutically acceptable salts thereof. In yet another embodiment, the présent invention is directed to any one of the compounds depicted in FIG. 8, or pharmaceutically acceptable salts thereof.
In some embodiments, the variables of Structural Formulae l-VI and XI(A)-XIV are each and independently as depicted in the compounds of FIGs. 3-8.
Each and independently as described above for the methods of the invention, the aforementioned compounds of the invention can be useful as inhibitors of influenza virus réplication in biological samples or in a patient. These compounds can also be useful in reducing the amount of influenza viruses (viral titer) in a biological sample or in a patient. They can also be useful for therapeutic and prophylactic treatment of infections caused by the influenza viruses in a biological sample or in a patient.
The présent invention also provides methods of preparing a compound of the invention. In one embodiment, the methods are directed to préparé compounds represented by Structural
Formula (IA) or pharmaceutically acceptable salts thereof. The methods comprise a step of reacting reacting compound A:
ci
H N- 4
R4 (A) with compound B :
a compound represented by Structural Formula (XX), as shown in Scheme A below:
Scheme A
The variables of Structural Formulae (IA) and (XX), and compounds (A) and (B) are independently as defined in any one of the embodiments described above. Ts is tosyl. Any suitable reaction condition known in the art, for example, in WO 2005/095400 and WO 2007/084557 for the coupling of a dioxaboraolan with a chloro-pyrimidine can be employed for the reaction between compound (A) and (B). For example, the reaction between compound (A) and (B) can be performed in the presence of Pd(PPh3)4. Spécifie exemplary conditions are described in the Exemplification below (e.g., General Schemes 5A, 6A, 7,11, -13316260
14, 16, 31, 32, 33, 40, 44, 49, 51, 52, 58, 60, 61,62, 63, 64, 66, 67, 68, 69, 70, 76).
In another embodiment, the methods comprise a step of reacting reacting compound C1 or
C2 with NH2R4 to form a compound represented by Structural Formula (XX), as shown in
Scheme B below:
The variables of Structural Formulae (IA) and (XX), compounds (C1) and (C2), and R4 of NH2R4 are independently as defined in any one of the embodiments described above. Ts is tosyl. Any suitable reaction condition known in the art, for example, in WO 2005/095400 and WO 2007/084557 for the coupling of an amine with a sulfinyl group can be employed for the reaction of compounds (C1) and (C2) with NH2R4. Spécifie exemplary conditions are described in the Exemplification below (e.g., General Schemes 13,15, 19, 20, 23, 30, 39, 41, 42, 44, 45, 50, 53, 54, 65, 72, 73, 74, and 77).
The methods described above with reference to Schemes A and B optionally and independently further comprises deprotecting the Ts group of the compound of Structural Formula (XX) to form the compound of Structural Formula (IA). Any suitable condition for deprotecting a Ts group known in the art can be employed in the invention. Spécifie exemplary conditions are described in the Exemplification below. The de-tosylation can generate the compounds of Structural Formula (IA) where R1 is -H. If desired, the R1 position can be alkylated by any suitable method known in the art to from the compounds of Structural Formula (IA) where R1 is alkyl.
Compounds (A), (B), (C1), (C2), and NH2R4 can be prepared by any suitable method known in the art. Spécifie exemplary synthethic methods are described below in the Exemplification below. For example, compound (C1) can be prepared as described in Scheme C: reaction between compounds (D) and (E), for example, in the presence of Pd(PPh3)4 can produce compound (F). Compound (F) can then be oxidated under suitable conditions, for example, by treatment with meta-chloroperbenzoic acid to form compound -13416260 (C). (See, for example, detailed experimental details described in the Exemplification for
General Scheme 44.)
Scheme C
Définitions and General Terminology
For purposes of this invention, the chemical éléments are identified in accordance with the Periodic Table of the Eléments, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general princîples of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausolito: 1999, and “March’s Advanced Organic Chemistry, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term substituted, whether preceded by the term optionally or not, refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may hâve a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. When the term “optionally substituted précédés a list, said term refers to ali of the subséquent substitutable groups in that list. If a substituent radical or structure is not identified or defîned as “optionally substituted, the substituent radical or structure is unsubstituted. For example, if X is optionally substituted C^Cjalkyl or phenyl; X may be either optionally substituted CrC3 alkyl or optionally substituted phenyl. Likewise, if the term “optionally substituted” follows a list, said term also refers to ail of the substitutable groups in the prior list unless otherwise indicated. For example: if X is C^Cgalkyl or phenyl wherein X is optionally and independently substituted by Jx, then both C-|.C3alkyl and phenyl may be optionally substituted by Jx. As is apparent to one having ordinary skill in the art, groups such as H, halogen, NO2, CN, NH2, OH, or OCF3 would not be substitutable groups.
The phrase up to, as used herein, refers to zéro or any integer number that is equal or less
-13516260 than the number following the phrase. For example, up to 3 means any one of 0,1,2, and
3. As described herein, a specified number range of atoms includes any integertherein. For example, a group having from 1 -4 atoms could hâve 1, 2, 3, or 4 atoms.
Sélection of substituents and combinations of substituents envisioned by this invention are those that resuit in the formation of stable or chemically feasible compounds. The terrn “stable, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, détection, and, specifically, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a température of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. Only those choices and combinations of substituents that resuit in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined wîthout undue expérimentation.
The terrn aliphatic’’ or aliphatic group, as used herein, means a straight-chain (i.e., unbranched), or branched, hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation but is non-aromatic. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Spécifie examples include, but are not limited to, methyl, ethyl, isopropyl, npropyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl and acetylene.
The terrn alkyl as used herein means a saturated straight or branched chain hydrocarbon. The terrn “alkenyl as used herein means a straight or branched chain hydrocarbon comprising one or more double bonds. The terrn alkynyl” as used herein means a straight or branched chain hydrocarbon comprising one or more triple bonds. Each of the alkyl”, alkenyl” or “alkynyl as used herein can be optionally substituted as set forth below. In some embodiments, the “alkyl” is CrCg alkyl or CrC4 alkyl. In some embodiments, the “alkenyl is C2-C6 alkenyl or C2-C4 alkenyl. In some embodiments, the alkynyl” is C2-C6 alkynyl or C2-C4 alkynyl.
The terrn cycloaliphatic (or “carbocycle or “carbocyclyl” or “carbocyclic) refers to a nonaromatic carbon only containing ring System which can be saturated or contains one or more units of unsaturation, having three to fourteen ring carbon atoms. In some embodiments, the number of carbon atoms is 3 to 10. In other embodiments, the number of carbon atoms is 4 to 7. In yet other embodiments, the number of carbon atoms is 5 or 6. The terrn includes monocyclic, bicyclic or polycyclic, fused, spiro or bridged carbocyclic ring
-13616260
Systems. The term also includes polycyclic ring Systems in which the carbocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the carbocyclic ring. “Fused” bicyclic ring Systems comprise two rings which share two adjoining ring atoms. Bridged bicyclic group comprise two rings which share three or four adjacent ring atoms. Spiro bicyclic ring Systems share one ring atom. Examples of cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Spécifie examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl. The term heterocycle (or heterocyclyl”, or heterocyclic” or non-aromatic heterocycle) as used herein refers to a non-aromatic ring system which can be saturated or contain one or more units of unsaturation, having three to fourteen ring atoms in which one or more ring carbons is replaced by a heteroatom such as, N, S, or O and each ring in the system contains 3 to 7 members. ln some embodiments, non-aromatic heterocyclic rings comprise up to three heteroatoms selected from N, S and O within the ring. In other embodiments, non-aromatic heterocyclic rings comprise up to two heteroatoms selected from N, S and O within the ring system. ln yet other embodiments, non-aromatic heterocyclic rings comprise up to two heteroatoms selected from N and O within the ring system. The term includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring Systems. The term also includes polycyclic ring Systems in which the heterocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the heterocyclic ring. Examples of heterocycles include, but are not limited to, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl, morpholino, including, for example, 3morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1 -pyrazolinyl, 3-pyrazolinyl,
4- pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
5- imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl, benzodithianyl, 3-(1 -alkyl)-benzimidazol-2-onyl, and 1,3-dihydro-imidazol-2-onyl.
The term aryl” (or “aryl ring or “aryl group) used alone or as part of a larger moiety as in “aralkyl, aralkoxy”, aryloxyalkyl”, or “heteroaryl refers to both carbocyclic or heterocyclic aromatic ring Systems. The term aryl” may be used interchangeably with the terms aryl ring or “aryl group.
“Carbocyclic aromatic ring” groups hâve only carbon ring atoms (typicalîy six to fourteen)
-13716260 and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring Systems in which two or more carbocyclic aromatic rings are fused to one another. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term “carbocyclic aromatic ring” or “carbocyclic aromatic”, as it is used herein, is a group in which an aromatic ring is “fused to one or more non-aromatic rings (carbocyclic or heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
The terms “heteroaryl”, “heteroaromatic, “heteroaryl ring, “heteroaryl group, “aromatic heterocycle or heteroaromatic group, used aione or as part of a larger moiety as in “heteroaralkyl” or heteroarylalkoxy, refer to heteroaromatic ring groups having five to fourteen members, including monocyclic heteroaromatic rings and polycyclic aromatic rings in which a monocyclic aromatic ring is fused to one or more other aromatic ring. Heteroaryl groups hâve one or more ring heteroatoms. Also included within the scope of the term “heteroaryl”, as it is used herein, is a group in which an aromatic ring is “fused” to one or more non-aromatic rings (carbocyclic or heterocyclic), where the radical or point of attachment is on the aromatic ring. Bîcyclic 6,5 heteroaromatic ring, as used herein, for example, îs a six membered heteroaromatic ring fused to a second five membered ring, wherein the radical or point of attachment is on the six membered ring. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyi or thiadiazolyl including, for example, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, benzisoxazolyl, isothiazolyi, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
As used herein, cyclo”, cyclic, “cyclic group” or “cyclic moiety”, include mono-, bi-, and tricyclic ring Systems including cycloaliphatic, heterocycloaliphatic, carbocyclic aryl, or heteroaryl, each of which has been previously defined.
As used herein, a “bîcyclic ring system includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings hâve at least one atom in common (e.g., 2 atoms in common). Bîcyclic ring Systems include bicycloaliphatics (e.g., bicycloalkyl
-13816260 or bicycloalkenyl), bîcycloheteroaliphatics, bicyclic carbocyclic aryls, and bicyclic heteroaryls.
As used herein, a bridged bicyclic ring System” refers to a bicyclic heterocycloalipahtic ring System or bicyclic cycloaliphatic ring System in which the rings are bridged. Examples of bridged bicyclic ring Systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1 Joctyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1 Joctyl, and2,6-dioxatricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring System can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, carbocyclic aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, (carbocyclic aryl)oxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, (carbocyclic aryljcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
As used herein, bridge” refers to a bond or an atom or an unbranched chain of atoms connecting two different parts of a molécule. The two atoms that are connected through the bridge (usually but not always, two tertiary carbon atoms) are denotated as “bridgeheads”. As used herein, the term spiro” refers to ring Systems having one atom (usually a quaternary carbon) as the only common atom between two rings.
The term “ring atom is an atom such as C, N, O or S that is in the ring of an aromatic group, cycloalkyl group or non-aromatic heterocyclic ring.
A “substitutable ring atom” in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. Thus, the term “substitutable ring atom does not include ring nitrogen or carbon atoms which are shared when two rings are fused. In addition, substitutable ring atom” does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to a moiety other than hydrogen.
The term heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).
As used herein an optionally substituted aralkyl can be substituted on both the alkyl and the aryl portion. Unless otherwise indicated as used herein optionally substituted aralkyl is
-13916260 optionally substituted on the aryl portion.
In some embodiments, an aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above, for example, in the définitions of JA, JB, JC1, JD1, and JE1. Other suitable substitutents include those listed as suitable for the unsaturated carbon of a carbocyclic aryl or heteroaryl group and additionally include the following: =0, =S, =NNHR', =NN(R’)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*. wherein each R‘ is independently t
selected from hydrogen or an optionally substituted Ci.6 aliphatic. Optional substituents on the aliphatic group of R* are selected from NH2, NH(C-t.4 aliphatic), N(Cv4 aliphatic)2, halogen, C14 aliphatic, OH, 0(04.4 aliphatic), NO2] CN, CO2H, CO2(Ci.4 aliphatic), O(halo C4. 4 aliphatic), or halofCi^ aliphatic), wherein each of the foregoing Cn^aliphatic groups of R* is unsubstituted.
In some embodiments, optional substituents on the nitrogen of a non-aromatic heterocyclic ring include those used above, for example, in the définitions of JB, J01 and JE1. Other suitable substituents include -R+, -N(R+)2, -C(O)R+, -CO2R\ -C(0)C(O)R+, -C(O)CH2C(0)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2, or -NR+SO2R+; wherein R+ is hydrogen, an optionally substituted C^e aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CH2(Ph), optionally substituted -(CH2)4.2(Ph); optionally substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, two independent occurrences of R+, on the same substituent or different substituents, taken together with the atom(s) to which each R+ group is bound, form a 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R+ are selected from NH2, NH(CV4 aliphatic), N(Ci.4 aliphatic)2, halogen, CM aliphatic, OH, 0(0,.4 aliphatic), NO2, CN, CO2H, CO2(ClJt aliphatic), O(halo CM aliphatic), or halofC^ aliphatic), wherein each of the foregoing Ci_4aliphatic groups of R+ is unsubstituted.
In some embodiments, a carbocyclic aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of a carbocyclic aryl or heteroaryl group are selected from those listed above, for example, in the définitions of JA, JB, JC1, JD1 and JE1. Other suitable substituents include: halogen; -R°; -OR°; -SR°; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R°; -O(Ph) optionally substituted with R°; -(CH2)i.2(Ph), optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°; -NO2; -CN; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; NR°C(O)N(R°)2; -NR°C(S)N(Ro)2; -NR°CO2R°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2; -14016260
NR°NR°CO2R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -CO2Ro; -C(O)R°; -C(S)R°; -C(O)N(R°)2; -C(S)N(Ro)2; -OC(O)N(R°)2; -OC(O)R°; -C(O)N(OR°) R°; -C(NOR°) R°; -S(O)2Ro; -S(O)3R°; -S02N(Ro)2; -S(O)R°; -NR°SO2N(R°)2; -NR°SO2R°; -N(OR°)R°; -C(=NH)-N(R°)2; or -(CH2)o.îNHC(0)R°; wherein each independent occurrence of R° is selected from hydrogen, optionally substituted Ci_6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph), or, two independent occurrences of R°, on the same substituent or different substituents, taken together with the atom(s) to which each R° group is bound, form a 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group of R° are selected from NH2, NH(CMaliphatic), N(C1.4aliphatic)2, halogen, Ci_4aliphatic, OH, O(CMaliphatic), NO2, CN, CO2H, CO2(Ci.4aliphatic), O(haloC,.4 aliphatic), or haloC1.4aliphatic, CHO, N(CO)(CM aliphatic), C(O)N(Ci.4 aliphatic), wherein each of theforegoing CMaliphatic groups of R° is unsubstituted.
Non-aromatic nitrogen containing heterocyclic rings that are substituted on a ring nitrogen and attached to the remainder of the molécule at a ring carbon atom are said to be N substituted. For example, an N alkyl pîperidinyI group is attached to the remainder of the molécule at the two, three or four position of the piperidinyl ring and substituted at the ring nitrogen with an alkyl group. Non-aromatic nitrogen containing heterocyclic rings such as pyrazinyl that are substituted on a ring nitrogen and attached to the remainder of the molécule at a second ring nitrogen atom are said to be N’ substituted-N-heterocycles. For example, an N' acyl N-pyrazinyl group is attached to the remainder of the molécule at one ring nitrogen atom and substituted at the second ring nitrogen atom with an acyl group. The term unsaturated, as used herein, means that a moiety has one or more units of unsaturation.
As detailed above, in some embodiments, two independent occurrences of R° (or R+, or any other variable similarly defined herein), may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring. Exemplary rings that are formed when two independent occurrences of R° (or R+, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R*, or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°)2, where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-1 -yl, piperazin-1 -yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R+, or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for
-14116260 example where a phenyl group is substituted with two occurrences of OR0
these two occurrences of R° are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring:
It will be appreciated that a variety of other rings can be formed when two independent occurrences of R° (or R+, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting.
In some embodiments, an alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain is optionally replaced with said other atom or group. Examples of such atoms or groups would include, but are not limited to those listed in the définitions of Q1, Y1, Q2 and Q3. Further examples include -NR-, -O-, -S-, -CO2-, -OC(O)-, -C(O)CO-, -C(O)-, -C(O)NR-, -C(=N-CN)-,
-NRCO-, -NRC(O)O-, -SO2NR-, -NRSO2-, -NRC(O)NR-, -OC(O)NR-, -NRSO2NR-,
-SO-, or —SO2—, wherein R is as defined above.
As used herein, an '‘amino group refers to -NRXRY wherein each of Rx and RY is independently -H, CrC6 aliphatic, a C3.7 non-aromatic carbocycle, a 5-6 membered carbocyclic aryl or heteroaryl, or a 4-7 membered non-aromatic heterocycle, each of which independently being defined herein and being optionally substituted. Suitable substituents for the carbocycle, carbocyclic aryl, heteroaryl, and heterocycl are each independently include halogen, cyano, hydroxy, oxo, -NH2, -NHtCh-Ce alkyl), -N(CrC6 alkyl)2, CrC6alkyl, -O(Ci-C6 alkyl), -C(O)OH, -C(O)O(CrC6 alkyl), -00(0)(0,-06 alkyl), -NHC(O)(C,-C6 alkyl), -NHC(O)O(C,-C6 alkyl), -C(O)NH(C,-C6 alkyl), and -C(O)N(C,-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), and -N(C,-C4 alkyl)z, -OCO(C,-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy. Suitable substituents for the C,-Ce aliphatic (including C,-C6 alkyl) include halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-Ce alkyl), -N(Ci-C6 alkyl)2, -O(Ci-C6 alkyl), -C(O)OH, -C(O)O(C,-C6 alkyl), -OC(O)(C,-C6 alkyl), -NHC(O)(C,-C6 alkyl), -NHC(0)0(C,-C6 alkyl), -C(O)NH(C,-Ce alkyl), -C(O)N(C,-Ce alkyl)2, phenyl, a 5-6 membered heteroaryl, a 5-6 membered non-aromatic heterocycle, and a C3-C7 carbocycle, wherein each of said alkyl groups is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -00(0^^ alkyl), -C02H, -CO2(Ci-C4 alkyl), and CrC4 alkoxy, and wherein each of said phenyl, heteroaryl, heterocycle and carbocycle is optionally and independently substituted with one or more substitutents described above for the
-I4216260 carbocycle, carbocyclic aryl, heteroaryl, and heterocycle represented by Rx and RY. In some embodiments, each of Rx and RY is independently -H, an optionally substituted aliphatic group, or an optionally substituted C3.8 non-aromatic carbocycle. In some embodiments, each of Rx and RY is independently -H or an optionally substituted Cve aliphatic group. In some embodiments, each of Rx and RY is independently -H or alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -NÎC^Cî alkyl)2, -OCO(CrC4 alkyl), -COfCrCi alkyl), -CO2H, -CO2(C-|-C4 alkyl), and Οι-Ο4 alkoxy. Examples of amino groups include -NH2, aliphatic amino, alkylamino, dialkylamino, or arylamino. As used herein, an “aliphatic amino group refers to -NRXRY wherein Rx is a Ον6 aliphatic group optionally substituted as described above; and RY is -H or a C1j6 aliphatic group optionally substituted as described above. As used herein, an ‘‘alkylamino” group refers to -NHRX wherein Rx is a 0,.6 alkyl group optionally substituted as described above. As used herein, a dialkylamino group refers to -NRXRY wherein each of Rx and RYis independently a alkyl group optionally substituted as described above. As used herein, an “arylamino” group refers to -NRXRY wherein Rx is 5-6 membered, carbocyclic aryl or heteroaryl, and RY is -H or 5-6 membered, carbocyclic aryl or heteroaryl, wherein each of said carbocyclic aryl and heteroaryl groups is independently and optionally substituted as described above. When the term “amino” is not the terminal group (e.g., alkylcarbonylamino), it is represented by NRX-, Rx has the same meaning as defined above. In one embodiment, the amino group is -NH2 or an aliphatic amino. In another embodiment, the amino group is -NH2, alkylamino or dialkylamino. In yet another embodiment, the amino group is -NH2 or an arylamino. In yet another embodiment, the amino group is -NH2, -NHfCrCe alkyl) or -N(CrC6 alkyl)2, wherein each of the alkyl groups is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NHÎCtCî alkyl), -N(CrC4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO/C,^ alkyl), and CrC4 alkoxy.
As used herein, an “amido” encompasses both “aminocarbonyl and “carbonylamino”. These terms when used alone or in connection with another group refer to an amido group such as N(RXRY)-C(O)- or RYC(O)-N(RX)- when used terminally and -C(O)-N(RX)- or -N(RX)C(O)- when used internally, wherein Rx and RY are defined above. Examples of amido groups include alkylamido (such as alkylcarbonylamino or alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido. In some embodiments, the amido group is -NHC(O)(Ci-C6 alkyl), -N(Cr C6 alkylJCiOXCrCe alkyl), -C(O)NH2, -CiOJNHiCrCe alkyl), or -C(O)NH(CrCe alkyl)2, wherein each of said alkyl is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2,
-14316260
-NHfCrCe alkyl), -Ni^-Ce alkyl)2, -000(0,-04 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(CrCA alkyl), and Ci-C4 alkoxy. In some embodiments, the amido group is -NHC(O)(CrC6 alkyl), N(Ci-C6 alkyOCiOXCrCe alkyl), -C(O)NH2, -C(O)NH(CrC6 alkyl), or -C(O)NH(CrC6 alkyl)2, wherein each of the alkyl groups is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C6 alkyl), -N(CrCe alkyl)2, -OCO(CrC4 alkyl), -00(0,-04 alkyl), -CO2H, -ΟΟ2(Ο,-Ο4 alkyl), and C1-C4 alkoxy.
As used herein, a urea group refers to the structure -NRX-CO-NRYRZ and a “thiourea group refers to the structure -NRX-CS-NRYRZ when used terminally and -NRX-CO-NRY- or NRX-CS-NRY- when used internally, wherein Rx, RY, and Rz are each independently as defined above.
As used herein, an acyl group refers to a formyl group or RX-C(O)- (such as -alkyl-C(O)-, also referred to as alkylcarbonyl) where Rx and '‘alkyl hâve been defined previously. Acetyl and pivaloyl are examples of acyl groups.
As used herein, a “carboxy group refers to -COOH, -COORX, -OC(O)H, -OC(O)RX when used as a terminal group; or -OC(O)- or -0(0)0- when used as an internai group, wherein Rx is as defined above.
The term “hydroxyPor “hydroxy or “alcohol moiety refers to -OH.
As used herein, an alkoxycarbonyl, which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as (alkyl-O)-C(O)-. As used herein, a “carbonyl” refers to -C(O)-.
As used herein, an “oxo refers to =0.
As used herein, the term “alkoxy, or “alkylthio, as used herein, refers to an alkyl group, as previously defined, attached to the molécule through an oxygen (“alkoxy” e.g., —0—alkyl) or sulfur (“alkylthio” e.g., -S-alkyl) atom.
As used herein, the terms halogen, “halo”, and “hal” mean F, Cl, Br, or I.
As used herein, the term “cyano or “nitrile refer to -CN or -CsN.
The terms alkoxyalkyl”, “alkoxyalkenyl, '‘alkoxyaliphatic’’, and “alkoxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups. The terms haloalkyl, “haloalkenyl”, haloaliphatic, and “haloalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms. This term includes perfluorinated alkyl groups, such as -CF3 and -CF2CF3.
The terms “cyanoalkyl”, “cyanoalkenyl, “cyanoaliphatic, and “cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups. In some embodiments, the cyanoalkyl is (NC)-alkyl-.
The terms aminoalkyl, aminoalkenyl, “aminoaliphatic, and “aminoalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups, wherein the amino group is as defined above. In some embodiments, the aminoaliphatic is
-14416260 a C1-C6 aliphatic group substituted with one or more -NH2 groups. In some embodiments, the aminoalkyl refers to the structure (RxRY)N-alkyl-, wherein each of Rxand RY independently is as defîned above. In some spécifie embodiments, the aminoalkyl is C1-C6 alkyl substituted with one or more -NH2 groups. In some spécifie embodiments, the aminoalkenyl is C1-C6 alkenyl substituted with one or more -NH2 groups. In some embodiments, the aminoalkoxy is -O(C1-C6 alkyl) wherein the alkyl group is substituted with one or more -NH2 groups.
The terms “hydroxyalkyl, “hydroxyaliphatic”, and ‘'hydroxyalkoxy mean alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups.
The terms alkoxyalkyl’’, alkoxyaliphatic”, and “alkoxyalkoxy mean alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups. For example, an “alkoxyalkyl refers to an alkyl group such as (alkyl-O)-alkyl-, wherein alkyl is as defîned above.
The term “carboxyalkyl means alkyl substituted with one or more carboxy groups, wherein alkyl and carboxy are as defîned above.
in some embodiments, each of the amino groups referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g., R6, R7, JE1, R, R’, R”, R*, Ra, Rb and Rc) above is independently -NH2, -NH(Ci-C6 alkyl), -NH(C3-CB carbocylce), -N(C!-C6 alkyl)2, or-N(CrC6 alkyl)(C3-CB carbocycle), wherein said alkyl and carbocycle groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH^-Cî alkyl), -N(CrC4 alkyl)2, -000(0,-04 alkyl), -00(0,-0, alkyl), -CO2H, -CO2(CrC4 alkyl), and 0,-0, alkoxy; each of the carboxy groups referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g., R6, R7, JE1, R, R’, R”, R*, Ra, Rb and Rc) above is independently -C(O)O(Ci-C6 alkyl), -00(0)(0,-06 alkyl), -C(O)O(C3-C6 carbocycle), -OC(O)(C3-C6 carbocycle), or -CO2H, wherein said alkyl and carbocylce groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C, alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; each of the amido groups referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g., R6, R7, JE1, R, R’, R, R*, Ra, Rb and Rc) above is independently -NHC(O)(C,-C6 alkyl), -N(C,-CB alkyl)C(O)(C,-C6 alkyl), -C(O)NH(C,-Ce alkyl), -C(O)N(C,-Ce alkyl)2, -NHC(O)(C3-Ce carbocycle), -N(C,-C6 alkyl)C(O)(C3-C6 carbocycle), -C(O)NH(C3-C6 carbocycle), -C(O)N(C,-CB alkyl)(C3-C6 carbocycle), or -C(O)NH2, wherein said alkyl and carbocycle groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -N(CrC4 alkyl)2, -0C0(CrC4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and Ci-C4 alkoxy; each of the aminoalkyl groups
-14516260 referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g,, Rs, R9, and R’’) above is independently a C1-C6 alkyl group substituted with one or more aminogroups independently selected from the group consisting of-NH2, -NH(C1-C4 alkyl), and -N(CrC4 alkyl)2; and each of the aminoalkoxy groups referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g,, R6, R7, R8, R9, R10, R11, R12, R13, R14, R, R', and R”) above is independently is a -O(C1-C6 alkyl) group wherein the alkyl group is substituted with one or more one or more aminogroups independently selected from the group consisting of-NH2, -NH(Ci-C4 alkyl), and -N(CrC4 alkyl)2.
In some embodiments, each of the amino groups referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g., R0, R7, JE1, R, R’, R, R*, Ra, Rb and Rc) above is independently -NH2, -NHîCtCb alkyl), ογ-Ν(Ο,-Ο6 alkyl)2, wherein said alkyl groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(CrC4 alkyl)2l -OCO(CrC4 alkyl), -00(0^ alkyl), -CO2H, -CO2(CrC4 alkyl), and CrC4 alkoxy; each of the carboxy groups referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g., R6, R7, JE1, R, R', R, R*, Ra, Rb and Rc) above is independently -0(0)0(0^ alkyl), -OC(O)(CrC6 alkyl), or -CO2H, wherein said alkyl groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -00(0^0^ alkyl), -CO2H, -002(0!-04 alkyl), and 0Ί-04 alkoxy; each of the amido groups referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g., R6, R7, JE1, R, R’, R”, R*, Ra, Rb and Rc) above is independently -NHC(O)(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(O)(Ci-C6 alkyl), -CtOJNHiCrCe alkyl), -CiOJNiCrCe alkyl)2, or -C(O)NH2, wherein said alkyl groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C!-C4 alkyl)2, -OCO(CrC4 alkyl), -C0(CrC4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and Ci-C4 alkoxy; each of the aminoalkyl groups referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g., Rs, R9, and R”) above is independently a C1-C6 alkyl group substituted with one or more aminogroups independently selected from the group consisting of -NH2, -NH(Ci-C4 alkyl), and -N(CtC4 alkyl)2; and each of the aminoalkoxy groups referred to in the descriptions for the variables of Structural Formulae l-VI and XI(A)-XIV (e.g., R6, R7, Ra, R9, R10, R11, R12, R13, R14, R, R’, and R) above is independently is a -O(C1-C6 alkyl) group wherein the alkyl group is substituted with one or more one or more aminogroups independently selected from the group consisting of -NH2, -NH(Ci-C4 alkyl), and -NtCrCi alkyl)2.
The terrn “protecting group and “protective group as used herein, are interchangeable and
-14616260 refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites. In certain embodiments, a protecting group has one or more, or specifically ail, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group, As would be understood by one skilled în the art, in some cases, the reagents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. Examples of protecting groups are detailed rn Greene, T. W., Wuts, P. G in “Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York; 1999 (and other éditions of the book), the entire contents of which are hereby incorporated by reference. The term “nitrogen protecting group”, as used herein, refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified for a protecting group above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
As used herein, the term “displaceable moiety or “leaving group” refers to a group that is associated with an aliphatic or aromatic group as defined herein and is subject to being displaced by nucleophilic attack by a nucleophile.
Unless otherwise indicated, structures depicted herein are also meant to include ail isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure. For example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention, unless only one of the isomers is drawn specifically. As would be understood to one skilled in the art, a substituent can freely rotate around any rotatable bonds. For example, a substituent drawn as also represents
Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, cis/trans, conformational, and rotational mixtures of the présent compounds are within the scope of the invention.
Unless otherwise indicated, ail tautomeric forms of the compounds of the invention are within the scope of the invention.
Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the présent structures except for the replacement
-14716260 of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14Cenriched carbon are within the scope of this invention. For example, compounds of Structural Formulae l-Vl (e.g., Structural Formulae I, IA, II, III, IV, V, and VI) and XI(A)-XIV (e.g., Structural Formulae ΧΙΑ, XIB, XIIA XIIB, XIII, and XIV) that hâve -D atthe position corresponding to R2 are also within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, especially deuterium analogs, can also be therapeutically useful.
The terms “a bond and “absent” are used interchangeably to indicate that a group is absent.
The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
Pharmaceutically Acceptable Salts, Solvatés, Chlatrates, Prodrugs and Other Dérivatives
The compounds described herein can exist in free form, or, where appropriate, as salts. Those salts that are pharmaceutically acceptable are of particular interest since they are useful in admînistering the compounds described below for medical purposes. Salts that are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some instances, for use in separating stereoisomeric forms of the compounds of the invention or intermediates thereof.
As used herein, the term pharmaceutically acceptable sait refers to salts of a compound which are, within the scope of sound medical judgment, suîtable for use in contact with the tissues of humans and lower animais without undue side effects, such as, toxicity, irritation, allergie response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et “ 1 al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suîtable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.
Where the compound described herein contains a basic group, or a sufficiently basic bioisostere, acid addition salts can be prepared by 1) reacting the purified compound in its free-base form with a suîtable organic or inorganic acid and 2) isolating the sait thus formed. In practice, acid addition salts might be a more convenient form for use and use of the sait amounts to use of the free basic form.
Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochlorîc acid, hydrobromic acid, phosphoric -14816260 acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycérophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmîtate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stéarate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Where the compound described herein contaîns a carboxy group or a sufficiently acidic bioisostere, base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the sait thus formed. In practice, use of the base addition sait might be more convenient and use of the sait form inherently amounts to use of the free acid form. Salts derived from appropriate bases include alkali métal (e.g., sodium, lithium, and potassium), alkaline earth métal (e.g., magnésium and calcium), ammonium and N+(CMalkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Basic addition salts include pharmaceutically acceptable métal and amine salts. Suitable métal salts include the sodium, potassium, calcium, barium, zinc, magnésium, and aluminium. The sodium and potassium salts are usually preferred. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Suitable inorganic base addition salts are prepared from métal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnésium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines which are frequently used in médicinal chemistry because of their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N’-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tétraméthylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tétraméthylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.
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Other acids and bases, while not in themselves pharmaceutically acceptable, may be employed in the préparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.
It should be understood that this invention includes mixtures/combinations of different pharmaceutically acceptable salts and also mixtures/combinations of compounds in free form and pharmaceutically acceptable salts.
In addition to the compounds described herein, pharmaceutically acceptable solvatés (e.g., hydrates) and clathrates of these compounds may also be employed in compositions to treat or prevent the herein identified disorders.
As used herein, the term “pharmaceutically acceptable solvaté, is a solvaté formed from the association of one or more pharmaceutically acceptable solvent molécules to one of the compounds described herein. The term solvaté includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
As used herein, the term “hydrate” means a compound described herein or a sait thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by noncovalent intermolecular forces.
As used herein, he term “clathrate means a compound described herein or a sait thereof in the form of a crystal lattice that contains spaces (e.g., channels) that hâve a guest molécule (e.g., a solvent or water) trapped within.
In addition to the compounds described herein, pharmaceutically acceptable dérivatives or prodrugs of these compounds may also be employed in compositions to treat or prevent the herein identified disorders.
A “pharmaceutically acceptable dérivative or prodrug includes any pharmaceutically acceptable ester, sait of an ester or other dérivative or sait thereof of a compound described herein which, upon administration to a récipient, is capable of providing, either directly or indirectly, a compound described herein or an inhibitorily active métabolite or residue thereof. Partîcularly favoured dérivatives or prodrugs are those that increase the bioavailability of the compounds when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic System) relative to the parent species.
As used herein and unless otherwise indicated, the term “prodrug means a dérivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound described herein. Prodrugs may become active upon such reaction under biological conditions, or they may hâve activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or dérivatives of compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates,
-15016260 biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include dérivatives of compounds described herein that comprise -NO, -NO2, -ONO, or-ON02 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed„ 5th ed).
A “pharmaceutically acceptable dérivative is an adduct or dérivative which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a métabolite or residue thereof. Examples of pharmaceutically acceptable dérivatives include, but are not limited to, esters and salts of such esters.
Pharmaceutically acceptable prodrugs ofthe compounds described herein include, without limitation, esters, amino acid esters, phosphate esters, métal salts and sulfonate esters.
Pharmaceutical Compositions
The compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the présent invention relates to a pharmaceutical composition comprising a compound of the invention described above, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the présent invention is a pharmaceutical composition comprising an effective amount of a compound ofthe présent invention or a pharmaceutically acceptable sait thereof and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
An “effective amount” includes a “therapeutically effective amount” and a prophylactically effective amount”. The term “therapeutically effective amount” refers to an amount effective in treating and/or ameliorating an influenza virus infection in a patient infected with influenza. The term “prophylactically effective amount refers to an amount effective in preventing and/or substantially lessening the chances or the size of influenza virus infection outbreak. Spécifie examples of effective amounts are described above in the section entitled Uses of Disclosed Compounds.
A pharmaceutically acceptable carrier may contain inert ingrédients which do not unduly inhibit the biological activîty of the compounds. The pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.
The pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, includes any and ail solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface -15116260 active agents, isotonie agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired, Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa,, 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the préparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. As used herein, the phrase “side effects encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcérations and érosions), nausea, vomiting, neurotoxicities, nephrotoxicities, rénal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated sérum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anémia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.
Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stéarate, lecithin, sérum proteins (such as human sérum albumin), buffer substances (such as twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloïdal silica, magnésium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylenepolyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its dérivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnésium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonie saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnésium stéarate, as well as
-15216260 coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be présent in the composition, according to the judgment of the formulator.
Administration Methods
The compounds and pharmaceutically acceptable compositions described above can be administered to humans and other animais orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable émulsions, microemulsions, solutions, suspensions, syrups and élixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable préparations, for example, stérile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The stérile injectable préparation may also be a stérile injectable solution, suspension or émulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringeris solution, U.S.P. and isotonie sodium chloride solution. In addition, stérile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the préparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterialretaining filter, or by incorporating sterilizing agents in the form of stérile solid compositions which can be dissolved or dispersed in stérile water or other stérile injectable medium prior to use.
In order to prolong the effect of a compound described herein, it is often désirable to slow the absorption of the compound from subeutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then dépends upon its rate of dissolution that, in turn, may dépend upon crystal size and crystalline form. Alternatively, -15316260 delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodégradable polymers such as polylactide-polyglycolide, Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodégradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
Compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the compounds described herein with suîtable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient température but liquid at body température and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stéarate, magnésium stéarate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or préféréntially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
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The active compounds can also be in microencapsulated form with one or more excipients as noted above, The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents/e.g., tableting lubricants and other tableting aids such a magnésium stéarate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or préféréntially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under stérile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the présent invention contemplâtes the use of transdermal patches, which hâve the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted réservoir. The term ''parentéral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, întralesional and intracranial injection or infusion techniques. Specifically, the compositions are administered orally, intraperitoneally or intravenously.
Stérile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The stérile injectable préparation may also be a stérile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonie sodium chloride solution. In addition, stérile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland
-15516260 fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride dérivatives are useful in the préparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a longchain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including émulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include, but are not limited to, lactose and corn starch. Lubricating agents, such as magnésium stéarate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingrédient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room température but liquid at rectal température and therefore will melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment contaîning the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds ofthis invention include, but are not limited to, minerai oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream contaîning the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, minerai oil, sorbitan monostearate,
-15616260 polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonie, pH adjusted stérile saline, or, specifically, as solutions in isotonie, pH adjusted stérile saline, either with orwithout a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions may also be administered by nasal aérosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavaîlability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The compounds for use in the methods of the invention can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrète units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.
EXEMPLIFICATION
Préparation of Compounds
The compounds disclosed herein, including those of Structural Formulae l-VI (e.g., Structural Formulae I, IA, II, III, IV, V, and VI) and XI(A)-XIV (e.g., Structural Formulae ΧΙΑ, XIB, XIIA, XIIB, XIII, and XIV) can be prepared by any suitble method known in the art, for example, WO 2005/095400 and WO 2007/084557. For example, the compounds depicted in FIGs. 3-8 can be prepared by any suitble method known in the art, for example, WO 2005/095400 and WO 2007/084557, and by the exemplary synthèses deserbied below. In particular, the compounds depicted in FIG. 8 can be prepared as described in WO 2005/095400 and WO 2007/084557. Synthèses of certain exemplary compounds of Structural Formulae l-VI and XI(A)XIV are described below. Generally, the compounds of Structural Formulae l-VI and XI(A)-XIV can be prepared as shown in those synthèses optionally with any desired appropriate modification.
General Analytical Methods.
As used herein the term RT (min) refers to the LCMS rétention time, in minutes, associated with the compound. Unless otherwise indicated, the method employed to obtain the reported rétention times is as follows:
-15716260
Column: YMC-Pack Pro Cig, 50 mm x 4.6 mm id
Gradient: 10-95 % methanol/H20. Flow rate: 1.5 ml/min. UV-vis détection.
Methodology for Synthesis and Characterization of Compounds
Synthèses of certain exemplary compounds of Structural Formulae l-VI (e.g., Structural Formulae I, IA, II, III, IV, V, and VI) and XI{A)-XIV (e.g., Structural Formulae ΧΙΑ, XIB, XIIA, XIIB, XIII, and XIV) are described below. NMR and Mass Spectroscopy data of certain spécifie compounds are summarized in Tables 1-5.
General Scheme 1
(S)-1-Boc-3-aminopiperidine, 'Pr2NEt, DMF, 90 °C; (b) TFA, CH2CI2 (c) 2(methoxymethyl)oxirane, EtOH, microwave, 140 °C (d) 1N LiOH, THF, microwave, 120 °C
Formation of (S)-tert-butyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-i>]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)piperidine-1-carboxylate (1b).
To a solution of 5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimidin-2-yl)-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (3.5 g, 7.5 mmol) and fert-butyl (3S)-3aminopiperidine-1-carboxylate (1.8 g, 9.0 mmol) in DMF (32 mL) was added diisopropylethylamine (2.6 mL, 15.1 mmol). The reaction mixture was heated at 90 °C for 75 minutes. The mixture was cooled to room temp and diluted into aqueous saturated NH4CI solution and extracted with EtOAc. The organic phase was washed with brine (3 times), dried (MgSO4), filtered and concentrated under vacuo. The resulting residue was purified via silica gel chromatography (0%-10% MeOH/CH2CI2) to afford the desired product 1b as a white solid. LCMS RT = 4.6 (M+1) 601.5, (M-1) 599.6.
-15816260
Formation of (S)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N(piperidin-3-yl)pyrimidin-4-amine (1c).
To a solution of tert-butyl (3S)-3-[[2-(5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin3-yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate, 1b, (2.1 g, 3.5 mmol) in CHzCl2 (30 mL) was added trifluoroacetic acid (20 mL). After stirring the reaction mixture at room température for 75 min, the mixture was concentrated under vacuo. The crude residue was diluted with EtOAc and neutralized with 1N sodium hydroxide solution. The aqueous phase was separated and extracted again with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated under vacuo to afford the desired product (1c) as a light yellow solid.
1H NMR (300 MHz, ctô-DMSO) □ 8.76 (d, J = 2.5, Hz, 1H), 8.50 (d, J =2.5 Hz, 1H), 8.44 (s, 1H), 8.27 (d, J = 4.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 6.9 Hz, 1H), 7.45 (d, J= 8.2 Hz, 2H), 4.17 (m, 1H), 3.17 (dd, J= 3.1, 11.8 Hz, 1H), 2.99-
2.94 (m, 1H), 2.67-2.60 (m, 1H), 2.38-2.34 (m, 1H), 2.06-2.02 (m, 1H), 1.77 1.73 (m, 1H) and 1.63 - 1.50 (m, 2H) ppm. LCMS RT = 2.1 (M+1) 501.5, (M-1) 499.5.
Formation of 1-((S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)piperidin-1-yl)-3-methoxypropan-2-ol (1 d).
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.20 g, 0.40 mmol) in éthanol was added 2(methoxymethyl)oxirane (0.04 mL, 0.40 mmol). The reaction mixture was heated in a microwave reactor at 140 °C for 5 minutes. The reaction was evaporated to dryness and the resulting residue was purified via silica gel chromatography (0-10 % MeOH: CHzCy to afford the desired product (1 d).
1H NMR (300 MHz, cf6-DMSO) □ 8.78 (d, J = 2.5 Hz, 1H), 8.49 (d, 3 = 2.4 Hz, 1H), 8.43 (d, J = 1.2 Hz, 1 H), 8.26 (d, J = 3.9 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 4.54-4.50 (m, 1H), 4.20 (m, 1H), 3.35-3.17 (m, 1H), 3.33 (s, 3H), 3.25 (m, 1H), 3.19 (d, 2H), 3.00 (m, 1H), 2.75 (d, J = 11.8 Hz, 1H), 2.44-2.26 (m, 4H), 1.93 (m, 1H), 1.73 (m, 2H), 1.63 (m, 1H) and 1.23 (m, 1H) ppm. LCMS RT = 2.4 (M+1) 589.6.
Formation of 1-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-fa]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)-3-methoxypropan-2-ol (537).
To a solution of 1-[(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5fluoro-pynmidin-4-yl]amino]-1-piperidyl]-3-methoxy-propan-2-ol, 1d, (0.15 g, 0.24 mmol) in THF was added 1N LiOH solution. The reaction mixture was heated in a microwave reactor at 120 °C for 5 minutes. The reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc (twice). The combined organic phases were dried (MgSO4), filtered and concentrated under vacuo. The
-I5916260 resulting solid was purified by silica gel chromatography (5-20% MeOH: CH2CI2) to afford the desired product (537) as a white solid.
1H NMR (300 MHz, c/6-DMSO DMSO) □ 12.35 (s, 1 H), 8.73 (d, J = 2.4 Hz, 1 H), 8.29 (d, J = 2.4 Hz, 1 H), 8.19 - 8.09 (m, 2H), 7.36 (d, J = 7.5 Hz, 1 H), 4.53 (dd, J = 4.5,
8.0 Hz, 1H), 4.27 (s, 1H), 3.77 - 3.72 (m, 1H), 3.36 - 3.20 (m, 3H), 3.22 (s, 3H), 3.03
-2.97 (m, 1H), 2.76 (d, J = 10.6 Hz, 1H), 2.44-2.14 (m, 2H), 2.08 (m, 2H), 1.99 -
1.94 (m, 1H), 1.71 -1.63 (m, 2H), 1.44 (m, 1H) and 1.23- 1.15 (m, 1H)ppm. LCMS
RT = 1.6 (M+1) 435.5.
Other analogs that can be prepared in the same manner as 537 are described below:
3-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)propane-1,2-diol (525) 1H NMR (300 MHz, c/6-DMSO) Π 12.31 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.28 (d, J =
2.4 Hz, 1H), 8.20 (s, 1H), 8.17 (d, J = 4.0 Hz, 1H), 7.33 (d, J =7.6 Hz, 1 H), 4.51 (m,
1H), 4.37 (s, 1H), 4.25 (m, 1H), 3.64 (m, 1H), 3.35 (s, 2H), 3.08-2.95 (m, 1H), 2.802.70 (m, 1H), 2.47-2.25 (m, 2H), 2.22-2.12 (m, 2H), 1.99- 1.90 (m, 1H), 1.701.60 (m, 2H) and 1.45 (m, 1H) ppm. LCMS RT = 1.5 (M+1) 421.5.
1-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1 -yl)-3-isopropoxypropan-2-ol (551 ).
1H NMR (300 MHz, cfô-DMSO) Π 12.32 (s, 1H), 8.72 (d, J= 2.4 Hz, 1H), 8.28 (d, J =
2.4 Hz, 1H), 8.19 - 8.16 (m, 2H), 7.32 (d, J= 8.0 Hz, 1H), 4.42 - 4.37 (m, 2H), 3.70 (s, 1H), 3.52 - 3.42 (m, 1H), 3.35 - 3.25 (m, 1H), 2.99 (m, 1H), 2.73 (m, 1H), 2.43 2.11 (m, 4H), 1.94 (m, 1H), 1.75- 1.60 (m, 2H), 1.52- 1.40 (Μ, 1H) and 1.10-0.99 (m, 6H). LCMS RT = 1.7 (M+1 ) 463.4, (M-1 ) 461.5.
(S)-1-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-16016260 ylamino)piperidin-1 -yl)butan-2-ol (538).
1H NMR (300 MHz, ctô-DMSO) □ 12.53 (s, 1H), 10.32 (s, 1H), 8.69 (dd, J = 2.5, 5.2 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.31 (m, 2H), 7.97 (s, 1H), 4.76 (m, 1H), 3.92 (m, 2H), 3.84 - 3.55 (m, 2H), 3.40 - 2.80 (m, 3H), 2.14 -1.90 (m, 3H), 1.80 - 1.74 (m, 2H), 1.65 (m, 1 H), 1.43 -1.23 (m, 2H) and 0.96 - 0.85 (m, 3H) ppm. LCMS RT = 1.6 (M+1) 419.6.
(S)-1-(3-(2-(5-chloro-1/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1~yl)-2-methylpropan-2-ol (546).
1H NMR (300 MHz, CDCI3) □ 9.60 (s, 1H), 8.87 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 2.3
Hz, 1H), 8.17 (d, J = 2.7 Hz, 1H), 8.09 (d, J = 3.3 Hz, 1H), 5.34 (d, J = 11.5 Hz, 1H),
4.45 - 4.42 (m, 1 H), 3.09 (d, J = 11.3 Hz, 1 H), 2.75 - 2.59 (m, 4H), 2.40 (s, 2H), 1.94
- 1.70 (m, 4H) and 1.27 (s, 6H) ppm. LCMS RT = 1.6 (M+1) 419.5.
(R) -3-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-i>]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)propane-1,2-diol (588).
1H NMR (300 MHz, DMSO) Ί 12.31 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.16 (d, J =4.0 Hz, 1H), 7.33 (d, J= 7.8 Hz, 1H), 4.47-4.44 (m, 1H), 4.35 (d, J = 4.0 Hz, 1H), 4.28-4.17 (m, 1H), 3.64- 3.62 (m, 1H), 3.17 (d, J = 5.2 Hz, 1H), 3.02-2.98 (m, 1H), 2.78-2.73 (m, 1H), 2.37 (ddd, J = 12.8, 5.2, 5.2 Hz, 2H), 2.22-2.10 (m, 2H), 1.99- 1.89 (m, 1H), 1.73-1.63 (m, 2H) and 1.46-1.43 (m, 1H) ppm. LCMS RT = 1.5 (M+1) 421.4. LCMS RT = 1.6 (M+1) 419.3.
(S) -3-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)pîperidin-1 -yl)propane-1,2-diol (587).
1H NMR (300 MHz, DMSO) □ 12.31 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.28 (d, J= 2.4 Hz, 1H), 8.20 (s, 1H), 8.16 (d, J= 4.0 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 4.34 (s, 1H), 4.27-4.23 (m, 1H), 3.62 (s, 1H), 3.35 (d, J = 5.5 Hz, 1H), 3.06-3.03 (m, 1H), 2.782.74 (m, 1H), 2.44 (d, J=5.0Hz, 1H), 2.27 (dd, J= 12.9, 6.9 Hz, 1H), 2.20-2.07 (m, 2H), 2.05- 1.90 (m, 1H), 1.75- 1.59 (m, 2H) and 1.49- 1.39 (m, 1H) ppm.
-16116260
1-((3S, 4S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-4methylpiperidin-1 -yl)-3-methoxypropan-2-ol (550).
1H NMR (300 MHz, cfâ-DMSO) □ 12.33 (s, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.28 (d, J =
2.4 Hz, 1H), 8.22-8.20 (m, 2H), 6.72 -6.62 (m, 1H), 4.61 (dd, J = 4.2, 10.0 Hz, 1H), 4.54 (m, 1H), 3.75-3.71 (m, 1H), 3.34- 3.22 (m, 1H), 3.22 (d, 3H), 2.88-2.42 (m, 4H), 2.41 - 2.25 (m, 4H), 1.93 (m, 1 H), 1.56 (m, 2H) and 0.90 (d, J = 6.7 Hz, 3H).
LCMS RT = 1.6 (M+1) 449.5.
3-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)-2-hydroxypropanamide (603).
1H NMR (300 MHz, DMSO) □ 12.31 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28-8.25 (m, 1H), 8.19 - 8.16 (m, 2H), 7.34 - 7.30 (m, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 4.24 (s, 1H), 3.99 (dd, J = 3.5, 7.6 Hz, 1H), 3.01 (d, J= 10.3 Hz, 1H), 2.81 -2.63 (m, 2H), 2.362.29 (m, 2H), 1.71 (s, 3H) and 1.51 -1.44 (m, 2H) ppm.
General Scheme 2
tert-butylbromoacetate, Na2CO3, DMF (b) 1N LiOH, THF, microwave, 120 °C, 10 min (c) TFA, CH2CI2
Formation of (S)-fert-butyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)piperidine-1 -carboxylate (2a).
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-/V[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.25 g, 0.50 mmol) in DMF was added tertbutylbromoacetate (0.08 mL, 0.55 mmol) and Na2CO3 (0.11 g, 0.99 mmol). The
-16216260 reaction mixture was stirred at room température for 6 h. The resulting thick white precipitate was diluted with aqueous saturated NaCl solution and washed with water.
The white solid was dissolved in CH2CI2 and the solution was dried (MgSO4), filtered and concentrated in vacuo. The crude was purifïed via silica gel chromatography (0%-5% MeOH/ CH2CI2) to afford the desired product, 2a, as a white solid.
1H NMR (300 MHz, d6-DMSO) Ί 8.76 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 3.6 Hz, 1H), 8.44 (s, 1 H), 8.26 (d, J = 3.9 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.2 Hz, 1H), 7.44 (d, J= 8.1 Hz, 2H), 4.18 (m, 1H), 3.19 (s, 2H), 3.03 - 2.99 (m, 1H), 2.782.73 (m, 1H), 2.45-2.30 (m, 2H), 2.37 (s, 3H), 1.99- 1.93 (m, 1H), 1.80- 1.60 (m, 2H), 1.46-1.40 (m, 1H)and 1.36 (s, 9H) ppm. LCMS RT = 2.8 (M+1) 615.6, (M-1) 613.6.
Formation of (S)-tert-butyl 2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)piperidin-1 -yl)ethanoate (2b).
To a solution of tert-butyl 2-[(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrïdin-3-yl]5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]acetate, 2a, (0.27 g, 0.44 mmol) in THF was added 1N LiOH solution. The reaction mixture was heated in microwave at 120 degrees for 10 minutes. The reaction mixture diluted with brine, extracted with EtOAc, then with 20% isopropanol/CH2CI2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting product, 2b, was used without further purification. LCMS RT = 2.0 (M+1) 461.5.
Formation of (S)-2-(3-(2-(5-chloro-1 H-pyrrolo[2,3-fe]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)ethanoic acid (577).
To a solution tert-butyl 2-[(3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5~fluoropyrimidin-4-yl]amino]-1-piperidyl]acetate, 2b, (0.12 g, 0.26 mmol) în CH2CI2 (4 mL) was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room température for 18 h and concentrated in vacuo. The crude residue was diluted with 5%MeOH/ CH2CI2 and the resulting white precipitate was filtered and washed with CH2CI2 to afford the desired product, 577, as trifluoroacetic acid sait.
1H NMR (300 MHz, d6-DMSO) □ 12.46 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.36 (d, J= 2.3 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 3.9 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 4.70-4.50 (m, 1H), 4.21 (s, 2H), 3.80 - 3.70 (m, 1H), 3.55 - 3.47 (m, 1H), 3.20 - 2.90 (m, 2H), 2.10 -
1.95 (m, 3H) and 1.69- 1.60 (m, 1H) ppm. LCMS RT = 1.9 (M+1) 405.4.
Other analogs that can be prepared in the same manner as 577:
-16316260
567
(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2I3-i>]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1 -yl)ethanamide (567).
1H NMR (300 MHz, c/6-DMSO) Π 12.29 (s, 1H), 8.72 (d, J = 2.4 Hz, 1 H), 8.28 (d, J =
2.4 Hz, 1 H), 8.21 (s, 1H), 8.17 (d, J = 4.0 Hz, 1H), 7.41 (d, J= 7.7 Hz, 1H), 7.29 (s,
H), 7.10 (s, 1 H), 4.35 - 4.29 (m, 1 H), 2.98 - 2.75 (m, 1 H), 2.92 (d, J = 6.8 Hz, 2H), 2.68 (d, J = 10.8 Hz, 1H), 2.29- 2.19 (m, 2H), 1.96- 1.92 (m, 1H), 1.80- 1.65 (m, 2H) and 1.53-1.42 (m, 1H) ppm. LCMS RT = 2.1 (M+1) 404.4, (M-1) 402.5.
2-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-Î>]pyridin-3-yl)-5-fluoropyrimidin-4- ylamino)piperidin-1-yl)propanamide (583).
1H NMR (300 MHz, c/6-DMSO) □□ΘΤΟ (d, J = 2.3 Hz, 1 H), 8.52 (d, J = 8.7 Hz, 1 H),
8.35 (dd, J= 5.0, 6.5 Hz, 2H), 4.10 (dd, J= 2.7, 7.0 Hz, 1H), 3.80-3.90 (m, 1H), 3.60
- 3.80 (m, 1H), 2.35-2.45 (m, 1H), 2.15-2.35 (m, 1H), 1.80- 1.95 (m, 1H), and 1.601.65 (m, 3H) ppm. LCMS (M+1 ) 418.4.
654
Cl
nh2 (S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyanopyrimidin-4ylamrno)piperidin-1 -yljethanamide (654),
LCMS RT = 2.9 (M+1 ) 411.4, (M-1) 409.4.
(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-ô]pyridin-3-yl)-5-methylpyrimidin-420 ylamino)piperidin-1-yljethanamide (620).
LCMS RT ~ 1.9 (M+1) 400.4, (M-1) 398.3.
-16416260
2-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)propanoic acid (573).
1H NMR (300 MHz, ctô-DMSO) Π 12.51 (s, 1H), 10.28 - 10.00 (m, 1H), 8.70 (s, 1H), 8.38 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H),8.30 (d, J = 4.2 Hz, 1H), 7.89-7.75 (m, 1H), 4.70 - 4.50 (m, 1 H), 4.33 - 4.29 (m, 1 H), 3.79 - 3.45 (m, 2H), 3.20 - 2.80 (m, 2H), 2.12-1.95 (m, 3H), 1.72- 1.60 (m, 1H) and 1.52 (d, J = 5.5 Hz, 3H) ppm.
2-((S)-3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)-N-methylpropanamide (606).
1H NMR (300 MHz, d6-DMSO) □ 8.69 (d, J= 12.7 Hz, 1H), 8.54 - 8.49 (m, 1H), 8.32 (dd, J = 4.8, 7.2 Hz, 2H), 4.83 - 4.76 (m, 1H), 4.02 (m, 1H), 3.95-3.71 (m, 2H), 3.31 - 3.10 (m, 1H), 2.86 (s, 3H), 2.33 (d, J= 9.9 Hz, 1H), 2.40-2.14 (m, 3H), 1.94 (s, 1H), 1.66- 1.58 (m, 3H) and 1.10 (d, J = 6.5 Hz, 3H) ppm. LCMS (M+1) 432.2.
(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1 -yl)-2-methylpropanoic acid (590).
1H NMR (300 MHz, MeOD) 008.81 (d, J= 2.3 Hz, 1H), 8.19 (t, J= 2.5 Hz, 2H), 7.98 (d, J = 4.2 Hz, 1H), 4.48 (s, 1H), 2.90 (d, J = 10.1 Hz, 1H). 2.74-2.66 (m, 2H), 2.60 (d, J= 5.7 Hz, 1H), 1.89- 1.83 (m, 2H), 1.67 (s, 1H), 1.25 (d, J = 4.9 Hz, 6H) ppm. LCMS (M+1) 433.4.
(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)-2-methylpropanamide (598).
LCMS RT = 1.8 (M+1) 432.4.
(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4ylamino)piperidÎn-1-yl)-N,2-dimethylpropanamide (599).
’H NMR (300 MHz, MeOD) .71 8.86 (d, J= 2.4 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1 H), 8.17
-16516260 (s, 1H), 8.03 (d, J = 4.1 Hz, 1H), 4.46 (dd, J =4.7, 8.8 Hz, 1H), 4.10 (q, J = 7.2 Hz,
H), 3.05 (d, J = 12.8 Hz, 1 H), 2.66 (s, 3H), 2.34 (dd, J = 11.3, 20.6 Hz, 2H), 2.08 (d,
J = 12.3 Hz, 1H), 1.89-1.71 (m, 2H), 1.66- 1.54 (m, 1H)and 1.19 (s, 6H)ppm.
LCMS (M+1) 433.4.
(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-i>]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperïdin-1-yl)-N,N,2-trïrnethylpropanamide (600).
1H NMR (300 MHz, MeOD) □ 8.81 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 8.02 (d, J = 4.0 Hz, 1H), 4.45-4.37 (m, 1 H), 3.61 (s, 3H), 2.97 (d, J= 8.8 Hz, 1H), 2.80 (s, 3H), 2.72 (s, 1H), 2.39 (t, J= 10.0 Hz, 2H), 2.15 (dd, J = 3.6, 12.7 Hz, 1H), 1.91 - 1.79 (m, 2H), 1.53- 1.47 (m, 1H) and 1.28 (s, 6H) ppm. LCMS (M+1) 460.5.
(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-Jb]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)-N-(2-methoxyethyl)-2-methylpropanamide (601).
1H NMR (300 MHz, MeOD) Π 8.88 (d, J= 2.3 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 8.02 (d, J = 4.1 Hz, 1H), 4.47-4.41 (m, 1H), 3.38 (dd, J = 1.6, 4.8 Hz, 4H), 3.12-3.07 (m, 1H), 2.73 (d, J= 10.8 Hz, 1H), 2.35-2.29 (m, 2H), 2.19-2.15 (m, 1H), 1.91-1.80 (m, 2H), 1.55 (s, 1H), 1.37 (s, 1H) and 1.20 (s, 6H) ppm..
(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-ô]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)-N-cyclopropyl-2-methylpropanamide (602).
1H NMR (300 MHz, MeOD) □ 8.82 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 8.01 (d, J = 4.0 Hz, 1H), 4.41 (m, 1H), 3.02 (d, J= 10.0 Hz, 1H), 2.59-2.47 (m, 1 H), 2.40 - 2.30 (m, 2H), 2.09 - 2.01 (m, 1 H), 1.89 - 1.85 (m, 1 H), 1.78 - 1.66 (m, 1H), 1.61 - 1.55 (m, 1H), 1.26-1.16 (m, 1H), 1.10 (d, J = 6.6 Hz, 6H),0.680.63 (m, 2H) and 0.44 - 0.40 (m, 2H) ppm. LCMS (M+1) 472.4.
General Scheme 3
-16616260
CF3CH2SO2CCI3, 'Pr2NEt, DMF (b) 1N LiOH, THF, microwave, 120 °C, 10 min
Formation of (S)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-ô]pyridin-3-yl)-5-fluoro-N-(1 -(2,2,2trifluoroethyl)piperidin-3-yl)pyrimidin-4-amine (3a).
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.17 g, 0.34 mmol) in DMF (1,5 mL) was added 2,2,2-trifluoroethyl trichloromethanesuffonate (0.19 g, 0.68 mmol), followed by 'Pr2NEt (0.24 mL, 1.36 mmol). The reaction mixture was stirred at room température for 18 h. The mixture was poured into brine and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4). filtered, and concentrated in vacuo. The crude residue was purifîed by silica gel chromatography (0-10% MeOH/CH2CI2) afforded the desired product, 3a, as a white solid.
1H NMR (300 MHz, d6-DMSO) δ 8.77 (d, J = 2.4 Hz, 1 H), 8.48 (d, J = 2.4 Hz, 1 H), 8.42 (s, 1 H), 8.27 (d, J = 3.9 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.44 (d, J= 8.2 Hz, 2H), 4.17 (m, 1H), 3.30- 3.18 (m, 3H), 2.90 (m, 1H), 2.442.32 (m, 2H), 2.35 (s, 3H), 1.95 (m, 1H), 1.72- 1.57 (m, 2H) and 1.51 -1.40 (m, 1H) ppm.
LCMS RT = 4.6 (M+1) 583.4, (M-1) 581.4.
Formation of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-/V-(1-(2,2,2trifluoroethyl)piperidin-3-yl)pyrimidin-4-amine (668).
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N[(35)-1-(2,2,2-trifluoroethyl)-3-piperidyl]pyrimidin-4-amine, 3a, (0.10 g, 0.18 mmol) in THF was added 1M LiOH (0.90 mL, 0.90 mmol) solution. The reaction mixture was heated in microwave at 120 °C for 10 minutes. The reaction mixture was diluted with brine, extracted with EtOAc, then with 20% isopropanol/CH2CI2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purifîed via silica gel chromatography (0-10 % MeOH:CH2CI2) to afford the desired product, 1339, as a white solid.
1H NMR (300 MHz, d6-DMSO) □ 12.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J =
2.4 Hz, 1H), 8.18-8.16 (m, 2H), 7.38 (d, J = 7.7 Hz, 1H), 4.22 - 4.17 (m, 1H), 3.31 3.16 (m, 3H), 2.90 (m, 1H), 2.40 (t, J = 10.2 Hz, 2H), 2.00- 1.95 (m, 1H), 1.77-1.60 (m, 2H) and 1.50- 1.38 (m, 1H) ppm. LCMS RT = 3.5 (M+1) 429.4, (M-1) 427.4.
Other analogs that can be prepared in the same manner as 668:
-16716260
Cl
595
Synthesis of (S)-2-(5-chloro-1 H-pyrrolo[2,3-i)]pyridÎn-3-yl)-N-(1 -(2,2difluoroethyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine (1).
1H NMR (300 MHz, cfô-DMSO) □ 12.31 (s, 1H), 8.72 (d, J =2.4 Hz, 1H), 8.28 (d, J =
2.4 Hz, 1H), 8.20 (s, 1H), 8.17 (d, J = 4.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1HJ.4.51 (m, 1H), 4.37 (s, 1 H), 4.25 (m, 1H), 3.64 (m, 1H), 3.35 (s, 2H), 3.08-2.95 (m, 1H), 2.802.70 (m, 1H), 2.47-2.25 (m, 2H), 2.22-2.12 (m, 2H), 1.99- 1.90 (m, 1H), 1.701.60 (m, 2H) and 1.45 (m, 1H) ppm.
LCMS RT = 2.7 (M+1) 411.4, (M-1) 409.4.
(S)-2-(5-chloro-1H-pyrrolo[2,3-i>]pyridin-3-yl)-A/-(1-(2,2-difluoroethyl)piperidin-3-yl)-5fluoropyrimidin-4-amine (595).
1H NMR (300 MHz, d6-DMSO) Π 12.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J =
2.4 Hz, 1H), 8.18-8.15 (m, 2H), 7.32 (d, J = 7.1 Hz, 1H), 4.20 (d, J = 7.1 Hz, 1H), 3.46 (t, J = 5.8 Hz, 2H), 3.19 (s, 3H), 3.10-3.06 (m, 1H), 2.82-2.78 (m, 1H), 2.572.50 (m, 2H), 2.11 -1.95 (m, 3H), 1.71 - 1.63 (m, 2H) and 1.48- 1.35 (m, 1H) ppm. LCMS RT = 1.7 (M+1 ) 405.4, (M-1) 403.4.
669 (S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridÎn-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)ethanenitrile (669).
1H NMR (300 MHz, cfô-DMSO) □ 12.31 (s, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.28 (d, J =
2.4 Hz, 1H), 8.19-8.17 (m, 2H), 7.47 (d, J= 7.7 Hz, 1H), 4.30-4.20 (m, 1H), 3.80 (s, 2H), 3.07-3.03 (m, 1H), 2.82-2.73 (m, 1H), 2.29-2.10 (m, 2H), 2.05-1.96 (m, 1H), 1.87- 1.65 (m, 2H) and 1.49-1.40 (m, 1H) ppm.; LCMS RT = 2.3 (M+1) 386.1, (M-1) 384.2.
General Scheme 4
-16816260
1/7-imidazole-2-carbaldehyde, Na(OAc)3BH, HOAc,
1,2-dichloroethane, 60 °C (b) 1N LiOH, THF, microwave, 120 °C, 10 min
Formation of (S)-N-(1-((1H-imidazol-2-yl)methyl)piperidin-3-yl)-2-(5-chloro-1-tosyl-1Hpyrrolo[2,3-Jb]pyridin-3-yl)-5-fluoropyrimidin-4-amine (4a),
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.16 g, 0.32 mmol) in 1,2-dichloroethane (2 mL) was added 1H-imidazole-2-carbaldehyde (0.03 g, 0.36 mmol) followed by 2 drops of acetic acid and Na(OAc)3BH (0.10 g, 0.49 mmol), The reaction mixture was heated at 60 °C for 18 h. The mixture was cooled to room température and diluted with aqueous saturated NaHCO3 solution. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-20% MeOH/CH2CI2) to afford the product, 4a.
1H NMR (300 MHz, d6-DMSO) □ 11.83 (s, 1 H), 8.75 (d, J = 2.4 Hz, 1 H), 8.48 (d, J =
2.4 Hz, 1H), 8.41 (s, 1H), 8.25 (d, J = 3.8 Hz, 1H), 8.07 (d, 7= 8.3 Hz, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.44 (d, 7 = 8.2 Hz, 2H), 7.00 - 6.80 (m, 2H), 4.22 (m, 1H), 3.58 (dd, J = 18.9, 13.8 Hz, 2H), 2.95 (m, 1H), 2.75-2.72 (m, 1H), 2.36 (s, 3H), 2.16-2.04 (m, 2H), 1.99 - 1.93 (m, 1H), 1.78 - 1.55 (m, 2H) and 1.45 - 1.30 (m, 1H) ppm.
Formation of (S)-N-(1-((1H-imidazol-2-yl)methyl)piperidin-3-yl)-2-(5-chloro-1Hpyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (589).
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N[(3S)-1-(1/7-imidazol-2-ylmethyl)-3-piperidyl]pyrimidin-4-amine, 4a, (0.08 g, 0.13 mmol) in THF (2,5 mL) was added 1M LiOH (0.67 mL, 0.65 mmol) solution. The reaction mixture was heated in microwave at 120 °C for 10 minutes. The mixture was cooled to room température and diluted with brine, The aqueous phase was extracted with CH2CI2, then twice with 20% îsopropanol/ CH2CI2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford the desired product, 589, as a white solid.
1H NMR (300 MHz, d6-DMSO) □ 8.77 (d, J = 2.4 Hz, 1 H), 8.48 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H), 8.27 (d, J = 3.9 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.62 (d, 7 = 7.5 Hz, 1H), 7.44 (d, 7 = 8.2 Hz, 2H), 4.17 (m, 1H), 3.30-3.18 (m, 3H), 2.90 (m, 1H), 2.44-16916260
2.32 (m, 2H), 2.35 (s, 3H), 1.95 (m, 1H), 1.72 - 1.57 (m, 2H) and 1.51 - 1.40 (m, 1H)
PPm.
LCMS RT = 1.6 (M+1) 427.4.
Other analogs which can be prepared in the same manner as 589:
N-(1-((1H-imidazol-5“yl)methyl)piperidin-3-yl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3yl)-5-fluoropyrimidin-4-amine (594).
1H NMR (300 MHz, d6-DMSO) □ 12.31 (s, 1H), 11.86- 11.77 (m, 1H), 8.70 (d, J =
2.2 Hz, 1H), 8.28 (d, J= 2.4 Hz, 1H), 8.15 (d, J = 3.9 Hz, 1H), 8.10 (d, J = 2.5 Hz,
1H), 7.54 (s, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.87 (s, 1H), 4.19 (m, 1H), 3.57 (d, J =
13.8 Hz, 1H), 3.48 (d, J= 13.8 Hz, 1H), 3.04 (d, J = 8.3 Hz, 1H), 2.80 (d, J= 10.4 Hz,
1H), 2.10-1.90 (m, 3H), 1.72- 1.62 (m, 2H) and 1.51 - 1.35 (m, 1H) ppm; LCMS RT = 1.6 (M+1) 427.4, (M-1) 425.4.
General Scheme 5A o
tert-butyl (3S)-3-aminopiperidine-1-carboxylate, 'Pr2NEt base, 2-propanol, 80 °C (b) 5chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl·1,3,2-dioxaborolan-2-yl)pyrrolo[2,3bjpyridine, DME/H2O, K2CO3, tetrakis triphenylphosphinepalladium(O), 90 °C (c) NaOMe / MeOH (d) isopropanol/HCI (e) methanesulfonyl chloride, 'Pr2NEt, CH2CI2/DMF
Formation of tert-butyl (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]piperidine-1carboxylate (5a).
To a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate (8.1 g, 40.4 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (6.6 g, 39.8 mmol) in isopropanol (80 mL) was
-17016260 added N,A/-diisopropyl-/V-ethylamine (9.0 mL, 51.7 mmol). The reaction mixture was warmed to 80 °C and stirred for 17 hours. Ail volatiles were removed at reduced pressure and the residue was dissolved in EtOAc. The organic layer was partitioned with water and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was dissolved in CH2CI2 and purified by silica gel chromatography (0 - 50% EtOAc /Hexanes) to afford the desired product, 5a. LCMS RT = 3.3 (M+1 ) 331.1.
Formation of terf-butyl (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate (1b).
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2- yi)pyrrolo[2,3-b]pyridine (1.8 g, 4.2 mmol) and terf-butyl (3S)-3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]piperidine-1-carboxylate, 5a, (1.2 g, 3.7 mmol) in DME (15 mL) and H2O (5 mL) was added K2CO3 (1.7 g, 12.1 mmol). The mixture was purged with nitrogen for 15 min. To the mixture was added tetrakis triphenylphosphine palladium(O) (0.2 g, 0.2 mmol) and the reaction mixture was heated at 90 °C for 3 days. The reaction was cooled down to room température and then diluted with EtOAc / H2O. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The resulting residue was dissolved in CH2CI2 and purified by silica gel chromatography (0-100 % EtOAc /Hexanes) to afford the desired product, 1b. LCMS RT = 4.6 (M+1) 601.2.
Formation of terf-butyl (3S)-3-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoropyrÎmidin-4-yl]amino]piperidine-1 -carboxylate (2b),
To a solution of terf-butyl (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-
3- yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate, 1b, (0.93 g, 1.55 mmol) in methanol (10 mL) was added sodium methoxide (10 mL of 1M solution). The reaction mixture was warmed to 45 “C. After stirring for 30 minutes the reaction was to cooled to room température and quenched by additon into water. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0 -100% EtOAc /Hexanes) to afford the desired product, 2b.
LCMS RT = 2.8 (M+1) 447.2.
Formation of (S)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(pipendin-3yl)pyrimidin-4-amine (5b).
To a suspension of terf-butyl (3S)-3-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate, 2b, (0.45 g, 1.01 mmol) in isopropanol (3 mL) was added propan-2-ol hydrochloride (1.5 mL of 5M solution, 7.500 mmol). The reaction mixture was warmed to 80 °C and stirred for 3 hours.
-17116260
The mixture was cooled to room température and ail volatiles were removed at reduced pressure. The resulting crude product, 5b, was used without further purification. LCMS RT = 1.5 (M+1) 347.1.
Formation of (SJ-Z-fS-chloro-IH-pyrrolop.S-bJpyridin-S-ylJ-S-fluoro-N-fl(methylsulfonyl)piperidin-3-yl)pyrimidin-4-amine (389).
To a solution of (S)-2-(5-chloro-1/-/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3yl)pyrimidin-4'amine hydrochloride, 5b, (0.04 g, 0.11 mmol ) in CH2CI2 (1.4 mL) and DMF (0.30 mL) was added /V,/V-diisopropyl-A/-ethylamine (0.30 mL, 1.70 mmol) followed by methanesulfonyl chloride (0.02 g. 0.20 mmol). The reaction mixture was allowed to stir at room température for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 389. LCMS RT =
1.8 (M+1) 425.3.
Other analogs that can be prepared in the same manner as 389:
(S)-2-(5-chlorO'1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(ethylsulfonyl)piperidin-3-yl)-5fluoropyrimidin-4-amine (393).
LCMS RT =1.8 (M+1) 439.3.
(S)-/V-(1-(butylsulfonyl)piperidin-3-yl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5 fluoropyrimidin-4-amine (390).
LCMS RT = 2.1 (M+1) 467.3.
(S)-2-(5-chloro-1H-pyrrolo(2,3-b]pyridin-3-yl)-N-(1-(cyclopropylsulfonyl)piperidin-3-yl)5-fluoropyrimidin-4-amine (391 ).
LCMS RT = 1.9 (M+1) 451.3.
(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(isopropylsulfonyl)piperidin-3-yl)pyrimidin-4-amine (394).
-17216260
LCMS RT = 1.9 (M+1) 453.3.
(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1(cyclopentylmethylsulfonyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine (392).
LCMS RT = 2.3 (M+1) 493.5.
General Scheme 5B
Formation of (R)-2-(5-chloro-1 H-pyrrolo[2,3-fa]pyridin-3-yl)-5-fluoro-/V-(1 (propylsulfonyl)piperidin-3-yl)pyrimidin-4-amine (316).
To a solution of 2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-A/-(piperidin-3yl)pyrimidin-4-amine, 5c, (0.40 g, 1.15 mmol) in 10:1 mixture of CH2CI2/DMF (8 mL) was added 'Pr2NEt (0.60 mL, 3.46 mmol) followed by 1-propanesulfonyl chloride (0.13 mL, 1.15 mmol). The reaction mixture was stirred at room température for 5 hours. The resulting residue was purified by preparatory HPLC (0.1%TFAH20/acetonîtrile) to afford the desired product, 316. LCMS RT = 2.5 (M+1) 453.3.
Other analogs that can be prepared in the same manner as 316:
(R)-2-(5-chloro-1H-pyrrolo[2,3-ô]pyridin-3-yl)-N-(1-(ethylsulfonyl)piperidin-3-yl)-5fluoropyrimidin-4-amine (321).
LCMS RT = 2.7 (M+1) 439.1.
(R)-2-(5-chloro-1H-pyrrolo[2,3-i>]pyridin-3-yl)-5-fluoro-N-(1-(isopropylsulfonyl)piperidin-3-yl)pyrimrdin-4-amine (322).
-17316260
LCMS RT = 2.9 (M+1) 453.1.
(S)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(propylsu1fonyl)-piperidin-
3-yl)pyrimidin-4-amine (306).
LCMS RT = 2.9 (M+1) 453.2.
General Scheme 5C
cyclobutanecarbonyl chloride, ‘Pr2NEt, CH2CI2/DMF
Formation of (S)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)(cyclobutyl)methanone (395).
To a solution of (S)-2-(5-chloro-1H-pyrroÎo[2,3-b]pyridin-3-yl)-5-fluoro-/\/-(piperidin-3yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.11 mmol ) in CH2CI2 (1.40 mL) and DMF (300 μ was added A/,A/-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) followed by cyclobutanecarbonyl chloride (0.01 g. 0.12 mmol). The reaction mixture was allowed to stir at room température for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0,1% ammonium formate-H20/acetonitrile) to afford the desired product, 395. LCMS RT =
1.9 (M+1) 429.3.
Other analogs that can be prepared in the same manner as 395:
(S)-1-(3-(2-(5-chloro-1H-pyrro1o[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)propan-1-one (435).
LCMS RT = 1.8 (M+1) 403.4.
(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2I3-b]pyridin-3-y!)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)-2-methylpropan-1-one (436)
LCMS RT = 1.9 (M+1) 417.4.
-17416260
(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidîn-1-yl)-2,2-dimethylpropan-1-one (437)
LCMS RT = 2,0 (M+1) 431.4.
(S)-(3-(2-(5-chIoro-1H-pyrrolo[2,3-i)]pyridin-3-yl)-5-fluoropyrimidîn-4ylamino)piperïdin-1-yl)(cyclopropyl)methanone (451)
LCMS RT = 1.8 (M+1) 415.4.
(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperîdin-1 -yl)-3-methoxypropan-1 -one (396)
LCMS RT =1.7 (M+1) 433.3.
(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)ethanone (434)
LCMS RT =1.6 (M+1) 389.4.
(R)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-ô]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)-3-methylbutan-1-one (318)
LCMS RT = 2.9 (M+1) 431.1.
(R)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriniidin-4ylamino)piperidin-1-y1)(cyclopropyl)methanone (317)
LCMS RT = 2.7 (M+1) 415.1.
-17516260
(R)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1yl)-3-methoxypropan-1-one (320)
LCMS RT = 2.5 (M+1) 433.1.
(R)-(3-(2-(5-chloro-1/-/-pyrrolo[2]3-d]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pÎperidin-1yl)(cyclobutyl)methanone (319)
LCMS RT = 2.8 (M+1) 429.1.
(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrïmidin-4-ylamtno)piperidin-1yl)-3-methylbutan-1-one (332)
LCMS RT = 2.0 (M+1) 431.2. (S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)piperidin-1yl)ethanone (485)
LCMS RT = 1.9 (M+1) 371.5.
(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1yl)-2-methoxyethanone (486)
LCMS RT = 1.9 (M+1) 401.5.
(S)-methyl 4-(3-(2-(5-chloro-1H-pyrrolo[2,3-ù]pyridin-3-yl)pyrimidin-4-ylamino)pîperidin-1-yl)-
4-oxobutanoate (487)
LCMS RT = 2.0 (M+1) 443.9.
-17616260
488
489 (S)-1-(3-(2-(5-chloro-1 H-pyrrolo[2,3-ù]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1 yl)-3-methoxypropan-1-one (488)
LCMS RT =1.9 (M+1) 415.5.
(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-P]pyrïdiri-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-3methylbutan-1-one (489)
LCMS RT = 2.1 (M+1) 413.5.
General Scheme 5D
1-methylcyclopropane-1-carboxylic acid, EDAC-HCI,
HOBt, 'Pr2NEt, CH2CI2/DMF
Formation of (S)-(3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1-yl)(1-methylcyclopropyl)methanone (445)
To a solution of (S)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-A/-(pîperidin-3yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.10 mmol) in CH2CI2 (1.4 mL) and DMF (0.3 mL) was added /V,A/-diisopropyl-N-ethylamine (0.3 mL, 1.72 mmol), followed by 3-(ethyliminomethyleneamino,)-/V, A/-dimethyl-propan-1 -amine hydrochloride (0.02 g, 0.12 mmol), 1-hydroxybenzotriazole hydrate (0.02 g, 0.12 mmol) and 1-methylcyclopropane-1-carboxylic acid (0.01 g, 0.12 mmol). The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H20/acetonitrile) to afford the desired product, 445. LCMS RT = 2.1 (M+1) 429.5.
Analogs that can be prepared in the same manner as 445:
-17716260
(S)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidin-1 -yl)(3-methyloxetan-3-yl)methanone (444)
LCMS RT = 1.7 (M+1) 445.4.
General Scheme 5E
isocyanatopropane, 'Pr2NEt, CH2CI2/DMF
Formation of (S)-3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)-N-isopropylpiperidine-1 -carboxamide (439).
To a solution of (S)-2-(5-chloro-1/-/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3yl)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2CI2 (1.4 mL) and DMF (0.3 mL) was added N,A/-diîsopropyl-N-ethylamine (0.300 mL, 1.720 mmol) followed by isocyanatopropane (0.120 mmol). The reaction mixture was stirred at room température for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formateH2O/acetonitrile) to afford the desired product, 439. LCMS RT = 1.8 (M+1) 432.4.
Other analogs that can be prepared in the same manner as 439.
(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimÎdin-4-ylamino)-/Vethylpiperidine-1-carboxamide (438).
LCMS RT =1.7 (M+1) 418.4.
Formation of 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-17816260 ylamino)-W-propylpiperidine-1-carboxamide (196).
To a solution of 2-(5-chloro-1/-/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-A/-(piperidin-3yl)pyrimidin-4-amine, 5b, (0.020 g, 0.058 mmol) in 1:1 mixture of CH2CI2/pyridine (2 mL) was added propylisocyanate (0.005 mL, 0.058 mmol). The reaction mixture was stirred at room température for 12 hours. The resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 196.
LCMS RT = 2.6 (M+1) 432.1, (M-1) 430.1.
324
(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-d]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-Wpropylpiperidine-1-carboxamide (324).
LCMS RT = 2.6 (M+1) 432.2. (S)-W-butyl-3-(2-(5-chloro-1H-pyrrolo[2,3-ô]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidine-1-carboxamide (323).
LCMS RT = 2.7 (M+1) 446.2.
(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidine-1 -carboxamide (507).
LCMS (TFA buffer); Rt 1.69 min, ES+ 390.
General Scheme 5F
methylchloroformate, 'Pr2NEt, CH2CI2/DMF
Formation of (S)-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropynmidin-4-ylamino)piperidine-1 -carboxylate (440).
-17916260
To a solution of (S)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-/\/-(piperidin-3yl)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2CI2(1.4 mL) and DMF (0.3 mL) was added N, A/-diisopropyl-/V-ethylamine (0.300 mL, 1.720 mmol) followed by methyl chloroformate (0.009 g, 0.120 mmol). The reaction mixture was stirred at room température for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 440.
LCMS RT =1.8 (M+1) 405.4.
Analogs that can be prepared in the same manner as 440:
(S)-ethyl 3-(2-(5-chlorO“1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidine-1-carboxylate (441).
LCMS RT = 1.9 (M+1) 419.4.
(S)-isopropyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)piperidine-1-carboxylate (442).
LCMS RT = 2.1 (M+1) 433.4.
General Scheme 5G
(2,5-dioxopyrrolidin-1 -yl) [(3S)-tetrahydrofuran-3-yl] carbonate, ’Pr2NEt, CH2CI2/DMF
Formation of (S)-((S)-tetrahydrofuran-3-yl) 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridm-3yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxylate (443).
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-y))-5-fluoro-A/-(piperidin-3yl)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2CI2(1.4 mL) and DMF (0.3 mL) was added A/,/V-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol)
-18016260 followed by (2,5-dioxopyrrolidin-1 -yl) [(3S)-tetrahydrofuran-3-yl] carbonate (0.028 g,
0.120 mmol). The reaction mixture was stirred at room température for 17 hours.
The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H20/acetonitrile) to afford the desired product, 443. LCMS RT = 1.8 (M+1) 463.3.
General Scheme 6A
a
6c
e
’Pr2NEt, THF (b) Pd(PPh3)4, 2M Na2CO3 80 ’C (c) 4N HCI/dioxane, MeOH, 80 ’C (d) (S)-2,5dioxopyrrolidin-1 -yl tetrahydrofuran-3-yl carbonate, 'Pr2NEt, THF (e) 25% NaOMe/MeOH or 1M LiOH, 150 ’C, microwave, 10 min.
Formation of fert-butyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-cyclobutylcarbamate (6a).
A mixture of 2,4-dichloro-5-fluoro-pyrimidine (0.97 g, 5.81 mmol) and 'Pr2NEt (2.53 mL, 14.50 mmol) in THF (50 mL) was treated with tert-butyl 3-aminoazetidine-1carboxylate (1.00 g, 5.81 mmol) and stirred at room température until complété by LCMS. The mixture was concentrated to dryness then diluted with water and extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford an oil that was purified by silica gel chromatography (0-100% petroleum ether/EtOAc gradient). Removal of the solvent under reduced pressure afforded 3.36g (89% yield) of a white solid after vacuum drying.
LCMS: RT = 3.2 min, ES+ 303.
Formation of tert-butyl 3-(2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)azetidine-1-carboxylate (6b).
A solution of fert-butyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-cyclobutylcarbamate, 6a, (0.39 g, 1.28 mmol) and 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)l-tosyl-IH-pyrrolop.S-bJpyridine (0.60 g, 1.39 mmol) in DME (10 mL) and 2M
-18116260
Na2CO3 (5 mL) was degassed with argon (3x vacuum and back fill) then treated with catalytic Pd(PPh3)4 and the mixture heated at 80 °C under argon. After 3h the solvent was concentrated to a reduced volume then diluted with EtOAc and filtered through florisil (40 mL pad) and washed with EtOAc. The solvent was concentrated in vacuo and the resulting dark residue purified with silica-gel chromatography (0-100% petroleum ether/EtOAc gradient) to afford 230 mg (32% yield) of 6b, as white-pink solid.
LCMS: RT = 4.7 min, ES+ 573.
Formation of N-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-amine hydrochloride (6c).
A suspension of tert-butyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)azetidine-1-carboxylate, 6b, (0.23 g, 0.40 mmol) in methanol (10 mL) was treated with 4N HCI/dioxane (5 mL, 20 mmol) then heated at 80 ’C for 30 minutes. The solvent was removed and the residue dried under vacuum to afford 240mg of a solid that was used without purification.
LCMS RT = 2.4 min, ES+473.
Formation of (S)-tetrahydrofuran-3-yl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)azetidine-1-carboxylate (422).
A suspension of A/-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-amine hydrochloride, 6c, (0.06 g, 0.11 mmol) in THF (1 mL) was treated with 'Pr2NEt (0.30 mL, 1.70 mmol) then solid (S)-2,5-dioxopyrrolidin-1 -yl tetrahydrofuran-3-yl carbonate (0.03 g, 0.11 mmol) was added. The resulting mixture was stirred for 2 hours at room température and then quenched with 200 FIL of morpholine and evaporated to dryness to afford (S)-tetrahydrofuran-3-yl 3-(2-(5chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1 carboxylate, 6d, which was used without purification. LCMS RT = 3.8 min, ES+ 588. (S)-tetrahydrofuran-3-yl 3-(2-(5-chJoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)azetidine-1-carboxylate, 6d, was dissolved in methanol (2 mL) and then treated with of 25% sodium methoxide/methanol (0.5 mL) and heated at 60 ’C in sealed tube. LCMS showed complété reaction after 10 minutes. The resulting solution was quenched with aqueous saturated NH4CI solution (0.5mL) then evaporated to dryness and the residue dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 25.9mg (55% yield) of the desired product, 422, as a solid. LCMS RT = 1.8 min, ES+433.
General Scheme 6B
-18216260
Formation of 2-(5-chloro-1-tosyi-1H-pyrrolo[2,3-b]pyndin-3-yl)-5-fluoro-W-(1(propylsulfonyl)azetidin-3-yl)pyrimidin-4-amine (423).
To a stirred suspension of A/-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.055 g, 0.110 mmol) in THF (1 mL) was added 'Pr2NEt (0.300 mL, 1.720 mmol) followed by propane-1sulfonyl chloride (0.012 mL, 0.108 mmol). The resulting homogenous light yellow solution mixture was heated at 50 ’C for one hour at which time LCMS showed complété reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60 ’C in sealed tube for 10 minutes. The resulting solution was quenched with aqueous saturated NH4CI solution (0.5mL) then evaporated to dryness. The resulting residue was dissolved in DMSO and purifïed by reverse phase HPLC (ammonium formate buffer) to afford 19.8 mg (43% yield) of the desired product, 423, as a solid. LCMS RT = 2.6 min, ES* 425.
Other analogs that can be prepared in a manner similar to 423:
Formation of 2-(5-chloro-1 H-pyrrolo[2,3-b]pyridÎn-3-yl)-N-( 1 -(cyclopentylmethylsulfonyl)azetidin-3-yl)-5-fluoropyrimidin-4-amine (469).
To a stirred solution of A/-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1/-/-pyrrolo[2,3-b]pyridin-
3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.03 g, 0.06 mmol) in dichloromethane (1 mL) was added 'Pr2NEt (0.33 pL, 1.90 mmol) followed by cyclopentylmethanesulfonyl chloride (0.01 g, 0.06 mmol). The resulting mixture was stirred 30 minutes at room température at which time LCMS showed complété reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60 ’C in sealed tube for 10
-18316260 minutes. The solution was quenched with aqueous saturated NH4CI solution (0.5mL) then evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 27.4 mg (88% yield) of the desired product, 469, as a solid. LCMS RT = 3.1 min, ES* 465.
Formation of 1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)azetidin-1-yl)-2-methoxyethanone (468).
According to the procedure for compound 469 using methoxyacetyl chloride afforded 11.7 mg (51 % yield) of 468, as a white solid. LCMS RT = 1.6 min, ES* 390.
Formation of 3-(2-(5-chloro-1W-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)azetidine-1-carboxamide (512).
According to the procedure for compound 469 using 61 mg (0.11 mmol) of 6c and isocyanatotrimethylsilane (15.14 pL, 0.11 mmol) afforded 87mg (79% yield) of 512, as a white solid: LCMS RT = 2.4 min, ES* 362.
General Scheme 7
a
2,4-dîchloro-5-fluoropyrimidine, 'Pr2NEt, THF (b) 5chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1-tosyl-1H-pyrrolo[2,3-f)]pyridine, Pd(PPh3)4, 2M Na2CO3 90°C (c) 4N HCI/dioxane, MeOH, 80 “C; (d)
-18416260 methanesulfonyl chloride, 'Pr2NEt, THF, RT (e) 25%
NaOMe/MeOH or 1M LiOH, 150 ’C, microwave, 10 min.
Formation of (S)-tert-butyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)pyrrolidine-1 carboxylate (7a).
To a mixture of 2,4-dichloro-5-fluoro-pyrimidine (1,75 g, 10.48 mmol) and 'Pr2NEt (3.27 mL, 18.78 mmol) in THF (50 mL) was added fert-butyl (3S)-3-aminopyrrolidine1-carboxylate (1.83 mL, 10.48 mmol) in THF (2 mL). The resulting solution was allowed to stir at room température for 2 hours. The mixture was concentrated to dryness, diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 3.41g of 7a, as a white foamy solid, LCMS RT = 3.0 min. ES+ 317.
Formation of (S)-tert-butyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)pyrrolidine-1 -carboxylate (7b).
A solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrolo[2,3’b]pyridine (2.41 g, 5.60 mmol) and fert-butyl (3S)-3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]pyrrolidine-1-carboxylate, 7a, (1.69 g, 5.30 mmol) in DME (34 mL) and 2M Na2CO3 (8.5 mL) was degassed with nitrogen (5 min) then treated with Pd(PPh3)4 (0.31 g, 0.27 mmol) then heated at 90 ’C overnight. The resulting dark solution was filtered through florisil, washed with EtOAc then concentrated in vacuo. The resulting residue was purified by silica-gel chromatography (0-100%) petroleum ether: EtOAc gradient. Removal of the solvent under reduced pressure afforded 1.33g (42% yield) of a white solid after vacuum drying. LCMS RT = 4.4 min. ES+ 588.
Formation of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)pyrrolidin-3-yl]pyrimidin-4-amine (7c).
A solution of fert-butyl (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3yl]-5-fluoro-pyrimidin-4-yl]amino]pyrrolidine-1 -carboxylate, 7b, (1.33 g, 2.27 mmol) in THF (25 mL) was treated with hydrogen chloride (12 mL of 4M solution in dioxane, 48.00 mmol) at room température. The reaction was then heated at 90 ’C until LCMS showed reaction was complété. The mixture was concentrated to dryness then dried under vacuum to afford 1,04g (88% yield) of 7c, as a tan solid. LCMS RT = 2.3 min. ES* 487.
Formation of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1(methylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-amine (398).
To a stirred suspension of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5fluoro-A/-[(3S)-pyrrolidin-3-yl]pyrimidin-4-amine hydrochloride, 7c, (0.05 g, 0.10
-18516260 mmol) in THF (1 mL) was added ’Pr2NEt (0.10 mL, 0.57 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.57 mmol). The resulting homogenous light yellow mixture was heated at 50 “C for one hour at which time LCMS showed complété reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in méthanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60 ’C in sealed tube until LCMS showed reaction was complété. The resulting solution was quenched with aqueous saturated NH4CI (0.5mL) then evaporated to dryness. The residue was dissolved in DMSO and purifîed by reverse phase HPLC (ammonium formate buffer) to afford 15.8 mg (37% yield) of 398, as a solid. LCMS RT = 1.7 min. ES* 411.
Other analogs that can be prepared in a manner similar to 398:
Formation of (S)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-/V-(1 (ethylsulfonyl)pyrrolidin-3-yl)-5-fluoropyrimidin-4-amine (399).
According to the procedure for compound 398 using 50 mg (O.IOmmol) of 7c and ethanesulfonyl chloride (54 pL, 0.57 mmol) afforded 21.7mg (49% yield) of 399, as a solid. LCMS RT = 1.8 min. ES+ 425.
Formation of (S)-2-(5-chloro-1 M-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-( 1 (isopropylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-amine (400).
According to the procedure for compound 398 using 2-propanesulfonyl chloride (82 mg, 0.57 mmol) afforded 17.9 mg (39% yield) of 400, as a solid. LCMS RT = 1.9 min. ES+ 439.
Formation of (S)-2-(5-chloro-1H-pyrrolo[2I3-blpyridin-3-yl)-W-(1(cyclopropylsulfonyl)pyrrolidin-3-yl)-5-fluoropyrÎmidÎn-4-amine (401).
-18616260
According to the procedure for compound 398 using cyclopropanesulfonyl chloride (81 mg, 0.57 mmol) afforded 17.1 mg (37% yield) of 401, as a solid. LCMS RT = 1.9 min. ES* 437.
Formation of (S)-W-(1-(butylsulfonyl)pyrrolidin-3-yl)-2-(5-chloro-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoropyrimidÎn-4-amine (402).
According to the procedure for compound 398 using 1-butanesulfony) chloride (90mg, 0.57 mmol) afforded 21 mg (45% yield) of 402, as a solid. LCMS RT = 2.1 min. ES* 453.
Formation of (S)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1 (cyclopentylsulfonyl)pyrrolïdin-3-yl)-5-fluoropyrimidin-4-amine (403).
According to the procedure for compound 398 using cyclopentanesulfonyl chloride (97 mg, 0.57 mmol) afforded 9.7 mg (20% yield) of 403, as a solid. LCMS RT = 2.1 min. ES* 465.
Formation of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1(propylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-amine (410).
According to the procedure for compound 398 using propylsulfonyl chloride (20 mg, 0.14 mmol) afforded 15.5 mg (36% yield) of 410, as a solid. LCMS RT = 2.0 min. ES* 439.
Formation of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1(cyclopentylmethylsulfonyl)pyrrolidin-3-yl)-5-fluoropyrimidin-4-amine (479).
-18716260
According to the procedure for compound 398 using cyclopentylmethyl sulfonyl chloride (30 mg, 0.16 mmol) afforded 26.7 mg (58% yield) of 479, as a solid. LCMS
RT = 2.3 min. ES+ 479.
Formation of (S)-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (476).
According to the procedure for compound 398 using methylchloroformate (20 mg, 0.21 mmol) afforded 13.6 mg (52% yield) of 476, as a trifluoroacetic acid sait after preparatory HPLC purification. LCMS (ammonium formate buffer) RT = 2.6 min. ES+
Formation of (S)-isopropyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (477).
According to the procedure for compound 476 using isopropyl chloroformate (20mg, 0.21 mmol) afforded 11.3mg (42% yield) of 477, as a trifluoroacetic acid sait after preparatory HPLC purification. LCMS (ammonium formate buffer) RT = 2.0 min. ES+ 419.
Formation of (3S)-(tetrahydrofuran-3-yl)methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-
3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (484),
According to the procedure for compound 398 using 2,5-dioxopyrrolidin-1 -yl (tetrahydrofuran-3-yl)methyl carbonate (0.023 g, 0.096 mmol) afforded 5.7 mg (10% yield) of 484, as a trifluoroacetic acid sait after preparatory HPLC purification. LCMS (ammonium formate buffer) RT = 2.6 min. ES+ 461.
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Formation of ((S)-3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)pyrrolidin-1-yl)(tetrahydrofuran-3-yl)methanone (478).
According to the procedure for compound 398 using tetrahydrofuran-3-carboxyiic acid (35 mg, 0.30 mmol) afforded 22.2mg (52% yield) of 478, as a solid. LCMS (TFA buffer) RT = 1.6 min. ES+ 431.
Formation of (S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)pyrrolidin-1-yl)ethanone (480).
According to the procedure for compound 398 using acetyl chloride (45 uL, 0.64 mmol) afforded 4.2 mg (18% yield) of 480, as a solid. LCMS (TFA buffer) RT = 1.6 min, ES+ 375.
Formation of (S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)pyrrolidin-1 -yl)-2-methoxyethanone (481).
According to the procedure for compound 398 using methoxyacetyl chloride (50 mg, 0.46 mmol) afforded 8.6 mg (33% yield) of 481, as a solid. LCMS (TFA buffer) RT = 1.6 min, ES+ 405.
Formation of (S)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)pyrrolidin-1-yl)(3-methyloxetan-3-yl)methanone (482).
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According to the procedure for compound 398 using 3-methyloxetane-3-carboxylic acid (15 mg, 0.13 mmol) afforded 17.7 mg (42% yield) of 482, as a solid. LCMS (TFA buffer) RT =1.6 min, ES* 431.
Formation of ((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)pyrrolidin-1-yl)(morpholin-2-yl)methanone (483).
According to the procedure for compound 398 using morpholine 2-carboxylic acid (25mg, 0.11 mmol) afforded 3.6mg (8% yield) of 483 as a solid.
LCMS (TFA buffer): Rt 1.4 min, ES* 446.
Using a procedure équivalent to that for the préparation of 7c, the other enantiomer (8a) can be obtained.
Analogs that can be prepared from compound 8a.
General Scheme 8
(S)-2,5-dioxopyrrolidin-1 -yl tetrahydrofuran-3-yl carbonate, 'Pr2NEt, THF, RT (b) 25% NaOMe/MeOH or 1M LiOH, 150°C, microwave, 10 min.
Formation of (R)-((S)-tetrahydrofuran-3-yl) 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3yl)-5-fluoropyrimidin-4-ylamino)pyrrolidïne-1-carboxylate (424).
According to the procedure for compound 398 using (R)-tert-butyl 3aminopyrrolidine-1-carboxylate and (S)-2,5-dioxopyrrolidin-1 -yl tetrahydrofuran-3-yl carbonate afforded 19.8mg (47% yield) of 424 as a solid. LCMS (TFA buffer) RT = 1.8 min, ES* 447
Formation of (R)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-19016260 ylamino)pyrrolidin-1 -yl)(3-methyloxetan-3-yl)methanone (473),
According to the procedure for compound 482 using (R)-2-(5-chloro-1-tosyl-1Hpyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-A/-(pyrrolidin-3-yl)pyrimidin-4-annine hydrochloride,
8a, and 3-methyloxetane-3-carboxylic acid (50 mg, 0.46 mmol) afforded 18.6 mg (44% yield) of 473, as a solid. LCMS (TFA buffer) RT = 1.6 min, ES+ 431.
Formation of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1(cyclopropylmethyl)pyrrolidin-3-yl)-5-fluoropyrimidin-4-amine (415).
A solution of (S)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-/\/(pyrrolidin-3-yl)pyrimidin-4-amine hydrochloride, 7c, (0.05 g, 0.10 mmol) in methanol (3 mL) was treated with cyclopropane carboxaldehyde (0.30 mmol), sodium cyanoborohydride (0.30 mmol) and potassium acetate (0.04 g, 0.30 mmol) then stirred at 60 °C until the reaction was complété. Aqueous workup afforded an oil that was dissolved in methanol (2 mL) then treated with of 25% sodium methoxide/methanol (0,5 mL) and heated at 60° C in sealed tube. LCMS showed complété reaction. The resulting solution was quenched with aqueous saturated NH4CI solution (0.5mL) then evaporated to dryness and the residue dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 6.2mg (17% yield) of 415 as a solid. LCMS RT = 1.5 min, ES+ 387.
Formation of N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimrdin-4-yl)-1(methylsulfonyl)azepan-4-amine (496).
According to the procedure for compound 398 using methanesulfonyl chloride afforded the desired product, 496, as a solid. LCMS RT = 1.8 min, ES+ 439.
Formation of 1-(4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-19116260 ylamino)azepan-1 -yl)ethanone (497).
According to the procedure for compound 398 using acetyl chloride afforded the desired product, 497, as a solid. LCMS RT = 1.7 min, ES* 403.
Formation of methyl 4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)azepane-1 -carboxylate (498).
According to the procedure for compound 398 using methyl chloroformate afforded the desired product, 498, as a solid. LCMS RT = 1.9 min, ES* 419.
Formation of 4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fliioropyrimidin-4ylamino)-/V,/V-dimettiylazepane-1-carboxamide (499),
According to the procedure for compound 398 using dimethyl carbamoyl chloride afforded desired product, 499, as a solid. LCMS RT = 1.8 min, ES* 432.
Formation of 4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrÎmidin-4ylamino)azepane-1-carboxamide (509).
According to the procedure for compound 398 using trimethylsilylisocyanate afforded desired product, 509, as a solid. LCMS RT = 1.6 min, ES* 404.
Formation of 4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)-N-methylazepane-1 -carboxamide (506).
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According to the procedure for compound 398 using methyl isocyanate afforded the desired product, 506, as a hydrochloride sait after treating with HCI/dioxane. LCMS
RT = 2,1 min, ES 418.
General Scheme 11
'Pr2NEt, THF (b) 5-chloro-1-(p-tolylsuifonyl)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine, Pd(Ph3P)4, Na2CO3, DME,
130 °C (c) HCI/dioxane, CH2CI2 (d) 3methoxypropanoyl chloride, 'Pr2NEt, CH2CI2/DMF
Formation of (R)-fert-butyl 3-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (11a).
To a solution of 2]4-dichloro-5-fluoropyrimidine (0.43 g, 2.59 mmol) and (R)-fert-butyl 3-(aminomethyl)piperidine-1-carboxylate (0.56 g, 2.59 mmol) in THF (50 mL) was added 'Pr2NEt (0.45 mL, 2.59 mmol). The reaction mixture was heated at 80 °C at for 8h. The solvent was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (5-30% EtOAc/hexanes) to afford the desired product, 11a. LCMS (M+1) 345.1.
Formation of (R)-tert-butyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimÎdin-4-ylamino)methyl)piperidine-1 -carboxylate (11b)
To a degassed solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.71 g, 1.65 mmol), (R)-fert-butyl 3-((2chloro-5-fluoropyrimidin-4-ylamino)methyl)-piperidine-1 -carboxylate, 11a, (1.19g, 3.60 mmol) and aqueous K2CO3 (2.48 mL of 2 M solution, 4.97 mmol) in THF (30 mL) was added bis(tri-terf-butylphosphine)palladium(0) (0.17 g, 0.33 mmol). The reaction mixture was degassed for an additional 15 min. The mixture was stirred at
-19316260 room température for 4 hours, concentrated in vacuo, and the resulting crude residue was purified by silica gel chromatography (10%-80% EtOAc/hexanes) to afford the desired product, 11b. LCMS (M+1) 461.4, (M-1) 460.7.
Formation of 2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3ylmethyl)pyrimidin-4-amine (11 c).
To a solution of (R)-fert-butyl 3-((2-(5-chloro-1H-pyrrolo[2,3-ô]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate, 11b, (0.13 g, 2.8 mmol) in 5% MeOH/CH2CI2 was added 0.7 ml 4N solution of HCI/dioxane. The reaction mixture was stirred at room température for 12 hours, The resulting precipitate was filtered and used without further purification. LCMS (M+1) 361.1.
Formation of (R)-1 -(3-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidm-4ylamino)methyl)piperidin-1 -yl)-3-methoxypropan-1 -one (327).
To a solution of 2-(5-chloro-1-tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-/V(piperidin-3-ylmethyl)pyrimidin-4-amine, 11c, (0.04 g, 0.11 mmol) in a 10:1 mixture of CH2CI2/DMF (1 mL) was added 'Pr2NEt (0.058 mL, 0.33 mmol) and 3methoxypropanoyl chloride (0.02 g, 0.17 mmol). After 12 hours, the solvent was concentrated in vacuo and the resulting crude was and the crude was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 327. LCMS (M+1) 447.3.
Other analogs that can be prepared in the same manner as 327:
113 104 (R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-i)]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2-methoxyphenyl)methanone (113).
LCMS RT = 2.9 (M+1) 479.4, (M-1) 477.6.
(/?)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-2-(thiophen-2-yl)ethanone (104).
LCMS RT = 2.8 (M+1) 485.3, (M-1) 483.4.
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111 (/?)-(3-((2-(5-chloro-1ff-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(3,5-difluorophenyl)methanone (108).
LCMS RT = 2.1 (M+1) 501.3.
(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)ethanone (111).
LCMS RT = 2.5 (M+1) 403.4.
107 (/?)-benzo[ÎJ]thiophen-2-yl{3-((2-(5-chloro-1W-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)methanone (107).
LCMS RT = 3.2 (M+1) 521.3.
(S)-1 -(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)ethanone (37).
LCMS RT = 2.5 (M+1) 403.3.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(furan-2-yl)methanone (102).
LCMS RT = 2.7 (M+1) 455.3, (M-1) 453.3.
(R)-2-(benzyloxy)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)ethanone (106).
LCMS RT = 3.0 (M+1) 509.3, (M-1) 507.5.
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126
(R)-2-fluoroethyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyndin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (126).
LCMS RT = 2.1 (M+1) 451.4.
(R)-(3-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriniÎdin-4ylamino)methyl)piperidin-1 -yl)(thiophen-2-yl)methanone (97).
LCMS RT = 2.9 (M+1) 471.2, (M-1) 469.6.
(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-2,2-dimethylpropan-1 -one (105).
LCMS RT = 3.0 (M+1) 445.3, (M-1) 443.4. (R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2,3-dimethylphenyl)methanone (157).
LCMS RT = 2.0 (M+1) 493.1.
110 (R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-5-fluoropyrimîdin-4ylamino)methyl)piperidin-1-yl)-2-phenoxyethanone (94).
LCMS RT = 2.9 (M+1) 495.3, (M-1) 493.5.
(R)-2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-2-oxoethyl ethanoate (110).
LCMS RT = 2.5 (M+1) 461.3, (M-1) 459.4.
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(S)-ethyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (33).
LCMS RT = 3.0 (M+1) 433.3, (M-1) 431.4.
(/?)-prop-1-en-2-yl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (74).
LCMS RT = 3.1 (M+1) 445.2, (M-1) 443.4.
(/?)-3-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carbonyl)pyrazine-2-carboxylic acid (82).
LCMS RT = 1.6 (M+1) 511.3.
(1S,2/?)-2-((R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyrÎdm-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carbonyl)cyclopropanecarboxylic acid (83).
LCMS RT = 1.6 (M+1) 473.4.
17 (S)-1-(3-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fliioropyriTTiidin-4ylamino)methyl)piperidin-1-yl)-2-methoxyethanone (45).
LCMS RT = 2.4 (M+1) 433.3, (M-1) 431.4.
(S)-allyl 3-((2-(5-chloro-1M-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (17).
LCMS RT = 3.1 (M+1) 445.3, (M-1) 443.4.
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(R) -prop-2-ynyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridÎn-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (122).
LCMS RT = 2.9 (M+1) 443.3, (M-1) 441.5.
(S) -ethyl 5-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)-5-oxopentanoate (19).
LCMS RT = 2.8 (M+1) 503.4, (M-1) 501.5.
(R) -but-2-ynyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (127).
LCMS RT = 3.1 (M+1) 457.3, (M-1) 455.6.
(S) -methyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridîn-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (23).
LCMS RT = 2.8 (M+1) 419.3, (M-1) 417.3.
(R) -allyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (119).
LCMS RT = 3.1 (M+1) 445.4, (M-1) 443.5.
(S) -but-2-ynyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (30).
LCMS RT = 3.1 (M+1) 457.3, (M-1) 455.6.
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(R) -tert-butyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (15).
LCMS RT = 2.7 (M+1) 461.3.
(S) -isobutyl 3-((2-(5-chloro-1H-pyrrolo[2,3-i>]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (28).
LCMS RT = 3.3 (M+1) 461.4.
(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamÎno)methyl)piperidin-1-yl)propan-1-one (32).
LCMS RT = 1.9 (M+1) 417.2.
(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)pÎpendin-1-yl)-2-methylpropan-1-one (34).
LCMS RT = 3.2 (M+1) 447.4, (M-1 )445.5.
(S)-isopropyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (35).
LCMS RT = 3.0 (M+1) 447.3, (M-1) 445.4.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(cyclopentyl)methanone (99).
LCMS RT = 3.1 (M+1) 457.3, (M-1) 455.4Λ
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(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyndin-3-yl)-5-fluoropyriniidin-4ylamino)methyl)piperidin-1-yl)but-2-en-1-one (41)
LCMS RT = 2.7 (M+1) 429.3, (M-1) 427.4.
(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-3,3-dimethylbutan-1-one (42)
LCMS RT = 3.1 (M+1) 459.3, (M-1) 457.4.
(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)-3,3,3-trifluoropropan-1 -one (44)
LCMS RT = 2.8 (M+1) 471.3, (M-1) 469.4.
(S)-2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-N,/V,N-trimethyl-2-oxoethanaminium (43)
LCMS RT = 2.4 (M+1) 460.3, (M-1) 458.5.
Ν' I
(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)pipendin-1 -yl)-2-(dimethylamino)ethanone (46)
LCMS RT = 2.2 (M+1) 446.4, (M-1) 444.5.
(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)-2-(pyridin-3-yl)ethanone (47)
LCMS RT = 2.4 (M+1) 480.3, (M-1) 478.6.
-20016260
(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)but-3-en-1-one (49)
LCMS RT = 2.7 (M+1 ) 429.3, (M-1 ) 427.4.
(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4 ylamino)methyl)piperidin-1-yl)-2-(1H-tetrazol-1-yl)ethanone (48)
LCMS RT = 2.4 (M+1) 471.3, (M-1) 469.4.
(/?)-5-((S)-3-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carbonyl)dihydrofuran-2(3H)-one (51)
LCMS RT =1.7 (M+1) 472.9.
(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4 ylamino)methyl)piperîdin-1 -yI)-2-( 1 H-îmîdazol-1 -yl)ethanone (50)
LCMS RT = 2.3 (M+1) 469.3, (M-1) 467.4.
(S)-1 -(3-((2-(5-chloro-1H-pyrrolo[2f3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)pent-4-yn-1 -one (52)
LCMS RT = 1.9 (M+1) 441.3.
(R)-5-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-5-oxopentanoic acid (53)
LCMS. RT = 1.8 (M+1) 475.3, (M-1 )473.4.
-20116260
(R)-2-(2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)pÎperidin-1-yl)-2-oxoethoxy)ethanoic acid (54)
LCMS RT = 1.7 (M+1) 477.3, (M-1) 475.4.
(1 S, 3R)-3-((R)-3-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carbonyl)cyc)opentanecarboxylic acid (55)
LCMS RT = 2.5 (M+1) 501.3, (M-1) 499.6.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2-fluorophenyl)methanone (58)
LCMS RT = 2.9 (M+1) 483.3, (M-1) 481.5.
(R)-5-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridÎn-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)-3,3-dimethyl-5-oxopentanoic acid (80)
LCMS RT = 1.9 (M+1) 503.3.
2-chloro-1 -((R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)propan-1-one (93)
LCMS RT = 2.9 (M+1) 451.2, (M-1) 449.4.
(R)-(3-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)(cyclohexyl)methanone (95)
LCMS RT = 3.2 (M+1) 471.3, (M-1) 449.4.
-20216260
(R)-tert-butyl 3-((2-(5-amino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (114)
LCMS RT = 2,7 (M+1) 461.3.
Cl
495
(R)-ethyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrinriidin-4-ylamino)methyl)piperidine1-carboxylate (495)
LCMS RT = 1.7 (M+1) 385.4.
(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-ù]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1 yi)-2-methoxyethanone (491)
LCMS RT =1,7 (M+1) 415.4,
493
494 (R)-1-(3-((2-(5-chloro-1H-pyrrolo[2]3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1yl)-3-methoxypropan-1-one (493)
LCMS RT =1.7 (M+1) 429.5.
(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1yl)-3-methylbutan-1-one (494)
LCMS RT = 1.9 (M+1) 427.5.
-20316260
(S)-2-methoxyethyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (24)
LCMS RT = 2.8 (M+1) 463.2, (M-1) 461.3.
(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-2-phenylethanone (56)
LCMS RT = 2.9 (M+1) 479.3, (M-1) 477.4.
(R) -1 -( 3-( ( 2 -( 5-c h I o ro-1 H-py rro lo[2,3 -b] py rîd i n-3-y I )-5-f I u o ropy ri m i d i n -4ylamino)methyl)piperidin-1-yl)-3-methylbut-2-en-1-one (57)
LCMS RT = 2.8 (M+1) 443.3, (M-1) 441.4.
(R)-4-(methoxycarbonyl)phenyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (63)
LCMS RT = 3.2 (M+1) 539.3, (M-1) 537.4.
(R)-phenyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (68)
LCMS RT = 3.2 (M+1) 481.4, (M-1) 479.4.
(R)-2-chlorophenyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)pîperidine-1 -carboxylate (70)
LCMS RT = 3.3 (M+1) 515.3, (M-1) 513.3.
-20416260 (R)-2-methoxyphenyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (69)
LCMS RT = 3.2 (M+1) 511.3.
71 72 (R)-p-tolyl 3-((2-(5-chloro-1W-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimÎdin-4ylamino)methyl)piperidine-1 -carboxylate (71)
LCMS RT = 3.4 (M+1) 495.3, (M-1) 493.4.
(R)-3-(trifluoromethyl)phenyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-510 fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (72)
LCMS RT = 3.5 (M+1) 549.3, (M-1) 547.4.
(R)-4-fluorophenyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (73)
LCMS RT = 3.3 (M+1) 499.3, (M-1) 497.4.
(R)-2-(1-(2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)-2-oxoethyl)cyclopentyl)ethanoic acid (81)
LCMS RT = 2.0 (M+1) 529.3.
85
-20516260 (R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2-chlorophenyl)methanone (84)
LCMS RT = 2.0 (M+1) 499.4.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(3,4-difluorophenyl)methanone (85)
LCMS RT = 2.1 (M+1) 501.3.
96 (R)-2-chloro-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)ethanone (92)
LCMS RT = 2.7 (M+1) 437.2, (M-1) 435.3.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyrîdin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2,6-dichlorophenyl)methanone (96)
LCMS RT = 2.9 (M+1) 535.2, (M-1) 533.2.
(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-2-(4-fluorophenyl)ethanone (98)
LCMS RT = 2.9 (M+1) 497.3, (M-1) 495.4.
(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)-2-cyclopentylethanone (100)
LCMS RT = 3.1 (M+1) 471.3, (M-1) 469.5.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidÎn-4ylamÎno)methyl)piperidin-1-yl)(pyrazin-2-yl)methanone (111)
-20616260
LCMS RT = 2.5 (M+1) 467.2, (M-1) 465.4.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimjdin-4ylamino)methyl)piperidin-1 -yl)(furan-2-yl)methanone (186)
LCMS RT = 2.7 (M+1) 455.3, (M-1) 453.3.
(R)-benzo[d][1,3]dioxol-5-yl(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamïno)methyl)piperidin-1 -yl)methanone (103)
LCMS RT = 2.8 (M+1 ) 509.3, (M-1 ) 507.5.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2,4-difluorophenyl)methanone (152)
LCMS RT = 2.8 (M+1) 501.3, (M-1) 499.4.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylarnino)methyl)piperidin-1-yl)(2-(methylamino)phenyl)methanone (112)
LCMS RT = 3.0 (M+1) 494.3, (M-1) 492.5.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylarnino)methyl)piperidin-1-yl)(3,4-dimethoxyphenyl)methanone (109)
LCMS RT = 2.7 (M+1) 525.3, (M-1) 523.4.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(3,5-dÎfluorophenyl)methanone (86)
LCMS RT = 2.8 (M+1) 501, (M-1) 499.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(6-fluoro-4H-benzo[d][1,3]dioxin-8-yl)methanone (142)
-20716260
LCMS RT = 2.8 (M+1) 541.5.
(R)-(3-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(o-tolyl)methanone (143)
LCMS RT = 2.9 (M+1) 479.4, (M-1) 477.6.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4 ylamino)methyl)piperidin-1-yl)(2-(trifluoromethyl)phenyl)methanone (146)
LCMS RT = 3.0 (M+1) 533.3, (M-1) 531.5.
145
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)rnethyl)pipendin-1-yl)(2,3-dihydrobenzofuran-6-yl)methanone (145)
LCMS RT = 2.9 (M+1) 507.3, (M-1) 505.5. (R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2,4-dichlorophenyl)mettianone (147)
LCMS RT = 3.2 (M+1) 533.3, (M-1) 531.4.
148 (R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2-ethoxyphenyl)methanone (158)
LCMS RT = 3.0 (M+1) 509.4, (M-1) 507.5.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyI)piperidin-1-yl)(2-methoxy-3-methylphenyl)methanone (148)
LCMS RT = 3.0 (M+1) 509.3, (M-1) 507.5.
-208- ,
(/?)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)(2,5-difluorophenyl)methanone (151 )
LCMS RT = 2.9 (M+1) 501.2, (M-1) 499.5.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2-phenoxyphenyl)methanone (150)
LCMS RT = 3.2 (M+1) 557.3, (M-1) 555.6.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2,4-dimethoxyphenyl)methanone (154)
LCMS RT = 2.3 (M+1) 525.3, (M-1) 523.2.
(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(cyclopropyl)methanone (325)
LCMS RT = 2.7 (M+1) 429.2.
272 268 (/?)-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)niethyl)piperidin-
1-yl)(2-methoxyphenyl)methanone (272)
LCMS RT = 2.5 (M+1) 461.3.
(R)-1-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4ylamino)methyl)piperidin-1-yl)ethanone (268)
LCMS RT = 2.1 (M+1) 369.3.
-20916260
(R)-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-
1-yl)(phenyl)methanone (271)
LCMS RT = 2.5 (M+1) 431.4.
(R)-1-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4ylamino)methyl)piperidin-1-yl)butan-1-one (270)
LCMS RT = 2.4 (M+1) 397.3.
(/?)-(3-((5-fluoro-2-(1H-pyrrolo[2,3-fa]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-
1-yl)(phenyl)propan-1-one (269)
LCMS RT = 2.3 (M+1) 383.3.
(S)-1-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4ylamino)methyl)piperidin-1-yl)butan-1-one (225)
LCMS RT = 2.4 (M+1) 397.4.
In a manner analogous to that of the préparation of compound 327, compounds with the opposite absolute stereochemistry, were prepared as follows:
General Scheme 12A.
12a
HN
T tert-butylisocyanate, pyridine, CH2CI2
Formation of (S)-N-tert-butyl-3-((2-(5-chloro-1H-pyrrolo[2I3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)methyl)piperidine-1 -carboxamide (20).
-21016260
To a solution of (R)-2-(5-chloro-1 /-/-pyrrolo[2,3-ô]pyridin-3-yl)-5-fluoro-N-(piperidin-3ylmethyl)pyrimidin-4-amine, 12a, (0.013 g, 0.036 mmol) in mixture of pyridîne/CH2CI2 (1 mL of 1:1 mixture was added tert-butyl isocyanate (0.005 mL, 0.046 mmol). The reaction mixture was stirred at 40 °C for 12h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 20. LCMS RT = 3.0 (M+1) 460.4, (M-1) 458.4.
Other analogs that can be prepared in the same manner as 20:
(R) -W-tert-butyl-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxamide (128)
LCMS RT = 3.0 (M+1) 460.4, (M-1) 458.4.
(S) -3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)W-(thiophen-3-yl)piperidine-1-carboxamide (22)
LCMS RT = 2.9 (M+1) 486.3, (M-1) 484.6.
(S)-ethyl 2-(3-((2-(5-chloro-1H-pyrro!o[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methy1)piperidine-1-carboxamido)ethanoate (25)
LCMS RT = 2.6 (M+1) 490.3, (M-1) 488.4.
(S)-ethyl 3-((2-(5-chloro-1H-pyrroloI2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carbonylcarbamate (26)
LCMS RT = 2.5 (M+1) 476.3, (M-1) 474.5.
HN^
-21116260 (S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)W-isopropylpiperidine-1 -carboxamide (27)
LCMS RT = 2.7 (M+1) 446.4, (M-1) 444.5.
(S)-3-((2-(5-chloro-1W-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)N-methylpiperidine-1-carboxamide (29)
LCMS RT = 2.4 (M+1) 418.3, (M-1) 416.1.
(S)-W-allyl-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxamide (39)
LCMS RT = 2.6 (M+1) 444.4, (M-1) 442.4.
(S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrÎmidin-4-ylamino)methyl)N-(pyridin-3-yl)piperidine-1-carboxamide (40)
LCMS RT = 2.5 (M+1) 481.3, (M-1) 479.4.
(/?)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)N-(3-fluorophenyl)piperidine-1 -carboxamide (75)
LCMS RT = 3.0 (M+1) 498.3, (M-1) 496.5.
(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)N-(3-methoxyphenyl)piperidine-1 -carboxamide (76)
LCMS RT = 2.9 (M+1) 510.3, (M-1) 508.5.
(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)N-(3-ethanoylphenyl)pîperidine-1-carboxamide (77)
-21216260
LCMS RT = 2.8 (M+1) 522.3, (M-1) 520.4.
(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)W-m-tolylpiperidine-1-carboxamide (78)
LCMS RT = 3.0 (M+1) 494.3, (M-1) 492.4.
(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)N-(3-(trifluoromethyl)phenyl)piperidine-1-carboxamide (79)
LCMS RT = 3.3 (M+1) 548.3, (M-1) 546.4.
(R)-ethyl 3-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-410 ylamino)methyl)piperidine-1-carboxamido)propanoate (118)
LCMS RT = 2.6 (M+1) 504.2, (M-1) 502.5.
(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-f1uoropyrimidin-4-ylamino)methyl)N-(5-methyl-2-(trifluoromethyl)furan-3-yl)piperidine-1 -carboxamide (120)
LCMS RT = 3.2 (M+1) 552.4, (M-1) 550.5.
(R)-methyl 2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxamidojethanoate (125)
LCMS RT = 2.6 (M+1) 490.4, (M-1) 488.6.
(R)-N-tert-butyl-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxamide (117)
LCMS RT = 2.8 (M+1) 486.3, (M-1) 484.5.
(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)N-(thiophen-2-yl)piperidine-1 -carboxamide (129)
-21316260
LCMS RT = 2.8 (M+1) 486.3, (M-1 )484.5.
(R)-methyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrÎmidin-4ylamino)methyl)piperidine-1 -carbonylcarbamate (131 )
LCMS RT =1.6 (M+1) 462.7.
(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidïn-4-ylamino)methyl)N-(4-methylthiophen-2-yl)piperidine-1-carboxamide (130)
LCMS RT = 2.0 (M+1) 500.6.
228 274 (S)-3-((5-fluoro-2-(1H-pyrrolo[2,3-t>]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-/V,/\/dimethylpiperidine-1-carboxamide (228)
LCMS RT = 2.3 (M+1) 398.3.
(R)-3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-Nmethylpiperidine-1 -carboxamide (274)
LCMS RT = 2.1 (M+1) 384.3.
275 276 (R)-A/-ethyl-3-((5-fluoro-2-(1 H-pyrrolo[2,3-t>]pyridin-3-yl)pyrimidin-4ylamino)methyl)piperidine-1-carboxamide (275)
LCMS RT = 2.2 (M+1) 398.4. (R)-3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyrïdin-3-yl)pyrimidin-4-ylamino)methyl)-A/propylpiperidine-1 -carboxamide (276)
LCMS RT = 2.3 (M+1) 412.4.
General Scheme 12B
-21416260
| r ....θ J Γ V-NH /Γ 'V-NH | F rv. | ...n -n'h | |
| a | yZ | / O | |
| Ck | |||
| N H | H | N H | |
| 12a | 36 | ||
| propylisocyanate, 'Pr2NEt, pyridine, CH2CI2 |
(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(methylsulfonyl)-piperidin-
3-yl)methyl)pyrimidin-4-amine (36).
To a solution of (R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3ylmethyl)pyrimidin-4-amine, 12a, (0.018 g, 0.050 mmol) and pyridine (0.7 mL) in CH2CI2 (0.7 mL) was added methanesulfonyl chloride (0.004 mL, 0.050 mmol). The reaction mixture was stirred at room température for 24 hours. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 36. LCMS RT = 2.7 (M+1) 439.3, (M-1) 437.3.
Other analogs that can be prepared in the same manner as 36:
(R)-2-(5-chloro-1H-pyrrolo[2I3-b]pyridin-3-yl)-N-((1-(cyclopropylsulfonyl)piperidin-3yl)methyl)-5-fluoropyrimidin-4-amine (61 )
LCMS RT = 2.8 (M+1) 465.3, (M-1) 463.3.
(R,E)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(styrylsulfonyl)piperidin-
3-yl)methyl)pyrinnidin-4-amine (60)
LCMS RT = 3.2 (M+1) 525.3.
(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(3methoxyphenylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine (62)
LCMS RT = 3.1 (M+1) 531.3, (M-1) 529.4.
-21516260 (/?)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(4fluorophenylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine (64)
LCMS RT = 3.1 (M+1) 519.3, (M-1) 517.4
(/?)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(3fluorophenylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine (65)
LCMS RT = 3.1 (M+1) 519.2, (M-1) 517.4.
(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(m-tolylsulfonyl)piperidin-
3-yl)methyl)pyrimidin-4-amine (66)
LCMS RT = 3.2 (M+1) 515.3, (M-1) 513.4
(/?)-N-((1-(3-bromophenylsulfonyl)piperidin-3-yl)methyl)-2-(5-chloro-1H-pyrrolo[2,3b]pyridÎn-3-yl)-5-fluoropyrimidin-4-amine (67)
LCMS RT = 3.3 (M+1) 579.2, (M-1) 577.2.
(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(phenylsulfonyl)piperidin-
3-yl)methyl)pyrimidin-4-amine (87)
LCMS RT = 2.1 (M+1) 501.3.
(R)-/V-((1-(3-bromophenylsulfonyl)piperidin-3-yl)methyl)-2-(5-chloro-1W-pyrrolo(2,3b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (88)
LCMS RT = 2.0 (M+1) 561.3.
(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(phenylsulfonyl)piperidin-
3-yl)methyl)pyrimidin-4-amine (89)
-21616260
LCMS RT = 2.1 (M+1) 507.2.
(/?)-2-(5-chloro-1H-pyrrolo[2,3-i>]pyridin-3-yl)-5-fluoro-N-((1-(2fluorophenylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine (90)
LCMS RT = 2.1 (M+1) 519.2.
(R)-2-(5-chloro-1H-pyrrolo[2,3-ô]pyridin-3-yl)-5-fluoro-N-((1-(1-methyl-1H-imidazol-4ylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine (91)
LCMS RT =1.8 (M+1) 505.3.
General Scheme 12C
(R)-3-bromo-2-methylpropan-1-ol, 'Pr2NEt, THF
Formation of (S)-3-((S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-
4-ylamino)methyl)piperidin-1 -yl)-2-methylpropan-1 -ol (135).
To a solution of (R)-3-bromo-2-methylpropan-1-ol (0.006 mL, 0.055 mmol) and (R)-2(5-chloro-1/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)-pyrimidin-4amine, 12a, (0Ό20 g, 0.055 mmol) in CH3CN (2 mL) was added K2CO3 (0.023 g, 0.165 mmol). The reaction mixture was heated at 80 °C at for 24h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 135. LCMS RT = 2.5 (M+1) 433.4, (M-1) 431.6.
Other analogs that can be prepared in the same manner as 135:
-21716260
140 141 (S)-1-{3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)pÎperîdin-1-yl)-3,3-dimethylbutan-2-one (140)
LCMS RT = 2.9 (M+1) 459.3, (M-1) 457.5.
(R)-3-((S)-3-((2-(5-chloro-1H-pyrrolo[2f3-b]pyrÎdin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-2-methylpropan-1-ol (141)
LCMS RT = 1.4 (M+1) 433.5.
139
137 (S)-2-(5-chloro-1tt-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-W-((1-(2-methylbenzyl)piperidin-
3-yl)methyl)pyrimidin-4-amine (139)
LCMS RT = 3.2 (M+1) 465.3, (M-1) 463.4.
(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridÎn-3-yl)-5-fluoro-/V-((1-(3-methylbenzyl)piperidin-
3-yl)methyl)pyrimidin-4-amine (137)
LCMS RT = 3.1 (M+1) 465.4, (M-1) 463.6.
134
133 (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1-(cyclohexyfmethyl)piperidin-3yl)methyl)-5-fluoropyrimidin-4-amine (134)
LCMS RT = 3.1 (M+1) 457.3, (M-1) 455.5.
(S)-2-(3-({2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrîmidin-4ylamino)methyl)piperidin-1-yl)ethanol (133)
LCMS RT = 2.3 (M+1) 405.3, (M-1) 403.6.
-21816260
132
138 (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-/V-((1-(2,2-dimethoxyethyl)piperidin-3yl)methyl)-5-fluoropyrimidin-4-amine (132)
LCMS RT = 2.2 (M+1) 449.7.
(S,E)-methyl 4-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidrn-4ylamino)methyl)piperidin-1-yl)but-2-enoate (138)
LCMS RT = 2.8 (M+1) 459.3, (M-1) 457.7.
666 (S)-4-(3-((2-{ 5-chloro-1 H-pyrroto[2.,3-b] pyridin-S-ylJ-S-fluoropyrimidin-Aylamino)methyl)piperidin-1-yl)butanenitrile (666)
LCMS RT = 2.6 (M+1) 428.3, (M-1) 426.5.
667
124 (S)-3-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)propanenitrile (667)
LCMS RT = 1.4 (M+1) 414.5.
(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-A/-((1-(pynmidin-2-yl)piperidin-3yl)methyl)pyrimidin-4-amine (124)
LCMS RT = 3.1 (M+1) 439.3 (M-H) 437.4.
General Scheme 13
-21916260
ζτ
Benzyl chloroformate, triethylamine, CH2CI2; (b) dimethylsulfoxide, oxalyl chloride, triethylamine, CH2CI2; (c) DAST, THF; (d) 10% Pd/C, MeOH, H2, ditert-butyl dicarbonate (e) LiOH, THF/MeOH/Water; (f) Pyridine, di-tert-butyl dicarbonate, NH4HCO3, 1,4Dioxane; (g) triethylamine, TFAA, CH2CI2; (h) Raney Ni, MeOH, H2; (i) 5-chloro-3-(5-fluoro-4(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3bjpyridine, 'Pr2NEt, THF, microwave, 130 °C 15 min.;
(j) NaOMe, MeOH (k) isoproponal/HCI, 45 °C; (I) 3methoxy propanoyl chloride, 'Pr2NEt, CH2CI2, DMF.
Formation of 1-benzyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate (13b).
To a cold (5 °C) solution of methyl 4-hydroxypiperidine-2-carboxylate, 13a, (5.17 g, 32.48 mmol) and triethylamine (6.00 mL, 43.05 mmol) in CH2CI2 (135 mL) was added dropwise benzyl chloroformate (6.20 mL, 43.43 mmol) over 10 min. The resulting solution was stirred at 5 °C for 1 hour and then allowed to warm to room température. The reaction mixture was diluted with water and the layers were separated. The aqueous was re-extracted with CH2CI2 and the combined organics were dried over MgSO4, filtered and evaporated to dryness. The crude was passed through a plug of silica gel, eluting with 30 - 80% EtOAc/Hexanes to afford the desired product, 13b.
-22016260 ’H NMR (300 MHz, CDCI3) Π 7.36 - 7.33 (m, 5H), 5.17 (s, 2H), 4.89 - 4.78 (m, 1H),
4.18-4.09 (m, 1H), 3.96 (s, 1H), 3.76 - 3.70 (m, 3H), 3.53-3.41 (m, 2H), 2.44 (s,
1H), 1.96 -1.91 (m, 1H) and 1.71 (s, 2H) ppm.
Formation of 1-benzyl 2-methyl 4-oxopiperidine-1,2-dicarboxylate (13c).
To a 500 ml flask, flamed dry under N2 was added CH2CI2 (65 mL) followed by oxalyl chloride (5.2 mL, 59.6 mmol). After cooling the reaction mixture to -78 °C, dimethyl sulfoxide (8.4 mL, 118.4 mmol) was added, followed by 1-benzyl 2-methyl 4hydroxypiperidine-1,2-dicarboxylate, 13b, (8.6 g, 29.2 mmol) in CH2Cl2 (65 mL). The reaction was allowed to stir at -78 °C for 45 min. To the mixture was added triethylamine (24.4 mL, 175.1 mmol) and the mixture was allowed to warm to room température. The reaction mixture was diluted with CH2CI2 and 1N HCl. The layers were separated and the aqueous phase was re-extracted with CH2CI2. The combined organic phases were washed with water, dried over MgSO4, filtered and evaporated to dryness. The crude was purifïed by silica gel chromatography (30 50% EtOAc/hexanes) to give the desired product, 13c.
1H NMR (300 MHz, CDCI3) □ 7.37 (s, 5H), 5.24 - 5.18 (m, 3H), 5.02 (s, 1H), 4.12 (q, J =7.1 Hz, 1H), 3.74-3.65 (m, 3H), 2.79 (d, J= 7.0 Hz, 2H) and 2.53 (s, 2H) ppm.
Formation of 1-benzyl 2-methyl 4,4-difluoropiperidine-1,2-dicarboxylate (13d).
To a cold (0 °C) solution of 1-benzyl 2-methyl 4-oxopiperidine-1,2-dicarboxylate, 13c, (7.4 g, 25.4 mmol) in THF (75 mL) was added (diethylamino)sulfurtrifluoride (25.0 mL, 189.2 mmol). After 2 hours at 0 °C, the reaction was quenched by the careful addition of water. The mixture was diluted with EtOAc and water. Solid NaHCO3 was added to adjust the pH to neutral. The layers were separated and the organic was washed with water, brine, dried over MgSO4l filtered and evaporated to dryness. The crude was passed through a plug of silica gel eluting with 15-20% EtOAc/hexanes to afford the desired product, 13d.
1H NMR (300 MHz, CDCI3) Π 7.37 - 7.31 (m, 5H), 5.30 - 5.06 (m, 3H), 4.45 - 4.22 (m, 1H), 3.76- 3.52 (m, 3H), 3.45 (d, J = 9.0 Hz, 1H), 2.76 (s, 1H) and 2.23- 1.93 (m, 3H) ppm.
Formation of 1-tert-butyl 2-methyl 4,4-difluoropiperidine-1,2-dicarboxylate (13e).
To a Parr flask (1L) was charged 10% palladium on carbon (0.57 g) and di-fert-butyl dicarbonate (4.47 g, 20.49 mmol). A solution of 1-benzyl 2-methyl-4,4difluoropiperidine-1,2-dicarboxylate, 13d, (4.28 g, 13.66 mmol) in methanol (150 mL) was added and hydrogen was introduced via parr shaker (46 PSI). The reaction mixture was shaken over weekend at room température. The mixture was filtered through Celite and washed throughly with CH2CI2. The filtrate was concentrated to dryness and redissolved in 10% EtOAc/hexanes. The crude was purifïed by silica gel chromatography (10-20% EtOAc/hexanes) to afford 5.1 g of a mixture of desired
-22116260 product, 13e, plus approximately 840 mg of conta min ated product. The resulting crude mixture was used directly in next step without further purification.
Ή NMR (300 MHz, CDCI3) Π 5.08 (s, 1 H), 4.89 (s, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.76 (s, H), 3.74 (s, 3H), 3.34 (s, 1 H), 3.29 (t, J = 7.2 Hz, 1 H), 2.77 (s, 1 H), 2.04 (m, 1 H) and 1.53 (s, 9H) ppm.
Formation of 1-(tert-butoxycarbonyl)-4,4-difluoropiperÎdine-2-carboxylic acid (13f) To a solution of 1-tert-butyl 2-methyl 4,4-difluoropiperidine-1,2-dicarboxylate, 13e, (4.6 g, 16.5 mmol) in THF (18 mL), methanol (18 mL) and H2O (9 mL) was added lithium hydroxide (3.45 g, 82.22 mmol). The reaction mixture was stirred at room température for 1 hour. All volatiles were removed under reduced pressure. The residue was diluted with a slight amount of water and ether. The layers were separated and the organic phase was discarded. The aqueous phase was acidified to pH 3 with the addition of aqueous saturated KHSO4 solution. The product was extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, filtered and evaporated to dryness. The resulting product was used without further purification.
1H NMR (300 MHz, CDCI3) □ 5.14 (s, 1H), 4.93 (s, 1H), 4.12 (q, J = 7.1 Hz, 1H), 3.28 (d, J = 6.3 Hz, 1 H), 2.75 (d, J = 8.7 Hz, 1 H), 2.06 (d, J = 8.5 Hz, 1 H), 1.99 -1.81 (m, 1H) and 1.47 (s, 9H) ppm.
Formation of tert-butyl 2-carbamoyl-4,4-difluoropiperidine-1-carboxylate (13g)
To a solution of 1-fert-butoxycarbonyl-4,4-difluoro-piperidine-2-carboxylic acid, 13f, (1.67 g, 6.30 mmol) in 1,4-dioxane (12 mL) was added pyridine (0.35 mL, 4.33 mmol), followed by di-tert-butyl dicarbonate (1.78 g, 8.17 mmol) and ammonium bicarbonate (0.63 g, 7.86 mmol). The reaction mixture was stirred at room température overnight. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with water, aqueous saturated KHSO4 solution, brine, dried over Na2SO4, filtered and evaporated to dryness. The crude residue was used without further purification.
Formation of tert-butyl 2-cyano-4,4-difluoropiperidine-1-carboxylate (13h)
To a solution of tert-butyl 2-carbamoyl-4,4-difluoro-piperidine-1-carboxylate, 13g, (1.72 g, 6.51 mmol) in CH2CI2 (50 mL) was added was Λ/,Ν-triethylamine (2.03 mL, 14.61 mmol) followed by the dropwise addition of (2,2,2-trifluoroacetyl)-2,2,2trifluoroacetate (1.02 mL, 7.32 mmol). After 15 minutes, the mixture was diluted with aqueous saturated NaHCO3 solution and the layers were separated. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The crude residue was passed through a plug of silica gel and eluted with 10 - 30%EtOAc/hexanes to afford the desired product, 13h.
-22216260 1H NMR (300 MHz, CDCIa) □ 5.43 (s, 1H), 4.19 (s, 1H), 3.25 (s, 1H), 2.36 (m, 1 H),
2.23-2.12 (m, 1H), 1.83 (s, 1H), 1.70 (s, 1H) and 1.53- 1.46 (m, 9H) ppm.
Formation of tert-butyl 2-(aminomethyl)-4,4-difluoropiperidine-1 -carboxylate (13i)
Raney nickel (0.36 mL, 5.40 mmol) was washed with MeOH (2X) and charged into a parr shaker. A solution of tert-butyl 2-cyano-4,4-difluoro-piperidine-1 -carboxylate,
13h, (1.33 g, 5.40 mmol) in méthanol (50 mL). The reaction mixture was subject to hydrogénation conditions ovemight on the parr shaker (46PSI). The mixture was filtered through celite and washed throughly with CH2CI2. Ail volatiles were removed at reduced pressure and the crude material was used without further purification.
Formation of tert-butyl 2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)methyl)-4,4-difluoropiperidine-1 -carboxylate (13j)
To a solution of tert-butyl 2-(aminomethyl)-4)4-difluoro-piperidine-1-carboxylate, 13i, (0.10 g, 0.41 mmol) and 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridine (0.18 g, 0.38 mmol) in THF (2 mL) was added 'Pr2NEt (0.20 mL, 1.15 mmol). The reaction mixture was heated în microwave at 130 °C for 15 minutes. The reaction was cooled to room température and the volatiles were removed under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes) to afford the desired product, 13j. LCMS (M-1) 649.52.
Formation of tert-butyl 2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-
4-ylamino)methyl)-4,4-difluoropiperidine-1-carboxylate (13k).
To a solution of tert-butyl 2-[[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-
5-fluoro-pyrimidin-4-yl]amino]methyl]-4,4-difluoro-piperidine-1-carboxylate, 13j, (0.23 g, 0.35 mmol) in méthanol (4 mL) was added sodium methanolate (4 mL of 25 %w/v,
18.51 mmol). The reaction mixture was allowed to stir at room température for 15 minutes. Ail volatiles were removed at reduced pressure and the residue was quenched with water. EtOAc was added and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The crude residue was pure enough to be used without further purification.
LCMS (M+1) 497.44, (M-1) 495.52.
Formation of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((4,4-difluoropiperidin-2yl)methyl)-5-fluoropyrimidin-4-amine (13m)
To a solution of tert-butyl 2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-y!amino)methyl)-4,4-difluoropiperidine-1-carboxylate, 13k, (0.09 g,
0.18 mmol) in 2-propanol (2 mL) was added propan-2-ol hydrochloride (2 mL of 6 M,
12.00 mmol). After stirring the reaction mixture at room température for 17 hours, an additional 1 mL of IPA/HCI was added and the reaction mixture was heated ai 45 °C for 1 hour. Ail volatiles were removed at reduced pressure and the residue was used
-22316260 directly in the next step without further purification. LCMS (M+1) 397.40, (M-1)
395.44.
Formation of 1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)-4,4-difluoropiperidin-1-yl)-3-methoxypropan-1-one (584)
To a solution of 2-(5-chloro-1/7-pyrrolo[2,3-b]pyridin-3-yl)-/V-[(4)4-difluoro-2piperidyl)methyl]-5-fluoro-pyrimidîn-4-amine, 13k, (0.086 g, 0.198 mmol) in CH2Cl2 (1 mL), DMF (0.5 mL) and 'Pr2NEt (0.10 mL, 0.57 mmol) was added 3methoxypropanoyl chloride (2.43 g, 0.20 mmol). The reaction mixture was stirred at room température for 17 hours. Ail volatiles were removed at reduced pressure and the residue was purified via silica gel chromatography to give a mixture enriched in desired product, 13, which was repurified via preparatory HPLC.
1H NMR (300 MHz, d6-DMSO) Π 12.45 (m, 1H), 8.71 (d, J=8.5 Hz, 1H), 8.31 (m, 2H), 8.01 (m, 1 H), 5.33 (s, 1H), 4.62 - 4.43 (m, 2H), 4.39 - 3.72 (m, 5H), 3.68 (s, 2H), 3.43 - 3.40 (m, 1H), 3.15 (s, 1H), 3.07 (s, 1H), 2.33 (s, 2H) and 2.08 (s, 2H) ppm: LCMS (M+1) 483.44, (M-1) 481.52.
Other analogs that may be prepared in the same manner as 584 are described below:
ci
N-((4-benzylmorpholin-2-yl)methyl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-5fluoropyrimidin-4-amine (388).
1H NMR (300 MHz, CDCI3) □ 9.14-9.09 (m, 1H), 8.81 - 8.71 (m, 1H), 8.29 (d, J =
2.3 Hz, 1 H), 8.07 (d, J = 2.5 Hz, 1H), 7.34 (s, 5H), 5.58-5.41 (m, 1H), 3.92-3.43 (m, 4H), 2.83 - 2.72 (m, 2H), 2.38 - 2.28 (m, 2H) and 1.62 (m, 2H) ppm. LCMS RT =
1.8 (M+1) 453.4.
2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-Nisopropylmorpholine-4-carboxamide (446).
LCMS RT =1.7 (M+1) 448.4
-22416260
Isopropyl 2-((2-(5-chloro-1H-pyrrolo(2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)morpholine-4-carboxylate (447).
LCMS RT = 2.0 (M+1) 449.3
2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((4-(isopropylsulfonyl)morpholin
2-yl)methyl)pyrimidin-4-amine (448).
LCMS RT =1.9 (M+1) 469.3
1-(2-((2-(5-chloro-1W-pyrrolo[2,3-b]pyrîdin-3-yl)-5-fluoropyrimidin-4- ylamino)methy1)morpholino)propan-1-one (449).
LCMS RT = 1.7 (M+1) 419.4
(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-415 ylamino)methyl)morpholino)(cyclopropyl)methanone (450).
LCMS RT = 1.7 (M+1) 431.4
fert-Butyl 3-((2-(5-chloro-1H-pynOlo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)morpholine-4-carboxy1ate (515).
-22516260 1H NMR (300 MHz, CDCI3)0C 10.38 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.49 (d, J =2.3
Hz, 1H), 8.38 (s, 1H), 8.08 (d, J = 3.4 Hz, 1H), 6.11 (d, J = 5.0 Hz, 1H), 4.44 (d, J =
9.4 Hz, 1H), 4.02-3.62 (m, 6H), 3.55 (dd, J = 2.4, 12.1 Hz, 1H), 3.35-3.27 (m, 1H) and 1.40 - 1.22 (m, 9H) ppm. LCMS RT = 2.5 (M+1) 463.5.
1-(3-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)morpholino)propan-1-one (516).
LCMS RT = 1.9 (M+1) 419.4
3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yf)-5-fluoropyrimidin-4-ylamino)methyl)-Wpropylmorpholine-4-carboxamide (517).
’H NMR (300 MHz, c/6-DMSO) Π 12.54 (s, 1H), 8.76 (d, J= 2.0 Hz, 1H), 8.46 (s,
1H), 8.32 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 3.9 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 6.30 (s, 1 H), 4.28 (s, 1H), 3.93 - 3.74 (m, 3H), 3.51 - 3.47 (m, 2H), 3.39 - 3.20 (m, 2H), 2.95 (dd, J= 6.2, 13.1 Hz, 3H), 1.35- 1.25 (m, 2H) and 0.76(1, J = 7.3 Hz, 3H) ppm. LCMS RT = 2.3 (M+1) 448.54.
Methyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)morpholine-4-carboxylate (526).
LCMS RT = 2.4 (M+1) 421.0.
Ethyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamÎno)methyl)morpholine-4-carboxylate (527).
-22616260
LCMS RT = 2.5 (M+1) 435.1.
Allyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyrÎdin-3-yl)-5-fluoropyrimidÎn-4ylamino)methyl)morpholine-4-carboxylate (528).
LCMS RT = 2.6 (M+1) 447.1.
1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yJ)-5-fluoropyrimidin-4ylamino)methyl)morpholino)-2-methylpropan-1 -one (529).
LCMS RT= 2.5 (M+1) 433.1.
-(3-((2-( 5-chloro-1 H-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4ylamino)methyl)morpholino)-2,2-dimethylpropan-1 -one (530).
LCMS RT = 1.9 (M+1) 447.1.
(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridiii-3-yl)-5-fliioropyrimidin-4ylamino)methyl)morpholîno)(cyclobutyl)methanone (531).
LCMS RT = 2.6 (M+1) 445.1.
2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((4-(methylsulfonyl)morpholin-3yl)methyl)pyrimidin-4-amine (532).
-22716260
LCMS RT = 2.4 (M+1) 441.0.
2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((4-(cyclopropylsulfonyl)morpholin-3yl)methyl)-5-fluoropyrimidin-4-amine (533).
LCMS RT = 2.4 (M+1) 467.0.
3-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)morpholine-4-carboxamîde (534).
LCMS RT = 2.0 (M+1) 406.0.
3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-NethylmorpholÎne-4-carboxamide (535).
LCMS RT = 2.2 (M+1) 434.1.
3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-Nisopropylmorpholine-4-carboxamide (536).
LCMS RT = 2.3 (M+1) 448.1.
-22816260 (R) -2-fluoroethyl 2-((2-(5-chloro-1H-pyrrolo[2,3-bJpyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (180).
LCMS RT = 2.1 (M+1) 451.4.
(S) -2-methoxyethyl 2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridÎn-3-yl}-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (161).
LCMS RT = 2.8 (M+1) 463.4.
(S)-2-chloroethyl 2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1 -carboxylate (163).
LCMS RT = 3.1 (M+1) 467.4.
(S)-prop-2-ynyl 2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (164).
LCMS RT = 3.0 (M+1) 443.5.
165 174 (S)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridîn-3-yl)-5-fluoropyriiïiidin-4ylamino)methyl)piperidin-1 -yl)(thiazol-2-yl)methanone (165).
LCMS RT = 2.8 (M+1) 472.5.
(S)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(3-methoxyphenyl)methanone (174).
LCMS RT = 2.8 (M+1) 495.6.
(S)-methyl 2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriniidin-4ylamino)methyl)piperidîne-1 -carboxylate (166).
-22916260
LCMS RT = 2.9 (M+1) 419.5.
(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-ÎJ]pyridÎn-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)ethanone (179).
LCMS RT = 2.5 (M+1) 403.4.
(S)-ethyl 2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidine-1-carboxylate (171).
LCMS RT = 3.0 (M+1) 433.3.
(R)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylarnino)methyl)piperidin-1 -yl)(3-methoxyphenyl)methanone (184).
LCMS RT = 2.7 (M+1) 495.5.
(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)propan-1-one (208).
LCMS RT = 1.9 (M+1) 417.2.
(R)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(2-methoxyphenyl)methanone (190).
LCMS RT =2.9 (M+1) 495.4.
(R)-(2-((2-(5-chloro-1H-pyrrolo[2,3-blpyridin-3-yi)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)(4-fluorophenyl)methanone (209).
LCMS RT = 2.0 (M+1) 483.1.
(R)-(2-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-23016260 ylamino)methyl)piperidin-1 -yl)(3-(trifluoromethyl)phenyl)methanone (210).
LCMS RT = 2.2 (M+1) 533.1.
(R)-4-chloro-1 -(2-((2-( 5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)butan-1 -one (278).
LCMS RT = 2.4 (M+1) 465.1.
(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-ô]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)pent-4-en-1 -one (279).
LCMS RT = 2.1 (M+1) 443.2.
(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino}methyl)piperïdin-1 -yl)-3,3,3-trifluoropropan-1 -one (280).
LCMS RT = 2.1 (M+1) 471.2. (R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)hex-5-yn-1-one (281).
LCMS (M+1) 454.2.
(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)-3-phenylpropan-1 -one (293).
LCMS RT = 3.1 (M+1) 493.2.
(R)-1-(2-((2-(5-chloro-1W-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-2-cyclohexylethanone (294).
LCMS RT = 3.3 (M+1) 485.2.
-23116260
(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)butan-1-one (295).
LCMS RT = 2,9 (M+1) 431.2.
(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1 -yl)pentan-1 -one (326).
LCMS RT = 3.0 (M+1) 445.2.
(S)-1-(2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrinriidin“4ylamino)methyl)piperidin-1 -yl)ethanone (256).
LCMS RT = 2.2 (M+1) 369.3.
(S)-1-(2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4ylamino)methyl)piperidin-1-yl)propan-1-one (257).
LCMS RT = 2.3(M+1) 383.3.
258
259 (S)-1-(2-((5-fluoro-2-(1H-pyrrolo[2,3-jb]pyrïdin-3-yl)pyrimidin-4ylamino)methyl)piperidîn-1 -yl)butan-1 -one (258).
LCMS RT = 2.5(M+1) 397.3. (S)-(2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrÎmidin-4-ylamino)methyl}piperidin-
1-yl)(phenyl)methanone (259).
LCMS RT = 2.4 (M+1) 431.3.
-23216260 (S)-(2-((5-fluoro-2-(1H-pyrrolo[2,3-6]pyridin-3-yl)pyrinnidin-4-ylamino)methyl)piperidÎn1-yl)(2-methoxyphenyl)methanone (260).
LCMS RT = 2.4 (M+1) 461.3.
(R)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-/V-((1-(methylsulfonyl)-piperidin-
2-yl)methyl)pyrimidin-4-amine (381).
LCMS RT = 2.7 min, (M+H) 439.3 (R)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(( 1 -(ethylsulfonyl)-piperidin-2yl)methyl)pyrimidin-4-amine (382).
LCMS RT = 2.9 min, (M+H) 453.3.
(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-/V-((1-(propylsulfonyl)piperidin-
2-yl)methyl)pyrimidin-4-amine (328).
LCMS RT = 2.2 min, (M+H) 467.1.
(R)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(2,2,2-trîfluoroethylsulfonyl)-piperidin-2-yl)methyl)pyrimidin-4-amine (383).
LCMS RT = 3.0 min, (M+H) 507.3.
(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-W-((1-(methylsulfonyl)-piperidin-
2-yl)methyl)pyrimidin-4-amine (384).
LCMS RT = 2.7 min, (M+H) 439.3.
-23316260 (R)-N-((1 -(butylsulfonyl)piperidin-2-yl)methyl)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3yl)-5-fluoropyrimidin-4-amine (329).
LCMS RT = 2.3 min, (M+H) 481.2
H
(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridÎn-3-yl)-5-fluoro-N-((1-(cyclopropylsulfonyl)piperidin-2-yl)methyl)pyrimidin-4-amine (386).
LCMS RT = 2.9 min, (M+H) 465.3.
(R)-2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-W-(( 1 -(3-ch!oropropylsulfonyl)piperidin-
2-yl)methyl)-5-fluoropyrimidin-4-amine (330).
LCMS RT = 2.2 min, (M+H) 501.1.
372 (R)-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-Nisopropylpiperidine-1-carboxamide (371).
LCMS RT = 1.8 min, (M+H) 412.2. (/?)-N-cyclopropyl-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidine-1 -carboxamide (372). '
LCMS RT = 1.9 min, (M+H) 424.2.
(R)-W-ethyl-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperïdîne-1 -carboxamide (373).
LCMS RT = 1.7 min, (M+H) 398.2. (/?)-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridÎn-3-yl)pyrimidin-4-ylamÎno)methyl)-Nmethylpiperidine-1-carboxamide (374),
LCMS RT = 1.6 min, (M+H) 384.2.
-23416260 (/?)-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-Npropylpiperidine-1 -carboxamide (375).
LCMS RT = 1.8 min, (M+H) 412.2.
General Scheme 14
14a
'Pr2NEt, isopropanol, 80 °C (b) 5-chloro-3-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)-1 -tosyl-1 Hpyrrolo[2,3-ô]pyrrdine, Pd(Ph3P)4, Na2CO3, DME, 130 °C (c) HCI/dioxane, CH2CI2 (d) propylisocyanate, pyridine, CH2CI2
Formation of 1-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol (14a).
To a solution of 2-(aminomethyl)cyclohexanol hydrochloride (0.09 g, 0.54 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.10 g, 0.60 mmol) in isopropanol (2 mL) was added 'Pr2NEt (0.21 mL, 1.20 mmol). The reaction mixture was heated at 80 °C for 12 hours. The reaction mixture was was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (25%-75% EtOAc/hexanes) to afford desired product, 14a.
LCMS (M+1) 260.1, (M-1) 258.3.
Formation of 2-((2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)cyclohexanol (14b)
-23516260
To a degassed solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.15 g, 0.35 mmol), 1-((2-chloro-5fluoropyrimidin-4-ylamino)methyl)cyclohexanol, 14a, (0.09 g, 0.35 mmol) and aqueous KOAc solution (1.04 mL of 1M solution, 1.04 mmol) in dimethylacetamide was added palladium triphenylphosphine (0.04 g, 0.03 mmol). The reaction mixture was heated at 140 °C in microwave for 15 min and then cooled to room température. The reaction mixture was filtered through celite, concentrated in vacuo, and the resulting crude residue was purified by by preparatory HPLC (0.1%TFAH2O/acetonitrile) to afford the desired product, 14b: LCMS RT = 2.6 (M+1) 530.3.
Formation of (2R)-2-((2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimîdin-4ylamino)methyl)cyclohexanol (12)
To a solution of 2-((2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-i)]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)methyl)cyclohexanol, 14b, (0.10 g, 0.19 mmol) in THF (3 mL) was added aqueous lithium hydroxide (1 mL of 1N solution). The reaction mixture was stirred at room température for 12 hours. The resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 12.
LCMS FIA RT = 1.9 (M+1) 376.2.
2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanol (13)
LCMS FIA RT = 1.8 (M+1) 362.2.
2-(2-(5-chloro-1H-pyrrolo[2,3-d]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclopentanol (14)
LCMS FIA RT = 1.0 (M+1) 348.3. 1
-23616260
657 (1R, 2S, 3R, 5F?)-3-(2-(5-chloro-1H-pyrrolo[2,3-t)]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-5(hydroxymethyl)cyclopentane-l ,2-diol (657) 1H NMR (300 MHz, DMSO) □ 12.41 (s, 1H), 8.80 (d, J =2.3 Hz, 1H), 8.28 (d, J =2.4 Hz, 1H), 8.25 (s, 1H), 8.17 (d, J = 4.0 Hz, 1H), 7.64 (s, 1H), 4.80 - 4.50 (m, 3H), 4.47 (dd, J = 7,5, 14.8 Hz, 1H), 3.89 (dd, J =5.3, 6.3 Hz, 1H), 3.77 (dd, J= 5.1,5.0 Hz, 1H), 3.50- 3.37 (m, 2H), 2.36 - 2.24 (m, 1H), 2.04 (dd, J =8.3, 13.5 Hz, 1H), 1.99 (s, 1H), 1.27 (td, J = 8.4,4.4 Hz, 1H) and 1.21 (s, 1H) ppm.
LCMS RT = 3.0 (M+1) 399.4.
H2N
14d (+/-)
HN'Bûc
Raney-Ni, H2 (50 PSI), EtOH (b) 15a, THF, 70 °C (c)TFA, CH2CI2 (d) 1N LiOH, THF, 120°C
Formation of tert-butyl trans-2-(aminomethyl)cyclohexylcarbamate (14d)
A solution of tert-butyl trans-2-cyanocyclohexylcarbamate and Raney-Ni in absolute EtOH was stirred under H2 atmosphère (50 PSI) for 24 hours. Filtration and évaporation of the solvent followed by flash chromatography (SiO2, 0-20% MeOHCH2CI2, gradient elution) provided the target compound, 14d, as a racemic mixture of trans isomers (286 mg, 66% yield): FIA (M+H) 229.33.
-2371
Formation of terf-butyl trans-2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyrîdin-3-yl)-5fluoro-pyrimidin-4-yl-amino)methyl)cyclohexylcarbamate (14e)
A mixture of 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1Hpyrrolo[2,3-b]pyridine, 15a, (0.42 g, 0.90 mmol) and terf-butyl frans-2-(aminomethyl) cyclohexylcarbamate (0.24 g, 1.06 mmol) were heated in THF (10 mL) to 70 °C. After 1.3 hours, the mixture was concentrated in vacuo. Flash chromatography (SiO2, 0-60% EA/Hex, gradient elution) provided the desired intermediate, terf-butyl frans-2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-d]pyridîn-3-yl)-5-fluoropyrimidin-4ylamino)methyl)cyclohexylcarbamate, 14e, as a racemic mixture of trans isomers, which was taken into the next reaction without further purification (0.52g , 92% yield).
Formation of N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (14f)
A solution of the terf-butyl frans-2-((2-(5-chloro-1-tosyl-1/-/-pyrrolo[2,3-b]pyridin-3-yl)-
5-fluoropyrimidin-4-ylamino)methyl)cyclohexylcarbamate, 14e, (0.52g) in CH2CI2 (5mL) was treated with TFA (2.5 mL) for 30 min. the solution was concentrated in vacuo and the resulting crude material was taken up in CH3CN and concentrated in vacuo several times to remove excess TFA and to provide the desired amine, 14f, as racemic mixture of trans isomers, as the TFA sait, which was sufficiently pure for use in the next reaction.
LCMS RT = 1.93 min, (M+H) 529.0
Formation of N-( (trans-2-ami nocy cl oh exyl)methy l)-2-(5-c h loro-1H-pyrrol o[2,3b]pyndin-3-yl)-5-f1uoropyrimidin-4-amine (555)
A solution of /V-((frans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoropyrimÎdin-4-amine, 14f, (0.050g, 0.077 mmol) in THF was treated with LiOH (0.5 mL, 1.0M) at 60 °C. After 5 min, at 120 °C, the solution was diluted with EtOAc, and washed with brine, filtered and concentrated in vacuo. Préparative HPLC provided the desired compound, 555, as a racemic mixture of trans isomers (12 mg, 33% yield).
5H NMR (300 MHz, MeOD) □ 8.75 (d, J = 2.4 Hz, 1H), 8.31 (d, J= 2.4 Hz, 1H), 8.29 (s, 1H), 8.24 (d, J =4.4 Hz, 1H), 3.96 (dd, J =5.8, 14.4 Hz, 1H), 3.73 (dd, J = 4.3, 14.3 Hz, 1H), 3.08-3.00 (m, 1H), 2.05- 1.87 (m, 3H), 1.80 (m, 3H) and 1.48-1.39 (m, 4H) ppm; LCMS RT = 1.9 min, (M+H) 375.0.
-23816260
General Scheme 14C
i: RCOCI, DIEA, CH2CI2 ii: 1N LiOH, THF, 120°C.
Formation of N-(trans-2-((2-(5-chloro-1H-pyrro1o[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-
4-ylamino)methyl)cyclohexyl)-2-methoxyethanamide (556)
To a cooled mixture of Λ/-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl·1^^ pyrrolo[2,3-ô]pyridin-3-yl)-5-fluoropyrimidin-4-amine (0.060 g, 0.093 mmol) and 'Pr2NEt (0.057 mL, 0.330 mmol) in CH2CI2 (2mL) at 0 °C, was added 2methoxyacetyl chloride (0.010 g, 0.098 mmol). After 5 min, the solution was allowed to warm to room température, After 3 hours, the mixture was concentrated in vacuo, taken up in THF (1 mL) and treated with LiOH (0,326 mL, 1.0 M solution) at 120 °C for 10 min. The resulting mixture was cooled to room température and partitioned and the aqueous layer extracted with EtOAc and the combined organics were concentrated in vacuo. Préparative HPLC provided the desired product, 556, as a racemic mixture of TFA salts (8.6 mg, 17% yield).
1H NMR (300 MHz, MeOD) Ί 8.74 (d, J = 2.3 Hz, 1 H), 8.42 (s, 1 H), 8.38 (d, J = 2.3 Hz, 1H), 8.27 (d, 7 = 5.4 Hz, 1H), 3.85-3.81 (m, 2H), 3.75 (d, 7 = 8.5 Hz, 2H), 3.26 (s, 3H), 1.97- 1.77 (m, 5H) and 1.43- 1.35 (m,4H) ppm; LCMS RT = 2.8 min, (M+H) 446.8.
The following analogs can be prepared in same manner as 556.
Formation of N-(trans-2-((2-(5-chloro-1H-pyrrolo[2,3-ô]pyridin-3-yl)-5-fluoropyrimidin-
4-ylamino)methyl)cyclohexyl)methanesulfonamide (557)
Sulfonamide 557 was prepared according to the procedure for compound 36 (Scheme 12B) using W-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1Hpyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, and methane sulfonyl chloride, afforded desired product, 557, as a racemic mixture of trans isomers.
-23916260 1H NMR (300.0 MHz, MeOD) □ 8.78 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 4.2 Hz, 1H),
8.37 (d, J =2.3 Hz, 1 H), 8.26 (d, J = 5.4 Hz, 1H), 4.12 (dd, J = 4.5, 13.7 Hz, 1H),
3.89 (dd, J = 7.1, 13.8 Hz, 1H), 3.26-3.16 (m, 1H), 3.00 (s, 3H), 2.18- 1.90 (m, 2H),
1.79 - 1.74 (m, 2H) and 1.50 - 1.25 (m, 4H) ppm; LCMS RT = 2.8 min, (M+H) 452.6.
Formation of 3-(trans-2-((2-(5-chloro-1W-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-
4-ylamino)methyl)cyclohexyl)-1,1-dimethylurea (564)
Urea 564 was prepared according to the procedure for compound 20 (Scheme 12A) using A/-((frans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, and dimethylcarbomoyl chloride, afforded desired product, 564, as a racemic mixture of trans isomers.
1H NMR (300.0 MHz, MeOD) ΓΊ 8.78 (d, J =2.4 Hz, 1H), 8.45 (d, J = 4.2 Hz, 1H), 8.37 (d, J =2.3 Hz, 1H), 8.26 (d, J =5.4 Hz, 1H), 4.12 (dd, J = 4.5, 13.7 Hz, 1 H).
3.89 (dd, J = 7.1, 13.8 Hz, 1H), 3.26-3.16 (m, 1H), 3.00 (s, 3H), 2.18-1.90 (m, 2H), 1.79 - 1.74 (m, 2H) and 1.50 - 1.25 (m, 4H) ppm; LCMS RT = 1.9 min, (M+H) 445.7.
General Scheme 15
(1S,2S)-cyclohexane-1,2-diamine, THF, 140 °C (b) AcCl, 'Pr2NEt, CK2CI2 (c) 1M LiOH, DCE, 150 °C, microwave 20 min.
Formation of (1S, 25)-/νΐ-(2-(5-εΙιΙθΓθ-14θ5νΙ-1Η^ΓΓθΙο[2,3-^ρνπ8ΐη-3^Ι)-5fluoropyrimidin-4-yl)cyclohexane-1,2-diamine (15b)
5-Chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3b]pyridine, 15a, (0.25 g, 0.53 mmol) and (1S,2S)-cyclohexane-1,2-diamine (0.12 g, 1.08 mmol) were dissolved in THF (3.0 mL), and heated to 140 °C for 20 minutes in a sealed vial. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography (0%-15% MeOH/CH2CI2) to provide product, 15b, as a white foamy solid (220 mg, 79% yield).
1H NMR (300 MHz, CDCI3) δ 8.85 (d, J =2.4 Hz, 1H), 8.52 (s, 1H), 8.40 (d, J =2.4 Hz, 1H), 8.13-8.09 (m, 3H), 7.31 - 7.28 (m, 2H), 5.14 (d, J =6.6 Hz, 1H), 3.96-3.85 (m, 1 H), 2.69 (td, J =10.2, 4.7 Hz, 1H), 2.40 (s, 3H), 2.33 (d, J =5.6 Hz, 1H), 2.12 - 2.06
-24016260 (m, 1H), 1.88 - 1.84 (m, 2H) and 1.60-1.21 (m, 4H) ppm; LCMS RT = 2.33 (M+1)
515.2.
Formation of N-[(1S, 2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexyl]acetamide (433).
( 1 S,2S)-A/-[2-[5-chloro-1 -(p-tolylsu Ifo ny l)py rrolo[5,4-b]py ridin-3-y l]-5-f luoro-py rim id i n-
4-yl]cyclohexane-1,2-diamine, 15b, (0.100 g, 0.194 mmol) was dissolved in dichloromethane (2 mL) and treated with 'Pr2NEt (0.075 g, 0.101 mL, 0.583 mmol). Acetyl chloride (0.021 mL, 0.291 mmol) was added and the reaction was allowed to stir at room température for 30 minutes. The volatiles were evaporated under reduced pressure, and the residue was dissolved in dichloroethane (2 mL) and treated with LiOH (0,097 mL of 1 M solution, 0.971 mmol). The réaction mixture was heated in the microwave at 150 °C for 10 minutes. The reaction was diluted with EtOAc (5 mL) and water (5 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2x5 mL), and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo to provide the crude product, which was purified by silica gel chromatography (0%-15% MeOH/CH2CI2) to provide N-[(1 S, 2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyllacetamide, 433, (34 mg, 44% yield).
1H NMR (300 MHz, c/6-DMSO) δ 13.03 (s, 1H), 9.10 (s, 1H), 9.05 (s, 1H), 8.67 (d, J =2.1 Hz, 1H), 8.48 (d, J =5.4 Hz, 1H), 8.43 (d, J =2.3 Hz, 1H), 7.97 (d, J =7.7 Hz, 1H), 4.15-4.07 (m, 1H), 3.93- 3.87 (m, 1 H), 2.20 - 2.15 (m, 1H), 1.99- 1.92 (m, 1H), 1.85 - 1.79 (m, 2H), 1.74 (s, 3H) and 1.52 - 1.36 (m, 4H) ppm; LCMS RT = 2.41 (M+1) 403.4.
General Scheme 16
16b
337 cyclohexane-cis-1,2-diamine, isopropanol, 'Pr2NEt (b)
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/7- pyrrolo[2,3-b]pyridine, Pd(PPh3)4, Na2CO3, DME:
DCE, 150 °C, microwave; (c) 1M LiOH 150 °C, microwave; (d) MeSO2CI, 'Pr2NEt, DMF:DCM.
Formation of N1-(2-chloro-5-fluoropyrimidin-4-yl)cyclohexane-c/'s-1,2-diamine (16a)
-24116260
2,4-Dichloro-5-fluoropyrimidine (0.50 g, 2.99 mmol) was dissolved in isopropanol (7 mL) and treated with 'Pr2NEt (1.50 mL, 8.98 mmol). Cyclohexane-c/s-1,2-diamine (0.46 g, 4.03 mmol) was added and the reaction was allowed to stir at room température overnight. The solvent was evaporated and the reaction mixture was diluted in EtOAc (15 mL) and washed with aqueous saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc (15 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the crude product. The resulting crude was purified by silica gel chromatography (5%-30% MeOH/CH2CI2) to provide 16a (370 mg, 50% yield) as a white solid.
1H NMR (300 MHz, CDCI3) δ 7.83 (d, J =2.8 Hz, 1H), 6.16 (s, 1H), 4.08 (s, 1H), 3.13 (d, 7=3.9 Hz, 1H) and 1.84 -1.44 (m, 8H) ppm; LCMS RT = 0.8 (M+1) 245.1.
Formation of /V1-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-
1,2-diamine (16b)
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine (0.26 g, 0.65 mmol) was dissolved in DME (8 mL) and treated with /V1-(2-chloro-5fluoropyrimidin-4-yl)cyclohexane-cis-1,2-diamine, 16a, (0.16 g, 0.65 mmol). Pd(PPh3)4 (0.10 mg, 0.08 mmol) and 2M aqueous Na2CO3 (3.25 mL) were added and the suspension was heated in the microwave to 150 ’C for 20 minutes. 1M aqueous LiOH (5 mL) was added, and the réaction was heated in the microwave to 150 °C for an addîtional 15 minutes. The organic solvent was evaporated under reduced pressure and the aqueous phase was extracted with CH2CI2 (2x20 mL), The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0%-100% CH2CI2/EtOAc) to provide product 16b (140 mg, 66% yield) as a brown foam. 1H NMR (300 MHz, d6-DMSO) δ 12.14 (s, 1H), 8.66 (d, 7=8.0 Hz, 1H), 8,29-8,22 (m, 3H), 7.81 (s, 2H), 7.28-7.19 (m, 2H), 4.55 (s, 1H), 3.74 (s, 1H) and 1.92-1.49 (m, 8H) ppm; LCMS RT = 1.8 (M+1 ) 327.2.
Formation of /V-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl]amino]cyclohexyl]methanesulfonamide (337) /V1-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-y])pyrimidin-4-yl)cyclohexane-1,2-diamine, 16b, (0.009 g, 0.027 mmol) was dissolved in an 8:2 mixture of CH2CI2/DMF (1 mL) and treated with 'Pr2NEt (0.019 mL, 0.110 mmol) and methanesulfonyl chloride (0,006 mL, 0,083 mmol), The reaction was stirred at room température overnight, concentrated in vacuo and the residue was purified by HPLC with 10%-90% acetonitrile/water with 0.03% TFA to provide compound 337.
1H NMR (300 MHz, C6-DMSO) δ 12.47 (s, 1H), 8.64 (d, J =7.8 Hz, 1H), 8.45 - 8.34 (m, 3H), 7.29 (dd, J =4,8, 7.8 Hz, 1H), 7,06 (d, J =7.5 Hz, 1H), 4.47 - 4.25 (m, 1H),
-24216260
4.05 - 3.89 (m, 1H), 2.80 (s, 3H), 1.95 - 1.62 (m, 6H) and 1.49 - 1.24 (τη, 2H) ppm.;
LCMS RT = 2.3 (M+1) 405.3.
The following compounds can be prepared in a manner sîmilar to the one described in either Scheme 15 or Scheme 16:
341
W-[c/s-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amÎno]' cyclohexyljpropanamide (341) 1H NMR (300 MHz, c/6-DMSO) δ 12.47 (s, 1H), 8.65 (d, J =8.1 Hz, 1H), 8.49-8.23 (m, 3H), 7.61 (d, J =7.8 Hz, 1H), 7.29 (dd, J =4.7, 8.0 Hz, 1H), 4.39 (d, J =19.5 Hz, 2H), 2.10 (q, J =7.6 Hz, 2H), 1.79- 1.64 (m, 6H), 1.48 (d, J =6.4 Hz, 2H) and 0.91 (t, J =7.6 Hz, 3H) ppm; LCMS RT = 2.3 (M+1) 383.4.
M-ic/s-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyrÎdin-3-yl)pyrimidin-4yl]amino]cyclohexyl]butanamide (342)
LCMS RT = 2.5 (M+1) 397.4.
N-[c/s-2-H5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl]amino]cyclohexyl]cyclopentanecarboxamide (343)
LCMS RT = 2.7 (M+1) 423.4.
N-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl]amino]cyclohexyl]benzamide (344)
LCMS RT = 2.7 (M+1) 431.4.
/V-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl]amino]cyclohexyl]propane-1-sulfonamide (346)
-24316260 1H NMR (300 MHz, cf6-DMSO) δ 12.41 (s, 1H), 8.65 (d, J =7.8 Hz, 1H), 8.38 - 8.33 (m, 3H), 7.28 (dd, J =4.7, 7.9 Hz, 1H), 7.06 (d, J =8.1 Hz, 1H), 4.36 (s, 1H), 3.88 (s, 1H), 2.83 (t, J =7.7 Hz, 2H), 1.85 - 1.70 (m, 6H), 1.59 (q, J =7.8 Hz, 2H), 1.47 - 1.24 (m, 2H) and 0.82 (t, J =7.4 Hz, 3H) ppm; LCMS RT = 2.6 (M+1) 433.3.
1-[c/s-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidÎn-4-yl]amino]cyclohexyl]-3propyl-urea (347) 1H NMR (300 MHz, D6-DMSO) δ 12.47 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.45-8.34 (m, 3H), 7.29 (dd, J = 4.8, 7.8 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 4.47-4.25 (m, 1H), 4.05- 3.89 (m, 1H), 2.80 (s, 3H), 1.95- 1.62 (m, 6H) and 1.49- 1.24 (m, 2H) ppm; LCMS RT = 2.4 (M+1) 412.4.
W-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl]amino]cyclohexyl]acetamide (348) 1H NMR (300 MHz, d6-DMSO) δ 12.53 (s, 1 H), 8.66 (d, J =7.6 Hz, 1 H), 8.43 (s, 1 H), 8.39 - 8.36 (m, 2H), 7.91 (d, J =7.9 Hz, 1 H), 7.32 (dd, J =4.7, 7.9 Hz, 1 H), 4.08 - 3.94 (m, 1H), 3.86 (d, J =8.4 Hz, 1H), 2.13 (d, J =24.3 Hz, 1H), 1.95 (d, J =10.2 Hz, 1H), 1.81 -1.73 (m, 2H), 1.73 (s, 3H) and 1.43-1.14 (m, 4H) ppm; LCMS RT = 2.2 (M+1) 369.4.
N-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]propanamide (349)
LCMS RT =2.7 (M+1) 417.3
N-[(1R, 2R)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]cyclopentanecarboxamide (351 )
LCMS RT = 3.1 (M+1) 457.3
N-[(1R, 2R)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrÎmidin-4yllaminolcyclohexyllbenzamide (352)
-24416260
LCMS RT = 3.0 (M+1) 465.3 /V-I(1R, 2R)-2-[[2-(5-chloro-1W-pyrrolo[2,3-b]pyrîdin-3-yl)-5-fluoro-pyrimidin-4yfjaminojcyclohexyljmethanesulfonamide (353)
LCMS RT = 2.7 (M+1) 439.4
N-[(1R, 2R)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]propane-1-sulfonamide (354)
LCMS RT = 3.0 (M+1) 467.3
-[(1 R, 2R)-2-[[2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-3-propyl-urea (355)
LCMS RT = 2.8 (M+1) 446.3.
N-[( 1 R, 2R)-2-[[5-ffuoro-2-(1 H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yljamïnojcyclotiexyljbutanamide (358)
LCMS RT = 2.5 (M+1) 397.4.
N-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yljaminojcyclohexyljcyclopentanecarboxamide (359)
LCMS RT = 2.7 (M+1) 423.4
N-[( 1 R, 2R)-2-[[5-fluoro-2-(1 H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yljaminojcyclohexyljbenzamide (360)
LCMS RT = 2.63 (M+1) 431.4.
N-[(1 R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl]amino]cyclohexyl]methanesulfonamide (361 ) 1H NMR (300 MHz, c/6-DMSO) δ 12.54 (s, 1H), 8.66 (d, J =8.0 Hz, 1H), 8.43-8.36 (m, 3H), 7.32 (dd, J =4.7, 7.9 Hz, 1 H), 7.21 (d, J =8.3 Hz, 1H), 4.16 (d, J =9.3 Hz,
-24516260
1H), 3.35 (d, J =9.8 Hz, 1H), 2.91 (d, J =8.9 Hz, 3H), 2.12-2.02 (m, 2H), 1.79-1.73
W-[(1R,2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrim!din-4yl]amino]cyclohexyl]propane-1-su1fonamide (362) 1H NMR (300 MHz, d6-DMSO) δ 12.43 (s, 1H), 8.68 (d, J =7.9 Hz, 1H), 8.38-8.33 (m, 3H), 7.29 (dd, J =4.7, 7.8 Hz, 1 H), 7.17 (d, J =8.6 Hz, 1H), 4.14 (d, J =6.9 Hz, 1 H), 3.33 - 3.26 (m, 1 H), 3.07 - 2.89 (m, 2H), 2.07 (d, J =12.6 Hz, 2H), 1.76 (d, J =7.9 Hz, 2H), 1.61-1.33 (m, 6H) and 0.90 (t, J =7.4 Hz, 3H) ppm; LCMS RT = 2.6 (M+1) 433.3.
/V-[Îrans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4 yl]amino]cyclohexyl]butanamide (363)
LCMS RT = 2.9 (M+1) 431.3.
/V-[(frans-2-[[2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]cyclopentanecarboxamide (364)
LCMS RT = 3.1 (M+1) 457.3.
/V-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yi}-5-fluoro-pyrimidiii-4yl]amino]cyclohexyl]benzamide (365)
LCMS RT = 3.0 (M+1) 465.3.
N-[trans-2-n2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]propane-1-sulfonamide (367)
LCMS RT = 3.0 (M+1) 467.3.
1-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-3-propyl-urea (368)
LCMS RT = 2.8 (M+1) 446.3.
-24616260
Cl
N H
425
Cl
426
Methyl N-[(1S, 2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-f1uoro-pyrimidin-4yl]amino]cyclohexyl]carbamate (425) 'H NMR (300 MHz, ctô-DMSO) δ 13.02 (s, 1H), 9.10 (s, 2H), 8.67 (s, 1H), 8.44 - 8.40 (m, 2H), 7.26 (d, J =6.5 Hz, 1H), 4.19 (s, 1H), 3.66 (d, J =9.8 Hz, 1H), 3.48 (s, 3H), 2.13 (s, 1 H), 2.02 (d, J =9.2 Hz, 1 H), 1.78 (d, J =9.6 Hz, 2H) and 1.47 - 1.34 (m, 4H) ppm; LCMS RT = 2.1 (M+1) 419.2.
1-[(1S, 2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyriinidin-4yl]amino]cyclohexyl]-3-methyl-urea (426) 1H NMR (300 MHz, d6-DMSO) δ 12.56 (s, 1H), 8.70 (d, J =2.2 Hz, 1H), 8.35 (dd, J =2.4, 6.8 Hz, 2H), 8.28 (d, J =4.2 Hz, 1H), 5.99 (d, J =7.0 Hz, 1H), 5.80 - 5.63 (m, 1H), 3.91 - 3.87 (m, 1H), 3.66 - 3.45 (m, 1H), 2.54 (s, 3H), 2.30 (d, J =13.0 Hz, 1H), 2.04 (d, J =46.9 Hz, 1 H), 1.78 (d, J =8.5 Hz, 2H) and 1.56 - 1.23 (m, 4H) ppm; LCMS RT = 2.5 (M+1) 419.5.
427
428
3-[(1 S, 2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-1,1 -dimethyl-urea (427) 1H NMR (300 MHz, P6-DMSO) δ 12.59 (s, 1H), 8.72 (d, J =2.3 Hz, 1H), 8.41 (d, J =2.7 Hz, 1H), 8.35 (d, J =2.3 Hz, 1H), 8.29 (d, J =4.4 Hz, 1H), 8.23 (s, 1H), 6.19 (d, J =7.8 Hz, 1H), 4.04-3.97 (m, 1H), 3.78-3.69 (m, 1H), 2.68 (s, 6H), 2.31 (d, 7=11.6 Hz, 1H), 1.95 (d, J =9.8 Hz, 1H), 1.79 (d, J=10.4 Hz, 2H) and 1.60- 1.32 (m, 4H) ppm; LCMS RT = 2.7 (M+1) 432.4.
/V-[(1S, 2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]methanesulfonamide (428) 1H NMR (300 MHz, 76-DMSO) δ 12.54 (s, 1H), 8.72 (d, J =2.3 Hz, 1H), 8.38 - 8.29 (m, 3H), 7.82 (s, 1H), 7.21 (d, J =8.3 Hz, 1H), 4.52 (brs, 1H), 4.12 - 4.05 (m, 1H), 2.92 (s, 3H), 2.09 (d, J =12.8 Hz, 2H), 1.78 (brs, 2H) and 1.49 - 1.39 (m, 4H) ppm; LCMS RT = 2.7 (M+1) 439.4.
-24716260
1-[c/s-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-3-methyl-urea (430) 1H NMR (300 MHz, c/6-DMSO) δ 12.61 (s, 1H), 8.68 (d, J =2.2 Hz, 1H), 8.39 - 8.31 (m, 4H), 6.12 (d, J =6.7 Hz, 1 H), 5.91 - 5.83 (m, 1H), 4.29 - 4.13 (m, 1H), 4.02 - 3.91 (m, 1H), 2.55 (s, 3H), 1.93 (d, J =12.8 Hz, 1H) and 1.74- 1.53 (m, 7H) ppm; LCMS RT = 2.6 (M+1) 418.5.
3-[c/s-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-1,1 -dimethyl-urea (431 ) 1H NMR (300 MHz, d6-DMSO) δ 12.54 (s, 1H), 8.68 (d, J =2.3 Hz, 1H), 8.33 - 8.29 (m, 3H), 7.96 (s, 1 H), 5.72 (d, J =6.9 Hz, 1H), 4.36 (s, 1 H), 4.10 (s, 1 H), 2.76 (s, 6H), 1.96 - 1.87 (m, 2H), 1.74- 1.63 (m, 4H) and 1.55- 1.45 (m, 2H) ppm; LCMS RT =
Methyl N-[c/s-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]carbamate (432) 1H NMR (300 MHz, d6-DMSO) δ 12.54 (s, 1H), 8.67 (d, J =2.2 Hz, 1H), 8.35-8.29 (m, 3H), 7.62 (s, 1H), 7.05 (d, J =7.2 Hz, 1H), 4.50 -4.40 (m, 1H), 4.20-4.10 (m, 1H), 3.46 (s, 3H), 1.87 (d, J =10.9 Hz, 2H), 1.71 -1.65 (m, 4H) and 1.43 (d, J =7.4 Hz, 2H) ppm; LCMS RT = 2.9 (M+1) 419.4.
N-[5-fluoro-2-(1H-pyrrolo[5,4-b]pyridin-3-yl)pyrimidin-4-yl]cyclohexane-cfs-1,2diamine (206)
LCMS RT =1.9 (M+1) 327.2.
trans-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexanol (207)
LCMS RT = 2.2 (M+1) 328.2.
c/s-2-[[5-fluoro-2-(1H-pyrrolo(2,3-b]pyrïdin-3-yl)pyrimidin-4-yl]amino]cyclohexanol (277)
-24816260
LCMS RT = 1.6 (M+1) 328.2.
N-[c/s-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]propanamide (333)
LCMS RT = 2.7 (M+1) 417.4.
N-[c/s-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]butanamide (334)
LCMS RT = 2.9 (M+1) 431.4.
N-[c/s-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]cyclopentanecarboxamide (335)
LCMS RT = 3.1 (M+1) 457.3.
W-[c/s-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]benzamide (336)
LCMS RT = 3.0 (M+1) 465.4.
/V-[c/s-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]propane-1-sulfonamide (338)
LCMS RT = 2.9 (M+1) 467.3.
1-[c/s-2-[[2-(5-chloro-1H-pyrrolo[2)3-b]pyridin-3-yl)-5-fluoro-pyrimÎdin-4yl]amino]cyclohexyl]-3-propyl-urea (339)
LCMS RT = 2.9 (M+1) 446.3.
-24916260
1-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-3-propyl-urea (350)
LCMS RT = 2.6 (M+1) 403,3.
N-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl]amino]cyclohexyl]propanamide (356)
LCMS RT = 2.3 (M+1) 383.4.
(1 R, 2R)-/V1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-4yl)cyclohexane-1,2-diamine (31)
LCMS RT = 2.2 (M+1) 411.2.
N1 -(5-fluoro-2-(1 H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-1,2-diamine (4)
LCMS RT = 2.2 (M+1) 327.2.
(1R, 2R)-N1-(5-chloro-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)cyclohexane-1,2-diamine (115)
LCMS RT = 1.3 (M+1) 377.2.
N1 -(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrinriidin-4-yl)cyclohexane-1,2diamine (116)
LCMS RT = 3.3 (M+1) 357.2.
N-[(1R, 2R)-2-[[2-(5-chloro-1H-pyrrolo[2I3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]butanamide (369)
LCMS RT = 2.9 (M+1) 431.3.
-[(1 R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl]amino]cyclohexyl]-3-propyl-urea (370)
LCMS RT = 2.4 (M+1) 412.4.
-25016260
2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(2-methoxycyclohexyl)-pyrimidin4-amine (412)
LCMS RT = 3.5 (M+1) 376.4.
Cbz
DPPA, Et3N, toluène, 110°C; ii
BnOH, 85 °C (b) LiOH, THF: H2O (c) Boc2O, pyridine, NH4HCO3, dioxane (d) BTIB, CH3CN:H2O.
Formation of (1S, 3R)-3-(ethoxycarbonyl)cyclohexanecarboxylic acid (18a)
O O
(1 S, 3F?)-3-(ethoxycarbonyl)cyclohexanecarboxylic acid can be prepared following the literature procedures described in : Barnett, C. J., Gu, R. L., Kobierski, Μ. E., WO-2002024705, Stereoselective process for preparing cyclohexyl amine dérivatives.
Formation of ethyl (1R, 3S)-3-benzyloxycarbonylaminocyclohexanecarboxylate (18b) (1S, 3R)-3-(Ethoxycarbonyl)cyclohexanecarboxylic acid, 18a, (10.0 g, 49.9 mmol) was dissolved in toluene (100 mL) and treated with triethylamine (7.6 mL, 54.9 mmol) and DPPA (12.2 mL, 54.9 mmol). The resulting solution was heated to 110 °C and stirred for 1 hour. After cooling to 70 °C, benzyl alcohol (7.7 mL, 74.9 mmol) was added, and the mixture was heated to 85 °C overnight. The resulting solution was cooled to room température, poured into EtOAc (150 mL) and water (150 mL)
-25116260 and the layers were separated. The aqueous layer was extracted with EtOAc (2x75 mL) and the combined organic extracts were washed with water (100mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0%-50% EtOAc/hexanes) to provide 18b (15.3 g, containing -25% benzyl alcohol), which was used for the next step without further purification.
Formation of (1R, 3S)-3-benzyloxycarbonylaminocyclohexanecarboxylic acid (18c) Ethyl (1R, 3S)-3-benzyloxycarbonylaminocyclohexanecarboxylate, 18b, (36 g, 117.9 mmol) was dissolved in THF (144.0 mL) and treated with a solution of LiOH (5.647 g, 235.8 mmol) in water (216.0 mL). After stirring ovemight, the reaction mixture was diluted with water (100 mL), washed with methyl tert-butyl ether (150 mL) and brought to pH 3 by addition of 3N HCl. The acidic solution was extracted with EtOAc (3x100 mL), and the combined organic layers were washed with water and brine, dried on Na2SO4 and concentrated in vacuo.
The crude product was triturated with methyl tert-butyl ether (30 mL) and filtered to provide a first crop of crystals. The filtrate was treated with heptane (20 mL), concentrated to 30 mL and allowed to stand at room température for 3 hours to provide a second crop of crystals that were collected by filtration for a total of 14.4 g (44%yield) 18c.
1H NMR (300 MHz, CDCI3) δ 7.38 - 7.33 (m, 5H), 5.11 (s, 2H), 4.68 (s, 1H), 3.55 (s, 1H), 2.44 (d, J =11.0 Hz, 1 H), 2.32 (d, J =11.7 Hz, 1H), 2.03- 1.86 (m, 3H) and 1.48 - 0.88 (m, 4H) ppm.
Formation of benzyl N-[(1S, 3R)-3-carbamoylcyclohexyl]carbamate (18d)
To a solution of (1R, 3S)-3-Benzyloxycarbonylaminocyclohexanecarboxylic acid, 18c, (10.0 g, 36.1 mmol) in 1,4-dioxane (300 mL) was added pyridine (2.9 mL, 36.1 mmol), followed by di-tert-butyl dicarbonate (10.7 mL, 46.9 mmol) and ammonium bicarbonate (10.1 g, 126.2 mmol). After 3 hours, another portion of di-tert-butyl dicarbonate (1.5 g, 6.8 mmol) and ammonium bicarbonate (1.5 g, 6.8 mmol) was added and stirring was continued ovemight. The reaction was quenched by addition of 2N HCl (400 mL) and stirred for 1 hour. The resulting suspension was filtered under reduced pressure, washed with 2N HCl (50mL), water (8x50mL) and hexanes (3x50mL) and vacuum dried to provide benzyl N-[(1 S, 3R)-3carbamoylcyclohexyljcarbamate, 18d, (9.1 g, 91%) as a white solid.
1H NMR (300 MHz, CDCI3) δ 7.40 - 7.24 (m, 5H), 5.08 (s, 2H), 3.58-3.44 (m, 1H), 2.38-2.21 (m, 1H), 2.17 (d, J =12.7, 1H), 2.05-1.78 (m, 8H), 1.54-0.97 (m, 5H).
Formation of benzyl N-[(1S, 3R)-3-aminocyclohexyl]carbamate (18e)
Benzyl A/-[(1 S, 3R)-3-carbamoylcyclohexyl]carbamate, 18d, (9.1 g, 32.9 mmol) was suspended in a mixture of acetonitrile (100 mL) and water (100 mL) and treated with
-25216260 . bis(trifluoroacetoxy)iodobenzene (15.5 g, 36.1 mmol). The suspension was allowed to stir at room température overnight and was then quenched with 1N HCl (WOmL). After évaporation of the acetonitrile, thé acidic aqueous solution was washed with EtOAc (2x150mL). The pH was adjusted to basic by addition of solid KOH and the resulting émulsion was extracted with EtOAc (3x200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide product 18e (6.2 g, 75% yield).
1H NMR (300 MHz, CDCI3) δ 7.31 - 7.45 (m, 5H), 5.11 (s, 2H), 4.90 (br. s., 1H), 3.58 (br. s., 1H), 2.72- 2.97 (m, 1H), 2.14 (d, J =11.90 Hz, 1H>, 1.87 -2.02 (m, 1H), 1.73 1.87 (m, 2H), 1.21 - 1.46 (m, 1H), 0.89 - 1.18 (m, 3H).
General Scheme 19
570
MeOCOCI, Et3N, THF (b) H2, Pd/C, EtOH (c) 5chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, THF, 130 °C, microwave (d) LiOH, 130 ’C, microwave.
Formation of methyl N-[(1R, 3S)-3-benzyloxycarbonyl-aminocyclohexyl]carbamate (19a)
Benzyl N-[(1S, 3R)-3-aminocyclohexyl]carbamate, 18e, (0.99 g, 3.99 mmol) was dissolved in THF (20 mL) and treated with methyl chloroformate (0.62 mL, 7.97 mmol), followed by triethylamîne (1.67 mL, 11.96 mmol). After stirring for 1 hour at room température, the solvent was evaporated under reduced pressure and the residue was diluted into 1:3 mixture of CH2CI2:EtOAc (130 mL) and washed with 1N HCl (50 mL) and 2N Na2CO3 (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the desired product, 19a, as a white solid (1.09g, 89% yield). i 1H NMR (300 MHz, CDCI3) δ 7.21 - 7.37 (m, 5H), 5.02 (s, 2H), 4.26 - 4.62 (m, 1H), 3.58 (s, 3H), 3.34 - 3.54 (m, 2H), 2.24 (d, J =11.71 Hz, 1H), 1.82 - 2.03 (m, 2H), 1.72 (dt, J =3.14, 13.93 Hz, 1H), 1.23 - 1.44 (m, 1H), 0.79 - 1.02 (m, 3H).
Formation of methyl N-[(1R, 3S)-3-aminocyclohexyl]carbamate (19b)
Methyl N-[(1 R, 3S)-3-benzyloxycarbonylaminocyclohexyl]carbamate, 19a, (1.09 g, 3.56 mmol) was dissolved in éthanol (100 mL) and treated with 10% Pd/C (0.38 g, 0.36 mmol). The flask was capped, degassed and fitted with a hydrogen balloon and
-25316260 allowed to stir overnight. The reaction mixture was filtered under nitrogen and concentrated in vacuo to provide the product, 19b, as a white solid.
1H NMR (300 MHz, CDCI3) δ 3.31 - 3.56 (m, 1H), 3.03 (s, 4H), 2.81 (t, J =10.67 Hz,
1H), 2.03-2.20 (m, 1H), 1.71 -2.01 (m, 3H), 1.27- 1.49 (m, 1H), 0.92-1.14 (m,
3H).
Formation of methyl N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fIuoropyrimidin-4-yl]amino]cyclohexyl]carbamate (570)
5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3bjpyridine, 19b, (2.04 g, 4.39 mmol) and methyl A/-[(1 R, 3S)-3-aminocyclohexyljcarbamate (0.60 g, 3.14 mmol) were suspended in THF (16 mL) and heated in the microwave to 130 °C for 20 minutes. Lithium hydroxide (15.67 mL of 1M solution, 15.67 mmol) was added, and the resulting mixture was heated in the microwave for 20 min at 130 °C. The resulting solution was diluted with water (150 mL) and ethyl acetate (200 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL) and t organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (40-100% EtOAc/hexanes) followed by treatment of the pure fractions with 4N HCl in dioxane to provide the hydrochloride of compound, 570, as an off white solid.
1H NMR (300 MHz, MeOD) δ 8.81 (d, J =2.1 Hz, 1 H), 8.20 (d, J =2.3 Hz, 1H), 8.15 (s, 1 H), 7.97 (d, J =4.1 Hz, 1 H), 4.26 - 4.18 (m, 1 H), 3.71 - 3.52 (m, 1 H), 3.59 (s, 3H), 2.36 (d, J =10.5 Hz, 1H), 2.18 (d, J =10.7 Hz, 1H), 2.04- 1.86 (m, 2H), 1.57 (s, 1H) and 1.43-1.15 (m, 3H) ppm; LCMS RT = 2.0 (M+1) 419.4 (M-1) 417.3.
General Scheme 20.
5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1 (p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, THF (b) CH2CI2, trifluoroacetic acid (c) acetyl chloride, Et3N, THF (d) LiOH, 130 °C, microwave.
Formation of tert-butyl N-[(1R, 3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate (20b) tert-Butyl A/-[(1 R, 3S)-3-aminocyclohexyl]carbamate, 20a, (0.15 g, 0.70 mmol) and 5chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-25416260 bjpyridine, 1a, (0.49 g, 1.05 mmol) were dissolved in THF (30 mL) and allowed to stir at room température overnight, The solvent was evaporated under reduced pressure and the residue was purified by two rounds of silica gel chromatography first with (0%-10% MeOH/CH2CI2) second with (10%-50% EtOAc/hexanes) to provide tert-butyl /V-[(1R, 3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3yl]-5’fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate (20b) (330 mg, 38%).
1H NMR (300 MHz, CDCl3) Π 8.74 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 8.09 (t, J =3.3 Hz, 2H), 7.29 (d, 7 = 8.1 Hz, 2H), 5.02 (d, 7 = 7.1 Hz, 1H), 4.47 (d, J = 7.7 Hz, 1H), 4.25 - 4.16 (m, 1H), 3.68 (d, J =2.0 Hz, 1H), 2.48 (d, J= 11.7 Hz, 1H), 2.38 (s, 3H), 2.26 (d, J = 12.8 Hz, 1H), 2.11 (d, J= 11.9 Hz, 1H), 1.95- 1.89 (m, 1H), 1.69- 1.56 (m, 1H), 1.44 (s, 9H) and 1.28-1.11 (m, 3H) ppm.
Formation of (1/?, 3S)-N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine (20c) ferf-Butyl Λ/-[(1 S, 3R)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate, 20b, (0.33 g, 0.53 mmol) was dissolved in CH2CI2 (10 mL) and treated with trifluoroacetic acid (2 mL). After stirring for 2 hours, the solvent was evaporated under reduced pressure and the resulting residue was passed through a polymer supported carbonate column to provide the free base of (1R, 3S)-N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine , 20c, (0.25 g, 0.43 mmol, 81%).
1H NMR (300 MHz, CDCI3) δ 8.76 (dd, 7=2.4, 6.3 Hz, 1H), 8.52 - 8.49 (m, 1H), 8.39 (d, J = 2.4 Hz, 1 H), 8.14 - 8.04 (m, 3H), 7.29 (d, J = 7.5 Hz, 2H), 5.61 (s, 1H), 4.28 4.16 (m, 1H), 3.19 - 3.10 (m, 1H), 2.39 (s, 3H), 2.39 - 2.31 (m, 1H), 2.08 - 1.90 (m, 3H), 1.63 - 1.50 (m, 1H) and 1.40 -1.17 (m, 3H) ppm .
Formation of N-[(1 R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexyl]acetamide (547) (1 R, 3S)-A/1 -[2-[5-chloro-1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (0.050 g, 0.097 mmol) was dissolved in THF (1.0 mL) and treated with triethylamine (0.041 mL, 0.290 mmol) and acetyl chloride (0.013 mL, 0.190 mmol). After stirring overnight, the solvent was evaporated and the residue was taken into THF (1.0 mL) and treated with 1M LiOH (1.0 mL, 1.0 mmol). The reaction mixture was heated in the microwave to 130 °C for 10 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5%-70% H20/acetonitrile with 0.1%TFA. The purified fractions were concentrated to dryness to provide the TFA sait of the product, which was dissolved in MeOH and passed through a polymer bound carbonate cartridge to provide the free base of product 547.
-25516260 1H NMR (300 MHz, MeOD) δ 8.81 (s, 1H), 8.20 (s, 1 H), 8.15 (s, 1H), 7.99 (d, J =4.1,
H), 4.23 (t, J =11.4, 1 H), 3.90 (t, J =11.4, 1 H), 2.35 (d, J =11.6, 1 H), 2.20 (d, J =
12.5, 1H), 2.00 (d, J =15.9, 2H), 1.92 (s, 3H), 1.67 (dd, J = 26.3, 13.2, 1H), 1.53 1.06 (m, 3H) ppm LCMS RT = 2.1 (M+1) 403.2.
The following compounds can be prepared by methods similar to those described in Scheme 19 and Scheme 20:
(1 R, 3S)-N1-[2-(5-chloro-1H-pyrrolo[2,3-b]pyrrdin-3-yl)-5-fluoro-pyrimidin-4yl]cyclohexane-1,3-diamine (542)
LCMS RT = 1.4 (M+1) 361.4.
N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyrÎdin-3-yl)-5-fluoro-pyrimidÎn-4yl]amino]cyclohexyl]acetamide (576) 1H NMR (300 MHz, MeOD) δ 8.81 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.99 (d, J =4.1, 1H), 4.23 (t, 7=11.4, 1H), 3.90 (t, 7 = 11.4, 1H), 2.35 (d, 7 = 11.6, 1H), 2.20 (d, 7 = 12.5, 1H), 2.00 (d, 7 = 15.9, 2H), 1.92 (s, 3H), 1.67 (dd, 7 = 26.3, 13.2, 1H), 1.53 1.06 (m, 3H) ppm; LCMS RT = 1.8 (M+1) 403 (M-1) 401.4.
Methyl N-[(1S, 3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4 yljaminojcyclohexyljcarbamate (548).
LCMS RT = 2.8 (M+1) 419.5.
3-[( 1 S, 3R)-3-[[2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4 yl]amino]cyclohexyl]-1,1-dimethyl-urea (549).
LCMS RT = 2.6 (M+1) 432.5.
N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-2-methoxy-acetamide (591 )
-25616260
Ή NMR (300 MHz, MeOD) δ 8.82 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.99 (d, J = 4.1 Hz, 1H), 4.29-4.21 (m, 1H), 4.04-3.96 (m, 1H), 3.87 (s,
2H), 3.40 (s, 3H), 2.34 (d, J = 11.6 Hz, 1H), 2.21 (d, J = 12.5 Hz, 1H), 2.02 - 1.93 (m,
2H), 1.74 - 1.62 (m, 1H) and 1.54 - 1.28 (m, 3H) ppm.
LCMS RT = 2.6 (M+1) 433.4.
2-methoxyethyl N-[(1 R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexyl]carbamate (592) 1H NMR (300 MHz, MeOD) δ 8.84 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.99 (d, J =3.97 Hz, 1H), 4.18-4.34 (m, 1H), 4.14 (br. s., 2H), 3.49-3.74 (m, 3H), 3.3 (s, 3H) 2.38 (d, J =9.06 Hz, 1H), 2.19 (d, J =13.41 Hz, 1H), 1.84 - 2.11 (m, 2H), 1.51 -1.78 (m, 1 H), 1.12 - 1.47 (m, 3H) ppm. LCMS RT = 2.5 (M+1) 463.4.
General Scheme 21:
tetrahydrofuran-2-carboxylic acid, EDC, HOBt, DIPEA, CH2C)2] rt (b) LiOH, 130’C, microwave
Formation of /V-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexyl]tetrahydrofuran-2-carboxamide hydrochloride (638).
To a solution of (1S, 3R)-A/1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-
5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (60 mg, 0.12 mmol) in CH2CI2 (3mL) was added tetrahydrofuran-2-carboxylic acid (20.3mg, 0.17 mmol), EDC (26.8 mg, 0.14 mmol), HOBt (17.8mg, 0.12 mmol) and DIPEA (60.2mg, 0.47 mmol), and the reaction mixture was stirred at room température overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (4mL) and treated with 1M aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was heated in the microwave to 130°C for 20 min. The solvent was evaporated under reduced pressure, and the residue was purifîed by HPLC, using 570% MeOH//H2O with 6mM HCl over 15 minutes. The purifîed fractions were concentrated to provide the hydrochloride of A/-[(1R, 3S)-3-[[2-(5-chloro-1 Hpyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]tetrahydrofuran-2carboxamide, 638.
-25716260 1H NMR (300 MHz, MeOD) □ 8.55 (d, J = 1.0 Hz, 1 H), 8.46 - 8.45 (m, 1 H), 8.29 8.27 (m, 2H), 4.28 (d, J = 6.1 Hz, 2H), 4.00 - 3.87 (m, 3H), 2.36 - 2.16 (m, 3H), 2.00 1.91 (m, 5H) and 1.75 -1.41 (m, 4H) ppm.
LCMS RT = 3.77 (M+1) 459.37, (M-1) 457.35.
The following compounds can be prepared by methods similar to those described in
Scheme 19, Scheme 20 and Scheme 21:
(1 R, 3S)-N1-[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]cyclohexane-1,3-diamine (542)
LCMS RT =1.4 (M+1) 361.4.
N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]acetamide (576) 1H NMR (300 MHz, MeOD) δ 8.81 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.99 (d, J =4.1, 1H), 4.23 (t, J =11.4, 1H), 3.90 (t, J = 11.4, 1H), 2.35 (d, J = 11.6, 1 H), 2.20 (d, J = 12.5, 1 H), 2.00 (d, J = 15.9, 2H), 1.92 (s, 3H), 1.67 (dd, J = 26.3, 13.2, 1H), 1.53 1.06 (m, 3H) ppm; LCMS RT = 1.8 (M+1) 403 (M-1) 401.4.
Methyl N-[(1 S, 3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]carbamate (548).
LCMS RT = 2.8 (M+1) 419.5.
3-[(1 S, 3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-1,1-dimethyl-urea (549).
LCMS RT = 2.6 (M+1) 432.5
| Cl | O | C! | O | ||
| φ. HN— | 7 N=< | .—F HN-Vox +o H — | Δ HN-^ | HN-\ ;o ' H | |
| 591 | 592 |
N-((1 R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-2-methoxy-acetamide (591 )
-25816260 1H NMR (300 MHz, MeOD) δ 8.82 (d, J = 2.4 Hz, 1 H), 8.21 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.99 (d, J = 4.1 Hz, 1H), 4.29 - 4.21 (m, 1H), 4.04- 3.96 (m, 1H), 3.87 (s,
2H), 3.40 (s, 3H), 2.34 (d, J= 11.6 Hz, 1H), 2.21 (d, J = 12.5 Hz, 1H), 2.02- 1.93 (m,
2H), 1.74- 1.62 (m, 1H) and 1.54 - 1.28 (m, 3H) ppm. LCMS RT = 2.6 (M+1) 433.4.
2-methoxyethyl N-[(1 R, 3S)-3-[[2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexyl]carbamate (592) 1H NMR (300 MHz, MeOD) δ 8.84 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.99 (d, J =3.97 Hz, 1H), 4.18 - 4.34 (m, 1H), 4.14 (br. s„ 2H), 3.49 - 3.74 (m, 3H), 3.3 (s, 3H) 2.38 (d, J =9.06 Hz, 1H), 2.19 (d, J =13.41 Hz, 1H), 1.84-2.11 (m, 2H), 1.51 - 1,78 (m, 1H), 1.12-1.47 (m, 3H) ppm. LCMS RT = 2.5 (M+1) 463.4.
N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pynmidin-4yl]amino]cyclohexyl]-3-hydroxy-2,2-dimethyl-propanamide hydrochloride (650) 1H NMR (300 MHz, MeOD) □ 8.56 - 8.54 (m, 2H), 8.34 (s, 1H), 8.30 (t, J= 5.4 Hz,
1H), 4.29 (t, J = 11.4 Hz, 1H), 3.93 (t, J = 11.6 Hz, 1H), 3.54 (s, 2H), 2.34 (d, J = 10.8 Hz, 1H), 2.18 (d, J = 11.4 Hz, 1H), 2.01 (d, J = 11.3 Hz, 2H), 1.73- 1.37 (m, 4H) and 1.15 (s, 6H) ppm. LCMS RT = 3.79 (M+1) 461.38, (M-1) 459.4.
W-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]tetrahydropyran-3-carboxamide hydrochloride (633) 1H NMR (300 MHz, MeOD) Π 8.64 (d, J =2.2 Hz, 1H), 8.51 (s, 1H), 8.36 (d,J= 2.2
Hz, 1H), 8.29 (d, J = 5.5 Hz, 1 H), 4.39 (t, J= 11.9 Hz, 1H), 3.93-3.82 (m, 3H), 3.543.30 (m, 2H), 2.52-2.43 (m, 1H), 2.37- 2.33 (m, 1H), 2.20 (d, J = 11.6 Hz, 1H), 2.01 (d, J= 11.3 Hz, 2H), 1.90- 1.88 (m, 1H), 1.83- 1.63 (m, 4H) and 1.59- 1.26 (m, 3H) ppm.
LCMS RT = 3.25 (M+1) 473.42, (M-1) 471.1.
N-[(1 R, 3S)-3-[[2-(5-chloro-1H-pyrro1o[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-3-hydroxy-propanamide hydrochloride (634) 1H NMR (300 MHz, MeOD) □ 8.61 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.35 (d, J = 2.0
Hz, 1 H), 8.29 (d, J = 5.5 Hz, 1 H), 4.37 (t, J = 11.2 Hz, 1 H), 3.95 (s, 1 H), 3.80 (s, 2H),
-25916260
2.42 (t, J= 5.5 Hz, 3H), 2.20 (d, J = 11.5 Hz, 1H), 2.03 (d, J = 11.0 Hz, 2H) and 1.76
-1.29 (m, 4H) ppm.
LCMS RT = 3.47 (M+1) 433.21, (M-1) 431.3.
N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyndin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-3-methyl-oxetane-3-carboxamide hydrochloride (635) 1H NMR (300 MHz, MeOD) □ 8.48 - 8.45 (m, 2H), 8.29 - 8.23 (m, 2H), 4.84 (d, J =
6.0 Hz, 1H), 4.38 (d, J = 6.0 Hz, 1 H), 4.26 - 4.23 (m, 1 H), 3.96 (s, 1H), 3.77-3.62 (m, 2H), 2.36 (s, 1H), 2.18 (d, J = 11.5 Hz, 1H), 2.02 (d, J= 12.3 Hz, 2H), 1.70-1.25 (m, 4H) and 1.59 (s, 3H) ppm. LCMS RT = 3.12 (M+1) 459.38, (M-1) 457.4.
Ci
N-[(1 R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]tetrahydropyran-4-carboxamide hydrochloride (636) 1H NMR (300 MHz, MeOD) Π 8.64 (d, J = 2.3 Hz, 1 H), 8.51 (s, 1 H), 8.36 (d, J = 2.3
Hz, 1H), 8.29 (d, J= 5.6 Hz, 1H), 4.44-4.36 (m, 1H), 3.96-3.87 (m, 3H), 3.47-3.37 (m, 2H), 2.49-2.35 (m, 2H), 2.21 (d, J= 12.4 Hz, 1H), 2.02 (d, J = 11.9 Hz, 2H) and
1.83- 1.23 (m, 8H) ppm. LCMS RT = 3.12 (M+1) 473.4, (M-1) 471.4.
N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4 yl]amino]cyclohexyl]-3-hydroxy-butanamide hydrochloride (640) 1H NMR (300 MHz, MeOD) □ 8.69 (d, J = 2.3 Hz, 1H), 8.51 (s, 1 H), 8.37 (d, J = 2.2 Hz, 1H), 8.29 (d, J =5.6 Hz, 1 H), 4.43 (t, J = 11.9 Hz, 1 H), 4.14 (q, J = 6.1 Hz, 1 H), 3.94 (t, J= 11.9 Hz, 1H), 2.40 - 2.19 (m, 4H), 2.03 (d, J = 8.2 Hz, 2H), 1.78- 1.69 (m, 1H), 1.59-1.44 (m, 3H) and 1.18 (d, J = 6.1 Hz, 3H) ppm. LCMS RT = 3.37 (M+1)
447.41, (M-1) 445.1.
N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridÎn-3-yl)-5-fluoro-pynmidin-4yl]amino]cyclohexyl]-2-hydroxy-propanamide hydrochloride (642) 1H NMR (300 MHz, MeOD) □ 8.68 (s, 1H), 8.56 (s, 1H), 8.39 (d, J= 1.5 Hz, 1 H), 8.31 (d, J= 5.3 Hz, 1H), 4.47 - 4.40 (m, 1 H), 4.15 (s, 1H), 3.98 (m, 1H), 2.41 (s, 1H), 2.23 (d, J = 10.6 Hz, 1 H), 2.04 (d, J = 11.0 Hz, 2H) and 1.77 - 1.36 (m, 7H) ppm. LCMS RT = 3.52 (M+1) 433.58, (M-1) 431.3.
-26016260
N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]tetrahydropyran-2-carboxamide hydrochloride (651) 1H NMR (300 MHz, MeOD) □ 8.56 - 8.51 (m, 2H), 8.33 - 8.29 (m, 2H), 4.30 (d, J =
3.0 Hz, 1 H), 3.98 (dd, 7=11.5, 23.4 Hz, 2H), 3.83 - 3,79 (m, 1 H), 3.55 (t, J = 8.9 Hz,
1H), 2.35 (d, J= 11.1 Hz, 1H), 2.19 (d, 7 = 11.2 Hz, 1H), 2.03 - 1.90 (m, 4H) and
1.73- 1.37 (m, 8H) ppm. LCMS RT = 4.1 (M+1) 473.41, (M-1) 471.4.
| W HN /ô | o Q y~o HN /0 | |
| —NH | n^-nh | |
| H | 652 | H 649 |
N-[(1 R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amîno]cyclohexyl]tetrahydrofuran-3-carboxamide hydrochloride (652) 1H NMR (300 MHz, MeOD) □ 8.72 (d, 7 = 2.3 Hz, 1H), 8.56 (s, 1H), 8.42 (d,7 = 2.2 Hz, 1H), 8.34 (d, 7 = 5.6 Hz, 1H), 4.51 - 4.43 (m, 1H), 4.02 - 3.88 (m, 3H), 3.86 - 3.78 (m, 2H), 3.07-3.02 (m, 1H), 2.42 (d, 7= 7.5 Hz, 1H), 2.25 (d, 7= 12.0 Hz, 1H), 2.19 - 2.06 (m, 4H) and 1.79 - 1,35 (m, 4H) ppm. LCMS RT = 3.9 (M+1) 459.41, (M-1) 457.4.
(S)-tetrahydrofuran-3-yl (1R, 3S)-3-(2-(5-chloro-1R-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexylcarbamate (649)
LCMS RT = 3.3 (M+1) 475,37, (M-1) 473.35.
N-((1R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexyl)-3-methoxypropanamide (611)
LCMS RT = 2.0 (M+1) 447.4, (M-1) 445.4.
N-[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]cyclohexane-cis-26116260
1,3-diamine (540)
LCMS RT =1.4 (M+1) 361.5.
H
452
O
W-[ciS-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4yljamino]cyclohexyl]acetamide (452) (prepared from cis/trans 1,3diamino cyclohexane; separated by HPLC from trans diastereomer)
LCMS RT = 1.3 (M+1) 403.1 (M-1) 401.1.
W-[f/'ans-3-[[2-(5-chJoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]acetamide acetamide (457) (separated by HPLC from cis diastereomer)
LCMS RT = 1.6 (M+1) 403.2 (M-1) 401.1.
1-[c;s-3-[[2-(5-chloro-1H-pyrrolo[2,3’b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-3-methyl-urea (455) (prepared from cis/trans 1,3diamino cyclohexane; separated by HPLC from trans diastereomer)
LCMS RT =1.7 (M+1) 416.2.
1-[frans-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4- yl]amino]cyclohexyl]-3-methyl-urea (458) (prepared from cis/trans 1,3-diamino cyclohexane; separated by HPLC from cis diastereomer)
LCMS RT = 0.8 (M+1) 418.2 (M-1) 416.1.
3-[c/s-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-
-26216260 yl]amino]cyclohexyl]-1,1 -dimethyl-urea (456) (prepared from cis/trans 1,3diamino cyclohexane; separated by HPLC from trans diastereomer)
LCMS RT = 1.5 (M+1) 432.2 (M-1) 430.2.
3-[frans-3-[[2-(5-chloro-1/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]-1,1 -dimethyl-urea (459) (prepared from cis/trans 1,3diamino cyclohexane; separated by HPLC from cis diastereomer)
LCMS RT = 1.5 (M+1) 432.2 (M-1) 430.2.
Methyl-cis-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yljaminojcyclohexylcarbamate (514) - (racemic cis mixture - prepared from cis-1,3diaminocyclohexane)
LCMS RT =1.3 (M+1) 418.8.
N-((1R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexyl)morpholine-4-carboxamide (647)
LCMS RT = 3.6 (M+1) 474.4 (M-1) 472.5.
/V-[3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidîn-4yl]amino]cyclohexy1]methanesulfonamide (454)
LCMS RT = 1.6 (M+1) 439.1 (M-1) 437.1.
(tetrahydrofuran-3-yl)methyl (1 R,3S)-3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexylcarbamate (648)
LCMS RT = 3.7 (M+1) 489.38, (M-1) 487.49.
General Scheme 22:
-26316260
a, b
4-tert-butoxycarbonylmorpholine-2-carboxylic acid, EDC, HOBt, 'Pr2NEt, CH2CI2, rt (b) CH2Cl2, TFA (c) LiOH, 130°C, microwave
Formation N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-
4-yl]amino]cyclohexyl]morpholine-2-carboxamide bishydrochloride (637)
To a solution of (1 S, 3R)-/V1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-
5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine (0.06 g, 0.12 mmol) in CH2CI2 (3 mL) was added 4-tert-butoxycarbonylmorpholine-2-carboxylic acid (40.4 mg, 0.17 mmol), EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.12 mmol) and 'Pr2NEt (0.06 g, 0.47 mmol), and the reaction mixture was stirred at room température overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in CH2CI2 (2 mL) and TFA (2 mL) and allowed to stir at room température for 2 hours. The resulting solution was concentrated in vacuo, dissolved in THF (4mL) and treated with 1N aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was heated in the microwave to 130 °C for 20 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% MeOH/H2O with 6mM HCl over 15 minutes. The purified fractions were concentrated to provide the bis-hydrochloride of W-[(1 R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]morpholine-2-carboxamide. 1H NMR (300 MHz, MeOD) Π 8.68 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 8.33 (d, 7 = 4.7 Hz, 1H), 4.44-4.35 (m, 2H), 4.21 (d, 7= 12.2 Hz, 1H), 4.04-3.92 (m, 2H), 3.58 (d, 7 = 12.3 Hz, 1H), 3.23- 3.08 (m, 2H), 2.37 (d, 7= 8.1 Hz, 1H), 2.23 (d, 7= 11.1 Hz, 1 H), 2.05 (d, J = 9.7 Hz, 2H), 1.72 (m, 2H) and 1.59 - 1.44 (m, 2H) ppm; LCMS RT = 2.4 (M+1) 474.43, (M-1) 472.4.
Other analogs that can be prepared in the same manner as 637 are described below:
-26416260
N-[( 1 R, 3S)-3-[[2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexyl]piperidine-4-carboxamide bishydrochloride (639) 1H NMR (300 MHz, MeOD) □ 8.66 (s, 1H), 8.60 (s, 1H), 8.38 (s, 1H), 8.31 (d, J = 4.7 Hz, 1H), 4.43 - 4.36 (m, 1H), 3.98 - 3.91 (m, 1H), 3.43 (d, J = 10.3 Hz, 2H), 3.03 (t, J = 10.6 Hz, 2H), 2.60 (s, 1H), 2.38 (d, J =10.2 Hz, 1H), 2.21 (d, J =10.6 Hz, 1H), 2.07 - 1.92 (m, 6H) and 1.74 - 1.30 (m, 4H) ppm.
LCMS RT = 2.4 (M+1) 472.46, (M-1) 470.4.
General Scheme 23
C
(1S, 2S)-cyclohexane-1,2-diamine, THF, 120 °C microwave (b) methyl-chloroformate, 'PrjNEt, CH2CI2 (c) LiAIH4, THF.
Formation of (1S, 2S)-N1-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-yl)cyclohexane-1,2-diamine (23b)
A solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridine, 23a, (0.50 g, 1.08 mmol) in THF (4 mL) was treated with (1S,2S)-cyclohexane-1,2-diamine (0.27 g, 2.37 mmol) and 'Pr2NEt (2.15 mmol) at 120 °C for 10 minutes. The mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH-CH2CI2) to provide the desired intermediate as a white solid (410 mg).
-26516260
LCMS RT = 2.2 (M+1) 515.5.
Formation of methyl (1S, 2S)-2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoro-pyrimidin-4-ylamino)cyclohexylcarbamate (23c)
To a mixture of (1S, 2S)-A/1 -(2-(5-chloro-1-tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-yl)cyclohexane-1,2-diamine, 23b, (0.18 g, 0.35 mmol) în dichloromethane (4 mL) at room température was added 'Pr2NEt (0.12 mL, 0.70 mmol) followed by methyl chloroformate (0.03 mL, 0.37 mmol). After 35 minutes, the mixture was diluted with EtOAc, washed successively with aqueous saturated NH4CI and aqueous saturated NaHCO3 and brine, dried over Na2SO4 filtered and concentrated in vacuo to provide the crude product sufficîently pure for use in the next reaction.
LCMS RT = 4.1 (M+1) 573.4.
Formation of (1S, 2S)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-
4-yl)-N2-methylcyclohexane-1,2-diamine (522)
To a stirred solution of methyl (1S, 2S)-2-(2-(5-chloro-1-tosyl-1H-pyrro)o[2,3d]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylcarbamate, 23c, (0.09 g, 0.16 mmol) in THF (3 mL) at room température was added LiAIH4 (0.06 g, 1.66 mmol) and the mixture was stirred at room température for additional 2 hours. The reaction was quenched with 0.06 mL KOH (5% aq) followed by water (3 x 0.06 mL). Then, additional Et2O (6 mL) was added and stirring was continued for 20 minutes. The milky white suspension was filtered and rinsed with EtOAc and the cake was rinsed with additional EtOAc. The combined organic phases were concentrated in vacuo and purified by préparative HPLC followed by préparative TLC to provide the desired product as the free base that was then converted to the HCl sait by treatment with HCl (4N in dioxane).
LCMS RT = 1.7 (M+1) 375.5.
General Scheme 24:
NaCNBH3, (CH2O)n, HOAc, CH3CN
Formation of (1S, 2S)-N1-(2-(5-chloro-1H-pyrrolo[2,3-d]pyridin-3-yl)-5-fluoropyrimidin-
4-yl)-N2, N2-dimethylcyclohexane-1,2-diamine (523)
-26616260
To a mixture of (1S, 2S)-N1-(2-(5-chloro-1H-pyrrolo[2,3-ù]pyridin-3-yl)-5fluoropyrimidin-4-yl)cyclohexane-1,2-diamine, 23b, (0.08 g, 0.22 mmol) in acetonitrile (1.6 mL) at room température was added formaldéhyde (0.09 mL of 37 %w/v, 1.11 mmol) followed by NaCNBH3 (0.04 g, 0.56 mmol). A gelatinous mix formed and after min the mixture became fluid again. After 4 hours, the reaction was quenched with mL of 2N NaOH and the mixture was stirred overnight. The mixture was diluted with EtOAc and stirred until ail solid dissolved. The layer was extracted with EtOAc several times, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (0-15% MeOH-CH2CI2) followed by preparatory HPLC provided the desired product, which was converted to the corresponding HCl sait with HCl (4N in dioxane).
1H NMR (300 MHz, MeOD) □ 8.65 (d, J = 2.3 Hz, 1H), 8.54 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 4.82 -4.72 (m, 1H), 3.66- 3.53 (m, 1H), 2.96 (s, 3H), 2.77 (s, 3H), 2.33 (d, J = 12.3 Hz, 2H), 2.10-1.97 (m, 2H) and 1.75 - 1.48 (m, 4H) ppm; LCMS RT = 1.7 (M+1) 389.5.
General Scheme 25:
2-(methoxymethyl)oxirane, methanol, 130°C, microwave (b) LiOH, 130°C, microwave
Formation of 1 -[[(1 R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimÎdin-4-yl]amino]cyclohexyl]amino]-3-methoxy-propan-2-ol (610)
To a solution of (1S, 3R)-A/1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-
5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (50 mg, 0.09 mmol) in methanol (2 mL) was added 2-(methoxymethyl)oxirane (9.4 mg, 0.11 mmol) and the reaction mixture was heated in the microwave to 140°C for 10 min. 1M aqueous LiOH (1.0 mL, 1.0 mmol) was added, and the reaction mixture was heated in the microwave to 130°C for 10 min.
The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% CH3CN//H2O with 0.1% TFA over 15 minutes. The purified fractions were concentrated, redisolved in MeOH and passed through a carbonate-PS column to -26716260 provide the free base of the desired product 1-[[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3bJpyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]amino]-3-methoxy-propan-2-ol, 610.
1H NMR (300 MHz, MeOD) □ 8.85 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.98 (d, J = 4.1 Hz, 1H), 4.20 (m, 1H), 3.82 (dd, J = 3.9, 8.2 Hz, 1H), 3.555 3.45 (m, 1H), 3.30 (s, 3H), 3.23 - 3.07 (m, 1H), 2.86 - 2.77 (m, 2H), 2.68 - 2.59 (m,
1H), 2.44 (d, J = 10.9 Hz, 1H), 2.15 (d, J = 9.8 Hz, 1H), 2.07- 1.94 (m, 2H), 1.65 1.56 (m, 1H) and 1.42 - 1.17 (m, 3H) ppm; LCMS RT = 1.52 (M+1) 449.42.
General Scheme 26:
20c
2-bromoacetamide, Na2CO3, DMF, rt (b) LiOH, 130°C, microwave.
Formation of 2-[[1R, 3S)-3-[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yf)-515 fluoropyrimidin-4-yl]amino]cyclohexylamino]-acetamide (593)
To a solution of (1 S, 3R)-A/1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-
5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (0.050 g, 0.100 mmol) in DMF (2 mL) was added 2-bromoacetamide (0.015 g, 0.100 mmol) and Na2CO3 (0.021 g, 0.190 mmol). The reaction mixture was stirred at room température overnight
1M aqueous lithium hydroxide (2.0 mL, 2.0 mmol) was added, and the reaction mixture was heated în the microwave to 130°C for 10 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% CH3CN//H2O with 0.1% TFA over 15 minutes. The purified fractions were concentrated, redisolved in MeOH and passed through a carbonate-PS column to provide the free base of the desired product 2-[[1 R,3S)25 3-[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexylamino]acetamide, 593.
1H NMR (300 MHz, MeOD) Π 8.85 (d, J =2.3 Hz, 1H), 8.22 (d, J =2.2 Hz, 1H), 8.15 (s, 1H), 7.99 (d, J = 4.1 Hz, 1H), 4.28 - 4.20 (m, 1 H), 2.82 - 2.73 (m, 1H), 2.65 (s, 2H), 2.40 (d, J= 10.2 Hz, 1H), 2.15 (d, J = 8.5 Hz, 1H), 2.05- 1.92 (m, 2H), 1.6430 1.55 (m, 1 H) and 1.44- 1.12 (m, 3H) ppm; LCMS RT = 1.47 (M+1) 418.21.
General Scheme 27:
-26816260
3-Aminocyclohexanol, 'Pr2NEt, THF, MW 130 °C; b) Ag2O, CaSO4, CH3I, r.t.; c) sodium methoxide, THF.
Formation of (S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexanol (27a).
To a solution of 5-chloro-3-(5-fluoro-4-(methylsulfonyl)pyrimidin-2-yl)-1-tosyl-1Hpyrrolo[2,3-b]pyridine, 1a, (1.09g, 2.34 mmol) and 3-aminocyclohexanol (0.32 g, 2.82 mmol) in THF was added DIEA (0.60 g, 4.69 mmol). The reaction mixture was heated at 130 °C in microwave for 10 min. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography to afford 550 mg of the desired product, 27a.
1H NMR (300 MHz, CDCI3) □ 8.88 (s, 1 H), 8.56 (s, 1 H), 8.40 (d, J = 2.4 Hz, 1 H), 8.12 -8.07 (m, 3H), 7.32-7.28 (m, 2H), 5.70 (m, 1H),4.35(m, 1 H), 4.10 (m, 1H), 2.40 (s, 3H), 2.32 (d, J= 12.3 Hz, 1H), 2.0-1.95 (m, 2H), 1.70-1.45 (m 4H).
Formation of 2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S)-3methoxycyclohexyl)pyrimidin-4-amine (27b).
To a suspension of methyl iodide (0.20 g, 0.41 mmol) and 3-[[2-[5-chloro-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-cyclohexanol, 27a, (0.47 g, 2.04 mmol) was added silver oxide (0.578 g, 4.07 mmol and calcium sulfate (0.28 g, 2.04(mmol). The reaction mixture was stirred at room température for 18h. The mixture was filtered through celite and the resulting filtrate was concentrated in vacuo. The resulting crude mixture was purified by silica gel chromatography to afford 120 mg of the desired product, 27b.
Ή NMR (300 MHz, CDCI3) □ 8.88 (s, 1H), 8.56 (s, 1H), 8.4 (d, J~ 2.4 Hz, 1H), 8.13 - 8.06 (m, 3H), 7.30 (d, J = 8.7 Hz, 2H), 6.00 (s, 1 H), 4.42-4.32 (m, 1 H), 3.60-3.50 (m, 1H), 3.4 (s, 3H), 2.4 (s, 3H), 2.25 (dd, J= 3.4, 9.7 Hz, 1H), 2.00-1.84 (m 3H), 1.75-1.60 (m, 3H), 1.60-1.50 (m, 1H).
-26916260
Formation of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S)-3methoxycyclohexyl)pyrimidin-4-amine (552).
To a solution of 2-[5-chloro-1-(p-toly1sulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-A/-(3methoxycyclohexyl)pyrimidin-4-amine, 27b, (0.08 g, 0.15 mmol) in THF were added a few drops of NaOMe. The reaction mixture was stirred at room température for 20 min. To the reaction mixture was added ethyl acetate and brine. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in CH3CN/H2O and the mixture was purified by preparatory HPLC to afford 23 mg of the desired product, 552.
1H NMR (300 MHz, CD3OD) □ 8.70 (d, J = 2.3 Hz, 1 H), 8.45 (s, 1 H), 8.35(d, J = 2.3 Hz, 1 H), 8.25(d, J = 5.4 Hz, 1 H), 4.35 (m, 1 H), 3.52 (m, 1 H), 3.4 (s, 3H), 2.53 (d, J = 12.1 Hz, 1H), 2.18 (d, J= 11.4 Hz, 2H), 2.05-1.95 (m, 1H), 1.65-1.4 (m, 3H), 1.381.25 (m, 1H); LCMS RT = 2.22 min (M+1) 376.23
(3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanol (524).
LCMS RT = 2.0 (M+1) 362.48.
3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl ethylcarbamate (608).
LCMS RT = 2.9 (M+1) 433.4.
General Scheme 28:
Dess-Martin periodinane, CH2CI2; b) CH3MgBr, THF; c) sodium methoxide, THF.
Formation of 3-(2-(5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5
-27016260 fluoropyrimidin-4-ylamino)cyclohexanone(28a).
To a solution of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrimidin-4-yl]amino]cyclohexanol, 27a, (0.54 g. 1.05 mmol) in 20 ml CH2CI2 was added Dess-Martin periodinane (0.62 g, 1.47 mmol). The suspension was stirred at room température for 6h. The reaction mixture was filtered through celite and the fîltrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (45% ethyl acetate/hexanes gradient) to afford 430mg of the desired product.
1H NMR (300MHz, CDCI3) □ 8.66 (d, J = 2.4 Hz, 1H), 8.42(s1 H), 8.31 (d, J = 2.3 Hz, 1H), 8.05-8.02 (m, 3H), 7.24-7.19 (m, 2H), 2.99 (d, 7=5.2 Hz, 1H), 4.56 (s, 1H), 2.85 (dd, 7 = 4.7, 13.9 Hz, 1H), 2.50-2.40 (m, 3H), 2.40 (s, 3H), 1.95-1.80 (m, 2H), 1.70-1.50 (m, 2H).
Formation of 3-(2-(5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1 -methylcyclohexanol (28b).
To a cold (0 °C) solution of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 28a, (0.47 g, 0.92 mmol) in THF (5 mL) was added méthylmagnésium bromide (3.30 ml of 1.4M solution, 4.58 mmol). The reaction mixture was stirred at 0 °C for 1h. The reaction mixture was diluted with ethyl acetate and aqueous saturated NH4CI solution. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The products were purified by silica chromatography with DCM and méthanol, two products were eluded with 95% DCM and 5% méthanol no séparation. The two diastereomers were taken on as a mixture without further purification.
LCMS (10-90% 3/5min(grad/run) w/FA) indicated 2 peaks for the desired products. Peak 1 : rétention time = 4.04 min (M + 1: 530.42); peak 2: rétention time = 4.18min (M + 1:530.45).
Formation of (3S)-3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yi)-5-fluoropyrimidin-4ylamino)-1-methylcyclohexanol (571 and 572).
To a solution of 3-(2-(5-chloro-1 -(phenylsulfonyl)-l H-pyrrolo[2,3-b]pyridîn-3-yl)-5fluoropyrimidin-4-ylamino)-1-methylcyclohexanol, 28b, in THF was added a few drops of 25% sodium methoxide at room température. The reaction mixture was stirred at room température for 5 min. The reaction mixture was diluted with ethyl acetate and brine. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The product was purified by preparatory HPLC to afford two diastereomers.
Diastereomer 1 - 571.
-27116260 1H NMR (300MHz, CD3OD) 008.78 (d, J = 2.2 Hz, 1H), 8.60 (s, 1H), 8.36 (s, 1H), 8.30 (dd,
J =5.6, 9.9 Hz, 1H), 4.85(m, 1 H) 2.25-1.95 (m, 3H), 1.86-1.6(m 4H), 1.40-1.3(m 2H), 1.3(s,
3H); LCMS RT 2.39 (M+1) 376.42.
Diastereomer 2 - 572.
1H NMR (300 MHz, CD3OD) 8.66 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 2.7 Hz, 1H), 8.38 (s, 1H), 8.258 (dd, J = 5.6, 9.5 Hz, 1 H), 4.6(s, 1 H), 2.00-1.50 (m, 9H), 1.30 (s, 3H);
LCMS RT 1.97 (M+1) 376.41.
3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridÎn-3-yl)-5-fluoropyrimidin-4-ylamino)-1ethynylcyclohexanol (617 and 618).
Diastereomer 1 - 617: LCMS RT = 3.6 (M+1) 386.4.
Diastereomer 2-618: LCMS RT = 3.2 (M+1) 386.3.
3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1vinylcyclohexanol (627 and 628).
Diastereomer 1 - 627; LCMS RT = 4.0 (M+1) 388.4.
Diastereomer 2 - 628: LCMS RT = 3.7 (M+1) 388.4.
3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1(hydroxymethyl)cyclohexanol (646).
LCMS RT = 3.4 (M+1) 392.4.
3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1ethylcyclohexanol (626).
LCMS RT = 4.1 (M+1) 390.4.
General Scheme 29
-27216260
2?a 25b
Formation of (3S)-3-(2-chloro-5-fluoropyriiTiidin-4-ylamino) cyclohexanol (29a).
The starting racemic alcohol, (3S)-3-aminocyclohexanol, was prepared following the procedure described by Bernardelli, P., Bladon, M., Lorthiois, E,, Manage, A., Vergne, F. and Wrigglesworth, R., Tetrahedron Asymmetry 2004, 15, 1451-1455. (3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol was prepared according to the procedure for compound 16a using (3S)-3-aminocyclohexanol, afforded desired product, 29a, as a solid.
Formation of (S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanone (29b).
To 700 ml DCM solution of 7.9g (32.16 mmol) (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4yl)amino]cyclohexanol, 29a, (7.90 g, 32.16 mmol) in CH2CI2 (700 mL) was added Dess-Martin reagent (17.73 g, 41.81 mmol). The reaction mixture was stirred at room température for 20 hours until TLC chromatography indicated reaction was complété. The reaction mixture was filtered through a pad of celite, and the resulting filtrate was washed with 200 mL of aqueous saturated NaHCO3 solution and 200 mL brine. The organic phase was dried with MgSO4, filtered and the solvent was removed under reduced pressure. The product was purifîed by silica gel chromatography (50% EtOAc/hexanes) to afford 7.3g of the desired product, 29b (93% yield).
1H NMR (300MHz, CD3OD) ΠΓΙΗ NMR (300 MHz, CDCI3) □ 7.96 - 7.93 (m, 1H), 7.28 (s, 1H), 5.12 (s, 1H), 4.57 -4.48 (m, 1H), 2.87 (dd, J = 4.8, 14.0 Hz, 1H), 2.51 2.23 (m, 4H), 2.12-2Ό2 (m, 1H); LCMS RT = 2.97 (M+1) 244.26.
Formation of (3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol (29c, 29d).
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (1.83 g, 7.49 mmol) in THF (100 mL) was added méthylmagnésium bromide (21.4 ml of 1.4M solution, 29.96 mmol) at room température, The reaction mixture was stirred at room température for 5 minutes. To the reaction mixture was added aqueous saturated NH4CI solution and EtOAc. The organic phase was washed with brine and dried with MgSO4, filtered and concentrated in vacuo. The two spots were separated by silica gel chromatography (120g silica gel column).
-27316260
Fraction-1 (29c); 1H NMR (300MHz, CD3OD) ΠΠ □ 7.81 (d, J= 2.8 Hz, 1H), 7.28 (d, J = 0.5 Hz, H), 4.47 (q, J = 3.8 Hz, 1 H), 1.92 - 1.87 (m, 2H), 1.82- 1.77 (m, 1 H),
1.69 (dd, J = 4.2, 14.0 Hz, 2H) and 1.56 - 1.48 (m, 4H) ppm; LCMS RT = 3.43 (M+1)
260.3.
Fraction-2 (29d); 1H NMR (300MHz, CD3OD) □ 7.87 (d, J = 2.8 Hz, H), 7.28 (s, H), 4.95 (d, J = 5.0 Hz, 1 H), 4.45 - 4.33 (m, 1H), 2.17 (s, H), 2.12-2.06 (m, 1H), 1.931.78 (m, 1H), 1.71 (dd, J = 3.1,5.6 Hz, 2H), 1.39- 1.25 (m, 4H) and 1.19-1.05 (m, 1H) ppm; LCMS RT = 3.10 (M+1) 260.29.
Formation of (3S)~3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-i>]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-methylcyclohexanol (29e, 29f).
Degassed a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.46g, 3.37 mmol), (3S)-3-[(2-chloro-5fluoro-pyrimidin-4-yl)amino]-1-methyl-cyclohexanol, 29c, (0.72g, 2.81 mmol) and Na2CO3 (4.21 mL of 2M solution, 8.433 mmol) in dimethoxyethane (15 mL) for 30 min with nitrogen. To the reaction mixture was added palladium tetrakistriphenylphosphane (0.16 g, 0.14 mmol). The reaction mixture was heated at 130 °C in Q-tube apparatus for 45 minutes. The reaction mixture was filtered through a pad of 1 cm of silica gel and 2 cm celite. The product was purified by silica gel chromatography (hexanes/EtOAc) to afford the desired product, 29e (63% yield). 1H NMR (300MHz, CD3OD) □ 8.81 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 3.3 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 5.7 Hz, H), 4.58 (t, J = 3.7 Hz, 1H), 2.39 (s, H), 1.98 - 1.93 (m, 2H), 1.86 (d, J = 4.0 Hz, 2H), 1.72 - 1.56 (m, 5H), 1.36 (d, J = 3.8 Hz, 3H) and 1.30 - 1.26 (m, 1H) ppm.
LCMS RT = 4.62 (M+1) 530.4.
The diastereomer, 29f, was made according to the same procedure as 29e, substituting 29d as the starting material for the Suzuki coupling procedure.
1H NMR (300MHz, CD3OD) □ 8.89 (d, J = 2.4 Hz, 1 H), 8.55 (s, 1 H), 8.39 (d, J = 2.4 Hz, 1H), 8.09 (t, J = 8.4 Hz, 2H), 8.08 (s, 1H), 7.29 (d, J = 8.2 Hz, 2H), 4.89 (d, J = 6.6 Hz, 1 H), 4.55 (m, 1 H), 2.39 (s, 3H), 2.24 (t, J = 1.8 Hz, 2H), 2.02 - 1.93 (m, 1 H), 1.77 (t, J =3.3 Hz, 2H), 1.46- 1.33 (m, 5H) and 1.29 - 1.15 (m, 1H) ppm. LCMS RT = 4.36 (M+1) 530.3.
Formation of (3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyrÎdin-3-yl)-5fluoropyrimidin-4-ylamino)-1-methylcyclohexanol (655, 656).
To a solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanol, 29f, (2.85 g, 5.38 mmol) in THF (200 mL) was added 1.5 ml 25%W/W sodium methoxide solution at room température. The reaction mixture was immediately înjected into LC/MS. LC/MS
-27416260 indicated the reaction was complété. The reaction mixture was diiuted with 200 ml EtOAc and the organic phase was washed twice with aqueous saturated NaHCO3 and then twice with brine. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (80g silica, 5% MeOH/CH2CI2) to afford 1.7 g of the desired product. The resultîng product was dissolved in 70 ml THF, to it was added 1.8 ml 5M HCI/IPA. The resultîng suspension was stirred for 1 hour at room température. The solvent was removed under reduced pressure to afford 1.7g of the desired product, 655 as an HCl sait.
1H NMR (300MHz, CD3OD) □□ 9.54 (s, 1H), 8.86 (d, J = 2.3 Hz, 1H), 8.31 (d, J =2.4 Hz, 1H), 8.15 (d, J = 2.7 Hz, 1H), 8.04 (d, J =3.5 Hz, 1H), 7.28 (s, H), 6.66 (s, 1 H), 4.62-4.59 (m, 1H), 1.96 - 1.88 (m, 4H), 1.81 (dd, J = 4.5, 14.9 Hz, 1H) and 1.68 1.57 (m, 6H) ppm; LCMS RT = 4.01 (M+1) 376.4,
The corresponding diastereomer, 656, can be prepared in the same fashion.
General Scheme 30
562, 563 mCPBA, CH2CI2 (b) NH4OH, water, 50 °C, 72 h (c) 5-chloro-3-(5-fluoro-4(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 'Pr2NEt, DMF, 90 °C, 17 h (d) 1N LiOH, THF, microwave, 120°C, 10 min.
Formation of 1-methyl-7-oxabicyclo[4.1.0]heptane (30a)
To a cold (0 °C) solution of 1-methylcyclohexene (3.0 g, 31.2 mmol) in CH2CI2 (150 mL) was added mCPBA (8,4 g, 48.7 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diiuted into aqueous saturated NaHCO3 solution and extracted with ether. The organic phase was washed again with aqueous saturated NaHCO3 solution, dried (MgSO4), filtered and concentrated in vacuo to afford the desired product as anoil that was used without further purification.
Formation of 2-amîno-1-methylcyclohexanol (30b)
To a solution of 1-methyl-7-oxabicyclo[4.1.0]heptane, 30a, (1.0 g, 7.1 mmol) in water was added ammonium hydroxide (6.0 mL, 154.1 mmol). The mixture was heated to
-27516260 °C for 48 hours. The mixture was diluted with water, extracted with EtOAc and then twice with 20%MeOH/CHCI3. The organic phases were dried (MgSO4), filtered and concentrated in vacuo to provide the desired product, 30b, as an amorphous white solid.
1H NMR (300.0 MHz, DMSO) δ 2.44 (dd, J = 3.4, 10.8 Hz, 1H), 1.64-1.45 (m, 4H),
1.28 - 1.01 (m, 4H) and 0.97 (s, 3H) ppm.
Formation of 2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)-1-methylcyclohexanol (30c)
To a solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.97 g, 2.09 mmol) and 2-amino-1methylcyclohexanol, 30b, (0.40 g, 3.13 mmol) in DMF (10 mL) was added 'Pr2NEt (0.73 mL, 4.17 mmol). The reaction mixture was heated at 90 C for 17 hours. The reaction mixture was cooled to room température and diluted into aqueous saturated NaCI solution. The aqueous phase was extracted twice with EtOAc. The organic phases were washed with twice with aqueous saturated NaCI solution, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-50% EtOAc/hexanes-loaded with CH2CI2) to afford the desired product, 30c, as a white solid.
1H NMR (300.0 MHz, DMSO) δ 9.00 (d, 7 = 2.4 Hz, 1H), 8.49 (dd, 7 = 2.4, 10.3 Hz, 1H), 8.42 (s, 1H), 8.23 (d, 7 = 4.1 Hz, 1H), 8.10-8.01 (m, 2H), 7.52-7.43 (m, 2H), 7.21 (d, 7= 9.1 Hz, 1H), 4.52 (s, 1H), 4.28 (s, 1H), 2.35 (s, 3H), 1.78- 1.50 (m, 6H), 1.34 (m, 2H) and 1.15 (s, 3H).
LCMS RT = 4.1 (M+1) 530.6.
Formation of 2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)-1 -methylcyclohexanol (562 and 563)
To a solution of 2-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrimidin-4-yl]amino]-1-methyl-cyclohexanol, 30c, (0.41 g, 0.77 mmol) in THF was added 1M LiOH solution. The reaction mixture was heated in microwave at 120 °C for 5 minutes. The reaction mixture diluted with water, twice extracted with EtOAc and then twice with 10% MeOH/CH2CI2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (5-20% MeOH: CH2CI2) to afford a white solid as a mixture of trans-enantiomers. The two trans-enantiomers were separated by chiral preparatory HPLC to afford 562 and 563.
Enantiomer 1 - 563: 1H NMR (300.0 MHz, DMSO) δ12.32 (s, 1 H), 8.86 (d, 7= 2.4 Hz, 1H), 8.28 (d, 7= 2.4 Hz, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 6.92 (d, 7= 8.2 Hz, 1H), 4.56 (s, 1H), 4.31 (dd, 7= 5.9, 8.6 Hz, 1H), 1.89- 1.35 (m, 8H) and 1.17 (s, 3H); LCMS RT = 2.5 (M+1) 376.4.
-27616260
General Scheme 31:
2,4-dichloro-5-fluoropyrimidine, acetonîtrile/isopropanol, reflux 1.5hrs. (b) 5-chloro-3(4,4]5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b)pyridine, Pd(PPh3)4, 2M Na2CO3, acetonitrile, 120 °C microwave 15 min,, (c) TBAF, THF,
Formation of (1R, 2S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyc1ohexane-1,2diol (31b).
The starting racemic diol, 31a, (1 R, 2S, 3S)-3-aminocyclohexane-1,2-diol, was prepared following the procedure described in: Org. Bio. Chem. (2008) 6, 3751 and 3762, Davies, et. al. To a solution of racemic diol 31a (0.66 g, 5.00 mmol) in acetonitrile (5 mL) and isopropanol (5 mL) was added 2,4-dichloro-5-fluoropyrimidine (0.84 g, 5.03 mmol) and 'Pr2NEt (3.25 g, 4.38 mL, 25.20 mmol). The reaction mixture was sealed and heated to 100 °C for 90 minutes and then concentrated to dryness. The crude was purified via silica gel chromatography (40%100% EtOAc/Hex) to afford a racemate, which was further purified via chiral HPLC séparation to give compound 31b (0.26 g) as a white solid.
1H NMR (300 MHz, MeOH-c(4) Π 7.80 (s, 1H), 4.60 (s, 6H), 4.10 (m, 1H), 3.80 (s, 1H), 3.60 (m, 1H), 3.20 (s, 1H), 3.15 (s, 2H), 1.50 - 1.70 (m, 5H), 1.20 (m, 1H) ppm. LCMS RT = 2.8 (M+1) 262.0, (M-1) 260.1.
Formation of (1R, 2S, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5ffuoropyrimidin-4-ylamino)cyclohexane-1,2-diol (31c).
To a deoxygenated solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yf)pyrrolo[2,3-b]pyridine (0.22 g, 0.51 mmol) and (1R, 2S, 3S)3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol, 31b, (0.08 g, 0.24 mmol) in acetonitrile (6 ml) was added 2M sodium carbonate (0.45 mL of 2 M solution, 0.894 mmol) and Pd(PPh3)4 (34.5 mg, 0.030 mmol). The reaction was
-27716260 sealed and heated to 120°C for 15 minutes in the microwave. The rxn was diluted with EtOAc and filtered thru florisil. The solution was concentrated to crude and purified via silica gel chromatography (DCM to 20% MeOH/DCM) to give compound
31c (0.11 g) as a pink solid.
LCMS RT = 3.8 (M+1) 532.2, (M-1) 530.2.
Formation of (1R, 2S, 3S)-3-(2-(5-chloro-1W-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol (632).
To a solution of (1R, 2S, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-P]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol, 31c, (0.11 g, 0.21 mmol) in THF was added TBAF (0.23 g, 0.84 mmol). The reaction was aged at room température 1 hour, quenched with 1N HCl (1 ml), and purified via reverse phase chromatography (5-70% MeCN/H20 with 0.1 % TFA). The product was desalted on an SPE bicarbonate cartridge, concentrated to dryness, and then triturated from MeOH to provide 18 mg of compound 632.
1H NMR (300 MHz, MeOH-d4) Π 8.42 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 4.15 (m, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 1.75 (m, 5H), 1.50 (m, 1H) ppm. LCMS RT = 3.0 (M+1) 378.2, (M-1) 376.0.
General Scheme 32:
Ts
2,4-dichloro-5-fluoropyrimidjne, acetonitrile, isopropanol, reflux 1.5 hours. (b) 5chloro-3-(4l4l5,5-tetramethy!-1,3l2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3bjpyridine, Pd(PPh3)4,2M Na2CO3, acetonitrile, 120 °C microwave, 15 min., (c) TBAF, THF
Formation of (1 S, 2S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1,2diol (32b).
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The starting racemic diol, 32a, (1S, 2S, 3S)-3-aminocyclohexane-1,2-diol, was prepared following the procedure described in: Org. Bio. Chem. (2008) 6, 3751 and
3762, Davies, et. al.
According to the method for cornpound 632, except use the racemate of diol 32a (0.07 g,
0.53 mmol), to give cornpound 32b (0.03 g, 0.11 mmol) as a white solid.
1H NMR (300 MHz, MeOH-c/4) Ί 7.90 (s, 1H), 4.45 (m, 1H), 3.80 (s, 1H), 3.62 (s, 1H), 1.40-1.80 (m,6H), 0.85 (m, 1H) ppm.
LCMS RT = 2.7 (M+1) 262.0.
Formation of (1S, 2S, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo [2,3-b]pyridin-3-yl)-510 fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol (32c).
According to the method for cornpound 31c, except use cornpound 32b (0.03 g, 0.11 mmol), to give cornpound 32c (0.06 g, 0.11 mmol).
LCMS RT = 3.9 (M+1) 532.2, (M-1) 530.3.
Formation of (1S, 2S, 3S)-3-(2-(5-chloro-1H-pyrrolo [2,3-b]pyridin-3-yl)-515 fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol (615).
According to the method for cornpound 624, except use cornpound 32c (0.06 g, 0.11 mmol) to give cornpound 615 (0.015 g, 0.035 mmol) as a white solid.
1H NMR (300 MHz, MeOH-d4) □ 8.83 (s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 8.30 (s,
H), 4.00 (bs, 2H), 0.60 - 0.90 (m, 4H), 0.50 (m, 2H) ppm.
LCMS RT = 3.7 (M+1) 378.3, (M-1) 376.3.
General Scheme 33
Ts
2,4-dichloro-5-fluoropyrimidine, acetonitrile, isopropanol, reflux 1.5 hours. (b) 5-chloro-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1Hpyrrolo[2,3-b]pyridine, Pd(PPh3)4,2M Na2CO3, acetonitrile, 120 °C microwave, 15 min., (c) TBAF,
THF.
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Formation of (1R, 2R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1,2diol (33b).
The starting racemic diol, 33a, (1R, 2R, 3S)-3-aminocyclohexane-1,2-diol, was prepared following the procedure described in: Org. Lett. (2009) 6, 1333, Davies, et. al. According to the method for compound 632, except use the racemate of diol 33a (0.13 g, 1.01 mmol) to give compound 33b (0.14 g, 0.53 mmol) as a white solid. 1H NMR (300 MHz, MeOH-d4) □ 7.90 (s, 1H), 4.05 (m, 2H), 3.70 - 3.80 (m, 0.6H), 1.95 (bs, 2.5H), 1.70 (m, 1.6H), 1.30- 1.60 (m, 5.4H) ppm; 13C-APT NMR (300 MHz, MeOH-d4) □ 148.6, 145.2, 140.0, 139.8, 78.9, 75.2, 55.4, 49.15 (m, MeOH-d4), 33.9, 31.9, 22.4 ppm.
LCMS RT = 2.4 (M+1) 262.0, (M-1) 260.1.
Formation of (1R, 2R, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo [2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol (33c).
According to the method for compound 31c, except use compound 33b (0.07 g, 0.26 mmol) to give compound 33c (0.008 g, 0.015 mmol). DME was used as solvent, not acetonîtrile. LCMS RT = 4.2 (M+1) 532.3, (M-1) 530.3.
Formation of (1R, 2R, 3S)-3-(2-(5-chloro-1H-pyrrolo [2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol (625).
According to the method for compound 624, except use compound 33c (0.008 g, 0.015 mmol to give compound 625 (0,005 g, 0.012 mmol).
1H NMR (300 MHz, MeOH-d4) □ 8.80 (s, 1 H), 8.48 (s, 1 H), 8.40 (s, 1 H), 8.20 (s,
1H), 4.5 (m, 1H), 3.55 (m, 2H), 2.12 (m, 2H), 1.95(m, 1H), 1.61 (m, 2H), 1.58 (m, 1H) ppm.
LCMS RT = 2.4 (M+1) 378.2, (M-1) 376.2.
The following compounds, 631, 616 and 624, are enantiomers of 632, 615 and 625 and can be prepared by isolation from chiral preparatory HPLC chromatography from their respective enantiomeric mixtures.
OH
Cl
General scheme 35
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(1S, 2S)-2-aminocyclohexanecarboxylic acid, 'Pr2NEt, Na2CO3, THF- CH3CN (3:1), 135 °C microwave; (b) 1N LiOH, THF, microwave, 120 °C (c) 4N HCl-dioxane, EtOH, 70 ’C.
Formation of (1 S, 2S)-2-(2-(5-chloro-1H-pyrrolo[2l3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylaminojcyclohexanecarboxylic acid (553).
A mixture of 5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimidin-2-yl)-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.49 g, 1,05 mmol), (1S,2S)-2-aminocyclohexanecarboxylic acid (0.30 g, 2.10 mmol), freshly ground Na2CO3 (0.22 g, 2.10 mmol), and 'Pr2NEt (0.37 mL, 2.10 mmol) in THF (10 mL) and CH3CN (2 mL) were heated in a sealed vessel to 130 °C for 30 minutes under microwave irradiation. The mixture was cooled to room température. A solution of 1N LiOH (3.1 mL, 3.1 mmol) was added and the mixture was stirred at 120 °C for 10 minutes under microwave irradiation. The mixture was acidified with 1N HCl until pH 2 under vigorous stirring. The newly formed solid was collected by vacuum filtration. The solid was washed with small amounts of water and EtOAc. The solid was dried in vacuo to provide the desired product.
1H NMR (300 MHz, MeOD) □ 8.89 (d, J = 2.4 Hz, 1 H), 8.44 (s, 1 H), 8.38 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1 H), 4.75 (m, 1H), 2.75-2.66 (m, 1H), 2.25-2.16 (m, 2H), 1.99- 1.89 (m, 2H), 1.71 -1.29 (m, 4H) ppm; LCMS RT = 2.0 min, (M+H) 390.4. Other analogs that can be prepared în the same manner as 553 are described below:
(+/-) trans-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanecarboxylic acid (541)
LCMS RT = 2.4 min, (M+H) 390.5.
-28116260
(1R, 2R)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4yiamino)cyclohexanecarboxylic acid (554) 1H NMR (300 MHz, MeOD) □ 8.89 (d, J = 2.4 Hz, 1H), 8.44 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.77 (m, 1H), 2.75 -2.66 (m, 1H), 2.24-2,17 (m, 2H), 1.94- 1.89 (m, 2H) and 1.74 - 1.36 (m, 4H) ppm.
LCMS RT = 2.3 min, (M+H) 390.4.
C/s-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanecarboxylic acid (559) 1H NMR (300 MHz, MeOD) Π 8.75 (d, J = 2.4 Hz, 1H), 8.38- 8.35 (m, 2H), 8.24 (d, J = 5.1 Hz, 1H), 4.70-4.62 (m, 1H), 3.25-3.17 (m, 1 H), 2.32 (m, 1H), 2.14-1.80 (m, 4H) and 1.68 - 1.54 (m, 3H) ppm.
LCMS RT = 2.3 min, (M+H) 389.8.
(1 S, 2R)-2-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanecarboxylic acid (579) 1H NMR (300 MHz, ctô-DMSO) □ 12.52 (s, 1 H), 8.68 (d, J = 2.3 Hz, 1 H), 8.33 (d, J = 2.5 Hz, 2H), 8.30 (d, J = 4.4 Hz, 1H), 7.57 (s, 1H), 4.53 (m, 1H), 3.05 (m, 1H), 2.152.07 (m, 1H), 1.96 (m, 1H), 1.81 - 1.76 (m, 3H) and 1.51 (m, 3H) ppm.
LCMS RT = 2.9 min, (M+H) 390.4.
(1 R, 2S)-2-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanecarboxylic acid (578)
1H NMR (300 MHz, d6-DMSO) □ 12.51 (s, 1 H), 8.68 (d, J = 2.3 Hz, 1 H), 8.33 (d, J = 2.3 Hz, 2H), 8.29 (d, J = 4.3 Hz, 1H), 7.55 (s, 1H), 4.53 (s, 1H), 3.05 (m, 1H), 2.13 (m, 1H), 1.96 (m, 1H), 1.79 (m, 3H) and 1.51 (m, 3H) ppm.
LCMS RT = 2.8 min, (M+H) 390.4.
-28216260
C/s-2-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclopentanecarboxylic acid (558) 1H NMR (300 MHz, MeOD) □ 8.78 (d, J = 2.4 Hz, 1 H), 8.38 (s, 1 H), 8.33 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 4.98 (dd, J= 7.2 Hz, 1H), 2.27-2.03 (m, 5H) and 1.86- 1.76 (m, 1H) ppm.
LCMS RT = 2.5 min, (M+H) 376.2.
(1R, 3S)-3-(2-(5“Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylaminojcyclopentanecarboxylic acid (566) 1H NMR (300 MHz, tÆ-DMSO) Π 12.42 (s, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.29 (m, 2H), 8.22 (d, J = 4.1 Hz, 1H), 7.87 (s, 1H), 4.56-4.49 (m, 1H), 2.87 (dd, J= 8.4, 25.0 Hz, 1H), 2.87 (s, 1H), 2.42 - 2.33 (m, 1 H), 2.15 - 2.04 (m, 1H), 2.00 - 1.85 (m, 3H) and 1.81 - 1.70 (m, 1H) ppm.
LCMS RT = 2.3 min, (M+H) 376.4.
(1 S, 3R)-3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclopentanecarboxylic acid (565) 1H NMR (300 MHz, c/6-DMSO) □ 12.48 (s. 1H), 8.71 (d, 2.3 Hz, 1H), 8.35 - 8.31 (m, 2H), 8.26 (d, J = 4.3 Hz, 2H), 8.02 (s, 1 H), 4.57 - 4.44 (m, 1 H), 2.87 (qn, J = 8.3 Hz, 1H), 2.39-2.32 (m, 1H), 2.15-2.05 (m, 1H), 2.00- 1.86 (m, 3H) and 1.82-1.70 (m, 1H) ppm.
LCMS RT = 2.4 min, (M+H) 376.4.
(1 R, 3S)-3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanecarboxylic acid (630)
Compound 630 was prepared in same fashion from intermediate 18c, by removal of Cbz-protecting group and reaction with intermediate 1 a, followed by removal of tosyl protecting group.
LCMS RT = 3.2 min, (M+H) 390.4, (M-H) 388.1.
-28316260
582 (+/-)
(+/-)
Trans-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino}-1methylcyclohexanecarboxylic acid (582) 1H NMR (300.0 MHz, c/6-DMSO) □ 12.46 (s, 1H), 8.72 (d, 0 = 2.4 Hz, 1H), 8.32 8.28 (m, 3H), 7.10 (d, J = 7.1 Hz, 1H), 4.27-4.20 (m, 1H), 2.26 (d, J= 10.1 Hz, 1H), 1.93 (m, 1H), 1.83 (m, 1H), 1.68 - 1.59 (m, 3H), 1.36 (m, 2H) and 1.24 (s, 3H) ppm. LCMS RT = 3.2 min, (M+H) 404.4.
Racemic trans-2-(2-(5-chloro-1H-pyrrolo[2,3-blpyridin-3-yl)-5-fluoropyrimidin-4ylamino)-1-ethylcyclohexanecarboxylic acid (586) 1H NMR (300 MHz, MeOD) 008.93 (s, 1H), 8.85 (m, 2H), 8.93 - 8.87 (m, 1H), 8.31 (dd, J =4.5, 1.2 Hz, 2H), 8.31 (dd, J = 4.5, 1.2 Hz, 2H), 8.30 (d, 0=2.3 Hz, 1H), 8.19 (d, J = 5.0 Hz, 1H), 5.26-5.20 (m, 1H), 3.37 (dd, 0= 3.3 Hz, 1.6, 2H), 3.33 (ddt, 0 = 6.6, 3.3, 1.6 Hz, 118H), 2.11 (dd, 0=8.0, 5.8 Hz, 2H), 1.80 (tdd, 0 = 21.2, 18.9, 11.6 Hz, 8H), 1.63 - 1.54 (m, 3H), 0.86 (q, 0 = 7.4 Hz, 4H) ppm.
LCMS RT = 2.9 min, (M+H) 418.4.
Racemic c/s-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-
1-ethylcyclohexanecarboxylic acid (585) 1H NMR (300 MHz, MeOD) O 8.80-8.76 (m, 1H), 8.37 (s, 1H), 8.35 (d, 0 = 2.3 Hz, 1H), 8.27 - 8.23 (m, 1H), 4.49 - 4.42 (m, 1H), 2.43 - 2.34 (m, 1H), 2.09 (d, 0 = 6.2 Hz, 1H), 1.98- 1.36 (m, 12H), 0.94 (dd, 0= 11.3, 3.8 Hz, 3H) ppm.
LCMS RT = 3.2 min, (M+H) 418.4.
670 671 (3S, 4R, 5R)-ethyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)-4-ethanamido-5-(pentan-3-yloxy)cycIohex-1-enecarboxylate (670)
H NMR (300.0 MHz, MeOD) d 8.64 (d, J = 2.3 Hz, 1H), 8.40 (s, 1H), 8.32 (d, J = 2.3
Hz, 1H), 8.29 (d, J = 5.0 Hz, 1H), 6.96 (m, 1H), 4.84 - 4.80 (m, 1H), 4.34 (m, 1H),
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4.29-4.19 (m, 3H), 3.54-3.47 (m, 1H), 3.15-3.07 (m, 1H), 2.68-2.58 (m, 1 H),
1.92 (s, 3H), 1.59 - 1.51 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H) and
0.89 (t, J = 7.4 Hz, 3H) ppm
LCMS RT = 3.6 (M+1) 559.4.
(3S, 4R, 5R)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-
4-ethanamido-5-(pentan-3-yloxy)cyclohex-1 -enecarboxylic acid (671 )
H NMR (300.0 MHz, MeOD) d 8.66 (d, J = 2.3 Hz, 1 H), 8.39 (s, 1 H), 8.32 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.0 Hz, 1H), 6.97 (m, 1H), 4.82 -4.79 (m, 1H), 4.34 (m, 1H), 4.25 (dd, J = 7.6, 10.1 Hz, 1H), 3.54 - 3.47 (m, 2H), 3.11 - 3.04 (m, 1H), 2.65 - 2.57 (m, 1H), 1.91 (s, 3H), 1.59 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H) and 0.89 (t, J = 7.4 Hz, 3H) ppm
LCMS RT = 3.1 (M+1) 531.4.
General Scheme 36
(1 S, 2S)-ethyl 2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidÎn-4ylamino)cyclohexanecarboxylate (561)
To a mixed slurry of (1 S, 2S)-2-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexane-1-carboxylic acid, 553, (0.090 g, 0.231 mmol), in éthanol (1.5 mL) at room température was added HCl (0.577 mL of 4 M solution, 2.309 mmol). The solution was warmed to 50 °C. After 6 hours, the mixture was basified with 1N NaOH, brine was added and the aqueous layer was and extracted repeatedly with EtOAc. The organic layer was dried over MgSO4, and filtered through a short plug of silica gel and concentrated in vacuo to provide the desired product.
1H NMR (300 MHz, MeOD) Ί 8.95 (s, 1H), 8.19 (m, 2H), 7.99 (s, 1 H), 4.61 (m, 1 H), 3.93 (m, 2H), 2.61 (m, 1H), 2.17-2.05 (m, 2H), 1.89- 1.32 (m, 7H) and 1.00 (m, 3H) ppm.
LCMS RT = 2.7 min, (M+H) 418.4.
The following compounds can also be prepared in a manner similar to the one described in Scheme 36.
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560
575 (1 R, 2R)-ethyl 2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriniidin-4ylamino)cyclohexanecarboxylate (560) 1H NMR (300 MHz, MeOD) □ 8.95 (s, 1H), 8.23-8.14 (m, 2H), 8.00 (m, 1H), 4.61 (m, 1H), 3.96-3.92 (m, 2H), 2.61 (m, 1H), 2.14-2.04 (m, 2H), 1.89- 1.35 (m, 7H) and 1.04 - 0.99 (m, 3H) ppm.
LCMS RT = 3.2 min, (M+H) 418.5.
(1 S, 2S)-methyl 2-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanecarboxylate (575) 1H NMR (300 MHz, d6-DMSO) □ 8.76 (d, J = 2.5 Hz, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.19 (s, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 4.47 -4.37 (m, 1H), 3.40 (s, 3H), 2.68 - 2.59 (m, 1 H), 2.05 - 1.97 (m, 2H), 1.84 - 1.75 (m, 2H), 1.63 - 1.40 (m, 3H) and 1.31 -1.23 (m, 1H) ppm.
LCMS RT = 3.1 min, (M+H) 404.4.
(1 S, 2S)-2-methoxyethyl 2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexanecarboxylate (574) 1H NMR (300 MHz, c/6-DMSO) d 8.74 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 4.42 (m, 1H), 4.02 3.86 (m, 2H), 3.35 - 3.23 (m, 2H), 3.08 (s, 3H), 2.69 - 2.60 (m, 1 H), 1.99 (m, 2H), 1.77 (m, 2H), 1.62 -1.40 (m, 3H) and 1.27 (m, 1 H) ppm.
LCMS RT = 3.0 min, (M+H) 448.4.
(1 R, 2R)-isopropyl 2-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanecarboxylate (568) 1H NMR (300 MHz, c/6-DMSO) □ 8.80 (d, J= 2.5 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 4.72 (qn, J = 6.2 Hz, 1H), 4.55-4.48 (m, 1H), 2.61 -2.54 (m, 1H), 1.96 (m, 2H), 1.77 (m, 2H), 1.63-1.41 (m, 3H), 1.30- 1.23 (m, 1 H) and 0.93 (d, J = 6,2 Hz, 6H) ppm.
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LCMS RT = 3.08 min, (M+H) 432.46.
569 (1S, 2S)-isopropyl 2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanecarboxylate (569) 1H NMR (300 MHz, d6-DMSO) □ 12.57 (s, 1H), 8.80 (d, J= 2.4 Hz, 1H), 8.36-8.28 (m, 4H), 4.75 (td, J= 12.5, 6.2 Hz, 1H), 4.52 (m, 1H), 2.65 - 2.56 (m, 1H), 2.00 (m, 2H), 1.83- 1.76 (m, 2H), 1.57- 1.42 (m, 3H), 1.32- 1.24 (m, 1H) and 0.94 (d, J = 6.2 Hz, 6H) ppm.
LCMS RT = 2.7 min, (M+H) 432.5.
General Scheme 37:
Préparation of c/s-2-amino-1-methylcyclohexanecarboxylic acid (37c)
37a 37b 37c (+/-)
NaH, iodomethane DMF (b) NH2OH- HCl, pyridine, EtOH (c)AI(Hg), THF-H2O(4:1).
Formation of ethyl 1-methyl-2-oxocyclohexanecarboxylate (37a):
The title compound was prepared following the procedure described in: Tetrahedron Letters (2005) 46, 681-685 and JCS, Perkin Trans 1(2000) 3277-3289.
Sodium hydride (1.48 g, 37.14 mmol, 60% in oil) was rinsed twice with hexanes to remove oil and suspended in DMF (57 mL) at 0 °C. Then, ethyl 2oxocyclohexanecarboxylate (5.40 mL, 33.76 mmol) was added over 5 minutes. The mixture was stirred for 20 minutes and Mel (2.21 mL, 35.45 mmol) was added over 10 minutes. The mixture was warmed to room température and after 30 minutes, diluted with EtOAc (150 mL) and quenched with saturated NH4CI. The layers were separated and the aqueous layer was extracted twice more with EtOAc (2 x 100mL). The organic layer was washed with brine (2 x) dried over MgSO4, filtered through silica gel and concentrated to provide the desired product (37a).
Formation of 3a-methyl-4, 5, 6, 7-tetrahydrobenzo[c]isoxazol-3(3aH)-one (37b):
-28716260
To a mixture of ethyl 1-methyl-2-oxo-cyclohexanecarboxylate, 37a, (2.05 g, 11.10 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.97 g, 13.96 mmol) and pyridine (0.99 mL, 12.20 mmol). The mixture was heated to 65 °C overnight. The solution was concentrated in vacuo and the crude material was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc twice more. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-35% EtOAc/hexanes) to afford the desired product, 37b.
’H NMR (300 MHz, CDCI3) □ 2.72 -2.65 (m, 1H), 2.29 (td, J= 13.3, 6.3 Hz, 1H), 2.18- 2.09 (m, 1H), 2.07-2.03 (m, 1H), 1.84- 1.79 (m, 1H), 1.76- 1.56 (m, 2H), 1.54 - 1.42 (m, 1H) and 1.40 (s, 3H) ppm.
Formation of trans-2-amino-1-methylcyclohexanecarboxylic acid (37c):
To a solution of 3a-methyl-4,5,6,7-tetrahydro-2,1-benzoxazol-3-one, 37b, (0.075 g, 0.490 mmol) in THF-H2O (2.5 mL of 4:1 mixture) at room température was added fresh AI(Hg) amalgam. Aluminum was amalgamated by dipping small strips of Aluminum foil in 2% HgCI2 solution, rinsing with water and EtOH. After 1 hour, an additional 65 mg AI(Hg) was added and the mixture was allowed to stir overnight. The thick gray émulsion that formed was filtered through celite and rinsed with water and THF. The clear solution was concentrated in vacuo, stripped with methanol and THF to remove residual water and concentrated in vacuo to provide the desired product as a glassy solid as mixture of trans and c/s îsomers (~9:1 ) with the trans isomer as the prédominant isomer. The product was sufficiently pure for use in the next reaction.
1H NMR (300 MHz, MeOD) Π 2.91 (dd, J = 3.9, 11.9 Hz, 1H), 2.25 (dd, J= 1.9, 13.4 Hz, 1H), 1.89- 1.85 (m, 1H), 1.78- 1.53 (m, 3H), 1.47 -1.32 (m, 2H), 1.21 (s, 3H) and 1.090.99 (m, 1H) ppm.
FIA (M+H) 158.1, (M-H) 156.2.
Formation of 2-amino-1-ethylcyclohexanecarboxylic acid:
This compound was prepared by the methods described above as an inséparable mixture of cts and trans isomers (70:30) and was used without further purification.
General Scheme 38
Préparation of CTs-2-amino-1-alkyl-cycJohexanecarboxylic acids:
nh2
,.C02Me
38c
LDA, iodoethane, THF (b) H2, Pd-C, MeOH
-28816260
An alternative scheme for the préparation cis-2-amino-1-alkyl-cyclohexanecarboxylic acid is exemplified above. The method is described in: (a) Nemoto, T.; Fukuyama,
T.; Yamamoto, E.; Tamura, S.; Fukuda, T.; Matsumoto, T.; Akimoto, Y.; Hamada, Y.
Org. Lett. 2007, 9 (5), 927-930. (b) Seebach, D,; Estermann, H. Tetrahedron Lett.
1987, 28 (27), 3103-3106.
(1R, 2S)-methyl 2-(benzyloxycarbonylamino)-1-ethylcyclohexanecarboxylate (38b)
To a cold (-78 °C) solution of /V-isopropylpropan-2-amine (0.77 mL, 5.49 mmol) in THF (7 mL) was added, dropwise, n-butyllithium (3.43 mL of 1.6 M solution, 5.49 mmol). The mixture was stirred at -78 °C for 10 minutes. Then a solution of methyl (1$, 2S)-2-benzyloxycarbony1aminocyclohexanecarboxylate, 38a, (0.40 g, 1.37 mmol) in THF (2.5 mL) was added over a period of 3 minutes. After 15 minutes, the mixture was warmed slightly (-40 °C) for 15 minutes and recooled to -78 °C for a further 10 minutes. Then, iodoethane (0.86 g, 0.44 mL, 5.49 mmol) was added, dropwise over 3-5 minutes. The reaction mixture was maintained at -78 °C for 2 hours and allowed to warm to room température overnight. The reaction was quenched with 5 mL aqueous saturated NH4CI solution, extracted with EtOAc (3 x), washed successively with 1N HCl and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-20% EA/Hex slow gradient elution) provided 275 mg (63% yield) of the desired product (38b). NMR indicated a diastereomeric ratio greater than 10 to 1 (cis vs trans).
1H NMR (300.0 MHz, MeOD) Π 7.35 - 7.28 (m, 5H), 6.62 (d, J = 9.2 Hz, 1 H), 5.07 (dd, J= 12.5, 16.6 Hz, 2H), 3.67 (s, 3H), 3.59 (td, J = 10.0, 4.6 Hz, 1H), 2.14 (m, 1 H), 1.76 - 1.29 (m, 9H) and 0.83 (t, J = 7.6 Hz, 3H) ppm.
(1R, 2S)-methyl 2-amino-1-ethylcyclohexanecarboxylate (38c)
A solution of methyl (1R, 2S)-2-benzyloxycarbonylamino-1-ethyl-cyclohexanecarboxylate, 38b, (0.27 g, 0.85 mmol) in MeOH (7.5 mL) was purged with nitrogen and a catalytic amount of Pd (5% Pd on carbon) was added. The solution was placed under H2 atmosphère and stirred at room température. After 1 hour, the MeOH solution suspension was filtered through celite, and concentrated in vacuo to provide the desired product (138 mg, 88% yield). The material was diluted in acetonitrile and concentrated to remove residual methanol.
1H NMR (300.0 MHz, MeOD) □ 3.69 (s, 3H), 2.71 (m, 1H), 2.07-2.01 (m, 1H), 1.82 (m, 2H), 1.71 - 1.27 (m, H), 1.64 (m, 2H), 1.56 - 1.27 (m, 5H) and 0.85 (t, J = 7.5 Hz, 3H) ppm.
General Scheme 39
-28916260 préparation of trans-2-amino-1-alkyl-cyclohexanecarboxylic acids:
Benzyl alcohol, toluene, 4 angstrom sieves, reflux (b) NaH, Mel, DMF (c) benzylamine, TiCI4, CH2CI2, then NaCNBH3, MeOH, 0 oC (d) H2, Pd-C, MeOH (e) 5-chloro-3-(5-fluoro-4methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, Na2CO3t THF/CH3CN, microwave irradiation 135 °C (f) HCl, CH3CN, dioxane, 80 °C.
A general method for the synthesis of frans-2-amino-1-alkyl-cyclohexanecarboxylic acids is shown in the scheme above.
Benzyl 2-oxocyclohexanecarboxylate (39b)
This compound was prepared following literature procedures described in: Matsuo, J. étal. Tetrahedon: Asymmetry 2007, 18, 1906-1910.
Benzyl 1-methyl-2-oxocycfohexanecarboxylate (39c)
This compound was prepared following the literature procedures described În: (a) Hayashi, Y.; Shoji, M.; Kishida, S. Tetrahedron Lett. 2005, 46, 681-685. (Winfield, C. J.; Al-Mahrizy, Z.; Gravestock, M.; Bugg, T. D. H. J. Chem. Soc., Perkin Trans. 1, 2000, 3277.
Trans-Benzyl 2-(benzylamino)-1-methylcyclohexanecarboxylate (39d)- (racemic trans) To a solution of benzyl 1-methyl-2-oxo-cyclohexanecarboxylate, 39c, (0.50 g, 2.03 mmol) and benzylamine (0.61 g, 0.63 mL, 5.75 mmol) in dichloromethane (10.0 mL), was added TiCI4 (1.93 mL of 1 M solution, 1.93 mmol) dropwise, at room température. The mixture was stirred for 2 hours. The mixture was cooled to 0 °C and a solution of NaBH3CN (0.21 g, 3.34 mmol) in MeOH was added dropwise over a period of 3 minutes. After 15 min, the solution was warmed to RT and stirred for an additional 45 min. Then, the mixture was diiuted with EtOAc, quenched with 10 mL 1M NaOH. The mixture was partitioned with Et2O and the aqueous layer was extracted several times with Et2O (2 x) and EtOAc (1 x). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-50% EtOAc-Hexanes gradient elution) and isolation of the
-29016260 major component provided the desired product (320 mg) as a single racemic trans isomer.
1H NMR (300.0 MHz, MeOD) □ 7.34-7.16 (m, 10H), 5.07 (dd, J= 12.4, 31.2 Hz, 2H), 3.78 (d, J= 13.0 Hz, 1H), 3.57 (d, J = 13.0 Hz, 1H), 2.96 (m, 1H), 1.86 (m, 1H), 1.74 - 1.57 (m, 3H), 1.52- 1.25 (m, 4H) and 1.20 (s, 3H) ppm.
Trans-2-Amino-1-methylcyclohexanecarboxylic acid (39e)
To a solution of racemic frans-benzyl (1S, 2S)-2-(benzylamino)-1-ethylcyclohexanecarboxylate, 39d, (0.32 g, 0.91 mmol) in MeOH (12.8 mL), was added
Pd (5% Pd on carbon, 0.07 g). The solution was degassed and placed under 50 PSI H2 (Parr shaker) overnight. The mixture was filtered through celite and the filtrate was rinsed with MeOH. Concentration of the mother liquor followed by acetonitrile azeotrope (2 x) to remove residual MeOH provided the desired product (162 mg).
1H NMR (300.0 MHz, MeOD) Π 3.22 (m, 1H), 1.93 (m, 1H), 1.77 (m, 2H), 1.57-1.23 (m, 5H) and 1.17 (s, 3H) ppm.
39f frans-2-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4yl]amino]-1-methyl-cyclohexanecarboxylic acid (39f)
To a vessel charged with 5-οΝθΓθ-3-(5-ίΙυοΓο-4-ηΊ6^ΐ5υΙί^Ι-ρνΓΪΐΌΪόΐη-2^Ι)-1-(ρtolylsulfonyl)pyrrolo[2,3-b]pyridine, 15a, (0.27 g, 0.58 mmol) and irans-2-amino-1methyl-cyclohexanecarboxylic acid, 39e, (0.08 g, 0.47 mmol) and freshly ground Na2CO3 (0.19 g, 1.75 mmol) was added anhydrous THF (4.5 mL) and CH3CN (0.9 mL). The vessel was sealed and heated to 135 °C for 35 min (microwave irradiation). LC-MS indicated complété consumption of starting material. Next, the reaction mixture was slowly poured into a vigorously stirred solution of 1N HCl (13.5 mL). The pH of the final solution was 1-2. The mixture was extracted with EtOAc (3 x), dried over Na2SO4 and filtered through Celite and concentrated in vacuo. Flash chromatography (SiO2, 0-10% MeOH-dichloromethane, gradient elution) provided a sticky yellow foam, which was suspended in acetonitrile. Sonication followed by évaporation of the solvent provided white amorphous solid (240mg, 74% yield) as a racemic mixture of trans stereoisomers.
1H NMR (300.0 MHz, MeOD) Π 9.02 (d, J= 2.4 Hz, 1H), 8.52 (s, 1H), 8.33 (d, J= 2.4 Hz, 1 H), 8.09 - 8.05 (m, 3H), 7.38 (d, J = 8.1 Hz, 2H), 5.04 (dd, J = 3.6, 9.5 Hz, 1 H), 2.38 (s, 3H), 2.09 (m, 1H), 1.83- 1.59 (m, 7H), 1.29 (s, 3H) and 1.23 (m, 1H) ppm.
-29116260
LCMS RT = 4.00 min, (M+H) 558.34.
Trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3’yl)-5-fluoro-pyrimidin-4-yl]amino]-1methyl-cyclohexanecarboxylic acid (643)
To a slurry of racemic frans-2-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3yl]-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylic acid, 39f, (0.047 g, 0.084 mmol) in CH3CN (2.35 mL) was added HCl (1.26 mL of 4 M solution, 5.05 mmol) in dioxane. The suspension became a clear solution. The vial was sealed and heated to 80 °C for 2 hours during which time a thick slurry formed. The slurry was allowed to cool to room température overnight. Additional CH3CN was added and the mixture was centrifuged. The organic layer was discarded and the solid was triturated with CH3CN three times more to provide an amorphous white solid as racemic mixture of trans stereoîsomers.
1H NMR (300.0 MHz, MeOD) Π 8.98 (d, J = 2.3 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J= 2.3 Hz, 1H), 8.30 (d, J= 5.7 Hz, 1H), 5.26 - 5.22 (m, 1H), 2.17 - 2.10 (m, 1H), 1.87 - 1.82 (m, 4H), 1.68 - 1.59 (m, 3H) and 1.36 (s, 3H) ppm.
LCMS RT = 3.30 min, (M+H) 404.36.
General scheme 40
fert-butylmagnesium chloride; l2, Et3N, THF, DME (b) 5-chloro-1 -(p-tolylsulfony 1)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3bjpyridine, DME/H2O, Na2CO3, tetrakis
-29216260 triphenylphosphinepalladium(O), 130 °C, microwave (c) mCPBA, CH2CI2 (d) (ÏS, 2S)-2aminocyclohexanecarboxylîc acid, Na2CO3, THF- CH3CN (3:1), 150 °C microwave.
Formation of 4-fert-butyl-2-chloro-5-fluoro-6-(methylthio)pyrimidine (40a)
To a cold (0 °C) solution of fert-butylmagnesium chloride (7.5 mL, 1M solution in THF, 7.5 mmol) in THF (15 mL) was added slowly a solution of 2-chloro-5-fluoro-4(methylthio)pyrimidine (0.9 g, 5.0 mmol) in 1,2-dimethoxyethane (5 mL). The reaction mixture was stirred at 15 °C for 1 hour, then cooled to 0 °C and triethylamine (0.7 mL, 5.0 mmol) was added, followed by the addition of a solution of iodine (1.3 g, 5.0 mmol) in tetrahydrofuran (3 mL). Water (10 mL) was added to quench the reaction and pH was adjusted to 1 using 6N hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (2x15 mL). The combined organic phases were washed with aqueous sodium thiosulfate and then brine, dried over MgSO4, filtered and concentrated in vacuo to give a brown solid which was used without further purification.
1H NMR (300.0 MHz, CDCI3) δ 2.52 (s, 3H), 1.30 (s, 9H) ppm.
LCMS (M+1) 233.0.
Formation of 3-(tert-butyl-5-fluoro-6-(methylthio)pyrimidin-2-yl)-5-chloro-1Hpyrrolo[2,3-b]pyridine (40b)
To a degassed solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan'2-yl)pyrrolo[2,3-b]pyridine (0.22 g, 0.50 mmol), 4-tert-butyl-2-chloro-5fluoro-6-thiomethoxypyrimidine, 40a, (0.12 g, 0.50 mmol) in 1,2-dimethoxyethane (3 mL) and aqueous Na2CO3 (0.75 mL of 2 M solution, 1.5 mmol) was added tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.03 mmol). The reaction mixture was degassed for an additional 15 minutes. The mixture was heated in a microwave at 150 °C for 20 minutes. Ethyl acetate (15 mL) was added. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0%100% EtOAc/hexanes) to afford the desired product, 40b (47 mg).
1H NMR (300 MHz, CDCI3) Π 10.82 (br, 1H), 8.81 (d, J =2.2 Hz, 1H), 8.27 (d, J =2.3 Hz, 1H), 8.20 (dd, J = 7.2, 2.2 Hz, 1H), 7.18 (s, 1H), 2.63 (s, 3H), 1.41 (s, 9H) ppm. LCMS (M+1) 352.3.
Formation of 3-(tert-butyl-5-fluoro-6-(methylsulfinyl)pyrimîdin-2-yl)-5-chloro-1Hpyrrolo(2,3-b]pyridine (40c)
To the solution of 3-(tert-butyl-5-fluoro-6-(methylthio)pyrimidin-2-yl)-5-chloro-1Hpyrrolo[2,3-ù]pyridine, 40b, (0.05 g, 0.11 mmol) in CH2CI2 (3.4 mL) was added
-29316260 mCPBA (0.02 g, 0.11 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was diluted with CH2CI2 (10 mL) and saturated NaHCO3 solution (5 mL). The aqueous layer was extracted with CH2CI2 (10 mL). The combined organic phases were washed again with aqueous saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product that was used without further purification.
1H NMR (300 MHz, CDCI3) □ 10.93 (br, 1H), 8.79 (d, J = 2.2 Hz, 1 H), 8.34 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.19 (s, 1H), 2.98 (s, 3H), 1.47 (s, 9H) ppm.
LCMS (M+1) 368.3.
Formation of (1S, 2S)-2-(6- tert-butyl-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid (629).
A mixture of 3-(tert-butyl-5-fluoro-6-(methylsulfinyl)pyrimidin-2-yl)-5-chloro-1 Hpyrrolo[2,3-d]pyridine, 40c, (0.05 g, 0.14 mmol), (1S, 2S)-2-aminocyclohexanecarboxylic acid (0.04 g, 0.27 mmol), freshly ground Na2CO3 (0.04 g, 0.41 mmol), and jPrzNEt (0.37 mL, 0.27 mmol) in THF (1 mL) and CH3CN (0.5 mL) was heated in a sealed vessel to 140 °C for 30 minutes under microwave irradiation. The mixture was cooled to room température. A solution of 1N HCl (0.5 mL, 0.5 mmol) was added and the mixture was concentrated to give a yellow solid, which was purified by reverse phase HPLC (0%-50% methanol in water) to afford the desired product, 629, as off-white solid.
1H NMR (300 MHz, DMSO) ΊΠ12.26 (s, 1H), 8.79 (d, J =2.4 Hz, 1H), 8.28 (d, J =
2.4 Hz, 1H), 8.13 (d, J = 2.7 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 4.34 (m, 1H), 2.62 (m, 1H), 2.05 (m, 2H), 1.75 (m, 2H), 1.57 (m, 2H), 1.39 (s, 9H) and 1.26 -1.17 (m, 2H) PPm.
LCMS (M+1) 446.23.
General Scheme 41
3-amino-1-methylpyrrolidin-2-one, DMA, 140 °C microwave; (b) i: LiOH, THF, microwave, 120 °C, or ii: NaOMe, MeOH. [.
Formation of 3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)-1 -methylpyrrolidîn-2-one (379)
-29416260
A solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(ptolylsulfony))pyrrolo[2,3-b]pyridine, 15a, (0.060 g, 0.129 mmol) in DMA (0.5 mL) was treated with 3-amino-1-methylpyrrolidin--2-one (0.030 g, 0.258 mmol) and the reaction was heated at 140 °C for 20 minutes. The reaction mixture was cooled to room température and then treated with 0.5 mL of 25% NaOMe in MeOH and heated at 50 °C for 15 min. The mixture was then partitioned between aqueous saturated Na2CO3 solution and EtOAc. The aqueous layer was extracted with EtOAc twice more and the combined organic phases were concentrated in vacuo. The crude material was purified by préparative HPLC. The isolated product was filtered through basic resin to remove residual TFA and provide the desired product.
’H NMR (300 MHz, MeOD) □ 8.72 (d, J= 2.3 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.11 - 8.07 (m, 2H), 4.94 (t, J = 9.3 Hz, 1H), 3.64 - 3.51 (m, 2H), 2.97 (s, 3H), 2.68 - 2.54 (m, 1H) and 2.37-2.23 (m, 1H) ppm.
LCMS RT = 2.3 min, (M+H) 361.3.
The following compounds can also be prepared in a manner similar to the one described in Scheme 41.
3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropynmidin-4-ylamino)pyrrolidin-2one (380) 1H NMR (300 MHz, MeOD) □ 8.79 (d, J= 2.4 Hz, 1H), 8.20 (d, J= 2.4 Hz, 1H), 8.13 (s, 1H), 8.07 (d, J =3.9 Hz, 1H), 4.91 (dd, J =8.7, 10.6 Hz, 1H), 3.61 - 3.46 (m, 2H), 2.68 - 2.58 (m, 2H) and 2.48 - 2.31 (m, 1H) ppm.
LCMS RT = 2.3 min, (M+H) 347.3.
(S)-3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1methylpiperidin-2-one (397) 1H NMR (300.0 MHz, DMSO) □ 8.65 (d, J = 2.5 Hz, 1 H), 8.27 (d, J = 2.4 Hz, 1 H), 8.20 - 8.19 (m, 2H), 7.63 (d, J = 7.8 Hz, 1H), 4.78 - 4.74 (m, 1H), 3.41 (t, J = 5.4 Hz, 2H), 3.17 (MeOH), 2.89 (s, 3H), 2.5D (DMSO), 2.18 - 2.15 (m, 1H) and 1.99 (d, J =
7.4 Hz, 2H) ppm.
LCMS RT = 2.2 min, (M+H) 375.4.
-29516260
(S)-3-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridÎn-3-yl)-5-fluoropyrimidin-4-ylamino)pipendin-
2-one (416)
LCMS RT = 1.6 min, (M+H) 361.3.
(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-y()-5-fluoropyrimidin-4-ylamino)azepan-2one (417) 1H NMR (300 MHz, DMSO) □ 12.33 (s, 1H), 8.74 (d, J= 2.3 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1 H), 8.21 (t, J = 3.7 Hz, 2H), 8.02 - 7.98 (m, 1 H), 7.21 (d, J = 5.8 Hz, 1 H), 4.86 (dd, J= 6.3, 10.5 Hz, 1 H), 3.51-3.41 (m, 1H), 3.25-3.16 (m, 1H), 2.13 -1.85 (m, 4H), 1.66 - 1.52 (m, 1H) and 1.40-1.20 (m, 1H) ppm.
LCMS RT = 1.7 min, (M+H) 375.4.
(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fliioropyrimidîn-4-ylamino)-1ethylpiperidin-2-one (460)
LCMS RT = 2.0 min, (M+H) 389.1. ‘ (S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1methylazepan-2-one (461)
LCMS RT = 2.0 min, (M+H) 389.1.
(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1ethylazepan-2-one (462) 1H NMR (300 MHz, cfâ-DMSO) □ 12.35 (s, 1H), 8.68 (d, J= 1.7 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.21 (m, 2H), 7.28 (d, J= 6.0 Hz, 1H), 4.98 (dd, J = 6.9, 10.7 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.84 (dd, J= 11.4, 15.5 Hz, 1H), 3.49-3.17 (m, 5H), 2.08 (d, J = 13.1 Hz, 1H), 1.95- 1.88 (m, 3H), 1.65- 1.58 (m, 1H), 1.42 (m, 1H) and 1.04 (t, J = 7.0 Hz, 3H) ppm.
-29616260
LCMS RT = 3.3 min, (M+H) 403.4.
(R)-5-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)pyrrolidin-2-one (503)
LCMS RT = 2.2 min, (M+H) 361.2.
(S)-3-(5-fluoro-2-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4y1amino)azepan-2-one (502).
LCMS RT = 2.3 min, (M+H) 409.
(S)-6-(2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-4-(4methoxybenzyl)-1,4-oxazepan-5-one (505)
LCMS RT = 3.1 min, (M+H) 497.7.
The starting amine for this compound v/as prepared following established procedures as described in: Blizzard, Timothy A.; Chen, Helen Y.; Wu, Jane Yang; Kim, Seongkon; Ha, Sookhee; Mortko, Christopher J.; Variankaval, Narayan; Chiu, Anna. 7-Oxo-2,6-Diazabicyclo[3.2.0]heptane-6-su!fonic acid dérivatives as b lactamase inhibitors and their préparation, pharmaceutical compositions and use in the treatment ofbacterial infections. PCT Int. Appl. (2008), 101pp. WO2008039420.
(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)azepan-2-one (500).
LCMS RT = 1.6 min, (M+H) 357.6.
(S)-3-(2-(5-fluoro-1/7-pyrrolo[2,3-/j]pyridin-3-yl)pyrimidin-4-ylamino)azepan-2-one (501)
LCMS RT = 1.6 min, (M+H) 341.4.
3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyndin-3-yl)-5-fluoropyrimidin-4-ylamino)-7,7- dimethylazepan-2-one (504)
-29716260
LCMS RT = 3.2 min, (M+H) 403.6.
The amine for this cornpound was prepared following procedures as described in; J.
A. Robl, E. Sieber-McMaster, R. Sulsky Synthetic routes for the génération of 7,7dialkyl-2-azepinones. Tetrahedron Letters (1996), 37(50), 8985-8988
General Scheme 42
3-amino-1-methylpyrrolidin-2-one, DMA, 140 °C microwave; (b) LiOH, THF, microwave, 120 °C (c) EDCI, HOAt, jPr2NEt, DCM-DMF (2:1).
6-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1,4oxazepan-5-one (513)
A mixture of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridine, 15a, (0.17 g, 0.36 mmol) and (6S)-6-amino-1,4oxazepan-5-one (0.06 g, 0.43 mmol) in DMF (2 mL) with 'Pr2NEt (0.10 mL, 0.57 mmol) was heated to 90 °C. After 1 hour, the température was raised to 100 °C. After 24 hours, the mixture was heated to 140 °C for 15 min (microwave). The mixture was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc twice more. The combined organic phases were dried organic over Na2SO4, filtered and concentrated in vacuo.
The resulting crude material (0.16 g) was treated with LiOH (1N solution, 1mL) in THF (3mL) overnight. LC-MS indicates hydrolysis of amide along with detosylation.
-29816260
The mixture was concentrated in vacuo and purified by préparative HPLC to provide semi pure product (23mg). This material was subjected to cyclization conditions without further purification.
To a flask was charged with the crude material (0.020 g, 0.051 mmol), EDCI (0.010 g, 0.056 mmol) and HOAt (0.002 g, 0.015 mmol) and DCM (1 mL) was added 'Pr2NEt (0.018 mL, 0.100 mmol) and DMF (0.5 mL). After 1 hour, additional EDCI was added (0.7 eq). After
3.5 hour, the reaction was complété and the mixture was concentrated in vacuo. Purification by préparative HPLC followed by removal of TFA sait by filtration through basic resin provided the desired product: LCMS RT = 1.9 min, (M+H) 377.5.
The starting amine for this compound was prepared following the established procedures as described în: J. A. Robl, E. Sieber-McMaster, R. Sulsky Synthetic routes for the génération of 7,7-dialkyl-2-azepinones. Tetrahedron Letters (1996), 37(50), 8985-8988.
General Scheme 43
The following are general procedures for conversion of the cyclohexane carboxylic acids,
553 or 35a, to carboxamides of type 43a:
a or b
Amine, HATU, DMF (b) BOC2O, NH4CO3i
1N LiOH.
, pyridine, DMF; (c) i: Amine, HATU, DMF; then ü:
Formation of (1 S, 2S)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-29916260 ylamino)-/V-ethylcyclohexanecarboxarnide (521 )
To a mixture of (1S, 2S)-2-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexane-1-carboxylic acid, 553, (0.049 g, 0.126 mmol) and HATU (0.056 g, 0.147 mmol) in DMF (1.0 mL) at room température was added ethylamine (0.189 mL of 2 M solution, 0.377 mmol). The mixture was stirred at room température until ail starting material had been converted as judged by HPLC. After 45 minutes, the mixture was partitioned between aqueous K2CO3 and EtOAc and the organic layer was separated and dried over Na2SO4 and concentrated in vacuo. Préparative HPLC provide the desired product as the TFA sait, which was converted to the parent compound by elution through a basic PSA cartridge with MeOH followed by concentration in vacuo. (14 mg, 30% yield).
1H NMR (300 MHz, MeOD) □ 8.93 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.18 (s, 1H), 7.99 (d, J = 4.0 Hz, 1H), 4.53 (ddd, J= 7.1, 11.1 Hz, 1H), 3.15-3.02 (m, 2H), 2.43-2.34 (m, 1H), 2.30- 2.26 (m, 1H), 1.97- 1.82 (m, 3H), 1.77- 1.65 (m, 2H), 1.47 - 1.35 (m, 2H) and 0.97 (t, J = 7.3 Hz, 3H) ppm. LCMS RT = 2.0 min,
520
(1 S, 2S)-2-(2-(5-chloro-1 H-pyrro!o[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylammo)-N,Ndiethylcyclohexanecarboxamide
LCMS RT = 2.26 min, (M+H) 445.58.
(+/-)
Formation of C/s-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexanecarboxamide (544) and C/s-2-(2-(5-chloro-1H-pyrrolo[2,3fa]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N,N-dimethylcyclohexanecarboxamide (543)
To a mixture of c/s-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyndin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexanecarboxyJic acid, 554, (0.30 g, 0.77 mmol) in DMF (5 mL) at room température was added pyridine (0.61 g, 0.62 mL, 7.70 mmol) followed by diterf-butyl dicarbonate (0.50 g, 2.31 mmol), and NH4CO3H (0.33 g, 4.22 mmol). The
-30016260 mixture was stirred overnight at room température. LC-MS indicated the presence of the desired primary amide as well as the N,A/-dimethylamide product. A 1 mL aliquot of the reaction solution was acidified with HOAc and diluted with DMSO. Préparative
HPLC chromatography provided small amounts both products.
Primary amide, 544, racemic mixture - (8.6mg): LCMS RT = 1.94 min, (M+H) 389.42. Dimethylamide, 543, racemic mixture - (3.7 mg): LCMS RT = 2.52 min, (M+H) 417.44.
H
Cl
518
Formation of (1 R, 2S)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)-N,N-diethylcyclohexanecarboxamide (518)
To a mixture of (1R, 2S)-2-[[2-[5-chloro-1-(p-tolyfsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5fluoro-pyrimidin-4-yl]amino]cyclohexane-1-carboxylic acid (0.050 g, 0.092 mmol), and HATU (0.045 g, 0.120 mmol) in DMF (1 mL) at room température was added A/,A/-diethylamine (0.138 mL of 2 M solution, 0.280 mmol). When the reaction appeared complété as judged by HPLC, LiOH (0.4 mL of 1 M solution, 0.4 mmol) in water was added. After 6 hours, LiOH (0.4 mL of 1 M, 0.4 mmol) was added again and the mixture was stirred overnight. The mixture was quenched with aqueous saturated NH4C) solution. Aqueous K2CO3 was added and the mixture was extracted with EtOAc (3 x), The combined organic phases were washed with aqueous saturated NH4CI solution, filtered and concentrated in vacuo. Préparative HPLC provided the desired product as the TFA sait which was converted to the HCl sait by treatment with HCl in MeOH followed by évaporation of the solvents (12.9 mg, 28% yield).
1H NMR (300 MHz, MeOD) 008.67 (d, J = 2.3 Hz, 1H), 8.53 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 5.5 Hz, 1 H), 4.75 - 4.73 (m, 1H), 3.74 -3.58 (m, 1H), 3.42 (m, 2H), 3.29 - 3.22 (m, 2H), 2.57 (m, 1H), 2.09 - 2.03 (m, 1H), 1.96 - 1.76 (m, 4H), 1.06 (t, J = 7.1 Hz, 3H) and 0.94 (t, J = 7.1 Hz, 3H) ppm. LCMS RT = 3.3 min, (M+H) 445.6.
Cl
Cl
539 (+/-)
519
-30116260 (1R, 2S)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-Nethylcyclohexanecarboxamide (519)
LCMS RT = 2.95 min, (M+H) 417.5.
C/s-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-Wmethylcyclohexanecarboxamide (539) - racemic mixture
LCMS RT = 2.13 min, (M+H) 403.44.
General Scheme 44
Pd(PPh3)4, sodium carbonate, DME/water, reflux (b) meta-chloroperbenzoic acid, dichloromethane, rt. (c)
I
20a, tetrahydrofuran, 50°C (d) trifluoroacetic acid, dichloromethane, rt. (e) morpholine-4-carbonyl chloride, dimethylformamide, rt (f) sodium methoxide, methanol, rt.
Formation of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1 H-pyrrolo[2,3bjpyridine (44b)
2-Chloro-5-fluoro-4-methylsulfanyl-pyrinnidine (34.1 g, 191.0 mmol), 5-fluoro-1-(ptolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (53.0 g, 127.3 mmol) and Na2CO3 (40.5 g, 381.9 mmol) were dissolved in a mixture of DME (795 mL) and water (159 mL). The mixture was purged with nitrogen for 20 minutes and treated with Pd(PPh3)4 (7.4 g, 6.6 mmol). After purging with nitrogen for another 20 minutes, the reaction was heated to reflux overnight, cooied to room température and diluted with water (600mL). The resulting suspension was stirred at room température for 30 minutes and the precipitate was then collected by filtration, washed with water and acetonitrile and dried at 50 °C to afford 48.2 g of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1Hpyrrolo[2,3-b]pyridine as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 8.70 - 8.58 (m, 2H), 8.54 - 8.41 (m, 2H), 8.09 (d, J
-30216260 = 8.4 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).
Formation of 5-fluoro-3-[5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl]-1 -tosyl-1 Hpyrrolo[2,3-b]pyridine (44c)
5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyndinel 44b, (48.2 g, 111.5 mmol) was dissolved in dichloromethane (2.3 L) and treated portionwise with m-CPBA (27.5 g, 122.6 mmol) while keeping the température below 20 °C. After addition was complété, the reaction was stirred at room température for 2 hours, then treated with another portion of m-CPBA (1.9 g) and stirred for another hour. The reaction mixture was washed with 12% aqueuous K2CO3 (2 x 1.0 L) and the organic layer was dried on Na2SO4 and concentrated in vacuo to provide 50 g of 5-fluoro-3-[5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl]-1 -tosyl1H-pyrrolo[2,3-b]pyridine as a yellow solid.
1H NMR (300 MHz, DMSO-d6) δ 9.11 (d, J =1.5 Hz, 1H), 8.69 (s, 1H), 8.65 (dd, J = 9.0, 2.9 Hz, 1H), 8.52 (dd, 7=2.8, 1.2 Hz, 1H), 8.11 (d, 7 = 8.4 Hz, 2H), 7.46 (d, 7 = 8.3 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H).
Formation of fert-butyl W-[(1R, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexy)]carbamate (44d)
5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-to)ylsu)fonyl)pyrrolo[2,3b]pyridine, 44c, (5.9 g, 10.5 mmol) and tert-butyl Λ/-[(1 R, 3S)-3aminocyclohexyljcarbamate (3 g, 12.60 mmol) were dissolved in THF (100 mL). The reaction mixture was heated to 50 °C for 6 hours, then cooled to room température. Celite was added and the solvent was removed under reduced pressure. The Celitesupported residue was purified by silica gel chromatography (20-80% EtOAc/hexanes gradient to provide 3.7 g of fert-butyl 3S)-3-[[5-fluoro-2-[5- fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4yl]amino]cyclohexyl]carbamate.
1H NMR (300 MHz, CDCI3) δ 8.51 (s, 1H), 8.46-8.41 (m, 1H), 8.29 (d, 7= 1.6 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.06 (d, 7= 3.2 Hz, 1H), 7.27 (d, 7=8.4 Hz, 2H), 4.91 (d, 7 = 8.0 Hz, 1 H), 4.41 (s, 1 H), 4.29 - 4.01 (m, 1 H), 3.64 (s, 1 H), 2.47 (d, 7 = 11.5 Hz, 1H), 2.36 (s, 3H), 2.24 (d, 7= 13.1 Hz, 1H), 2.08 (d, 7= 10.9 Hz, 1 H), 1.91 (d, 7 = 13.8 Hz, 1H), 1.43 (s, 9H), 1.30 - 1.03 (m, 4H).
Formation of (1 S, 3R)-N1-[5-fluoro-2-[5-fluoro-1-{p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-
3-yl]pyrimidin-4-yf]cyclohexane-1,3-diamine (44e) fert-Butyl /7-((1 R, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate, 44d, (3.7 g, 6.2 mmol) was dissolved in dichloromethane (105 mL) and treated with trifluoroacetic acid (31 mL). After 5 minutes, the volatiles were evaporated under reduced pressure, and the resulting
-30316260 residue was treated with 1N NaOH (75 mL). The resulting precipitate was collected by filtration, washed with water (3 x 30 mL) and vacuum dried to provide 2.7 g of (1 S,
3R)-A/1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4yl]cyclohexane-1,3-diamine as a white solid.
1H NMR (300 MHz, MeOD) d 8.56 (dd, J = 8.0, 3.9 Hz, 2H), 8.35 - 8.26 (m, 1H), 8.12 (dd, J= 10.3, 6.1 Hz, 3H), 7.43 (d, J = 8.4 Hz, 2H), 4.36-4.21 (m, 1H), 3.28-3.13 (m, 1H), 2.48 (d, J= 12.3 Hz, 1H), 2.46 (s, 3H), 2.25 - 1.97 (m, J= 17.3, 10.6, 4.1 Hz, 4H), 1.76- 1.28 (m, 3H).
Formation of N-[(1 R, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl] morpholine-4-carboxamide (44f) (1 S, 3R)-/V1 -[5-fluoro-2-[5-fluoro-1 -(p-tolyIsulfonyt)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-
4-yl]cyclohexane-1,3-diamine, 44e, (2.3 g, 4.6 mmol) was dissolved in DMF (50mL) and treated with morpholine-4-carbonyl chloride (2.1 g, 13.8 mmol) and DIPEA (4.2 g, 5.6 mL, 32.3 mmol). After one hour, the resulting solution was diluted with water (400 mL) and stirred for an additionaî two hours. The resulting precipitate was collected by filtration, washed with water (3 x 50 mL) and dried to provide the crude product. This material was purified by flash chromatography on a 40g column using EtOAc/DCM 20-100%, to provide 2.0 g of A/-[(1R, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4carboxamide as a white solid.
1H NMR (300 MHz, DMSO-dô) δ 8.53 - 8.43 (m, J = 11.9, 2.7 Hz, 3H), 8.22 (d, J = 3.9 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 2H), 7.44 (d, 7 = 8.3 Hz, 2H), 6.32 (d, 7 = 7.5 Hz, 1H), 4.05 (s, 7= 19.4 Hz, 1H), 3.62 (s, 1H), 3.58- 3.45 (m, 4H), 3.27-3.18 (m, 4H), 2.36 (s, 3H), 2.12 (d, 7= 11.7 Hz, 1H), 1.99 (d, 7 = 9.5 Hz, 1H), 1.83 (d, 7= 10.3 Hz, 2H), 1.53-1.11 (m, 7= 32.3, 22.8, 10.9 Hz, 4H).
Formation of W-[(1R, 3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3yl)pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide (706) /V-[(1R, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide, 44f, (2,0 g, 3.2 mmol) was suspended in methanol (50 mL) and treated with 25% sodium methoxide in methanol (19.9 mL, 92.3 mmol). After stirring for 1 hour, the solvent was evaporated under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was collected, dried on Na2SO4 and concentrated to provide the crude product as a yellow solid. This material was purified by silica gel chromatography on a 40g column, using DCM/MeOH 1-6%. The purified fractions were treated with 2N HCl in ether and concentrated to provide 1.5 g of /V-[(1 R, 3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]-morpholine-4-carboxamide as a white
-30416260 solid.
44e ίο
Formation of (1 S, 3R)-/V1-(2-fluoro-5-(5-fluoro-1W-pyrrolo[2,3-b]pyridin-3yl)phenyl)cyclohexane-1,3-diamine (44e)
To a solution of tert-butyl (1R, 3S)-3-(2-fluoro-5-(5-fluoro-1-tosyl-1H-pyrrolo-[2,3ù]pyridin-3-yl)phenylamino)cyclohexylcarbamate, 44d, (0.65 g, 1.09 mmol) in methylene chioride (22 mL) was added hydrogen chioride (2.71 mL of 4M solution in
1,4-dioxane, 10.86 mmol). The reaction was heated to 50 °C and stirred for 6 hours. The mixture was cooled to room température and concentrated in vacuo, producing a yellow solid. The crude residue was purified via silica gel chromatography (2550% Ethyl Acetate/hexanes gradient). Desired fractions were combined and concentrated in vacuo to produce 350 mg of 44e as a yellow powder.
Synthesis of 1-cyano-N-((1R, 3S)-3-(2-fluoro-5-(5-fluoro-1H-pyrrolo[2,3-h]pyridin-3yl)phenylamino)cyclohexyl)cyclopropanecarboxamide (871)
To a solution of 1-cyano-1-cyclopropane-carboxylic acid (0.058 g, 0.527 mmol) in THF at room température was added HATU (0.200 g, 0.527 mmol) followed by N,Ndiisopropylethylamine (0.334 mL, 1.91 mmol). The solution was stirred for 10 minutes. (1 S, 3R)-N1-(2-fluoro-5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3yl)phenyl)cyclohexane-1,3-diamine, 44e, (0.200 g, 0.584 mmol) was then added and solution stirred at room température for 4 hours. The mixture was concentrated in vacuo and purified via silica gel chromatography (30-60% Ethyl Acetate/hexanes) to give 80 mg of 871 as off-white solid.
1H NMR (300 MHz, DMSO) δ 12.80 (s, 1H), 8.95 (s, 1H), 8.78 (s, 1H), 8.43 (d, J = 5.2 Hz, 1 H), 8.37 (d, J = 1.6 Hz, 1 H), 8.07 (d, J = 7.9 Hz, 1 H), 4.22 (s, 2H), 3.80 (S, 1H), 2.17-1.94 (m, 2H), 1.90-1.71 (m, 2H), 1.71-1.06 (m, 8H).
-30516260
General Scheme 45
4-chlorobutanoyl chloride, Et3N, CH2CI2; (b) KOtBu, THF; (c) H2, Pd-C, MeOH; (d) 45c, Na2CO3, THFCH3CN, 135 °C; (e) 4M HCl, dioxane-CH3CN.
Formation of benzyl (1 S, 3R)-3-(4-chlorobutanamido)cyclohexylcarbamate (45a)
To a stirred slurry of benzyl N-[(1S, 3R)-3-aminocyclohexyl]carbamate, 18e, (0.97 g, 3.41 mmol) in CH2C)2 (34 mL), was added Et3N (1.00 mL, 7.15 mmol), followed by
4-chlorobutanoy) chloride (0.40 mL, 3.58 mmol). After stirring at room température, the mixture was diluted with CH2Cl2, washed with 1N HCl (2 x), 1N NaOH (2x), and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 1.07 g of the desired product.
ήΗ NMR (300 MHz, MeOD) □ 7.33 - 7.26 (m, 5H), 5.04 (s, 2H), 3.73 - 3.65 (m, 1H), 3.56 (t, J = 6.5Hz, 2H), 3.44 (dq, J = 3.9, 15.6 Hz, 1H), 2.33 - 2.28 (m, 2H), 2.11 1.97 (m, 3H), 1.90 - 1.75 (m, 3H), 1.45 - 1.28 (m, 1 H) and 1.18 -1.02 (m, 3H) ppm.
Formation of benzyl (1 S, 3R)-3-(2-oxopyrrolidin-1-yl)cyclohexylcarbamate (45b)
To a slurry of benzyl (1$, 3/?)-3-(4-chlorobutanamido)cyc)ohexylcarbamate, 45a, (0.21 g, 0.58 mmol) in THF (8.2 mL) was added potassium ferf-butoxide (0.08 g, 0.69 mmol) at room température. After stirring at room température for 25 h, the mixture was quenched with aqueous saturated NH4CI and extracted with Et2O (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-100% EtOAc-hexanes, gradient) provided a single fraction consisting of desired product and a small amount of starting material (168 mg). This material was immediately subjected to deprotection conditions.
-30616260 1H NMR (300 MHz, MeOD) □ 7.33 - 7.27 (m, 5H), 5.04 (s, 2H), 3.95 - 3.88 (m, 1H),
3.58 - 3.38 (m, 3H), 2.38 - 2.28 (m, 2H), 2.11 - 1.76 (m, 6H), 1.63 (d, J = 2.7 Hz, 1H),
1.46 - 1.34 (m, 3H) and 1.21 -1.06 (m, 2H) ppm.
Formation of 1-((1R, 3S)-3-aminocyclohexyl)pyrrolidin-2-one (45c)
A degassed solution of benzyl (1 S, 3R)-3-(2-oxopyrro)idin-1-yl)cyclohexylcarbamate, 45b, (0.165 g, 0.522 mmol) and Pd on C (10% wet, Degussa, 0.050 g, 0.024 mmol) in MeOH (15 mL) was placed under H2 atm (balloon). After 105 min, TLC (10% MeOH-DCM) indicated complété consumption of startîng material. H2 was removed and the solution filtered and concentrated in vacuo. The crude product was azeotroped with CH3CN (2 x) to remove any residual MeOH and provided the desired product (96 mg): FIA (M + H*) 183.27
Formation of 1-((1 R, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-one (45d)
A mixture of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.14 g, 0.29 mmol) and 1-((1R, 3S)-3aminocyclohexyl)pyrrolidin-2-one, 45c, (0.10 g, 0.53 mmol) and Na2CO3 (0.09 g, 0.88 mmol) freshly ground, in THF (2.25 mL) and CH3CN (0.45 mL) and heat to 135 °C for 30 min. The mixture was slowly poured into 15 mL 1M HCl and extracted with EtOAc (5 x). The combined organic layers were washed with brine, dried over Na2SO4 and filtered and concentrated in vacuo. Flash chromatography (SiO2, 020% MeOH-CH2CI2 gradient) provided the final product as a sticky residue.
Trituration with CH3CN provided an off white powder (105 mg) which was impure, but which was taken directly to the final deprotection step.
LC/MS R; = 3.90 min, (M+H) 589.49.
Formation of 1-((1 R, 3S)-3-(2-(5-chloro-1H-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-one (956)
A mixture of partially purified 1-((1 R, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3b]pyridin-3-yl)-5-f)uoropyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-one, 45d, (0.105 g, 0.180 mmol) in CH3CN (5mL) was treated with HCl (2 mL of 4 M, 8.00 mmol) in dioxane at 70 °C. After 2H, the mixture was cooled to room température. Then CH3CN was added and the solid that precipitated was triturated with more CH3CN (3 x). Préparative HPLC provided the desired product as the HCl sait (35 mg).
1H NMR (300 MHz, MeOD) □ 8.72 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.29 (d, J =5.5 Hz, 1H), 4.54-4.47 (m, 1 H), 4.13 (t, J = 11.8 Hz, 1H), 3.573.45 (m, 2H), 2.42 - 2.36 (m, 2H), 2.25 (m, 1H), 2.15 - 2.00 (m, 4H), 1.90 -1.59 (m, 4H) and 1.53- 1.43 (m, 1H) ppm; LC/MS RT = 3.15 min, (M+H) 429.53.
General Scheme 46
-30716260
46b 46c
30% ammonium hydroxide, water, 50°C (b) Acetyl chloride, diisopropylethylamine, dichloromethane, rt.
(c) 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 -tosyl-1 H-py rrolo[2,3-b]py rid ine, Pd(PPh3)4.2M sodium carbonate, acetonitrile, 130 °C, mîcrowave
Formation of (1S, 3S)-1-(aminomethyl)-3-(2-chloro-5-fluoropyrimidin-4ylamino)cyclohexanol (46b)
2-Chloro-5-fluoro-N-[(3S, 5S)-1-oxaspiro[2.5]octan-5-yl]pyrimidin-4-amine, 46a, (0.19 g, 0.73 mmol) was dissolved in water (75 mL) and treated with 30% ammonium hydroxide (10 mL, 86.0 mmol). The suspension was heated to 50 °C for 5 hrs then allowed to stir at room température overnight. The volatiles were evaporated under reduced pressure, and the residue, (1S, 3S)-1-(aminomethyl)-3-(2-chforo-5-fluoropyrimidin-4-ylamino)cyclohexanol, was taken into the next step without further purification.
Formation of N-{[(1S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1hydroxycyclohexyljmethyljacetamide (46c) (1S, 3S)-1-(aminomethyl)-3-(2-ch)oro-5-fluoropyrîmidin-4-ylamino)cyclohexanol, 46b, (0.19 g, 0.69 mmol) was dissolved in dichloromethane (15 mL) and treated with DIPEA (1.20 mL, 6.91 mmol) and acetyl chloride (0.10 mL, 1.38 mmol). After 5 minutes, the reaction mixture was diluted into 1N HCl (30 mL), and the aqueous layer was brought to a basic pH by addition of 1N NaOH. The resulting suspension was extracted with dichloromethane (50 mL). The organic layer was dried on Na2SO4 and concentrated in vacuo to provide the crude product, which was purified by silica gel chromatography (20-100% EtOAc/hexanes gradient) to afford 195 mg of N-{[(1 S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1hydroxycyclo-hexyl]methyl}acetamide as a white foamy solid. LCMS RT = 2.82 (M+1) 317.33.
Formation of N-{[(1S, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1 -hydroxycyclohexyljmethyl} acetamide (857) /V-{[( 1 S, 3S)-3-(2-chloro-5-fluoropyrimîdin-4-ylamino)-1 -hydroxycyclohexyl]-methyl}acetamide, 46c, (0.2 g, 0.6 mmol) was dissolved in acetonitrile (6 mL) and treated
-30816260 with 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine (0.5 g, 1.2 mmol) followed by Pd(PPh3)4 (0.07 g, 0.06 mmol). Aqueous 2M sodium carbonate (3.0 mL, 6.1 mmol) was added, and the vial was sealed and heated in the microwave to 130 °C for 30 min. The organic layer was collected and concentrated in vacuo to provide the crude product, which was dissolved in DMSO and purified by HPLC using 5-70% MeOH/H2O with 6mM HCl over 15 minutes to provide after concentration 75 mg of A/-{[(1 S, 3S)-3-(2-(5-chloro1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1 hydroxycyclohexyljmethyljacetamide hydrochloride as an off-white crystalline solid. Ή NMR (300 MHz, DMSO-c/6) 5 13.02 (s, 1H), 9.22 (s, 1H), 9.03 (d, J =2.4 Hz, 1H), 8.71 (d, J =2.1 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 7.81 (t, J = 5.8 Hz, 1H), 4.64 (d, J = 8.0Hz, 1H), 3.16-2.99 (m, 2H), 2.09 - 1.73 (m, 3H), 1.85 (s, 3H), 1.73- 1.42 (m, 3H), 1.28 (dd, J = 27.5, 10.6 Hz, 2H).; LCMS RT = 3.47 (M+1) 433.37
General Scheme 47
tert-butyl N-methyl-N-(2-oxoethyl)carbamate, diisopropylethylamine, THF/EtOH, 70 °C (b) HCI/dioxane, THF/MeOH (c) bis(4-nitrophenyl) carbonate, diisopropylethylamine, DMF.
Formation of tert-butyl 2-((1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexyl-amîno)ethyl(methyl)carbamate (47b)
In a flask containing (1 S, 3R)-A/1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-yl)cyclohexane-1,3-diamine, 47a, (0.14 g, 0.39 mmol) in THF/EtOH was added tert-butyl A/-methyl-/V-(2-oxoethyl)carbamate (0.10 g, 0.58 mmol) and diisopropylethylamine (0.13 mL, 0.77 mmol). The solution was heated at 70 °C for min. Sodium triacetoxyborohydride (0.08 g, 0.39 mmol) was added. The solution was stirred at room température for 12 hrs. The solution was filtered and the solvent
-30916260 evaporated under reduced pressure. The resultîng residue was purified by HPLC using 5-70% MeOH/H2O with 6mM HCl to provide the desired product.
Formation of (1 S, 3R)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin4-yl)-/V3-(2-(methylamino)ethyl)cycJohexane-1,3-diamine (47c)
In a flask containing tert-butyl 2-((1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3yl)-5-fluoropyrimidin-4-ylamino)cyclohexylamino)ethyl(methyl)carbamate, 47b, (0.02 g, 0.04 mmol) in dichloromethane/MeOH mixture was added HCl in Dioxane (3.86 mL of 4 M solution, 15.44 mmol). The solution was stirred at room température for 12 hrs. The solvent was evaporated under reduced pressure and used without further purification.
Formation of 1-((1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexyl)-3-methylimidazolidin-2-one (958)
In a flask containing (1S, 3R)-N1 -(2-(5-chloro-1 H-pyrrolo[2I3-b]pyridin-3-yl)-5fluoropyrimidin-4-yl)-/V3-(2-(methylamino)ethyl)cyclohexane-1,3-diamine, 47c, (0.020 g, 0.048 mmol) in DMF was added diisopropylethylamine (0.025 mL, 0.144 mmol) and bis(4-nitrophenyl) carbonate (0.016 g, 0.053 mmol). The reaction mixture was stirred at room température for 3 hrs. The resultîng residue was purified by HPLC using 5-70% MeOH/H2O with 6mM HCl to provide the desired product.
General Scheme 48
2-Methoxyethanamine, HATU, DIEA, CH3CN, DMF
Formation of (1R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamîno)-N-(2-methoxyethyl)cyclohexanecarboxamide (789) (1 R, 3S)-3-[[2-(5-chloro-1 /7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]cyclohexanecarboxylic acid (HCl salt)(0.05 g, 0.12 mmol), HATU (0.09 g, 0.24 mmol), diisopropylethylamine (0.06 g, 0.47mmol) and 2-methoxyethanamine (0.04 g, 0.47 mmol) were stirred together in 1 ml each of DMF and CH3CN at room température ovemight. Ail volatiles were removed with a stream of nitrogen and heat. The residue was dissolved in méthanol and purification with phase preparatory HPLC with 10 - 90% MeOH/water (HCl modifier) gave the desired product as the HCl sait.
-31016260
General Scheme 49
Cl
F
methyl(triphenyl)phosphonium bromide, (bis(trimethylsilyl)amino)lithium, THF (b) 3 chloroperoxybenzoic acid, MeOH, H2O. (c) methylsulfanylsodium, THF (d) 5-chloro-1-(p tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, Na2CO3t tetrakis triphenylphosphinepalladium(O), CH3CN (e) 3-chloroperoxybenzoic acid, CH2CI2 (f)
NaOMe, MeOH
Formation of (S)-2-chloro-5-fluoro-N-(3-methylenecyclohexyl)pyrimidin-4-amine (49a) To a suspension of methyl(triphenyl)phosphonium bromide (0.86 g, 2.40 mmol) in THF (100 mL) in a flamed dry flask was added (bis(trimethylsilyl)amino)lithium (2.40 mL of 1 M solution, 2.40 mmol) at room température. The reaction mixture was allowed to stir at room température for 1 hr. A solution of (S)-3-(2-chloro-5fluoropyrimidin-4-ylamino)cyclohexanone, 29b, (0.48 g, 2.00 mmol) in 20 mL of THF was added. The reaction was allowed to stir at room température for 2 hrs. The mixture was quenched by pouring into brine and the aqueous phase was extracted with EtOAc. The layers were separated and the organic was dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100%EtOAc/hexanes gradient) to afford 270 mg of the desired product LCMS RT: 3.83 min, (M+1 ): 242.2.
Formation of 2-chloro-5-fluoro-N-((3R, 5S)-1-oxaspiro[2.5]octan-5-yl)pyrimidin-4amine (49b, 49c)
-31116260
3-chloroperoxybenzoic acid (0.40 g, 1.79 mmol) was added to a solution of (S)-2chloro-5-fluoro-A/-(3-methylenecyclohexyl)pyrimidin-4-amine, 49a, (0.27 g, 1.12 mmol) in water (0.6 mL) and MeOH (1.5 mL) at room température. The reaction mixture was allowed to stir at room température for 1 hr. The mixture was diluted with EtOAc and washed with aqueous saturated NaHCO3 solution. The organic phase was dried (MgSO4), filtered and evaporated to dryness. The crude residue was purifîed via silica gel chromatography (0-100% EtOAc/hexanes gradient) which yielded both diastereomers, 49b and 49c. The isoiated upper (less polar) spot, 49b, was carried forward: LCMS RT = 3.21 (M+1) 258.2.
Formation of (1 R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-(methylthiomethyl)cyclohexanol (49d)
2-chloro-5-fluoro-/V-((3R, 5S)-1-oxaspiro[2.5]octan-5-yl)pyrimidin-4-amine, 49b, (0.10 g, 0.38 mmol) was dissolved in THF (2 mL). Methylsulfanylsodium (0.08 g, 1.15 mmol) was added to the reaction and the mixture was allowed to stir at room température for 3 hrs. An additional 36 mg portion of methylsulfanylsodium in THF (2 mL) was added and the reaction mixture was stirred overnight at room température. After LCMS showed starting material was still présent, the reaction was warmed to 50 °C and stirred for 1 hr. The reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The crude residue was purifîed via silica gel chromatography (0-100%Etoac/hexanes gradient). The product (contaminated with small amount of staring material) was carried on to the next step without further purification. LCMS RT = 3.56 (M+1) 306.2.
Formation of (1 R, 3S)-3-(2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-(methylthiomethyl)cyclohexanol (49e)
To a solution of (1R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1(methylthiomethyl)cyclohexanol, 49d, (0.09 g, 0.28 mmol) in CH3CN (4 mL) was added 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine (0.14 g, 0.33 mmol) followed by aqueous Na2CO3 (0.42 mL of 2 M solution, 0.83 mmol). The reaction was degassed with nitrogen for 15 min and tetrakis triphenylphosphinepalladium(O) (0.02 g, 0.01 mmol) was added. The reaction was heated to 140 °C via microwave irradiation for 20 minutes. The mixture was cooled to room température and was diluted with water/EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purifîed via silica gel chromatography (0-100% EtOAc/ hexanes gradient).
1H NMR (300 MHz, DMSO) δ 8.76 (d, J = 1.8 Hz, 1H), 8.47 (d, J =8.1 Hz, 1H), 8.30 (t, J = 26.7 Hz, 1H), 8.05 (d, J = 8.1 Hz, 2H), 7.95 - 7.45 (m, 2H), 7.43 (s, 1H), 4.81
-31216260 (s, 1H), 4.32 - 3.84 (m, 1H), 2.70 (d, J = 19.5 Hz, 2H), 2.36 (s, 2H), 2.14 (s, 1H),
2.13 (s, 1H), 2.14-1.94 (m, 2H), 2.14-1.59 (m, 6H), 1.48-0.83 (m, 3H).
Formation of (1R, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimîdin-4-ylamino)-1-(methylsulfonylmethyl)cyclohexanol (49f)
To a coid (0 °C) solution of (1R, 3S)-3-(2-(5-chloro-1-tosyl-1/7-pyrrolo[2,3-b]pyridin-3yl)-5-fluoropyrimidin-4-ylamino)-1-(methylthiomethyl)cyclohexanol, 49e, (0.044 g, 0.077 mmol) in CH2CI2 (2 mL) was added 3-chloroperoxybenzoic acid (0.034 g, 0.155 mmol). After stirring for 1 hour at 0°C, the mixture was diluted with water and CH2CI2. The layers were separated and the organic was washed with aqueous saturated NaHCO3 soin., dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc/ hexanes gradient). LCMS RT = 4.20 (M+1) 608.3.
Formation of (1R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)-1 -(methylsulfonylmethyl)cyclohexanol (886)
To a solution of (1R, 3S)-3-(2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-(methylsulfonylmethyl)cyclohexanoll 49f, (0.045 g, 0.074 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25 %w/v, 9.255 mmol). The reaction mixture was allowed to stir at room température for 5 minutes, after which the mixture was quenched with the addition of aqueous saturated NH4CI solution and then diluted with EtOAc. The layers were separated and the organic was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-10% MeOH/ CH2CI2 gradient).
General Scheme 50 ,OH .OTBS
50a c
d b
OH
860
AIMe3, [Rh2(cod)2CI2], (S)-BINAP, THF, 0 °C (b)
TBSCI, imidazole, DMAP, DMF (c) 3 chloroperoxybenzoic acid, CH2CI2 (d) sodium azide, NH4CI, MeOH, H2O (e) H2, Pd-C (10%), EtOAc (f) 5chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-31316260 tosyl-1 H-pyrrolo[2,3-b]pyridine, 'Pr2NEt, microwave, °C (g)TBAF, THF
Formation of (R)-1-methylcyclohex-2-enol (50a) ln a 1000 mL flamed-dried round bottom flask, a mixture of (S)-BINAP (6.2 g, 10.0 mmol) and Rh2(cod)2CI2 (2.1 g, 4.2 mmol) in anhydrous THF (350 mL), was stirred under nitrogen for 30 minutes at room température. The homogeneous red reaction mixture was then cooled to 0 “C and cyclohex-2-en-1-one (16.0 g, 166.4 mmol) was added followed by dropwise addition of neat trimethylaluminium (12.4 g, 16.5 mL, 166.4 mmol). The mixture was allowed to warm to room température for 30 min and then stirred for 1 hour. The reaction was monitored by NMR and a worked up aliquot indicated complété conversion to tertiary alcohol.
When the reaction was complété, its température was lowered to 0°C and quenched carefully with aqueous saturated NH4CI solution (500 mL). The layers were separated and the aqueous phase was further washed with ether (5 X 100 mL) and the combined organics were dried (MgSO4) filtered over a celite pad and concentrated in vacuo to a yellow-brownish crude oil. Vacuum distillation (38 °C at 0.5-1 mm Hg), provided 13.9 g (72%) of light amber color oil.
Formation of (R)-tert-butyldimethyl(1-methylcyclohex-2-enyloxy)silane (50b)
To a solution of (R)-1-methylcyclohex-2-enol, 50a, (1.00 g, 8.91 mmol) in 20 dry DMF at room température was added 4H-imidazole (1.82 g, 26.74 mmol), tertbutyldimethylchlorosilane (2.02 g, 13.33 mmol) and a catalytic amount of 4dimethylaminopyridine (0.11 g, 0.89 mmol). The resulting mixture was stirred at room température overnight. It was then diluted with ether, washed consecutively with water, citric acid and water. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The colorless crude oil 1.98 g was used directly in the next step without further purification.
Formation of tert-butyldimethyl((1R, 2R, 6R)-2-methyl-7-oxabicyclo[4.1.0]heptan-2yloxy)silane (50c)
3-chlorobenzenecarboperoxoic acid (2.47 g, 11.00 mmol) was added in one portion to a stirred solution of (R)-fert-butyldimethyl(1-methylcyclohex-2-enyloxy)silane, 50b, (1.98 g, 8.87 mmol) and sodium hydrogen carbonate in 30 mL of dry dichloromethane at room température under nitrogen. The resulting mixture was stirred for 20 hours. Then, 25% sodium sulfite solution (30 mL) was added and the resulting biphasic mixture was stirred for 15 minutes. The 2 layers were separated and the aqueous layer was extracted with dichloromethane (2X20 mL). The combined organic phases were washed with aqueous saturated NaHCO3, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by silica gel
-31416260 chromatography (0-10% EtOAc-hexanes gradient) to provide 647 mg of compound
50c.
Formation of (1R, 2R, 3S)-3-azido-1-(tert-butyldimethylsilyloxy)-1-methylcyclo-hexan2-ol(50d)
To a stirred solution of tert-butyl-dimethyl-[[(1R, 5R, 6R)-5-methyl-7oxabicyclo[4.1.0)heptan-5-yl]oxy] silane, 50c, (0.05 g, 2.15 mmol) in methanol (5 mL) and H2O(0.6 mL) was added NH4CI (0.23 g, 0.15 mL, 4.30 mmol), followed by portion wise addition of sodium azide (0.42 g, 1.26 mL, 6.45 mmol). The resulting reaction mixture was warmed to 60 °C, stirred for 12 h, at which point TLC-analysis revealed traces of the starting material. The reaction mixture was cooled to ambient température, quenched with H2O (2 mL), concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (3 x 15 mL), washed with brine (10 mL), dried over MgSO4, frlter and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2.5-10 % ethyl ether in hexanes gradient) to afford 254 mg of (1 R, 2S, 6R)-2-azido-6-[fert-butyl(dimethyl)silyl]oxycyclohexanol, 50d, as a clear oil.
Formation of (1R, 2R, 3S)-3-amino-1-(tert-butyldimethylsilyloxy)-1-methylcyclohexan2-ol(50e)
A solution of azide, 50d, (0.25 g; 0.89 mmol) in 20 mL of ethyl acetate was hydrogenated with Degussa palladium (20 mole%) under 1 atmosphère of hydrogen overnight. The reaction mixture was filtered over celite and the celite was eluted with 2 X 10 mL of EtOAc. The filtrate was concentrated in vacuo to afford 230 mg of an oil that was used directly for the next step without further purification.
Formation of (1R, 2R, 6S)-2-(tert-butyldimethylsilyloxy)-6-(2-(5-chloro-1-tosyl-1Hpyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrrmidin-4-ylamino)-2-methylcyclohexanol (50f)
To a stirred suspension of (1 R, 2R, 6S)-6-amino-2-[fert-butyl(dimethyl)silyl]oxy-2methyl-cyclohexanol, 50e, (0.16 g, 0.62 mmol) in THF (8 mL) in a microwave sealed tube vessel was added 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl1H-pyrrolo[2,3-b]pyridine, 1a, (0.29 g, 0.63 mmol) followed by A/-ethyl-/V-isopropylpropan-2-amîne (0.13 mL, 0.74 mmol). The resulting reaction mixture was capped and warmed to 70 °C, stirred for 14 h. The reaction mixture was cooled to ambient température, added water (2 mL), concentrated under reduced pressure to remove THF. The crude product was diluted with ethyl acetate (25 mL), insoluble material (sulfone 1a) was removed by filtration. The organic layer was separated, washed with brine (2x5 mL), dried over Na2SO4, filter and concentrated under reduced pressure. The crude product was purified by silica-gel plug using 10-30 % ethyl acetate in hexanes as eluant to afford 350 mg of (1R, 2R, 6S)-2-[tert-31516260 butyl(dîmethyl)silyl]oxy-6-[[2-methyl[5-chloro-1 -(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin3-yl]-5-fluoro-pyrîdin-4-yl]amino]cyclohexanol (50f).
Formation of (1R, 2R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yJ)-5-fluoropyrimidin-4-ylamino)-1 -methylcyclohexane-1,2-diol (860)
To a stirred solution of (1R, 2R, 6S)-2-[tert-butyl(dimethyl)silyl]oxy-6-[[2-methyl[5chloro-1 -(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyridin-4yl]amino]cyclohexanol, 50f, (0.11 g; 0.16 mmol) in THF (2 mL) at room température, was added tetrabutylammonium fluoride (1.5 equiv) and the reaction mixture stirred for 1.5 h, at which point HPLC-analysis revealed no starting material but the detosylated product was observed with minor desilylation. An additional équivalent of TBAF was added and the reaction mixture was stirred at room température overnight. The reaction mixture was suspended in ethyl acetate (10 mL), washed with H2O (2x4 mL), aqueous saturated NH4CI solution (2 mL) and brine (2 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to provide 139 mg of crude. The crude residue was purified by reverse phase HPLC (5-95% MeOH/water w/ HCl buffer over 15 minutes), to afford 15 mg of desired product, 860. LCMS M+1 = 392.34.
General Scheme 51
NaH, BnBr, THF, 60 “C (b) 3-chloroperoxybenzoic acid, CH2CI2, 0 °C (c) H2SO4, MeOH (d) TBSCI, imidazole, DMAP, DMF (e) H2, Pd-C (10%), EtOAc (f) triphenylphosphine, diisopropylazadicarboxylate, diphenylphosphoryl azide, THF (g) H2, Pd-C (10%), EtOAc (h) 2,4-dichloro-5-fluoropyrimidine, K2CO3,
-31616260
CH3CN/IPA (i) TsOH, MeOH (j) 5-chloro-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1Hpyrrolo[2,3-b]pyridine, aq Na2CO3, CH3CN, microwave, 120 °C (k) LiOH, H2O/THF, microwave, 120 °C.
Formation of ((cyclohex-2-enyloxy)methyl)benzene (51a)
A solution of cyclohex-2-en-1-ol (10.0 g, 101.9 mmol) in anhydrous THF (100 mL) was added to a stirred suspension containing sodium hydride (8.0 g, 199.7 mmol) (60% dispersion in oil) and benzyl bromide in anhydrous THF (250 mL) maintained at 50 °C. The resulting solution was stirred at 55-60 °C for 18 h. After cooling to ambient température, water was added to quench the reaction and the mixture was diluted with ether (500 mL). The organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuo to an oil that was subjected to a short silica plug filtration to provide 16.1g of desired product 51a that was used directly in the next step without further purification.
Formation of racemic cis and trans-1-benzyloxy)-7-oxabicyclo[4.1.0]heptane (51b and 51c)
A solution of benzyl ether 51a (16.10 g, 0.89 mol) in 500 mL of CH2CI2 at 0 °C was treated with 77% m-CPBA (21.08 g; 0.09 mol) portîonwise. The reaction mixture was stirred at 0 “C for 2h then at room température for 12h. When the reaction is complété, it was quenched with sodium thiosulfate (100 mL) and the organic phase was further washed with another 100 mL of sodium thiosulfate, followed by aqueous NaHCO3 solution, 5% NaOH (200 mL) and finally water. The organic phase was dried (Na2SO4) and concentrated in vacuo to afford an oil that was purified by silica gel chromatography (5% to 20% Et2O/ hexanes) to afford 11.44 g of trans-epoxide 51b and 3.95 g of c/s-epoxide 51c were isolated (66:34 ratio).
Formation of racemic 1-benzyloxy-3-methoxycyclohexan-2-ol (51d)
A solution of c/s-1-benzyloxy)-7-oxabicyclo[4.1.0]heptane, 51c, (2.0 g; 9.8 mmol) in 0.2N sulfuric acid (9.8 mmol) in 30 mL of anhydrous methanol was stirred at room température for 30 minutes. The reaction was diluted with water and extracted with ether. The organic phase was dried (Na2SO4) and concentrated in vacuo to afford 2.31 g of an oil that was used directly in the next step without further purification.
Formation of racemic [1-benzyloxy-3-methoxy-2-cyclohexanoxy]fert-butyldimethylsilane (51e)
To a solution of 1-benzyloxy-3-methoxy-cyclohexan-2-ol, 51 d, (2.31 g, 9.78 mmol), fert-butyl-chlorodimethyl-silane (2.21 g, 2.73 mL, 14.66 mmol) in 20 dry DMF at room température was added 4H-imidazole (1,997 g, 29.33 mmol) and a catalytic amount
-31716260 of 4-dimethylaminopyridine (0.12 g, 0.98 mmol). The resulting mixture was stirred at room température overnight. It was then diluted with ether, washed with water, aqueous saturated citric acid solution and water again. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The colorless crude oil was used directly in the next step without further purification.
Formation of racemic [1-Hydroxy-3-methoxy-2-cyclohexanoxy]tert-butyldimethylsilane (51f)
A solution of racemic [1-benzyloxy-3-methoxy-2-cyclohexanoxy]tert-butyldimethylsilane, 51e, (3.4 g, 9.7 mmol) was dissolved in ethyl acetate (50 mL) and hydrogenated under 45 PSI of hydrogen with Pd-C 10% for 1 h. The reaction mixture was filtered over a nylon/fiberglass filter to provide, after concentration in vacuo 2.72 g of desired product 51 f. This material was used directly in the next step without further purification.
Formation of racemic [1-Azido-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane (51g)
To a solution of racemic [1-Hydroxy-3-methoxy-2-cyclohexanoxy]tert-butyldimethylsilane, 51 f, (2.5 g; 9.6 mmol) in 60 mL of dry THF at room température was added, triphenylphosphine (5.0 g; 19.2 mmol), DIAD (3.9 g; 19.2 mmol) and dîphenylphosphoryl azide (5.3 g; 19.2 mmol) and the reaction mixture was stirred at room température for 60h. The solvent was concentrated in vacuo and the résultant oil was purified by silica gel chromatography (10% Et2O-Hexane to ether gradient) to afford 2.57 g of the desired product 51g.
Formation of racemic [1-Amino-3-methoxy-2-cyclohexanoxy]terf-biityl-dimethylsilane (51 h)
A solution of racemic [1-Azido-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51g, (2.57 g; 6.3 mmol) in 20 mL of ethyl acetate was hydrogenated with Pd-C 10% (5 mole %; Degussa) at 45 PSI in a Parr hydrogénation apparatus for 1 h. The reaction mixture was filtered over a nylon and glass fiber filter and concentrated in vacuo to provide 2.32 g of the desired product 51h as a white solid.
Formation of racemic /V-((1-2-(tert-butyldimethylsilyloxy)-3-methoxycyclohexyl)-2chloro-5-fluoropyrimidin-4-amine (51 i)
In a flask was placed racemic [1-Amino-3-methoxy-2-cyclohexanoxy]tert-butyldimethylsilane, 51h, (2.32 g; 6.26 mmol). To this was added MeCN and IPA (1.5:1 v/v) to a total volume of 125 mL. To the solution was added dîpotassium carbonate (4.32 g, 31.30 mmol) and the mixt ure was allowed to stir 30 minutes at room température (to remove any water that might be présent). To this mixture was added 2, 4-dichloro-5-fluoro-pyrimidine (3.14 g, 18.78 mmol) and the mixture was stirred at room température for 60h. The reaction was filtered thru celite and concentrated in
-31816260 vacuo. The crude residue was purified by silica gel chromatography (20-100%
Ether/hexanes gradient) to afford 2.27g pure racemate compound 51 i.
Formation of (1R, 2S, 6R)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-6-methoxycyclohexanol (51 j)
To a solution of compound racemic 6/-((1-2-(tert-butyldimethylsilyloxy)-3methoxycyclohexyl)-2-chloro-5-fluoropyrimidin-4-amine, 51 i, (1.96 g, 5.03 mmol) in 30 mL of MeOH was added p-TsOH (1.73 g; 10.06 mmol). The reaction mixture was stirred at room température for 3h and then was concentrated to dryness. The residue was dissolved in EtOAc (125 mL) and washed with aqueous potassium carbonate 1M (2 X 50 mL), then brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give, after SFC enantiomers séparation (50% EtOH-50% CO2; 10 mL/min; 100 bar) 635 mg of chiral alcohol 51 j as a white solid.
Formation of (1R, 2S, 6R)-2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-6-methoxycyclohexanol (51 k)
In a microwave tube was placed 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.10 g, 0.23 mmol). To this was added acetonitrile (0.61 mL) and the solution was deoxygenated with nitrogen. To the reaction was added (1R, 2S, 6R)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-6methoxy-cyclohexanol, 51 j, (0.04 g, 0.14 mmol) and palladium catalyst (24 mg), and then aqueous sodium carbonate (0.21 mL of 2 M solution, 0.41 mmol). The reaction was sealed and heated to 120 °C in the microwave reactor for 15 min. The reaction was diluted with ethyl acetate (40 mL), filtered thru florisil, and concentrated in vacuo to give crude as a green solid. This was purified by silica gel chromatography (2075% EtOAc/hexanes gradient). Used resulting product directly in the next step. LCMS (M+1) = 546.35.
Formation of (1R, 2S, 6R)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-6-methoxycyclohexanol (831 )
In a microwave via! was placed azaindole 51k (0.050 g; 0Ό92 mmol). To this was added 3 mL of THF and 0.9 mL of 0.8 M LÎOH. The vial was sealed and heated to 120 °C for 15 minutes in the microwave. When the reaction is complété, it was neutralized with 9 équivalents of 1N HCl (0.704 mL), then aqueous saturated NaHCO3 solution was added and the organic phase was separated and loaded onto silica gel for purification and eluted w/ 2% MeOH to 12% gradient over 10 minutes (4 g column) to provide 34.5 mg (91%) desired product 831.
General Scheme 52
-31916260
LDA, iodomethane, THF, -78 °C (b) SOCI2, DMF, CH2CI2, reflux, then NH4OH (c) TMSOTf, îodine, Et3N, pentane, CH2CI2 (d) Boc20, DMAP, CH2CI2 (e) 1,8-Diazabicyclo[5.4.0]undec-7-ene, toluene, reflux (f) Cs2CO3, MeOH (g) H2, Pd-C (5%), MeOH, 2 days (h) HCl, MeOH; 2,4-dichloro-5-fluoropyrimidine, 'Pr2NEt, DMF; SFC chiral séparation (i) 5-chloro-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl1H-pyrrolo[2,3-b]pyridine, Pd(Ph3P)4, Na2CO3, THF/H2O, reflux (j) NaH, MeOH (k) LiOH, H2O/MeOH (I) benzotriazol-1-yl(bis(dimethylamino)methylene]oxonium hexafluorophosphate, 'Pr2Net, THF, NH4CI.
Formation of 1-methylcyclohex-3-ene-1-carboxylic acid (52a)
W-isopropylpropan-2-amine (50.1 g, 69.5 mL, 495.5 mmol) was dissolved in 50 mL of THF. To the solution was added n-butyllithium (174.4 mL of 2.5 M solution in hexanes, 436.0 mmol) at -78 °C. The resulting solution was stirred for 30 minutes at -78 °C. To the reaction was then added cyclohex-3-ene-1-carboxylic acid (25.0 g,
-32016260
198.2 mmol) and the reaction was allowed to warm to 60 °C for 2 hrs. The reaction was cooled to room temp and iodomethane (29.5 g, 13.0 mL, 208.1 mmol) was added and the reaction was allowed to stir overnight and then quenched with 1 N HCl until the pH < 4. The crude product was extracted into CH2CI2 and water. The organic phase was concentrated in vacuo to a yellow oil (27 g) and used without further purification. MS/RT: 141.09 (M+H)/1.65
Formation of 1-methylcyclohex-3-ene-1-carboxamide (52b)
To a solution of 1-methylcyclohex-3-ene-1-carboxylic acid, 52a, (54.0 g, 385.2 mmol) dîssolved in CH2CI2 (200 mL) was added thionyl chloride (56.2 mL, 770.4 mmol) and 1 mL of DMF. The reaction was warmed to reflux for 3 hrs, then cooled and . 1 concentrated in vacuo. The residue was redissolved in 200 mL of CH2CI2. To the reaction was added ammonium hydroxide (148.2 mL of 13 M solution, 1.9 mol) slowly. The reaction was stirred overnight. The reaction was extracted into CH2CI2 and water. The organic phase was concentrated in vacuo and purified via flash silica gel chromatography (EtOAc), yielding 25 g of 1-methylcyclohex-3-ene-1carboxamide. MS/RT: 139.96 (M+H)/2.66
Formation of 4-iodo-1-methyl-6-azabicyclo[3.2.1Joctan-7-one (52c)
A solution of 1-methylcyclohex-3-ene-1-carboxamide, 52b, (5.0 g, 35.9 mmol) dîssolved in 100 mL of pentane and CH2CI2 was cooled to 0 °C and treated with triethylamine (11.0 mL, 79.0 mmol) and trimethylsilyl-triflate (14.3 mL, 79.0 mmol) sequentially. The resulting mixture was stirred for 1 hour at room température. The lower layer was removed via pipette. The upper pentane layer was concentrated in vacuo and the resulting residue was dîssolved in THF (100 mL). To the stirred reaction was added iodine (20.1 g, 79.02 mmol) and the reaction was allowed to stir overnight at room température. After quenching with Na2SO3 and NaHCO3, the reaction was partitioned between CH2CI2 and water. The organic layers were combined, dried over Na2SO4, concentrated in vacuo to a dark yellow oil (9.5 g) that was used without further purification. MS/RT: 266.06(M+H)/2.39
Formation of tert butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (52d)
To a solution of 4-iodo-1-methyl-6-azabicyclo[3.2.1]octan-7-one, 52c, (9.5 g, 35.8 mmol) in CH2CI2 (100 mL) was added DMAP (0.2 g, 1.8 mmol), triethylamine (15.0 mL, 107.5 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.8 g, 35.8 mmol). The reaction was stirred overnight at room température. The product was extracted into CH2CI2 and water. The organic layer was concentrated in vacuo and the residue was purified via silica gel chromatography (4:1 Hexanes:EtOAc), yielding 7.6 g. MS/RT: 366.06 (M+H)/3.95
Formation of tert butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-32116260 carboxylate (52e).
To a solution of fert-butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo[3.2.1]octane-6carboxylate, 52d, (7.6 g, 20.8 mmol) in 100 mL of toluene was added 1,8diazabicyclo[5.4.0]undec-7-ene (6.2 mL, 41.6 mmol). The reaction was warmed to reflux and stirred overnight. The reaction was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (4:1 Hexanes:EtOAc), yielding 4.9 g of the desired product, 52e. MS/RT: 238.14 (M+H)/3.33
Formation of methyl 5-(fert-butoxycarbonylamino)-1-methylcyclohex-3enecarboxylate (52f)
To a solution of fert-butyl 1-methyl-7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate, 52e, (4.93 g, 20.78 mmol) in MeOH (100 mL) was added césium carbonate (13.54 g, 41.56 mmol). The reaction was stirred overnight and then concentrated in vacuo. The césium salts were precipitated with Et2O and filtered. The ether filtrate was evaporated to give 5.5 g of a yellow oil that was used without further purification. MS/RT: 270.17 (M+H)/3.64
Formation of methyl 5-(fert-butoxycarbonylamino)-1-methylcyclohexanecarboxylate (52g)
Methyl 5-(te/t-butoxycarbonylamino)-1-methylcyclohex-3-enecarboxylate, 52f, (5.59 g, 20.75 mmol) was dissolved in 100 mL of MeOH. To the stirred solution was added 5% palladium on carbon (1.11 g, 10.38 mmol) and the reaction was stirred under a hydrogen balloon for 2 days. The reaction was filtered through celite, and the filtrate was concentrated in vacuo and used without further purification. MS/RT: 272.24(M+H)/3.62
Isolation of (1R, 3S)-methyl 3-(2-chIoro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate (52h).
A stirred solution of methyl 5-(fert-butoxycarbonylamino)-1methylcyclohexanecarboxylate, 52g, (5.63 g, 20.75 mmol) in MeOH (20 mL) was treated with HCl gas for 10 minutes. The resulting solution was stirred at room température for 1 hour, then concentrated to dryness and redissolved in THF (50 mL). To the reaction mixture was added ’Pr2NEt (10.84 mL, 62.25 mmol) and 2, 4dichloro-5-fluoro-pyrimidine (5.20 g, 31.12 mmol) sequentially. The réaction was stirred at reflux overnight, concentrated in vacuo and resulting residue was purified by silica gel chromatography (1:1 Hexane:EtOAc), yielding 2.2 g of the racemic product as a yellow oil. 300 mg of the racemic methyl 3-(2-chloro-5-fluoropyrimidin-
4-ylamino)-1-methylcyclohexanecarboxylate was submitted for SFC chiral séparation, yielding 100 mg of the desired product, 52h, as a yellow oil. MS/RT: 302.16 (M+H)/3.68
Formation of (1R, 3S)-methyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-32216260 fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate (52i)
In a 25 mL round-bottomed fiask were combined (1R, 3S)-methyl 3-(2-chloro-5fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52h, (0.061 g, 0.202 mmol), 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dîoxaborolan-2-yl) pyrrolo[2,3-b]pyridine (0.096 g, 0.222 mmol), disodium carbonate (0.064 g, 0.607 mmol) in 5 mL of THF and 1 ml of water. The reaction mixture was degassed via a stream of nitrogen. To the reaction was added tetrakis triphenyl phosphine palladium (0) (0,021 g, 0.202 mmol) and the reaction was stirred at reflux overnight. The reaction was concentrated in vacuo and purified by silica gel chromatography (4:1 Hexanes.EtOAc), yielding 85 mg of desired product, 52i. MS/RT: 572.33 (M+H)/6.27
Formation of (1R, 3S)-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate (52j)
To a stirred solution of (1R, 3S)-methyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52i, (0.085 g, 0.149 mmol) in 10 mL of MeOH was added NaH (0,004 g, 0.178 mmol) at room température. The resulting suspension was stirred for 2 hrs, quenched with solid NH4CI. The mixture was concentrated in vacuo and purified via silica gel chromatography (3:1 Hexane:EtOAc), yielding 55 mg of the desired product, 52j. MS/RT: 418.32 (M+H)/3.30 (1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1methylcyclohexanecarboxylic acid (826)
To a solution of (1R, 3S)-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52), (0.035 g, 0.083 mmol) dissolved in MeOH (5 mL) and water (1 mL) was added LiOH (0.004 g, 0.168 mmol). The reaction was allowed to stir for 2 days at room température and then concentrated to dryness. The residue was washed with éthanol. The combined éthanol washings were concentrated in vacuo, yielding 30 mg of desired product as an off white solid.
1H NMR: (300 MHz, DMSO) □ 12.34 (s, H), 8.74 (d, J = 2.3 Hz, H), 8.33 (d, J = 2.3 Hz, H), 8.28 (d, J = 1.6 Hz, H), 8.17-8.12 (m, H), 4.34 (s, H), 4.29 (s, H), 3.89 (s, H), 3.55 (d, J= 6.3 Hz, H), 3.32 (s, H), 2.50 (s, H), 2.29 (s, H), 1.95 - 1.90 (m, H), 1.82 (d, J = 6.6 Hz, H), 1.76 (s, 3 H), 1.67 (s. H), 1.55 (s, H), 1.44 - 1.42 (m, H), 1.31 (s, H), 1.23 (s, H), 1.17 (s, H), 1.07 (s, H), 0.84 (d, J = 6.9 Hz, H) and-0.00 (d, J= 1.0 Hz, H) ppm; MS/RT: 404.24 (M+H)/3.39.
Formation of (1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-
4-yl]amino]-1 -methyl-cyclohexanecarboxamide (924) (1R, 3S)-3-[[2-(5-chloro-1/-/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]1-methyl-cyclohexanecarboxylic acid, 826, (0.050 g, 0.108 mmol), benzotriazol-1-yl-32316260 [bis(dimethylamino)methylene]oxonium hexafluorophosphate (0,081 g, 0.216 mmol) and /V-ethyl-N-isopropyl-propan-2-amine (0.075 mL, 0.432 mmol) were combined in 5 mL of THF. To the reaction was then added ammonia hydrochloride (0.002 g, 0.032 mmol) and the reaction was allowed to stir ovemight at room température. After concentration under reduced pressure, the mixture was purified by reverse phase HPLC chromatography, yieldîng 3.3 mg of desired product.
1H NMR (300 MHz, MeOD) □ 8.85 (d, J = 2.4 Hz, H), 8.22 (d, J = 2.3 Hz, H), 8.16 (s, H), 7.99 (d, J = 4.1 Hz, H), 7.86 (s, H), 3.48 (d, J = 7.0 Hz, H), 2.80 (s, H), 2.15 (s, H), 2.0 (s, H), 1.86 (qn, J= 3.3 Hz, H), 1.80 (s, 3 H), 1.74 (m, 2 H), 1.44 (s, 6H); LC/MS: 403.34 (M+H), RT =1.77.
Formation of 2-(5-chloro-1W-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S, 3R)-3isocyanato-3-methylcyclohexyl)pyrimidin-4-amine (52m).
To a solution of (1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylic acid, 826, (0.100 g, 0.216 mmol) and (azido(phenoxy)phosphoryl)oxybenzene (0.093 mL, 0.432 mmol) in 10 mL of toluene was added 1 mL of N-ethyl-N-isopropyl-propan-2-amine. The reaction was warmed to reflux ovemight. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (EtOAc), yieldîng 40 mg of desired product as a white foam.
MS/RT: 401.23 (M+H)/3.89
Formation of N-((1R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-methylcyclohexyl)pyrrolidine-1-carboxamide (926)
A solution of 2-(5-chloro-1/-/-pyrrolo[2]3-b]pyridin-3-yl)-5-fluoro-A/-((1S, 3R)-3isocyanato-3-methylcyclohexyl)pyrimidin-4-amine, 52m, (0.035 g, 0.087 mmol) in 3
-32416260 mL of NMP with 0.5 mL of pyrrolidine was warmed to 200 °C in a microwave for 30 minutes. The reaction was then concentrated in vacuo and purified by reverse phase HPLC chromatography, yielding 8.7 mg of desired product as a tan solid.
1H NMR: (300.0 MHz, MeOD) □ 8.76 (d, J = 2.4 Hz, H), 8.44 - 8.38 (m, 2 H), 8.27 (d,
J =5.6 Hz, H), 4.87 (d, J= 5.1 Hz, H), 4.64-4.56 (m, 4 H), 3.38- 3.19 (m, 2 H),
2.65 (s, 2 H), 2.46 (m, H), 2.42 (s, 3 H), 2.16 (s, H), 2.07 (t, J = 12.0 Hz, H), 2.00 (s, H), 1.88 (q, J = 6.6 Hz, H), 1.88 (s, H), 1.70 (s, H) and 1.61 (d, J = 12.8 Hz, H) ppm; MS/RT: 472.38.
General Scheme 53 o2n
H2, Pd-C, MeOH; (b) Na2CO3, THF-CH3CN, 135 °C;
(c) NaOMe, MeOH, DCM; (d) NaOH, MeOH, THF.
Formation of (+/-)-2, 3-Trans-methyl 3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate (53a)
-32516260
This compound was prepared as a mixture of trans isomers (endo : exo = 84 ; 16) following literature procedures described in: Chang, Linda L.; Truong, Quang; Doss,
George A.; MacCoss, Malcolm; Lyons, Kathryn; McCauley, Ermengilda; Mumford,
Richard; Forrest, Gail; Vincent, Stella; Schmidt, John A.; Hagmann, William K.
Bioorg. Med. Chem. Lett. 2007, 17(3), 597-601.
Formation of (+/-)-2,3-Trans-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate (53b)
A mixture of (+/-)-2, 3-trans-methyl 3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate, 53a, (0.32 g, 1.62 mmol) and Pd-C (10%) in MeOH was purged and placed under H2 atm (50 PSI) and shaken overnight. The mixture was filtered through celite, concentrated in vacuo and azeotroped twice with CH3CN to remove traces of MeOH. 1H NMR of the crude mixture indicated the presence of both the endo and exo products (84 : 16 = endo : exo) which were taken directly into the next reaction without further purification.
Formation of (+/-)-2,3-Trans-methyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2,1]heptane-2-carboxylate (53c)
A mixture of 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1Hpyrrolo[2,3-b]pyridine, 1a, (0.46 g, 1.00 mmol) and (+/-)-frans-m ethyl 3aminobicyclo[2.2.1]heptane-2-carboxy!ate, 53b, (0.27 g, 1.60 mmol) (84 : 16 = endo : exo) and freshly ground Na2CO3 (0.32 g, 2.99 mmol in THF (3.7 mL) and CH3CN (1.2 mL) was heated to 120 °C for 20 min in microwave. The reaction mixture was filtered and the solid was rinsed with Et2O and THF. The organic layer was concentrated in vacuo to provide crude product which was purified by silica gel chromatography (0-40% EtOAc/hexanes, gradient) to provide the desired product (352 mg) as an inséparable mixture of trans-endo and trans-exo isomers (endo : exo = 85 : 15) as indicated by NMR.
LC/MS R( = 6.13 min, (M+H) 570.34.
(+/-)-2,3-trans-encfo-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate (53d) & (+/-)-2,3-trans-exo-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrrmidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate (53d)
To a solution of trans-endo- and frans-exo-methyl 3-(2-(5-chloro-1 -tosyl-1 Hpyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2carboxylate, 53c, (0.18 g, 0.31 mmol) in MeOH (3mL) and CH2CI2 (1mL) was added NaOMe (3 mL of 25 %w/v, 13.88 mmol). After 90 sec, NH4CI solution (5 mL) was added to quench the reaction. The mixture was partitioned between aqueous NH4CI (half saturated) and EtOAc. The aqueous layer was extracted again and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-15% MeOH-DCM, gradient)
-32616260 gave the desired products as a mixture, (white solid): 112 mg 1H NMR indicated desired product existed as a mixture of endo and exo isomers (endo : exo = 84 : 16) which was taken forward into the hydrolysis step.
(+/-)-2,3-7rans-exo-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamîno)bicyclo[2.2.1]heptane-2-carboxylate (53d): minor isomer (exo): LC/MS (method: m117) R, = 3.17 min, (M+H) 416.27.
(+/-)-2,3-Trans-endo-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate (53d): major isomer (endo): LC/MS (method: m117) R( = 3.49 min, (M+H) 416.27.
946 (+/-) 947 (+/-) (946) (+/-)-2,3-trans-endo-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylic acid &
(947) (+/-)-2,3-trans-exo-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-
4-ylamino)bicyclo[2.2.1]heptane-2-carboxylic acid
To a stirred solution of starting methyl esters, 53d, (0.076 g, 0.183 mmol) (84 : 16 = endo : exo) in THF (0.60 mL) and MeOH (0.10 mL), was added NaOH (0.10 mL of 2 M, 0.201 mmol). The reaction progress was monitored by TLC, After 30 min, additional NaOH (0.18 mL of 2 M solution, 0.37 mmol) and MeOH (0.18 mL) was added. The mixture was stirred at room température for a further 16 hours. The mixture was neutralized with HCl (1M) and concentrated in vacuo. Purification by préparative HPLC provided 52 mg of the major isomer (946) and 11mg of the minor isomer (947) as the hydrochloric acid salts.
(946) major (endo) isomer: 1H NMR (300 MHz, MeOD) δ 8.82 (d, J = 2.2 Hz, 1 H), 8.48 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.31 (d, J = 5.6 Hz, 1H), 5.11 (m, 1H), 2.85 (br s, 1 H), 2.68 (br s, 1H), 2.62 (d, J = 4.8 Hz, 1H), 1.92 (d, J = 10.1 Hz, 1H) and 1.77-1.51 (m, 5H) ppm; LC/MS Rf = 3.51, (M+H) 402.32.
(947) minor (exo) isomer: 1H NMR (300 MHz, MeOD) δ 8.87 (d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 5.7 Hz, 1H), 4.73 (d, J = 3.3 Hz, 1 H), 3.12 (m, 1H), 2.76 (br s, 1H), 2.56 (d, J = 4.2 Hz, 1H), 1.86 (d, J = 9.5 Hz, 2H), 1.79- 1.49 (complex m, 2H) and 1.51 (embedded d, J = 10.4 Hz, 2H) ppm; LC/MS Rt= 3.42, (M+H) 402.32.
-32716260 (1184) (2S,3S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriniidin-4yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
1184
Compound 1184 was made in a similar fashion as described above for compounds 5 946 and 947.
(1070) (2S,3S)-3-((2-(5-fluoro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4yl)amino)bicyclo[2.2.2]octane-2-carboxy1ic acid
1070
Compound 1070 was made in a similar fashion as described above for compounds
946 and 947.
General Scheme 54
54a
Cyanogen Chloride, DMF, 0 °C , (b) Pd(OH)2/Carbon,
H2; 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 'Pr2NEtfTHF 45
-32816260 °C, (c) Na/MeOH, (d) (n-Bu)2SnO, TMSN3, toluene,
110°C.
Formation of benzyl (1S, 3R)-3-cyanocyclohexylcarbamate (54a)
A suspension of benzyl Λ/-[(1 S, 3R)-3-carbamoylcyclohexyl]carbamate, 18d, (0.69 g,
2.50 mmol) in DMF (10 mL) at 0 °C was treated with 2, 4, 6-trichloro-1,3, 5-triazine (0.61 g, 3.29 mmol) and allowed to stir while slowly warming to room température. After 20 minutes, the solution became gold in color. After 1 hour a precipitate had formed. Stirred for an additional 3 hours then quenched with îce water (100 mL) and extracted with CH2CI2 (2x125 mL) then washed with 1N HCl (100 mL). The organic layer was concentrated in vacuo to afford an 730 mg of a residue that was purified using a pad of silica gel (45 mL) using 30% EtOAc/hexanes as eluent to afford 621 mg of a white solid after vacuum drying.
1H NMR (300 MHz, CDCI3) ΠΠ7.45 - 7.30 (m, 5H), 5.09 (s, 2H), 4.67 (s, 1H), 3.49 (s, 1H), 2.66 - 2.32 (m, 2H), 2.16 -1.79 (m, 3H), 1.52 - 1.03 (m, 4H).
Préparation of (1R, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexanecarbonitrile (54b)
Benzyl Λ/-[(1 S, 3R)-3-cyanocyclohexyl]carbamate (0.26 g, 1.02 mmol) was dissolved in THF (15 mL) and treated with 0.13 g of 20% Pearlman's catalyst (50% wet by weight). The suspension was degassed with hydrogen for 2 min then placed under static hydrogen atmosphère. After 135 min, TLC showed no remaining starting material. The suspension was filtered through celite, washed with THF and degassed with nitrogen followed by the addition of 'Pr2NEt (0.21 mL, 1.23 mmol) and
5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3- bjpyridine, 1a, (0.48 g, 1.02 mmol). The mixture was allowed to stir ovemight at 45 °C then concentrated to dryness, absorbed on silica-gel and purified by silica gel chromatography using 0-60% EtOAc/hexanes gradient to afford 293 mg of a white solid.
1H NMR (300 MHz, CDCI3) δ 8.74 (d, J = 2.4 Hz, 1H), 8.49 (s, 1H), 8.39 (d, J = 2.4
Hz, 1H), 8.15-8.05 (m, 3H), 7.37-7.23 (m, 2H), 5.01 (d, J = 6.2 Hz, 1H), 4.13 (s,
1H), 2.75 (d, J =23.0 Hz, 1H), 2.58 (s, 1H), 2.38 (s, 3H), 2.20 (d, 7=9.1 Hz, 2H), 2.03 (d, J = 7.8 Hz, 1 H), 1.78 - 1.43 (m, 4H), 1.26 (s, 1 H).
Préparation of (1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-
4-ylamino)cyclohexanecarbonitrile (54c) (1 R, 3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrimidin-4-yl]amino]cyclohexanecarbonitrile, 54b, (0.29 g, 0.55 mmol) was suspended in MeOH (15 mL) and sodium métal added and the mixture heated at 45 °C. The sodium dissolved in advance of the compound. The mixture was allowed to
-32916260 stir until complété by TLC and LCMS. Concentrated to reduced volume then quenched with 1:1 aqueous saturated NH4CI:water mixture (1 ml) then concentrated to dryness. The residue was diluted with EtOAc and washed with water and brine. The organic layer was concentrated in vacuo to give 0.3 g of a yellow solid that was adsorbed on silica-gel and purified using 40g isco column with the following gradient using 20% MeOH.DCM as the eluent: 0-25%/6 min hold 4 min; 25-50%/4 min hold 9 min to give 146 mg of a white solid. LCMS (10-90% MeOH:water with formic acid).LCMS RT 4.01 ES+ 371, ES- 369.
Préparation of {1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-
4-ylamino)cyclohexanecarboxamide (847)
A sample of (1R, 3S)-3-(2-(5-chloro-1/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-
4-ylamino)cyclohexanecarbonitrîle was treated with 4N HCI/dioxane and heated at 78 °C overnight. Concentrated to dryness then quenched with aqueous saturated sodium bicarbonate and CH2CI2 were added to give a slurry. Filtered and extracted with CH2CI2. The organic phase was dried over Na2SO4 and concentrated in vacuo to give 189 mg of an orange residue that was purified by silica gel chromatography (0-10% MeOH:CH2CI2 gradient) to afford 9.9 mg of a solid: LCMS (10-90% MeOH:water with formic acid): RT 3.79 min ES+ 389.
Préparation of N-((1S, 3R)-3-(1H-tetrazol-5-yl)cyclohexyl)-2-(5-chloro-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (855)
A suspension of dibutyl(oxo)tin (0.016 g, 0.064 mmol) and (1R, 3S)-3-[[2-(5-chloro1/-/-pyrrolo[2l3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-carbonitrile (54c) (0.043 g, 0.107 mmol) in toluene (3 mL) was treated with azido(trimethyl)silane (0.200 mL, 1.507 mmol). The mixture was heated in a sealed tube at 120 °C overnight. The mixture was absorbed onto silica-gel and purified by silica gel chromatography (25-50% gradient of 20%MeOH:DCM containing 0.5% AcOH modifier). The combined fractions were concentrated to dryness to give a residue that was triturated with ether then dried under vacuum at 45 °C to afford 44mg of a yellow solid.
1H NMR (300 MHz, DMSO) δ 12.33 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.41 -8.04 (m, 3H), 7.62 (d, J = 7.4 Hz, 1H), 4.30 (s, 1H), 3.54 - 3.06 (m, 3H), 2.67 - 2.31 (m, 1 H), 2.23- 1.33 (m, 6H).
General Scheme 55
-33016260
hydroxylamine-HCI, EtOH; (b) 5-ethyl-2-methylpyridinium borane, HCl, MeOH; (c) N(oxomethylene)carbamoyl chloride, THF; (d) NaOMe, MeOH.
Formation of (S)-3-(2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanone oxime (55a)
To solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-510 fluoro-pyrimidin-4-yl]amino]cyclohexanone (0.41 g, 0.81 mmol) in EtOH (8.2 mL) was added hydroxylamine hydrochloride (0.11 g, 1.61 mmol). The reaction mixture was stirred at room température overnight. Then the mixture was warmed to 70 °C for 15 min. The reaction mixture was concentrated in vacuo, suspended in EtOAc-DCM, washed with half saturated brine (2 x) and fîltered through a SiO2 plug. The resulting residue was azeotroped with CH3CN (2x) to provide an off white powder which was used without further purification.
-33116260 ’H NMR (300 MHz, MeOD) □ 8.78 (d, J =2.4 Hz, 1H), 8.51 (d, J= 10.8 Hz, 1H),
8.32 (d, J= 2.3 Hz, 1H), 8.10-8.04 (m, 3H), 7.38 (d, J = 8.2 Hz, 2H), 4.29-4.15 (m,
1H), 3.79-3.74 (m, 0.6H), 2.41 (m, 1H), 2.38 (s, 3H), 2.30-2.16 (m, 2H), 2.06-1.84 (m, 4H) and 1.66 -1.59 (m, 2H) ppm; LC/MS (method: m120) R( = 3.90 min, (M+H)
529.44.
Cl
(55b) &
(55c)
2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1 S,3R)-3(hydroxyamino)cyclohexyl)pyrimidin-4-amine (55c) &
2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fl uoro-N-((1S,3S)-3(hydroxyamino)cyclohexyl)pyrimidin-4-amine (55b) :
To a stirred solution of (S)-3-(2-(5-chloro-1-tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexanone oxime (0.20 g, 0.38 mmol) and HCl (0.19 mL of 6 M, 1.134 mmol) in MeOH (10 mL) was added (5-ethyl-2-methyl-pyridinium borane (0.12 mL, 0.76 mmol) at room température. After 30 min, the reaction was quenched with NaHCO3. The mixture was extracted successively with Et2O, EtOAc, CH2CI2 and EtOAc. Each organic portion was washed with brine and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 20-100% EtOAc-hexanes) provided the cis-4 (74 mg) and trans-3 (64 mg) isomers.
2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1 S, 3S)-3(hydroxyamino)cyclohexyl)pyrimidin-4-amine (stereoisomer- 3) 1H NMR (300 MHz, MeOD) □ 8.83 (d, J = 2.4 Hz, 1 H), 8.50 (s, 1 H), 8.33 (d, J = 2.4 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.37 (d, J=8.4 Hz, 1H), 4.24-4.17 (m, 1H), 3.07-3.00 (m, 1H), 2.34 (m, 1H), 2.14-2.08 (m, 1H), 1.93 (t, J = 3.5 Hz, 2H), 1.66 - 1.53 (m, 1H) and 1.44- 1.12 (m, 3H) ppm; LC/MS RT = 3.64 min, (M+H) 531.47.
2-(5-chloro-1-tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3(hydroxyamino)cyclohexyl)pyrimidin-4-amine (stereoisomer - 4) 1H NMR (300 MHz, MeOD) □ 8.84 (d, J = 2.4 Hz, 1 H), 8.53 (s, 1 H), 8.32 (d, J = 2.4 Hz, 1H), 8.07-8.04(m, 1H), 7.37 (d, J=8.2 Hz, 1H), 4.58-4.54 (m, 1H), 3.26-3.23
-33216260 (m, 1 H), 2.38 (s, 3H), 1.98 - 1.83 (m, 4H) and 1.69 - 1.60 (m, 4H) ppm; LC/MS RT =
3.67 min, (M+H) 531.47,
2-((1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)-1,2,4-oxadiazolidine-3,5-dione (796)
To a solution of 2-(5-chloro-1-tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-/V-((1 S, 3R)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine, 55b, (0.072 g, 0.136 mmol) in THF (2 mL) at 0 °C was added N-(oxomethylene)carbamoyl chloride (0.014 mL, 0.176 mmol). A white solid formed immediately. The slurry was shaken and sonicated to make an even suspension/slurry. Then, CH2CI2 (1 mL)) was added to help solvaté the slurry. After 135 min, the mixture was treated with NaOMe (2 mL, 25% w/v). After 2 min, the mixture was quenched with saturated NH4CI and acidified with 1M HCl. The mixture was extracted with EtOAc (3x) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Préparative HPLC provided the desired product (25mg).
1H NMR (300 MHz, MeOD) Π 8.73 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.31 (br s, 1 H), 4.34 (m, 1 H), 2.60 - 2.56 (m, 1H), 2.27 (m, 1 H), 2.08 (m, 3H) and 1.89 - 1.78 (m, 3H) ppm; LC/MS RT = 3.12 min, (M+H) 446.45.
2-((1 S, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)cyclohexyl)-1,2,4-oxadiazolidine-3,5-dione (798) 1H NMR (300 MHz, MeOD) □ 8.67 (s, 1 H), 8.56 (s, 1 H), 8.38 (s, 1 H), 8.31 (br s, 1 H), 4.47 (m, 1H), 4.21 (m, 1H), 2.41 (m, 1 H), 2.22 (m, 1H), 2.10 - 1.90 (m, 3H), 1.72 (m, 2H) and 1.50 (m, 1 H) ppm; LC/MS RT = 3.37 min, (M+H) 446.34.
paraformaldéhyde, methoxyphosphonoyloxymethane, 4A sieves, toluene, 90 °C , (b) NaOMe, MeOH.
Formation of fSj-dimethyl (3-(2-(5-εΐΊΐθΓθ-1-ίθ5νΙ-1Η-ργΓΓθΙο(2,3-^ργι^ΙΐΊ-3-γΙ)-5fluoropyrîmidin-4-ylamino)piperidin-1-yl)methylphosphonate (56a)
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-A/-[(3S)-3piperîdyl]pyrimidin-4-amine, 1c, (2.00 g, 3.99 mmol) in dry toluene was added 4 angstrom molecular sieves and methoxyphosphonoyloxymethane (0.97 g, 0.81 mL, 8.78 mmol).
-33316260
While stirrîng under nitrogen, paraformaldéhyde (0.90 g, 9.98 mmol) was added portionwise. The mixture was heated at 90 °C for 90 minutes. The reaction was cooled to room température, diluted with aqueous saturated NaHCO3 solution, extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 0-10% MeOH/CH2CI2 gradient to afford 2.0 g of desired product. LCMS RT = 4.47 (M+H) 623.3.
Formation of (S)-dimethyl (3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)piperidin-1-yl)methylphosphonate (690)
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-N-[(3S)-1 (dimethoxyphosphorylmethyl)-3-piperîdyl]-5-fluoro-pyrimidin-4-amine, 56a, (1.00 g, 1.61 mmol) in MeOH (40 mL) was added sodium methanolate (20 mL of 25 %w/v, 92.55 mmol) and the reaction mixture was stirred at room température for 30 minutes. Ail volatiles were removed at reduced pressure and the resulting residue was diluted with aqueous saturated NH4CI solution and extracted twice with CH2CI2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography using 0-10% MeOH:CH2CI2 gradient to provide 270 mg of a white solid.
1H NMR (300.0 MHz, DMSO) □ 12.33 (s, 1H), 8.70 (d, 7 = 2.4 Hz, 1H), 8.28 (d, 7 = 2.4 Hz, 1H), 8.20 (d, 7=2.6 Hz, 1H), 8.17 (d, 7 = 4.0 Hz, 1H), 7.35 (d, 7 = 7.8 Hz, 1H), 4.27 - 4.17 (m, 1H), 3.67 (s, 3H), 3.64 (s, 3H), 3.21 - 3.16 (m, 1H), 2.96-2.90 (m, 3H), 2.33-2.20 (m, 2H), 1.99- 1.94 (m, 1H), 1.80- 1.60 (m, 2H) and 1.47-1.35 (m, 1H) ppm; LCMS RT = 3.84 (M+1) 469.47.
General Scheme 57
NH
pyrazole-1-carboxamidine hydrochloride, 'Pr2NEt, 4A sieves, toluene, 90 °C (b) NaOMe, MeOH.
Formation of ((S)-3-(2-(5-chforo-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimÎdin-4-ylamîno)piperidine-1 -carboximidamide (57a)
To a solution of pyrazole-1-carboxamîdine hydrochloride (0.12 g, 0.80 mmol) and 2[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3piperidyl]pyrimidin-4-amîne, 1c, (0.40 g, 0.80 mmol) in DMF (0.9 mL) was added ’Pr2NEt (0.14 mL, 0.80 mmol). The reaction mixture was stirred at room température for 4 hours. The mixture was diluted into water, filtered, washed with additional water, then ether. The filtrate was concentrated in vacuo. The resulting residue was
-33416260 purified by silica gel chromatography using 5-20% MeOH/CH2CI2 gradient (product elutes with 20% MeOH) to afford 190 mg of the desired product.
1H NMR (300 MHz, DMSO) il 8.73 (d, J = 2.2 Hz, 1H), 8.50 - 8.45 (m, 2H), 8.33 (d, J = 3.7 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7.0 Hz, 1H), 7.53 - 7.42 (m, J = 9.0 Hz, 6H), 3.87 (d, J = 13.6 Hz, 1 H), 3.17 (d, J = 5.2 Hz, 1H), 3.03 (q, J = 10.9 Hz, 2H), 2.36 (s, 3H), 2.11 (d, J = 9.9 Hz, 1H), 1.90 (d, J = 12.6 Hz, 1H), 1.68 (dd, J = 24.5, 13.9 Hz, 2H); LCMS RT = 3.07 (M+1) 543.34.
Formation of (S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrîmidin-4ylamino)piperidine-1-carboximidamide(881)
To a solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxamidîne, 57b, (0.18 g, 0.32 mmol) in MeOH (5 mL) was added sodium methanolate (3 mL of 25 %w/v, 13.88 mmol) and the reaction was stirred at room température. After 5 min, the mixture was concentrated in vacuo to light yellow solid. The crude residue was purified via preparatory HPLC (MeOH/1% aqueous HCl) to afford the desired product.
1H NMR (300 MHz, DMSO) □ 12.79 (s, 1H), 8.77 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 7.52 (s, 3H), 4.29 (s, 1H), 4.08 (d, J = 12.6 Hz, 1H), 3.90 (d, J= 13.7 Hz, 1H), 3.16-2.95 (m, 2H), 2.17 (d, J = 9.7 Hz, 1H), 1.92 (d, J = 8.5 Hz, 1H), 1.81 -1.57 (m, 2H); LCMS RT = 2.03 (M+1) 389.27.
General Scheme 58
3-bromoprop-1-ene, Zn dust, DMF (b) 5-chloro-3(4,4l5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl1 H-pyrrolo[2,3-b]pyridine, Pd(Ph3P)4, Na2CO3, acetonitrile, water, 120 °C, microwave, (c) OsO4, pyridine, 4-methylmorpholine-N-oxide, tert-butanol, water, THF, 120 °C (d) NaOMe, MeOH.
Formation of (3S)-1-allyl-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanol (58a)
-33516260
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (0.60 g, 2.46 mmol) and 3-bromoprop-1-ene (0.43 mL, 4.92 mmol) in DMF was added Zn dust (0.32 g, 4.92 mmol). Thè reaction was stirred at room température for 3 days. The mixture was diluted into aqueous saturated NH4CI solution, extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using 0-50% EtOAc/hexanes gradient to afford 553 mg of desired product, 58a, as an oil. LC/MS - two peaks corresponding to two diastereomeric products: 286.4 (M+H), RT = 3.41 and 3.78.
Formation of (1 R, 3S)-1-allyl-3-(2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)cyclohexanol and (1R, 3S)-1-allyl-3-(2-(5-chloro-1 -tosyl-1 Hpyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanol (58b and 58c)
In a microwave tube was placed 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.57 g, 1.32 mmol) and (3S)-1 -allyl-3{(2-chloro-5-fluoro-pyrimidin-4-y!)amino]cyclohexanol, 58a, (0.32 g, 1.10 mmol) in acetonitrile (12 mL) and Na2CO3 (1.65 mL of 2 M aqueous solution, 3.31 mmol). The mixture was deoxygenated with nitrogen for 15 min. To the mixture was added tetrakis triphenyl phosphine palladium (0) (0.03 g, 0.02 mmol). The reaction was sealed and heated to 120 °C for 20 min. The mixture was diluted with brine, extracted twice with CH2CI2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography using a 10-60% EtOAc/hexanes gradient to afford two diastereomers:
Diastereomer 1 (more polar spot - 58c): LCMS RT = 4.45 min, (M+H) = 556.48 Diastereomer 2 (less polar spot - 58b): LCMS RT = 4.48 min (M+H) = 556.48 Formation of 3-((1 R, 3S)-3-(2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)propane-1,2-diol (58d)
To a solution of (3S)-1 -allyl-3-[[2-[5-chloro-1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanol, 58c, (0.30 g, 0.54 mmol) in 2-methyl2-propanol (9.23 mL), THF (3.69 mL) and water (1.85 mL) was added pyridine (0.09 mL, 1.08 mmol) and osmium tetroxide (0.27 mL of 2.5 %w/v, 0.03 mmol) and 4methylmorpholine N-oxide (0.07 mL, 0.65 mmol). The reaction mixture was heated to 80 °C for 20 hours. After cooling to room température, the mixture was diluted into aqueous saturated sodium bisulfite solution and extracted twice with 20% isopropanol/CH2CI2. The combined organic phases were washed with more aqueous saturated sodium bisulfite solution, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography
-33616260 using 5-10% MeOH/CH2CI2 gradient to afford 175 mg of the desired product as a racemic mixture, 58d.
1H NMR (d6-DMSO) □ 8.77 (t, J = 2.6 Hz, 1 H), 8.48 (d, J = 2.4 Hz, 1 H), 8.42 (d, J = 6.0 Hz, 1H), 8.25 - 8.23 (m, 1H), 8.07 (d, J = 7.4 Hz, 2H), 7.74 (dd, J = 7.6, 13.5 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 4.97 (d, J = 12.8 Hz, 1H), 4.76-4.72 (m, 1H), 4.544.51 (m, 1H), 4.31 (m, 1H), 3.83 (m, 1H), 2.36 (s, 3H), 1.99 - 1.91 (m, 2H), 1.77 1.63 (m, 4H) and 1.57 -1.46 (m, 4H) ppm; LCMS RT = 4.31 (M+H) 590.5.
Formation of 3-((1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)propane-1,2-diol (718)
To a solution of 3-((1R, 3S)-3-(2-(5-chloro-1-tosyl-1/7-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)propane-1,2-diol, 58d, (0.11 g, 0.18 mmol) in MeOH (5 mL) was added sodium methanolate (2 mL of 25 %w/v solution,
9.26 mmol) and the reaction mixture was stirred at room température. After 20 min, the reaction mixture was diluted with aqueous saturated NH4CI solution and extracted twice with 20% IPA/CH2CI2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification via silica gel chromatography using 5-20% MeOH: CH2CI2 gradient to afford 56 mg of a white solid.
1H NMR (300 MHz, d6-DMSO) Π 12.29 (s, 1H), 8.71 (t, J = 2.3 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 2.8, 4.5 Hz, 1H), 8.15 (t, J = 3.7 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.77 (dd, J = 3.8, 10.5 Hz, 1H), 4.54 (t, J = 5.6 Hz, 1H), 4.32 (m, 1H), 3.86 (m, 1H), 2.00 - 1.97 (m, 2H), 1.82 - 1.63 (m, 4H) and 1.59 1.45 (m, 4H) ppm; LCMS RT = 3.71 (M+1) 436.48.
General Scheme 59
benzyloxyphosphonoyloxymethylbenzene, triethylamine, 95 °C, microwave, (b) NaOMe, MeOH.
-33716260
Formation of dibenzyl (1 S, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimid!n-4-ylannino)-1-hydroxycyclohexyl phosphonate and dibenzyl (1R, 3S)3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-y1)-5-fluoropyrimidin-4-ylamino)-’lhydroxycyclohexylphosphonate (59a and 59b)
To a solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5fluoro-pyrimidin-4-yl]amino]cyclohexanone, 28a, (0.40 g, 0.78 mmol) in benzyloxyphosphonoyloxymethylbenzene (2.58 mL, 11.67 mmol) was added triethylamîne (0.22 mL, 1.56 mmol). The reaction mixture was heated to 95 °C for 15 hours. The mixture was diluted with aqueous saturated NaHC03 solution, extracted with EtOAc, washed again with aqueous saturated NaHC03 solution. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to white solid. The crude product was purified via silica gel chromatography using 0-10% MeOH/CH2CI2 gradient to afford 518 mg of a mixture of diastereomers, which contains somebenzyloxyphosphonoylmethylbenzene. The mixture was used without further purification in the next step. LCMS RT = 4.6 (M+H) 776.32.
Formation of dimethyl (1S, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-hydroxycyclohexylphosphonate and dimethyl (1 R, 3S)3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1hydroxycyclohexylphosphonate (741, 742)
To a solution of (1R, 3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-
5-fluoro-pyrimidin-4-yl]amino]-1-dibenzyloxyphosphoryl-cyc)ohexanol and (1S, 3S)-3[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4yl]amino]-1-dibenzyloxy in MeOH was added sodium methanolate and the reaction was stirred at room température. After 15 min, the reaction mixture was diluted with aqueous saturated NH4CI solution and extracted twice with 20% IPA/CH2CI2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography using 0-5% MeOH.'CH2CI2 to elute impurity, 5%-10% to elute bottom two spots.
Diastereomer 1 [741]: 1H NMR (300 MHz, DMSO) Π 12.32 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H),
8.27 (d, J= 2.4 Hz, 1H), 8.26 (d, 4= 2.8 Hz, 1H), 8.18 (d, J = 3.9 Hz, 1 H), 7.34 (d, 4 = 7.1 Hz, 1H), 5.77 (d, 4 = 2.9 Hz, 1H), 4.60 (s. 1H), 3.73 (dd, J= 10.1,6.3 Hz, 6H), 2.30-2.15 (m, 1H), 2.04- 1.86 (m, 1H), 1.85- 1.50 (m, 6H); LCMS RT = 3.82 (M+1) 470.5.
Diastereomer 2 [742]: 1H NMR (300 MHz, DMSO) □ 12.30 (s, 1H), 8.75 (d, 4 = 2.4 Hz, 1H),
8.27 (d, 4 = 2.4 Hz, 1H), 8.18 (d, J = 2.8 Hz, 1H), 8.14 (d, 4 = 4.0 Hz, 1H), 7.44 (d, 4= 7.7 Hz, 1H), 5.38 (s, 1 H), 4.55-4.36 (m, 1 H), 3.71 (d, 4 = 3.1 Hz, 3H), 3.68 (d, 4=3.2 Hz, 3H), 2.16-2.01 (m, 2H), 2.00- 1.72 (m, 3H), 1.71 -1.41 (m, 2H), 1.39- 1.18 (m, 1H); LCMS RT = 3.70 (M+1) 470.5.
-33816260
29b
60a 60b
Formation of Ethyl 2-((1 R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoate (60a)
Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N2. THF (8.0 mL) was added, then a solution of chloro(trimethyl)silane (0.63 mL, 4.93 mmol) in THF (8.0 mL) was added and stirred for 15 min at room température then heated to reflux. After cooling to room température, a solution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly to the zinc mixture. Then, a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (2.00 g, 8.21 mmol) in THF (6.0 mL) was added. The mixture was refluxed for 2 hours then concentrated in vacuo. EtOAc and aqueous saturated NaHCO3 solution were added and the product was extracted with additional EtOAc (3x), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (Hexanes:EtOAc) separated 2 products. The first peak was 60a (2.05 g, 6.18 mmol, 75%). LCMS+: 332.20 at 3.57 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of Ethyl 2-((1R, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoate (60c)
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)pyrrolo[2,3-b]pyridine (0.31 g, 0.72 mmol) in acetonitrile (6.0 mL) was added
-33916260 ethyl 2-((1 R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1 -hydroxycyclohexyl)ethanoate, 60a, (0.20 g, 0.60 mmol) and degassed under N2. Na2CO3 (0.90 mL of 2 M, 1.81 mmol) was added followed by Pd(PPh3)4 (0.10 g, 0.09 mmol). The reaction was sealed and microwaved at 120 °C for 30 min. The material was concentrated under reduced pressure then diluted in EtOAc and aqueous saturated NaHCO3, then extracted with additional EtOAc (3x), dried (Na2SO4) and concentrated in vacuo. The material was diluted in DCM and silica gel chromatography (Hexanes: EtOAc) gave 217 mg of product 60c. LC MS+: 602.49 at 4.62 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of 2-((1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoic acid (60d)
To a solution of ethyl 2-((1R, 3S)-3-(2-(5-chloro-1-tosyl-1/-/-pyrrolo[2,3-b]pyridin-3-yl)-
5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoate, 60c, (0.14 g, 0.22 mmol) in THF (5.0 mL) was added LiOH (1.12 mL of 1 M aqueous solution, 1.12 mmol). The reaction was microwaved at 130 ’ C for 30 min, neutralized with HCl (0.56 mL of 2 M, 1.12 mmol) and concentrated under reduced pressure, diluted in toluene and concentrated (2x) to give 60d which was used without further purification. LC MS+: 420.30 at 3.05 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of 2-((1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo(2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)-N-methylethanamide (751)
To a solution of 2-((1 R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoic acid, 60d, (0.032 g, 0.076 mmol) in MeCN (1.6 mL) and DMF (1.6 mL) was added HATU (0.058 g, 0.152 mmol), Methanamine (0.154 mL of 2 M solution, 0.305 mmol) and 'Pr2NEt (0.053 mL, 0.305 mmol). The réaction was heated to 60 °C overnight then concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Water/HCI.MeOH). Pure fractions were combined and concentrated in vacuo to give 29 mg of 751 as the HCl sait.
General Scheme 61
-34016260
Formation of Ethyl 2-((1S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1hydroxycyclohexy!)propanoate (61b). (Step A):
Zinc dust (1.21 g, 18.47 mmol, 3 eq.) was heated with a heat gun under N2. THF (6.0 mL) was added then a solution of chloro(trimethyl)silane (0.47 mL, 3.69 mmol) in THF (6.0 mL) was added and stirred for 15 min at room température then heated to reflux and cooled. A solution of ethyl 2-bromopropanoate (3.34 g, 18.47 mmol) and (3S)-3-[(2-chloro-5-fluoro-pyrimîdin-4-yl)amino]cyclohexanone (61a) (1.50 g, 6.16 mmol) in THF (6.0 mL) was added to the zinc mixture slowly. This mixture was refluxed for 2 hours then concentrated in vacuo. EtOAc and aqueous saturated NaHCO3 were added and the product was extracted with EtOAc (3x), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (Hexanes:EtOAc) separated 2 products. The first product eluted at 20-35% ethyl acetate and second product eluted at 35-40%. The fractions of the 2nd product were concentrated in vacuo to give 760 mg of 61b. LCMS+: 346.23 at 3.35 min (10-90% MeOH, 3/5 grad/run, FormicAcid).
Formation of Ethyl 2-((1 S, 3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)propanoate (61c).
To a solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)pyrrolo[2,3-b]pyridine (0.21 g, 0.38 mmol) in acetonitrile (3.6 mL) was added ethyl 2-((1 S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1 -hydroxycyclohexyl)propanoate (61b) (0.12 g, 0.35 mmol) and degassed under N2. Na2CO3 (0.52 mL of 2 M aqueous solution, 1.041 mmol) was added followed by Pd(PPh3)4 (0.06 g, 0.052 mmol). The reaction was sealed and heated in a microwave at 120 DC for 30 min. The material was concentrated under reduced pressure and then diluted in EtOAc and aqueous saturated NaHCO3, then extracted with additional EtOAc (3x). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The material was diluted in CH2CI2 and silica gel chromatography (Hexanes:EtOAc) gave
-34116260 product 200 mg of 61c. LCMS+: 600.35 at 4.22 min (10-90% MeOH, 3/5 grad/run,
Formic Acid).
Formation of 2-((1 S, 3S)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin4-ylamino)-1-hydroxycyclohexyl)propanoic acid (61 d).
To a solution of ethyl 2-((1 S, 3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)propanoate (61c) (0.20 g, 0.33 mmol) in THF (3 mL) was added LiOH (3 mL of 1 M aqueous solution, 3.0 mmol). The reaction was allowed to stir over 2 days at room température then neutralized with HCl (1.5 mL of 2M, 3.0 mmol) and concentrated to dryness, diluted in toluene and concentrated again (2x) to give 61d which was used without further purification. LCMS+: 418,32 at 2.62 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of (4P, 5S, 7S)-7-(5-fluoro-2-(5-fluoro-1H-pyrroIo[2,3-b]pyridin-3yl)pyrimidin-4-ylamino)-4-methyl-1-oxa-3-azaspiro[4.5]decan-2-one (967).
To a solution of 2-[(1S, 3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3yl)pyrimidin-4-yl]amino]-1-hydroxy-cyclohexyl]propanoic acid (61 d) (0Ό95 g, 0.228 mmol) in toluene (5 mL) and triethylamine (0.048 mL, 0.341 mmol) was added (azido(phenoxy)phosphoryl)oxybenzene (0.059 mL, 0.273 mmol). The reaction was heated to 120 °C in a sealed tube overnight. The reaction was concentrated in vacuo and purified by reverse phase HPLC (Water/HCI:MeOH) to separate the diastereomers. To remove a trace amount of leftover starting material, the first peak was diluted in MeOH (1 mL) and passed through a PL-HCO3 MP SPE cartridge to obtain the free base. This material was then salted (HCl in water) and concentrated in vacuo to give 16 mg of 967 as the HCl sait.
General Scheme 62
OE( b
Cl b
,0 ci
OEt c
Cl
Cl
Ts
Formation of (S)-ethyl 2-(3-(2-chloro-5-fluoropyrimidin-4ylamino)cyclohexylidene)ethanoate (62a).
-34216260
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (29b) (2.00 g, 8.21 mmol) in toluene (40 mL) was added ethyl 2triphenylphosphoranylideneacetate (4.29 g, 12.31 mmol). The reaction was refluxed overnight then concentrated in vacuo and purified by silica gel chromatography (Hexanes:EtOAc). The desired product eluted at 15% ethyl acetate. Clean fractions were combined and concentrated to give 2.57 g of 62a. LCMS+: 314.18 at 3.75 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of Ethyl 2-((3S)-3-(2-chloro-5-fluoropyrimidin-4-y1amino)-1(nitromethyl)cyclohexyl)ethanoate (62b)
To a solution of (S)-ethyl 2-(3-(2-chloro-5-fluoropyrimidin-4ylamino)cyclohexylidene)ethanoate, 62a, (2.58 g, 8.22 mmol) in nitromethane (44.53 mL, 822.3 mmol) was added 1,1,3,3-tetramethylguanîdine (1.55 mL, 12.33 mmol). The reaction was refluxed overnight then concentrated in vacuo and purified by silica gel chromatography (Hexanes:EtOAc) then a second chromatography (CH2CI2:20% MeOH in CH2CI2). Fractions contaîning pure product were combined and concentrated to give 1.8 g of 62b LCMS+: 375.32 at 3.64 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of (7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3one (62c)
To a solution of ethyl 2-((3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1(nitromethyl)cyclohexyl)ethanoate, 62b, (1.60 g, 4.27 mmol) in MeOH (20 mL) was added Raney Nickel (0.03 g, 0.43 mmol). The reaction was shaken on a Parr apparatus at 40 psi of H2 overnight. The reaction was filtered, concentrated in vacuo and purified by silica gel chromatography (CH2CI2:20% MeOH in CH2CI2) to give 155 mg of 62c. LCMS+: 299.13 at 2.87 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of (7S)-7-(2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-ylamino)-2-azaspiro[4.51decan-3-one (62d).
To a solution of 5-chloro-1-(p-tolylsuifony 1)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)pyrrolo[2,3-b]pyrîdine (0.083 g, 0.195 mmol) in acetonitrile (1.6 mL) was added (7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one (62c) (0.053 g, 0.177 mmol) and degassed under N2. Aqueous Na2CO3 (0.266 mL of 2 M solution, 0.5320 mmol) was added followed by Pd(PPh3)4 (0.031 g, 0.027 mmol). The reaction was sealed and heated in a microwave at 120 °C for 30 min then concentrated in vacuo. The material was diluted in CH2CI2 and silica gel chromatography using a gradient of Hexanes:EtOAc then 20% MeOH in CH2CI2. Pure fractions were combined and concentrated to give 91 mg of 62d. LCMS+: 569.26 at 4.20 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of (7S)-7-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-34316260 ylamino)-2-azaspiro[4.5]decan-3-one (969).
To a solution of (7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan3-one, 62d, (0.091 g, 0.159 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25 %w/v, 9.255 mmol). The reaction was stirred for 0.5 hours then concentrated in vacuo. The material was purified by reverse phase HPLC (Water/HCI.MeOH) to give a mixture of diastereomers. The fractions containing pure product were combined and concentrated to give 50 mg of the HCl sait of 969.
General Scheme 63
Formation of ethyl 2-((1 S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1bydroxycyclohexyl)ethanoate (63a)
Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under hl2. THF (8.0 mL) was added, then a solution of chloro(trimethyl)silane (0.63 mL, 4.93 mmol) în THF (8.0 mL) was added and stirred for 15 min at room température then heated to reflux and cooled. A solution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly to the zinc mixture, then a solution of (3S)-3-[(2-chloro-5fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (2.00 g, 8.21 mmol) in THF (6.0 mL) was added. The mixture was refluxed for 2 hours then concentrated in vacuo. EtOAc and aqueous saturated NaHCO3 solution were added and the product was extracted with additional EtOAc (3x), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (Hexanes: EtOAc) separated 2 products. Fractions containing the second (minor) peak were combined and concentrated to give 470 mg of 63a. LCMS+: 332.13 at 3.2 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of (5S, 7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-oxa-3azaspiro[4.5]decan-2-one (63b).
To a solution of ethyl 2-((1 S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1hydroxycyclohexyl)ethanoate, 63a, (0.40 g, 1.20 mmol) in dry MeOH (6 mL) was added hydrazine (0.75 mL, 23.4 mmol). The reaction was stirred overnight at room
-34416260 température then concentrated under a stream of N2. The reaction was diluted with HCl (20 mL of a 1M solution, 20 mmol) until acidic and cooled to 0° - 5° C. Then NaNO2 (1.44 mL of a 1M solution, 1.44 mmol) was added slowly. 1:1 Benzene:CHCI3 (20 mL) was added and the mixture was stirred. The organic layer was separated and added slowly to refluxing benzene. This was refluxed for 0.5h then concentrated. Silica gel chromatography (CH2Cl2:20% MeOH in CHZCI2) gave 92 mg of pure product 63b. LCMS+: 301.15 at 2.76 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of (5S, 7S)-7-(2-chloro-5-fluoropyrimÎdin-4-ylamino)-3-methyl-1-oxa-3azaspiro[4.5]decan-2-one (63c)
A solution of (5S, 9S)-9-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-1-oxa-3azaspiro[4.5]decan-2-one, 63b, (0.049 g, 0.163 mmol) in DMF (8.2 mL) was cooled to 0 °C. NaH (0.010 mg, 0.244 mmol) was added followed by Mel (0.011 mL, 0.179 mmol). The reaction was allowed to warm to room température ovemight. The reaction was quenched with water and concentrated in vacuo. Aqueous saturated NaHCO3 solution was added and the product was extracted with EtOAc (3x), washed with brine, dried (Na2SO4) and concentrated in vacuo. The material was purified using silica gel chromatography (CH2CI2:20% MeOH in CH2CI2) to give 63b. LCMS+: 315.19 at 2.83 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Formation of (5S,7S)-7-(2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]py ridin-3-y l)-5fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one (63d)
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)pyrrolo[2,3-b]pyridine (0.031 g, 0.0724 mmol) in acetonitrile (0.570 mL) was added (5S, 7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-methyl-1 -oxa-3azaspiro[4.5]decan-2-one, 63c, (0.019 g, 0.060 mmol) and degassed under N2. Na2CO3 (0.091 mL of 2 M, 0.1810 mmol) was added followed by Pd(PPh3)4 (0.010 g, 0.009 mmol). The réaction was sealed and heated in a microwave at 120 ’C for 30 min. The mixture was then concentrated in vacuo. The material was diluted in CH2CI2 and silica gel chromatography (Hexanes:EtOAc then 20% MeOH in CH2CI2) gave product 63d. LCMS+: 585.25 at 4.17 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
(5S,7S)-7-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-3methyl-1-oxa-3-azaspiro[4.5]decan-2-one (971)
To a solution of (5S, 7S)-7-(2-(5-chloro-1-tosyl-1/7-pyrro)o[2,3-b]pyridin-3-y))-5fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one, 63d, (0.035 g, 0.060 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25 %w/v, 9.255 mmol). The mixture was stirred for 30 min then concentrated in vacuo and purified by
-34516260 reverse phase HPLC (Water/HCI:MeOH). Pure fractions were combined and concentrated in vacuo to afford product 971 as the HCl sait.
General Scheme 64
Formation of (3S)-3-[[2-[5-chloro-1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrimidin-4-yl]amino]cyclohexanone (64a)
A microwave tube was placed 5-chloro-1-(p-tolylsulfonyl)-3-(4,4l5,5-tetramethyl· 1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (2.13 g, 4.93 mmol) and (3S)-3-[(2chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone in DME (22.2 mL) and aqueous Na2CO3 (5.13 mL of 2 M solution, 10.26 mmol) solution. The mixture was deoxygenated with nitrogen for 20 min. To the reaction mixture was added tetrakis triphenylphosphane palladium (0.47 g, 0.41 mmol). The reaction was sealed and heated to 120 °C for 30 min. The reaction was diluted with ethyl acetate (40 mL), filtered through Celite. The filtrate was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification via silica gel chromatography using 10-80% EtOAc/ hexanes gradient afforded (3S)-3-[[2-[5-chloro-1 -(p-tolylsulfonyl)pyrrolo[2,3b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 64a.
Formation of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfony l)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrimidin-4-yl]amino]-1-trimethylsilyloxy-cyclohexanecarbonitrile (64b)
To a solution of (3S)-3-[[2-[5-ch)oro-1 -{p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5fluoro-pyrîmidin-4-yl]amino]cyclohexanone, 64a, (0.58 g, 1.13 mmol) in CH2CI2 (20 mL) was added diiodozinc (0.36 g, 1.13 mmol) and trimethylsilylformonîtrile (0.30 mL, 2.26 mmol) at room température. The reaction was refluxed overnight. The mixture was purified by silica gel chromatography to afford 600 mg of (3S)-3-[[2-[5chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1trimethyl-silyloxy-cyclohexanecarbonitrile, 64b.
Formation of (1S, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-
4-yl]amino]-1-hydroxy-cyclohexanecarboxylic acid (64c)
-34616260 (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-ylj-5-fluoro-pyrimidin-4yl]amino]-1-trimethylsilyloxy-cyclohexanecarbonitrile, 64b, (0.57 g, 0.93 mmol) was heated in HCl (20 mL of 12 M solution, 240.0 mmol) at 80 °C in a sealed tube overnight. The solvent was evaporated and the crude product was purified by preparatory HPLC to provide 200 mg of (1S, 3S)-3-([2-(5-chloro-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1 -hydroxy-cyclohexanecarboxylic acid, 64c.
1H NMR (300 MHz, MeOD) Cl 8.70 (d, J= 2.2 Hz, 1H), 8.47 (s, 1H), 8.37 (d, J = 2.2 Hz, 1 H), 8.28 (d, J = 5.5 Hz, 1 H), 5.37 - 4.57 (m, 49H), 3.38 - 3.26 (m, 26H), 2.42 (dd, J= 13.3, 4.2 Hz, 2H), 2.15 (d,J= 10.4 Hz, 1H), 2.07 - 1.87 (m, 3H), 1.77 (dd, J = 18.1, 8.6 Hz, 3H); LCMS: 406.35 (M+1).
Formation of (1S, 3S)-3-[[2-(5-chloro-1M-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-
4-yl]amino]-N-ethyl-1 -hydroxy-cyclohexanecarboxamide (779) (1S, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]1-hydroxy-cyclohexanecarboxylic acid, 64c, (0.040 g, 0.090 mmol) was dissolved in DMF (3 mL), then 'Pr2NEt (0.047 mL, 0.271 mmol) and ethanamine (0.135 mL of 2 M solution, 0.271 mmol) was added, followed by HATU (0.080 g, 0.210 mmol). The reaction was stirred at room température for another 2 hours. The solution was evaporated and the product was purified by Preparatory HPLC to afford 10 mg of (1 S, 3S)-3-[[2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]A/-ethyI-1 -hydroxy-cyclohexanecarboxamide, 779.
1H NMR (300 MHz, MeOD) d 8.72 (d, J = 2.2 Hz, 2H), 8.48 (s, 2H), 8.34 (dd, J = 23.7, 3.9 Hz, 3H), 4.99 (d, J = 5.4 Hz, 3H), 4.88 (s, 1 H), 4.85 - 4.67 (m, 32H), 3.44 2.95 (m, 4H), 2.29 (dd, J = 13.5, 4.1 Hz, 3H), 2.11 (d, J = 9.5 Hz, 2H), 2.04- 1.80 (m, 7H), 1.76 (s, 3H), 1.13 (t, J = 7.2 Hz, 4H); LCMS: 433.42 (M+1).
General Scheme 65
-34716260
Formation of 3-amino-2-hydroxy-cyclohexanecarboxylic acid (65a)
2- Hydroxy-3-nitro-benzoic acid (5.0 g, 27.3 mmol) was mixed with HCl (125 mL of 0.5 M, 62.5 mmol) and dioxoplatinum (1.0 g, 4.4 mmol) in a hydrogénation bottle. The mixture was placed on a Parr shaker (50 psi H2) for 24 hours. The catalyst was filtered and washed with hot H2O. The filtrate was evaporated to provide 3-amino-2hydroxy-cyclohexanecarboxylic acid as a mixture of stereoisomers which was utilized to the next step without further purification.
Formation of 3-[[2-[5-chloro-1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylic acid (65b)
5-chloro-3-{5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3b]pyridine, 65a, (0.30 g, 0.64 mmol), 3-amino-2-hydroxy-cyclohexanecarboxylic acid (0.19 g, 0.97 mmol), 'Pr2NEt (0.45 mL, 2.58 mmol) in DMF (23.2 mL) solution was heated in microwave at 130 °C for 10 min. The solvent of the reaction mixture was removed under reduced pressure and the residue was purified by preparatory HPLC to give 240 mg of 3-[(2-[5-chloro-1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylic acid, 65b, as a mixture of stereoisomers.
Formation of 3-[[2-[5-chloro-1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrÎmidin-4-yl]amino]-/V-ethyl-2-hydroxy-cyclohexanecarboxamide (65c)
3- [[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4yl]amino]-2-hydroxy-cyclohexanecarboxylic acid, 65b, (0.100 g, 0.179 mmol) was dissolved in DMF (2 mL) and 'Pr2NEt (0.124 mL, 0.714 mmol) and ethanamine hydrochloride (0.029 g, 0.357 mmol) was added at room température. Then HATU (0.081 g, 0.214 mmol) was added to the solution at room température. After 30 min, EtOAc was added and the mixture was washed with 1 N HCl, aqueous saturated NH4CI solution, and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used in the next step without further purification.
Formation of 3-[[2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4yl]amino]-N-ethyl-2-hydroxy-cyclohexanecarboxamide (815)
3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4yl]amino]-N-ethyl-2-hydroxy-cyclohexanecarboxamide, 65c, was treated with NaOMe in MeOH. The product was purified by preparatory HPLC to provide 3-[[2-(5-chloro1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-N-ethyl-2-hydroxycyclohexanecarboxamide as a mixture of stereoisomers. LCMS: 433.35 (M+1).
General Scheme 66
-34816260
CO;Me
Ο
66a 66b
d
Cl 66 e
Formation of Methyl-1-methylcyclohex-2-ene-1 -carboxylate (66a)
To a cold (0 °C) solution of freshly distilled A/-isopropylpropan-2-amine (4.20 mL, 29.96 mmol) in THF (150 mL) under argon was added dropwise nBuLi (12.65 mL of 2.2 M solution, 27.82 mmol). After 15 min the solution was cooled to -78 °C and dry HMPA (4.84 mL, 27.82 mmol) was added. The mixture was stirred for 30 min at -78 °C and methyl cyclohexene-1-carboxylate (3.00 g, 21.40 mmol) was then added. After stirring an additional 10 min, methyl iodide (2.00 mL, 32.10 mmol) was added.
The solution was then allowed to warm to -5 °C over 2 h. An aqueous saturated solution of NH4CI was poured into the orange mixture. After dilution with hexanes and washing with brine, the organic layer was dried over Na2SO4 and carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification.
1H NMR (300 MHz, CDCI3) Π 5.77 (dt, J= 10.1, 3.5 Hz, 1 H), 5.66 (s, 1H), 3.71 3.58 (m, 3H), 2.16 (ddd, J= 12.9, 7.0, 3.4 Hz, 1H), 2.03- 1.88 (m, 2H), 1.72-1.53 (m, 2H), 1.49 - 1.37 (m, 1H), 1.32 -1.14 (m, 3H).
Formation of racemic c/s-methyl 5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate (66b)
Methyl 1-methylcyclohex-2-ene-1 -carboxylate, 66a, (3.30 g, 21.40 mmol) was treated with 3-chloroperoxybenzoic acid (7.39 g, 42.80 mmol) in CH2CI2 (75 mL) at room température for 2 hours. The solution was clear but white precipitate was observed after 1 hour. The resulting white solid was filtered and washed with hexanes, and the filtration was diluted with EtOAc and washed with aqueous saturated NaHCO3 solution followed by brine. The organic phase was then dried over Na2SO4, concentrated in vacuo and the crude residue was purified by silica gel chromatography (Hexanes/Ethyl acetate 100/0 to 10/1 gradient) to provide two products. The less polar spot is a colorless oil, which is assigned by 1H NMR to be c/s-methyl 5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate (1.2 g) and the second fraction is a white solid, which is trans-methyl -5-methyl-7-oxabicyclo[4.1.0]heptane-
5-carboxylate (2.2 g).
-34916260
Racemic cis-isomer (66b): 1H NMR (300 MHz, CDCI3) δ 3.67 (d, J = 4.3 Hz, 3H),
3.23-3.12 (m, 1H), 3.08 (d, J = 3.8 Hz, 1H), 2.02- 1.78 (m, 2H), 1.68 (dtd, J =9.7,
6.8, 3.2 Hz, 1H), 1.49-1.27 (m, 2H), 1.25- 1.15 (m, 3H), 1.06 (ddd, J = 9.1,7.4, 3.2
Hz, 1H).
Formation of racemic methyl -3-azrdo-2-hydroxy-1-methyl-cyclohexanecarboxylate (66c)
Racemic σ/δΊΤ)βίΐΊγΙ-5-ΓηθΙΐΊγΙ-7-οχ3ΝογοΙο[4.1.0]ΐΊθρί3ηθ-5-ο3^)θχγΐ3ίβ, 66b, (2.2 g, 12.93 mmol) was added to a flask containing MeOH (90 mL) and H2O (10 mL) under nitrogen atmosphère. NH4CI (1.38 g, 0.90 mL, 25.86 mmol) and NaN3 (2.52 g, 38.79 mmol) were then added to the reaction mixture. The mixture was heated to reflux for 16 hours. The solvent was evaporated under reduced pressure and the oil was taken up in H2O and extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. The crude product was purified by silica gel chromatography to afford 900 mg of racemic methyl-3-azido-2-hydroxy-1-methylcyclohexanecarboxylate.
1H NMR (300 MHz, CDCI3) δ 3.74 (d, J = 3.1 Hz, 3H), 3.64 - 3.43 (m, 2H), 3.25 3.05 (m, 1H), 2.25-2.09 (m, 1H), 2.00 (ddd, J = 9.7, 4.8, 2.9 Hz, 1H), 1.73-1.50 (m, 1H), 1.40 (d, J = 6.3 Hz, 3H), 1.32- 1.03 (m, 3H).
Formation of racemic methyl-3-amîno-2-hydroxy-1-methyl-cyclohexanecarboxylate (66d)
A solution of racemic methyl-3-azido-2-hydroxy-1-methyl-cyclohexane-carboxylate, 66c, (0.90 g, 4.22 mmol) in a mixture of MeOH (50 mL) and AcOH (10 mL) was stirred under a hydrogen atmosphère (balloon) with the presence of palladium (0.50 g, 0.47 mmol) overnight at room température. The mixture was filtered through a celite bed and washed with MeOH. The combined filtrâtes were evaporated to provide methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate as a oil. Et2O was added and the resulted acetic acid sait was stirred for 0.5 hour and was then filtered to give 1.0 g of racemic methyl-3-amino-2-hydroxy-1-methylcyclohexanecarboxylate acetic acid sait as a white solid.
Formation of racemic Methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amÎno]-2-hydroxy-1methyl-cyclohexanecarboxylate (66e)
To a solution of 2,4-dichloro-5-fluoro-pyrimidine (0.43 g, 2.58 mmol) and racemic methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate acetic acid sait, 66d, (0.58 g, 2.35 mmol) in THF (10 mL) and MeOH (8 mL) at room température was added jPr2NEt (1.23 mL, 7.04 mmol). After stirring the reaction overnight at room température, the solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography (Hexanes/EtOAc 100/0 to 0/100, Rf=0.7 in Hexanes/EtOAc 2/1) to provide 650 mg of racemic methyl-3-[(2-chloro-5
-35016260 fluoro-pyrimidin-4-yl)amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66e, as a white solid, LCMS: 318.16 (M+1).
Formation of racemic Methyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3yl]-5-fluoro-pyrîmidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate (66f)
To a solution of racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2hydroxy-1-methyl-cyclohexanecarboxylate, 66e, (0.65 g, 2.05 mmol) and 5-chloro-1(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.32 g, 3.05 mmol) in THF (20 mL) was added aqueous Na2CO3 (3.52 mL of 2 M solution, 7.04 mmol). The solution was degassed with N2 for 20 minutes. Tetrakis triphenylphosphane palladium (0) (0.14 g, 0.12 mmol) was added and the mixture was refluxed ovemight. LCMS showed good conversion, but some starting materials remained. More degassed 2 N Na2CO3 was added followed by another portion of Tetrakis triphenylphosphane palladium (0.14 g, 0.12 mmol). The reaction was refluxed for another 4 hours. The mixture was cooled to room température, extracted with EtOAc. The organic phase was washed by brine and dried over
Na2SO4. After évaporation of solvent the crude mixture was purified by silica gel chromatography (Hexanes/EtOAc 100/0 to 0/100) to provide 1.0 g of racemic methyl3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66f. LCMS: 588.26 (M+1).
Formation of (1 S, 2S, 3S)-3-[[2-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylic acid (928)
Racemic methyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoropyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66f, (0.100 g, 0.170 mmol) was dissolved in MeOH (1 mL) and THF (1 mL) and treated with aqueous LiOH (0.24 mL of 1 M solution, 0.24 mmol) and the reaction was heated to reflux ovemight. The reaction was cooled to room température and the resultîng material directly purified by preparatory HPLC to afford 20 mg of racemic 3-[[2-(5chloro-1/-/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1methyl-cyclohexanecarboxylic acid. The enantiomers of the racemic material were separated by chiral SFC purification to afford 6 mg of (1 R, 2R, 3R)-3-[[2-(5-chloro1/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amrno]-2-hydroxy-1 -methylcyclohexanecarboxylic acid and 6 mg of (1S, 2S, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methylcyclohexanecarboxylic acid. LCMS: 420.36 (M+1).
General Scheme 67
-35116260
F
67b eTc OEt
Pd/C (wet, Degussa), hydrogen, EtOH (b) 2,4dichloro-5-fluoropyrimidine, 'Pr2NEt, THF, reflux (c) LiOH, THF/water, 50°C (d) DPPA, Et3N, THF, 85 °C (e) 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1-tosyl-1 H-pyrrolo[2,3-t)]pyridine, XPhos, Pd2(dba)3, K3PO4, 2-methylTHF, water, 125 °C (f)
Formation (1R, 3S)-ethyl 3-aminocyclohexanecarboxylate (67b)
To a solution of (1F?, 3S)-ethyl 3-(benzyloxycarbonylamino)cyclohexane-carboxylate, 18b, (14.0 g, 45.9 mmol) in éthanol (3 mL) was added Pd/C (wet, Degussa (2.4 g, 2.3 mmol). The mixture was evacuated and then stirred under atmosphère of nitrogen at room température overnight. The reaction mixture was filtered through a pad of celite and the resulting filtrate concentrated in vacuo to provide an oil that was used without further purification.
Formation (1 R, 3S)-ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate (67c)
To a solution of (1F?, 3S)-ethyl 3-aminocyclohexanecarboxylate, 67b, (5.1 g, 24.1 mmol) and 2,4-dichloro-5,-fluoropyrimidine (6.0 g, 36.0 mmol) in THF (60 mL) was added diisopropylethylamine (9.6 mL, 55.4 mmol). The mixture was heated to reflux overnight. The reaction was cooled to room température and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes
-35216260 gradient) to provide 6.7 g of (1 R, 3S)-ethyl 3-(2-chloro-5-fluoropyrimidin-4ylaminojcyclohexane-carboxylate as a white solid: LCMS RT = 3.1 (M+H) 302.2.
Formation (1 R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid (67d)
To a solution of (1 R, 3S)-ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate, 67c, (20.0 g, 66.3 mmol) in THF (150 mL) was added added a solution of LiOH hydrate (8.3 g, 198.8 mmol) in 100ml water. The reaction mixture was stirred at 50 °C overnight, To the reaction mixture was added HCl (16.6 mL of 12 M solution, 198.8 mmol) and EtOAc. The organic phase was washed with brine and dried over MgSO4 and the solvent was removed under reduced pressure to afford
17.5 g of product that was used without further purification: 1H NMR (300 MHz, CDCI3) δ 7.91 (d, J = 2.7 Hz, 2H), 5.24 (d, J= 7.3 Hz, 2H), 4.19-4.03 (m, 3H), 3.84 -3.68 (m, 3H), 2.59 (ddd, J= 11.5, 8.2, 3.6 Hz, 2H), 2.38 (d, J= 12.4 Hz, 2H), 2.08 (d, J= 9.6 Hz, 6H), 1.99- 1.76 (m, 5H), 1.63-1.34 (m, 6H), 1.32- 1.15 (m, 4H).
Formation N-((1 R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide (67e)
A solution of (1 R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid, 67d, (8.2 g, 30.0 mmol), (azido(phenoxy)phosphoryl)oxybenzene (9.7 mL, 45.0 mmol) and triethylamine (5.8 mL, 42.0 mmol) in THF (200 mL) was degassed under nitrogen for 15 minutes. The reaction mixture was heated at 85 °C for 30 minutes until LC/MS indicated complété consumption of carboxylic acid, 67d. To the reaction mixture was added pyrrolidine (7.5 mL, 90Ό mmol) and the reaction was heated at 85 °C for an additional 15 min. The mixture was diluted into brine and extracted with EtOAc. The organic phase was separated, dried over MgSO4. The product was isolated (6.25 g) by filtration after partial removal of solvent in vacuo: 1H NMR (300 MHz, CDCI3) δ 7.87 (d, J = 2.8 Hz, 2H), 5.04 (d, J = 8.1 Hz, 2H), 4.09 (ddd, J = 26.9, 13.4, 5.6 Hz, 4H), 3.91 - 3.71 (m, 2H), 3.32 (t, J = 6.5 Hz, 7H), 2.45 (d, J= 11.5 Hz, 2H), 2.08 (dd, J = 22.1, 12.0 Hz, 4H), 1.96- 1.82 (m, 9H), 1.54 (dd, J = 18.6, 8.5 Hz, 2H), 1.22-1.01 (m, 6H).
Formation N-((1R, 3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3y1)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide (67f)
A solution of /V-((1 R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide, 67e, (6.8 g, 20.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (12.5 g, 30.0 mmol) and K3PO4 (17.0 g, 80.0 mmol) in 2-methyl THF (180 mL) and water (20 mL) was degassed under nitrogen for 30 min. To the mixture was added dicyclohexyl-[2(2,4,6-triisopropylphenyl)phenyl]phosphane (XPhos) (1.1 g, 2.4 mmol) and Pd2(dba)3
-35316260 (0.5 g, 0.5 mmol). The reaction mixture was heated in a pressure bottle at 125 °C for
2.5 hr. The reaction mixture was filtered through celite, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (8%MeOH/CH2CI2) to afford 11.5 g of the desired product: 1H NMR (300 MHz, CDCI3) δ 8.54 (s, 1 H), 8.49 (dd, J = 9.0, 2.8 Hz, 1 H), 8.32 (d, J = 2.1 Hz, 1H), 8.13 (d, J = 8.3 Hz, 2H), 8.07 (d, J =3.2 Hz, 1H), 7.30 (d, J =8.5 Hz, 2H), 4.98 (d, J= 6.3 Hz, 1H), 4.37- 4.16 (m, 1H), 4.08 (d, J = 7.3 Hz, 1H), 3.99-3.80 (m, 1 H), 3.33 (t, J = 6.5 Hz, 4H), 2.52 (d, J = 11.6 Hz, 1 H), 2.39 (s, 3H), 2.29 (d, J = 11.3 Hz, 1H), 2.12 (d, J = 11.1 Hz, 1H), 1.99-1.81 (m, 5H), 1.70- 1.55 (m, 1H), 1.221.08 (m, 2H).
Formation N-((1 R, 3S)-3-(5-fluoro-2-(5-fluoro-1 H-pyrrolo[2,3-b]pyridin-3-yl)-pyrrmidin-
4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide (895)
A solution of A/-((1R, 3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide, 67f, (11.5 g, 19.3 mmol) in THF (150 mL) was added sodium methoxide (4.173 g, 19.31 mmol). After stirring the reaction mixture for 2 minutes, the mixture was poured into an aqueous saturated solution of NaHCO3. The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (10%MeOH/CH2CI2) to afford 6.5g of the desired product. The product was converted to an HCl sait by dissolving in MeOH (100 mL) and adding 2.4 mL of 12M HCl solution at room température. The solution was stirred at for 1 hour and the HCl sait precipitated out and filtered to provide 7.05g of the HCl sait: 1H NMR (300 MHz, DMSO) δ 9.36 (s, 2H), 9.05 (d, J = 3.0 Hz, 2H), 8.49 (d, J= 5.6 Hz, 2H), 8.41 (dd, J= 2.6, 1.4 Hz, 2H), 8.31 (d, J = 9.5 Hz, 2H), 5.92 (s, 3H), 4.24 (s, 3H), 3.64 (s, 2H), 3.18 (t, J = 6.6 Hz, 7H), 2.07 (dt, J = 22.7, 11.5 Hz, 4H), 1.87 (t, J = 12.6 Hz, 4H), 1.77 (dd, J = 8.0, 5.3 Hz, 7H), 1.651.13 (m, 8H).
General Scheme 68
-35416260
X
Ts b
”'NH
»F
TsCI, NaH, DMF, 45 °C (b) methyl iodide, K2CO3,
DMF (c) bromine, CHCI3, 0 °C to rt (d) bis(pinacol)diborane, palladium (II) dichloro bis(tricyclohexylphosphane), KOAc, 2-methylTHF, 125 °C (e) (R)-A/-((1R, 3S)-3-((2-chloro-5fluoropyrimidin-4-yl)amino)cyclohexyl)-3fluoropyrrolidine-1-carboxamide, XPhos, Pd2(dba)3, K3PO4, 2-methylTHF, water, 125 °C
Formation of 5-fluoro-1-tosyl-1 H-pyrrolo[2,3-b]pyridin-4-ol (68a)
To a solution of 5-fluoro-1/-/-pyrrolo[2,3-b]pyridin-4-ol (1.2 g, 7.9 mmol) in 80 mL DMF at 0 °C was added toluenesulfonyl chloride (1.8 g, 9.5 mmol) followed by NaH (0.8 g, 19.7 mmol, 60% w/w). The reaction was slowly warmed to 45 °C after 3 hours and stirred for an additional 3 hours. The mixture was then concentrated in vacuo. The crude oil was dissolved in 100 mL EtOAc and washed with water (2x50 mL) and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (10% EtOAc/Hexanes) to afford 1.5 g of the desired product.
Formation of 5-fluoro-4-methoxy-1-tosyl-1 H-pyrrolo[2,3-b]pyridine (68b)
To a solution of 5-fluoro-1 -tosyl-1 /-/-pyrrolo[2,3-b]pyridin-4-ol, 68a, (0.70 g, 2.29 mmol) in DMF (25 mL) was added methyliodide (0.14 mL, 2.29 mmol) and K2CO3 (0.32 g, 2.29 mmol). The reaction mixture was stirred for 3 hours at ambient température. The reaction was diluted with deionized water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 720 mg of the desired product that was used in next step without further purification.
Formation of 5-fluoro-4-methoxy-3-bromo-1 -tosyl-1 H-pyrrolo[2,3-b]pyridine (68c)
-35516260
To a cold (0 °C) solution of 5-fluoro-4-methoxy-1-tosyl-1H-pyrrolo[2,3-Z)]pyridine,
68b, (0,79 g, 2.45 mmol) in chloroform (50 mL) was added bromine (0.13 mL, 2,45 mmol). The reaction mixture was stirred at 0 °C for 3 hours and then slowly warmed to ambient température. The mixture was diluted with deionized water and quenched with aqueous sodium bicarbonate. The aqueous phase was extracted with methylene chioride and dried over sodium sulfate. The resulting solid was purified via silica gel chromatography (15-30% EtOAc/Hexanes) to give 170 mg of the desired product.
Formation of S-fluoro-^methoxy-S-^AS^-tetramethyl-US^-dioxaborolan-Z-ylJ-l10 tosyl-1H-pyrrolo[2,3-b]pyridine (68d)
To a solution of 5-fluoro-4-methoxy-3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 68c, (0.17 g, 0.43 mmol) in 2-Me-THF (9 mL) in a microwave vial was added bis(pinacol)diborane (0.16 g, 0.64 mmol), followed by potassium acetate (0,23 g, 1.06 mmol) and palladium (II) dichloro bis(tricyclohexylphosphane) (0.02 g, 0.02 mmol). Réaction vial was sealed and irradiated with microwaves at 125 °C for 90 minutes. The mixture was filtered and purified via silica gel chromatography (10-30% EtOAc/Hexanes) to afford 100 mg of the desired product.
Formation of (R)-3-fluoro-N-((1R, 3S)-3-((5-fluoro-2-(5-fluoro-4-methoxy-1Hpyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide (1104):
To a solution of 5-fluoro-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1tosyl-1H-pyrrolo[2,3-b]pyridine, 68d, (0.100 g, 0.220 mmol) in 2-Me-THF (2 mL) was added (R)-/\/-((1 R, 3S)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)cyclohexyl)-3fluoropyrrolidine-1-carboxamide (0.060 g, 0.170 mmol). Potassium phosphate (0.130 g, 0.600 mmol) and deionized water (0.5 mL) were then added and solution was degassed under a flow of nitrogen for 10 minutes. 2-Dicyclohexylphosphino2',4’,6’-triisopropylbiphenyl (XPhos) (0.006 g, 0.012 mmol) and tris(dibenzylideneacetone)-dipalladium (0) (0.023 mg, 0.026 mmol) were then added and solution was again degassed under flow of nitrogen for 5 minutes. Vial was sealed and heated to 80 °C for 3 hours. Solution cooled to ambient température and was filtered and concentrated in vacuo. The crude oil was redissolved in anhydrous THF (5 mL) and a solution of 2N LiOH (2 mL) was added. The reaction mixture was heated to 80 °C for 2 hours. Solution was cooled to ambient température and concentrated in vacuo. Purification by préparative HPLC afforded 6 mg of the desired product.
General Scheme 69
-35616260
NaCN, LiCIO4, CH3CN (b) 5-fluoro-1-(p-tolylsulfonyl)3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrolo[2,3-b)pyridine, NazCO3, Pd(PPh3)4, dimethoxyethane, 120 °C (c) sodium methoxide, MeOH
Formation of 2-((1 S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)-ethanenitrile (69a)
A suspension of 2-chloro-5-fluoro-N-[(3S)-1-oxaspiro[2.5]octan-7-yl]pyrimidin-4amine, 49c, (0.50 g, 1.94 mmol), NaCN (0.11 g, 2.33 mmol) and lithium perchlorate (0.25 g, 2.33 mmol) in CH3CN was heated ai 100 °C in a pressure tube for 3h. The mixture was diluted into EtOAc and the organic phase was washed with aqueous saturated NaHCO3 solution, dried with MgSO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purifîed by silica gel chromatography (EtOAc/hexanes) afforded the desired product: 1H NMR (300.0 MHz, CDCI3) Π 7,78 (d, J = 2.7 Hz, 1 H), 4.85 (d, J = 6.6 Hz, 1 H), 4.28 (qn, J = 4.0 Hz, 1H), 2.45 (s, 2H), 2.16 (d, J = 13.0 Hz, 1H), 2.05 (d, J= 11.7 Hz, 1H), 1.80 -1.71 (m, 3H), 1.46- 1.28 (m, 2H) and 1.17- 1.06 (m, 1H) ppm; LCMS RT = 2.15 (M+H) 285.34.
Formation of 2-((1 S, 3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1 H-pyrrolo[2,3-b]pyridin-3yl)pyrimidin-4-ylamîno)-1-hydroxycyclohexyl)ethanenitrile (69b)
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine, 44a, (0.23 g, 0.55 mmol), 2-((1 S, 3S)-3-(2-chloro-5fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)-ethanenitrile, 69a, (0.14 g, 0.50 mmol) and Na2CO3 (0.75 mL of 2M solution, 1.50 mmol) in dimethoxyethane (15 mL) was degassed with nitrogen for 30 min. To the reaction mixture was added
-35716260 palladium; triphenylphosphane (0.03 g, 0.03 mmol) and continued to degas the solution for 15 min. The réaction mixture was heated at 120 °C in a pressure tube for 45min. The reaction mixture was filtered through celite and the filtrate was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (40%EtOAc/Hexanes) to afford 150 mg of desired product: LCMS RT = 3.55 (M+H) 539.42.
2-((1 S, 3S)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1hydroxycyclohexyl)ethanenitrile (979)
To a solution of 2-((1 S, 3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1/7-pyrrolo[2,3-b]pyridin-3yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanenitrile, 69b,(0.14 g, 0.26 mmol) in méthanol (10 mL) was added sodium methoxide (0.06 g, 0.26 mmol). After stirring at room température for 2 minutes, the reaction mixture was diluted into EtOAc and brine. The separated organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10%MeOH/CH2CI2) to afford 46 mg of desired product: 1H NMR (300.0 MHz, MeOD) □ 8.65 (dd, J= 2.8, 9.6 Hz, 1H), 8.19 (s, 1H), 8.14 (dd, 7 = 2.0,
2.5 Hz, 1H), 7.98 (d, 7 = 4.1 Hz, 1H), 4.66 (dd, 7 = 8.0, 15.8 Hz, 1H), 2.64 (s, 2H), 2.20 (d, 7= 12.6 Hz, 2H), 2.01 (dd, 7= 3.4, 9.8 Hz, 2H), 1.84- 1.75 (m, 1H), 1.631.47 (m, 2H), 1.33 (dd, J = 3.6, 12.4 Hz, 1H) ppm; LCMS RT = 2.31 (M+H) 385.45.
General Scheme 70
fert-butyl A/-(A/-tert-butoxycarbonyl-C-pyrazol-1-ylcarbonimidoyl)carbamate, CH2CI2 (b) 5-fluoro-1-(ptolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, Na2CO3,
-35816260
Pd(PPh3)4, dimethoxyethane, 120 °C (c) sodium methoxide, THF, MeOH
Formation of tert-butyl (fert-butoxycarbonylamino)((1R, 3S)-3-(2-chloro-5fluoropyrimidin-4-ylamino)cyclohexylamino)methylenecarbamate (70b)
To a solution of (1S, 3R)-A/1-(2-chloro-5-fluoro-pyrimidin-4-yl)cyc)ohexane-1,3diamine, 70a, (0.122 g, 0.500 mmol) in CH2CI2 (10 mL) was added tert-butyl Λ/-(Λ/tert-butoxycarbonyl-C-pyrazol-1-yl-carbonimidoyl)carbamate (0.155 g, 0.500 mmol). The reaction mixture was stirred at room température for 2 days. The reaction mixture was concentrated in vacuo and used without further purification: 1H NMR (300 MHz, CDCI3) δ 11.51 (s, 3H), 8.29 (d, J = 8.3 Hz, 3H), 7.88 (d, J = 2.8 Hz, 3H), 5.01 (d, J =7.4 Hz, 3H), 4.28-4.18 (m,4H), 2.48 (d, J = 11.7 Hz, 3H), 2.12 (d, J = 9.4 Hz, 3H), 1.87 (dd, J = 10.3, 3.5 Hz, 3H), 1.52 (s, 24H), 1.50 (s, 25H), 1.24-1.10 (m, 8H); LCMS RT = 3.97 (M+H) 487.12.
Formation of tert-butyl N-[N-[(1R, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamimÎdoyl]-carbamate (70c)
Degassed a solution of (Z)-tert-butyl (fert-butoxycarbonylamino) ((1R, 3S)-3-(2chloro-5-fluoropyrimidin-4-ylamino)cyc|ohexylamino) methylenecarbamate, 70b, (0.200 g, 0.411 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (0.205 g, 0,493 mmol) and Na2CO3 (0.616 mL of 2M solution, 1.232 mmol) in dimethoxyethane (15 mL) for 30 min. To the mixture was added palladium triphenylphosphane (0.023 g, 0.021 mmol) and the reaction mixture was heated in a pressure tube at 120 °C for 45 min. The reaction mixture was filtered through a pad of celite and the filtrate concentrated in vacuo. Attempted purification of the resulting residue by silica gel chromatography (10% MeOH/CH2CI2) yielded a mixture containing mostly desired product that was used without further purification: LCMS RT = 2.30 (M+H) 641.02.
Formation of 1-((1 R, 3S)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-
4-ylamino)cyclohexyl)guanidine (1143)
To a solution of tert-butyl Λ/-[Λ/-[(1 R, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl] carbamimidoyljcarbamate, 70c, (0.100 g, 0.156 mmol) in THF (20 mL) was added sodium methoxide (0.033 g, 0.156 mmol) at room température. After 1 minute, the reaction mixture was diluted into EtOAc and aqueous saturated NaHCO3 solution. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 95mg of the desired product. To 10 ml MeOH solution of the product was added hydrochlorîde/IPA (0.031 mL of 5 M solution, 0.156 mmol). The reaction
-35916260 mixture was stirred at room température for 1 hour after which the solvent was removed under reduced pressure to afford the product, as hydrochloride sait: 1H NMR (300 MHz, MeOD) δ 8.63 (s, 1H), 8.40 (dd, J = 9.1,2.7 Hz, 1H), 8.36 (s, 1H), 8.32 (d, J = 5.5 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 3.78-3.53 (m, 1H), 2.41 (d, J = 11.7 Hz, 1H), 2.28 (d, J= 12.0 Hz, 1H), 2.18-1.98 (m, 2H), 1.69 (dd, J = 23.6, 11.8 Hz, 2H), 1.56- 1.28 (m, 2H); LCMS RT = 1.45 (M+H) 387.06.
General Scheme 71
HO
DBU, methyl 2-chlorooxazole-4-carboxylate, DMF, 75 °C (b) LiOH, THF
Formation of methyl 2-((1R, 3S)-3-(5-fluoro-2r(5-fluoro-1-tosyl-1H-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexylamino)oxazo)e-4-carboxylate (71a)
To a solution of (1S, 3R)-A/1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine, 44e, (0.089 g, 0.178 mmol) in DMF (1.5 mL) was added methyl 2-chlorooxazole-4-carboxylate (0.031 g, 0.195 mmol), followed by DBU (0.029 mL, 0.195 mmol). The reaction mixture was allowed to stir at room température overnight. The reaction was warmed to 75 °C and allowed to stir for 3 hours. Added an additional 16 mg of the chlorooxazole ester and the reaction was heated at 75 °C overnight. The mixture was diluted into water and EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-20%MeOH/CH2CI2) to afford 28 mg of desired product; LCMS RT = 3.73 (M+1) 624.12.
Formation of 2-((1 R, 3S)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-
4-ylamino)cyclohexylamino)oxazole-4-carboxylic acid (1144)
To a solution of methyl 2-[[(1 R, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]-amino]oxazole-4carboxylate, 71a, (0.028 g, 0.045 mmol) in THF (1 mL) was added LiOH (1 mL of 1 M solution, 1.000 mmol) and the reaction mixture was warmed to 130 °C via microwave irradiation. After heating and stirring for 20 minutes, the mixture was cooled to room température. Ail volatiles were removed under a stream of nitrogen
-360i and heat. The crude residue was suspended in MeOH and a few drops of trifluoroacetic acid were added to protonate molécule (solution occurs). The mixture was filtered and purified by reverse phase HPLC (5-95% CH3CN/H2O) to afford 5 mg of the desired product as a TFA sait: 1H NMR (300 MHz, MeOD) □ 08.83 (s, 1H), 8.67 -8.09 (m, 4H), 2.67 (s, 3H), 2.18 (m, 5H), 1.34 (d, J = 29.6 Hz, 3H); LCMS RT =1.78 (M+1) 456.07.
General Scheme 72
NaHCO3, Br2, H2O (b) NaOH (c) TMSCI, MeOH (d) sodium methoxide, MeOH, 150 °C (e) sodium borohydride, MeOH (f) ethyl 2-(tertbutoxycarbonylamino)-2-oxo-acetate, DEAD, PPh3, 85 °C (g) NaOH, MeOH (h) trifluoroacetic acid, CH2CI2, 1N HCI/ether (i) 5-fluoro-3-(5-fluoro-4( methy Isu If i ny I) py ri m i d i n-2-y I)-1 -tosyl-1 H-pyrrolo[2,3b]pyridine, !Pr2NEt, THF (j) lithium hydroxide, THF (k) DPPA, Et3N, pyrrolidine.
Formation of 6-bromohexahydro-2H-3,5-methanocyclopenta[b]furan-2-one (72a)
To a solution of bicyclo[2.2.1]hept-5-ene-3-carboxylic acid (25,0 mL, 204.3 mmol) in NaHCO3 (51.5 g, 612.9 mmol) in water was added bromine (32.7 g, 204.3 mmol) dropwise at 0 °C. The solution was stirred for 1 hour and extracted with ether, and the organic phase was washed successively with 1 N Na2S2SO3 solution and brine, and the organic phase was then dried (Na2SO4), filtered and concentrated in vacuo to afford 30 g of crude product that was used without further purification.
-36116260
Formation of 6-oxonorbornane-2-carboxylic acid (72b)
6-bromohexahydro-2H-3,5-methanocyclopenta[b]furan-2-one, 72a, (28.0 g, 129.0 mmol) was treated with NaOH (258.0 mL of 2 M solution, 516.0 mmol) in H2O (350 mL) for 2 hour at room température. The reaction mixture was acidified with conc. HCl, extracted with Et2O. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH/CH2CI2 gradient) to provide 16 g of 6oxonorbornane-2-carboxylic acid.
Formation of Endo methyl 6-oxonorbornane-2-carboxylate (72c)
A solution of 6-oxonorbornane-2-carboxylic acid, 72b, (16.0 g, 103.8 mmol) in methanol (350.0 mL) was treated with TMSCI (42.04 g, 49.11 mL, 387.0 mmol). The reaction mixture was stirred at room température overnight. Solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (10% EtOAc/hexanes) to provide 12 g of Endo methyl 6oxonorbornane-2-carboxylate.
Formation of Exo methyl 6-oxonorbornane-2-carboxy1ate (72d)
Endo methyl 6-oxonorbornane-2-carboxylate, 72c, (3.5 g, 20.8 mmol) was heated in a sealed tube in sodium methoxide (2.1 mL of 2 M solution in methanol, 4.2 mmol) at 150 °C for 17 hours. The solvent was evaporated and the crude product was purified by silica gel chromatography (0-16% EtOAc/hexanes gradient) to afford 3.3 g of starting endo methyl 6-oxonorbornane-2-carboxylate as the first fraction (PMA staining) and 4.0 g of the desired exo product as the second spot. The recovered starting material was treated with the same conditions again to generate another 1.0 g desired exo-product.
Formation of methyl 6-hydroxynorbornane-2-carboxylate (72e)
To a solution of exo methyl 6-oxonorbornane-2-carboxylate, 72d, (4.7 g, 27.9 mmol) in MeOH (50 mL) was added sodium borohydride (1.6 g, 41.9 mmol) in five portions at 0 °C. TLC showed completed conversion after 2 hours. Aqueous saturated NH4CI solution was added to quench the reaction. The MeOH was evaporated under reduced pressure and then the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes, Rf = 0.5 in 50% EtOAc/hexanes) to afford 3.96 g of the desired product: 1H NMR (300 MHz, CDCI3) Π 4.23 - 4.06 (m, 1H), 3.56 (s, 3H), 3.37 (s, 1 H), 3.03 (dd, J = 8.9, 5.5 Hz, 1 H), 2.41 (d, J = 3.9 Hz, 1 H), 2.13 (s, 1H), 1.93- 1.69 (m, 2H), 1.63- 1.42 (m, 1H), 1.34 (ddt, J= 10.3, 3.2, 1.6 Hz, 1H), 1.20 (dd, J= 10.4, 0.7 Hz, 1 H), 0.77 (dt, J= 12.6, 3.4 Hz, 1H).
-36216260
Formation of methyl 6-(N-(fert-butoxycarbonyl)-2-ethoxy-2-oxoacetamido)bicycle [2.2.1]heptane-2-carboxylate (72f)
To a cold (0 °C) solution of methyl 6-hydroxynorbornane-2-carboxylate, 72e, (3.2 g, 18.8 mmol) in THF (150 mL) was added ethyl 2-(tert-butoxycarbonylamino)-2-oxoacetate (4.9 g, 22.6 mmol) and triphenylphosphine (5.9 g, 22.6 mmol) followed by dropwise addition of diisopropyl azodicarboxylate (4.5 g, 22.6 mmol). The reaction was then heated to 85 °C and maintained at that température for 2 days. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to provide 6 g of methyl 6-(A/-(tert-butoxycarbonyl)-2-ethoxy-2-oxoacetamido)bicyclo[2.2.1]heptane-2carboxylate: LCMS 392.34 (M+Na+); 1H NMR (300 MHz, CDCI3) δ 4.26 (q, J= 7.2 Hz, 2H), 4.08 (dt, J= 14.3, 7.2 Hz, 1H), 3.62 (d, J = 2.1 Hz, 3H), 2.72 (s, 1H), 2.422.26 (m, 2H), 2.08 - 1.80 (m, 2H), 1.80 - 1.51 (m, 3H), 1.45 (s, 9H), 1.38 - 1.25 (m, 3H).
Formation of 6-(tert-butoxycarbonylamino)norbornane-2-carboxylic acid (72g)
To a solution of methyl 6-[tert-butoxycarbonyl-(2-ethoxy-2-oxoacetyl)amino]norbornane-2-carboxylate, 72f, (0.80 g, 2.17 mmol) in methanol (20 mL) was added NaOH (4.33 mL of 2N solution, 8.66 mmol) at room température. The reaction mixture was stirred overnight. The mixture was diluted into 0.5 N HCl in ice, and extracted twice with EtOAc. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to afford 600 mg of desired product that was used wîthout further purification
Formation of 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid (72h)
A solution of 6-(tert-butoxycarbonylamino)norbornane-2-carboxylic acid, 72g , in dichlorométhane (5 mL) was treated with trifluoroacetic acid (5 mL) for 1 hour at room température. The solvent was evaporated under reduced pressure and the resulting product was dissolved in 2 mL TFA and added to a stirring 1N HCl in Et2O solution. After stirring the mixture for 0.5 hour, the resulting precipitate was filtered and washed with dry Et2O to give 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid.
Formation of 6-(5-fluoro-2-(5-fluoro-1 H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4ylamino)bicyclo[2.2.1]heptane-2-carboxylic acid (72j)
To a solution of 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(ptolylsulfonyl)pyrrolo [2,3-b]pyridine (0.187 g, 0.417 mmol) and 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid, 72h, (0.080 g, 0.417 mmol) in THF (3 mL) was added diisopropylethylamine (0.291 mL, 1.670 mmol). The reaction mixture was heated at 80 ’C overnight. Aqueous LiOH (3 mL of 2M solution, 6.000 mmol) was
-36316260 added and the mixture was heated for another 7 hours. The mixture was diluted with
MeOH, neutralized with trifluoroacetic acid, filtered and the resulting filrate was purified by preparatory HPLC chromatography to afford 50 mg of desired product.
Formation of N-[6-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl]amino]norbornan-2-yl]pyrrolidine-1-carboxamide (1045)
To a solution of 6-[[5-fluoro-2-(5-fluoro-1/-/-pyrrolo[2]3-b]pyridin-3-yl)pyrimidin-4yl]amino]norbornane-2-carboxylic acid, 72j, (0.030 g, 0.078 mmol) in THF (0.375 mL) was added trîethylamine (0.032 mL, 0.234 mmol) and (azido(phenoxy)phosphoryl)oxybenzene (0.018 mL, 0.085 mmol). The reaction mixture was heated to 95 °C for 2.5 hours, cooled down to 5 ’C, and treated with pyrrolidîne (0.010 mL, 0.117 mmol). The reaction was stirred for 3 days at room température. The reaction mixture was injected directly into a preparatory HPLC System for purification to provide the product as a racemic mixture. The single enantiomers were obtaîned by séparation using SFC chiral purification to afford 5,7 mg of the desired product as well as 1.4 mg of the enantiomer.
General Scheme 73
'Pr2NEt, THF, reflux (b) 1N LiOH, THF/H2O, 130 °C, mîcrowave
Formation of (1R, 2R, 3S)-3-((5-f!uoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3yl)pyrimidin-4-yl)amino)cycloheptane-1,2-diol (73b)
Aminodiol, 73a, was synthesized by following the literature procedure (JOC 2009, 74, 6735). Aminodiol (0.040 mg), diisopropylethylamine (0.054 mL, 0.310 mmol) and
5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidîn-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3bjpyridine (0.139 g, 0.310 mmol) in THF was refluxed overnight. The solution was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc/CH2CI2) to give 43 mg of desired product as a white solid: 1H NMR (300 MHz, CDCI3) δ 8.40 (q, J = 2.8 Hz, 2H), 8.22 (d, J = 1.8 Hz, 1 H), 8.08 - 7.94 (m, 3H), 7.20 (d, J= 10.1 Hz, 3H), 5.26 (d, J = 4.9 Hz, 1H), 4.21 -3.99(m, 1H), 3.84 (s, 1H), 3.75-3.57 (m, 1H), 3.43 (t, J = 8.7 Hz, 1H), 2.73 (s, 1H), 2.30 (s, 3H), 2.11 1.85 (m, 2H), 1.84-1.36 (m, 8H), 1.18 (s, 2H), 0.79 (dd, J = 15.0, 6.8 Hz, 2H). LCMS (+ H): M/Z = 530.29
Formation of (1R, 2R, 3S)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-36416260 yl)pyrimidin-4-yl)amino)cycloheptane-1,2-diol (984)
LiOH (0.5 mL of 1N solution, 0.5 mmoL) was added to (1 R, 2R, 3S)-3-((5-fluoro-2-(5-fluoro1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cycloheptane-1,2-diol, 73a, in THF (3 mL). The reaction mixture was heated in microwave at 130 °C for 40 minutes. HCl (0.5 mL of 1.25 N solution in MeOH) and MeOH was added to the mixture. The solution was purified by préparative HPLC (MeCN/H2O 10-70%) to give desired product as TFA sait. Neutralization and re-acidification with hydrogen chioride (1N in MeOH) afforded the desired product (28 mg) as a white solid (HCl sait): 1H NMR (300 MHz, MeOD) δ 8.52 (s, 1H), 8.48 (d, 7=2.8 Hz, 1H), 8.34 (s, 1H), 8.28 (d,7=5.6 Hz, 1H), 4.62-4.35 (m, 1H), 3.65 (m, 2H), 2.11 -1.43 (m, 8H); 19F NMR (282 MHz, MeOD) δ-137.38 --137.51 (m, 1H),-156.06 (d, 7 = 5.6 Hz, 1H); LCMS (+ H): M/Z = 376.28.
General Scheme 74
Cul, 2-(2- methylpropanoyl)cyclohexanone, DMF (b)
H21 Pd/C, MeOH (c) 5-fluoro-3-(5-fluoro-4methylsulfiny)-pyrimidin-2-yl)-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridine (d) 1N LiOH, THF/H2O, 130 °C microwave.
Formation of benzyi ((1 S, 3R)-3-(pyrazin-2-ylamino)cyclohexyl)carbamate (74a)
A suspension of Cul (0.006 g, 0.030 mmol), benzyi A/-[(1S, 3R)-3-aminocyclohexyljcarbamate, 18e, (0.075 g, 0.302 mmol) and césium carbonate (0.197 g, 0.604 mmol) in DMF was evacuated and refilled with nitrogen multiple times. 2-iodopyrazine (0.036 mL, 0.362 mmol) and 2-(2- methylpropanoyl)cyclohexanone (0.020 mL g, 0.121 mmol) were then added and the reaction was stirred at room température overnight. The reaction was diluted into ethyl acetate and aqueous saturated sodium bicarbonate. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was
-36516260 purified by silica gel chromatography (0-10% MeOH/CHzCh) to afford 40 mg of the desired product as yellow solid.
Formation of (1R, 3S)-/V1-(pyrazin-2-yl)cyclohexane-1,3-diamine (74b)
To a solution of benzyl Λ/-[(1 S, 3R)-3-(pyrazin-2-ylamino)cyclohexyl]carbamate, 74a, (0.040 g, 0.123 mmol) in methano) (10 mL) was added 10% Pd/C (0.043 g,
0.040 mmol) and the resulting suspension was stirred under an atmosphère of hydrogen for three hours until LCMS indicated completion of the reaction. The solution was filtered through a bed of celite and concentrated in vacuo to give a yellow solid, which was used without further purification.
Formation of (1 S, 3R)-/V1 -(5-fluoro-2-(5-fluoro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3yl)pyrimidin-4-yl)-N3-(pyrazin-2-yl)cyclohexane-1,3-diamine (74c)
A solution of (1F?, 3S)-/\/1-pyrazin-2-ylcyclohexane-1,3-diamine 74b, diisopropylethylamine (0.30 mmol) and 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridrne (0.06 g, 0.13 mmol) in THF (3 mL) was refluxed overnight. The mixture was then concentrated in vacuo and the resulting residue was purified by silica gel chromatography (0-20% MeOH/CHjChgradient) to afford 39 mg of desired product: 1H NMR (300 MHz, CDCI3) δ 8.91 - 8.72 (m, 1 H), 8.50 (d, J = 11.8 Hz, 1 H), 8.38 (t, J = 7.5 Hz, 1 H), 8.06 (dd, J = 14.8, 5.9 Hz, 3H), 7.88 (d, J = 1.4 Hz, 1 H), 7.82 (s, 1 H), 7.62 (t, J = 6.8 Hz, 1H), 7.33 (dd, J = 16.6, 7.1 Hz, 3H), 5.91 (s, 1H), 4.27 (s, 1H), 3.98 (t, J= 11.3 Hz, 1H), 2.59 (d, 7 = 12.0 Hz, 1H), 2.39 (s, 3H), 2.34-2.09 (m, 2H), 1.99 (d, 7= 14.0 Hz, 1H), 1.72 (dd, 7=26.6, 13.1 Hz, 1H), 1.48-1.08 (m, 4H).
LCMS (+ H): M/Z = 593.25
Formation of (1S, 3/?)-/V1-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-
4-yl)-W3-(pyrazin-2-yl)cyclohexane-1,3-diamine (985)
LiOH (0.3 mL of 1N solution, 0.3 mmoL) was added to a solution of (1S, 3F?)-/V1-(5-fluoro-2(5-fluoro-1-tosyl-1H-pyrrolo[2t3-b]pyridin-3-yl)pyrimidin-4-yl)-/\/3-(pyrazin-2-yl)cyclohexane1,3-diamine, 74c, (35 mg) in THF (3 mL) and the reaction was heated in the microwave at 130 °C for 40 minutes. A solution of HCl (0.5 mL of a 1,25N in MeOH) was added and the resulting solution was purified by Gilson HPLC (MeCN/H2O 10-70% in 8 mins) to give pure TFA sait product. Neutralization and re-acidification with hydrogen chloride (1.25N in MeOH) afforded 23 mg of the HCl sait of the desired product as a light yellow solid: 1H NMR (300 MHz, MeOD) δ 8.76 (d, 7 = 2.4 Hz, 1 H), 8.63 (s, 1 H), 8.41 (d, 7 = 2.3 Hz, 1 H), 8.36 (d, 7= 5.7 Hz, 1H), 8.16 (s, 1 H), 7.96 (s, 1H), 7.76 (s, 1H), 4.51 (m, 7 = 11.8 Hz, 1H), 4.163.92 (m, 1H), 2.35-2.14 (m, 2H), 2.09 (m, 7= 13.8 Hz, 1H), 1.63 (d, 7 = 11.8 Hz, 4H); 10F NMR (282 MHz, MeOD) δ -155.25 (s, 1 H); LCMS (+ H): M/Z = 439.24.
General Scheme 75
-36616260
NaBH4, MeOH (b) 5-fluoro-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1 -tosyl-1 H-pyrrolo[2,3bjpyridine, 2-Me-THF, water, K3PO4, Pd(PPh3)4, XPhos, Tris(dibenzylideneacetone)dipalladium,reflux (c) bis(2,5-dioxopyrrolidin-1 -yl) carbonate, 'Pr2NEt, CH3CN (d) (3R)-3-fluoropyrrolidine,, 'Pr2NEt, CH3CN (e) 2N LiOH, THF
Formation of (1R, 3S)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)cyclohexanol (75a) Mixed (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 18e, (1.05 g, 4.31 mmol) in MeOH (20 mL) and dichloromethane (10 mL) and cooled to -78 eC using an external dry-ice/acetone bath and monitored with an internai thermometer. After 30 minutes, NaBH4 (0.16 g, 4.31 mmol) was added in one portion and continued to stir. (slight exotherm) and then cooled back down to -78°C. The reaction was monitored by HPLC for consumption of starting material as it was allowed to warm to room température overnight. The reaction was diluted with brine and EtOAc. The organic phase was dried (MgSO4), fîltered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography to afford 1.0g of a colorless foamy solid: LCMS method m201:10-90 CH3CN/H2O, formic acid modifier, 5 minutes, (C18); RT = 2.08min, MH+ = 246.21.
Formation of (1R, 3S)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridïn-3yl)pyrimidin-4-yl)amino)cyclohexanol (75b)
-36716260
K3PO4 (2.59 g, 12.21 mmol) in water (6 mL) and 2-Me-THF (20 mL) was purged with a flow of nitrogen for 30 min. Added (1R,3S)-3-[(2-chloro-5-fluoro-pyrimidin-4yl)amino]cyclohexanol, 75a, (1.00 g, 4.07 mmol) and 5-fluoro-3-(4,4,5,S-tétraméthylia, 2-dioxaborol an-2-yl)-1-tosy 1-1 H-pyrrolo[2,3-b]pyridi ne, 44a, (2.03 g, 4,88 mmol) and then purged with nitrogen for another 15 min. The reaction was then heated to 70 ’C and then charged with Tris(diberizylideneacetone)dipalladium (0.07 g, 0,08 mmol) and X-Phos (0.14 g, 0.28 mmol) under nitrogen. (Note Color changed from purple to hunier green). The reaction was heated to reflux for 1 h and 20 min. The reaction was cooled slowly to room température overnight. The mixture was treated with 100 mL of brine and 100 mL of ethyl acetate and separated the two layers. The aqueuous phase was extracted again with EtOAc (50 mL). Combined organic layers and passed through a plug of fluoracil, dried over Na2SO4] decanted and removed the solvent by rotoevaporation to give crude product which was then purified by silica gel chromatography (25-50% EtOAc/Hexanes) to afford the desired product.
2,5-dioxopyrrolidin-1-yl ((1S, 3R)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3i>]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl) carbonate (75c)
To a solution of (1R, 3S)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3yl)-pyrimidin-4-yl)amino)cyclohexanol, 75b, (0.50 g, 1.00 mmol) and N,Ndiisopropylethylamine (1.40 mL, 10.01 mmol) was added bis(2,5-dioxopyrrolidin-1 -yl) carbonate (1.28 g, 5.01 mmol) in CH3CN (4 mL) and stirred at room température overnight. Used reaction mixture as is in next reaction. Using LCMS method m201:10-90 CH3CN/H2O, formic acid modifier, 5 minutes, (C18); RT = 3.73min, MH+= 641.43 (strong).
Formation of (R)-(1 S, 3R)-3-((5-fluoro-2-(5-fluoro-1 -tosyl-1 H-pyrrolo[2,3-fa]pyndin-3yl)pyrimidin-4-yl)amino)cyclohexyl 3-fluoropyrrolidine-1-carboxylate (75d)
To (2,5-dioxopyrrolidin-1-yl) [(1 R, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(ptolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl] carbonate, 75c, (0.125 g, 0.195 mmol) already in acetonitrile was added (3R)-3-fluoropyrrolidine (0.445 g, 4.991 mmol) and the reaction mixture was stirred at room température for 20 hours; The reaction was monitored by HPLC until no more starting material was remaining. The reaction mixture was concentrated in vacuo and was carried on into the next reaction without further purification.
Formation of (S)-(1 S, 3R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amîno)cyclohexyl 3-fluoropyrrolidine-1-carboxylate (1151)
To a solution of crude (R)-(1 S, 3R)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1 H-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl 3-fluoropyrrolidine-1 -carboxylate, 75d, (0.119 g, 0.019mmol) in THF (2mL) was added 5mL 2N LiOH (10 mmol). The
-36816260 reaction mixture was heated at 50 °C for 2 hours. The mixture was diluted into aqueous saturated ammonium chloride (2mL), and extracted with EtOAc (2 x 10mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified on the semi-prep HPLC, 10-70% CH3CN/H2O; Three runs; homogeneous fractions were combined and the solvent removed under a stream of nitrogen and then removed residual solvent on roto-evaporator to afford 74 mg of the desired product: LCMS RT = 2.15 min (M+H) 461.51.
General Scheme 76
Rh/AI2O3, H20.100 ’C, 105 atm H2, 19 hrs (b) 2,4dichloro-5-fluoropyrimidine, IPA, MeCN, room température (c) CDI, 'Pr2NEt, (S)-3-fluoropyrrolidine, THF, RT, 2 days (d) 5-fluoro-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3bjpyridine, MeTHF, K3PO4, X-Phos, Pd2dba3, H2O, microwa’ve, 120 ‘C, 20 minutes (e) 25% NaOMe in MeOH, RT, 30 min. (f) SFC séparation
Formation of 5-methylcyclohexane-1,3-diamine (76a)
The 3-meihyl-5-nitroaniline (10.0 g, 65.7 mmol) was added to water (146 ml) and treated with 6N HCl (22.5 ml, 135.0 mmol) and 5% Rhodium on Alumina (1.9 g, 0.9 mmol). The mixture was charged to 105 atm of Hydrogen and heated to 100 ’C for 19 hours. The reaction was cooled and filtered through celite and concentrated to dryness to give 5-methylcyclohexane-1,3-dîamine dihydrochloride (12.9 g, 64.5 mmol) as a racemic mixture. The sait (6;5 g, 32.5 mmol) was dissolved in isopropyl alcohol (100 ml) and acetonitrile (100 ml) and treated with potassium carbonate (25.2 g, 182.0 mmol). The mixture was stirred at room température overnight, filtered thru celite, and concentrated in vacuo to afford 2.2 g of 5-methylcyclohexane1,3-diamine as a racemic brown oil: LCMS RT = 0.41 (M+1) 128.9.
Formation of N1-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3-diamine
-36916260 (76b)
To a solution of 5-methylcyclohexane-1,3-diamine, 76a, (2,2 g, 17.2 mmol) in isopropyl alcohol (40 ml) and acetonitrile (40 ml) was added 2,4-dichloro-5fluoropyrimidine (1.4 g, 8.6 mmol). The mixture was stirred at room température overnight, concentrated to dryness, and purified on silica gel eluted with 1-20% methanol/dichloromethane, to give 0.6 g of racemic A/1-(2-chloro-5-fluoropynmidin-4yl)-5-methylcyclohexane-1,3-diamine: 1H NMR (300 MHz, MeOD) δ 7.85 (d, J =3.5 Hz, 1H), 4.07 (ddd, J = 11,9, 7.9, 4.1 Hz, 1H), 3.54 (qd, J = 11.3, 4.2 Hz, 1H), 2.82 (tt, J = 11.4, 3.7 Hz, 1H), 2.16 (dd, J= 15.0, 13.0 Hz, 1H), 1.89 (t, J= 13.4 Hz, 2H), 1.50 (dd, J = 76.0, 21.9 Hz, 2H), 1.10 (dt, J = 17.9, 9.0 Hz, 1H), 0.99 (dd, J = 8.5, 5.0 Hz, 3H), 0.81 (ddd, J = 23.8, 12.0, 8.2 Hz, 1H); LCMS RT = 1.24 (M+1) 259.1.
Formation of (3S)-N-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5-methylcyclohexyl)-3fluoropyrrolidine-1-carboxamide (76c)
To a solution of A/1-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3diamine, 76b, (0.14 g. 0.54 mmol) in THF (2.5 ml) was added carbonyldiimidazole (0.10 g, 0.60 mmol) and 'Pr2NEt (0.28 mL, 1.62 mmol). The reaction was aged 2 hours at room temp, and treated with (S)-3-fluoropyrrolidine hydrochloride (0.07 g, 0.54 mmol). The reaction was stirred at room température for 2 days and then concentrated to dryness to afford 202 mg of (3S)-N-(3-((2-chloro-5-fluoropynmidin-4yl)amino)-5-methylcyclohexyl)-3-fluoropyrrolidine-1-carboxamîde which was used without purification: LCMS RT = 2.46 (M+1) 374.2, (M-1) 372.
Formation of (3S)-3-fluoro-N-(3-((5-fluoro-2-(5-fluoro-1-tosyl-1 H-pyrrolo[2,3-b] pyridin3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide (76d)
To a solution of (3S)-/\/-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5-methylcyclohexyl)-3-fluoropyrro)idine-1-carboxamide, XXc, (0.101 g, 0.270 mmol) in 2methyltetrahydrofuran (4 ml) was added potassium phophate (0.090 g, 0.950 mmol) in water (1.2 ml), x-phos (0.027 g, 0.057 mmol), and Pd2dba3 (0.015 g, 0.016 mmol). The reaction was heated in a microwave at 120 C, for 20 minutes, and the organic phase was filtered thru a pad of florisil and the filtrate concentrated in vacuo. The crude was purified on silica gel eluted with EtOAc to afford 127 mg of racemic (3S)3-fluoro-N-(3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide: LCMS RT = 3.58 (M+1) 628.3, (M-1) 626.
Formation of (S)-3-fluoro-N-((1R, 3S, 5R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3b]pyridîn-3-yl)pyrimidin-4-yl)amino)-5-methylçyclohexyl)pyrrolidine-1-carboxamide (76e)
To a solution of (3S)-3-fluoro-N-(3-((5-fluoro-2-(5-fluoro-1-tosyl-1 H-pyrrolo[2,3
-37016260
b]pyridin-3-y l)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1 -carboxamide, 76d, (0.090 g, 0.143 mmol) in MeOH (2.5 ml) was added 25% sodium methoxide in methanol (2 ml). The reaction was stirred at room température for 30 minutes and quenched with aqueous saturated NH4CI. The methanol was removed in-vacuo and the residue was extracted with EtOAc and water. The organics were dried over sodium sulfate and concentrated to dryness. The resulting crude racematewas purified by SFC séparation on a chiral column. The second peak was concentrated in vacuo to afford 32 mg of enantiomerically pure (S)-3-fluoro-N-((1R, 3S, 5R)-3-((5fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5methylcyclohexyl)pyrrolidine-1-carboxamide as a white solid: LCMS RT = 1.89 (M+1) 474.2, (M-1) 472.4; SFC RT = 3.2 min., 15% MeOH @ 5mL/min on an ODH (4.6*100), 100 bar, 35C, 220nm; 1H NMR (300 MHz, DMSO) δ 12.26 (s, 1H), 8.41 (dd, J = 9.9, 2.8 Hz, 1H), 8.32-8.18 (m, 2H), 8.14 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 6.02 (d, J = 7.9 Hz, 1H), 5.28 (d, J= 53.6 Hz, 1H), 4.35-4.00 (m, 1H), 3.81 -3.09 (m, 12H), 2.24- 1.77 (m, J= 41.2, 26.1, 10.6 Hz, 4H), 1.74-1,51 (m, 1H), 1.51 -1.22 (m, 1H), 1,14-0.70 (m, 4H).
(R)-nopinone, O-methylhydroxylamine hydrochloride, pyridine, EtOH (b) nBuLi, THF, -78 °C, ethylformate (c) NaBH4, MeOH (d) TBDPSCI, imidazole, DMF (e) BH3-THF, THF, 75 °C (f)
5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1 H-pyrrolo[2,3-b]pyridine, 'Pr2NEt, 75 °C (g) HCl, dioxane
Formation of (1R, 5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyl oxime (77a)
To a solution of (1S, 5R)-6,6-dimethylnorpinan-2-one (3.09 g, 22.35 mmol) in éthanol (70 mL) was added O-methylhydroxylamine hydrochloride (2,05 g, 24.59 mmol) and pyridine (1.29 mL, 15.92 mmol). Heated reaction mixture to 80 °C for 4 hours. Removed solvent under reduced pressure. Diluted residue with 1N HCl and extracted twice with ether. The combined organic phases were washed with aqueous saturated NaHCO3, dried (MgSO4), filtered, concentrated in vacuo to afford
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3.36 g of a colorless oil (mixture of oxime isomers) that was used without further purification.
Formation of (1R, 3S, 5R)-2-(methoxyimino)-6,6-dimethylbîcyclo[3.1.1]heptane-3carbaldehyde (77b)
To a coid (-78 °C) solution of (1R, 5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one Omethyl oxime, 77a, (1.27 g, 7.59 mmol) in THF (33 mL) was added dropwise a solution of n-butyllithium (3.34 mL of 2.5 M solution in hexanes, 8.35 mmol). After stirring the mixture 20 min at -78 °C ethyl formate (0.61 mL, 7.59 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 3 hours and then quenched by pouring into aqueous saturated NaHCO3 solution. The mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 810 mg yellow oil: LCMS RT = 3.54 (M+H) 196.28.
Formation of (1R, 3S, 5R)-3-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1Iheptan-2-one O-methyl oxime (77c)
To a solution of (1R, 3S, 5R)-2-(methoxyimino)-6,6-dimethylbicyclo [3.1.1]heptane-3carbaldehyde, 77b, (0.70 g, 3.58 mmol) in methanol (15 mL) was added sodium borohydride (0.16 g, 4.30 mmol). After stirring at room température for 30 minutes, the reaction was diluted into aqueous saturated NaHCO3 solution and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-50% EtOAc/Hexanes gradient) to afford 330 mg of the desired alcohol as mixture of oxime isomers.
Formation of (1R, 3S, 5R)-3-(((tert-butyldiphenylsilyl)oxy)methy1)-6,6-dimethylbicyclo[3.1,1]heptan-2-one O-methyl oxime (77d)
To a solution of (1R, 3S, 5R)-3-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]-heptan-2one O-methyl oxime, 77c, (0.32 g, 1.60 mmol) in DMF (6 mL) was added tertbutylchlorodiphenylsilane (0.55 g, 2.00 mmol) and imidazole (0.22 g, 3.20 mmol). The reaction mixture was stirred at room température for 18 hours. The reaction was diluted into aqueous saturated NH4CI solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-15% EtOAc/Hexanes gradient) to afford 200 mg of one oxime isomer and 197 mg of second oxime isomer.
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Formation of (1R, 3S, 5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethylbicyclo[3.1,1]heptan-2-amine (77e)
To a solution of (1 R, 3S, 5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyl oxime, 77d, (0.20 g, 0.46 mmol) in THF (3 mL) was added borane-THF (1.38 mL of 1 M solution, 1.38 mmol). The reaction was heated to 75 °C for 18 hours. The mixture was diluted into 1N NaOH (50 mL) and extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford 178 mg of a colorless oil that was used without further purification: LCMS RT = 2.53 (M+H) 408.54.
Formation of W-((1R, 2S, 3S, 5R)-3-(((fert-butyldiphenylsilyl)oxy)methyl)-6,6dimethylbicycIo[3.1.1]heptan-2-yl)-2-(5-chloro-1-tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-amîne (77f)
To a solution of (1R, 3S, 5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-amine, 77e, (0.20 g, 0.46 mmol) and 5-chloro-3-(5-fluoro-4(methylsulfinyl)pyrimidin-2-yl)-1 -tosyl-1 H-pyrrolo[2,3-b]pyridine (0.14 g, 0.30 mmol) in DMF (1.5 mL) was added diisopropylethylamine (0.11 mL, 0.61 mmol). The reaction was heated to 75 °C for 18 hours. The mixture was diluted into aqueous saturated NH4CI solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-5% MeOH/CH2CI2 gradient) to afford 78 mg of the desired product.
Formation of ((1R, 2S, 3S, 5R)-2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5fluoropyrimidin-4-yl)amino)-6,6-dimethylbÎcyclo[3.1.1]heptan-3-yl)methanol (1229)
To a solution of A/-((1R, 2S, 3S, 5R)-3-(((ferï-butyldiphenylsilyl)oxy)methyl)-6,6dimethylbicyclo[3.1.1 ]heptan-2-yl)-2-(5-chloro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-
5-fluoropyrimidin-4-amine, 77f, (0.037 g, 0.046 mmol) in acetonîtrile (1.1 mL) was added HCl (0.221 mL of a 4 M solution in dioxane, 0.883 mmol). The mixture was heated to 70 °C for 18 h, during which a precipitate formed. The reaction was concentrated in vacuo and triturated three times with CH3CN to afford 4 mg of the desired product as a white solid: 5H NMR (300.0 MHz, MeOD) ΠΠ8.72 - 8.64 (m, 1H), 8.39 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 5.2 Hz, 1H), 4.71 (d, J = 6.3 Hz, 1H), 3.67 - 3.57 (m, 2H), 2.33 - 2.26 (m, 1H), 2.10 (m, 1H), 1.78 - 1.70 (m, 1H), 1.28- 1.25 (m, 7H) and 1.19 (s, 3H) ppm; LCMS RT = 3.13 (M+H) 416.42.
Influenza Antiviral Assay
Antiviral assays were performed using two cell-based methods:
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A 384-well microtiter plate modification of the standard cytopathic effect (CPE) assay method was developed, similar to that of Noah, et al. (Antiviral Res. 73:50-60, 2006). Briefly, MDCK cells were incubated with test compounds and influenza A virus (A/PR/8/34), at a low multiplicity of infection (approximate MOI=0.005), for 72 hours at 37°C, and cell viability was measured using ATP détection (CelITiter Glo, Promega Inc.). Control wells containing cells and virus show cell death while wells containing cells, virus, and active antiviral compounds show cell survival (cell protection). Different concentrations of test compounds were evaluated, in quadruplicate, for example, over a range from approximately 20 DM to 1 nM. Doseresponse curves were prepared using standard 4-parameter curve fitting methods, and the concentration of test compound resulting in 50% cell protection, or cell survival équivalent to 50% of the uninfected wells, was reported as the IC50.
A second cell-based antiviral assay was developed that dépends on the multiplication of virus-specific RNA molécules in the infected cells, with RNA levels being directly measured using the branched-chain DNA (bDNA), hybridization method (Wagaman et al, J. Virol Meth, 105:105-114, 2002), Inthis assay, cells are initially infected in wells of a 96-well microtiter plate, the virus is allowed to replicate in the infected cells and spread to additional rounds of cells, then the cells are lysed and viral RNA content is measured. This assay is stopped earlier that the CPE assay, usually after 18-36 hours, while all the target cells are still viable. Viral RNA is quantitated by hybridization of well lysâtes to spécifie oligonucleotide probes fixed to wells of an assay plate, then amplification of the signal by hybridization with additional probes linked to a reporter enzyme, according to the kit manufacturées instructions (Quantigene 1.0, Panomics, Inc.). Minus-strand viral RNA is measured using probes designed for the consensus type A hémagglutination gene. Control wells containing cells and virus were used to define the 100% viral réplication level, and dose-response curves for antiviral test compounds were analyzed using 4parameter curve fitting methods. The concentration of test compound resulting in viral RNA levels equal to that of 50% of the control wells were reported as EC50. Virus and Cell culture methods: Madin-Darby Canine Kidney cells (CCL-34 American Type Culture Collection) were maintained in Dulbecco’s Modfied Eagle Medium (DMEM) supplemented with 2mM L-glutamine, 1,000U/ml penicillin, 1,000 ug/ml streptomycin, 10 mM HEPES, and 10% fêtai bovine medium. For the CPE assay, the day before the assay, cells were suspended by trypsinization and 10,000cells per well were distributed to wells of a 384 well plate in 50 □!. On the day of the assay, adhèrent cells were washed with three changes of DMEM containing 1 ug/ml TPCK-treated trypsin, without fêtai bovine sérum. Assays were initiated with the addition of 30 TCID50 of virus and test compound, in medium containing 1 Dg/ml
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TPCK-treated trypsin, in a final volume’of 50 lII. Plates were incubated for 72 hours at 37°C in a humidified, 5% CO2 atmosphère. Alternative^, cells were grown in DMEM + fetal bovine sérum as above, but on the day of the assay they were trypsinized, washed 2 times and suspended in serum-free EX-Cell MDCK cell medium (SAFC Biosciences, Lenexa, KS) and plated into wells at 20,000 cells per well. These wells were then used for assay after 5 hours of incubation, without the need for washing.
Influenza virus, strain A/PR/8/34 (tissue culture adapted) was obtained from ATCC (VR-1469). Low-passage virus stocks were prepared in MDCK cells using standard methods (WHO Manual on Animal Influenza Diagnosis and Surveillance, 2002), and TCID50 measurements were performed by testing serial dilutions on MDCK cells in the 384-well CPE assay format, above, and calculating results using the Karber method.
Mean IC50 values (mean ail) for certain spécifie compounds are summarized in Tables 1-5:
A: IC5o(mean ail) < 5 CM;
B 5ΠΜ 5 IC50(mean ail) i 20 ΠΜ;
C IC5t)(mean ail) > 10 DM;
D IC50(mean ail) > 20 ΠΜ;
E IC50 (mean ail) >3.3 DM.
Mean EC50 values (mean ail) for certain compounds are also summarized in Tables 1-5;
A: EC50(mean ail) < 5 DM;
B 5ΠΜ < EC50(mean ail) < 10 ΠΜ;
C EC5o (mean ail) > 3.3 ΠΜ;
D EC50 (mean ail) >10 CM.
As can be seen in Tables 1-5, a lot of compounds of the invention showed positive effect on the survial of the A/PR/8/34 infected cells, and inhibitory effect on the réplication of A/PR/8/34 influenza virus. Exemplary IC50 and EC50 values are as follows: Compound 428 had 0.03 ΠΜ of IC50; Compound 895 had 0.0008 DM of ICS0 and 0.001 ΠΜ of EC50;
Compound 833 had 5.6 ΠΜ of ICS0 and 3.5 DM of EC50.
Table 1: IC50, EC50, NMR and LCMS Data of Compounds of FIG. 3:
| I | E | LC M | LC | ||
| Compo | C | C | S_ | M | |
| und | 5 | 5 | Pl | S_ | |
| Nos. | 0 | 0 | us | RT | NMR |
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| 1 | A | 41 1.3 8 | 2.6 9 | H NMR (300.0 MHz, DMSO) d 12.32 (S, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.18-8.16 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 6.33 (t, J = 4.4 Hz, 0.25H), 6.15 (t, J = 4.3 Hz, 0.5H), 5.96 (t, J = 4.3 Hz, 0.25H), 4.22 (d, J = 7,6 Hz, 1H), 3.13 (d, J = 11.2 Hz, 1H), 2.88 (m, 1H), 2.81 (ddd, J = 15.5, 4.2, 4.2 Hz, 2H), 2.30 - 2.20 (m, 2H), 1.98 (m, 1H), 1.72-1.61 (m, 2H) and 1.491,36 (m, 1H) ppm | |
| 2 | 47 5 | 3.5 8 | 1H NMR (CD3OD): 1.1-1.3 (3H, m), 1.40- 1.50 (3H, m), 1.55-2.10 (4H, m), 2.40- 2.45 (1 H. m), 3.3-3.5 (2H, m), 3.75-4.10 (4H. m). 5.4-5.5 (1H. m), 8.05-8.20 (3H, m), 8.70-8.80 (1H, m) | ||
| 3 | 44 6.1 4 | 2.9 6 | 1H NMR (DMSO): 1.39 (4H, m), 1.542 (1H, m), 1.74 (2H, m), 2.33 (1H, m), 2.61 (1 H, m), 2.88 (1 H, m), 4.18 (1H, m), 4.37 (1H, m), 5.21 (1H, m), 6.84 (2H, d), 7.33 (2H, d), 7.60 (2H, m), 8.23 (3H, m), 8.63 (1H, d), 12.33 (1H, s) | ||
| 4 | D | 32 7 | 1.2 | 500MHz, MeOD-d4: 8.83(dd,1H), 8.45(s,1H), 8.42(dd,1H), 8.32(d,1H),7.65(d,2H), 7.42(dd,1H), 7.18(d,2H), 4.55(m,1H), 3.4(m,1H), 2.3(s,3H),2.2(m,2H), 1.95(m,2H), 1.5(m,4H) | |
| 5 | 38 5,3 | 1.7 4 | |||
| 6 | 40 1.3 | 1.6 8 | |||
| 7 | D | 37 1.1 | 1.6 3 | ||
| 8 | 42 1.1 | 1.8 2 | H NMR (500 MHz, DMSO-d6) 12.98 (s, 1H), 9.24 (s, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.21 (d, J |
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| = 7.0 Hz, 1H), 6.65 (d, J = 6.7 Hz, 1H), 3.81 - 3.43 (m, 4H), 2.36 (t, J = 1.8 Hz, 1H), 2.19 (d, J = 10.1 Hz, 1H), 1.62 (s, 6H), 0.00 (TMS) | |||||
| 9 | 40 3.1 | 1.6 9 | H NMR (500 MHz, DMSO-d6) 13.01 (s, 1H), 9.40 (s, 1H), 8.85 (d, J = 6.9 Hz, 1H), 8.63 (s, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 7.0 Hz, 1H), 6.66 (s, 1H), 5.29 - 5.05 (m, 1H), 3.86 - 3.16 (m, 4H), 1.65 (d, J = 10.6 Hz, 2H), 1.60 (s, 6H), 0.00 (TMS) | ||
| 10 | 40 3.1 | 1.7 4 | H NMR (500 MHz, DMSO-d6) 12.99 (d, J =6.1 Hz, 1H), 9.39 (s, 1H), 8.84 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 8.18 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.295.05 (m, 1H), 3.87 - 3.15 (m, 4H), 1.64 (d, J = 10.8 Hz, 2H), 1.59 (s, 6H), 0.00 (TMS) | ||
| 11 | A | A | 36 2.2 | 1.8 | |
| 12 | D | 37 6.2 | 1.9 | ||
| 13 | A | 36 2.2 | 1.8 | ||
| 14 | B | A | (400 MHz, DMSO-d6) : 12.80 (s, exchanged with D2O, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.22 (d, J=2.8 Hz, 1H), 8.14 (d, J=4.0 Hz, 1H), 7.46 (br. d, J=6.4 Hz, exchanged with D2O, 1 H),4.82 (d, J=3.6 Hz, 1H), 4.27 (quintet, J=6.4 Hz, 1H), 4.14 (quintet, J=5.6 Hz, 1H), 2.202.10 (m, 1H), 1.94-1.77 (m, 1H), 1.771.70 (m, 2H), 1.65-1.50 (m, 2H). | ||
| 15 | B | A | 46 1.3 | 2.6 8 | H NMR (300 MHz, DMSO-d6) 12.32 (s, 1 H), 8.72 (d, J = 2.5 Hz, 1 H), 8.28 (d, J = 2.4 Hz, 1 H), 8.19-8.15(01, 1 H), 7.75 (d, J = 5.3 Hz, 1 H), 3.89 (s, 1 H), |
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| 3.69 (s, 1 H), 3.53 - 3.45 (m, 2 H), 3.45 (s, 1 H), 2.89 - 2.49 (m, 2 H), 1.90-1.68 (m, 3 H), 1.28 (m, 2 H), 1.28 (s, 9 H) | |||||
| 16 | D | A | 46 1.3 | 2.6 3 | H NMR (300 MHz, DMSO-d6) 12.31 (s, 1 H), 8.71 (d, J = 2.5 Hz, 1 H), 8.27 (d, J = 2.4 Hz, 1 H), 8.20 - 8.15 (m, 2 H), 7.74 (d, J = 5.9 Hz, 1 H), 3.88 (d, J = 3.8 Hz, 2 H), 3.71 (d, J = 11.3 Hz, 1 H), 3.53 - 3.35 (m, 3 H), 2.86 (t, J = 10.4 Hz, 1 H), 1.90 (s, 2 H), 1.68 (d, J = 9.1 Hz, 1 H), 1.41 (s, 2 H), 1.28 (s, 9 H), |
| 17 | B | A | 44 5.3 | 3.1 | |
| 18 | B | A | 44 3.3 | 2.9 | |
| 19 | D | 50 3.4 | 2.8 | ||
| 20 | B | 46 0.4 | 3 | ||
| 21 | A | A | 45 1.3 | 2.9 | |
| 22 | A | A | 48 6.3 | 2.9 | |
| 23 | A | A | 41 9.3 | 2.8 | |
| 24 | D | 46 3.2 | 2.8 | ||
| 25 | A | A | 49 0.3 | 2.6 | |
| 26 | A | A | 47 6.3 | 2.5 | |
| 27 | A | A | 44 6.4 | 2.7 | |
| 28 | D | A | 46 1.4 | 3.3 | |
| 29 | B | 41 8.3 | 2.4 |
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| 30 | B | A | 45 7.3 | 3.1 | |
| 31 | A | A | 41 1.2 | 2.2 2 | (400 MHz, DMSO-d6) : 12.73 (s, exchanged with D2O, 1H), 8.85 (s, 1H), 8.65 (d, J= 5.6Hz, 1H), 8.37 (d, J=6.8 Hz, 1H), 8.03-7.89 (m, 4H, addition of D2O changed to d, J = 7.6Hz, 1H), 4.03-3.98 (m, 1H), 3.603.50 (m, 1H), 2.18-1.95 (m, 2H), 1.771.23 (m, 6H). |
| 32 | A | A | 41 7.4 | 2.6 | |
| 33 | A | A | 43 3.3 | 3 | |
| 34 | A | 43 1.4 | 2.8 | ||
| 35 | D | 44 7.4 | 3.2 | ||
| 36 | A | A | 43 9.3 | 2.7 | |
| 37 | A | A | 40 3.3 | 2.4 | |
| 38 | A | A | 45 7.4 | 3.1 | |
| 39 | A | A | 44 4.4 | 2.6 | |
| 40 | D | 48 1.3 | 2.5 | ||
| 41 | A | A | 42 9.3 | 2.7 | |
| 42 | D | 45 9.3 | 3.1 | ||
| 43 | D | 46 0.3 | 2.4 | ||
| 44 | A | A | 47 1.3 | 2.8 | |
| 45 | A | A | 43 | 2.4 |
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| 3.3 | |||||
| 46 | D | 44 6.3 | 2.5 | ||
| 47 | A | A | 48 0.3 | 2.4 | |
| 48 | D | 47 1.3 | 2.4 | ||
| 49 | A | A | 42 9.3 | 2.7 | |
| 50 | D | 46 9.3 | 2.3 | ||
| 51 | A | A | 47 2.9 | 1.7 | |
| 52 | A | A | 44 1.3 | 1.9 | |
| 53 | B | 47 5.3 | 1.8 | ||
| 54 | B | 47 7.3 | 1.7 | ||
| 55 | A | A | 50 1.3 | 2.5 | |
| 56 | A | A | 47 9.3 | 2.9 | |
| 57 | A | A | 44 3.3 | 2.8 | |
| 58 | A | 48 3.3 | 2.9 | ||
| 59 | A | A | 42 9.3 | 2.7 | |
| 60 | A | A | 52 7 | 3.2 | |
| 61 | A | A | 46 5.3 | 2.8 | |
| 62 | A | A | 53 1.3 | 3.1 | |
| 63 | D | 53 9.3 | 3.2 |
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| 64 | B | A | 51 9.3 | 3.1 | |
| 65 | A | A | 51 9.2 | 3.1 | |
| 66 | A | A | 51 5.3 | 3.2 | |
| 67 | A | A | 57 9.2 | 3.3 | |
| 68 | B | A | 48 1.4 | 3.2 | |
| 69 | A | A | 51 1.3 | 3 2 | |
| 70 | A | A | 51 5.3 | 3.3 | |
| 71 | B | 49 5.3 | 3.4 | ||
| 72 | B | 54 9.3 | 3.5 | ||
| 73 | B | 49 9.3 | 3.3 | ||
| 74 | A | A | 44 5.2 | 3.1 | |
| 75 | A | A | 49 8.3 | 3 | |
| 76 | A | A | 51 0.3 | 2.9 | |
| 77 | B | 52 2.3 | 2.8 | ||
| 78 | A | A | 49 4.3 | 3 | |
| 79 | B | 54 8.3 | 3.3 | ||
| 80 | A | A | 50 3.3 | 1.9 | |
| 81 | A | A | 52 9.3 | 2 | |
| 82 | D | 51 | 1.6 |
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| 1,3 | |||||
| 83 | D | 47 3,4 | 1.6 | ||
| 84 | A | A | 49 9.4 | 2 | |
| 85 | B | A | 50 1.3 | 2.1 | |
| 86 | A | A | 50 1.3 | 2.1 | |
| 87 | A | A | 50 1.3 | 2.1 | |
| 88 | A | A | 56 1.3 | 2 | |
| 89 | A | A | 50 7.2 | 2.1 | |
| 90 | A | A | 51 9.2 | 2.1 | |
| 91 | A | A | 50 5.3 | 1.8 | |
| 92 | A | A | 43 7.2 | 2.7 | |
| 93 | A | A | 45 1.2 | 2.9 | |
| 94 | A | A | 49 5,3 | 2.9 | |
| 95 | A | A | 47 1.3 | 3.2 | |
| 96 | B | 53 5.2 | 2.9 | ||
| 97 | A | A | 47 1.2 | 2.9 | |
| 98 | A | A | 49 7.3 | 2.9 | |
| 99 | A | A | 45 7.3 | 3.1 | |
| 100 | A | A | 47 1.3 | 3.1 |
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| 101 | A | A | 46 7.2 | 2.5 | |
| 102 | A | A | 45 5.3 | 2.7 | |
| 103 | A | 50 9.3 | 2.8 | ||
| 104 | A | A | 48 5.3 | 2.8 | |
| 105 | A | A | 44 5.3 | 3 | |
| 106 | A | A | 50 9.3 | 3 | |
| 107 | A | A | 52 1.3 | 3.2 | |
| 108 | A | A | 50 1.3 | 2.8 | |
| 109 | A | A | 52 5.3 | 2.7 | |
| 110 | A | A | 46 1.3 | 2.5 | |
| 111 | A | A | 40 3.2 | 2.4 | |
| 112 | A | A | 49 4.3 | 3 | |
| 113 | A | A | 49 5.3 | 2.8 | |
| 114 | D | 44 2.5 | 1.6 | ||
| 115 | D | 37 7.2 | 1.2 86 | (400 MHz, DMSO-d6) : 12.99 (m, exchanged with D2O, 1 H), 9.01 (m, exchanged with D2O, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 8.32 (overlapped s, 1H), 8.29 (overlapped br.s, exchanged with D2O,1H), 7.507.20 (m, exchanged with D2O, 1H), 4.47 -4.40 (m, 1 H), 3.53 -3.45 (m, 1H), 2.19 (br. d, J=10.0Hz, 1H), 2.08 (br. d, |
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| J=10.4 Hz, 1H), 1.84 (br. d, J=10.4 Hz, 2H), 1.60-1.29 (m, 4H). | |||||
| 116 | D | 35 7.2 | 3.2 67 | (400 MHz, DMSO-d6) : 12.70 (br. hump, exchanged with D2O, 1H), 8.72 (s, 1 H), 8.36 (s, 1H), 8.20-8.06 (overlapped hump, exchanged with D2O, 1H, + a s for an impurity), 7.47 (d, J=7.6 Hz, 1H), 7.35-7.0(overlapped m, exchanged with D2O, 2H), 7.10 (overlapped d, J=8.0 Hz, 1 H), 4.394.35 (m, 1H), 3.16-3.10 (m, 1H), 2.28 (s, 3H), 2.18-1.35 (m, 8H). | |
| 117 | A | A | 48 6.3 | 2.8 | |
| 118 | B | 50 4.2 | 2.6 | ||
| 119 | A | A | 44 5.4 | 3.1 | |
| 120 | A | A | 55 2.4 | 3.2 | |
| 121 | D | 44 6.4 | 2.2 | ||
| 122 | A | A | 44 3.3 | 2.9 | |
| 123 | B | A | 46 1.5 | 3.4 | |
| 124 | A | A | 43 9.3 | 3.1 | |
| 125 | A | A | 49 0.4 | 2.6 | |
| 126 | A | A | 45 1.3 | 2.9 | |
| 127 | A | A | 45 7.3 | 3.1 | |
| 128 | A | A | 46 0.4 | 3 | |
| 129 | A | A | 48 | 2.9 |
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| 6.4 | |||||
| 130 | A | 50 0.6 | 2 | ||
| 131 | A | A | 46 2.7 | 1.6 | |
| 132 | D | 44 9.7 | 2.2 | ||
| 133 | D | 40 5.3 | 2.3 | ||
| 134 | B | 45 7.3 | 3.1 | ||
| 135 | D | 43 3.4 | 2.5 | ||
| 136 | D | 46 9.3 | 3.2 | ||
| 137 | D | 46 5.4 | 3.1 | ||
| 138 | D | 45 9.3 | 2.8 | ||
| 139 | D | 46 5.3 | 3.2 | ||
| 140 | D | 45 9.3 | 2.9 | ||
| 141 | D | 43 3.5 | 1.4 | ||
| 142 | A | A | 54 1.5 | 2.8 | |
| 143 | A | A | 47 9.4 | 2.9 | |
| 144 | D | A | 53 3.3 | 3 | |
| 145 | A | A | 50 7.3 | 2.9 | |
| 146 | A | A | 53 3.3 | 3 | |
| 147 | A | A | 53 3.3 | 3.2 |
-38516260
| 148 | A | A | 50 9.3 | 3 | |
| 149 | A | A | 50 9.4 | 3 | |
| 150 | B | 55 7.3 | 3.2 | ||
| 151 | A | A | 50 1.4 | 2.9 | |
| 152 | A | A | 50 1.2 | 2,9 | |
| 153 | A | A | 49 5.3 | 2.8 | |
| 154 | B | A | 52 5.4 | 2.8 | |
| 155 | A | A | 47 9.4 | 2.9 | |
| 156 | A | A | 49 9.4 | 3 | |
| 157 | A | A | 49 3.1 | 2 | |
| 158 | A | 51 0 | 2 | ||
| 159 | B | A | 41 8.3 | 2 3 | |
| 160 | D | A | 45 1.4 | 2.1 | |
| 161 | D | A | 46 3.4 | 2.8 | |
| 162 | D | A | 48 0.3 | 2.8 | |
| 163 | B | A | 46 7.4 | 3.1 | |
| 164 | D | A | 44 3.5 | 3 | |
| 165 | D | 47 2.5 | 2.8 | ||
| 166 | B | A | 41 | 2.9 |
-38616260
| 9.5 | |||||
| 167 | D | B | 44 4.4 | 2.7 | |
| 168 | B | A | 43 2.3 | 2.6 | |
| 169 | D | B | 49 0.5 | 2.7 | |
| 170 | D | A | 44 6.4 | 2.7 | |
| 171 | D | B | 43 3.3 | 3 | |
| 172 | D | 49 5.5 | 3.2 | ||
| 173 | A | A | 40 3.3 | 2.5 | |
| 174 | D | 49 5.6 | 2.8 | ||
| 175 | A | A | 41 8.5 | 2.4 | |
| 176 | D | A | 46 7,3 | 2.3 | |
| 177 | A | A | 44 4.4 | 2.7 | |
| 178 | A | A | 44 6.4 | 2.8 | |
| 179 | A | A | 40 3.4 | 2.5 | |
| 180 | A | A | 45 1.3 | 2.9 | |
| 181 | B | A | 44 3.4 | 3 | |
| 182 | A | A | 43 2.3 | 2.6 | |
| 183 | B | A | 43 3.3 | 3 | |
| 184 | D | 49 5.5 | 2.7 |
-38716260
| 185 | A | A | 46 3.4 | 2.8 | |
| 186 | A | A | 47 2.4 | 2.8 | |
| 187 | A | A | 48 0.3 | 2.8 | NMR 1H (CDCI3): 8.7 (s, 1H), 8.6 (s, 1H), 8.3 (s, IH), 8.1 (s, 1H), 4.7 (m, 1H), 4.2 (m, 1 H), 1.3-3.7 (m, 15H). |
| 188 | A | A | 41 9.4 | 2.9 | |
| 189 | A | A | 49 0.5 | 2.7 | |
| 190 | B | 49 5.4 | 3.1 | ||
| 191 | A | A | 44 6.3 | 2.7 | |
| 192 | A | A | 46 0.4 | 2.9 | |
| 193 | B | A | 47 4.4 | 3.1 | |
| 194 | A | A | 43 1.2 | 2.9 | |
| 195 | B | 51 3.2 | 2.5 | ||
| 196 | A | A | 43 2.1 | 2.6 | |
| 197 | A | A | 44 6.2 | 2.7 | |
| 198 | A | A | 45 3.1 | 2.9 | |
| 199 | A | A | 43 9.1 | 2.8 | |
| 200 | A | A | 45 3.1 | 2.9 | |
| 201 | D | A | 48 1.1 | 2.6 | |
| 202 | A | A | 47 8.2 | 2.7 |
-38816260
| 203 | A | A | 45 8.2 | 2.8 | |
| 204 | A | A | 46 2.2 | 2.5 | |
| 205 | A | A | 47 6.2 | 2.6 | |
| 206 | A | 32 7.2 | 1.8 5 | H NMR (300.0 MHz, DMSO) d 12,14 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.29 8.22 (m, 3H), 7.81 (s, 2H), 7.28 - 7.19 (m, 2H), 4.55 (s, 1 H), 3.74 (s, 1 H) and 1.92- 1.49 (m, 8H) ppm | |
| 207 | A | A | 32 8.2 | 2.2 2 | |
| 208 | A | A | 41 7.2 | 1.9 | |
| 209 | A | A | 48 3.1 | 2 | |
| 210 | D | B | 53 3.1 | 2.2 | |
| 211 | B | 36 9.3 | 2.2 7 | ||
| 212 | A | 38 3.3 | 2.4 2 | ||
| 213 | D | 41 7.3 | 2.4 5 | ||
| 214 | D | 44 7.3 | 2.3 5 | ||
| 215 | D | 38 4.3 | 2.2 7 | ||
| 216 | D | 35 5.3 | 2.0 8 | ||
| 217 | B | 35 5.3 | 1.9 3 | ||
| 218 | A | A | 36 9.4 | 2.0 8 | |
| 219 | D | 38 3.3 | 2.2 3 |
-38916260
| 220 | A | 38 4.3 | 2.1 2 | ||
| 221 | B | 41 7.3 | 2.3 4 | ||
| 222 | D | 44 7.3 | 2.2 5 | ||
| 223 | B | 36 9.3 | 2.1 2 | ||
| 224 | B | 38 3.3 | 2.2 7 | ||
| 225 | B | 39 7.4 | 2.3 8 | ||
| 226 | A | 43 1.3 | 2.4 9 | ||
| 227 | B | 46 1.3 | 2.4 9 | ||
| 228 | B | 39 8.3 | 2.3 1 | ||
| 229 | D | 37 0.3 | 2.0 5 | ||
| 230 | D | 38 4.3 | 2.2 3 | ||
| 231 | D | 39 8.3 | 2.3 5 | ||
| 232 | B | 43 2.3 | 2.6 | ||
| 233 | B | A | 37 0.3 | 1.9 | |
| 234 | B | 38 4.3 | 2.0 4 | ||
| 235 | B | 39 8.3 | 2.2 | ||
| 236 | B | 43 2.4 | 2.3 8 | ||
| 237 | B | 38 4.3 | 2.0 5 | ||
| 238 | B | 39 | 2.1 |
-39016260
| 8.3 | 9 | ||||
| 239 | D | 36 9.3 | 2.2 7 | ||
| 240 | D | 38 3.3 | 2.4 3 | ||
| 241 | B | 41 7.3 | 2.4 8 | ||
| 242 | D | 44 7.3 | 2.4 5 | ||
| 243 | D | 38 4.4 | 2.2 6 | ||
| 244 | D | 35 5.3 | 1.9 7 | ||
| 245 | B | 36 9.3 | 2.0 8 | ||
| 246 | D | 38 3.3 | 2.1 9 | ||
| 247 | D | 38 4.3 | 2.1 5 | ||
| 248 | D | 37 0.3 | 2.0 5 | ||
| 249 | D | 38 4.3 | 2.2 3 | ||
| 250 | D | 39 6.5 | 2.3 6 | ||
| 251 | B | 43 2.3 | 2.6 4 | ||
| 252 | D | 37 0.4 | 1.8 9 | ||
| 253 | D | 38 2.4 | 1.9 9 | ||
| 254 | D | 39 8.3 | 2.1 2 | ||
| 255 | B | 43 2.4 | 2.3 7 | ||
| 256 | B | 36 9.3 | 2.2 |
-39116260
| 257 | B | 38 3.3 | 2.3 1 | ||
| 258 | B | 39 7.3 | 2.4 6 | ||
| 259 | B | 43 1.3 | 2.4 2 | ||
| 260 | D | 46 1.3 | 2.3 6 | ||
| 261 | B | 39 8.3 | 2.3 5 | ||
| 262 | D | 41 2.4 | 2.2 7 | ||
| 263 | B | 44 6.3 | 2.6 | ||
| 264 | B | 38 4.3 | 2.1 2 | ||
| 265 | D | 39 8.4 | 2.2 3 | ||
| 266 | B | 41 2.3 | 2.3 8 | ||
| 267 | B | 44 6.4 | 2.6 | ||
| 268 | B | 36 9.3 | 2.0 8 | ||
| 269 | B | 38 3.3 | 2.2 7 | ||
| 270 | B | 39 7.3 | 2.4 2 | ||
| 271 | B | 43 1.4 | 2.4 9 | ||
| 272 | D | 46 1.3 | 2.4 6 | ||
| 273 | B | 39 8.3 | 2.3 1 | ||
| 274 | B | 38 4.3 | 2.0 5 | ||
| 275 | B | 39 | 2.2 |
-39216260
| 8.4 | |||||
| 276 | D | 41 2.4 | 2.3 1 | ||
| 277 | A | A | 32 8.2 | 1.5 6 | |
| 278 | D | 46 5.1 | 2.4 | ||
| 279 | A | A | 44 3.2 | 2.1 | |
| 280 | A | A | 47 1.2 | 2.1 | |
| 281 | A | A | 45 5.2 | 2.1 | |
| 282 | A | A | 48 6.1 | 2 | |
| 283 | B | 57 8.2 | 2.4 | ||
| 284 | A | A | 45 8.2 | 2 | |
| 285 | D | 49 8.2 | 1.6 | ||
| 286 | D | 51 6.2 | 1.7 | ||
| 287 | D | 48 8.2 | 1.9 | ||
| 288 | B | 48 8.2 | 1.9 | ||
| 289 | D | 50 1.2 | 1.6 | ||
| 290 | B | 52 9.2 | 1.8 | ||
| 291 | D | 48 8.2 | 1.9 | ||
| 292 | D | 48 1.2 | 1.6 | ||
| 293 | A | A | 49 3.2 | 3.1 |
-39316260
| 294 | D | 48 5.2 | 3.3 | ||
| 295 | A | A | 43 1.2 | 2.9 | |
| 296 | B | (400 MHz, CDCI3) : 8.85 ( d. J = 2.0Hz, 1H), 8.80 ( br s, 1H), 8.29 ( d, J = 2.4Hz, 1H), 8.11 ( d, J = 2.8Hz, 1 H), 8.07 (d, J = 3.2Hz, 1H), 6.19( br. hump, 1H), 5.16 ( qunîtet, J = 7.6Hz, 1 H), 3.78-3.50 ( sériés of m, 4H), 2.161.91( sériés of m, 4H), 1.58 ( d, J = 7.6Hz, 3H) | |||
| 297 | B | (400 MHz, CDCI3) : 8.95 ( br. hump, exchanged withy D2O, 1H), 8.83 ( d, J = 2.0Hz, 1H), 8.29( d, J = 2.4Hz, 1H), 8.11 ( d, J = 2.4 Hz, addtion of D2O changed to s, 1 H), 8.07 ( d, J = 3.2Hz, 1H), 6.40( br. d, J = 5.6Hz, 1H), 5.16 ( qunitet, J = 6.8Hz, addition of D2O changed to q, J = 6.8Hz, 1H), 3,073.50 ( sériés of m, 4H), 1.70-1.60 ( sériés of m, 6H), 1.55 ( d, J = 6.4Hz, 3H) | |||
| 298 | D | (400 MHz, CDCI3) : (400 MHz, CDCI3) : 9.15 ( br. hump, exchanged with D2O, 1H), 8.83 (d, J = 2.4Hz, 1H), 8.30( d, J = 2.4Hz, 1H), 8.11 ( d, J = 2.8Hz, 1H), 8.07 (d, J = 3.2Hz, 1 H), 6.29 (d, J 6.4Hz, exchanged with D2O, 1H), 5.30 ( quintet, J = 6.8Hz, addtion of D2O changed wtih q, J = 6.8Hz, 1H), 3.90-3.80 ( m, 4H), 2.60-2.40 ( m, 4H), 2.33 (s, 3H), 1.57( d, J= 7.2 Hz, 3H). | |||
| 299 | D | (400 MHz, CDCI3) : 9.15 ( br. hump, exchanged with D2O, 1H), 8.83 ( br. s , 1H), 8.30 ( br. s, 1H), 8.11-8.07 (m, 2H), 6.99 ( br. s, exchanged with D2O, 1H), 5.40-5.30 (m, 1H), 3.90-3.40 ( |
-39416260
| m, 8H), 2.14 ( s, 3H), 1.57 (d overlapped with moisture, J= 7.2 Hz, 3H). | |||||
| 300 | B | (400 MHz, CDCI3) : 9.10 ( br. hump, exchanged with D2O, 1 H), 8.83 ( br. s, 1H), 8.30 ( br. s, 1H), 8.11 (br. s, 1H), 8.09 (d, J = 1.2Hz, 1H), 6.24 ( br. d, J = 5.2Hz, exchanged with D2O, 1 H), 5.30 ( quintet, J = 7.2Hz, addtion of D2O changed wtih q, J = 6.8Hz, 1 H), 3.90-3.80 ( m, 8H), 1.54 (overlaped d, J= 7.2 Hz, 3H). | |||
| 301 | B | 46 0.4 | 1.7 12 | (400 MHz, DMSO-d6, 7) : 8.69 (d, J=2.4 Hz, 1H), 8.25 (d, J=2.8 Hz, 1H), 8.19 (d, J=3.6 Hz, 1H), 8.16 (br.s, 1H), 5.25-5.15 (m, 1H), 3.82-3.25 (m, 8H), 1.93 (br. s, 3H), 1.80-170 ( m, 2H), 1.43 (d, J=6.8 Hz, 3H). | |
| 302 | B | (400 MHz, DMSO-d6) : 8.56 (d, J=2.0 Hz, 1H), 8.31 (br. s, 1H), 8.13 (d, J=1.6 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H), 5.17 (dq, J=7.6, 6.8 Hz, 1H), 3.77-3.70 ( m, 1H), 3.67-3.49 (m, 3H), 2.10-2.01 (m, 2H), 1.95-1.90 (m, 2H), 1.57 (d, J=6.8 Hz, 3H). | |||
| 303 | D | (400 MHz, DMSO-d6) :9.375 ( br. hump, exchanged with D2O, 1 H), 8.84 (d, J=1.6 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.0Hz, 1H), 8.07 (d, J=3.2 Hz, 1H), 6.36 ( br. d, J = 6.8Hz, 1 H), 5,33 (q,J= 6.8 Hz, 1H), 3.71-3.61 (m, 4H), 1.71-1.61 (m, 6H), 1.56 (d, J=6.4 Hz, 3H). | |||
| 304 | D | (400 MHz, DMSO-d6) : 9.09 (s, exchanged with D2O, 1 H), 8.83 (d, J=2.0 Hz, 1H), 8.31 (br. s, 1H), 8.12 (d, J=2.8 Hz, 1H), 8.08 (d, J=3.6 Hz, 1H), 6.28 (d, J = 6.8Hz, exchanged with |
-39516260
| D2O, 1H), 5.31 (dq J=7.2, 6.8 Hz, 1H), 3.80-3.70 (m, 4H), 2.55-2.40 (m, 4H), 2.34 (s, 3H), 1.56 (d,J=7.2 Hz, 3H). | |||||
| 305 | A | A | 46 0.3 | 2.5 8 | |
| 306 | A | A | 45 3.2 | 2.5 | |
| 307 | D | 46 2.3 | 2.4 18 | (400MHz, CDCI3): 8.90 (br. s, exchanged with D2O, 1 H), 8.80 ( d, J = 2.0Hz, 1H), 8.31 ( d, J = 2.8Hz, 1H), 8.10 ( s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 6.20 ( br. s, exchanged with D2O, 1H), 5.40-5.35( m, 1H), 3.74 ( s, 3H), 3.903.40 ( sériés of m, 8H), 1.58 ( d, J = 7.6Hz, 3H) | |
| 308 | D | (400MHz, CDCI3): 9.11 ( s, exchanged with D2O, 1H), 8.80 ( s, 1 H), 8.31 (s, 1H), 8.10-8.08 (m, 2H), 6.17 ( br. s, exchanged with D2O, 1 H), 5.40-5.35 ( m, 1 H), 3.90-3.40 ( sériés of m, 8H), 2.14 ( s,3H), 1.59 ( overlapped d, J = 6.4Hz, 3H) | |||
| 309 | B | (400MHz, DMSO-d6): 12.07 ( s, exchanged with D2O, 1H), 8.69 ( d, J = 2.4Hz, 1 H), 8.25( d, J = 2.4Hz, 1H), 8.18 (d, J = 3.6Hz, 1H), 8.17 ( overlapped br. s, 1H), 7.16 ( br. s, 1 H), 5.20-5.05 ( m, 1 H), 3.90-3.40 ( sériés of m, 8H), 2.56 ( overlapped s with DMSO-d6 signal, 3H), 1.43( br. s, 3H), 1.40-1.20 (m, 2H) | |||
| 310 | D | (400MHz, CDCI3): 9.28 ( s, exchanged with D2O, 1H), 8.81 ( d, J = 2.0Hz, 1H), 8.29 (d, J = 2.0Hz, 1 H), 8.11 (d, J = 3.3Hz, 1H), 8.10 (d, J = 2.4Hz, 1H), 6.22 ( br. d, J = 6.4Hz, 1H), 5.32 ( quiniet, 6.4Hz, addition of D2O changed to q, J = 6.4Hz, 1H), 3.74 ( s, |
-39616260
| 3H), 3.68- 3.49 ( sériés of m, 8H), 1.57 ( d, J = 6.4Hz, 3H) | |||||
| 311 | D | (400MHz, CDCI3): 9.04 ( s, exchanged with D2O, 1H), 8.81 ( d, J = 2.0Hz, 1H), 8.29 (br. d, J = 2.0Hz, 1 H), 8.11 (d, J = 2.4Hz, 1H), 8.09 ( d, J = 3.2Hz, 1H), 6.23( br. d, J = 6.8Hz, 1H), 5,31 ( quiniet, J = 6.8Hz, addition of D2O changed to q, J = 6.8Hz, 1H), 3.683.49 (sériés of m, 8H), 1.57 (d, J = 6.8Hz, 3H) | |||
| 312 | A | A | (400MHz, CDCI3):9.72 ( s, exchanged with D2O, 1H), 8.83 ( d, J = 2.4Hz, 1H), 8.29 (d, J = 2.0Hz, 1H), 8.13 (d, J = 2.0Hz, 1H), 8.08 ( d, J = 4.4Hz, 1H), 6.07 ( d, J = 7,6Hz, exchanged with D2O, 1H), 4,95 ( qunitet, J = 7.2Hz, 1H), 4.68 ( q, J = 7.6Hz, 1H), 4.36 ( d, J = 8.4Hz, 1H), 4.18-4.07 ( m, 2H), 2.40-2.30 ( m, 2H), 1.54 ( d, J = 7.2Hz, 3H). | ||
| 313 | B | A | (400MHz, DMSO-d6, 80oC): 12.07 ( s, exchanged with D2O, 1H), 8.71 ( d, J = 2.4Hz, 1H>, 8.26 (d, J = 2.0Hz, 1 H), 8.21 (d, J = 2.0Hz, 1H), 8.17( br. s, 1H), 7.14 ( br. s , exchanged with D2O, 1H), 5.20-5.10 (m, 1H), 3.70-3.50 ( m, 8H), 1.54 ( d, J = 7.2Hz, 3H), 1.951.80 (m, 2H) | ||
| 314 | B | B | (400MHz, CDCI3):9.80 ( s, exchanged with D2O, 1H), 8.83 ( d, J = 2.4Hz, 1H), 8.30( d, J = 2.0Hz, 1H), 8.13 ( d, J = 2.0Hz, 1 H), 8.08 ( d, J = 4.4Hz, 1 H), 6.08 ( d, J = 6.4Hz, exchanged with D2O, 1 H), 4,95 ( qunitet, J = 7.2Hz, 1H), 4.68 ( q, J = 7.6Hz, 1H), 4.36 ( d, J = 8.0Hz, 1H), 4.18-4.07 ( m, 2H), 2.40-2.30 ( m, 2H), 1.55 ( d, J = 7,2Hz, |
-39716260
| 3H). | |||||
| 315 | B | D | (400MHz, DMSO-d6, 80oC): 12.08 ( s, exchanged with D2O, 1 H), 8.69 ( d, J = 2.4Hz, 1H), 8.24 (d, J = 2.0Hz, 1H), 8.18 (d, J = 2.0Hz, 1H), 8.16 (br. s, 1H), 7.14 (br.d, J = 7.2Hz, exchanged withD2O, 1H), 5.20-5.10 (m, 1 H), 3.70-3.50 ( m, 8H), 1.46 ( d, J = 7.2Hz, 3H), 1.95-1.80 (m, 2H) | ||
| 316 | B | A | 45 3.3 | 2.4 8 | |
| 317 | B | A | 41 5.1 | 2.7 | |
| 318 | D | A | 43 1.1 | 2.9 | |
| 319 | D | A | 42 9.1 | 2.8 | |
| 320 | B | B | 43 3.1 | 2.5 | |
| 321 | B | A | 43 9.1 | 2.7 | |
| 322 | D | A | 45 3.1 | 2.9 | |
| 323 | D | A | 44 6.2 | 2.7 | |
| 324 | B | A | 43 2.2 | 2.6 | |
| 325 | B | A | 42 9.2 | 2.7 | |
| 326 | B | A | 44 5.2 | 3 | |
| 327 | A | A | 44 7.2 | 1.8 | |
| 328 | D | 46 7.1 | 2.2 | ||
| 329 | D | 48 1.2 | 2.3 |
-39816260
| 330 | A | A | 50 1.1 | 2.2 | |
| 331 | A | A | 46 5.1 | 2.2 | 1H NMR (300.0 MHz, MeOD) d 8.83 (d, J = 2.3 Hz, 1 H), 8.24 (s, 1 H), 8.22 (d, J = 2.4 Hz, 1 H), 8.01 (d, J = 3.9 Hz, 1 H), 4.44 (m, 1 H), 4.06 (dd, J = 9.2, 13.8 Hz, 1H), 3.77 (dd, J = 6.3, 13.8 Hz, 1H), 3.71 (m, 1H), 2.47 (m, 1H), 1.87- 1.66 (m, 6H) and 1.00 - 0.92 (m, 4H) ppm |
| 332 | A | A | 43 1.2 | 2 | |
| 333 | B | 41 7.4 | 2.7 | ||
| 334 | B | 43 1.4 | 2.8 5 | ||
| 335 | D | 45 7.3 | 3.1 4 | ||
| 336 | D | 46 5.4 | 3.0 3 | ||
| 337 | B | A | 43 9.3 | 2.6 6 | |
| 338 | D | 46 7.3 | 2.9 3 | ||
| 339 | B | 44 6.3 | 2.8 5 | ||
| 340 | A | A | 40 3.3 | 2.6 | |
| 341 | D | 38 3.4 | 2.3 | H NMR (300.0 MHz, DMSO) d 12.47 (s, 1H), 8.65 (d, J = 8.1 Hz, 1H), 8.498.23 (m, 3H), 7.61 (d, J = 7.8 Hz, 1H), 7.29 (dd, J = 4.7, 8.0 Hz, 1H), 4.39 (d, J = 19.5 Hz, 2H), 2.10 (q, J = 7.6 Hz, 2H), 1.79- 1.64 (m, 6H), 1.48 (d, J = 6.4 Hz, 2H) and 0.91 (t, J = 7.6 Hz, 3H) ppm | |
| 342 | D | 39 7.4 | 2.4 8 |
-39916260
| 343 | D | 42 3.4 | 2.7 1 | ||
| 344 | D | 43 1.4 | 2.6 7 | ||
| 345 | D | 40 5.3 | 2.3 | H NMR (300.0 MHz, DMSO) d 12.47 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.45- 8.34 (m, 3H), 7.29 (dd, J = 4.8, 7.8 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 4.47- 4.25 (m, 1H), 4.05-3.89 (m, 1H), 2.80 (s, 3H), 1.95- 1.62 (m, 6H) and 1.491.24 (m, 2H) ppm | |
| 346 | D | 43 3.3 | 2.5 6 | H NMR (300.0 MHz, DMSO) d 12.41 (s, 1H), 8.65 (d, J = 7.8 Hz, 1 H), 8.388.33 (m, 3H), 7.28 (dd, J = 4.7, 7.9 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 4.36 (s, 1 H), 3.88 (s, 1 H), 2.83 (t, J = 7.7 Hz, 2H), 1.85 - 1.70 (m, 6H), 1.59 (q, J = 7.8 Hz, 2H), 1.47 - 1.24 (m, 2H) and 0.82 (t, J = 7.4 Hz, 3H) ppm | |
| 347 | D | 41 2.4 | 2.4 1 | H NMR (300.0 MHz, DMSO) d 12.47 (s, 1 H), 8.64 (d, J = 7.8 Hz, 1 H), 8.45 8.34 (m, 3H), 7.29 (dd, J = 4.8, 7.8 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 4.474.25 (m, 1H), 4.05 - 3.89 (m, 1H), 2.80 (s, 3H), 1.95 - 1.62 (m, 6H) and 1.49 1.24 (m, 2H) ppm | |
| 348 | D | 36 9.4 | 2.1 9 | H NMR (300.0 MHz, DMSO) d 12.53 (s, 1H), 8.66 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 8.39 - 8.36 (m, 2H), 7.91 (d, J = 7.9 Hz, 1H), 7.32 (dd, J =4.7, 7.9 Hz, 1H), 4.08 - 3.94 (m, 1H), 3.86 (d, J = 8.4 Hz, 1H), 2.13 (d, J = 24.3 Hz, 1H), 1.95 (d, J = 10.2 Hz, 1H), 1.81 -1.73 (m, 2H), 1.73 (s, 3H) and 1.43-1.14 (m, 4H) ppm | |
| 349 | D | 41 7.3 | 2.7 4 | ||
| 350 | B | 41 | 2.7 |
-40016260
| 7.3 | 4 | ||||
| 351 | D | 45 7.3 | 3.1 1 | ||
| 352 | D | 46 5.3 | 3.0 3 | ||
| 353 | D | 43 9.4 | 2.7 4 | ||
| 354 | D | 46 7.3 | 3.0 4 | ||
| 355 | D | 44 6.3 | 2.8 1 | ||
| 356 | D | 38 3.4 | 2.3 3 | ||
| 357 | D | (400 MHz, CDCI3, 75oC) : 12.07 (br. s exchanged with d2O, 1H), 8.69 (s, J=2.4 Hz, 1H), 8.25 (s, J=4.0 Hz, 1H), 8.19 (s, J=4.0 Hz, 1H), 8.15 (br. s, 1H), 7.15 ( br. s, exchanged with D2O, 1H), 5.20-5.10 (q, 1H), 3.62-3.55 (m, 8H), 3.03 (s, 3H), 1.76 (d, J=2.4 Hz, 2H), 1.43-1.41 (d, J=8,0Hz, 3H). | |||
| 358 | D | 39 7.4 | 2.4 5 | ||
| 359 | D | 42 3.4 | 2.6 7 | ||
| 360 | D | 43 1.4 | 2.6 3 | ||
| 361 | D | 40 5.3 | 2.3 7 | H NMR (300.0 MHz, DMSO) d 12.54 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.438.36 (m, 3H), 7.32 (dd, J = 4.7, 7.9 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.16 (d, J = 9.3 Hz, 1H), 3.35 (d, J = 9.8 Hz, 1H), 2.91 (d, J = 8.9 Hz, 3H), 2.12 - 2.02 (m, 2H), 1.79- 1.73 (m, 2H) and 1.641.15 (m, 4H) ppm | |
| 362 | D | 43 3.3 | 2.6 3 | H NMR (300.0 MHz, DMSO) d 12.43 (s, 1H), 8.68 (d, J = 7.9 Hz, 1H), 8.38- 8.33 (m, 3H), 7.29 (dd, J = 4.7, 7.8 Hz, |
-40116260
| 1H), 7.17 (d, J =8.6 Hz, 1H), 4.14 (d, J = 6.9 Hz, 1 H), 3.33 - 3.26 (m, 1 H), 3.07 - 2.89 (m, 2H), 2.07 (d, J = 12.6 Hz, 2H), 1.76 (d, J = 7.9 Hz, 2H), 1.61 - 1.33 (m, 6H) and 0.90 (t, J = 7.4 Hz, 3H) ppm | |||||
| 363 | D | 43 1.3 | 2.8 8 | ||
| 364 | D | 45 7.3 | 3.1 1 | ||
| 365 | D | 46 5.3 | 3.0 3 | ||
| 366 | A | A | 43 9.2 | 2.7 4 | |
| 367 | B | 46 7.3 | 2.9 9 | ||
| 368 | D | 44 6.3 | 2.8 1 | ||
| 369 | D | 43 1.3 | 2.8 5 | ||
| 370 | D | 41 2.4 | 2.4 1 | ||
| 371 | D | 41 2.2 | 1.7 8 | ||
| 372 | B | B | 42 4.2 | 1.8 7 | |
| 373 | B | D | 39 8.2 | 1.6 9 | |
| 374 | D | 38 4.2 | 1.6 1 | ||
| 375 | B | B | 41 2.2 | 1.8 | |
| 376 | B | 32 7.1 4 | 1.4 6 | ||
| 377 | I D | 31 3.3 | 1.3 8 |
-40216260
| 3 | |||||
| 378 | D | (300 MHz, DMSO-d6) : 12.35 ( br. s, exchanged with D2O, 1 H), 8.72 (d, J = 2.4Hz, 1H), 8.29 (d, J = 2.1Hz, 1H), 8.21 (s, 1H), 8.17 (d, J=3.9 Hz, 1H), 7.80 (br. s, exchanged with D20,1H), 7.10 ( s, exchanged with D2O, 1 H), 2.27-2.11 (m, 2H), 1.96 (m, 2H), 1.55 (m, 2H), 1.40-1.18 (m, 3H). | |||
| 379 | B | A | 36 1.3 | 2.3 | 1H NMR (300.0 MHz, MeOD) d 8.72 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.11-8.07 (m, 2H), 4.94 (t, J = 9.3 Hz, 1H), 3.64 - 3.51 (m, 2H), 2.97 (s, 3H), 2.68 - 2.54 (m, 1H) and 2.37 2.23 (m, 1H) ppm |
| 380 | B | 34 7.3 | 2.2 7 | 1H NMR (300.0 MHz, MeOD) d 8.79 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 8.07 (d, J = 3.9 Hz, 1H), 4.91 (dd, J = 8.7, 10.6 Hz, 1H), 3.61 - 3.46 (m, 2H), 2.68 - 2.58 (m, 2H) and 2.48 - 2.31 (m, 1H) ppm | |
| 381 | A | A | 43 9.3 | 2.7 2 | |
| 382 | A | A | 45 3.3 | 2.8 6 | |
| 383 | A | A | 50 7.3 | 3.0 1 | |
| 384 | A | 43 9.3 | 2.7 2 | ||
| 385 | A | 45 3.3 | 2.8 2 | ||
| 386 | A | 46 5.3 | 2.9 | ||
| 387 | B | 50 7.2 | 2.4 9 | ||
| 388 | D | 45 3.4 | 1.8 4 | ||
| 389 | A | A | 42 | 1.8 |
-40316260
| 5.3 | |||||
| 390 | A | A | 46 7.3 | 2.1 | |
| 391 | A | A | 45 1.3 | 1.9 | |
| 392 | A | A | 49 3.5 | 2.3 | |
| 393 | A | A | 43 9.3 | 1.8 | |
| 394 | A | A | 45 3.3 | 1.9 | |
| 395 | A | A | 42 9.3 | 1.9 | |
| 396 | A | A | 43 3.3 | 1.7 | |
| 397 | A | A | 37 5.3 6 | 2.2 1 | 1H NMR (300.0 MHz, DMSO) d 8.65 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.20-8.19 (m, 2H), 7.63 (d, J = 7.8 Hz, 1 H), 4.78 - 4.74 (m, 1 H), 3.41 (t, J = 5.4 Hz, 2H), 3.17 (MeOH), 2.89 (s, 3H), 2.50 (DMSO), 2.18 - 2.15 (m, 1H) and 1.99 (d, J = 7.4 Hz, 2H) ppm |
| 398 | A | A | 41 1 | 1.7 | |
| 399 | A | 42 5 | 1.8 | ||
| 400 | B | 43 9 | 1.9 | ||
| 401 | B | 43 7 | 1.9 | ||
| 402 | B | 45 3 | 2.1 | ||
| 403 | B | 46 5 | 2.1 | ||
| 404 | D | 43 9 | 2 | ||
| 405 | B | 41 | 1.7 |
-40416260
| 1 | |||||
| 406 | D | 45 3 | 2.1 | ||
| 407 | D | 42 5 | 1.8 | ||
| 408 | D | 43 9 | 1.9 | ||
| 409 | B | 43 7 | 1.9 | ||
| 410 | B | 43 9 | 2 | ||
| 411 | A | A | 36 1.4 | 1.9 4 | |
| 412 | A | A | 37 6.4 | 3.5 3 | |
| 413 | D | 36 1.3 | 2.4 1 | ||
| 414 | A | A | 36 1.3 | 2.4 6 | |
| 415 | D | 38 7 | 1.5 | ||
| 416 | A | A | 36 1.3 | 1.5 6 | |
| 417 | A | A | 37 5.3 | 1.6 8 | 1H NMR (300.0 MHz, DMSO) d 12.33 (S, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1 H), 8.21 (t, J = 3.7 Hz, 2H), 8.02- 7.98 (m, 1 H), 7.21 (d, J = 5.8 Hz, 1H), 4.86 (dd, J = 6.3, 10.5 Hz, 1H), 3.51 -3.41 (m, 1H), 3.25-3.16 (m, 1H), 2.13-1.85(111, 4H), 1.661.52 (m, 1H) and 1.40- 1.20 (m, 1H) ppm |
| 418 | A | 42 1.3 7 | 1.7 9 | 1H NMR (300.0 MHz, DMSO) d 13.11 (d, J =9.6 Hz, 1H), 13.05 (s, H), 9.30 (s, 1H), 8.72 (d, 1H), 8.62 (d, 1H), 8.49 (s, 1H), 8.18 (d, 1H), 6.83 (s, H), 6.72 (d, 1H), 4.30 (m, 1H), 3.88 (m, 1H), 3.76(m, 1H)3.46(m, 1H), 3.10-3.01 |
-40516260
| (m, 4H), 2.12 (m, 1H), 1,92 (m, 1H), 1.68-1.61 (m, 2H), 1.20 (t, 3H), and - 0.00 (TMS) ppm | |||||
| 419 | A | A | 44 9.3 9 | 2.0 8 | 1H NMR (300.0 MHz, DMSO) d 13.08 (s, 1H), 8.70 (d, 1H), 8.60 (d, 2H), 8.48 (s, 1H), 8.18-8.12 (m, 1H), 6.64 (d, 1 H). 5.91 (s, H), 4.30 (m, 1H), 3.88 (m, 1H), 3.76(m, 1H) 3.46 (m, 1H), 3.103.01 (m, 4H), 2.08 (m, 1H), 1.91 (m, 1H), 1.61 (dd, 4H), 1.47 (m, 2H), 0.86 (t, 3 H), and -0.00 (TMS) |
| 420 | D | 46 1 | 2.8 3 | ||
| 421 | B | 44 7 | 1.8 | ||
| 422 | D | 43 3 | 1.8 | ||
| 423 | D | 42 5 | 2 | ||
| 424 | D | 44 7 | 1.8 | ||
| 425 | A | A | 41 9.2 1 | 2.1 3 | H NMR (300.0 MHz, DMSO) d 13.02 (s, 1H), 9.10 (s, 2H), 8.67 (s, 1H), 8.44 - 8.40 (m, 2H), 7.26 (d, J = 6.5 Hz, 1H), 4.19 (s, 1H), 3.66 (d, J = 9.8 Hz, 1H), 3.48 (s, 3H), 2.13 (s, 1H), 2.02 (d, J = 9.2 Hz, 1H), 1.78 (d, J = 9.6 Hz, 2H) and 1.47 - 1.34 (m, 4H) ppm |
| 426 | A | A | 41 9.5 | 2.5 3 | H NMR (300.0 MHz, DMSO) d 12.56 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.35 (dd, J = 2.4, 6.8 Hz, 2H), 8.28 (d, J = 4.2 Hz, 1H), 5.99 (d, J = 7.0 Hz, 1H), 5.80 - 5.63 (m, 1H), 3.91 - 3.87 (m, 1H), 3.66-3.45 (m, 1H), 2.54 (s, 3H), 2.30 (d, J = 13.0 Hz, 1H), 2.04 (d, J = 46.9 Hz, 1H), 1.78 (d, J = 8.5 Hz, 2H) and 1.56 - 1.23 (m, 4H) ppm |
| 427 | D | 43 | 2.6 | H NMR (300.0 MHz, DMSO) d 12.59 |
-40616260
| 2.4 | 9 | (s, 1H), 8.72 (d, J = 2.3 Hz, 1 H), 8.41 (d, J = 2.7 Hz, 1 H), 8.35 (d, J = 2.3 Hz, 1H), 8.29 (d, J =4.4 Hz, 1H), 8.23 (s, 1H), 6.19 (d, J = 7.8 Hz, 1H), 4.04 3.97 (m, 1H), 3.78-3.69 (m, 1H), 2.68 (s, 6H), 2.31 (d, J = 11.6 Hz, 1 H), 1.95 (d, J = 9.8 Hz, 1H), 1.79 (d, J = 10.4 Hz, 2H) and 1.60 - 1.32 (m, 4H) ppm | |||
| 428 | A | A | 43 9.4 | 2.7 1 | H NMR (300.0 MHz, DMSO) d 12.54 (s, 1H), 8.72 (d, J = 2.3Hz, 1H), 8.388.29 (m, 3H), 7.82 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.52 (brs, 1H), 4.12-4.05 (m, 1H), 2.92 (s, 3H), 2.09 (d, J = 12.8 Hz, 2H), 1.78 (brs, 2H) and 1.49 -1.39 (m, 4H) ppm |
| 429 | B | 40 3.4 | 2.5 7 | ||
| 430 | A | 41 8.5 | 2.5 7 | H NMR (300.0 MHz, DMSO) d 12.61 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.39 8.31 (m, 4H), 6.12 (d, J = 6.7 Hz, 1H), 5.91 -5.83 (m, 1H), 4.29-4.13(m, 1 H), 4.02 - 3.91 (m, 1 H), 2.55 (s, 3H), 1.93 (d, J = 12.8 Hz, 1H) and 1.741.53 (m, 7H) ppm | |
| 431 | A | 43 2.4 | 2.7 7 | H NMR (300.0 MHz, DMSO) d 12.54 (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 8.338.29 (m, 3H), 7.96 (s, 1H), 5.72 (d, J = 6.9 Hz, 1H), 4.36 (s, 1H), 4.10 (s, 1H), 2.76 (s, 6H), 1.96- 1.87 (m, 2H), 1.741.63 (m, 4H) and 1.55 - 1.45 (m, 2H) ppm | |
| 432 | D | 41 9.4 | 2.8 5 | H NMR (300.0 MHz, DMSO) d 12.54 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.358.29 (m, 3H), 7.62 (s, 1H), 7.05 (d, J = 7.2 Hz, 1 H), 4.50 - 4.40 (m, 1 H), 4.20 4.10 (m, 1H), 3.46 (s, 3H), 1.87 (d, J = 10.9 Hz, 2H), 1.71 - 1.65 (m, 4H) and 1.43 (d, J = 7.4 Hz, 2H) ppm |
-40716260
| 433 | A | A | 40 3.4 | 2.4 1 | H NMR (300.0 MHz, DMSO) d 13.03 I (s, 1H), 9.10 (S, 1H), 9.05 (s, 1 H), 8.67 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 5.4 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 4.15 - 4.07 (m, 1H), 3.93 - 3.87 (m, 1H), 2.20-2.15 (m, 1H), 1.99- 1.92 (m, 1H), 1.85- 1.79 (m, 2H), 1.74 (s, 3H) and 1.52 - 1.36 (m, 4H) ppm |
| 434 | A | A | 38 9.4 | 1.6 | |
| 435 | A | A | 40 3.4 | 1.8 | |
| 436 | A | 41 7.4 | 1.9 | ||
| 437 | D | 43 1.4 | 2 | ||
| 438 | A | A | 41 8.4 | 1.7 | |
| 439 | A | A | 43 2.4 | 1.8 | |
| 440 | A | A | 40 5.4 | 1.8 | |
| 441 | B | 41 9.4 | 1.9 | ||
| 442 | B | 43 3.4 | 2.1 | ||
| 443 | A | A | 46 1.3 | 1.8 | |
| 444 | A | A | 44 5.4 | 1.7 | |
| 445 | A | 42 9.4 | 1.9 | ||
| 446 | D | 44 8.4 | 1.7 | ||
| 447 | D | 44 9.3 | 2 |
-40816260
| 448 | D | 46 9.3 | 1.9 | ||
| 449 | B | 41 9.4 | 1.7 | ||
| 450 | B | 43 1.4 | 1.7 | ||
| 451 | B | 41 5.4 | 1.8 | ||
| 452 | A | A | 40 3.1 4 | 1.2 61 97 5 | |
| 453 | A | A | 41 9 | 1.1 78 42 8 | |
| 454 | A | A | 43 9.1 1 | 1.5 48 66 7 | |
| 455 | A | A | 41 8.1 6 | 1.6 90 09 3 | |
| 456 | A | A | 43 2.1 7 | 1.5 18 18 3 | |
| 457 | A | A | 40 3.2 2 | 1.5 7 | |
| 458 | A | A | 41 8.1 6 | 0.7 6 | |
| 459 | A | A | 43 2.1 7 | 1.4 6 | |
| 460 | A | A | 38 | 2.0 |
-40916260
| 9.1 4 | 1 | ||||
| 461 | A | A | 38 9.1 4 | 2.0 5 | |
| 462 | B | A | 40 3.1 5 | 2.2 4 | 1H NMR (300.0 MHz, DMSO) d 12.35 (s, 1H), 8.68 (d, J = 1.7 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.21 (m, 2H), 7.28 (d, J = 6.0 Hz, 1H), 4.98 (dd, J = 6.9, 10.7 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.84 (dd, J = 11.4, 15.5 Hz, 1H), 3.49-3.17 (m, 5H), 2.08 (d, J = 13.1 Hz, 1H), 1.95 - 1.88 (m, 3H), 1.65- 1.58 (m, 1H), 1.42 (m, 1H) and 1.04 (t, J = 7.0 Hz, 3H) ppm |
| 463 | D | A | 47 5.2 | 2.2 6 | DMSOd-6: 13.21 (s, 1H), 9.29 (d, 1H), 8.76 (d, 1 H), 8.60 (s, 1 H), 8.47 (s, 1 H), 8.17 (d, 1H), 6.67 (d, 1H), 4.29 (m, 1H), 3.75 (m, 1 H), 3.46 (m, 1H), 3.07 - 2.98 (m, 3H), 2.27 - 1.45 (m, 12H), 1.28 - 1.24 (m, 2H), -0.00 (s, H) ppm |
| 464 | A | A | 43 5.1 4 | 2.0 3 | DMSOd-6: 13.21 (s, 1H), 9.29 (d, 1H), 8.76 (d, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.17 (d, 1H), 6.67 (d, 1H), 4.29 (m, 1H), 3.75 (m, 1 H), 3.46 (m, 1H), 3.07 - 2.98 (m, 3H),2.2-2.1(m, 1H), 1.852.0(m, 1H), 1,72-1.57(m, 4H), 0.95(t, 3H) |
| 465 | B | 43 5.1 4 | 2 | DMSO d-6: 13.21 (s, 1 H), 9.29 (d, 1 H), 8.76 (d, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.17 (d, 1H), 6.67 (d, 1H), 4.25(m, 1H), 3.79(m, 1H), 3.53(m, 1H), 3.37(m, 1H), 3.17(m, 1H), 2.14(m, 1H), 1.90(m, 1H), 1.66-1.60(m, 1H), 1.21(d, 6H). | |
| 466 | B | 40 7.1 2 | 1.8 5 | DMSO d-6: 13.21 (s, 1 H), 9.29 (d, 1 H), 8.76 (d, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.17 (d, 1H), 6.67 (d, 1H), 4.4(m, 1H), |
-4 ΙΟ16260
| 3.75(d, 1 H), 3.4(m, 1H), 3.1(m, 1H), 2.9(s, H), 2.10-1.9(m, 2H), 1.8-1.65(m, 2H). | |||||
| 467 | D | 43 1.4 | 1.6 | ||
| 468 | B | 39 1.3 | 1.6 | ||
| 469 | D | 46 5.3 | 2.3 | ||
| 470 | D | 47 9.3 | 2.3 | ||
| 471 | A | 37 5.3 | 1.6 | ||
| 472 | B | 40 5.3 | 1.6 | ||
| 473 | B | 43 1.3 | 1.6 | ||
| 474 | D | 44 6.3 | 1.4 | ||
| 475 | D | 46 1,3 | 2.6 | ||
| 476 | B | 39 1.3 | 2.6 | ||
| 477 | D | 41 9.4 | 2 | ||
| 478 | B | 43 1.3 | 1.6 | ||
| 479 | D | 47 9.3 | 2.3 | ||
| 480 | A | 37 5.3 | 1.6 | ||
| 481 | B | 40 5.3 | 2.2 | ||
| 482 | A | 43 1.3 | 1.6 | ||
| 483 | D | 44 6.3 | 1.4 |
-41116260
| 484 | B | 46 1,3 | 2.6 | ---------—'--- | |
| 485 | B | 37 1.4 6 | 1.8 9 | 1H NMR (300.0 MHz, DMSO) d 13.09 (s, H), 9.3 (s, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.57 (d, 1H), 8.47 (s, 1H), 8.188.14 (m, 1H), 6.66-6.58 (m, 1 H), 4.5(d, 1H), 4.43-4.05 (m, 1H), 4.29 (s, H), 3.88 (d, 2H), 3.34 - 3.08 (m, 2H), 2.13 (s, 1H), 2,07 (s, 1H), 1.91 1.56 (m, 3H), 0.00 (TMS) | |
| 486 | B | 40 1.4 8 | 1.8 7 | ||
| 487 | B | 44 3.9 | 1.9 7 | ||
| 488 | D | 41 5.5 | 1.9 | ||
| 489 | A | 41 3.5 1 | 2.1 2 | ||
| 490 | A | A | 38 5.4 3 | 1.7 | 1H NMR (300.0 MHz, DMSO) d 13.12 (s, 1H), 9.52 (s, 1H), 8.73 (d, 1H), 8.65 (d, 1H), 3.45 (d, 1H), 8.14 (d, 1H), 6.63 (d, 1 H), 4.29 (d, 1 H), 4.04 {d, 1H), 3.80 - 3.32 (m, 3H), 3.10 - 3.02 (m, 1H), 2.07 (s, 3H), 1.99 (m,2H), 1.8-1.6 (m, 2H), 1.55 - 1.24 (m, 2H) and -0.00 (TMS) ppm |
| 491 | A | 41 5.4 3 | 1.7 | ||
| 492 | B | 45 7.4 9 | 1.7 9 | ||
| 493 | A | A | 42 9.4 6 | 1.7 4 | |
| 494 | B | 42 | 1.9 |
-4I216260
| 7.5 2 | 2 | ||||
| 495 | B | 40 1.4 8 | 1.8 3 | 1H NMR (300.0 MHz, DMSO) d 13.12 (s, 1H), 9.44 (d, 1H), 8.73 (d, 1H), 8.65 (d, 1 H), 8.45 (d, 1H), 8.14 (d, J = 7.2 Hz, H), 6.80 (d, 1H), 6.63 (d, 1 H), 3.9(dd, 1H) 3.76 (dd, 1 H), 3.60-3.50 (m, 3H), 3.47 -(s, 3H), 3.05-2.8 (m, 2H), 1.93 (m, 2H), 1.83 (d, 2H), 1.42- 1.35 (m, 2H), and -0.00 (TMS) ppm | |
| 496 | B | 43 9.3 | 1.8 | ||
| 497 | A | A | 40 3.3 | 1.7 | |
| 498 | A | 41 9.3 | 1.9 | ||
| 499 | A | A | 43 2.5 | 1.8 | |
| 500 | A | A | 35 7.6 2 | 1.6 2 | 1H NMR (300.0 MHz, DMSO) d 13.02 (s, 1H), 8.73 (d, 1H), 8.66 (d, 1 H), 8.42 (d, 1H), 8.16 (d, 1H), 8.06 (t, 1H), 6.83 (d, 1H), 5.05-4.99 (m, 1H), 3.52- 3.42 (m, 1 H), 3.36 (d, H), 3.28 - 3.24 (m, 1H), 2.50 (qn, J = 1.8 Hz, H), 2.001.80 (m, 4H), 1.77 - 1.64 (m, 1H), 1.34 (m, 1H), 1.28 (s, H), 1.06 (t, J = 7.0 Hz, H) and 0.00 (TMS) ppm |
| 501 | B | 34 1.3 8 | 1.5 6 | 1H NMR (300.0 MHz, DMSO) d 12.96 (s, 1H), 8.66 (d, 1H), 8.46-8.41 (m, 2H), 8.16 (d, 1H), 8.05 (d, 1H), 6.80 (d, 1H), 5.00 (dd, 1 H), 3.54 - 3.40 (m, 1H), 3.26 - 3.21 (m, 1 H), 2.50 (qn, J = 1.8 Hz, H), 2.03- 1.86 (m, 4H), 1.64 (t, 1H), 1.36 (t, 1H) and -0.00 (TMS) ppm | |
| 502 | A | A | 40 9.3 | 2.6 | |
| 503 | A | 36 1.2 | 2.1 7 |
-41316260
| 504 | B | A | 40 3.3 | 2.8 5 | |
| 505 | B | 49 7.7 2 | 3.0 5 | ||
| 506 | A | A | 41 8.5 | 2.0 9 | 1H NMR (300.0 MHz, DMSO) d 13.06 (s, 1H), 9.24 (s, 1H), 9.05 (d, J = 2.4 Hz, 1 H), 8.66 (d, J = 2.3 Hz, 1 H), 8.52 8.45 (m, 2H), 4.35 (d, J = 8.0 Hz, 1H), 3.81 (qn, J = 6.1 Hz, 1H), 3.59-3.39 (m, 2H), 3.18 (t, J = 11.6 Hz, 1 H), 2.61 (d, J = 16 Hz, 3H) and 2.12 -1.67 (m, 6H) ppm |
| 507 | A | A | 39 0.4 2 | 1.6 9 | |
| 508 | D | 39 7.3 7 | 1.5 9 | ||
| 509 | A | A | 40 4.4 5 | 1.6 7 | |
| 510 | D | 34 3.3 9 | 0.6 5 | ||
| 511 | D | 34 3.4 2 | 1.2 9 | ||
| 512 | D | B | 36 1.3 | 2.3 6 | |
| 513 | B | A | 37 7.4 6 | 1.8 9 | |
| 514 | A | A | 41 8.7 8 | 1.2 6 | 1H NMR (300.0 MHz, MeOD) d 8.83 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.99 (d, J = 4.1 Hz, 1H), 4.29 - 4.17 (m, 1H), 3.67 - 3.60 (m, 1H), 3.60 (s, 3H), 2.37 (m, 1H), |
-4>416260
| 2.19 (m, 1H), 2.07- 1.90 (m, 2H), 1,72 -1.60 (m, 1H), 1.40- 1.25 (m, 2H) and -0.00 (TMS) ppm | |||||
| 515 | D | 46 3.5 | 2.4 7 | 1H NMR (300.0 MHz, CDCI3) d 10.38 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.38 (s, 1H), 8.08 (d, J = 3.4 Hz, 1H), 7.26 (s, CDCI3), 6.11 (d, J = 5.0 Hz, 1H), 4.44 (d, J = 9.4 Hz, 1H), 4.02 - 3.62 (m, 6H), 3.55 (dd, J = 2.4, 12.1 Hz, 1 H), 3.35-3.27 (m, 1H) and 1.40 - 1.22 (m, 9H) ppm | |
| 516 | B | 41 9.4 | 1.9 1 | ||
| 517 | B | 44 8.5 4 | 2.2 6 | 1H NMR (300.0 MHz, DMSO) d 12.54 (s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 3.9 Hz, 1 H), 8.08 (d, J = 7.5 Hz, 1H), 6.30 (s, 1H), 4.28 (s, 1H), 3.93 3.74 (m, 3H), 3.51 - 3.47 (m, 2H), 3.39 - 3.20 (m, 2H), 2.95 (dd, J = 6.2, 13.1 Hz, 3H), 1.35 - 1.25 (m, 2H) and 0.76 (t, J = 7.3 Hz, 3H) ppm | |
| 518 | D | 44 5.6 | 3.3 | 1H NMR (300.0 MHz, MeOD) d 8.67 (d, J = 2.3 Hz, 1H), 8.53 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 5.5 Hz, 1 H), 4.75 - 4.73 (m, 1 H), 3.74 - 3.58 (m, 1H), 3.42 (m, 2H), 3.29 - 3.22 (m, 2H), 2.57 (m, 1H), 2.09-2.03 (m, 1H), 1.96 - 1.76 (m, 4H), 1.06 (t, J = 7.1 Hz, 3H) and 0.94 (t, J = 7.1 Hz, 3H) ppm | |
| 519 | B | 41 7.4 9 | 2.9 5 | ||
| 520 | D | 44 5.5 8 | 2.2 6 | ||
| 521 | B | 41 7.5 | 2.3 4 | 1H NMR (300.0 MHz, MeOD) d 8.93 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.3 Hz, |
-41516260
| 3 | 1H), 8.18 (s, 1H), 7.99 (d, J = 4.0 Hz, 1H), 4.53 (ddd, J = 7.1, 11.1 Hz, 1H), 3.15 - 3.02 (m, 2H), 2.43-2.34 (m, 1H), 2.30-2.26 (m, 1H), 1.97-1.82 (m, 3H), 1.77- 1.65 (m, 2H), 1.47- 1.35 (m, 2H) and 0.97 (t, J = 7.3 Hz, 3H) ppm | ||||
| 522 | D | 37 5.4 6 | 1.6 8 | ||
| 523 | D | 38 9.5 4 | 1.7 2 | 1H NMR (300.0 MHz, MeOD) d 8.65 (d, J = 2.3 Hz, 1H), 8.54 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 4.82-4.72 (m, 1H), 3.66 - 3.53 (m, 1H), 2.96 (s, 3H), 2.77 (s, 3H), 2.33 (d, J = 12.3 Hz, 2H), 2.10 - 1.97 (m, 2H) and 1.75 - 1.48 (m, 4H) ppm | |
| 524 | A | A | 36 2.4 8 | 1.9 5 | |
| 525 | A | A | 42 1.5 2 | 1.4 8 | 1H NMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1 H), 8.17 (d, J = 4.0 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1H), 4.54 (m, 1H), 4.44 (s, 1H), 4.36 (m, 1H), 3.64 (s, 1H), 3.40 (m, 1 H), 3.03 (t, J = 11.0 Hz, 1H), 2.77 (m, 1H), 2.47 - 2.25 (m, 2H), 2.22 2.12 (m, 2H), 1.99- 1.90 (m, 1H), 1.70 -1.60 (m, 2H) and 1.45 (m, 1H) ppm |
| 526 | B | A | 42 1 | 2 3 6 | |
| 527 | D | D | 43 5.1 | 2.4 9 | |
| 528 | B | D | 44 7.1 | 2.6 4 | |
| 529 | B | D | 43 3.1 | 2.4 5 |
-41616260
| 530 | D | B | 44 7.1 | 1.9 3 | |
| 531 | B | A | 44 5.1 | 2.5 6 | |
| 532 | B | A | 44 1 | 2.4 | |
| 533 | B | A | 46 7 | 2.4 | |
| 534 | B | A | 40 6 | 1.9 6 | |
| 535 | B | D | 43 4.1 | 2.1 7 | |
| 536 | B | D | 44 8.1 | 2.3 4 | |
| 537 | A | A | 43 5.5 4 | 1.5 6 | 1H NMR (300.0 MHz, DMSO) d 12.35 (s, 1H), 8.73 (d, J = 2.4 Hz, 1 H), 8.29 (d, J = 2.4 Hz, 1H), 8.19-8.09 (m, 2H), 7.36 (d, J = 7.5 Hz, 1H), 4.53 (dd, J = 4.5, 8.0 Hz, 1H), 4.27 (s, 1H), 3.77 3.72 (m, 1H), 3.36 - 3.20 (m, 3H), 3.22 (s, 3H), 3.03 - 2.97 (m, 1H), 2.76 (d, J = 10.6 Hz, 1H), 2.44 - 2.14 (m, 2H), 2.08 (m, 2H), 1.99 - 1.94 (m, 1H), 1.71 -1.63 (m, 2H), 1.44 (m, 1H) and 1.23 1.15 (m, 1H) ppm |
| 538 | A | A | 41 9.5 5 | 1.6 1 | 1H NMR (300.0 MHz, DMSO) d 12.53 (s, 1H), 10.32 (s, 1H), 8.69 (dd, J = 2.5, 5.2 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.31 (m, 2H), 7.97 (s, 1H), 4.76 (m, 1 H), 3.92 (m, 2H), 3.84 - 3.55 (m, 2H), 3.40 - 2.80 (m, 3H), 2.14 - 1.90 (m, 3H), 1.80 - 1.74 (m, 2H), 1.65 (m, 1 H), 1.43 - 1.23 (m, 2H) and 0.96 - 0.85 (m, 3H) ppm |
| 539 | B | A | 40 3.4 4 | 2.1 3 | |
| 540 | A | A | 36 | 1.4 |
-41716260
| 1.5 | 3 | ||||
| 541 | A | A | 39 0.4 6 | 2.4 3 | |
| 542 | B | B | 36 1.3 7 | 1.4 2 | |
| 543 | A | A | 41 7.4 4 | 2.5 2 | |
| 544 | D | A | 38 9.4 2 | 1.9 4 | |
| 545 | A | 37 6.4 6 | 37 5.1 3 | 1H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.56 (s, 1H), 4.31 (dd, J = 5.9, 8.6 Hz, 1H), 1.89- 1.35 (m, 8H), 1.17 (s, 3H)and 0.00 (TMS) ppm | |
| 546 | A | 41 9.4 9 | 41 8.1 7 | 1H NMR (300.0 MHz, CDCI3) d 9.60 (s, H), 8.87 (d, J = 2.3 Hz, H), 8.33 (d, J = 2.3 Hz, H), 8.17 (d, J = 2.7 Hz, H), 8.09 (d, J = 3.3 Hz, H), 8.04 (s, H), 7.28 (s, H), 5.34 (d, J = 11.5 Hz, H), 4.45 - 4.42 (m, H), 3.09 (d, J = 11.3 Hz, H), 2.98 (s, H), 2.90 (d, J = 0.5 Hz, H), 2.72 (d, J = 12.9 Hz, H), 2.62 (d, J = 6.3 Hz, H), 2.40 (s, H), 1.94 (d, J = 11.6 Hz, H), 1.86- 1.72 (m, H). 1.62 (s, H), 1.27 (s, H) and 1.22 (s, H) ppm | |
| 547 | A | 40 3.2 2 | 3.9 9 | 1H NMR (300 MHz, MeOD) d 8.81 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.99 (d, J = 4.1, 1H), 4.23 (t, J = 11.4, 1H), 3.90 (t, J = 11.4, 1H), 2.35 (d, J = 11.6, 1H), 2.20 (d, J = 12.5, 1H), 2.00 (d, J = 15.9, 2H), 1.92 (s, 3H), 1.67 (dd, J = 26.3, 13.2, 1H), 1.53-1.06 (m, 3H) |
-41816260
| ppm LCMS | |||||
| 548 | A | 41 9.4 6 | 2.8 2 | ||
| 549 | A | 43 2.5 | 2.6 | ||
| 550 | A | 44 9.4 8 | 44 8.1 8 | 1H NMR (300.0 MHz, DMSO) d 12.33 (s, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.22 - 8.20 (m, 2H), 6.72-6.62 (m, 1H), 4.61 (dd, J =4.2, 10.0 Hz, 1H), 4.54 (m, 1H), 3.75-3.71 (m, 1H), 3.34 - 3.22 (m, 1H), 3.22 (d, 3H), 2.88 - 2.42 (m, 4H), 2.41 - 2.25 (m, 4H), 1.93 (m, 1H), 1.56 (m, 2H), 0.90 (d, J = 6.7 Hz, 3H) and -0.00 (TMS) ppm | |
| 551 | A | 46 3.5 1 | 46 2.1 9 | 1H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19-8.16 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 4.42-4.37 (m, 2H), 3.70 (s, 1H), 3.52 - 3.42 (m, 1H), 3.35 - 3.25 (m, 1H), 2.99 (m, 1H), 2.73 (m, 1H), 2.43-2.11 (m, 4H), 1.94 (m, 1H), 1.75- 1.60 (m, 2H), 1.52-1.40 (M, 1 H), 1.10 - 0.99 (m, 6H) and 0.00 (TMS) ppm | |
| 552 | A | 37 6.2 3 | 2.2 2 | CD3OD: 8.7(d, 1H), 8.45(s, 1H), 8.35(d, 1H), 8.25(d, 1H), 4.37(t, 1H), 3.58-3.48(m, 1 H), 3.4(s, 3H), 2.55(dd, 1H), 2.23-2.1 (m, 2H), 2.05-1,95(m, 1H), 1.7-1.4(m, 3H), 1.35-1.25(m, 1H), O.OO(TMS) | |
| 553 | A | A | 39 0.3 5 | 2.0 5 | 1H NMR (300.0 MHz, MeOD) d 8.89 (d, J = 2.4 Hz, 1H), 8.44 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.75 (m, 1H), 2.75 - 2.66 (m, 1H), 2.25 - 2.16 (m, 2H), 1.99 - 1.89 (m, 2H), 1.71 -1.29 (m, 4H) and 1.37 (m, |
-41916260
| contaminant) ppm | |||||
| 554 | C | B | 39 0.4 1 | 2.3 | 1H NMR (300.0 MHz, MeOD) d 8.89 (d, J =2.4 Hz, 1H), 8.44 (s, 1H), 8.38 (d, J = 2.4 Hz, 1 H), 8.29 (d, J = 5.6 Hz, 1H), 4.77 (m, 1H), 2.75 - 2.66 (m, 1 H), 2.24-2.17 (m, 2H), 1.94- 1.89 (m, 2H) and 1.74- 1.36 (m, 4H) ppm |
| 555 | C | A | 37 5 | 1.9 3 | 1H NMR (300.0 MHz, MeOD) d 8.75 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.29 (s. 1H), 8.24 (d, J = 4.4 Hz, 1H), 3.96 (dd, J = 5.8, 14.4 Hz, 1H), 3.73 (dd, J = 4.3, 14.3 Hz, 1H), 3.083.00 (m, 1H), 2.05- 1.87 (m, 3H), 1.80 (m, 3H) and 1.48 - 1.39 (m, 4H) ppm |
| 556 | C | A | 44 6.8 | 2.8 | 1H NMR (300.0 MHz, MeOD) d 8.74 (d, J = 2.3 Hz, 1H), 8.42 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 5.4 Hz, 1 H), 3.85 - 3.81 (m, 2H), 3.75 (d, J = 8.5 Hz, 2H), 3.26 (s, 3H), 1.97 -1.77 (m, 5H) and 1.43 - 1.35 (m, 4H) ppm |
| 557 | A | 45 2.6 | 2.8 | 1H NMR (300.0 MHz, MeOD) d 8.78 (d, J = 2.4 Hz, 1 H), 8.45 (d, J = 4.2 Hz, 1 H), 8.37 (d, J = 2.3 Hz, 1 H), 8.26 (d, J = 5.4 Hz, 1 H), 4.12 (dd, J = 4.5, 13.7 Hz, 1H), 3.89 (dd, J =7.1, 13.8 Hz, 1H), 3.26-3.16 (m, 1H), 3.00 (s, 3H), 2.18-1.90 (m, 2H), 1.79- 1.74 (m, 2H) and 1.50 - 1.25 (m, 4H) ppm | |
| 558 | A | A | 37 6.2 | 2.4 9 | 1H NMR (300.0 MHz, MeOD) d 8.78 (d, J = 2.4 Hz, 1 H), 8.38 (s, 1 H), 8.33 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1 H), 4.98 (dd, J = 7.2 Hz, 1 H), 2.27 2.03 (m, 5H) and 1.86 - 1.76 (m, 1 H) ppm |
| 559 | A | A | 38 9.8 | 2.2 7 | 1H NMR (300.0 MHz, MeOD) d 8.75 (d, J = 2.4 Hz, 1 H), 8.38 - 8.35 (m, 2H), 8.24 (d, J = 5.1 Hz, 1H),4.70-4.62 (m, 1H), 3.25-3.17 (m, 1H), 2.32 (m, 1H), |
-42016260
| 2.14-1.80 (m, 4H) and 1.68- 1.54 (m, 3H) ppm | |||||
| 560 | C | D | 41 8.4 6 | 3.2 1 | H NMR (300.0 MHz, MeOD) d 8.95 (s, 1H), 8.23 - 8.14 (m, 2H), 8.00 (m, 1H), 4.61 (m, 1H), 3.96 - 3.92 (m, 2H), 2.61 (m, 1H), 2.14-2.04 (m, 2H), 1.89 - 1.35 (m, 7H) and 1.04-0.99 (m, 3H) ppm |
| 561 | B | A | 41 8.4 1 | 2.7 3 | H NMR (300.0 MHz, MeOD) d 8.95 (s, 1H), 8.19 (m, 2H), 7.99 (s, 1 H), 4.61 (m, 1H), 3.93 (m, 2H), 2.61 (m, 1H), 2.17-2.05 (m, 2H), 1.89- 1.32 (m, 7H) and 1.00 (m, 3H) ppm |
| 562 (enantio mer 1) | C | A | 37 6.4 3 | 8.6 2 | H NMR (300.0 MHz, DMSO) d 8.85 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.14 (d, J = 4.2 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 4.52 (s, 1 H), 4.32 - 4.25 (m, 1 H), 1.90 -1.33 (m, 8H) and 1.15 (s, 3H) ppm |
| 563 (enantio mer 2) | A | A | 37 6.4 3 | 11. 16 | H NMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.16 (d, J =4.2 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 4.54 (s, 1H), 4.30 (t, J = 8.8 Hz, 1H), 1.86 - 1.25 (m, 8H) and 1.16 (s, 3H) ppm |
| 564 | C | A | 44 5.7 | 1.9 1 | |
| 565 | B | A | 37 6.3 9 | 2.4 3 | H NMR (300.0 MHz, DMSO) d 12.48 (s, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.35 8.31 (m, 2H), 8.26 (d, J = 4.3 Hz, 2H), 8.02 (s, 1H), 4.57 - 4.44 (m, 1H), 2.87 (qn, J = 8.3 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.15-2.05 (m, 1H), 2.00-1.86 (m, 3H) and 1.82 - 1.70 (m, 1 H) ppm |
| 566 | A | A | 37 6.4 | 2.3 4 | H NMR (300.0 MHz, DMSO) d 12.42 (s, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.29 (m, 2H), 8.22 (d, J = 4.1 Hz, 1H), 7.87 |
-42116260
| (s, 1 H), 4.56 - 4.49 (m, 1 H), 2.87 (dd, J = 8.4, 25.0 Hz, 1H), 2.87 (s, 1H), 2.422.33 (m, 1H), 2.15-2.04 (m, 1H), 2.00 -1.85 (m, 3H) and 1.81 -1.70 (m, 1H) ppm | |||||
| 567 | A | A | 40 4.4 2 | 2.1 3 | H NMR (300.0 MHz, DMSO) d 12.29 (s, 1H), 8.72 (d, J = 2.4 Hz, 1 H), 8.28 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 8.17 (d, J = 4.0 Hz, 1 H), 7.41 (d, J = 7.7 Hz, 1H), 7.29 (s, 1H), 7.10 (s, 1H), 4.354.29 (m, 1H), 2.98-2.75 (m, 1H), 2.92 (d, J = 6.8 Hz, 2H), 2.68 (d, J = 10.8 Hz, 1H), 2.29-2.19 (m,2H), 1.96- 1.92 (m, 1 H), 1.80 - 1.65 (m, 2H) and 1.53- 1.42 (m, 1H) ppm |
| 568 | C | D | 43 2.4 6 | 3.0 8 | H NMR (300.0 MHz, DMSO) d 8.80 (d, J = 2.5 Hz, 1 H), 8.27 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 4.72 (qn, J = 6.2 Hz, 1H), 4.55-4.48 (m, 1H), 2.61 -2.54 (m, 1 H), 1.96 (m, 2H), 1.77 (m, 2H), 1.63-1.41 (m, 3H), 1.30- 1.23 (m, 1 H) and 0.93 (d, J = 6.2 Hz, 6H) ppm |
| 569 | C | D | 43 2.4 8 | 2.6 9 | H NMR (300.0 MHz, DMSO) d 12.57 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.36 - 8.28 (m, 4H), 4.75 (td, J = 12.5, 6.2 Hz, 1 H), 4.52 (m, 1 H), 2.65 - 2.56 (m, 1 H), 2.00 (m, 2H), 1.83- 1.76 (m, 2H), 1.57 -1.42 (m, 3H), 1.32- 1.24 (m, 1H) and 0.94 (d, J = 6.2 Hz, 6H) ppm |
| 570 | A | A | 41 9.4 2 | 2 | H NMR (300.0 MHz, MeOD) d 8.81 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 7.97 (d, J = 4.1 Hz, 1H), 4.26-4.18 (m, 1H), 3.71 - 3.52 (m, 1H), 3.59 (s, 3H), 2.36 (d, J = 10.5 Hz, 1H), 2.18 (d, J = 10.7 Hz, 1H), 2.04 - 1.86 (m, 2H), 1.57 (s, 1H) and 1.43- |
-42216260
| 1.15 (m, 3H) ppm | |||||
| 571 (diastere orner 1) | A | A | 37 6.4 1 | 1.9 7 | CD3OD: 8.69(d, 1H), 8.55(s, 1H), 8.38(d, 1H), 8.33(d, 1H),4.62(m, 1H), 2.0-1.6(m, 8H), 1.35(s, 3H) |
| 572 (diastero emer 2) | A | A | 37 6.4 2 | 2.3 9 | CD3OD: 8.78(d, 1 H), 8.55(s, 1H), 8.35(s, 1H), 8.25(d, 1H), 4.8(m, 1H), 2.25-1.95(m 2H), 1.80-1.60(m, 4H), 1.45-1.3(m, 2H), 1.3(s, 3H) |
| 573 | A | 41 9.4 2 | 1.8 7 | H NMR (300.0 MHz, DMSO) d 12.51 (s, 1H), 10.28- 10.00 (m, 1H), 8.70 (s, 1H), 8.38 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 4.2 Hz, 1H), 7.897.75 (m, 1H), 4.70-4.50 (m, 1H), 4.33 -4.29 (m, 1H), 3.79-3.45 (m, 2H), 3.20 - 2.80 (m, 2H), 2.12 -1.95 (m, 3H), 1.72- 1.60 (m, 1H)and 1.52 (d, J = 5.5 Hz, 3H) ppm | |
| 574 | A | 44 8.4 1 | 2.9 9 | 1H NMR (300.0 MHz, DMSO) d 8.74 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 4.42 (m, 1H), 4.02 - 3.86 (m, 2H), 3.35 - 3.23 (m, 2H), 3.08 (s, 3H), 2.69 - 2.60 (m, 1H), 1.99 (m, 2H), 1.77 (m, 2H), 1.62 1.40 (m, 3H) and 1.27 (m, 1H) ppm | |
| 575 | A | 40 4.3 8 | 3.1 2 | 1H NMR (300.0 MHz, DMSO) d 8.76 (d, J = 2.5 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 4.474.37 (m, 1H), 3.40 (s, 3H), 2.68 - 2.59 (m, 1H), 2.05- 1.97 (m, 2H), 1.84- 1.75 (m, 2H), 1.63 - 1.40 (m, 3H) and 1.31 - 1.23 (m, 1H) ppm | |
| 576 | A | 40 3.4 | 1.7 8 | 1H NMR (300 MHz, MeOD) d 8.81 (s, 1 H), 8.20 (s, 1H), 8.15 (s, 1H), 7.99 (d, J =4.1, 1 H), 4.23 (t, J = 11.4, 1H), 3.90 (t, J = 11.4, 1H), 2.35 (d, J = 11.6, 1H), 2.20 (d, J = 12.5, 1H), 2.00 (d, J = |
-42316260
| 15.9, 2H), 1.92 (s, 3H), 1.67 (dd, J = 26.3, 13.2, 1H), 1.53-1.06 (m, 3H). | |||||
| 577 | A | 40 5.4 | 1.9 5 | 1H NMR (300.0 MHz, DMSO) d 12.46 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1 H), 8.29 (d, J = 3.9 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 4.70-4.50 (m, 1H), 4.21 (s, 2H), 3.80 - 3.70 (m, 1 H), 3.55 - 3.47 (m, 1H), 3.20-2.90 (m, 2H), 2.101.95 (m, 3H) and 1.69 - 1.60 (m, 1H) ppm | |
| 578 | A | A | 39 0.4 1 | 2.8 2 | 1H NMR (300.0 MHz, DMSO) d 12.51 (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 2.3 Hz, 2H), 8.29 (d, J = 4.3 Hz, 1H), 7.55 (s, 1H), 4.53 (s, 1H), 3.05 (m, 1H), 2.13 (m, 1H), 1.96 (m, 1H), 1.79 (m, 3H) and 1.51 (m, 3H) ppm |
| 579 | A | 39 0.3 6 | 2.9 2 | 1H NMR (300.0 MHz, DMSO) d 12.52 (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 2.5 Hz, 2H), 8.30 (d, J = 4.4 Hz, 1H), 7.57 (s, 1H), 4.53 (m, 1H), 3.05 (m, 1H), 2.15-2.07 (m, 1H), 1.96 (m, 1H), 1.81 - 1.76 (m, 3H) and 1.51 (m, 3H) ppm | |
| 580 | A | 37 6.4 4 | 2.2 8 | 1H NMR (300.0 MHz, MeOD) d 8.88 (d, 1 H), 8.45 (s, 1H), 8.39 (d, J1H), 8.26 (d, H), 4.53 (t, 1H), 3.95-3.88 (m, 1H),2.03- 1.81 (m, 7H), 1.69 (m, 1 H), O.O(TMS), | |
| 581 | A | 39 0.4 2 | 3 | 1H NMR (300.0 MHz, MeOD) d 8.80 (d, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 4.43 (d, 1 H), 2.17 - 1.75 (m, 8H), 1.74 (m,2H), 1.65 (s, 3H), 0.00(TMS) | |
| 582 | A | 40 4.4 3 | 3.2 1 | 1H NMR (300.0 MHz, DMSO) d 12.46 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.32- 8.28 (m, 3H), 7.10 (d, J = 7.1 Hz, 1 H), 4.27-4.20 (m, 1H), 2,26 (d, J = 10.1 |
-42416260
| Hz, 1H), 1.93 (m, 1H), 1.83 (m, 1H), 1.68 - 1.59 (m, 3H), 1.36 (m, 2H) and 1.24 (s, 3H) ppm | |||||
| 583 | A | 41 8.4 5 | 1.6 5 | 1H NMR (300.0 MHz, MeOD) d 8.72 (d, 1 H), 8.6 (d, 1H), 8.3(m, 2H), 4.1(m, 1H), 3.9-3.8 (m, 1H), 3.75-3.50(dd, 1H), 2.45-2.35(m, 1H), 2.35-2.15(m, 2H), 1.95-1.85(m 1H), (1,65(dd, 3H), O.OO(TMS) ppm | |
| 584 | A | 48 3.4 4 | 2.5 2 | 1H NMR (300.0 MHz, DMSO) d 12.45 (m, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.31 (m, 2H), 8.01 (m, 1H), 5.33 (s, 1H), 4.62 - 4.43 (m, 2H), 4.39 - 3.72 (m, 5H), 3.68 (s, 2H), 3.43 - 3.40 (m, 1 H), 3.15 (s, 1H), 3.07 (s, 1H), 2.33 (s, 2H) and 2.08 (s, 2H) ppm | |
| 585 | A | 41 8.4 1 | 3.2 1 | 1H NMR (300 MHz, MeOD) ? 8.80 ? 8.76 (m, 1H), 8.37 (s, 1H), 8.35 (d, J = 2.3, 1H), 8.27 ? 8.23 (m, 1H), 4.49 ? 4.42 (m, 1H), 2.43 7 2.34 (m, 1H), 2.09 (d, J = 6.2, 1H), 1.98 ? 1.36 (m, 12H), 0.94 (dd, J = 11.3, 3.8, 3H). | |
| 586 | A | A | 41 8.3 8 | 2.9 5 | 1H NMR (300 MHz, MeOD) ? 8.93 ? 8.85 (m, 2H), 8.93 ? 8.87 (m, 1H), 8.31 (dd, J = 4.5, 1.2, 2H), 8.31 (dd, J = 4.5, 1.2, 2H), 8.30 (d, J = 2.3, 1H), 8.19 (d, J =5.0, 1H), 5.26 ? 5.20 (m, 1H), 3.37 (dd, J = 3.3, 1.6, 2H), 3.33 (ddt, J = 6.6, 3.3, 1.6, 118H), 2.11 (dd, J = 8.0, 5.8, 2H), 1.80 (tdd, J = 21.2, 18.9, 11.6, 8H), 1.63 ? 1.54 (m, 3H), 0.86 (q, J = 7.4, 4H) |
| 587 | A | A | 42 1.4 | 1.5 6 | |
| 588 | A | A | 42 1.4 | 1.5 6 | |
| 589 | A | 42 7.4 | 1.5 6 | H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 11.99 (m, 1H), 8.70 (d, J = 2.3 |
-42516260
| 2 | Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 4.0 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1 H), 7.32 (d, J = 7.3 Hz, 1H), 6.93 (s, 2H), 4.31 (s, 1H), 4.19 (m, 1H), 3.66 (d, J = 14.0 Hz, 1H), 3.55 (d, J = 14.0 Hz, 1H), 3.01 (m, 1H), 2.77 (m, 1H), 2.151.90 (m, 3H), 1.75 -1.68 (m, 1H) and ,1.49 - 1.37 (m, 1H) ppm | ||||
| 590 | C | 43 3.3 7 | 2.0 9 | H NMR (300.0 MHz, MeOD) d 8.81 (d, 1H), 8.19 (d, 2H), 7.98 (d, 1H), 4.48 (s, 1H), 2.92 -2.86 (m, 1H), 2.802.56(m, 3 H), 1.94-1.83 (m, 3H), 1.72 - 1.65 (m, 1 H), 1.25(d, 6H), 0.00 (s, H) PPm | |
| 591 | A | A | 43 3.4 1 | 2.6 | H NMR (300.0 MHz, MeOD) d 8.82 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.99 (d, J = 4.1 Hz, 1H), 4.29-4.21 (m, 1H), 4.04-3.96 (m, 1H), 3.87 (s, 2H), 3.40 (s, 3H), 2.34 (d, J = 11.6 Hz, 1H), 2.21 (d, J = 12.5 Hz, 1H), 2.02- 1.93 (m, 2H), 1.741.62 (m, 1 H) and 1.54 - 1.28 (m, 3H) PPm |
| 592 | A | 46 3.4 2 | 2.5 2 | 1H NMR (300 MHz, METHANOL-d4) Shift 8.84 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.99 (d, J = 3.97 Hz, 1H), 4.184.34 (m, 1H), 4.14 (br. s., 2H), 3.493.74 (m, 3H), 3.3 (s, 3H) 2.38 (d, J = 9.06 Hz, 1H), 2.19 (d, J = 13.41 Hz, 1H), 1.84-2.11 (m, 2H), 1.51 -1.78 (m, 1H), 1.12-1.47 (m, 3H) | |
| 593 | I A | 41 8.2 I 1 | 1.4 7 | H NMR (300.0 MHz, MeOD) d 8.85 (d, J =2.3 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.99 (d, J = 4.1 Hz, 1H), 4.28 -4.20 (m, 1H), 2.82-2.73 (m, 1H), 2.65 (s, 2H), 2.40 (d, J = 10.2 Hz, 1H), 2.15 (d, J = 8.5 Hz, 1H), 2.05 1.92 (m, 2H), 1.64 - 1.55 (m, 1 H) and |
-42616260
| 1.44-1.12 (m, 3H) ppm | |||||
| 594 | A | A | 42 7.3 7 | 1.6 1 | H NMR (300.0 MHz, DMSO) d 12.31 (s, 1 H), 11.86 - 11.77 (m, 1 H), 8.70 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 3.9 Hz, 1H), 8.10 (d, J = 2.5 Hz, 1 H), 7.54 (s, 1 H), 7.31 (d, J = 7.6 Hz, 1H), 6.87 (s, 1H), 4.19 (m, 1H), 3.57 (d, J = 13.8 Hz, 1 H), 3.48 (d, J = 13.8 Hz, 1H), 3.04 (d, J = 8.3 Hz, 1H), 2.80 (d, J = 10.4 Hz, 1H), 2.10-1.90 (m, 3H), 1.72 - 1.62 (m, 2H) and 1.51 1.35 (m, 1H) ppm |
| 595 | A | A | 40 5.3 Ί | 1.6 5 | H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.18- 8.15 (m, 2H), 7.32 (d, J = 7.1 Hz, 1H), 4.20 (d, J = 7.1 Hz, 1H), 3.46 (t, J = 5.8 Hz, 2H), 3.19 (s, 3H), 3.10-3.06 (m, 1H), 2.822.78 (m, 1H), 2.57 - 2.50 (m, 2H), 2.11 - 1.95 (m, 3H), 1.71 -1.63 (m, 2H) and 1.48- 1.35 (m, 1H) ppm |
| 596 | A | A | 40 2.3 4 | 2.9 9 | H NMR (300.0 MHz, MeOD) d 8.86 (d, J =2.3 Hz, 1H), 8.38 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.25 (d, J = 5.1 Hz, 1H), 4.59 (d, J = 8.1 Hz, 1H), 3,00 (d, J = 8.0 Hz, 1H), 2.62 (m, 1H), 2.55 (m, 1H), 2.11 (d, J = 10.4 Hz, 1H), 1.85 - 1.59 (m, 3H) and 1.51 -1.36 (m, 2H) PPm |
| 597 | C | A | H NMR (300.0 MHz, MeOD) d 8.78 (d, J =2.3 Hz, 1H), 8,37 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 4.9 Hz, 1H), 4.71 -4.67 (m, 1H), 3.25- 3.22 (m, 1H), 2.94 (m, 1 H), 2.77 (m, 1H), 1.86 (d, J = 11.0 Hz, 1 H) and 1.70 - 1.58 (m, 5H) ppm | ||
| 598 | A | A | 43 2.4 | 1.8 3 | H NMR (300.0 MHz, MeOD) d 8.86 (d, J =2.4 Hz, 1H), 8.22 (d, J = 2.3 Hz, |
-42716260
| 1 | 1H), 8.17 (s, 1H), 8.02-7.97 (m, 1H), 4.45 (m, 1 H), 3.14 (d, J = 10.8 Hz, 1 H), 2.75 (d, J = 10.3 Hz, 1H), 2.38 - 2.26 (m, 2H), 2.12 - 2.08 (m, 1H), 1.92- 1.70 (m, 2H), 1.66- 1.55 (m, 1H), 1.20 (d, J = 7.5 Hz, 6H), 0.00 (TMS) ppm | ||||
| 599 | A | A | 44 6.4 6 | 2.2 8 | H NMR (300.0 MHz, MeOD) d 8.86 (d, J = 2.4 Hz, H), 8.23 (d, J = 2.3 Hz, H), 8.17 (s, H), 8.03 (d, J =4.1 Hz, H), 4.46 (m, 1H), 3.05 (d, J = 12.8 Hz, 1 H), 2.66 (s, 3H), 2.34 (dd, J = 11.3, 20.6 Hz, 2H), 2.08 (d, J = 12.3 Hz, 1H), 1.89 -1.71 (m, 2H), 1.66- 1.54 (m, 1H), 1.10 (d, J = 6.4 Hz, 6H), and -0.00 (TMS) ppm |
| 600 | A | A | 46 0.4 6 | 2.3 1 | H NMR (300.0 MHz, MeOD) d 8.81 (d, J = 2.4 Hz, H), 8.22 (d, J = 2.4 Hz, H), 8.14 (s, H), 8.02 (d, J = 4.0 Hz, H), 4.45-4.37 (m, 1H), 3.61 (s, H), 2.97 (d, J = 8.8 Hz, 1H), 2.80 (s, 3H), 2.802.75(m, 1H), 2.39-2.32 (m, 2H), 2.32 (s, H), 2.15 (dd, J = 3.6, 12.7 Hz, 1H), 1.91 - 1.79 (m, 2H), 1.53- 1.47 (m, 1H), 1.10 (d, J = 6.8 Hz, 6H), and -0.00 (TMS) ppm |
| 601 | A | A | 49 0.4 7 | 2 | H NMR (300.0 MHz, MeOD) 8.88 (d, J = 2.3 Hz, H), 8.23 (d, J = 2.3 Hz, H), 8.17 (s, H), 8.02 (d, J = 4.1 Hz, H), 4.47 - 4.41 (m, 1H), 3.38 (m, H), 3.32 3.23 (m, 4H), 3.24(s, 3H), 3.12 - 3.07 (m, 1H), 2.73 (d, J = 10.8 Hz, 1H), 2.35-2.29 (m, 2H), 2.19-2.15 (m, 1H), 1.91 - 1.80 (m, 2H), 1.47-1.42 (m, 1H), 1.10 (d, J =6.5 Hz, 6H), and0.00 (s, H) ppm |
| 602 | A | A | 47 2.4 2 | 2.3 1 | H NMR (300.0 MHz, MeOD) d 8.82 (d, J = 2.4 Hz, H), 8.22 (d, J = 2.3 Hz, H), 8.15 (s, H), 8.01 (d, J = 4.0 Hz, H), |
-42816260
| 4.41 (m, 1H), 3.02 (d, J = 10.0 Hz, 1H), 2.59 - 2.47 (m, 2H), 2.40 - 2.30 (m, 2H), 2.09-2.01 (m, 1H), 1.89-1.85 (m, 1H), 1.78-1.66 (m, 1H), 1.61 1.55 (m,1H), 1.10 (d, J = 6.6 Hz, 6H), 0.68 - 0.63 (m, 2H), 00.44 - 0.40 (m, 2H) and 0.00 (s, H) ppm | |||||
| 603 | A | A | 43 4.2 | 1.5 4 | H NMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 1.5 Hz, 1H), 8.20 - 8.16 (m, 2H), 7.32 (s, 1H), 7.19 - 7.11 (m, 1H), 5.20 (s, 1H), 4.24 (s, 1H), 3.99 (s, 1H), 3.01 (d, J = 9.0 Hz, 1H), 2.70- 2.64 (m, 2H), 2.36 - 2.27 (m, 3H), 1.94 (s, 1H), 1.71 (s, 2H) and 1.48 (s, 1H) ppm |
| 604 | A | A | 46 1.2 | 1.7 9 | H NMR (300.0 MHz, DMSO) d 8.68 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.19-8.14 (m,2H), 7.33 (d, J = 7.5 Hz, 1H), 4.21 (t, J = 5.9 Hz, 2H), 4.00 - 3.96 (m, 1 H), 3.54 (t, J = 7.6 Hz, 1H), 3.15 (d, J = 8.9 Hz, 1H), 3.032.91 (m, 1H), 2.78 (d, J = 10.5 Hz, 1H), 2.11 - 1.92 (m, 3H), 1.71 (s, 2H), 1.431.35 (m, 1H), 1.27 (s, 3H), 1.22 (s, 1H) and 1.14 (s, 3H) ppm |
| 605 | C | C | 39 1.0 7 | 1.4 25 | H NMR (300.0 MHz, DMSO) d 12.51 (s, 1H), 8.72 - 8.57 (m, 3H), 8.35 - 8.32 (m, 3H), 7.94 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 7.9 Hz, 1H), 5.02 (m, 1H), 3.69 (m, 1H), 3.333.24 (m, 4H), 2.29 (s, 1 H) and 2.122.06 (m, 2H) ppm |
| 606 | A | A | 43 2.1 5 | 1.6 2 | |
| 607 | C | C | 43 3.1 8 | 1.8 7 | H NMR (300.0 MHz, DMSO) d 12.48 (s, 1H), 8.68 (s, 1H), 8.32 - 8.29 (m, 3H), 7.68 (d, J = 2.5 Hz, 1H), 4.77- |
-42916260
| 4.73 (m, 1H), 4.27 -4.10 (m, 2H), 3.76 - 3.40 (m, 2H), 3.19 - 3.04 (m, 2H) and 2.15- 1.83 (m, 6H) ppm. 2.05 and 2.03 (acetyl rota mers, two burried s, 3 H) | |||||
| 608 | A | A | 43 3.3 6 | 2.8 8 | H NMR (300.0 MHz, DMSO) d 9.03 (s, 1 H), 8.65 (s, 1 H), 8.48 (d, J = 5.1 Hz, 1H), 8.41 (s, 1H), 4.64 (s, 1H), 4.27 (s, 1H), 2.97 (m, 2H), 2.30 (d, J = 10.5 Hz, 1H), 2.06 (s, 2H), 1.91 (d, J = 11.2 Hz, 2H), 1.64 - 1.23(m, 5H), 0.99 (t, J = 6.9 Hz, 3H), and 0.00 (TMS), ppm |
| 609 | A | A | 43 3.3 2 | 2.7 9 | H NMR (300.0 MHz, MeOD) d 8.68(s, 1H), 8.64 (s, 1 H), 8.37 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1H), 5.15 (s, 1 H), ,4.71-4.63 (m, 1H), 3.33 (d, J = 11.6 Hz,1H), 3.10(m,2H), 2.26 (m, 2H), 2.04 (m,3H), 1.83 (m, 1H), 1.70 -1.50 (m, 2H), 1.03 (m, 3H), and 0.00 (TMS) ppm |
| 610 | A | C | 44 9.4 2 | 1.5 2 | H NMR (300.0 MHz, MeOD) d 8.85 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.98 (d, J = 4.1 Hz, 1H), 4.20 (m, 1H), 3.82 (dd, J = 3.9, 8.2 Hz, 1 H), 3.55 - 3.45 (m, 1 H), 3.30 (s, 3H), 3.23 - 3.07 (m, 1 H), 2.86 - 2.77 (m, 2H), 2.68 - 2.59 (m, 1H), 2.44 (d, J = 10.9 Hz, 1H), 2.15 (d, J =9.8 Hz, 1H), 2.07- 1.94 (m, 2H), 1.65-1.56 (m, 1H) and 1.42-1.17 (m, 3H) ppm |
| 611 | A | A | 44 7.4 | 1.9 5 | H NMR (300.0 MHz, MeOD) d 8.78 (d, J = 2.3 Hz, 1H), 8.19 (d, J =2.2 Hz, 1H), 8.14 (s, 1H), 7.96 (d, J = 4.0 Hz, 1H), 4.25-4.18 (m, 1H), 3.96-3.88 (m, 1H), 3.61 (t, J = 6.2 Hz, 2H), 3.31 (s, 3H), 2.39 (t. J = 6.2 Hz, 2H), 2.37 (d, J = 17.1 Hz, 1H), 2.18 (d, J = 12.0 Hz, 1H), 2.03-1.91 (m, 2H), 1.67 (q, J = 13.4 Hz, 1H) and 1.45- 1.22 (m, 3H) |
^3016260
| ppm | |||||
| 612 | A | A | 41 8.3 7 | 4.5 9 | H NMR (300.0 MHz, MeOD) d 8.77 (s, 1H), 8.37 (d, J = 2.7 Hz, 2H), 8.26 (d, J = 4.7 Hz, 1H), 4.46 (m, 1H), 2.39 (m, 1H), 2.10 (m, 1H), 1.92-1.35 (m, 8H) and 0.93 (t, J = 7.7 Hz, 3H) ppm |
| 613 | A | A | 38 8.1 3 | 1.8 2 | |
| 614 | A | A | 45 9.3 5 | 3.0 6 | H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.72 (s, 1H), 8.29 (s, 1H), 8.18 (s, 2H), 7.31 (d, J = 6.2 Hz, 1H), 6.10 (d, J = 5.3 Hz, 1H), 4.16 (s, 2H), 3.04 (s, 1 H), 2.79 (d, J = 8.6 Hz, 1H), 2.59 (d, J = 9.9 Hz, 2H), 2.26 (t, J = 9.5 Hz, 2H), 1.94 (s, 1H), 1.72 (s, 2H) and 1.48 (s, 1 H) ppm |
| 615 | A | A | 37 8.3 | 3.5 9 | |
| 616 | C | C | 37 8.3 | 3.7 4 | |
| 617 (diastero mer 1) | A | A | 38 6.3 5 | 3.5 8 | H NMR (300.0 MHz, DMSO) d 13.15 (s, H), 9.58 (s, 1H), 9.49 (d, J = 6.4 Hz, 111 H), 9.23 (s, H), 8.59 (s, H), 8.52 (d, J = 5.0 Hz, 1 H), 8.42 (s, 1 H), 4.52 (s, 1H), 3.34 (s, 1H), 3.17 (s, 1H), 2.11 (s, 2H), 1.96 - 1.85 (m, 4H), 1.5-1.2 (m, 2H), and -0.00 (s, H) ppm |
| 618 (diastero mer 2) | A | A | 38 6.3 4 | 3.1 6 | H NMR (300.0 MHz, DMSO) d 13.13 (s, 1H), 9.45 (s, 1H), 9.28 (s, 1H), 8.66 (s, 1H), 8.51 (d, J =5.1 Hz, 1H), 8.42 (s, 1H), 4.61 (s, 1H), 3.33 (s, 1H), 3.17 (s, 1H), 2.16 (d, J = 12.5 Hz, H), 2.06 (s, 1 H), 2.02 - 1.78 (m, 4H), 1.66 1.60 (m, 2H), 1.46 (m, 1H), and 0.00 (s, H) ppm |
| 619 | A | A | 44 6.2 | 2.2 3 | H NMR (300.0 MHz, DMSO) d 12.30 (s, 1H), 8.71 (s, 1H), 8.28 (s, 1H), 8.17 |
-43116260
| 3 | (d, J = 6.9 Hz, 2H), 7.42 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 4.73 (d, J = 7.4 Hz, 1H), 4.23 (s, 1H), 3.51 (d, J = 5.8 Hz, 1H), 3.17 (dd, J = 9.2, 17.9 Hz, 1H), 3.04 (d, J = 10.9 Hz, 2H), 2.89 (s, 1H), 2.63 (d, J = 5.6 Hz, 1 H), 2.25 (d, J = 11.4 Hz, 1H), 2.18 - 2.07 (m, 2H), 1.70 (d, J = 11.3 Hz, 2H) and 1.43 - 1.35 (m, 1H) ppm | ||||
| 620 | B | A | 40 0.4 1 | 1.9 2 | |
| 621 | A | A | 44 5.4 5 | 2.3 9 | |
| 622 | A | A | 43 1.4 2 | 2.4 6 | |
| 623 | A | A | 43 5.4 | 3.6 2 | H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.69 (s, 1H), 8.35-8.25 (m, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 3.9 Hz, 1 H), 7.51 (d, J = 6.7 Hz, 1 H), 5.02 - 4.60 (m, 3H), 4.37 - 4.20 (m, 3H), 3.62 - 3.40 (m, 2H), 3.17 - 2.62 (m, 2H), 2.10 (s, 1H) and 1.85-1.60 (m, 3H)ppm |
| 624 | A | B | 37 8.1 5 | 2.4 9 | MeOH d4 8.8 (d, 1H); 8.2 (d, 1 H); 8.1 (s, 1H); 7.9 (d, 1 H); 4.2 (dd, 1H_); 3.6 (dt, 1H); 3.4 (dd, 1H); 2.2 (bd, 1H); 2.05 (bd, 1H); 1.8 (dr, 1H); 1.6 (m, 1H); 1.4 (m, 2H). |
| 625 | A | A | 37 8.3 4 | 2.4 2 | MeOH d4 8.8 (d, 1H); 8.2 (d, 1H); 8.1 (s, 1H); 7.9 (d, 1H); 4.2 (dd, 1HJ; 3.6 (dt, 1H); 3.4 (dd, 1H); 2.2 (bd, 1H); 2.05 (bd, 1H); 1.8 (dr, 1H);1.6 (m, 1 H); 1.4 (m, 2H). |
| 626 | A | A | 39 0.3 | 4.0 5 | H NMR (300.0 MHz, CDCI3) d 8.87 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 2.3 Hz,1 |
-43216260
| 9 | H), 8.17 (d, J = 2,7 Hz, 1H), 8.03 (d, J = 3.5 Hz, 1 H), 7.28(CDCI3), 6.8 (s, 1H), 4.67 (m, 1H), 2.1-1.88 (m, 4H), 1.8-1.50 (m,7H), 0.99 (t, J = 7.5 Hz, 3H) ppm | ||||
| 627 (diastero mer 1) | A | A | 38 8,3 6 | 4.0 1 | H NMR (300.0 MHz, CDCI3) d 9.65 (s,1 H), 8.97 (s, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 3.4 Hz, 1H), 7.28(s, CDCI3), 6.75 (s, 1H), 6.06 (dd, J = 10.7, 17.3 Hz, 1H), 5.32 (d, J = 3.9 Hz, 1 H), 5.18 (d, J = 10.8 Hz, 1H), 4.66 (qn, J =4.0 Hz, 1 H),2,08 - 1.86 (m, 4H), 1.79 -1.61 (m, 6H), 1pp |
| 628 (diastero mer 2) | A | A | 38 8.3 7 | 3.6 5 | H NMR (300.0 MHz, CDCI3) d 9.62 (s, 1H), 8.95 (s, 1H), 8.34 (3, 1H), 8.20 (s, 1H), 8.10(s, 1H), 7.28(s, CDCI3), 6.03 (dd, J = 10.7, 17.3 Hz, 1H), 5.39 5.30 (m, 1H), 5.10 (d, J = 10.7 Hz, 1H),4.87-4.81 (m, 1H), 4.76-4.64 (m, 1H), 2.29-2.24 (m, 2H), 2.192.02 (m, 2H), 1.84 - 1.78 (m, 3H), 1.62-1.21 (m, 3H), ppm |
| 629 | A | A | 44 6.2 3 | 4.4 5 | |
| 630 | A | A | 39 0.3 6 | 3.9 5 | H NMR (300.0 MHz, MeOD) d 8.72 (s, 1H), 8.53 (s, 1H), 8.39 (s, 1 H), 8.30 (s, 1H), 4.65-4.60 (m, 1H), 2.66 (t, J = 11,3 Hz, 1H), 2.46 (d, J = 10.2 Hz, 1H), 2.17-2.04 (m, 3H) and 1.57- 1.44 (m, 4H) ppm |
| 631 | A | A | 37 8.1 5 | 3.1 | |
| 632 | A | A | 37 8.1 5 | 2.9 7 | _ |
-43316260
| 633 | A | A | 47 3.4 2 | 3.2 5 | H NMR (300.0 MHz, MeOD) d 8.64 (d, J =2.2 Hz, 1H), 8.51 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 5.5 Hz, 1H), 4.39 (t, J = 11.9 Hz, 1 H), 3.93 - 3.82 (m, 3H), 3.54 - 3.30 (m, 2H), 2.52 2.43 (m, 1H), 2.37-2.33 (m, 1H), 2.20 (d, J = 11.6 Hz, 1H), 2.01 (d, J = 11.3 Hz, 2H), 1.90- 1.88 (m, 1H), 1.831.63 (m, 4H) and 1.59- 1.26 (m, 3H) ppm |
| 634 | A | A | 43 3.2 1 | 3.4 7 | H NMR (300.0 MHz, MeOD) d 8.61 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.35 (d, J = 2.0 Hz, 1 H), 8.29 (d, J = 5.5 Hz, 1 H), 4.37 (t, J = 11.2 Hz, 1H), 3.95 (s, 1H), 3.80 (s, 2H), 2.42 (t, J = 5.5 Hz, 3H), 2.20 (d, J = 11.5 Hz, 1H), 2.03 (d, J = 11.0 Hz, 2H) and 1.76 - 1.29 (m, 4H) ppm |
| 635 | A | A | 45 9.3 8 | 3.1 2 | H NMR (300.0 MHz, MeOD) d 8.48 8.45 (m, 2H), 8.29 - 8.23 (m, 2H), 4.84 (d, J = 6.0 Hz, 1 H), 4.38 (d, J = 6.0 Hz, 1H), 4.26 - 4.23 (m, 1H), 3.96 (s, 1H), 3.77-3.62 (m, 2H), 2.36 (s, 1H), 2.18 (d, J = 11.5 Hz, 1H), 2.02 (d, J = 12.3 Hz, 2H), 1.70- 1.25 (m, 4H) and 1.59 (s, 3H) ppm |
| 636 | A | A | 47 3.4 | 3.1 2 | H NMR (300.0 MHz, MeOD) d 8.64 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.44 - 4.36 (m, 1H), 3.96 - 3.87 (m, 3H), 3.47 - 3.37 (m, 2H), 2.49 - 2.35 (m, 2H), 2.21 (d, J = 12.4 Hz, 1H), 2.02 (d, J = 11.9 Hz, 2H) and 1.83 - 1.23 (m, 8H) ppm |
| 637 | A | A | 47 4.4 3 | 2.3 9 | H NMR (300.0 MHz, MeOD) d 8.68 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 8.33 (d, J = 4.7 Hz, 1H), 4.44-4.35 (m, 2H), 4.21 (d, J = 12.2 Hz, 1H), 4.04 - 3.92 |
-43416260
| (m, 2H), 3.58 (d, J = 12.3 Hz, 1H), 3.23 - 3.08 (m, 2H), 2.37 (d, J = 8.1 Hz, 1H), 2.23 (d, J = 11.1 Hz, 1H), 2.05 (d, J = 9.7 Hz, 2H), 1.72 (m, 2H) and 1.59 - 1.44 (m, 2H) ppm | |||||
| 638 | A | A | 45 9.3 7 | 3.7 7 | H NMR (300.0 MHz, MeOD) d 8.55 (d, J = 1.0 Hz, 1H), 8.46-8.45 (m, 1H), 8.29 - 8.27 (m, 2H), 4.28 (d, J = 6.1 Hz, 2H), 4.00 - 3.87 (m, 3H), 2.36 - 2.16 (m, 3H), 2.00 -1.91 (m, 5H) and 1.75 1.41 (m, 4H) ppm |
| 639 | C | C | 47 2.4 6 | 2.3 9 | H NMR (300.0 MHz, MeOD) d 8.66 (s, 1H), 8.60 (s, 1H), 8,38 (s, 1H), 8.31 (d, J =4.7 Hz, 1H), 4.43-4.36 (m, 1H), 3.98-3.91 (m, 1H), 3.43 (d, J = 10.3 Hz, 2H), 3.03 (t, J = 10.6 Hz, 2H), 2.60 (s, 1H), 2.38 (d, J = 10.2 Hz, 1H), 2.21 (d, J = 10.6 Hz, 1H), 2.07- 1,92 (m, 6H) and 1,74- 1.30 (m, 4H) ppm |
| 640 (diastero mer 1) | A | A | 44 7.4 1 | 3.3 7 | H NMR (300.0 MHz, MeOD) d 8.69 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.43 (t, J = 11.9 Hz, 1H),4.14 (q, J = 6.1 Hz, 1H), 3.94 (t, J = 11.9 Hz, 1H), 2.40 - 2.19 (m, 4H), 2.03 (d, J = 8.2 Hz, 2H), 1.78- 1.69 (m, 1H), 1.59-1.44 (m, 3H) and 1.18 (d, J = 6.1 Hz, 3H) ppm |
| 641 (diastero mer 2) | A | A | 44 7.4 1 | 3.4 7 | H NMR (300.0 MHz, MeOD) d 8.69 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.43 (t, J = 11.9 Hz, 1H), 4.14 (q, J = 6.1 Hz, 1H), 3.94 (t, J = 11.9 Hz, 1H), 2.40 - 2.19 (m, 4H), 2.03 (d, J = 8.2 Hz, 2H), 1,78- 1.69 (m, 1H), 1.59-1.44 (m, 3H) and 1.18 (d, J = 6.1 Hz, 3H) PPm |
| 642 | A | A | 43 | 3.5 | H NMR (300.0 MHz, MeOD) d 8.68 (s, |
-43516260
| 3.3 8 | 2 | 1 H), 8.56 (s, 1 H), 8.39 (d, J = 1.5 Hz, 1H), 8.31 (d, J = 5.3 Hz, 1 H), 4.47- 4.40 (m, 1H), 4.15 (s, 1H), 3.98 (m, 1H), 2.41 (s, 1H), 2.23 (d, J = 10.6 Hz, 1H), 2.04 (d, J = 11.0 Hz, 2H) and 1.77 - 1.36 (m, 7H) ppm | |||
| 643 | A | A | 40 4.3 6 | 3.3 | H NMR (300.0 MHz, MeOD) d 8.98 (d, J = 2.3 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 5.7 Hz, 1H), 5.26-5.22 (m, 1H), 2.17-2.10 (m, 1H), 1.87- 1.82 (m, 4H), 1.68-1.59 (m, 3H) and 1.36 (s, 3H) ppm |
| 644 | C | C | 41 8.4 | 3.3 7 | H NMR (300.0 MHz, MeOD) d 8.87 (d, J = 2.3 Hz, 1 H), 8.45 (s, 1 H), 8.38 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 5.6 Hz, 1 H), 5.26-5.23 (m, 1H), 2.14-2.09 (m, 1H), 1.96- 1.72 (m, 6H), 1.59 (s, 3H) and 0.87 (t, J = 7.4 Hz, 3H) ppm |
| 645 | A | A | 41 8.4 1 | 3.3 7 | H NMR (300.0 MHz, MeOD) d 8.87 (d, J = 2.3 Hz, 1H), 8.46 (s, 1H), 8.37 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 5.6 Hz, 1H), 5.25-5.23 (m, 1H), 2.17-2.09 (m, 1 H), 1.98 - 1.74 (m, 6H), 1.58 (m, 3H) and 0.87 (t, J = 7.4 Hz, 3H) ppm |
| 646 | A | A | 39 2.3 5 | 3.3 5 | H NMR (300.0 MHz, DMSO) d 12.30 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.20- 8.15 (m, 2H), 4.57-4.54 (m, 1H), 4.4-4.3(s, 1H), 4.08-4.01 (m, 1H), 3.37 - 3.29 (m, 2H), 3.17 (d, J = 5.3 Hz, H), 2.50(qn, J = 1,7Hz DMSO), 1.99 (s, 1 H), 1.91 (d, J = 3.6 Hz, H), 1.77- 1.65 (m, 6H), 1.59 (d, J = 7.5 Hz, 1H). |
| 647 | A | A | 47 4.4 | 3.5 9 | H NMR (300.0 MHz, MeOD) d 8.56 (s, 1 H), 8.50 (d, J = 2.2 Hz, 1 H), 8.30 (t, J = 5.6 Hz, 1 H), 8.31 (s, 1H), 4.26 (t, J = 11.2 Hz, 1H), 3.82 (t, J = 11.1 Hz, 1H), 3.65 - 3.61 (m, 4H), 3.39 - 3.36 (m, |
-43616260
| 4H), 2.36 (d, J = 10.0 Hz, 1H), 2.17 (d, J = 12.0 Hz, 1H), 2.02 (d, J = 10.2 Hz, 2H) and 1.70- 1.32 (m, 4H) ppm | |||||
| 648 | A | A | 48 9.3 8 | 3.6 7 | H NMR (300.0 MHz, MeOD) d 8.65 (s, 1 H), 8.52 (d, J = 1.6 Hz, 1 H), 8.37 (d, J = 2.0 Hz, 1H), 8.28 (dd, J = 2.9, 5.5 Hz, 1 H), 4.39 (s, 1 H), 4.06 - 3.54 (m, 7H), 2.55 - 2.38 (m, 2H), 2.19 (d, J = 10.7 Hz, 1H), 2.03- 1.99 (m, 3H) and 1.691.24 (m, 5H) ppm |
| 649 | A | A | 47 5.3 7 | 3.3 2 | H NMR (300.0 MHz, MeOD) d 8.79 (d, J = 2.3 Hz, 1 H), 8.51 (s, 1 H), 8.44 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H), 5.22 (dd, J = 4.4, 6.0 Hz, 1H), 4.534.45 (m, 1H), 4.21 - 3.50 (m, 5H), 2.52 - 2.43 (m, 1 H), 2.27 - 2.04 (m, 5H) and 1.72 - 1.27 (m, 4H) ppm |
| 650 | A | A | 46 1.3 8 | 3.7 9 | H NMR (300.0 MHz, MeOD) d 8.56 - 8.54 (m, 2H), 8.34 (s, 1H), 8.30 (t, J = 5.4 Hz, 1H), 4.29 (t, J = 11.4 Hz, 1H), 3.93 (t, J = 11.6 Hz, 1 H), 3.54 (s, 2H), 2.34 (d, J = 10.8 Hz, 1H), 2.18 (d, J = 11.4 Hz, 1 H), 2.01 (d, J = 11.3 Hz, 2H), 1.73- 1.37 (m, 4H) and 1.15 (s, 6H) PPm |
| 651 | A | A | 47 3.4 1 | 4.1 | H NMR (300.0 MHz, MeOD) d 8.56 - 8.51 (m, 2H), 8.33 - 8.29 (m, 2H), 4.30 (d, J = 3.0 Hz, 1H), 3.98 (dd, J = 11.5, 23.4 Hz, 2H), 3.83 - 3.79 (m, 1 H), 3.55 (t, J =8.9 Hz, 1H), 2.35 (d, J = 11.1 Hz, 1H), 2.19 (d, J = 11.2 Hz, 1H), 2.03- 1.90 (m, 4H) and 1.73 - 1.37 (m, 8H) PPm |
| 652 | A | A | 45 9.4 1 | 3.8 6 | H NMR (300.0 MHz, MeOD) d 8.72 (d, J = 2.3 Hz, 1H), 8.56 (s, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 5.6 Hz, 1H), 4.51 -4.43 (m, 1H), 4.02-3.88 (m, 3H), 3.86 - 3.78 (m, 2H), 3.07 - 3.02 |
-43716260
| (m, 1 H), 2.42 (d, J = 7.5 Hz, 1 H), 2.25 (d, J = 12.0 Hz, 1H), 2.19-2.06 (m, 4H) and 1.79- 1.35 (m, 4H) ppm | |||||
| 653 | A | A | 41 8.4 | 3.3 7 | H NMR (300.0 MHz, MeOD) d 8.87 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.19 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 3.7 Hz, 1H), 4.90 (m, 1H), 2.12 (m, 2H), 1.76 -1.58 (m, 7H) and 0.86 (t, J = 7.3 Hz, 3H) ppm |
| 654 | B | B | 41 1.3 7 | 2.8 7 | |
| 655 (diastero mer 1) | A | A | 37 6.3 9 | 3.9 3 | H NMR (300.0 MHz, CDCI3) d 10.63 (s, 1H), 8.85 - 8.82 (m, 1H), 8.27 (dd, J = 2.4, 12.5 Hz, 1H), 8.17-8.14 (m, 1 H), 8.03 (d, J = 3.4 Hz, 1H), 7.28 (s, H), 4.84 (d, J = 6.3 Hz, 1H), 4.58 (dq, J = 3.9, 15.7 Hz, 1H), 2.26 (d, J = 12.0 Hz, 2H), 2.09 - 1.95 (m, 2H), 1.84 1.75 (m, 3H), 1.47 - 1.32 (m, 5H) and 1.22 (td, J = 12.4, 5.2 Hz, 1H) ppm |
| 656 (diastero mer 2) | A | A | 37 6.3 8 | 4.0 1 | H NMR (300.0 MHz, CDCI3) d 9.54 (s, 1H), 8.86 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.7 Hz, 1H), 8.04 (d, J = 3.5 Hz, 1H), 7.28 (s, H), 6.66 (s, 1H), 4.62-4.59 (m, 1H), 1.96- 1.88 (m, 4H), 1.81 (dd, J = 4.5, 14.9 Hz, 2H) and 1.68 - 1.57 (m, 5H) ppm |
| 657 | C | C | 39 4.4 1 | 2.9 7 | H NMR (300.0 MHz, DMSO) d 12.41 (s, 1H), 8.80 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.25 (s, 1H), 8.17 (d, J = 4.0 Hz, 1H), 7.64 (s, 1H), 4.80- 4.50 (m, 3H), 4.47 (dd, J = 7.5, 14.8 Hz, 1H), 3.89 (dd, J = 5.3, 6.3 Hz, 1H), 3.77 (dd, J = 5.1, 5.0 Hz, 1H), 3.50- 3.37 (m, 2H), 2.36 - 2.24 (m, 1H), 2.04 (dd, J = 8.3, 13.5 Hz, 1H), 1.99 (s, 1H), 1.27 (td, J = 8.4, 4.4 Hz, 1H) and 1.21 |
-43816260
| (s, 1H) ppm | |||||
| 658 | A | A | 45 9.2 9 | 3.5 | |
| 659 | A | A | 44 5.2 1 | 3.4 1 | |
| 660 | A | A | 44 5.2 1 | 3.3 5 | |
| 661 | A | A | 39 5.1 7 | 2.1 3 | |
| 662 | A | A | H NMR (300.0 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J = 2.8, 9.8 Hz, 1H), 8.27 (q, J = 1.3 Hz, 1H), 8.21 (d, J = 2.7 Hz, 1H), 8.16 (d, J =4.0 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 4.49 (m, 1 H), 4.39 (d, J = 4.0 Hz, 1H), 4.24 - 4.21 (m, 1H), 3.64-3.61 (m, 1H), 3.05-3.02 (m, 1 H), 2.77 (t, J = 9.7 Hz, 1H), 2.36 (ddd, J = 4.8, 12.7, 12.7 Hz, 2H), 2.18 2.12 (m, 2H), 1.95-1.91 (m, 1H), 1.76 -1.72 (m, 1H) and 1.66 -1.41 (m, 2H) ppm | ||
| 663 | A | A | 44 5.3 4 | 2.6 4 | |
| 664 | A | A | 43 1.2 6 | 2.4 8 | |
| 665 | A | A | 43 1.2 6 | 2.5 3 | |
| 666 | D | 42 8.3 | 2.6 | ||
| 667 | D | 41 4.5 | 1.4 |
-43916260
| 668 | A | 42 9.3 | 3.5 1 | H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.18-8.16 (m, 2H), 7.38 (d, J = 7.7 Hz, 1 H), 4.22-4.17 (m, 1H), 3.31 - 3.16 (m, 3H), 2.90 (m, 1H), 2.40 (t, J = 10.2 Hz, 2H), 2.00 - 1.95 (m, 1 H), 1.77 - 1.60 (m, 2H) and 1.50 - 1.38 (m, 1H) ppm | |
| 669 | A | A | 38 6.0 8 | 2.2 6 | H NMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19-8.17 (m, 2H), 7.47 (d, J = 7.7 Hz, 1H), 4.30 - 4.20 (m, 1H), 3.80 (s, 2H), 3.07 - 3.03 (m, 1H), 2.82 -2.73 (m, 1H), 2.29 - 2.10 (m, 2H), 2.05 - 1.96 (m, 1 H), 1.87 -1.65 (m, 2H) and 1.49 -1.40 (m, 1H) ppm |
| 670 | C | C | 55 9.4 2 | 3.5 7 | H NMR (300.0 MHz, MeOD) d 8.64 (d, J = 2.3 Hz, 1H), 8.40 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.0 Hz, 1H), 6.96 (m, 1H), 4.84-4.80 (m, 1H), 4.34 (m, 1H), 4.29 - 4.19 (m, 3H), 3.543.47 (m, 1H), 3.15-3.07 (m, 1 H), 2.68 - 2.58 (m, 1 H), 1.92 (s, 3H), 1.59 -1.51 (m, 4H), 1.26 (t. J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H) and 0.89 (t, J = 7.4 Hz, 3H) ppm |
| 671 | C | C | 53 1.4 | 3.1 4 | H NMR (300.0 MHz, MeOD) d 8.66 (d, J = 2.3 Hz, 1 H), 8.39 (s, 1 H), 8.32 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.0 Hz, 1H), 6.97 (m, 1H), 4.82-4.79 (m, 1H), 4.34 (m, 1 H), 4.25 (dd, J = 7.6, 10.1 Hz, 1H), 3.54- 3.47 (m, 2H), 3.11 -3.04 (m, 1H), 2.65 - 2.57 (m, 1H), 1.91 (s, 3H), 1.59 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H) and 0.89 (t, J = 7.4 Hz, 3H) ppm |
Table 2: IC50, EC50t NMR and LCMS Data of Compounds of FIGs. 4 and 5:
-44016260
| Compoun d Nos. | I C 5 0 | E C 5 0 | LCM S_ Plus | LCM S_ RT | NMR |
| 672 | A | A | 432. 28 | 3.83 | |
| 673 | A | A | 448. 28 | 3.81 | |
| 674 | A | A | 405. 15 | 3.16 | |
| 675 | C | C | 428. 32 | 2.2 | |
| 676 | A | A | 445. 34 | 2.45 | |
| 677 | A | A | 404. 38 | 3.32 | H NMR (300.0 MHz, MeOD) d 8.93 (d, J = 2.4 Hz, 1H), 8.21 - 8.19 (m, 2H), 7.97 (d, J = 4.0 Hz, 1H), 4.81 (dd, J = 2.8, 9.4 Hz, 1H), 2.24-2.16 (m, 1H), 2.11 2.05 (m, 1H), 1.74 (m, 2H), 1.63- 1.52 (m, 4H) and 1.26 (s, 3H) PPm |
| 678 | A | A | 388. 44 | 3.13 | H NMR (300.0 MHz, MeOD) d 8.67 (dd, J =2.4, 9.1 Hz, 1H), 8.47 (s, 1H), 8.34-8.31 (m, 2H), 5.27-5.23 (m, 1H), 2.12 - 2.04 (m, 1H), 1.88- 1.80 (m,4H), 1.66 -1.56 (m, 3H) and 1.35 (s, 3H) PPm |
| 679 | A | A | 471. 06 | 3.28 | |
| 680 | A | A | 471. 19 | 3.31 | |
| 681 | I A | A | 447. 5 | 3.65 | H NMR (300.0 MHz, MeOD) d 8.69 (d, J = 2.3 Hz, 1H), 8.49 (s, 1H), 8.36 (t, J = 2.2 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1 H), 4.42 (t, J = 3.8 Hz, 1H), 3.89 (t, J = 3.5 Hz, |
-44116260
| 1H), 2.33 (d, J = 6.0 Hz, 1H), 2.22 (d, J = 11.4 Hz, 1H), 2.00 (d, J = 11.8 Hz, 2H), 1.78- 1.39 (m, 4H) and 1.34 (d, J = 8.3 Hz, 6H) ppm | |||||
| 682 | A | A | 473. 49 | 3.96 | H NMR (300.0 MHz, MeOD) d 8.68 (d, J = 1.7 Hz, 1H), 8.49 (d, J = 0.8 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 4.47 -4.38 (m, 1H), 3.94-3.87 (m, 3H), 2.33 - 2.19 (m,3H), 2.04 -1.88 (m, 3H), 1.90- 1.73 (m, 2H), 1.73-1.41 (m, 4H) and 1.36 (d, J = 8.6 Hz, 3H) ppm |
| 683 | A | A | 417. 49 | 3.85 | H NMR (300.0 MHz, MeOD) d 8.67 (d, J = 2.3 Hz, 1 H), 8.51 (s, 1H), 8.37 (d, J =2.3 Hz, 1H), 8.28 (d, J = 5.6 Hz, 1H), 4.46- 4.36 (m, 1H), 3.95-3.87 (m, 1H), 2.35 (d, J = 11.7 Hz, 1H), 2.23- 2.16 (m, 3H), 2.02 (d, J = 10.5 Hz, 2H), 1.77- 1.64 (m, 1H), 1.58 -1.43 (m, 2H), 1.40- 1.23 (m, 1H) and 1.11 (t, J = 7.6 Hz, 3H) ppm |
| 684 | A | A | 429. 49 | 3.86 | H NMR (300.0 MHz, MeOD) d 8.61 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1 H), 4.424.32 (m, 1H), 3.96-3.88 (m, 1H), 2.35 (d, J = 11.7 Hz, 1H), 2.19 (d, J = 12.0 Hz, 1H), 2.04-2.00 (m, 2H), 1.72- 1.27 (m, 5H) and 0.88 - 0.70 (m, 4H) ppm |
| 685 | A | A | 431. 49 | 3.87 | H NMR (300.0 MHz, MeOD) d 8.60 (d, J = 2.3 Hz, 1H), 8.56- 8.52 (m, 1H), 8.33 (dd, J = 2.3, 5.7 Hz, 1H), 8.28 (d, J = 5.6 Hz, |
^4216260
| 1H), 4.39-4.30 (m, 1H), 3.94- 3.86 (m, 1H), 2.48-2.34 (m, 2H), 2.17 (d, J = 11.8 Hz, 1H), 1.99 (d, J = 11.8 Hz, 2H), 1.71 - 1.67 (m, 1H), 1.62- 1.27 (m, 3H) and 1.10 (d, J = 6.1 Hz, 6H) ppm | |||||
| 686 | A | A | 443. 49 | 3.99 | H NMR (300.0 MHz, MeOD) d 8.62 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.35 (d, J = 2.3 Hz, 1 H), 8.28 (d, J = 5.6 Hz, 1H), 4.43- 4.32 (m, 1H), 4.00-3.92 (m, 1 H), 2.31 (d, J = 11.8 Hz, 1H), 2.21 (d, J = 12.1 Hz, 1H), 2.04- 1.97 (m, 2H), 1.76- 1.58 (m, 2H), 1.53 - 1.33 (m, 2H), 1.32 (s, 3H), 1.18 1.03 (m, 2H) and 0.63 - 0.55 (m, 2H) ppm |
| 687 | A | C | 450. 2 | 3.43 | |
| 688 | A | A | 475. 41 | 4.65 | |
| 689 | A | A | 445. 47 | 3.7 | H NMR (300.0 MHz, MeOD) d 8.69 (d, J = 2.3 Hz, 1H), 8.49 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1 H), 4.48- 4.41 (m, 1H), 4.00-3.93 (m, 1H), 2.35 (d, J = 6.0 Hz, 1H), 2.22 (d, J = 11.3 Hz, 1H), 2.03 (d, J = 13.0 Hz, 2H), 1.74- 1.35 (m, 4H), 1.18-1.14 (m, 2H) and 0.99- 0.86 (m, 2H) ppm |
| 690 | A | A | 469. 47 | 3.84 | H NMR (300.0 MHz, DMSO) d 12.33 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.6 Hz, 1H), 8.17 (d, J = 4.0 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 4.27-4.17 (m, 1H), 3.67 (s, 3H), 3.64 (s, 3H), 3.21 - 3.16 |
-44316260
| (m, 1H), 2.96-2.90 (m, 3H), 2.33 -2.20(m, 2H), 1.99- 1.94 (m, 1H), 1.80- 1.60 (m, 2H) and 1.47 -1.35 (m, 1H) ppm | |||||
| 691 | A | A | |||
| 692 | A | A | 420. 3 | 3.13 | |
| 693 | A | A | 448. 32 | 3.51 | |
| 694 | A | A | 420. 3 | 2.94 | |
| 695 | A | A | 448. 32 | 3.3 | |
| 696 | A | A | 390. 42 | 3.29 | 1H NMR (300 MHz, DMSO) d 12.55 (bs, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.16 (s, 1H), 8.10 (d, J = 4.0 Hz, 1H), 7.94 (bs, 1H), 4.11 (bs, 1H), 2.26-2.02 (m, J = 10.7 Hz, 3H), 2.00- 1.69 (m, J = 32.8, 20.4 Hz, 4H), 1.68-1.21 (m, 5H). |
| 697 | A | A | 447. 49 | 3.91 | H NMR (300.0 MHz, MeOD) d 8.71 (s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 8.28 (d, J = 5.5 Hz, 1H), 4.46-4.38 (m, 1H), 3.69-3.61 (m, 1H), 2.37 (d, J = 11.7 Hz, 1H), 2.18 (d, J = 10.6 Hz, 1H), 2.07- 1.98 (m, 2H), 1.74-1.62 (m, 1H), 1.57- 1.39 (m, 2H), 1.39 -1.25 (m, 1H) and 1.19 (d, J = 6.1 Hz, 6H) ppm |
| 698 | A | A | 447. 48 | 3.6 | H NMR (300.0 MHz, MeOD) d 8.71 (s, 1H), 8.50 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 5.3 Hz, 1H), 4.46-4.39 (m, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.62 (t, J = 11.5 Hz, 1H), 2.38 (d, J = 11.1 Hz, 1H), 2.18 (d, J = 11.0 Hz, |
-44416260
| 1H), 2.07 - 1.99 (m, 2H), 1.71 - 1.49 (m, 4H), 1.35- 1.22 (m, 2H) and 0.93 (s, 3H) ppm | |||||
| 699 | A | A | 461. 51 | 4.18 | H NMR (300.0 MHz, MeOD) d 8.70 (s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 8.28 (d, J = 5.3 Hz, 1H), 4.46-4.39 (m, 1H), 3.77 (d, J = 6.5 Hz, 2H), 3.70-3.62 (m, 1H), 2.38 (d, J = 11.8 Hz, 1H), 2.18 (d, J = 10.6 Hz, 1H), 2.07- 1.99 (m, 2H), 1.88- 1.84 (m, 1 H), 1.71 - 1.28 (m, 4H) and 0.91 (d, J = 4.5 Hz, 6H) ppm |
| 700 | A | A | 433. 49 | 4 | H NMR (300.0 MHz, MeOD) d 8.70 (s, 1H), 8.50 (s, 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.28 (d, J = 5.5 Hz, 1H), 4.46-4.38 (m, 1H), 4.01 (q, J = 7.0 Hz, 2H), 3.66 (t, J = 11.7 Hz, 1H), 2.38 (d, J = 11.3 Hz, 1H), 2.18 (d, J = 11.0 Hz, 1H), 2.07- 1.99 (m, 2H), 1.751.62 (m, 1H), 1.57- 1.39 (m, 2H) and 1.36 -1.19 (m, 4H) ppm |
| 701 | A | A | 457. 48 | 4.03 | H NMR (300.0 MHz, MeOD) d 8.69 (s, 1H), 8.49 (s, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.27 (d, J = 5.4 Hz, 1 H), 4.55 (s, 2H), 4.37 (t, J = 11.6 Hz, 1H), 3.70- 3.57 (m, 1H), 2.37 (d, J = 10.7 Hz, 1H), 2.17 (d, J = 11.2 Hz, 1H), 2.07- 1.98 (m, 2H), 1.78 (s, 3H) and 1.70-1.22 (m, 4H)ppm |
| 702 | I A | A | 443. 46 | 3.84 | H NMR (300.0 MHz, MeOD) d 8.69 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 4.61 (s, 1H), 4.41 (t, J = 11.7 Hz, 1H), 3.65-3.53 (m, 3H), 2.37 (d, |
-44516260
| J =8.2 Hz, 1H), 2.17 (d, J= 10.9 Hz, 1H), 2.02 (t, J = 13.2 Hz, 2H) and 1.70- 1.27 (m, 4H) ppm | |||||
| 703 | A | A | 417. 52 | 3.66 | H NMR (300.0 MHz, MeOD) d 8.54 (s, 1H), 8.39 (dd, J = 2.7, 9.1 Hz, 1H), 8.34(s, 1H), 8.29 (d, J = 5.5 Hz, 1H), 4.49-4.41 (m, 1H), 4.04-3.97 (m, 1 H), 3.88 (s, 2H), 3.41 (s, 3H), 2.35 (d, J = 11.8 Hz, 1H), 2.21 (d, J = 11.2 Hz, 1H), 2.02 (d, J = 11.7 Hz, 2H) and 1.73 - 1.36 (m, 4H) ppm |
| 704 | A | A | 457. 56 | 3.77 | H NMR (300.0 MHz, MeOD) d 8.51 (s, 1H), 8.39 (d, J = 9.1 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 4.41 (t, J = 11.3 Hz, 1H), 4.03 (d, J = 10.5 Hz, 1H), 3.91 (t, J = 11.3 Hz, 1H), 3.79-3.76 (m, 1H), 3.51 (d, J = 7.5 Hz, 1 H), 2.31 (d, J= 11.2 Hz, 1H), 2.20 (d, J = 12.4 Hz, 1H), 2.00- 1.89 (m, 4H) and 1.67 -1.33 (m, 8H) ppm |
| 705 | A | A | 403. 49 | 3.47 | H NMR (300.0 MHz, MeOD) d 8.54 (s, 1H), 8.40 (dd, J = 2.6, 9.1 Hz, 1H), 8.36 (s, 1H), 8.28 (d, J = 5.5 Hz, 1H), 4.43 (t, J = 11.7 Hz, 1H), 3.68-3.61 (m, 4H), 2.39 (d, J = 11.1 Hz, 1H), 2.19 (d, J = 11.2 Hz, 1H), 2.03- 1.99 (m, 2H) and 1.65 - 1.25 (m, 4H) ppm |
| 706 | A | A | 458. 53 | 3.42 | H NMR (300.0 MHz, MeOD) d 8.52 (s, 1H), 8.37 (dd, J = 2.7, 9.1 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J =5.6 Hz, 1H), 4.43 (t, J = 11.8 Hz, 1H), 3.81 (t, J = 11.6 Hz, 1H), 3.65-3.62 (m,4H), 3.37-3.34 (m, 4H), 2.35 (d, J = 11.7 Hz, 1H), 2.22 (d, J = 11.8 Hz, 1H), |
-44616260
| 2.01 (d, J = 11.0 Hz, 2H) and 1.66 - 1.29 (m, 4H) ppm | |||||
| 707 | |||||
| 708 | A | A | 432. 5 | 3.49 | H NMR (300.0 MHz, MeOD) d 8.86 (d, J = 2.2 Hz, 1H), 8.47 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.31 (d, J = 5.6 Hz, 1H), 5.22- 5.19 (m, 1H), 2.15-2.10 (m, 1H), 2.01 - 1.72 (m, 6H), 1.64-1.53 (m, 3H), 1.40-1.13 (m, 2H) and 0.90 (t, J = 7.2 Hz, 3H) ppm |
| 709 (enantiom er 1, see 710) | A | A | 390. 46 | 4.11 | H NMR (300.0 MHz, CDCI3) d 9.89 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.30 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 3.4 Hz, 1H), 7,28 (s, H), 6.81 (d, J = 5.6 Hz, 1H), 4.65-4.61 (m, 1H), 2.04 (d, J = 12.8 Hz, 1H), 1.87- 1.84 (m, 3H), 1.77-1.71 (m, 3H), 1.651.55 (m, 2H), 1.38- 1.22 (m, 3H) and 0.92 - 0.85 (m, 3H) ppm |
| 710 (enantiom er 2, see 709) | A | A | 390. 47 | 4.02 | H NMR (300.0 MHz, CDCI3) d 10.15 (s, 1H), 8.90 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 2.4, 7.3 Hz, 1H), 8.16 (d, J =2,7 Hz, 1H), 8.05-8.02 (m, 1 H), 7.30 (d, J = 11.4 Hz, H), 4.85 (d, J = 8.2 Hz, 1H), 4.68-4.55 (m, 1H), 2.302.24 (m, 2H), 2.10-1.95 (m, 1H), 1.81 - 1.72 (m, 5H), 1.66-1.49 (m, 2H), 1.45-1.16 (m, 3H) and 1.01 - 0.90 (m, 3H) ppm |
| 711 | C | C | 503. 52 | 2.91 | 1HNMR (300 MHz, MeOD) d 8.94 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.45-8.31 (m, 2H), 5.25 (d, J = 9.4 Hz, 1H), 4.15-3.95 (m, |
-44716260
| 2H), 3.84 (t, J = 10.8 Hz, 2H). 3.52 (t, J = 14.1 Hz, 3H), 3.26- 3.03 (m, 3H), 2.66 (s, 2H). 2.40 - 2.13 (m, 3H), 2.02 (d, J = 32.7 Hz, 4H), 1.82-1,46 (m, 3H). | |||||
| 712 | A | A | 402. 47 | 3.98 | H NMR (300.0 MHz, DMSO) d 12.28 (s, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H). 8.18 (s, 1H), 8.11 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 5.98-5.84 (m, 1H),5.06 (s, 1H), 5.02 (d, J = 2.8 Hz, 1H), 4.524.42 (m, 1H), 4.20 (s, 1H), 2.19 (d, J = 7.3 Hz, 2H), 2.06 (d, J = 11.8 Hz, 1H), 1.95- 1.77 (m, 2H), 1.57 (d, J = 12.0 Hz, 2H), 1.44 (t, J = 12.3 Hz, 1H) and 1.28-1.16 (m, 2H) ppm |
| 713 | A | A | 402. 49 | 4.13 | H NMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19(5, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.00- 5.86 (m, 1H), 5.09-5.03 (m, 2H), 4.67 (s, 1 H), 4.36 - 4.33 (m, 1H), 2.33 (d, J = 7.0 Hz, 2H), 1.86- 1.70 (m, 3H) and 1.651.35 (m, 5H) ppm |
| 714 | A | A | 435. 34 | 3.3 | |
| 715 | A | A | 491. 39 | 3.68 | |
| 716 | A | A | 477. 37 | 3.75 | |
| 717 | A | A | 436. 48 | 3.71 | H NMR (300.0 MHz, DMSO) d 12.28 (d, J = 2.0 Hz, 1H), 8.79 (dd, J = 2.4, 5.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.7 |
-44816260
| Hz, 1H>, 8.12 (dd, J = 1.5, 4.0 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 4.73 (t, J = 3.9 Hz, 1H), 4.554.51 (m, 2H), 3.85-3.82 (m, 1H), 2.02- 1.87 (m, 3H), 1.72-1.41 (m, 5H) and 1.31 -1.19 (m, 2H) PPm | |||||
| 718 | A | A | 436. 49 | 3.6 | H NMR (300.0 MHz, DMSO) d 12.29 (s, 1H), 8.71 (t, J = 2.3 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 2.8, 4.5 Hz, 1H), 8.15 (t, J = 3.7 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.77 (dd, J = 3.8, 10.5 Hz, 1H), 4.54 (t, J = 5.6 Hz, 1H), 4.32 (m, 1H), 3.86 (m, 1H), 2.001.97 (m, 2H), 1.82- 1.63 (m, 4H) and 1.59 - 1.45 (m, 4H) ppm |
| 719 | A | A | 443. 5 | 4.07 | H NMR (300.0 MHz, DMSO) d 12.58 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.36- 8.23 (m, 4H), 7.81 (t, J = 5.5 Hz, 1H), 4.17 (d, J = 7.5 Hz, 1H), 2.94 (t, J = 6.0 Hz, 2H), 2.43-2.35 (m, 1H), 2.14-1.22 (m, 8H), 0.91 -0.80 (m, 1 H), 0.40 -0.31 (m, 2H) and 0.20 - 0.10 (m, 2H) ppm |
| 720 | A | A | 459. 5 | 3.99 | H NMR (300.0 MHz, DMSO) d 12.72 (s, 1H), 8.65 (s, 1H), 8.54 (s, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.39-8.37 (m, 2H), 4.42-4.08 (m, 3H), 4.02 -3.88 (m, 2H), 3.64 -3.57 (m, 1H), 3.18-3.12 (m, 3H) and 2.12 -1.19 (m, 9H) ppm |
| 721 | A | A | 417. 5 | 3.93 | H NMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.14 (d, J = 4.0 Hz, |
-44916260
| 1H), 7.71 (s, 1H), 7.53 (d, 1H), 4.19-4.06 (m, 1H), 3.05 (dd, J = 5.6, 7.1 Hz, 2H), 2.33 (m, 1H), 2.13-1.20 (m, 8H) and 0.98 (t, 3H) ppm | |||||
| 722 | A | A | 447. 52 | 4.11 | H NMR (300.0 MHz, DMSO) d 13.14 (s, 1H), 9.50-9.45 (m, 1H), 9.26 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 5.60 (s, H), 5.50 (s, 1H), 4.39 (s, 1H), 2.94 (d, J = 7.3 Hz, 1H), 2.81 (qn, J = 6.3 Hz, 1H), 2.51 (s, H), 2.32 (d, J = 7.0 Hz, 2H), 2.08 (s, 2H), 1.87- 1.64 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H) and -0.00 (s, H) ppm |
| 723 | A | A | 445. 5 | 4.03 | 1H NMR (300 MHz, MeOD) d 8.66 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.51 - 4.28 (m, 1H), 4.01-3.80 (m, 1H), 2.40-2.15 (m, 2H), 2.11 -1.86 (m, 2H), 1.84- 1.26 (m, 4H), 1.18 (s, 9H) |
| 724 | A | A | 428. 45 | 3.69 | 1H NMR (300 MHz, MeOD) d 8.69 (d, J = 1.9 Hz, 1H), 8.53 (s, 1H), 8.38 (d, J = 1.7 Hz, 1H), 8.29 (d, J = 5.3 Hz, 1H), 4.524.34 (m, 1H), 4.02-3.84 (m, J = 11.5 Hz, 1H), 3.52 (s, 2H), 2.40 (d, J = 12.0 Hz, 1H), 2.22 (d, J = 10.9 Hz, 1H), 2.14-1.97 (m, 2H), 1.81 - 1.23 (m, 4H). |
| 725 | A | A | 446. 48 | 2.47 | 1H NMR (300 MHz, MeOD) d 8.73 (d, J = 1.6 Hz, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.37 (t, J = 7.8 Hz, 1H), 8.31 (d, J = 5.2 Hz, 1H), 4.56-4.37 (m, 1H), 4.13-3.98 |
-45016260
| (m, 1H), 3.93 (s, 2H), 2.92 (d, J = 3,6 Hz, 6H), 2.43 (d, J = 12.4 Hz, 1H), 2.22 (d, J = 12.4 Hz, 1H), 2.07 (t, J = 13.1 Hz, 2H), 1.831.24 (m,4H). | |||||
| 726 | A | A | 443. 53 | 3.92 | 1H NMR (300 MHz, MeOD) d 8.61 (d, J = 2.3 Hz, 1H), 8.53 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.474.24 (m, 1H), 4.01 -3.77 (m, 1H), 3.14-2.98 (m, 1H), 2.41 - 1.01 (m, 14H). |
| 727 | A | A | 457. 51 | 4.04 | 1HNMR (300 MHz, MeOD) d 8.68 (d, J = 2.3 Hz, 1H), 8.52 (s, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 5.6 Hz, 1H), 4.51 4.30 (m, 1H), 4.04-3.80 (m, 1H), 3.25-3.04 (m, 1 H), 2.39 (d, J = 20.1 Hz, 1H), 2.22 (d, J = 12.3 Hz, 1H), 2.02 (d, J = 12.9 Hz, 2H), 1.94- 1.24 (m, 4H), 1.12 (dd, J = 10.1, 3.0 Hz, 6H), 1.040.94 (m, J =9.4,4.3 Hz, 1H), 0.75-0.62 (m, 1H). |
| 728 | A | A | 459. 56 | 4.17 | 1HNMR (300 MHz, MeOD) d 8.68 (d, J = 2,3 Hz, 1H), 8.49 (d, J = 22.9 Hz, 1H), 8.36 (t, J = 5.8 Hz, 1H), 8.28 (d, J = 5.6 Hz, 1H), 4.53-4.27 (m, J = 11.6, 8.2, 3.7 Hz, 1 H), 4.02-3.83 (m, J = 15.7, 7.7 Hz, 1H), 2.37 (d, J = 12.0 Hz, 1H), 2.22 (d, J = 12.1 Hz, 1H), 2.06 (d, J= 14.0 Hz, 2H), 2.06 (s, 2H), 1.82- 1.15 (m,4H), 1.01 (s, 9H). |
| 729 | A | A | 486. 54 | 2.78 | |
| 730 | A | A | 488. | 3.82 |
-45116260
| 52 | |||||
| 731 | C | C | (400MHz, DMSO-d6): 12.33 (br s, exchanged with D2O, 2H), 8.72 (d, J=1.6Hz , 1H), 8.27(d, J=2.4Hz, 1H), 8.20 (s, 1H), 8.13 (d, J=3.6Hz, 1H), 7.47(d, J=7.2H z,exchanged with D20,1 H), 4.04-4.02 (m, 1H), 2.17-2.00 (m, 5H), 1.63-1.39 (m, 4 H). | ||
| 732 | A | A | (400MHz, CDCI3):12.33(s, 1 H), 8.75(d, J=2.4Hz,1H), 8.28(d,J=2.4Hz,1H), 8. 18(s,1H), 8.12(d, J=4Hz,1H), 7.49(d,J=8Hz,1H),4.3(t,J=5.2Hz,1 H),4,04-3.97(m,1H), 3.48- 3.43(m,1H),3.38-3.34(m,2H), 2.09-2.0(m,1H),1.95- 1.93(m,1H),1.81-1.25(m,7H). | ||
| 733 | A | A | (400MHz, DMSO-d6): 12.33(br s, exchanged with D2O, 1H), 8.27(d, J=2Hz, 1 H), 8.19(s,1H), 8.11(d, J=3.6Hz,1H), 7.39(d, J=6.4Hz, Exchanged with D2O.1H), 4. 05(brs, 1H), 2.39(s,1H), 2.14-2.12(m,2H), 1.77-1.61(m,6H). | ||
| 734 | A | A | 443. 4 | 3.39 | 1H NMR (300 MHz, MeOD) d 8.71 (d, J = 2.3 Hz, 1H), 8.49 (s, 1H), 8.38 (d, J =2.3 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.45 (s, 1 H), 3.91 (s, 1H), 3.77 -3.50 (m, 2H), 2.35 (d, J = 10.0 Hz, 1H), 2.22 (d, J = 11.9 Hz, 1H), 2.02 (d, J = 11.7 Hz, 2H), 1.71 (d, J = 14.0 Hz, 1H), 1.38 (tdd, J = 16.2, 11.9, 4.6 Hz, 6H), 1.08 (t, J = 5.5 Hz, 3H), 1.04-0.94 (m, 1H), 0.61 -0.49 (m, 1H). |
-45216260
| 735 | A | A | 529. 46 | 4.62 | |
| 736 | A | A | 489. 4 | 4.56 | |
| 737 | A | A | 485. 44 | 4.57 | |
| 738 | A | A | 439. 37 | 3.31 | 1H NMR (300 MHz, MeOD) d 8.60 (d, J = 37.9 Hz, 1H), 8.33 (d, J = 23.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1H), 6.00 (t, J = 54.0 Hz, 1H), 4.42 (s, 1H), 4.01 (s, 1H), 2.47-2.31 (m, 2H), 2.23 (d, J = 10.9 Hz, 1H), 2.12-1.97 (m, 2H), 1.77-1.17 (m, 5H), 0.95-0.83 (m, 1H). |
| 739 | A | C | 486. 52 | 2.16 | 1H NMR (300 MHz, MeOD) d 8.65 (d, J = 45.0 Hz, 1H), 8.34 (d, J = 23.5 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7,22 (d, J =7.6 Hz, 1H), 4.45 (s, 1H), 4.01 (s, 1H), 3.72 (s, 1 H), 3.45 (s, 1H), 3.10 (d, J = 11.3 Hz, 1H), 2.82 (d, J = 12.1 Hz, 3H), 2.36 (s, 1H), 2.28-1.25 (m, 16H). |
| 740 | A | 447. 53 | 3.98 | H NMR (300 MHz, MeCD) d 8.73(s, 1H), 8.45(s, 1H), 8.37(d, J = 2.1 Hz, 1H), 7.25(d, J = 5.5 Hz, 1H), 4.89-4.8 (m,1H), 3.022.95(m, 2H), 2.86(d, J = 0.5 Hz, 1H), 2.65(d, J = 12.0 Hz, 1H), 2.46(d, J = 12.2 Hz, 1H), 2.031.98(m, 1H), 1.9-1.8(01, 1H), 1.78-1.68(01, 1H), 1.5- 1.3(m, 2H), 0.95(t, J = 7.3 Hz, 3H) and 0.0(s, TMS) | |
| 741 | A | 470. 46 | 3.82 | 1H NMR (300 MHz, DMSO) d 12.32 (s, 1H), 8.70 (d, J = 2.4 Hz, 1 H), 8.27 (d, J = 2.4 Hz, 1H), |
-45316260
| 8.26 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 3.9 Hz, 1H>, 7.34 (d, J = 7.1 Hz, 1H), 5.77 (d, J = 2.9 Hz, 1H), 4.60 (s, 1H), 3.73 (dd, J = 10.1, 6.3 Hz, 6H), 2.30-2.15 (m, 1H), 2.04- 1.86 (m, 1H), 1.85-1.50 (m, 6H). | |||||
| 742 | A | 470. 49 | 3.7 | 1HNMR (300 MHz, DMSO) d 12.30 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1 H), 8.18 (d, J = 2.8 Hz, 1H), 8.14 (d, J =4.0 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 5.38 (S, 1 H), 4.55-4.36 (m, 1H), 3.71 (d, J = 3.1 Hz, 3H), 3.68 (d, J = 3.2 Hz, 3H), 2.16 2.01 (m,2H), 2.00- 1.72 (m, 3H), 1.71 - 1.41 (m, 2H), 1.39-1.18 (m, 1H). | |
| 743 | A | A | 419. 34 | 2.86 | |
| 744 | A | A | 419. 34 | 2.61 | |
| 745 | A | A | 447. 5 | 3.8 | 1HNMR (300 MHz, MeOD) d 8.70 (d, J = 18.1 Hz, 1H), 8.50 (s, 1H), 8.38 (d, J = 10.4 Hz, 1H), 8.30 (s, 1H), 4.54 (s, 2H), 4.19 (s, 2H), 3.42 (s, 3H), 2.95 (d, J = 15.2 Hz, 3H), 2.25 (d, J = 11.8 Hz, 1H), 2.09 (s, 2H), 1.98-1.39 (m, J = 62.5 Hz, 5H). |
| 746 (racémie mixture of diastereo mer 1 with respect 1 OH of the cyclohexyl | A | A | 422. 48 | 3.6 |
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| ring, see 755) | |||||
| 747 | A | A | 448. 48 | 3.42 | |
| 748 | A | 448. 5 | 3.51 | ||
| 749 | A | A | 422. 47 | 3.6 | |
| 750 | A | A | 447. 36 | 3.07 | |
| 751 | A | A | 433. 35 | 2.88 | |
| 752 | A | A | 447, 36 | 2.78 | |
| 753 | A | A | 454. 4 | 3.32 | |
| 754 | A | C | 406. 35 | 3.16 | 1HNMR (300 MHz, MeOD) d 8.70 (d, J = 2.2 Hz, 1H), 8.47 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 5.5 Hz, 1H), 5.37- 4.57 (m, 49H), 2.42 (dd, J = 13.3, 4.2 Hz, 2H), 2.15 (d, J = 10.4 Hz, 1H), 2.07- 1.87 (m, 3H), 1.77 (dd, J = 18.1, 8.6 Hz, 3H). |
| 755 (racemic mixture of diastereo mer 2 with respect 1OH of the cyclohexy! ring, see 746) | A | C | 406. 35 | 3.03 | |
| 756 | A | A | 472. 45 | 2.24 |
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| 757 | A | A | 399, 52 | 3.29 | 1HNMR (300 MHz, MeOD) d 9.00 (d, J = 7.7 Hz, 1H), 8.59 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 7.69 (d, J = 5.3 Hz, 1H), 4.54-4.32 (m, 1H), 4.18-3.99 (m, 1H), 3.88 (s, 2H), 3.40 (s, 3H), 2.44 (d, J = 11.6 Hz, 1H), 2.13 (d, J = 10.9 Hz, 1H), 1.97 (t, J = 13.6 Hz, 2H), 1.77- 1.28 (m, 4H). |
| 758 | A | A | 427. 4 | 3.26 | 1HNMR (300 MHz, MeOD) d 8.71 (dd, J = 14.6, 2.9 Hz, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.42 (t, J = 11.9 Hz, 1H), 3.95 (t, J = 11.6 Hz, 1H), 2.39 (d, J = 12.1 Hz, 1H), 2.272.12 (m, 1H), 2.03 (d, J = 10.0 Hz, 2H), 1.95 (s, 1H), 1.70 (d, J = 13.1 Hz, 1H), 1.61 - 1.18 (m, 8H). |
| 759 | A | A | 460. 48 | 2.15 | 1H NMR (300 MHz, MeOD) d 8.72 (d, J = 1.8 Hz, 1H), 8.57- 8.44 (m, 1 H), 8.38 (d, J = 1.4 Hz, 1H), 8.29 (d, J = 5.0 Hz, 1H), 4.45 (s, 1H), 4.00 (s, 1H), 3.86 (d, J = 8.5 Hz, 1H), 2.97-2.80 (m, 7H), 2.47 (s, 1 H), 2.22 (d, J = 11.5 Hz, 1H), 2.06 (d, J = 11.1 Hz, 2H), 1.84 -1,19 (m, 9H). |
| 760 | A | A | (400MHz, DMSO-d6): 12.35 (br s, 1H), 8.75 (d, J=2.4Hz,1H), 8.29(d,J=2Hz,1 H), 8.28.17(m,2H), 6.97(d,J=6.8Hz, 1H), 4.6-4.54(m,1H),4.5(brs, 1 H),3.58-3.48( m,2H),2.57(s,1H),2.332.227(m,2H),1.76- 1.69(m,2H),1.61- 1.59(m,1H),1.43-1.32(m12H ) |
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| 761 | A | A | (400MHz, DMSO-d6): 12.35 (br s, 1H), 8.75(d,J=2.4Hz,1H), 8.29(d,J=2Hz,1H), 8.28.17(m,2H), 6.97(d,J=6.8Hz, 1H), 4.6-4,55(m,1 H),4.5(br s, 1 H),3.58-3.5(m,2 H),2.56(s,1H),2.332.227(m,2H),1.76- 1.69(m,2H),1.61- 1.59(m,1H),1.43-1.32(m,2H) | ||
| 762 | A | A | 406. 35 | 3.23 | |
| 763 | A | A | 406. 35 | 3.06 | 1HNMR (300 MHz, MeOD) d 8.70 (d, J = 2.2 Hz, 1 H), 8.47 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 5.5 Hz, 1H), 5.374.57 (m, 49H), 3.38-3.26 (m, 26H), 2.42 (dd, J = 13.3,4.2 Hz, 2H), 2.15 (d, J = 10.4 Hz, 1H), 2.07- 1.87 (m, 3H), 1.77 (dd, J = 18.1,8.6 Hz, 3H). |
| 764 | A | A | 420. 36 | 3.2 | 1HNMR (300 MHz, MeOD) d 8.70 (d, J = 2.3 Hz, 1H), 8.50 (s, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 5.5 Hz, 1H), 4.91 4.77 (m, 27H), 3,77 (s, 3H), 3.38 -3.26 (m, 39H), 2.45 (dd, J = 13.2, 3.8 Hz, 2H), 2.20 (d, J = 9.8 Hz, 1H), 2.06 (s, 1H), 2.00-1.82 (m, 3H), 1.82- 1.23 (m, 5H). |
| 765 | A | A | 453. 38 | 3.34 | |
| 766 | A | A | 449. 41 | 3.4 | |
| 767 | A | A | 487. 42 | 3.56 | |
| 768 | A | A | 486. 46 | 2.24 |
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| 769 | A | C | 415. 5 | 2.75 | 1HNMR (300 MHz, MeOD) d 8.84 (s, 1H), 8.31 (s, 2H), 6.99 (s, 1H), 4.42 (s, 1H), 4.08 (s, 1H), 3.90 (s, 2H), 3.42 (s, 3H), 2.40 (s, J = 20.9 Hz, 1H), 2.26- 1.85 (m, J = 27.0 Hz, 3H), 1.79- 1.20 (m, 4H). |
| 770 | A | A | 469. 44 | 3.22 | NMR 1H (MeOH-d4): 9.0 (s, 1H), 8.6 (m, 2H), 8.3 (m, 2H), 8.1 (s, 1H), 4.5 (m, 1H), 4.1 (m, 1H), 3.9 (s, 3H), 1.3-2.6 (m, 10H). |
| 771 | A | A | 472. 45 | 2.21 | |
| 772 | A | A | 455. 43 | 2.97 | |
| 773 | A | A | 451. 4 | 3.31 | NMR 1H (MeOH-d4): 8.7 (s, 1H), 8.5 (s, 1H), 8.3 (s, 1H), 8.2 (d, 1H), 4.7 (s, 1H), 4.15-4.5 (m,4H), 3.7 (t, 1H), 2.4 (m, 1H), 2.2 (m, 1H), 2.0 {t, 2H), 1.2-1.8 (m, 4H). |
| 774 | A | C | 472. 45 | 2.21 | NMR 1H (MeOH-d4): 8.7 (d, 2H), 8.3 (d, 2H), 4.4 (m, 1H), 3.6-4.0 (m, 3H), 3.3 (s, 3H), 2.9 (m, 3H), 2.0-2.5 (m, 6H), 1.2-1.8 (m, 4H). |
| 775 | A | A | 435. 34 | 3.21 | 1H NMR (300 MHz, MeOD) d 7.40 (d, J = 2.1 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J = 2.2 Hz, 1 H), 7.03 (d, J = 5.6 Hz, 1H), 2.71 (dt, J = 13.2, 6.7 Hz, 1H), 2.55 (dt, J = 18.3, 9.2 Hz, 1H), 2.26 (s, 3H), 0.90-0.67 (m, 2H), 0.58 (d, J = 13.5 Hz, 1H), 0.53-0.37 (m, 2H), 0.37-0.18 (m, 1H). |
| 776 | A | A | 392. 34 | 2.9 | 1H NMR (300 MHz, MeOD)’d 7.40 (d, J = 2.1 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 2.71 (dt, J = 13.2, 6.7 Hz, 1H), 2.55 (dt, J |
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| = 18.3, 9.2 Hz, 1H), 2.26 (s, 3H), 0.90-0.67 (m, 2H), 0.58 (d, J = 13.5 Hz, 1H), 0.53-0.37 (m, 2H), 0.37-0.18 (m, 1H). | |||||
| 777 | C | C | 410. 32 | 2.37 | |
| 778 | A | A | 507. 53 | 3.54 | 1HNMR (300 MHz, DMSO) d 12.32 (s, 1H), 8.72 (dd, J = 4.9, 2.4 Hz, 1 H), 8.28 (d, J = 2.4 Hz, 1H), 8.22-8.09 (m, 2H), 7.45 (dd, J = 16.1, 8.1 Hz, 1H), 6.85 (d, J = 11.9 Hz, 1H), 4.51 -4.41 (m, 1H), 4.32-4.16(m, 2H), 3.84 -3.71 (m, 2H), 3.60 (s, 1H), 3.26 (d, J = 2.6 Hz, 3H), 2.70-2.56 (m, J = 22.6 Hz, 1H), 2.45 (s, 1H), 2.17-1.92 (m, 2H), 1.771.41 (m, 4H), 1.33-1.11 (m, 2H). |
| 779 | A | A | 433. 42 | 3.22 | 1H NMR (300 MHz, MeOD) d 8.72 (d, J = 2.2 Hz, 2H), 8.48 (s, 2H), 8.34 (dd, J = 23.7, 3.9 Hz, 3H), 4.99 (d, J = 5.4 Hz, 3H), 4.88 (s, 1H), 4.85-4.67 (m, 32H), 3.44-2.95 (m, 44H), 2.29 (dd, J = 13.5, 4.1 Hz, 3H), 2.11 (d, J = 9.5 Hz, 2H), 2.04-1.80 (m, 7H), 1.76 (s, 3H), 1.13 (t, J = 7.2 Hz, 4H). |
| 780 | A | A | 487. 36 | 3.57 | |
| 781 | A | A | 394. 32 | 2.81 | |
| 782 | A | A | 424. 5 | 3.96 | |
| 783 | A | A | 456. 39 | 2.9 | |
| 784 | A | A | 473. 41 | 3.29 |
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| 785 | A | A | 461. 44 | 3.59 | |
| 786 | A | A | 419. 34 | 3.01 | |
| 787 | A | A | 382. 399 | 2.47 | (400MHz, DMSO-d6): 12.36 (s, exchanged with D2O, 1H), 8.71 (d, J=2.4Hz, 1 H), 8.29 (d, J=1.6Hz, 1 H), 8.25 (s,1H), 8.18 (d,J=4Hz,1H),7.58 (d,J=7.2Hz, excha nged with D20,1 H), 4.27 (br s, 1 H), 2.15-2.06 (m,6H), 1.751.69 (m,2H). |
| 788 | A | A | 362. 399 | 2.68 | (400MHz, DMSO-d6): 12.34 (s,exchanged with D2O.1H), 8.72 (d,J=2.4Hz,1H)„ 8.28 (d,J=2.4Hz,1H), 8.20 (d,J=2.4Hz,1H), 8.13 (d,J=4.4Hz,1H), 7.5 (d,J=6Hz, exc hanged with D2O,1 H), 4.42 (br s, exchanged with D2O,1H), 4.04 (t,J=3.6Hz,1H), 3. 88 (s,1H), 1.89-1.6( |
| 789 | A | A | H NMR (300.0 MHz, DMSO) d 12.90 (s, 1H), 8.96 (s, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 8.42 (d, J = 5.1 Hz, 2H), 7.85 (t, J = 5.4 Hz, 1 H), 4.22 (d, J = 7.8 Hz, 1 H), 3.34 - 3.17 (m, 7H) and 2.09- 1.26 (m, 9H) ppm | ||
| 790 | A | A | 406. 49 | 3.87 | H NMR (300.0 MHz, CDCI3) d 14.46 (s, 1H), 8.81 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.96 (t, J = 1.6 Hz, 1H), 7.34 (d, J = 11.5 Hz, H), 4.59 (d, J = 3.1 Hz, 1H), 3.94 (s, 2H), 2.04-1.70 (m, 8H), 1.68 (m, 2H), and 0.00 (s, H) ppm |
| 791 | A | A | 434. 38 | 3.26 |
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| 792 | A | A | 434. 38 | 2.9 | |
| 793 | A | A | 406. 5 | 3.69 | H NMR (300.0 MHz, CDCI3) d 9.47 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.27 (d, J =2.3 Hz, 1 H), 8.16 (d, J = 2.7 Hz, 1H), 8.06 (d, J = 3.4 Hz, 1H), 7.28 (s, H), 4.85 (s, 1H), 4.75 (m, 1H), 4.01 -3.97 (m, 2H), 3.07 (s, 1H), 2.50 (m, 2H), 2.30 (m, 1H), 2.10 (m, 1H), 1.89- 1.79 (m, 4H), 1.36 (m, 3H) and 0.99 (s, 1H) ppm |
| 794 | B | A | 449. 48 | 3.9 | |
| 795 | A | A | 432. 39 | 3.86 | 1HNMR (300 MHz, CDCI3) d 8.80(1 H, s), 8.25(1 H, s), 8.0 (1 H, s), 7.95(1 H, s), 5.2(1 H, m), 4.25 (2H, q), 1.95-1.45 (8 H, m), I. 25 (3 H, s), 1.15 (3 H, t) ppm. |
| 796 | A | A | 446. 45 | 3.12 | H NMR (300.0 MHz, MeOD) d 8.73 (s. 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.31 (brs, 1H), 4.34 (m, 1H), 2.60-2.56 (m, 1H), 2.27 (m, 1H), 2.08 (m, 3H) and 1.89- 1.78 (m, 3H) ppm |
| 797 | A | A | 450. 5 | 3.86 | 1H NMR (300 MHz, DMSO) d 12.30 (s, 1H), 8.73 (t, J = 2.7 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.8 Hz. 1H), 8.14 (d, J = 3.9 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 5.29 (d, J = 5.0 Hz, 1H), 4.79-4.65 (m, 2H), 4.37 (s, 1H), 3.23 - 3.14 (m, 2H), 2.02 (dd, J = 40.1, 10.3 Hz, 1H), 1.91 -1.64 (m, 7H), 1.59 - 1.44 (m, 3H), 1.19 (d, J = 10.6 Hz, 3H). |
| 798 | A | A | 446. 34 | 3.37 | H NMR (300.0 MHz, MeOD) d 8.67 (s, 1H), 8.56 (s, 1H), 8.38 (s, |
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| 1H), 8.31 (brs, 1H),4.47(m, 1H), 4.21 (m, 1H), 2.41 (m, 1H), 2.22 (m, 1H), 2.10-1.90 (m, 3H), 1.72 (m, 2H) and 1.50 (m, 1 H) ppm | |||||
| 799 | A | A | 433. 43 | 3,01 | |
| 800 | A | A | 433. 42 | 2.66 | |
| 801 (racemic mixture of diastereo mer 1, see 802) | A | A | 461. 44 | 3.35 | |
| 802 (racemic mixture of diastereo mer 2, see 801) | A | A | 461. 44 | 2.81 | |
| 803 | A | A | 461. 44 | 2.94 | |
| 804 | A | A | 404. 3 | 3.45 | H NMR (300.0 MHz, MeOD) d 8.84 (s, H), 8.61 (s, H), 8.36 (s, H), 8.30 (d, J = 5.1 Hz, H), 5.57 (s, H), 3.5(1 H, M), 1.97-1.3 (m, 8 H), 0.93 (s, 3H), , ppm |
| 805 | A | A | 403. 34 | 2.98 | H NMR (300.0 MHz, MeOD) d 8.85 (d,J = 2.4 Hz, H), 8.22 (d, J = 2.3 Hz, H), 8.16 (s, H), 7.99 (d, J =4.1 Hz, H), 7.86 (s, H), 3.48 (d, J = 7.0 Hz, H), 2.80 (s, H), 2.15 (s, H), 2.0 (s, H), 1.86 (qn, J = 3.3 Hz, H), 1.80 (s, H), 1.74 (s, H), 1.44 (s, H). |
| 806 | A | A | 417. 36 | 3.1 | H NMR (300.0 MHz, CDCI3) d 9.01 (s, H), 8.77 (d, J = 2.4 Hz, H), 8.21 (d, J = 2.4 Hz, H), 8.06- |
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| 7.96 (m, H), 3,44 (s, H), 3.42 (d, J = 4,0 Hz, H), 3.41 (t, J = 4.0 Hz, H), 2.19-1.66 (m, H), 1.97 (s, H) and 1.56 (s, H) ppm | |||||
| 807 | A | A | 431, 37 | 3.24 | |
| 808 | C | A | 392. 34 | 2,9 | |
| 809 | A | A | 392. 34 | 2.9 | 1HNMR (300 MHz, DMSO) d 13.10 (s, 1H), 9.20 (d, J = 2.7 Hz, 1H), 8.93-8.67 (m, 2H), 8.49 (d, J = 5.6 Hz, 1H), 8.39-8.30 (m, OH), 4.78 (s, 1H), 3.54 (s, 1H), 3.17 (s, 2H), 2.51 (s, 4H), 2.02- I. 63 (m, 3H), 1.46 (dd, J =41.3, II. 6 Hz, 3H),1.18(s, 3H). |
| 810 | A | A | H NMR (300.0 MHz, DMSO) d 8.69 (d, J = 2.4 Hz, 1H), 8.21 - 8.18 (m, 2H), 8.10 (d, J =4.0 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 5.84-5.70 (m, 1H), 5.07-5.00 (m, 2H), 4.27 (t, J = 4.0 Hz, 1H), 3.50 (d, J = 7.2 Hz, 3H), 2.39 (d, J = 8.3 Hz, 3H), 2.32-2.07 (m, 2H) and 1.821.08 (m, 5H) ppm | ||
| 811 | A | A | 447. 36 | 3.18 | |
| 812 | A | A | 447. 36 | 2.7 | |
| 813 | A | A | 447. 36 | 2.79 | |
| 814 | A | A | H NMR (300.0 MHz, DMSO) d 12.92 (s, 1H), 9.02-8.88 (m, 2H), 8.64 (s, 1H), 8.41 (s, 2H), 4.29 (s, br1H), 4.00- 3.35 (m, 8H) and 2.17-1.27 (m, 10H) PPm |
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| 815 | A | A | 433. 35 | 2.92 | |
| 816 | A | A | 406. 29 | 3.24 | |
| 817 | A | A | 439. 3 | 1.48 | |
| 818 | A | A | 465. 34 | 1.73 | |
| 819 | A | A | 505. 3 | 1.47 | |
| 820 | A | A | 493. 3 | 2 | |
| 821 | A | A | (400MHz, DMSO-d6): 12.34 (s, exchanged with D2O,1H),8.76(s,1H),8.28 (s,1H ),8.19 (s,1H), 8.14 (d,J=4Hz,1H),7.54 (d,J=6.8Hz, exchanged withD2O,1H), 4.71-4. 66 (m,1H),4.59(d,J=3.2Hz, exchanged withD2O,1H),4.27 (br s,1H), 2.23-2.20(m,1 H), 1.981.57(m, 10H) | ||
| 822 | A | A | (400MHz,DMSO-d6): 12.34 (s, exchanged withD2O,1H), 8.73 (d,J=1.6Hz,1H),8.2 8d,J=2Hz,1H),8.21 (s, 1 H),8.15(d, J=3.6Hz, 1 H),7.49 (d,J=7.2Hz, exchanged with D2O, 1 H),4.75(d,J=3.6Hz,exchanged withD2O,1H), 4.49-4.44 (m,1H), 4.22-4.21 (m,1H), 2. 34-1.50 (m, 8H) | ||
| 823 | A | A | 448. 39 | 3.67 | |
| 824 | A | A | 448. 39 | 3.05 | |
| 825 | A | A | 404. | 3.38 |
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| 3 | |||||
| 826 | A | A | 404. 3 | 3.38 | H NMR (300.0 MHz, DMSO) d 12.34 (s, H), 8.74 (d, J = 2.3 Hz, H), 8.33 (d, J = 2.3 Hz, H), 8.28 (d, J = 1.6 Hz, H), 8.17-8.12 (m, H), 4.34 (s, H), 4.29 (s, H), 3.89 (s, H), 3.55 (d, J = 6.3 Hz, H), 3.32 (s, H), 2.50 (s, H), 2.29 (s, H), 1.95- 1.90 (m, H), 1.82 (d, J = 6.6 Hz, H), 1.76 (s, H), 1.67 (s, H), 1.55 (s, H), 1.44-1.42 (m, H), 1.31 (s, H), 1.23 (s, H), 1.17 (s, H), 1.07 (s, H), 0.84 (d, J = 6.9 Hz, H) and -0.00 (d, J = 1.0 Hz, H) ppm |
| 827 | A | A | 404. 37 | 2.72 | |
| 828 | A | A | 377. 37 | 1.9 | |
| 829 | A | A | 470. 4 | 2.95 | |
| 830 | A | B | 392. 34 | 2.98 | MeOD d4: 8.8 (d, 1H); 8.5 (s, 1H); 8.4 (d,1H); 8.3 (d, 1H); 4.5 (dd,1H); 3.6 (dd, 1H); 3.3 (dd, 1H); 2.3 (m, 2H); 2.1 (m, 1H); 1.9 (m, 1H); 1.6 (app t, 2H); 1.3 (m, 1H). |
| 831 | A | A | 392. 34 | 2.98 | MeOD d4: 8.8 (d, 1H); 8.5 (s, 1H); 8.4 (d,1H); 8.3 (d, 1H); 4.5 (dd,1H); 3.6 (dd, 1H); 3.3 (dd, 1H); 2.3 (m, 2H); 2.1 (m, 1H); 1.9 (m, 1H); 1.6 (app t, 2H); 1.3 (m, 1H). |
| 832 | A | A | 376. 34 | 2.94 | MeOD d4: 8.8 (d, 1H); 8.65 (s, 1H); 8.45 (d,1H); 8.35 (d, 1H); 4.2 (dd,1H); 3.4 (dd, 1H); 2.2 (m, 2H); 2.0 (m, 1H); 1.6 (m, 4H); 1.2 (d, 3H). |
-46516260
| 833 | B | A | 376. 34 | 2.94 | MeODd4: 8.8 (d, 1H); 8.65 (s, 1H); 8.45 (d,1H); 8.35 (d, 1H); 4.2 (dd,1H); 3.4 (dd, 1H); 2.2 (m, 2H); 2.0 (m, 1H); 1.6(m,4H); 1.2 (d, 3H). |
| 834 | A | A | 442. 37 | 3.25 | H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19 - 8.18 (m, 2H), 7.31 (d, J = 7.1 Hz, 1H), 5.76 (s, 1H), 5.26 (t. J = 6.4 Hz, 1H), 4.58 (s, 1H), 3.87-3.74 (m, 2H), 2.50 (qn, J = 1.8 Hz, H), 2.01 - 1.80 (m, 3H), 1.74- 1.50 (m, H) and -0.00 (TMS) ppm |
| 835 | A | A | 442. 37 | 2.84 | H NMR (300.0 MHz, DMSO) d 12.30 (s, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.28 (d, J =2.3 Hz, 1H), 8.19-8.13 (m, H), 7.44 (d, J = 7.6 Hz, H), 5.22-5.17 (m,2H), 4.48-4.45 (m, 1H), 3.80 (td, J = 15.9, 7.4 Hz, H), 3.18 (d, J = 5.2 Hz, 2H), 2.51 (s, H), 2.09 (d, J = 11.4 Hz, 1H), 2.03 (s, 1H), 1.921.80 (m, 1H), 1.70 (t, J = 12.3 Hz, H), 1.70- 1.60 (m, 3H), 1.42 (dd, J = 9.9, 12.9 Hz, 1H), 1.26 (dd, J = 11.5, 22.0 Hz, 1H) and-0.00 (s, H) ppm |
| 836 | A | A | 483. 39 | 3.37 | |
| 837 | A | A | 483. 39 | 2.93 | |
| 838 | A | C | 388. 37 | 4.02 | |
| 839 | A | 433. 4 | 3.69 | 1H NMR (300 MHz, MeOD) d 8.83 (d, J = 2.1 Hz, 1H), 8.49 (s, 1H), 8.38 (d, J = 1.9 Hz, 1H), |
-46616260
| 8.26 (d, J = 5.6 Hz, 1H), 3.49- 3.14 (m, 3H), 2.68 (s, OH), 2.19 (d, J = 14.2 Hz, 1H), 2.09 (d, J = 13.0 Hz, 1H), 1,96 (s, 4H), 1.76 (s, 2H), 1.49 (d, J = 41.9 Hz, 3H). | |||||
| 840 | A | 438. 32 | 3.68 | H NMR (300.0 MHz, DMSO) d 12.29 (s, 1H), 8.78 (dd, J = 2.4, 6.6 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 1.9 Hz, 1H), 8.13 (dd, J = 0.8, 4.0 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 4.834.78 (m, 1 H), 4.52 (t, J = 3.6 Hz, 1H), 2.97-2.82 (m, 2H), 2.58 (d, J = 1.4 Hz, 3H), 2.19-1.81 (m, 3H), 1.72- 1.57 (m, 2H), 1.541.32 (m, 1H) and 1.31 -1.12 (m, 2H) ppm | |
| 841 | A | A | 390. 5 | 2.97 | (400 MHz, DMSO-d6) : 12.8 (br.s, exchanged with D2O, 1H), 8.68 (br.s, 1H), 8.40-8.38 (m, 2H), 4.59-4.57 (m, 1H), 2.36-2.11 (m, 4H), 2.11-2.06 (m, 1H), 1. 921.79 (m, 2H), 1.46-1.44 (m, 2H). |
| 842 | A | 454. 37 | 3.47 | H NMR (300.0 MHz, DMSO) d 13.06 (s, 1H), 9.35 (d, J = 6.4 Hz, 1H), 9.10 (d, J = 2.5 Hz, 1H), 8.74 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H), 4.67 (d, J = 7.7 Hz, 1H), 3.41 -3.25 (m, 2H), 3.02 (s, 3H), 2.29 (d, J = 11.8 Hz, 1 H) and 2.08 - 1.35 (m, 8H) ppm | |
| 843 | A | A | 525. 43 | 3.58 | |
| 844 | A | A | 525. 43 | 3.09 | |
| 845 | A | 449. 41 | 3.36 | 1H NMR (300 MHz, MeOD) d 8.36 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 4.25 (brs, 1 H), 4.14 - 3.79 |
-46716260
| (m, 3H), 3.44 (s, 3H), 2.38 (brs, 1H), 2.17 (brs, 1H), 2.09-1.92 (m, 2H), 1.79- 1.29 (m, J=62.8 Hz, 4H). | |||||
| 846 | A | 390. 399 | 2.91 | (400 MHz, DMSO-d6) : 12.61 (br.s, exchanged with D2O, 1H), 8.69 (s, 1H), 8.41-8.30 (m,3H), 3.54-3.43 (m, 2H), 2.74-2.68 (m, 1H), 2.46-2.42 (1H), 2.15-2. 08 (m, 2H), 1.82 (br.s, 3H), 1.571.47 (m, 2H). | |
| 847 | A | 389. 35 | 3.79 | ||
| 848 | A | 376. 399 | 2.79 | (400 MHz, DMSO-d6) : 12.6 (br.s, exchanged with D2O, 1H), 8.70 (s, 1H), 8 .40-8.30 (m, 3H), 4.65-4.60 (m, 1H), 3.01-2.93 (m, 1H), 2.28-1.95 (m,4H), 1.86- 1.72 (m, 2H). | |
| 849 | A | 390. 399 | 2.89 | (400 MHz, DMSO-d6) : 12.90 (br.s, exchanged with D2O, 1H), 9.20 (br.s, ex changed with D2O, 1H), 8.65 (s, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.39 (d, J=2Hz, 1H), 3.56-3.49 (m, 3H), 2.85-2.80 (m, 1H), 2.01-1.89 (m, 3H), 1.77-1.67 (m, 2H), 1.44-1.39 (m, 1H). | |
| 850 | A | (400MHz, DMSO-d6): 12.32 (br s, exchanged with D20,1 H), 8.75 (s, 1H), 8. 28 (s, 1H), 8.20 (s, 1H), 8.14 (d, J=3.6Hz, 1H), 7.6 (d, J=6.4Hz, exchanged with D2O, 1H), 4.58-4.53 (m, 1H), 2.27 (d, J=7.2Hz, 2H), 2.19-1.67 (m, 5H), 1.36-1.2 9(m,1 H). | |||
| 851 | A | A | 483. 39 | 3.6 | |
| 852 | A | A | 483. | 3.05 |
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| 39 | |||||
| 853 | A | 438. 36 | 3.58 | H NMR (300.0 MHz, DMSO) d 12.29 (s, 1H>, 8.78 (s, 1H), 8.268.18(m, 3H), 7.44 (s, 1H), 5.05- 4.30 (m, 2H), 3.08-2.74 (Μ, 1H) and 2.26-0.92 (m, 12H) ppm | |
| 854 | A | A | 454. 27 | 2.64 | H NMR (300.0 MHz, DMSO) d 12.30 (s, 1H), 8.79 (d, J = 2.3 Hz, 1H), 8.27 (d, J =2.3 Hz, 1H), 8.19 (d, J = 2.7 Hz, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 4.90 (s, 1H), 4.51 (t, J = 3.9 Hz, 1H), 3.01 (s, 3H), 2.24 (d, J = 12.3 Hz, 1H), 2.09- 1.79 (m, 4H), 1.71 -1.41 (m, 3H) and 1.36 -1.05 (m, 2H) ppm |
| 855 | A | A | 414. 35 | 3 | 1HNMR (300 MHz, DMSO) d 12.33 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.41 - 8.04 (m, 3H), 7,62 (d, J =7.4 Hz, 1H), 4.30 (s, 1H), 3.54-3.06 (m, 3H), 2.67-2.31 (m, 1H), 2.23- 1.33 (m, 6H) |
| 856 | A | A | 424. 34 | 3.63 | H NMR (300.0 MHz, CDCI3) d 8.85 (q, J =2.3 Hz, H), 8.17 (dd, J = 2.3, 21.3 Hz, 2H), 8.00 (d, J = 3.5 Hz, 1H), 5.03 (s, H), 4.64 4.55 (m, 1 H), 4.38 (dd, J = 4.0, 8.3 Hz, 1H), 4.01 -3.88 (m, 2H), 2.45- 1.90 (m, 4H), 1.51 -1.25 (m, 3H) and 0.00 (s, H) ppm |
| 857 | A | A | 433. 37 | 3.47 | 1H NMR (300 MHz, DMSO) d 13.02 (s, 1H), 9.22 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.81 (t, J = 5.8 Hz, 1H), 4.64 (d, J = 8.0 Hz, 1H), 3.16-2.99 (m, 2H), 2.09- 1.73 (m, 3H), 1.85 (s, |
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| 3H), 1.73- 1.42 (m, 3H), 1.28 (dd, J = 27.5, 10.6 Hz, 2H). | |||||
| 858 | A | A | 490. 36 | 2.78 | |
| 859 | A | A | 424. 41 | 3.8 | H NMR (300.0 MHz, MeOD) d 8.73 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 3.7 Hz, 1H), 4.57 (s, 1H), 4.50 (d, 1H), 4.10-3.80(m, 2H), 2.21 -1.60 (m, 8H) and 0.00 (s, H) ppm |
| 860 | A | A | 392. 34 | 2.82 | MeOD4: 8.75 (d, 1H); 8.5 (s, 1H); 8.4 (d, 1 H); 8.25 (d, 1H);7.7 (d, 1H); 7.2 (d, 1H); 4.5 (ddd, 1H); 3.65 (d, 1 H); 2.35 (s, 1H); 2.1 (m, 1H); 1.85 (m, 2H); 1.6 (m, 3H); 1.35 (s, 3H). |
| 861 | A | A | 362. 33 | 2.43 | MeOD4 8.55 (dd, 1H); 8.2 (d, 2H); 8.0 (d, 1H); 7.7 (d, 1H); 7.2 (d, 1H); 4.2 (ddd, 1H); 3.6, (ddd, 1H); 3.4 (dd, 1H); 2.4 (s, 2H); 2.2 (m, 1H); 2.1 (m, 2H);1.8(m, 1H); 1.4 (m, 3H). |
| 862 | A | A | 442. 44 | 3.77 | 1H NMR (300 MHz, DMSO) d 12.28 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1 H), 8.15 (s, 1H), 8.11 (d, J = 4.0 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.38 (s, 1H), 6.22 (t, J = 2.0 Hz, 1H), 4.67 (s, 1H, OH), 4.49-4.38 (m, 1H), 4.10 (s, 2H), 2.05-1.80 (m, 2H), 1.72-1.55 (m, 2H), 1.52-1.40 (m, 2H), 1.35-1.14 (m,2H). |
| 863 | A | A | 503. 42 | 3.36 |
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| 864 | A | A | 503. 42 | 3.46 | |
| 865 | A | A | 517. 43 | 3.57 | |
| 866 | A | A | 416. 33 | 2.75 | 1HNMR (300 MHz, MeOD) d 8.53 (s, 1H), 8.38-8.30 (m, 2H), 8.28 (d, J = 5.6 Hz, 1H), 4.40 (ddd, J = 11.9, 8.2, 3.9 Hz, 1H), 3.78 (ddd, J = 11.9, 8.2, 3.8 Hz, 1H), 2.89 (s, 6H), 2.33 (d, J = 11.6 Hz, 1H), 2.21 (d, J = 11.4 Hz, 1H), 2.05- 1.96 (m, J = 6.8, 4.1 Hz, 3H), 1.67- 1.33 (m, 4H). |
| 867 | A | A | 503. 35 | 2.79 | |
| 868 | A | A | 503. 35 | 2.93 | |
| 869 | A | A | 376. 28 | 2.6 | 1H NMR (300 MHz, MeOD) d 8.65 (dd, J = 9.6, 2.8 Hz, 1H), 8.20 (s, 1H), 8.17-8.09 (m, 1H), 8.01 (d, J = 4.0 Hz, 1H), 4.53 (s, 1H), 3.60 (s, 2H), 1.89 (dd, J = 28.7, 12.9 Hz, 3H), 1.74- 1.41 (m, 5H), 1.28 (s, 3H). |
| 870 | A | A | 457 | 2.84 | 1H NMR (300 MHz, DMSO) d 12.23 (s, 1H), 8.41 (dd, J = 9.9, 2.8 Hz, 1H), 8.24 (d, J = 13.1 Hz, 2H), 8.14 (d, J = 4.0 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 4.12 (s, 1 H), 3.76 (d, J = 11.2 Hz, 2H), 3.383.15 (m, 3H), 2.35 (dd, J = 12.6, 8.6 Hz, 1H), 2.04 (dd, J = 25.4, 9.8 Hz, 2H), 1.89-0.99 (m, 10H). |
| 871 | A | A | 438. 34 | 2.89 | |
| 872 | A | A | 376. 28 | 2.57 |
-47116260
| 873 | A | A | 486. 46 | 2.98 | 1H NMR (300 MHz, MeOD) d 8.49 (s, 1H), 8.41 (dd, J = 9.0, 2.6 Hz, 1H), 8.35 (s, 1 H), 8.28 (d, J = 5.6 Hz, 1H), 4.55 -4.37 (m, 1H), 3.83 (d, J = 12.8 Hz, 2H), 3.59- 3.43 (m, 2H), 2.50-2.28 (m, 3H), 2.22 (d, J = 10.6 Hz, 1H), 2.01 (d, J = 11.6 Hz, 2H), 1.74- 1.25 (m, 5H), 1.15 (d, J = 6.2 Hz, 6H). |
| 874 | A | A | 486. 46 | 2.9 | 1H NMR (300 MHz, MeOD) d 8.51 (s, 1H), 8.42 (d, J = 9.0 Hz, 1H), 8.35 (s, 1H), 8.28 (d, J = 5.3 Hz, 1 H), 4.46 (s, 1H), 3.95-3.76 (m, J = 11.0 Hz, 2H), 3.76-3.61 (m, 2H), 3.61 -3.51 (m, 1H), 3.50 -3.39 (m, 2H), 2.43-2.28 (m, 1H), 2.22 (d, J = 12.0 Hz, 1H), 2.01 (d, J = 11.0 Hz, 2H), 1.53 (ddd, J = 44.1,27.8, 15.6 Hz, 4H), 1.32- 1.10 (m, 6H). |
| 875 | A | A | 401. 3 | 3.01 | H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.29-8.26 (m, 2H), 8.17 (d, J = 3.9 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 4,31 (s, 1H), 2.85 (d, J = 5.9 Hz, 2H), 2.51 (t, J = 1.7 Hz, H), 2.08- 1.98 (m, 1H), 1.77- 1.64 (m, 4H), 1.50 (d, J =6.3 Hz, 3H) and 0.00 (s, H) ppm |
| 876 | A | A | 489. 34 | 2.99 | |
| 877 | A | A | 489. 34 | 2.75 | |
| 878 | A | A | 374. 21 | 1.64 | |
| 879 | A | A | 483. 45 | 2.35 |
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| 880 | A | A | 427. 4 | 2.97 | |
| 881 | C | C | 389. 27 | 2.03 | 1HNMR (300 MHz, DMSO) d 12.79 (s, 1H), 8.77 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 7.52 (s, 3H), 4.29 (s, 1H), 4.08 (d, J = 12.6 Hz, 1H), 3.90 (d, J = 13.7 Hz, 1H), 3.16-2.95 (m, 2H), 2.17 (d, J = 9.7 Hz, 1H), 1.92 (d, J = 8.5 Hz, 1H), 1.81 1.57 (m, 2H). |
| 882 | A | A | 401. 3 | 2.73 | H NMR (300.0 MHz, MeOD) d 8.86 (d, J =2.4 Hz, 1H), 8.19 - 8.16 (m, 2H), 7.97 (d, J = 4.0 Hz, 1H), 4.69-4.58 (m, 1H), 2.65 (s, 2H), 2.26- 1.98 (m, 3H), 1.84 (d, 1H), 1.79- 1.73 (m, 1H), 1.67- 1.47 (m, 2H), 1.36-1.21 (m, 1H) and 0.00 (TMS) ppm |
| 883 | A | A | 457. 38 | 3.55 | 1H NMR (300 MHz, DMSO) d 12.25 (s, 1H), 8.63-8.02 (m, 4H), 7.62 (dd, J = 62.6, 7.2 Hz, 2H), 3.90 (t, J = 60.4 Hz, 4H), 2.47-0.73 (m, 15H). |
| 884 | E | A | 471. 39 | 3.74 | |
| 885 | A | A | 420. 24 | 3.09 | |
| 886 | A | A | 454. 26 | 3.62 | H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.28-8.24 (m, 2H), 8.17 (d, J = 3.8 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 5.34 (s, 1 H), 4.32 (s, 1H), 3.41 (s, 2H), 3.04 (s, 3H), 2.22 (d, J = 11.7 Hz, 1H), 2.121.69 (m, 4H) and 1.52 (d, J = 8.7 Hz, 3H) ppm |
-47316260
| 887 | A | C | 420. 24 | 3.09 | |
| 888 (diastereo mer 1, see 889) | A | A | 420. 36 | 3.93 | H NMR (300.0 MHz, MeOD) d 8.81 (d, J = 2,4 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 7.97 (d, J = 4.0 Hz, 1 H), 4.50 (s, 1H), 4.28-4.18 (m, 1H), 3.72 (dd, J = 4.2, 9.1 Hz, 2H), 2.02 (d, J =6.3 Hz, 1H), 1.89-1.81 (m, 4H), 1.69- 1.55 (m, 3H), 1,26 1.20 (m, 4H) and -0.00 (s, H) ppm |
| 889 (diastereo mer 2, see 888) | A | A | 420. 37 | 3.94 | H NMR (300.0 MHz, MeOD) d 8.79 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 7.99 (d, J = 4.0 Hz, 1 H), 4.47 (dd, J = 3.6, 7.6 Hz, 1H), 4.25-4.17 (m, 1H), 2.10 (dd, J = 3.7, 13.4 Hz, 1H), 1.91 - 1.77 (m, 3H), 1.69 -1.50 (m, 4H), 1.20 (d, J =9.4 Hz, 2H) and -0,00 (TMS) ppm |
| 890 | A | A | 472. 42 | 3.6 | |
| 891 | A | A | 456. 4 | 3.82 | |
| 892 | A | A | 472. 41 | 3.69 | |
| 893 | A | A | 486. 42 | 3.6 | |
| 894 | A | A | 486. 44 | 3.6 | |
| 895 | A | A | 442. 42 | 3.7 | |
| 896 | A | A | 500. 42 | 3.77 | |
| 897 | A | A | 458. 42 | 3.48 | |
| 898 | A | A | 472. | 3.51 |
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| 42 | |||||
| 899 | A | A | 401 | 3.6 | 1H NMR (300 MHz, DMSO) d 12.30 (s, 1H), 8.41 (dd, J = 9.8, 2.9 Hz, 1H), 8.24 (d, J = 9.7 Hz, 2H), 8.13 (d, J = 4.0 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H),4.15(s, 1H), 3.73 (s, 1H), 2.22 - 1.91 (m, 4H), 1.82 (d, J = 11.1 Hz, 2H), 1.29 (ddd, J = 54.3, 34.3, 10.3 Hz, 4H), 0.97 (t, J = 7.6 Hz, 3H). |
| 900 | A | A | 413 | 3.56 | 1H NMR (300 MHz, DMSO) d 12.23(s, 1H), 8.40 (dd, J = 9.9, 2.9 Hz, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 8.13 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1 H), 7.48 (d, J = 7.5 Hz, 1 H), 4.15 (s, 1 H), 3.72 (s, 1H), 2.22- 1.73 (m, 4H), 1.62-1.04 (m, 5H), 0.75-0.53 (m, 4H). |
| 901 | A | A | 442. 37 | 2.97 | |
| 902 | A | A | 472. 43 | 3.41 | |
| 903 | A | A | 472. 48 | 3.65 | |
| 904 | A | A | 472. 38 | 2.72 | |
| 905 | A | A | 472. 38 | 2.61 | |
| 906 | A | A | 472. 38 | 2.67 | |
| 907 | A | A | 486. 4 | 2.88 | |
| 908 | A | A | 457. 35 | 2.53 | |
| 909 | A | A | 499. 38 | 2.62 |
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| 910 | A | A | 486. 4 | 3.02 | |
| 911 | A | A | 506. 29 | 2.57 | |
| 912 | A | A | 460. 35 | 2.79 | |
| 913 | A | A | 456. 39 | 2.98 | |
| 914 | A | A | 486. 4 | 2.79 | |
| 915 | A | A | 456. 39 | 2.98 | |
| 916 | A | A | 500. 41 | 3.1 | |
| 917 | A | 454. 34 | 2.54 | ||
| 918 | A | 508. 34 | 3.38 | ||
| 919 | A | 470. 4 | 1.59 | ||
| 920 | A | 384. 34 | 1.74 | ||
| 921 | A | 488. 38 | 1.92 | ||
| 922 | A | 481. 4 | 1.79 | H NMR (300.0 MHz, MeOD) d 8.44-8.41 (m, 2H), 8.32 (dd, J = 1.6, 2.7 Hz, 1H), 8.24 (d, J = 5.5 Hz, 1H), 4.42 (t, J = 11.8 Hz, 1H), 3.79 (t, J = 11.6 Hz, 1H), 3.65 (td, J = 10.2, 4.7 Hz, 2H), 3.54 (qn, J = 1.6 Hz, 1H), 2.97 (dt, J = 12.5, 4.2 Hz, 1H), 2.34 (d, J = 10.7 Hz, 1H), 2.21 (d, J = 12.1 Hz, 1H), 2.03- 1.87 (m, 4H) and 1.79- 1.23 (m, 7H) ppm |
-47616260
| 923 | A | 499. 38 | 1.57 | H NMR (300.0 MHz, MeOD) d 8,53 (dd, J = 2.8, 9.6 Hz, 1H), 8.18-8.08 (m, 2H), 7,99 (d, J = 4.1 Hz, 1H), 4.25 (dt, J = 15.2, 4.8 Hz, 1 H), 4.04 (d, 2H), 3.833.68 (m, 1 H), 2.80 (dd, J = 2.5, 25.7 Hz, 2H), 2.46 - 2,35 (m, 2H), 2.21 (d, J = 10.7 Hz, 1H), 1.97 (s, 1H), 1.80- 1.75 (m, 2H), 1.631,29 (m, 3H) and 1.22 (d, J = 4.8 Hz, 4H) ppm | |
| 924 | A | 403. 34 | 1.77 | ||
| 925 | C | 398. 35 | 1.75 | ||
| 926 | A | 472. 38 | 2.08 | H NMR (300.0 MHz, MeOD) d 8.76 (d, J = 2.4 Hz, H), 8.44 - 8.38 (m, H), 8.27 (d, J = 5.6 Hz, H), 4.87 (d, J = 5.1 Hz, H), 4.64- 4.56 (m, H), 3.38-3.19 (m, H), 2.65 (s, H), 2.46 (s, H), 2.42 (s, H), 2.16 (s, H), 2.07 (t, J = 12.0 Hz, H), 2.00 (s, H), 1.88 (q, J = 6.6 Hz, H), 1.88 (s, H), 1.70 (s, H) and 1.61 (d, J = 12.8 Hz, H) ppm | |
| 927 | C | 420. 36 | 1.8 | ||
| 928 | A | 420. 36 | 1.79 | ||
| 929 | 431. 19 | 1.82 | H NMR (300.0 MHz, MeOD) d 8.85 (d, J = 2.4 Hz, H), 8.22 (d. J = 2.3 Hz, H), 8.15 (s, H), 7.99 (d, J =4.1 Hz, H), 7.70 (d, J = 8.0 Hz, H), 7.64 (s, H), 5.49 (s, H), 5.01 (s, H), 4.95 (s, H), 4.88 (s, H), 4,56-4.47 (m, H), 3.53 (d, J = 1.7 Hz, H), 3.35-3.17 (m, H), 3.07 (s, H), 2.66 (s, H), 2.36 (s, |
-47716260
| H), 2.13 (d, J = 9.6 Hz, H),2.02- 1.98 (m, H), 1.89 (s, H). 1.83- 1.77 (m, H), 1.73- 1.68 (m, H), 1.63 (s, H), 1.49- 1.42 (m, H), 1.36 (s, H), 1.28 (s, H), 1.20- 1.07 (m, H) and 0.01 (d, J = 3.3 Hz, H) ppm | |||||
| 930 | 417. 19 | 1.84 | H NMR (300.0 MHz, MeOD) d 8.86 (d, J = 2.4 Hz, H), 8.26 8.22 (m, H), 8.15 (s, H), 8.037.98 (m, H), 7.67 (s, H), 7.62 (s, H), 5.47 (d, J = 10.7 Hz, H), 5.09 (d, J = 6.6 Hz, H), 5.01 (s, H), 4.88 (s, H), 4.61 (s, H), 4.52 (dd, J =7,1, 15.2 Hz, H), 4.52 (s, H), 3.72 (s, H), 3.66 (s, H), 3.60 (d, J = 7.1 Hz, H), 3.54-3.43 (m, H), 3.34 (s, H), 3.31 (qn, J = 1.6 Hz, H), 3.08 (t, J = 1.7 Hz, H), 2.762.71 (m, H), 2.13 (d, J = 12.7 Hz, H), 2.01 (d, J = 8.5 Hz, H), 1.83 1.76 (m, H), 1.72- 1.67 (m, H), 1.63 (s, H), 1.42 (s, H), 1.37 (d, J = 6.5 Hz, H), 1.29-1.15 (m, H), 0.98 (s, H), 0.83 (s, H), 0.20 (s, H), 0,07 (s, H), 0.00 (TMS) and0.20 (s, H) ppm | ||
| 931 | 494. 39 | 2.04 | |||
| 932 | A | A | 416. 44 | 2.93 | |
| 933 | A | A | 453. 4 | 1.5 | |
| 934 | A | A | 476. 09 | 1.92 | |
| 935 | A | A | 478. 08 | 1.89 | |
| 936 | A | A | 460. | 1.76 |
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| 1 | |||||
| 937 | A | A | 474. 6 | 2.02 | |
| 938 | A | A | 388. 11 | 1.87 | |
| 939 | A | A | 392. 41 | 2.42 | |
| 940 | 490. 1 | 2.04 | |||
| 941 | 472. 13 | 1.79 | H NMR (300.0 MHz, MeOD) d 8.70 (d, J = 2.2 Hz, H), 8.51 8.43 (m, H), 8.33 (s, H), 8.10 (d, J = 5.6 Hz, H), 4.77 (s, H), 4.63 4.53 (m, H), 4,15 (d, J = 4.5 Hz, H), 3.98-3.90 (m, H), 3.84 (t, J = 5.0 Hz, H), 3.63-3.53 (m, H), 3.48-3.41 (m, H), 3.21 (s, H), 3.16 (s, H), 3.11 (s, H), 2.82 (s, H), 2.65 (s, H), 2.49 (d, J = 9.8 Hz, H), 2.13-1.90 (m, H), 1.861.72 (m, H), 1.67 (s, H), 1.62 1.51 (m, H), 1.33 (dd, J = 6.5, 17.5 Hz, H) and -0.00 (TMS) ppm | ||
| 942 | 466. 2 | 1.66 | |||
| 943 | 456. 13 | 1.92 | H NMR (300.0 MHz, MeOD) d 12.44 (s, H), 8.49-8.46 (m, H), 8.33 (s, H), 8.23 (d, J = 5.6 Hz, H). 7.31 -7.25(m, H), 7.19 (d, J = 7.9 Hz, H), 7.12 (s, H), 7.07 (t, J =7.2 Hz, H), 4.90 (d, J = 12.9 Hz, H), 4.81 (d, J = 6.3 Hz, H), 4.75 (s, H), 4.69 (s, H), 4.60 (t, J = 11.1 Hz, H), 4.58 (s, H), 4.23 (s, H), 4.06 (d, J = 8.5 Hz, H), 3.72 (s, H), 3.54 (s, H), 3.44 3.39 (m, H), 3.32-3.25 (m, H), 3.18 (t, J = 1.7 Hz, H), 3.15 (s, |
-47916260
| H), 3.08-3.07 (m, H), 2.98 (s, H), 2.65 (s, H), 2.47 (d, J = 12.5 Hz, H), 2.05 (q, J = 11.9 Hz, H), 2.00 (s, H), 1.91 - 1.83 (m, H), 1.73 (d, J = 9.7 Hz, H), 1.64 (s, H), 1.56 (d, J = 12.6 Hz, H), 1.45 (s, H), 1.37 (d, J = 6.9 Hz, H), 0.20 (s, H), 0.07 (s, H), 0.01 --0.02 (m, H), -0.20 (s, H), -2.49 (s, H) and 2.71 (s, H) ppm | |||||
| 944 | 482. 1 | 1.93 | |||
| 945 | A | A | 402. 399 | 2.23 | (400MHz, DMSO-d6): 12.35 (br s, exchanged with D2O.1H), 9.18 (br s, excha nged with D2O, 1H), 8.75 (s,1H), 8.28 (s,1H), 8.19 (s,1H), 8.15 (d, J=3.2Hz,1H), 4.38 (br s,1H), 3.01 (d, J=10Hz,1H), 2.8 (s,1H), 2.58 (s,1H), 1.68 (d, J=9.2Hz, 1H), 1.56-1.22 (m,5H) |
| 946 | A | A | 402. 399 | 1.88 | (400MHz, DMSO-d6): 12.15 (br s, exchanged with D2O, 3H), 8.77 (d, J=2.4Hz , 1H), 8.28 (d, J=2Hz, 1H), 8.20 (s, 1 H), 8.17 (d, J=4Hz,1H), 7.78 (d, J=6Hz,1H), 4.66-4.65 (m,1H), 2.7-2.65 (m,2H), 1.72 (d, J=9.6Hz, 1H), 1.58-1.32 (m, 5H) |
| 947 | A | A | 402. 32 | 3.42 | H NMR (300.0 MHz, MeOD) d 8.87 (d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J = 1.9 Hz, 1 H), 8.30 (d, J = 5.7 Hz, 1H), 4.73 (d, J = 3.3 Hz, 1H), 3.12 (m, 1H), 2.76 (brs, 1H), 2.56 (d, J = 4.2 Hz, 1H), 1.86 (d, J =9.5 Hz, 2H), 1.79 - 1.49 (complex m, 2H) and J 1.51 (embedded d, J = 10.4 Hz, |
-48016260
| 2H) ppm | |||||
| 948 | A | A | 417. 36 | 3.11 | |
| 949 | A | A | 417. 29 | 2.99 | |
| 950 | A | 430. 41 | 3 | ||
| 951 | A | A | 431. 37 | 2.98 | NMR 1H (MeOH-d6): 8.7 (s, 1H), 8.5 (s, 1H), 8.35 (s, 1 H), 8.3 (s, 1H), 4.5 (m, 1H), 4.3 (m, 2H), 3.9 (m, 1H), 3.7 (m, 2H), 2.2 (m, 2H), 1.3-2.1 (m, 6H). |
| 952 | A | A | 430. 83 | 2.83 | |
| 953 | A | A | 430. 43 | 3.17 | |
| 954 | A | A | 444. 36 | 3.33 | |
| 955 | A | A | 458. 37 | 3.58 | |
| 956 | A | A | 429. 53 | 3.15 | H NMR (300.0 MHz, MeOD) d 8.72 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 5.5 Hz, 1H), 4.54- 4.47 (m, 1 H), 4.13 (t, J = 11.8 Hz, 1H), 3.57-3.45 (m, 2H), 2.42- 2.36 (m, 2H), 2.25 (m, 1H), 2.152.00 (m, 4H), 1.90- 1.59 (m, 4H) and 1.53- 1.43 (m, 1 H) ppm |
| 957 | A | A | 544. 4 | 3.62 | |
| 958 | A | A | 444. 4 | 3.21 | NMR 1H (MeOH-d4): conclusive with structure. |
| 959 | A | A | 431. 37 | 3.21 |
-48116260
| 960 | A | A | 431. 37 | 3.24 | |
| 961 | A | A | 431. 37 | 3.05 | |
| 962 | A | A | 431. 37 | 3.09 | |
| 963 | A | A | 445. 38 | 3.39 | |
| 964 | A | A | 445. 38 | 3.16 | |
| 965 | A | A | 415. 37 | 2.9 | |
| 966 | A | A | 415. 37 | 2.9 | |
| 967 | A | A | 415. 37 | 2.64 | |
| 968 | A | A | 415. 37 | 2.72 | |
| 969 | A | A | 415. 31 | 2.94 | |
| 970 | A | A | 431. 3 | 3.16 | |
| 971 | A | A | 431. 3 | 3.01 | |
| 972 | A | A | 415. 31 | 2.94 | |
| 973 | A | A | 415. 31 | 2.95 | |
| 974 | A | A | 416. 33 | 1.79 | |
| 975 | A | A | 415. 37 | 1.82 | |
| 976 | A | A | 415. 37 | 1.72 | |
| 977 | A | A | 399. 53 | 2.17 |
Table 3: lC50, EC50, NMR and LCMS Data of Compounds of FIG. 6
-48216260
| Com Ρ· Nos. | Cell Flu, MDC K proie ction, ATP (Ail: IC50: uM)( Mean (Ail)) | Cell Influe nza HA(-) 30 hr A/PR/ 8 bDNA :bDN A EC50 uM(M ean (Ail)) | LC MS _PI us | L C M S_ R T | NMR |
| 979 | A | A | 385 .48 | 2. 31 | H NMR (300.0 MHz, MeOD) d 8.65 (dd, J = 2.8, 9.6 Hz, 1H), 8.19 (s, 1H), 8.14 (dd, J = 2.0, 2.5 Hz, 1H), 7.98 (d, J =4.1 Hz, 1H), 4.75-4.65 (m, 1H), 2.64 (s, 2H), 2.20 (d, J = 12.6 Hz, 2H), 2.01 (dd, J = 3.4, 9.8 Hz, 2H), 1.84- 1.75 (m, 1H), 1.631.47 (m, 2H), 1.33 (dd, J = 3.6, 12.4 Hz, 1H) and 0.00 (TMS) Ppm |
| 980 | A | A | 432 .26 | 2. 46 | DMSO d6: 12.5 (bs, 1H); 8.75 (d, 1H); 8.65 (d, 1H); 8.3 (m, 4H); 7.7 (m, 2H); 7.2 (bs, 1H); 4.5 (bs, 1H); 2.7 (s, 3H); 2.3 9dd, 1H); 2.0 (m, 2H); 1.8-1.2 (m, 8H); 0.8 (t, 3H). |
| 981 | A | A | 399 .25 | 1. 65 | 1H NMR (300 MHz, MeOD) d 8.52 (s, 1H), 8.46-8.23 (m, 3H), 4.51 (t, J = 11.9 Hz, 1H), 3.23 (s, 1H), 3.04 (d, J = 7.3 Hz, 3H), 2.44 (s, 2H), 2.25 (d, J = 11.9 Hz, 1H), 2.11 (d, J= 12.7 Hz, 1H), 2.01 -1.80(m, 2H), |
-48316260
| 1.72 (d, J = 12.4 Hz, 2H), 1.47 (s, 2H), 1.30 (t, J = 7.3 Hz, 5H). | |||||
| 982 | A | A | 399 .25 | 1. 64 | 1HNMR (300 MHz, MeOD) d 8.52 (s, 1H), 8.30 (d, J = 5.6 Hz, 3H), 4.50 (t, J = 12.1 Hz, 1H), 3.48 (s, 2H), 3.35 (s, 2H), 3,04 (q, J = 7.3 Hz, 5H), 2.25 (d, J = 3.5 Hz, 4H), 2.02- 1.82 (m, 2H), 1.70 (t, J = 12.5 Hz, 2H), 1.58 - 1,35 (m, 3H), 1.30 (t, J = 7.3 Hz, 8H). |
| 983 | A | A | 486 .2 | 1. 83 | |
| 984 | A | A | 376 .28 | 1. 58 | |
| 985 | A | A | 439 .24 | 1. 94 | |
| 986 | A | A | 458 .24 | 1. 66 | |
| 987 | A | A | 401 .83 | 2. 12 | |
| 988 | A | A | 401 .9 | 1. 99 | |
| 989 | B | A | 474 .3 | 1. 45 | NMR 1H (MeOH-d4):8.3 (m, 2H), 8.1 (s, 1H), 4.4 (t, 1H), 3,8 (t, 1H), 3.6 (m, 4H), 3.4 (m, 4H), 2.3 (m, 1H), 2.2 (m, 1H), 2.0 (m, 2H), 1.3-1.7 (m,4H). |
| 990 | A | A | 429 .26 | 1. 92 | |
| 991 | C | C | 429 .26 | 1. 96 | |
| 992 | A | A | 526 .3 | 1. 99 | in MeOH-d4 |
-48416260
| 993 | A | A | 438 .21 | 1. 83 | |
| 994 | A | A | 512 .3 | 1. 83 | NMR 1H (MeOH-d4): 8.6 (d, 1H), 8.4 (s, 1H), 8.3 (d, 1H), 8.2 (m, 1H), 4.3 (t, 1H), 3.8 (t, 1H), 3.5-3.6 (m, 3H), 3.1 (m, 2H), 2.8 (t, 1H), 2.3 (m, 3H), 2.2 (m, 2H), 2.0 (m, 2H), 1.85 (m, 1H), 1.31.75 (m, 4H). |
| 995 | A | A | 470 .5 | 2. 04 | 1H NMR (300 MHz, DMSO) d 8.41 (dd, J = 9.8, 2.9 Hz, 1H), 8.33 - 8.04 (m, 2H), 7.49 (d, J = 7.4 Hz, 1H), 6.21 (d, J = 8.0 Hz, 1H), 4.61 (s, 3H), 4.11 (d, J = 7.9 Hz, 1H), 3.90 (s, 3H), 3.66- 3.42 (m, 1H), 2.18-1.90 (m, 2H), 1.87 - 1.69 (m, 2H), 1.580.68 (m, 8H) |
| 996 | A | A | 470 .49 | 2. 23 | 1H NMR (300 MHz, DMSO) d 8.41 (dd, J = 9.8, 2.9 Hz, 1H), 8.32 -8.04 (m, 2H), 7,49 (d, J = 7.6 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 4.61 (S, 3H), 4.09 (s, 1H), 3.90 (s, 3H), 3.66-3.41 (m, 1H), 2.17-1.89 (m, 2H), 1.78 (dd, J = 10.3, 7.1 Hz, 2H), 1.650.69 (m, 8H). |
| 997 | A | A | 526 .3 | 2 | |
| 998 | C | C | 526 .3 | 2 | |
| 999 | A | A | 508 .28 | 2. 09 | |
| 1000 | A | A | 476 .22 | 1. 86 | |
| 1001 | A | A | 467 .27 | 1. 94 | |
| 1002 | A | A | 481 | 2. |
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| .28 | 2 | ||||
| 1003 | A | A | 526 .39 | 2. 29 | |
| 1004 | A | A | 543 .41 | 1. 45 | |
| 1005 | A | A | 541 .49 | 1. 57 | |
| 1006 | A | A | 526 .39 | 2. 25 | |
| 1007 | A | A | 526 .39 | 2. 25 | |
| 1008 | A | A | 429 .45 | 2. 64 | CDCI3: 9.6 (m, 1 H); 8.5 (dd, 1H); 8.25 (m, 2H); 8.1 (d, 1H); 4.8 (appt, 1H); 4.5 (m, 1H); 3.4 (m, 1H); 2.8 (s, 3H); 2.6 (m, 1H); 2.25 (m, 1H); 1.9 (m, 3H); 1.5-1.0 (m, 5H) |
| 1009 | A | A | 443 .7 | 2. 81 | CDCI3:9.4(m, 1H); 8.6 (dd, 1H); 8.25 (bs, 2H); 8.1 (d, 1H); 4.8 (appt, 1H); 4.6 (m, 1H); 3.5 (m, 2H); 3.1 (m, 1H); 2.6 (m, 1H); 2.25 (m, 1H); 1.9 (m, 3H); 1.5-1.0 (m, 6H) |
| 1010 | A | A | 487 .29 | 1. 93 | CDCI3: 9.6 (m, 1H); 8.5 (dd, 1H); 8.25 (bs, 2H); 8.0 (d, 1H); 4.75 (app t, 1H);4.5 (m, 1H); 4.25 (m, 1H); 3.6 (m, 1H); 3.55 (s, 3H); 3.5 (m, 2H); 2.7 (m, 1H); 2.26 (appt, 1H); 2.0 (m, 3H); 1.9 (m, 3H); 1.5-1.0 (m, 7H) |
| 1011 | A | A | 473 .28 | 1. 79 | |
| 1012 | A | C | 504 .06 | 2. 09 |
-48616260
| 1013 | A | A | 486 .47 | 2. 52 | 1HNMR (d6-DMSO) 12.10 (s, 1H), 8.48-8.45 (m, 1H), 8.408.32 (m, 3H), 6.12 (d, J =7.8 Hz, 1 H), 4.27-4.09 (m, 2H), 3.723.47 (m, 1 H), 3.41-3.11 (m, 2H), 2.17-1.98 (m, 3H), 1.90-1.72 (m, 4H), 1.60-1.37 (m, 2H), 1.321.20 (m, 1H) |
| 1014 | A | A | 441 .45 | 2. 07 | 1H NMR (300 MHz, DMSO) d 12.26 (s, 1 H), 8.53-8.01 (m, 3H), 7.89 (s, 1H), 7.60 (d, J = 7.4 Hz, 1H), 4.33-3.68 (m, 4H), 2.74 (s, 2H), 2.23 (d, J = 13.1 Hz, 1H), 2.08- 1.73 (m, 3H), 1.70- 1.08 (m, 3H). |
| 1015 | A | A | 527 .47 | 1. 38 | 1H NMR (300 MHz, DMSO) d 12.61 (s, 1H), 8.38 (ddd, J = 9.6, 8.6, 2.9 Hz, 4H), 6.17 (d, J = 7.5 Hz, 1H), 4.20 (d, J = 10.5 Hz, 1H), 3.91 (d, J = 30.8 Hz, 4H), 3.72-2.96 (m, 11 H), 2.37- 1.68 (m,6H), 1.52-1.10(m, 4H). |
| 1016 | A | A | 468 .42 | 1. 68 | 1H NMR (300 MHz, DMSO) d 12.67 (s, 1H), 9.15 (s, 1H), 8.49 (dd, J = 9.3, 3.8 Hz, 3H), 8.28 (d, J = 2.0 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 4.32 (s, 1H), 3.67 (s, 1H), 3.57-3.46 (m, 3H), 3.25-3.19(m, 3H), 2.91 -2.61 (m, 2H), 2.51 (dt. J = 3.6, 1.8 Hz, 4H), 2.23-1.81 (m, 4H), 1.54- 1.37 (m, 2H), 1.32-1.23 (m, 3H). |
| 1017 | A | A | 429 .26 | 1. 84 | |
| 1018 | A | A | 429 .26 | 1. 83 |
-48716260
| 1019 | A | A | 500 .41 | 1. 78 | |
| 1020 | A | A | 514 .42 | 1. 91 | |
| 1021 | A | A | 514 .42 | 1. 85 | |
| 1022 | A | A | 460 .48 | 1. 76 | 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1H), 8.29-8.20 (m, 2H), 8.14 (d, J = 4.0 Hz, 1 H), 7.54 (d, J = 7.3 Hz, 1H), 6.04 (d, J = 7.9 Hz, 1H), 5.37 (s, 1H), 5,19 (s, 1H), 4.11 (d, J = 4.5 Hz, 1H), 3.63 (d, J = 7.6 Hz, 1H), 3.573.40 (m, 2H), 3.23 (ddd, J = 18.1, 10.3, 5.4 Hz, 2H), 2.17 2.01 (m, 3H), 1.90- 1.74 (m, 2H), 1.52- 1.20 (m, 4H). |
| 1023 | A | A | 499 .45 | 2. 15 | H NMR (300.0 MHz, MeOD) d 8.51 (dd, J = 2,8, 9.6 Hz, 1H), 8.18-8.15 (m, 2H), 7.99 (d, J = 4.1 Hz, 1H), 4.75 (s, H), 4.31 4.19 (m, H), 3.82-3.73 (m, 2H), 3.76 (dd, J = 3,6, 11.9 Hz, 1H), 3.54-3.45 (m, 1H), 2.68 (s, 3H), 2.36 (d, J = 11.8 Hz, 1H), 2.22- 1.90 (m, 6H), 1.62 (s, H), 1.52- 1.24 (m, 4H) and -0.00 (TMS) ppm |
| 1024 | A | A | 427 .27 | 2. 07 | |
| 1025 | A | A | 427 .27 | 2. 04 | |
| 1026 | A | A | 413 .26 | 1. 94 | |
| 1027 | B | A | 413 .26 | 1. 9 |
-48816260
| 1028 | A | A | 414 .34 | 2. 36 | 1H NMR (300 MHz, MeOD) d 8.56 (dd, J = 9,2, 2.8 Hz, 1H), 8.47 (s, 1H), 8.37-8.32(m, 1H), 8.30 (d, J = 5.6 Hz, 1H), 5.17 (d, J = 6.9 Hz, 1H), 3.69 (s, 3H), 2.96 (d, J =6.8 Hz, 1H), 2.192.11 (m, 1H), 2.09-2.02 (m, 1H), 1.74 (complex m, 9H). |
| 1029 | A | A | 443 .27 | 1. 97 | CDCI3: 9.75 (bs,1H); 8.6 (dd, 1H); 8.25 (d, 1H); 8.23 (s, 1H); 8.15 (d, 1H); 4.8 (d, 1H);4.6 (m, 1H); 3.5 (m, 3H); 3.1 (m, 1H); 2.75 (bd, 1H); 2.25 (bd, 1H); 2.0 (m, 2H); 1.4 (d, 3H);1.25(t, 3H). |
| 1030 | A | A | 443 .27 | 1. 99 | CDCI3: 9.75 (bs,1H); 8.5 (dd, 1H); 8.25 (d, 1H); 8.23 (s, 1H); 8.0 (d, 1H);4.8 (d, 1H); 4.5 (m, 1H); 3.5 (m, 2H); 3.4 (m, 1H); 2.5 (bd, 1H); 2.1 (bd, 1H); 1.7 (m, 3H); 1.4 (ddd, 1H); 1.2 (m, 6H). |
| 1031 | A | A | 416 .46 | 1. 69 | |
| 1032 | A | A | 510 ,52 | 2. 1 | |
| 1033 | A | A | 479 .39 | 2. 08 | 1H NMR (300 MHz, DMSO) d 12.23 (s, 1H), 8.50-8.46 (m, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1H), 8.26 (dd, J = 2.7, 1.5 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.73 (td, J =7.7, 1.8 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.31 -7.15(m, 2H), 6.32 (t, J = 5.8 Hz, 1H), 6.14 (d, J = 7.8 Hz, 1H), 4.29 (d, J =5.8 Hz, 2H), 4.22-3.97 (m, 1H), 3.57 (d, J = 7.7 Hz, 1H), |
-48916260
| 2.21 -2.10 (m, J = 11.0 Hz, 1H), 2.07- 1.98 (m, 1H), 1.95-1.72 (m, 2H), 1.59-0.88 (m, 4H). | |||||
| 1034 | A | A | 400 .37 | 2. 15 | 1H NMR (300 MHz, MeOD) d 8.58 (dd, J = 9.3, 2.8 Hz, 1H), 8.41 (s, 1 H), 8.29 (dd, J = 2.7, 1.7 Hz, 1H), 8.22 (d, J = 5.3 Hz, 1H), 5.10 (d, J = 6.9 Hz, 1H), 2.89 (d, J = 7.0 Hz, 1H), 2.17 (brs, 1H), 2.03 (br s, 1H), 1.991.49 (m, 7H). |
| 1035 | A | A | 444 .42 | 1. 81 | |
| 1036 | A | A | 472 .5 | 1. 67 | NMR 1H (MeOH-d4): 8.4 (m, 2H), 8.25 (m, 2H), 4.4 (m, 1H), 3.8 (m, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 2.35 (m, 1H), 2.2 (m, 1 H), 2.0 (m, 2H), 1.8 (m, 2H), 1.15- 1.46 (6H). |
| 1037 | C | C | 470 .4 | 1. 72 | |
| 1038 | A | A | 470 .4 | 1. 73 | |
| 1039 | A | A | 458 .43 | 1. 61 | H NMR (300.0 MHz, CDCI3) d 7.70 (s, H), 7.28 (s, H), 7.11 (s, H), 5.31 (s, H), 4.17-4.02 (m, H), 3.78 (s, H), 3.73 (q, J = 7.0 Hz, H), 3.49 (s, H), 2.97 (s, H), 2.90 (s, H), 2.65 (s, H), 2.03 (d, J = 11.7 Hz, H), 1.87 (s, H), 1.29- 1.21 (m, H) and 0.93 (d, J = 6.7 Hz, H) ppm |
-49016260
| 1040 | A | A | 428 .43 | 1. 67 | H NMR (300.0 MHz, CDCI3) d 10.54 (s, H), 8.53 (dd, J = 2.8, 9.4 Hz, H), 8.50 (s, H), 8.258.06 (m, H), 7.30 (d, J = 10.7 Hz, H), 5.96 (s, H), 5.32 (s, H), 4.95 (d, J = 8.0 Hz, H), 4.87 (d, J = 6.6 Hz, H), 4.27-4.11 (m, H), 4.02- 3.92 (m, H), 3.77 (t, J = 6.2 Hz, H), 3.51 (s, H), 2.92 (s, H), 2.73-2.67 (m, H), 2.45 2.37 (m, H), 2.26 (d, J = 10.3 Hz, H), 2.18 (d, J = 3.9 Hz, H), 2.12 (s, H), 2.06- 1.95 (m, H), 1.89 (s, H), 1.87 (q, J = 3.4 Hz, H), 1.73 (d, J = 8.6 Hz, H), 1.67 (s, H), 1.63- 1.58 (m, H), 1.331.26 (m, H), 1.17 (t, J = 11.6 Hz, H), 0.94 (d, J = 6.6 Hz, H), 0.85 -0.68 (m, H), 0.61 (t, J = 7.0 Hz, H), 0.62 (s, H) and 0.53 (d, J = 7.2 Hz, H) ppm |
| 1041 | A | A | 486 .46 | 1. 95 | 1H NMR (300 MHz, MeOD) d 8.42 (dd, J = 9.2, 2.8 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 8.34 - 8.29 (m, 1H), 8.26 (d, J = 5.5 Hz, 1H), 4.43 (dd, J = 14.0, 10.0 Hz, 1H), 3.99- 3.90 (m, 1H), 3.75 (ddd, J = 15.3, 7.6, 3.6 Hz, 2H), 3.40 (d, J = 5.3 Hz, 3H), 3.35 (s, 3H), 2.36 (d, J = 11.9 Hz, 1H), 2.22 (d, J = 12.9 Hz, 1H), 2.04- 1.75 (m, 7H), 1.68 1.19 (m, 6H). |
| 1042 | A | C | 457 .5 | 1. 31 | |
| 1043 | A | A | |||
| 1044 | A | A | 454 .53 | 1. 91 |
-49116260
| 1045 | A | A | 454 .4 | 1. 9 | |
| 1046 | C | C | 479 .41 | 2. 08 | 1H NMR (300 MHz, DMSO) d 12.23 (d, J = 2.3 Hz, 1 H), 8.518.35 (m, J = 8.5, 4.9, 1.7 Hz, 3H), 8.32-8.19 (m, 2H), 8.14 (d, J =4.0 Hz, 1H), 7.63 (dt, J = 7.8, 1.9 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.36- 7.25 (m, 1H), 6.27 (t, J =6.0 Hz, 1H), 6.00 (d, J = 7.9 Hz, 1 H), 4.22 (d, J = 6.0 Hz, 2H), 4.17-3.98 (m, J = 10.5, 6.4 Hz, 1H), 3.67-3.44 (m, J = 7.8 Hz, 1H), 2.16 (d, J = 11.3 Hz, 1H), 2.03 (d, J = 11.7 Hz, 1H), 1.95 - 1.70 (m, J = 25.5, 11.7 Hz, 2H), 1.53-0.93 (m, J = 33.7, 28.1, 12.8 Hz, 4H). |
| 1047 | A | A | 501 .5 | 1. 65 | |
| 1048 | A | A | 396 .41 | 2. 17 | 1H NMR (300 MHz, MeOD) d 9.07 (d, J = 6.8 Hz, 1H), 8.568.50 (m, 2H), 8.37 (d, J = 5.6 Hz, 1H), 7.55 (dd, J =8.1,5.1 Hz, 1H), 5.21 (d, J = 6.8 Hz, 1H), 3.73 (s, 3H), 3.00 (d, J = 6.6 Hz, 1H), 2.21-2.15 (m, 1H), 2.10-2.05 (m, J = 5.8 Hz, 1 H), 1.99- 1.52 (m, 9H). |
| 1049 | A | A | 440 .62 | 2 | 1HNMR (300 MHz, MeOD) d 9.08 (d, J = 7.2 Hz, 1H), 8.58 (s, 1H), 8.55 (dd, J = 5.3, 0.8 Hz, OH), 8.34 (d, J = 5.6 Hz, 1H), 7.74 (dd, J = 8.0, 5.4 Hz, 1H), 4.49-4.37 (m, 1H), 3.93 - 3.81 (m, 1H), 3.67 -3.56 (m, 4H), 3.39-3.31 (m, 4H), 2.42 (d, J = 11.1 Hz, 1H), 2.17 -2.05 (m, J = |
-49216260
| 11.4 Hz, 1H), 1.99 (burried m, 3H), 1.67 - 1.26 (m, 5H). | |||||
| 1050 | A | A | 456 .57 | 2. 71 | 1H NMR (300 MHz, DMSO) d 12.23 (s, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1 H), 8.22 (ddd, J = 28.3, 14.1.2.7 Hz, 3H), 7.49 (d, J = 7.7 Hz, 1H), 5.79 (d, J = 7.9 Hz, 1H), 4.20-4.00 (m, 1H), 3.61 (d, J = 8.0 Hz, 1H), 3.49-3.36 (m, 1H), 3.17 (d, J = 5.2 Hz, 1H), 2.84-2.65 (m, 1H), 2.221.72 (m, 5H), 1.48-1.10 (m, 5H), 0.98 (dd, J = 6.6, 1.8 Hz, 3H). |
| 1051 | A | A | 456 .44 | 2. 6 | 1H NMR (300 MHz, DMSO) d 12.23 (d, J = 2.3 Hz, 1H), 8.42 (dd, J = 9.9, 2.9 Hz, 1H), 8.22 (ddd, J = 28.6, 14.3, 2.8 Hz, 3H), 7.49 (d, J = 7.4 Hz, 1H), 5.79 (d, J = 7.9 Hz, 1H), 4.21 3.99 (m, 1H), 3.61 (d, J = 7.9 Hz, 1H), 3.40 (dd, J = 9.7, 7.3 Hz, 1H), 3.14 (dd, J = 17.0, 7.6 Hz, 1H), 2.71 (dd, J = 9.7, 8.0 Hz, 1H), 2.20- 1.73 (m, 5H), 1.54-1.11 (m, 5H), 0.98 (d, J = 6.6 Hz, 3H). |
| 1052 | A | A | 456 .67 | 2. 75 | 1H NMR (300 MHz, DMSO) d 12.23 (d, J = 2.1 Hz, 1H), 8.42 (dd, J =9.9, 2.9 Hz, 1H), 8.22 (ddd, J = 30.6, 15.3, 2.8 Hz, 3H), 7.49 (d, J = 7.5 Hz, 1H), 5.74 (d, J = 7.9 Hz, 1H),4.07 (d, J = 5.2 Hz, 1H), 3.88 (dd, J = 8.7, 4.5 Hz, 1H), 3.69 - 3.50 (m, |
-49316260
| 1H), 3.27-3.24 (m, 1H), 3.17 (t, I J = 3.7 Hz, 1H), 2.21 - 1.66 (m, 5H), 1.38 (dd, J = 41.1, 29.2 Hz, 5H), 1.04 (d, J = 6.2 Hz, 3H). | |||||
| 1053 | A | A | 456 .27 | 2. 65 | 1H NMR (300 MHz, DMSO) d 12.23 (d, J = 2.1 Hz, 1H), 8.42 (dd, J = 9.9, 2.9 Hz, 1H), 8.22 (ddd, J = 27.2, 13.6, 2.8 Hz, 3H), 7.49 (d, J = 7.5 Hz, 1H), 5.75 (d, J = 8.0 Hz, 1 H), 4.264.02 (m, 1H), 3.97-3.83 (m, 1H), 3.72-3.53 (m, 1 H), 3.31 (s, 1H), 3.16 (s, 1H), 2.15-1.64 (m, 5H), 1.44 (s, 5H), 1.04 (d, J = 6.2 Hz, 3H). |
| 1054 | A | A | 472 .42 | 2. 34 | 1H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.42 (dd, J = 9.9, 2.8 Hz, 1H), 8.27 (dd, J = 2.7, 1.4 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.14 (d, J =4.0 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.29 (s, 1H), 6.70 (s, 1H), 5.91 (d, J = 8.0 Hz, 1H), 4.11 (s, 1H), 3.90 (d, J = 3.0 Hz, 1H), 3.62 (d, J = 8.1 Hz, 1H), 3.27 (d, J = 4.2 Hz, 2H), 2.11 (d, J = 10.4 Hz, 1H), 1.99 (s, 2H), 1.93- 1.77 (m, 4H), 1.75 (s, 1H), 1.54-1.21 (m, 5H). |
| 1055 | A | A | 472 .41 | 2. 34 | |
| 1056 | A | A | 486 .33 | 1. 89 | |
| 1057 | A | C | 486 I 4 | 1. 89 |
-49416260
| 1058 | A | A | 472 .43 | 2. 67 | 1H NMR (300 MHz, MeOD)d 8.46 (dd, J = 10.0, 2.8 Hz, 1H), 8.17-7.91 (m, 2H), 4.28-4.08 (m, 1H), 3.88-3.71 (m, 1 H), 3.62 (d, J = 5.1 Hz, 3H), 3.463.32 (m, 4H), 2.87 (s, 3H), 2.32 (d, J = 11.9 Hz, 1H), 2.15 (d, J = 12.9 Hz, 1H), 2.03- 1.85 (m, 2H), 1.67- 1.20 (m, 4H). |
| 1059 | A | A | 495 | 2. 03 | |
| 1060 | A | A | 508 | 1. 42 | |
| 1061 | A | A | 474 | 1. 89 | NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.15-8.34 (m, 3H), 4.4 (m, 1H), 3.8 (m, 1H), 3.5 (m, 2H), 3.5 (m, 2H), 3.3 (m, 2H), 2.9 (s, 1H), 2.4 (m, 1H), 2.2 (m, 1H), 2.0 (m, 2H), 1.2-1.5 (m, 4H), 1.1 (t, 3H). |
| 1062 | A | A | 458 | 1. 68 | |
| 1063 | A | A | 444 | 1. 91 | |
| 1064 | A | A | 504 .5 | 1. 91 | H NMR (300.0 MHz, MeOD) d 8.44 (dd, J = 2.8, 9.6 Hz, H), 8.14 (t, J =4.5 Hz, H), 8.13 (s, H), 7.98- 7.94 (m, H), 7.70 (s, H), 7.06 (s, H), 6.28 (d, J = 7.3 Hz, H), 5.49 (s, H), 4.83 (s, H), 4.52 (s, H), 4.22-4.09 (m, H), 3.75 (dd, J = 3.8, 11.4 Hz, H), 3.69 (s, H), 3.57-3.30 (m, H), 3.26 (s, H), 3.10 (s, H), 2.99 (s, H), 2.87 (d, J = 8.6 Hz, H), 2.36 -2.33 (m, H), 2.19 (d, J = 12.2 Hz, H), 2.03 (d, J = 10.6 Hz, H), 1.95- 1.89 (m, H), 1.65 (s, H), |
-49516260
| 1.61 -1.52 (m, H), 1.43-1.13 (m, H) and -0.00 (s, H) ppm | |||||
| 1065 | A | A | 486 | 1. 96 | |
| 1066 | A | A | 474 | 1. 82 | |
| 1067 | A | A | 474 | 1. 89 | in MeOH-4 |
| 1068 | A | A | 474 | 1. 86 | in MeOH-d4 |
| 1069 | A | A | 484 | 1. 99 | |
| 1070 | A | A | 400 .39 | 2. 15 | 1HNMR (300 MHz, MeOD) d 8.66 (dd, J = 9.6, 2.8 Hz, 1H), 8.19 (s, 2H), 7.98 (d, J = 4.1 Hz, 1H), 4.91 (d, J = 6.8 Hz, 1H), 2.75-2.63 (m, 1H), 2.18-1.41 (m, 10H). |
| 1071 | A | A | 400 .56 | 2. 15 | 1H NMR (300 MHz, MeOD) d 8.66 (dd, J = 9.6, 2.8 Hz, 1H), 8.19 (s, 2H), 4.90 (d, J = 6.9 Hz, 1H), 2.75-2.64 (m, 1H), 2.15- 1.42 (m, 10H). |
| 1072 | A | A | 537 | 2. 09 | 1H NMR (300 MHz, DMSO) d 12.55 (s, 1H), 8.40 (t, J = 3.1 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 8.33 (t, J = 3.7 Hz, 2H), 6.43 (d, J = 7.7 Hz, 1H), 4.19 (d, J =7.2 Hz, 1H), 3.66 (d, J = 7.4 Hz, 1H), 3.48 (dd, J = 13.1,5.9 Hz, 4H), 3.35- 3.25 (m, 1H), 2.67 (d, J = 7.0 Hz, 2H), 2.21 - 1.80 (m, 6H), 1.56- 1.22 (m, |
-49616260
| 4H). | |||||
| 1073 | A | A | 490 | .1, 99 | |
| 1074 | A | A | 490 | 2. 01 | |
| 1075 | A | A | 458 | 2. 04 | NMR 1H (MeOH-d4):8.44 (s, 1H), 8.4 (d, 1H), 8.3 (m, 1H), 8.2 (d, 1H), 4.3-4.4 (m, 2H), 3.8 (m, 1H), 3.2 (q, 2H), 2.2-2.34 (m, 2H), 2.0 (m, 2H), 1.3-1.6 (m, 4H), 1.1 (m, 8H). |
| 1076 | A | A | 473 | 1. 33 | NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.4 (dd, 1H), 8.3 (m, 1H), 8.26 (d, 1H), 4.4-4.45 (m, 1H), 3.8 (m, 1H), 3.5-3,7 (m, 2H), 3.3 (m, 2H), 2.95 (m, 9H), 2.35 (m, 1H), 2.2 (m, 2H), 1.95 (m, 2H), 1.25-1.55 (m, 5H). |
| 1077 | A | A | 474 .43 | 1. 68 | H NMR (300.0 MHz, MeOD) d 8.47-8.25 (m, H), 7.98 (s, H), 4.95 (s, H), 4.89 (s, H), 4.82 (s, H), 4.49-4.40 (m, H), 4.21 4.10 (m, H), 4.01 (s, H), 3.92 (s, H), 3.54 (t, J = 1.7 Hz, H), 3.443.30 (m, H), 3.07 (t, J = 1.6 Hz, H), 2.99 (s, H), 2.87 (d, J = 6.6 Hz, H), 2.65 (s, H), 2.51 (q, J = 12.1 Hz, H), 2.36-2.31 (m, H), 2.24 -2.04 (m, H), 1.99 (s, H), 1.81 (d, J = 11.6 Hz, H), 1,71 1.66 (m, H), 1.61 - 1.45 (m, H), 1.40- 1.37 (m, H), 1.18-1.08 (m, H), 0.19 (s, H), -0.00 (TMS) and -0.20 (s, H) ppm |
-49716260
| 1078 | A | A | 481 | 1. 91 | NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.17-8.33 (m, 3H), 4.4 (m, 1H), 3.75 (m, 1H), 3.6 (m, 2H), 2.7-2.9 (m, 3H), 2.4 (m, 1H), 2.2 (m, 1H), 2.05 (m, 2H), 1.2-1.7 (m,4H), 0.9 (m, 2H), 0.75 (m, 2H). |
| 1079 | A | A | 472 .37 | 2. 11 | 1H NMR (300 MHz, DMSO) d 12.23 (s, 1H), 8.42 (dd, J = 9.9, 2.9 Hz, 1H), 8.30 - 8.19 (m, 2H), 8.13 (d, J = 4.0 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 5.77 (t, J = 6.3 Hz, 1H), 4.66 (s, 1 H), 4.204.04 (m, 1H), 3.71-3.50 (m, J = 7.7 Hz, 1H), 3.30 (q, J = 5.3 Hz, 1H), 3.18 (dd, J =7.8, 4.8 Hz, 2H), 3.04 (d, J = 10.5 Hz, 1H), 2.11 (d, J = 11.6 Hz, 1H), 2.00 (d, J = 9.5 Hz, 1H), 1.88-1.59 (m, 4H), 1.52- 1.32 (m, 2H), 1.35-1.18(m, 5H). |
| 1080 | A | A | 500 | 2. 01 | NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.26-8.33 (m, 3H),4.36 (m, 1H), 4.05 (m, 1H), 3.9 (m, 1H), 3.75 (m, 2H), 3.3 (m, 2H), 3.2 (m, 2H), 2.4 (m, 1H), 2.2 (m, 2H), 1.8-2.0 (m, 5H), 1.2-1.6 (m, 5H), 1.1 (t, 3H). |
| 1081 | A | A | 512 | 1. 84 | NMR 1H (MeOH-d4): 8.4 (s, 1H), 8.25-8.35 (m, 3H), 4.7 (s, 2H), 4.35 (m, 1H), 3,8 (m, 1H), 3.35 (q, 2H), 2.2-2.3 (m, 5H), 2.0 (m, 2H), 1.3-1.8 (m, 4H), 1.1 (t, 3H). |
-49816260
| 1082 | B | A | 498 .35 | 2. 69 | 1H NMR (300 MHz, CDCI3) d 10.71 (s, 1H), 8.53 (d, J = 9.9 Hz, 1H), 8.20 (s, 1H), 8.11 (d, J = 2.9 Hz, 1H), 4.87 (d, J = 6.9 Hz, 1H), 4.29 (d, J = 6.9 Hz, 1H), 4.14 (m, 1H), 3.82 (m, 4H), 3.34 (m, 4H), 2.56 (s, 1H), 2.30 (m, 1H), 2.05 (m, 1H)„ 1.91 (m 1H), 1.81 - 1.42 (m, 2H), 1.41 - 0.87 (m, 7H). |
| 1083 | A | A | 456 .2 | 2. 74 | 1HNMR (300 MHz, MeOD) d 8.33-8.21 (m, 2H), 8.11 (dd, J = 9.3, 2.3 Hz, 1H), 4.38 (m, 1H), 3.51(4 H), 3.72 (m, 1H), 2.85 (s, 3H), 2.30 (m, 1H), 2.10 (m, 1H), 2.02- 1.88 (m, 6H), 1.57-1.30 (m, 4H). |
| 1084 | A | A | 486 .46 | 1. 76 | |
| 1085 | A | A | 458 .5 | 2. 05 | |
| 1086 | A | A | 444 .61 | 1. 87 | |
| 1087 | A | A | 458 .56 | 2. 04 | |
| 1088 | C | C | 482 .46 | 2. 87 | 1H NMR (300 MHz, MeOD) d 8.40 (d, J = 10.0 Hz, 1H), 8.01 (dd, J = 17.7, 2.5 Hz, 2H), 4.14 (s, 1H), 3.84- 3.53 (m, 2H), 3.28 (s, 3H), 2.28 (d, J = 11.9 Hz, 1H), 2.11 (s, 1H), 2.05- 1.76 (m, 6H), 1.61 - 1.00 (m, 9H). |
| 1089 | A | A | 424 .69 | 1. 77 | 1H NMR (300 MHz, MeOD) d 9.32-9.10 (m, 1H), 8.67 (s, 1H), 8.65-8.59 (m, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.87 (dd, J = 8.1, 5.6 Hz, 1H), 4.53-4.34 (m, |
-49916260
| 1H), 3.97-3.79 (m, 1H), 2.42 I (d, J = 11.5 Hz, 1H), 2.11 (d, J = 10.5 Hz, 1 H), 2.05- 1.83 (m, 5H), 1.70- 1.33 (m, 4H). | |||||
| 1090 | A | A | 382 .61 | 1. 96 | 1H NMR (300 MHz, MeOD) d 9.00 (dd, J = 8.1, 1.5 Hz, 1H), 8.46 (dd, J = 5.0, 1.4 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H), 7.47 (dd, J = 8.1, 5.0 Hz, 1H), 5.21- 5.10 (m, J = 6.8 Hz, 1H), 3.01 - 2.87 (m, J = 6.8 Hz, 1H), 2.23- 2.12 (m, 1H), 2.06- 1.98 (m, 1H), 1.98- 1.47 (m, 7H). |
| 1091 | A | A | 472 .25 | 1. 77 | |
| 1092 | A | A | 472 .25 | 1. 77 | |
| 1093 | A | A | 488 .19 | 1. 9 | |
| 1094 | A | A | 488 .19 | 1. 9 | |
| 1095 | A | A | 514 .41 | 2. 33 | 1H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1H), 8.29-8.25 (m, J = 1.4 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.23 (d, J = 7.7 Hz, 1H), 4.21 -3.92 (m, 3H), 3.60 (s, 1 H), 3.17 (d, J = 5.2 Hz, 2H), 2.11 (d, J = 12.4 Hz, 1H), 2.00 (d, J = 7.9 Hz, 1H), 1.81 (d, J = 10.7 Hz, 2H), 1.62 (d, J = 11.8 Hz, 2H), 1.521.17 (m, 6H), 1.02 (d, J = 9.4 Hz, 8H). |
| 1096 | A | A | 456 .45 | 2. 01 | |
| 1097 | A | A | 488 | 1. |
-50016260
| 56 | |||||
| 1098 | A | A | 460 ,39 | 2. 38 | 1H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8,42 (dd, J = 9.9, 2.8 Hz, 1H), 8.29-8.01 (m, 3H), 7.50 (d, J = 7.1 Hz, 1H), 5.84 (d, J = 7.8 Hz, 1H), 5.60 (d, J = 8.2 Hz, 1H), 4.29- 3.99 (m, 1H), 3.72 (dd, J = 12.8, 6.6 Hz, 1H), 3.52 (d, J = 8.1 Hz, 1H), 3.253.05 (m, 4H), 2.19-1,68 (m, 3H), 1.52-1.11 (m, 3H), 1.00 (d, J = 6.7 Hz, 3H). |
| 1099 | A | A | 470 .35 | 2, 2 | 1HNMR (300 MHz, DMSO) d 12.26 (d, J = 2.4 Hz, 1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.23 (ddd, J = 30.4, 15.2, 2.7 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 6.14 (d, J = 8.0 Hz, 1H), 4.50 (d, J = 10.5 Hz, 2H), 4.25-3.95 (m, 1H), 3.62 (dd, J = 12.4, 6.7 Hz, 2H), 3.25- 3.03 (m, 2H), 2.190.90 (m, 10H). |
| 1100 | 474 | 1. 55 | |||
| 1101 | A | A | 502 .5 | 1. 76 | |
| 1102 | A | A | 571 .14 | 1. 65 | 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.29-8.25 (m, J = 2.8,1.5 Hz, 1H), 8.23 (s, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 5.97 (d, J = 7.8 Hz, 1H), 4.20-4.08 (m, J = 5.2 Hz, 1H), 4.08-3.98 (m, 2H), 3.97- 3.86 (m. J = 11.5, 8.4 Hz, 1H), 3.30-3.23 (m, 1H), 3.17 (d, J = 5.2 Hz, 1H), 3.07 (d, J = 5.4 Hz, 1H), 2.18-2.07 (m, J = |
-50116260
| 11.8 Hz, 1H), 2.06- 1.93 (m, J = 10.5 Hz, 1H), 1.92- 1.74 (m, 6H), 1.76- 1.63 (m, 2H), 1.42 (dd, J = 23.4, 11.6 Hz, 2H), 1.35 -1.15(m, 3H), 0.81 (dd, J = 13.3, 6.8 Hz, 6H). | |||||
| 1103 | A | A | 486 | 1. 72 | 1HNMR (300 MHz, DMSO) d 8.36 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 1.5 Hz, 1H), 8.20 (s, 1H), 8.11 (d, J = 3.8 Hz, 1H), 7.43 (s, 1H), 6.13 (d, J = 7.5 Hz, 1H), 5.76 (s, 1H), 4.13 (s, 2H), 3.24- 2.98 (m, 4H), 2.27- 2.20 (m, 1H), 2.01 (d, J = 11.5 Hz, 3H), 1.81 (d, J = 11.6 Hz, 2H), 1.63- 0.93 (m, 11H). |
| 1104 | A | A | 490 ,43 | 1. 59 | 1H NMR (300 MHz, d6-DMSO) □ Π12.70 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 8.26 (d, J=17.1 Hz, 1H), 6.02 (d, J = 7.2 Hz, 1H), 5.37 (s, 1H), 5.19 (s, 1H), 4.33 (s, 1H), 4.13 (s, 3H), 2.27 (s,1H), 2.10(s, 3H), 1.77 (s, 5H), 1.48-1.14 (m, 6H) |
| 1105 | A | A | 474 .4 | 1. 5 | NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.25-8.33 (m, 3H), 4.4 (m, 1H), 4.1 (d,2H), 3.8(m,1H), 3,5 (dd, 2H), 2.3-2,4 (m, 2H), 2.0 (d, 2H), 1.3-1.6 (m, 4H). |
| 1106 | A | A | 502 .43 | 2. 35 | 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1H), 8.30-8.05 (m, 3H), 7.54 (d, J = 7.5 Hz, 1H), 5.96 (d, J =7.8 Hz, 1H), 4.26- 3.93 (m, 1H), 3.80 (s, 2H), 3,59 (s, 1H), 3.33-3.16(m, 8H), 1.93 (dd, J |
-50216260
| = 67.2, 22.0 Hz, 4H), 1.60-0.89 (m, 5H). | |||||
| 1107 | A | A | 502 .02 | 2. 38 | 1HNMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J = 9.9, 2.8 Hz, 1H), 8.35-8.01 (m, 3H), 7.54 (d, J = 7.5 Hz, 1H), 5.96 (d, J = 7.8 Hz, 1H), 4.13 (s, 1H), 3.80 (s, 2H), 3.69 - 3.44 (m, 1H), 3.28 (d, J = 9.4 Hz, 7H), 2.04 (d, J = 32.3 Hz, 2H), 1.83 (d, J = 8.8 Hz, 2H), 1.33 (dt, J = 25.0, 12.2 Hz, 5H). |
| 1108 | A | A | 516 .71 | 2. 2 | 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.65-7.90 (m, 4H), 7.53 (d, J =6.6 Hz, 1H), 6.29 (d, J = 6.9 Hz, 1H), 4.12 (s, 1H), 3.72-2.94 (m, 11H), 2.04 (d, J = 30.8 Hz, 2H), 1.72 (d, J = 44.2 Hz, 3H), 1.32 (d, J = 56.3 Hz, 5H). |
| 1109 | A | A | 516 .41 | 2. 39 | 1H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.27 (dd, J = 48.0, 38.1 Hz, 4H), 7.55 (s, 1H), 6.36 (s, 1H), 4.12 (s, 1H), 3.81 - 2.81 (m, 11H), 2.21 -1.68 (m, 5H), 1.32 (d, J =53.8 Hz, 6H). |
| 1110 | A | A | 458 .5 | 2. 02 | |
| 1111 | A | A | 472 .51 | 1. 72 | |
| 1112 | A | A | 472 .45 | 1. 73 | |
| 1113 | A | A | 472 .45 | 1. 73 | |
| 1114 | A | A | 487 | 1. | t |
-50316260
| .48 | 64 | ||||
| 1115 | A | A | 521 .5 | 1. 5 | NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.3-8.35 (m, 3H), 6.37-6.7 (tt, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.5-3.75 (m, 5H), 2.18-2.4 (m, 2H), 2.0 (d, 2H), 1.3-1.7 (m, 4H). |
| 1116 | B | C | 445 .45 | 1. 64 | |
| 1117 | A | A | 501 .56 | 2. 16 | |
| 1118 | A | A | 486 .5 | 1. 68 | NMR 1H (MeOH-d4): 8.27-8.32 (m, 4H), 4.4 (m, 1H), 3.35 (m, 1H), 2.4-2.64 (m, 2H), 1.8-2.2 (m, 4H), 1.4-1.75 (m, 4H). |
| 1119 | A | A | 474 .24 | 1. 89 | |
| 1120 | A | A | 490 .23 | 2. 01 | |
| 1121 | A | A | 490 .23 | 2. 01 | |
| 1122 | A | A | 456 .26 | 1. 93 | |
| 1123 | A | A | 456 .26 | 1. 93 | |
| 1124 | A | A | 472 .25 | 2. 06 | |
| 1125 | A | A | 472 .19 | 2. 06 | |
| 1126 | A | A | 474 .24 | 1. 89 | |
| 1127 | A | A | 492 .08 | 2. 82 | 1H NMR (300 MHz, DMSO) d 12.25 (s, 1H), 8.41 (dd, J = 9.8, 2.7 Hz, 1H), 8.30-8.05 (m, 2H), 7.50 (s, 1H), 7.23 (td, J = 6.1, 2.9 Hz, 5H), 6.17 (d, J = 8.3 Hz, 1H), 5.80 (d, J = 7.9 Hz, 1H), 4.73 (s, 1H), 4.11 (d, J = 5.3 Hz, |
-50416260
| 1H), 3.50 (s, 1H), 2.21-1.66 (m, 4H), 1.28 (dd, J = 14.7, 9.7 Hz, 7H). | |||||
| 1128 | A | A | 458 .41 | 2. 87 | 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J = 9.9, 2.9 Hz, 1H), 8.23 (ddd, J = 29.2, 15.1,2.7 Hz, 3H), 7.53 (d, J = 7.4 Hz, 1H), 5.97 (d, J = 7.8 Hz, 1H), 4.11 (d, J = 5.2 Hz, 1H), 3.62 (d, J =7.8 Hz, 1H), 3.15 (dd, J = 9.6, 6.3 Hz, 2H), 2.74 (s, 2H), 2.05 (dd, J = 27.0, 11.4 Hz, 2H), 1.81 (d, J = 11.2 Hz, 2H), 1.55- 1.06 (m, 7H), 0.86 (t, J = 7.2 Hz, 3H). |
| 1129 | A | A | 444 .41 | 2. 59 | 1H NMR (300 MHz, DMSO) d 12.26 (d, J = 2.1 Hz, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1H), 8.23 (ddd, J = 30.0, 15.0, 2.7 Hz, 3H), 7,53 (d, J =7.5 Hz, 1H), 5.98 (d, J = 7.9 Hz, 1H),4.353.94 (m, 1H), 3.63 (d, J = 8.8 Hz, 1H), 3.22- 3.02 (m, 2H), 2.75 (s, 2H), 2.05 (dd, J = 26.7, 11.8 Hz, 2H), 1.81 (d, J = 10.5 Hz, 2H), 1.37 (ddd, J = 41.6, 24.7, 8.1 Hz, 6H), 0.79 (t, J = 7.4 Hz, 3H). |
| 1130 | A | A | 444 .1 | 2. 6 | |
| 1131 | A | A | 430 .07 | 2. 47 | 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.23 (ddd, J = 29.8, 15.3, 2.7 Hz, 2H), 7.53 (d, J = 7.5 Hz, 1H), 6.00 (d, J = 7.9 Hz, 1H), 4.11 (d, J = 5.2 Hz, 1H), |
-50516260
| 3.62 (d, J = 9.3 Hz, 1 H), 3.25- l 3.06 (m, 2H), 2.74 (s, 2H), 2.05 (dd, J = 28.7, 11.2 Hz, 2H>, 1.81 (d, J = 10.5 Hz, 1H), 1.55-1.09 (m, 4H), 0.96 (t, J = 7.0 Hz, 2H). | |||||
| 1132 | A | A | 486 .1 | 2. 46 | 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1H), 8.20 (dd, J = 32.6, 8.6 Hz, 2H), 7.53 (d, J = 7.7 Hz, 1H), 5.90 (d, J = 7.9 Hz, 1H), 4.28 - 3.92 (m, 2H), 3.62 (d, J = 7.1 Hz, 1H), 3.45-3.08 (m, 9H), 2.21 - 1.68 (m, 5H), 1.53-0.89 (m, 6H). |
| 1133 | A | A | 488 .19 | 1. 88 | 1HNMR (300 MHz, MeOD) d 8.36 (dd, J = 9.4, 2.6 Hz, 1H), 8.28 (m, 2H), 5.13 (s, 2H),4.35 (m, 1 H), 3.79 (s, 1H), 3.67- 3.56 (m, 4H), 3.39-3.32 (m, 4H), 2.33 (m, 1H), 2.16 (m, 1H), 1.98 (m, 2H), 1.69-1.20 (m, 4H). |
| 1134 | A | A | 442 | 2. 3 | NMR 1H (MeOH-d4); 8.5 (s, 1H), 8.3 (m, 3H), 4.4 (m, 1H), 3.6 (m, 4H), 2.6 (m, 1H), 1.5-2.3 (m, 12H). |
| 1135 | A | A | 484 .42 | 2. 32 | 1HNMR (300 MHz, DMSO) d 12.23 (s, 1H), 8.42 (dd, J = 9.8, 2.7 Hz, 1H), 8.33-8.06 (m, 3H), 7.49 (d, J = 7.7 Hz, 1H), 6.15 (d, J = 7.7 Hz, 1H), 4.24 (s, 3H), 3.55 (d, J = 12.5 Hz, 3H), 2.83 (d, J = 12.5 Hz, 2H), 1.99 (s, 2H), 1.72 (ddd, J = 33.2, 19.4, 9.2 Hz, 5H), 1.46- 1.02 (m, 4H). |
| 1136 | A | A | 417 .48 | 1. 99 |
-50616260
| 1137 | A | A | 459 .52 | 2 | |
| 1138 | A | A | 345 .16 | 0. 55 | 1HNMR (300 MHz, DMSO) d 12.40 (s, 1H), 8.56-8.13 (m, 2H), 7.89 (s, 2H), 4.37 (s, 6H), 3.21 (d, J = 22.3 Hz, 1H), 2.27 (s, 1H), 2.01 (s, 1H), 1.63-1.14 (m, 2H). |
| 1139 | A | A | 472 .32 | 2. 06 | 1H NMR (300 MHz, MeOD) d 8.55 (dd, J = 9.8, 2.7 Hz, 1H), 8.08 (m, 2H), 5.12 (m, 2H), 4.19 (m, 1H), 3.80 (m, 1H), 2.33 (m, 1H), 2.17 (m, 1H), 2.06- 1.77 (m, 8H), 1.69-1.21 (m, 4H). |
| 1140 | A | A | 443 .53 | 2. 29 | 1HNMR (300 MHz, CDCI3) δ 9.91 (s, 1H), 8.51 (dd, J = 9.4, 2.8 Hz, 1H), 8.26 (dd, J= 2.6, I. 7 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.07 (d, J= 3.5 Hz, 1H), 5.42 (d, J= 6.2 Hz, 1H), 5.10- 4.92 (m, J = 7.8, 3.9 Hz, 1H), 4.48-4.30 (m, 1H), 3.42 (q, J = II. 8, 6.1 Hz, 4H), 2.44 (dt, J = 12.9 Hz, 1H), 2.11 - 1.81 (m, 7H), 1.75-1.46 (m, 3H) |
| 1141 | A | A | 467 .52 | 1. 78 | |
| 1142 | A | A | 403 .15 | 1. 7 | H NMR (300.0 MHz, MeOD) d 8.67 (d, J = 2.3 Hz, 1 H), 8.61 (s, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 5.5 Hz, 1 H), 4.50- 4.43 (m, 1H), 3.70-3.63 (m, 1H), 3.31 (qn, J = 1.6 Hz, H), 2.47-2.39 (m, 1H), 2.30 (d, J = 12.1 Hz, 1H), 2.15-2.08 (m, 2H), 1.70 (q, J= 11.9 Hz, 2H), 1.50-1.14 (m, 2H) and -0.00 |
-50716260
| (TMS) ppm | |||||
| 1143 | A | A | 387 .06 | 1. 45 | |
| 1144 | A | A | 456 .07 | 1. 78 | 1HNMR (300 MHz, MeOD) d 8.83 (s, 1H), 8.67-8.09 (m, 4H), 2.67 (s, 3H), 2.18 (dd, J = 101.0,49.9 Hz, 5H), 1.34 (d, J = 29.6 Hz, 3H). |
| 1145 | A | A | 1H NMR (300 MHz, DMSO) d 12.24 (d, J = 2.3 Hz, 1H), 8.43 (dd, J = 9.8, 2.9 Hz, 1H), 8.26 (dd, J = 2.7, 1.5 Hz, 1H), 8.16 (d, J = 3.8 Hz, 1H), 7.78 (s, 1H), 7.50 (d, J = 7.3 Hz, 1H), 4.58 4.18 (m, 1H), 3.42 -3.32 (m, 1H), 2.11 (d, J = 13.1 Hz, 2H), 1.98- 1.69 (m, 4H), 1.68-1.14 (m, 4H), 0.92 (t, J = 7.4 Hz, 3H). | ||
| 1146 | A | A | 1HNMR (300 MHz, DMSO) d 12.25 (d, J = 2.1 Hz, 1H), 8.43 (dd, J = 9.8, 2.9 Hz, 1H), 8.26 (dd, J = 2.8, 1.5 Hz, 1H), 8.21 8.10 (m, 2H), 7.80 (s, 1H), 7.48 (d, J = 7.4 Hz, 1 H), 4.59-4.22 (m, 1H), 3,33 - 3.20 (m, 4H), 2.31 -1.96 (m, 2H), 1.94-1.16 (m, 7H), 0,92 (t, J = 7.4 Hz, 3H). | ||
| 1147 | A | A | 1H NMR (300 MHz, DMSO) d 12.24 (s, 1H), 8.39 (dd, J = 9.8, 2.8 Hz, 1H), 8.32-8.26 (m, 1H), 8.20 (dd, J = 9.7, 3.2 Hz, 1H), 7.89 (s, 1H), 7.24 (t, J = 22.3 Hz, 1 H), 4.37 (s, 1H), 3.47 (d, J = 7.8 Hz, 1H), 2.18 (d, J = 10.5 |
-50816260
| Hz, 1H), 2.03- 1.14 (m,9H), 0.96 (t, J = 7.3 Hz, 3H). · | |||||
| 1148 | A | A | 1H NMR (300 MHz, DMSO) d 12.30 (s, 1H), 8.39 (dd, J = 9.8, 2.9 Hz, 1H), 8.28 (dd, J = 2.7, 1.5 Hz, 1H), 8.18 (dd, J =4.9, 3.0 Hz, 1H), 7.92 (s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 4.32 (s, 1H), 3.40 (d, J = 8.5 Hz, 1H), 2.14 (d, J = 12.7 Hz, 1H), 1.97-1,17 (m, 9H), 1.10-0.80 (m, 3H). | ||
| 1149 | A | A | 445 .51 | 2. 37 | |
| 1150 | A | A | 457 .47 | 2. 47 | |
| 1151 | A | A | 461 .51 | 2. 15 | |
| 1152 | A | A | 493 .5 | 2. 39 | |
| 1153 | A | A | 443 .21 | 1. 99 | |
| 1154 | A | A | 1H NMR (300 MHz, MeOD) d 8.63- 8.40 (m, 1H), 8.31 -8.03 (m, 2H), 7.99 (dd, J = 3.9, 1.1 Hz, 1H), 4.49 (t, J = 11.5 Hz, 1 H), 3.44- 3.25 (m,3H), 3.223.08 (m, 1H), 2.29 (dd, J =40.0, 12.5 Hz, 2H), 2.13-1.16 (m, 8H), 1.00 (q, J = 7.0 Hz, 3H). | ||
| 1155 | A | A | 457 .28 | 2. 16 | |
| 1156 | A | A | 457 .28 | 2. 13 | |
| 1157 | A | A | 443 .21 | 2. 11 |
-50916260
| 1158 | A | A | 443 .41 | 2. 09 | 1H NMR (300 MHz, MeOD) d 8.63- 8.40 (m, 1H), 8.23-8.12 (m, 2H), 8.04 (t, J = 4.4 Hz, 1H), 4.56 (dd, J = 7.7, 3.8 Hz, 1H), 3.64- 3.47 (m, 1H), 2.28 (dd, J = 13.6,4.0 Hz, 1H), 2.19-1.46 (m, 9H), 1.01 -0.73 (m, 3H). |
| 1159 | A | A | 457 .22 | 2. 25 | |
| 1160 | A | A | 457 .22 | 2. 21 | |
| 1161 | A | A | 360 .47 | 1. 68 | |
| 1162 | A | A | 430 .14 | 2. 5 | 1H NMR (300 MHz, DMSO) d 12.32 (s, 1H), 8.78 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 4.8, 3.4 Hz, 2H), 7.60 (d, J = 6.9 Hz, 1H), 4.74 (t, J = 6.4 Hz, 1H), 3.64 (d, J = 17.5 Hz, 3H), 2.95 (d, J = 6.9 Hz, 1H), 2.03- 1.30 (m, 11 H). |
| 1163 | C | C | 470 .46 | 1. 58 | |
| 1164 | A | A | 470 .46 | 1. 65 | |
| 1165 | A | A | 441 .64 | 2. 75 | 1H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.70-8.02 (m, 3H), 7.63 (dd, J = 63.2, 7.4 Hz, 2H), 4.13 (s, 1H), 3.70 (s, 1H), 2.23-0.92 (m, 18H). |
| 1166 | A | A | 455 .65 | 2. 96 | 1H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.62-7.97 (m, 3H), 7.59 (dd, J = 41.7, 7.6 Hz, 2H), 4.13 (s, 1H), 3.71 (s, 1H), 2.21 -0.92 (m, 20H). |
| 1167 | C | C | 543 .6 | 2. 55 |
-5 ΙΟ16260
| 1168 | A | C | 444 .49 | 1. 78 | |
| 1169 | A | A | 486 .52 | 1. 74 | |
| 1170 | A | A | 531 .57 | 2. 02 | |
| 1171 | C | A | 577 .51 | 2. 57 | |
| 1172 | A | A | 501 .5 | 2. 16 | |
| 1173 | A | A | 442 .29 | 2. 94 | 1HNMR (300 MHz, DMSO) d 12.33 (d, J =2.4 Hz, 1H), 8.78 (dd, J = 19.9, 2.5 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.13 (d, J =4.1 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 4.47-4.21 (m, 2H), 2.12 (s, 2H), 1.76- 1.33 (m, J = 25.6, 14.7 Hz, 11H), 1.19 (d, J = 9.9 Hz, 3H), 1.08 (d, J = 7.0 Hz, 1H). |
| 1174 | C | C | 583 .52 | 1. 77 | 1H NMR (300 MHz, MeOD) d 8.49 (d, J = 6.1 Hz, 1H),8.42 (d, J = 2.6 Hz, OH), 8.39 (s, 1H), 8.35 (s, 1H), 8.29 (d, J = 5.6 Hz, 1H), 8.19 (d, J = 4.1 Hz, OH), 4.74-4.58 (m, 1 H), 4.38 (dt, J = 42.8, 21.3 Hz, 2H), 3.84 (dd, J = 16.3, 6.7 Hz, 1H), 3.70-3.58 (m, 1H), 3.48 (s, 1H), 3.31 (dt, J = 3.2, 1.6 Hz, 6H), 3.02 (s, 1H), 2.61 (t, J = 11.7 Hz, 1 H), 2.21 (d, J = 6.0 Hz, 3H), 2.11 -1.86 (m, 5H), 1.86 - 1.27 (m, 7H), 0.92 (d, J = 6.1 Hz, 6H). |
-51116260
| 1175 | A | A | 456 .35 | 2. 98 | 1H NMR (300 MHz, DMSO) d 12.33 (s, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 4.1 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 4.33 (s, 1H), 4.23- 3.97 (m, J = 25.1, 15.2 Hz, 1H), 2.05 (bd s, J = 34.2 Hz, 2H), 1.91 - 1.31 (m, 14H), 0.83 (t, J = 7.0 Hz, 3H). |
| 1176 | A | A | 401 .17 | 1. 72 | |
| 1177 | A | A | 417 .16 | 1. 95 | 1H NMR (300 MHz, d6-DMSO) δ 12.39(s, 1H), 8.74 (d, 7 = 2.4 Hz, 1H), 8.55 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.27 (d, 7=2.4 Hz, 1H), 8.18 (d, 7 = 4.0 Hz, 1H), 7.44 (d, 7 = 7.2 Hz, 1H), 4.51 -4.31 (m, 1H), 4.13-3.93 (m, 3H), 3.17 (d, J = 5.3 Hz, 1H), 2.11 - 1.89 (m, 1H), 1.881.49 (m, 2H), 1.48 - 1.13 (m, 2H) |
| 1178 | A | A | 430 .22 | 2. 5 | 1H NMR (300 MHz, DMSO) d 12.32 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 4.9, 3.2 Hz, 2H), 7.60 (d, J = 6.9 Hz, 1H), 4.73 (t, J = 6.3 Hz, 1 H), 4.07 (q, J = 5.3 Hz, 2H), 3.61 (s, 3H), 3.17 (d, J = 5.3 Hz, 4H), 2.95 (d, J =6.7 Hz, 1H), 2.02- 1.35 (m, 10H). |
| 1179 | A | A | 1H NMR (300 MHz, DMSO) d 12.32 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.24-8.11 (m, 2H), 7.60 (d, J = 6.9 Hz, 1H), 4.74 (t, J = |
-51216260
| 6.8 Hz, 1H), 4.07 (q, J = 5.3 Hz, 2H), 3.63 (s, 3H), 2.95 (d, J = 6.6 Hz, 1H), 2.06- 1.33 (m, 10H). | |||||
| 1180 | A | A | 467 .46 | 1. 8 | |
| 1181 | A | A | 459 .09 | 2, 26 | 1H NMR (300 MHz, CDCI3) d 8.24 (s, 1H), 8.02 (d, J = 3.6 Hz, 1H), 4.36 (d, J =6.8 Hz, 1H), 3.91 (s, 2H), 3.74- 3.64 (m, 3H), 3.49 - 3.30 (m, 3H), 2.68 (s, 1H), 2.23 (s, 1H), 2.09 (s, 1H), 1.91 (s, 1H), 1.58 (d, J = 13.4 Hz, 2H), 1.22 (dd, J = 21.2, 9.9 Hz, 3H). |
| 1182 | A | A | 486 .65 | 2. 05 | 1HNMR (300 MHz, DMSO) d 8.30-8.05 (m, 1H), 7.60 (dd, J = 7.3, 2.4 Hz, 1H), 7.31 (dd, J = 5.0, 2.1 Hz, 1H), 4.09 (m, 1H), 3.57 (m, 1H), 3.17 (m, 4H), 1.99 (m, 2H), 1.77 (m, Hz, 4H), 1.56 -1.10 (m, 3H). |
| 1183 | A | A | 416 .31 | 3. 04 | 1H NMR (300 MHz, MeOD) d 8.94 (d, J = 2.3 Hz, 1H), 8.21 (d, J =2.2 Hz, 1H), 8.16 (s, 1H), 8.00 (d, J = 4.1 Hz, 1H),4.92 (d, J = 6.8 Hz, 1H), 2.76 (d, J = 6.8 Hz, 1H), 2.07 (d, J = 23.8 Hz, 2H), 1.89- 1.46 (m, 7H). |
| 1184 | A | A | 416 .13 | 2. 26 | 1HNMR (300 MHz, MeOD) d 8.92 (d, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 8.02 (d, J = 4.2 Hz, 1H), 4.94 (d, J = 6.9 Hz, 1H), 2.78 (d, J = 6.7 Hz, 1H), 2.13-2.02 (m, 3H), 1.93-1.45 (m, 7H). |
| 1185 | A | A | 360 | 1. |
-5I316260
| .15 | 71 | ||||
| 1186 | A | A | 570 .68 | 1. 56 | |
| 1187 | A | A | 444 .01 | 2. 61 | 1H NMR (300 MHz, DMSO) d 12.74 (s, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.58 (s, 1H), 8.438.34 (m, 2H), 4.94 -4.84 (m, 1H), 4.08 (ddd, J = 7.1, 2.3 Hz, 2H), 3.01 (d, J = 6.8 Hz, 1H), 2.05- 1.99 (m, 1H), 1.98-1.84 (m, 2H), 1.65 (complex m, J = 79.2 Hz, 8H), 1.13 (t, J = 7.1 Hz, 3H). |
| 1188 | A | A | 396 .24 | 1. 97 | 1H NMR (300 MHz, MeOD) d 8.49 (ddd, J = 27.3, 9.7, 2.9 Hz, 1H), 8.25- 8.08 (m, 2H), 8.01 (dd, J = 9.2, 4.1 Hz, 1H), 7.73 (dd, J = 23.6, 2.3 Hz, 1H), 7.56- 7.43 (m, 1H), 6.28 (dt, J = 7.3, 2.4 Hz, 1H), 4.73-4.27 (m, 2H), 2.60- 1.58 (m, 9H). |
| 1189 | C | A | 461 | 4. 64 | (400 MHz, DMSO-d6) : 12.01 (b s, exchanged with D2O; 1 H), 8.73 (d, J=2 Hz; 1H), 8.23 (d, J=2Hz; 1H), 8.10 (dd, J=13.6, 4.4Hz; 2H), 7.29 (bs, exchanged with D2O; 1 H), 3.87- 3.86 (m, 1H), 3.58-3.52 (m, 2H), 3.35-3.19 (m, 2H), 2.07-1.95 (m, 2H), 1.88-1.70 |
| 1190 | 474 .2 | 2. 03 | |||
| 1191 | 476 .15 | 2. 34 | |||
| 1192 | 432 .11 | 2. 27 |
51416260
| 1193 | A | A | 500 .22 | 2. 04 | 1H NMR (300 MHz, MeOD) d 8.45 (dd, J = 9.6, 2.7 Hz, 1H), 8.36-8.18 (m, 2H), 5.17 (t, J = 7.1 Hz, 1H), 4.42 (m, 1 H), 3.77 (m, 1H), 3.29 (m,4H), 2.342.19 (m, 2H), 2.08- 1.84 (m, 4H), 1.74- 1.28 (m, 4H), 0.98 (t, J = 7.4 Hz, 3H). |
| 1194 | B | A | 500 .28 | 2. 23 | |
| 1195 | 563 .24 | 2. 47 | in DMSO-d6 and D20 exchange | ||
| 1196 | A | A | 388 .43 | 1. 84 | |
| 1197 | A | A | 415 .18 | 1. 96 | 1HNMR (300 MHz, MeOD) d 8.91 (d, J = 2.3 Hz, 1H), 8.44 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 5.30 (d, J = 6.9 Hz, 1H), 2.86 (d, J = 6.8 Hz, 1H), 2.12-2.03 (m, 2H), 1,98- 1.64 (m, 6H), 1.63-1.52 (m, 2H). |
| 1198 | 486 .27 | 1. 99 | |||
| 1199 | 486 .43 | 2. 14 | |||
| 1200 | 485 .1 | 2. 34 | |||
| 1201 | 458 .98 | 2. 18 | |||
| 1202 | 406 .43 | 1. 79 | 1H NMR (300 MHz, DMSO) d 12.08 (s, 1H), 8.73 (ddd, J = 7.9, 4.4, 1.5 Hz, 1H), 8.41 -7.98 (m, 3H), 7.47 (dd, J = 41.7, 7.0 Hz, 1H), 7.19 (ddd, J = 14.2, 7.9, 4.7 Hz, 1H), 5.82 -5.63 (m, 2H), 4.71 (d, J = 73.1 Hz, 1H), 4.31 (d, J= 11.2 Hz, 1H), 2.36- |
-51516260
| 1.55 (m, 13H). | | |||||
| 1203 | 490 .23 | 1. 99 | 1HNMR (300 MHz, CDCI3) d 11.09 (s, 1H), 8.11 (s, 1H), 8.05 (m, 1H), 7.86 (d, J = 3.5 Hz, 1H), 5.32-4.78 (m, 4H), 4.14 (d, J = 8.0 Hz, 1H), 3.84 (s, 1H), 3.74-3.18 (m, 6H), 2.67 (d, J = 11.7 Hz, 1H), 2.33- 1.75 (m, 7H), 1.48- 1.27 (m, 2H), 1.26 0.95 (m, 4H). | ||
| 1204 | 457 .06 | 2. 04 | |||
| 1205 | 417 .16 | 1. 77 | |||
| 1206 | 429 .58 | 1. 94 | |||
| 1207 | 431 .5 | 1. 94 | |||
| 1208 | 429 .5 | 1. 85 | |||
| 1209 | 456 .42 | 1. 88 | |||
| 1210 | 472 .47 | 1. 75 | |||
| 1211 | 486 .42 | 1. 88 | |||
| 1212 | 396 .44 | 1. 94 | 1H NMR (300 MHz, DMSO) d 12.28 (s, 1H), 8.59-8.07 (m, 4H), 7.90-7.36 (m, 3H), 6.25 (dt, J = 16.0, 2.0 Hz, 1H), 4.79- 4.15 (m, 2H), 2.36 (d, J = 8.8 Hz, 1H), 2.19-1.55 (m, 6H), 1.50-1.10 (m, 1H). |
-51616260
| 1213 | 480 .65 | 2. 16 | |||
| 1214 | 411 .49 | 1. 74 | |||
| 1215 | 460 .23 | 1. 91 | |||
| 1216 | 444 .23 | 2. 15 | |||
| 1217 | 430 .39 | 2. 26 | 1HNMR (300 MHz, DMSO) d 12.38 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.55 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 3.8 Hz, 1H), 8.22 - 8.16 (m, J =4.8 Hz, 2H), 7.47 (d, J = 31.1 Hz, 2H), 5.23 (t, J = 8.1 Hz, 1H), 4.11 (q, J = 5.1 Hz, 1H), 3.17 (d, J = 5.2 Hz, 2H), 1.09 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H). | ||
| 1218 | 406 .18 | 1. 8 | |||
| 1219 | 406 .44 | 1. 79 | 1H NMR (300 MHz, DMSO) d 12.08 (s, 1H), 8.86- 8.63 (m, 1H), 8.39-7.90 (m, 3H), 7.53 (d, J = 7.5 Hz, 1H), 7.21 (dd, J = 7.9, 4.7 Hz, 1H), 5.74 (s, 1H), 4.27 (d, J = 10.5 Hz, 2H), 2.89 (s, 1H), 2.79-2.66 (m, 1 H), 2.15 (d, J =48.2 Hz, 6H), 1.931.17 (m, 4H) | ||
| 1220 | 424 .44 | 2. 1 | 1H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.45 (dd, J = 9.8, 2.8 Hz, 1H), 8.30-8.08 (m, 3H), 7.45 (d, J = 6.9 Hz, 1 H), 4.86 (s, 1H), 4.59 (s, 1H), 2.35-1.94 (m, 7H), 1.81 (d, J = 5.5 Hz, 5H). | ||
| 1221 | 424 | 2. |
-5I716260
| .45 | 02 | ||||
| 1222 | 440 .46 | 2. 22 | |||
| 1223 | 440 .5 | 2. 34 | 1H NMR (300 MHz, DMSO) d 12.35 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.40-8.01 (m, 3H), 7.48 (d, J = 6.7 Hz, 1H),4.84(s, 1H), 4.59 (S, 1H), 2.35-1.56 (m, 13H). | ||
| 1224 | 461 .19 | 2. 46 | 1H NMR (300 MHz, DMSO) d 12.56 (s, 1H), 8.72 (t, J = 8.2 Hz, 1H), 8.54 (t, J = 5.7 Hz, 1H), 8.40 (t, J = 7.9 Hz, 1H), 8.33 (t, J = 3.4 Hz, 2H), 7.79 (d, J = 7.3 Hz, 1H), 4.66 (t, J = 8.0 Hz, 1H), 3.81 (qd, J = 17.5, 5.8 Hz, 2H), 1.78 (td, J = 28.9, 16.0 Hz, 6H), 1.18 (s, 5H). | ||
| 1225 | 517 .24 | 2. 99 | 1HNMR (300 MHz, DMSO) d 12.44 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 2.8 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 4.0 Hz, 1 H), 8.20 (s, 1H), 7.55 (s, 1 H), 4.72 (t, J = 8.4 Hz, 1H), 4.17 (d, J = 9.2 Hz, 1H), 1.90 (s, 2H), 1.68 (d, J = 21.4 Hz, 4H), 1.32-0.95 (m, 5H), 0.84 (s, 9H). | ||
| 1226 | 388 .5 | 1. 8 | |||
| 1227 | 510 .23 | 2. 12 | |||
| 1228 | 411 .67 | 1. 79 | MeOD4; 8.5 (dd, 1H); 8.26 (s, 1H); 8.25 (dd, 1H); 7.95 (d, 1H); 4.6 (app d, 1H), 4.25 (m, 1H); 4.25 (m, 1H); 3.3 (m, 4H); 2.75 (m, 2H); 2.5 (app d, 1H); 2.2 (m, 4H); 1.7 (m, 2H). |
IB16260
| 1229 | 416 .42 | 2. 29 | H NMR (300.0 MHz, MeOD) d 8.72-8.64 (m, 1H), 8.39 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 5.2 Hz, 1 H), 4.71 (d, J =6.3 Hz, 1 H), 3.67- 3.57 (m, 2H), 2.33-2.26 (m, 1H), 2.10 (m, 1H), 1.78- 1.70 (m, 1H), 1.28- 1.25 (m, 7H) and 1.19 (s, 3H) ppm | ||
| 1230 | A | A | 443 .04 | 2. 48 | 1HNMR (300 MHz, CDCI3) d 8.15 (d, J = 1.2 Hz, 1H), 8.08 (d, J =6.3 Hz, 1H), 7.88 (d, J = 3.3 Hz, 1H), 3.80 (d, J = 11.2 Hz, 1H), 3.68 (s, 1H), 3.26 (d, J = 6.4 Hz, 4H), 2.56 (d, J = 11.8 Hz, 1H), 2.14 (d, J = 12.8 Hz, 1H), 1.99 (d, J = 10.3 Hz, 1H), 1.9 |
| 1231 | A | A | 422 .5 | 1. 68 | NMR 1H (MeOH-d4):8.5 (dd, 1H), 8.15 (m, 2H), 8Ό (d, 1H), 4.2 (m, 1H), 3.75 (m, 1H), 2.3 (d, 1H), 2.2 (d, 1H), 1.9 (m, 2H), 1.2-1.6 (m, 4H). |
| 1232 | A | A | 450 .5 | 1. 8 | NMR 1H (MeOH-d4): 8.2 (m, 4H), 4.5 (m, 1H), 3.9 (m, 1H), 2.2 (m, 4H), 1.3-1.6 (m, 4H). |
Table 4:1C50, EC50, NMR and LCMS Data of Compounds of FIG. 7
| Cell | |||||
| Cell Flu, | Influen | ||||
| MDCK | za | ||||
| C | protecti | HA(-) | |||
| 0 | on, ATP | 30 hr | NMR | ||
| m | (Ail: | A/PR/8 | LC | LC | |
| P- | IC50: | bDNA | MS | MS | |
| N | uM)(Mea | (Ail: | _PI | _R | |
| os | n (Ail)) | EC50: | us | T |
-519-
| uM)(M ean (AH)) | |||||
| 13 00 | D | 33 4 | 1,8 | ||
| 13 01 | (400 MHz, CDCI3): 9.97 {br. s, exchanged with D20,1H), 8.95 (d, J=2.0 Hz, 1H), 8.28 (s, 1H), 8,18 (s, 1H), 8.15 (d, J=6.0 Hz, 1H), 6.21 (d, J=4.8 Hz, 1H), 6.16 (br. s, exchanged with D2O, 1H), 3.45-3.35 (br. hump, 1H), 2.95-2.85 (br. hump, 1H), 2.62.4 (br. hump, 3H), 1.98-1.7 (m, 4H), 1.59 (s, 3H), 1.57 (s, 3H), 1.16 (d, J=5.6 Hz, 3H) | ||||
| 13 02 | B | (400 MHz, CDCI3) : 9.95 (br. hump, exchanged with D2O, 1H), 8.95 (s, 1H), 8.28 (d, J=1.6 Hz, 1H), 8.18 (s, 1H), 8.14 (d, J=6.0 Hz, 1H), 6.19 (d, J=6.0 Hz, 1H), 5.72 (s, exchanged with D2O, 1 H), 3.6-3.4 (m, 4H), 2.90-2.80 (m, 2H), 2.1-2.05 (m,2H), 1.52 (s, 6H) | |||
| 13 03 | D | 36 0 | 2.6 | 500MHz, CDCI3: 10.8(br ex,1H), 9.12(d,1H), 8.75(s,1H), 8.45(d,1H), 8.35(d,1H), 7.5(dd,1H), 7.31(d,1H), 7.29(d,1H), 7.24(m,2H), 6.3(d,1H) 5.62(dt,1H), 2.9(m,2H), 2.23(dm,2H), 2.0(m,2H) | |
| 13 04 | 36 0 | 2.6 | 500MHz, CDCI3: 10.8(br ex,1H), 9.12(d,1H), 8.75(s,1H), 8.45(d,1H), |
-52016260
| 8.35(d,1H), 7.5(dd,1H), 7.31(d,1H), 7.29(d,1H), 7.24(m,2H), 6.3(d,1H) 5.62(dt,1H), 2.9(m,2H), 2.23(dm,2H), 2.0(m,2H) | |||||
| 13 05 | 34 2 | 2.3 | |||
| 13 06 | 34 2 | 2.3 | 500MHz MeOD-d4: 8.65(d,1H), 8.42(s.1H), 7.9(d,1H), 7.24(dd,2H), 7.13(m,4H), 6.5(d,1H), 5.65(m,1H), 2.8(m,3H), 2.2(m,1H), 2.08(m,1H)1.9(m,3H) | ||
| 13 07 | A | A | 38 0.2 | 3.5 2 | DMSO d6 12.2 (s, 1H); 8.7 (s, 1H); 8.3 (s, 1H); 8.15 (m, 2H); 7.0 (d, 1H); 5.4 (d, 1 H); 4.8 (d, 1H);4.4 (bs, 1H); 4.1 (bs, 1H); 1.9-1.6 (m, 6H) |
| 13 08 | 37 0 | 2.1 | 500MHz : MeOD-d4: 8.9(d,1H), 8.4(s,2H), 8.3(d,1H), 7.4(m,1H), 2.1 (m,1H), 1.9(m,2H), 1.8(m,2H), 1.75(m,2H), 1.3(m,6H) | ||
| 13 09 | 32 6 | 2.1 | |||
| 13 10 | 32 7 | 0.4 | 500MHz, MeOD-d4: 8.75(dd,1H), 8.42(s,1H), 8.39(dd,1H), 8.25(d,1H),7.69(d,2H), 7.35(dd,1H), 7.2(d,2H), 4.36(m,1H), 3.40(t,1H), 3.2(m,1H),2.3(m,5H), 2.00(qin,1H), 1.7(m,4H) | ||
| 13 11 | 32 8.3 | 2 | |||
| 13 12 | A | A | 32 8.3 | 2 |
-52116260
| 13 13 | D | 33 0.1 | 2.2 5 | (300 MHz, CDC13) 10.68 (br s, 1H), 8.56 (dd, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 4.95 (d, 1H), 4.14 (m, 1 H), 2.20 (m, 2 H), 1.89-1.31 (m, 7 H) | |
| 13 14 | D | 36 2 | 2.3 | ||
| 13 15 | B | 36 0.2 | 3.0 5 | (CDCI3, 300 MHz) 8.76 (d, 1H), 8.28 (d, 1H), 7.99 (d, 1H), 7.98 (s, 1H), 4,92 (d, 1H), 4.11 (m, 1H), 3.89 (s, 3H), 2.21 (m, 2H), 1.89-1.23 (m, 8H) | |
| 13 16 | D | (400 MHz, CDCI3) : 9.16 ( s, exchanged with D2O, 1H), 9.07 (d , J = 2.0Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.17 (d, J=2.4 Hz, addition of D2O changhed to s, 1H), 8.07 (d, J=3.6 Hz, 1H), 5.28 ( s, excha nged with D2O, 1H), 2.98-2.95 (m, 1H), 1.05-1.00 (q, 2H), 0.75-0.71 (m, 2H). | |||
| 13 17 | B | (400 MHz, CDCI3) : 8.98 (s, exchanged with D2O, 1H), 8.92 (s, 1H), 8.28 (br. s, 1H), 8.17 ( br. s, 1H), 7.98 (s, 1H), 4.42 (d, J= 6.4 Hz, addition of D2O changed to s, 1 H), 4.20 -4.15 (m, 1H), 2.25 (b r. d, J=11.2 Hz, 2H), 2.03 (s, 3H), 1.88 (br. d, J=12.4 Hz, 2H), 1.78-1.75 (m, J=13.2 Hz, 1H), 1.61-1.50 (m, 2H), 1.33-1.27 (m, 3H). |
-52216260
| 13 18 | A | A | 31 2.1 | 1.9 6 | H NMR (300 MHz, CDCI3) 10.72 (s, 1 H), 8.85 (dd, J = 1.3, 7.9 Hz, 1 H), 8.38 (d, J = 3.9 Hz, 1 H), 8.25 (s, 1 H), 8.05 (d, J = 3.5 Hz, 1 H), 7.23 (dd, J = 4.8, 8.0 Hz, 1 H), 4.97 (d, J = 6.5 Hz, 1 H), 4.23-4.13 (m, 1 H), ,2.222.18 (m, 2 H), 1.91-1.26 (m, 8 H) |
| 13 19 | B | 32 7.1 | 1.5 | H NMR (300 MHz, d4 méthanol) 8.24 (d, 1 H), 7.99 (s, 1H),I 7.92 (d, 1H), 7.88 (d, 1H), 4t15(m, 1H), 2.15 (m, 2 H), 1.91-1.26 (m, 8 H) | |
| 13 20 | D | 36 0.2 | 2.3 | ||
| 13 21 | D | 36 0.2 | 2.3 | ||
| 13 22 | D | 37 4.2 | 2.4 | ||
| 13 23 | D | 36 2.2 | 1.5 | ||
| 13 24 | D | 32 8.2 | 2.0 7 | H NMR (300 MHz, CDCI3) 10.84 (s, 1 H), 8.91 (d, J = 2.2 Hz, 1 H ), 8.29- 8.14 (m, 3 H), 6.13 (d, J = 5.9 Hz, 1 H), 4.96 (s, 1 H), 3.86 (s, 1 H), 2.15-1.48 (m, 10 H) | |
| 13 25 | D | (400 MHz, DMSO-d6) : 12.35 (br. s, exchanged with D2O, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, additon of D2O changed to s, 1 H), 8.20 (d, J=2.4 Hz, 1H), 8.16 (d, J=3.6 Hz, 1H), 7.84 (br. d, J=6.4 Hz, exchanged with D2O, 1 H), 4.64 (sextet, J=8.0 |
-52316260
| Hz, addition of D20 changed to quintet, J=8.0 Hz, 1H), 2.49-2.19 (m, 2H), 2.17-2.10 (m, 2H), 1.80-1,72 (m, 2H). | |||||
| 13 26 | B | (400 MHz, DMSO - d6) : 12.31 (br. s, exchanged with D2O, 1H), 8.75 (br. d, J=2.4 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 8.13 (d, J=3.6 Hz, 1H), 7.557.50 (m, exchanged with D2O, 1H),4.47-4.40 (m, 1H). 2.06-2.0 (m, 2H), 1.80-1.50 (m, 6H). | |||
| 13 27 | D | (400 MHz, DMSO-d6) : 12.87 (d, J=2.4 Hz, exchanged with D2O, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8,16 (d, J=4,0 Hz, 1H), 8.11(d, J=2.4 Hz, addition of D2O changed to s, 1H), 6.70 (s,1H), 4.90 ( br. s, exchanged with d2O, 1H), 3.79 ( s, 2H), 2.25-2.20 (m, 2H), 1.95-1.85 (m, 2H), 1.801.62 (m,4H). | |||
| 13 28 | A | A | (400 MHz, DMSO-d6) : 12.49 (s, exchanged with D2O, 1H), 10.1 (s, exchanged with D2O, 1H), 8.72 (br. s, 1H), 8.29 (br. s, 1H), 8.23-8.20 (m, 2H), 4.70-4.50 (m, 1H), 3.94 (br. s, 2H), 2.69 (s, 3H), 2.32 (s, 2H), 2.19-2.00 (m,6H). | ||
| 13 29 | D | 36 1,2 | 1.4 |
-52416260
| 13 30 | D | 36 1.2 | 1.4 | ||
| 13 31 | D | (400 MHz, DMSO-d6) : 12.30 (s, exchanged with D2O, 1H), 8.66 (d, J=2.4 Hz, 1H), 8.40 (s, exchanged with D2O, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.24 (d, J=3.6 Hz, 1H), 8.03 (d, J=2.8 Hz, 1H), 3.57 (s, 3H),2.79-2.73 (m, 2H), 2.452.38 (m, 2H), 2.05-1.96 (m, 2H). | |||
| 13 32 | D | (400 MHz, DMSO-d6) : 13.11 (s, exchanged with D20,1H), 9.22 (s, exchanged with D2O, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.32 (s, exchanged with D2O, 2H), 8.07 (s, 1H), 4.20-4.17 (m,1H), 3.15-3.10 (m, 1H), 2.16-2.10 (m, 7H), 1.70-1.59 (m, 4H). | |||
| 13 33 | D | 34 2 | 0.2 5 | (d4-methanol, 300 MHz) 8.88 (d, 1H), 8.63 (s, 1H), 8.48 (d, 1H), 8.36 (d, 1H), 3.89 (dd, 2H), 3.73-3.59 ( m, 2H), 3.02 (dd, 2H), 2.44 (m, 1H), 2.02 ( brdd, 2H), 1.80 (m, 1H), 1.59 (m, 1H) | |
| 13 34 | D | 37 7.1 | 3.8 63 | (400 MHz, DMSO-d6 + D2O) : 8.64 (d, J = 2.4Hz, 1 H), 8.51 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.36 (s, 1H), 4.13-4.10 (m, 1H>, 3.10-3.0 (m, 1H), 2.10 (br. d, J=10 Hz, 4H), 1.66-1.42 (m, 4H). |
-52516260
| 13 35 | D | 40 6.1 | 3.2 17 | (400 MHz, DMSO-d6) : 12.39 (s, exchanged with D2O, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.15 (d, J=2.8 Hz, 1H), 6,60 (s, exchanged with D2O, 1H), 2.25 (d, J=13.2 Hz, 2H),1.95 (br. t, J=11.6 Hz, 2H), 1.59-1.40 (m, 6H). | |
| 13 36 | D | 39 6.1 | 5.1 6 | (400 MHz, DMSO-d6) : 8.66 (d, J=1.6 Hz, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 6.59 (d, J=6.8 Hz, exchanged with D20,1 H), 4.27-4.20 (m, 1H), 1.95 (br. s, 2H), 1.81 (br. s, 2H), 1,68(br. d, J=11.2 Hz, 2H), 1.54-1.42 (m,4H). | |
| 13 37 | A | A | 41 1.2 | 1.1 66 | (400 MHz, DMSO-d6 + D2O) : 8.67 (d, J=2.4 Hz, 1H), 8.50 (s, 1 H), 8.36 (d, J = 2.4Hz, 1H), 8.06 (s, 1H), 4.27-4.20 (br.s, 1H), 3.50-3.40 (m, 1H), 2.10-1.50 (m, 8H). |
| 13 38 | D | 37 6.2 | 2.1 3 | NMR 1H DMSO-d6: 12.6 (s, 1H), 8.9 (s, 1H), 8.4 (m, 3H), 8.0 (m, 1H), 4.8 (bs, 1H), 3.7 (s, 2H), 1.1-1.6 (m, 10H). | |
| 13 39 | D | 38 6.2 5 | 2.8 5 | NMR 1H DMSO-d6: 12.7 (s,1H), 8.7 (m, 1H), 8.4 (m, 4H), 7.6 (m, 2H), 5.5 (bs, 1H), 4.1 (m, 1H), 1.0-2.3 (m, 14H). | |
| 13 40 | A | A | 40 0.3 | 3.2 2 | |
| 13 41 | B | 35 5.4 | 3.1 | ||
| 13 42 | A | A | 42 8.2 | 2.8 4 |
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| 13 43 | D | 37 5,3 | 1.3 9 | (d4-methanol, 300 MHz) 8.83 (d, 1H), 8.44 and 8.29 (2s, 1H), 8.24 (d, 1H), 8.18 (s, 1H), 8.05 (d, 1H), 3.72 (dd, 1H), 3.51 (m, 2 H), 2.84-2.64 (m, 3 H), 2.77 (s, 3 H), 2.44 (m, 1 H), 2.15-1.99 (m, 2 H), 1.79 (m, 1 H), 1.36 (m, 1 H) | |
| 13 44 | A | A | 41 3.3 | 2.9 | |
| 13 45 | A | A | 36 1.2 | 1.5 | |
| 13 46 | D | 36 1.2 | 0.7 | ||
| 13 47 | B | 35 8.1 | 2.1 | ||
| 13 48 | D | 31 3.2 | 2.1 5 | ||
| 13 49 | D | 31 3.2 | 2 | ||
| 13 50 | D | 31 3.2 | 2.0 8 | ||
| 13 51 | B | 32 7.2 | 2.1 5 | ||
| 13 52 | D | 32 7.2 | 2.1 5 | ||
| 13 53 | A | A | 32 7.2 | 2.1 9 | |
| 13 54 | B | B | 34 2.2 | 1.6 | |
| 13 55 | D | 31 3.6 | 1.0 4 | ||
| 13 56 | B | 37 5.1 5 | 1.6 1 | ||
| 13 57 | A | 34 7 | 1.3 |
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| 13 58 | A | A | 36 3.3 | 1.3 | |
| 13 59 | B | 34 7.3 | 1.3 | ||
| 13 60 | D | 36 7.3 | 1.4 | ||
| 13 61 | A | 36 9.5 | 1.5 3 | ||
| 13 62 | C | C | 36 1.3 | 2.1 | |
| 13 63 | A | A | 48 1.3 7 | 3.5 6 | H NMR (300.0 MHz, MeOD) d 8.77 (d, J = 2.3 Hz, 1H), 8.30 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 7.58-7.54 (m, 5H), 4.944.87 (m, 1H), 4.45 (dd, J = 13.1, 30.3 Hz, 2H), 3.783.54 (m, 2H), 3.47 -3.37 (m, 1H), 2.46-2.40 (m, 1H) and 2.09 (m, 1H) ppm |
| 13 64 | A | C | 34 8.1 1 | 3.4 6 | |
| 13 65 | A | A | 36 2.3 3 | 3.2 9 | H NMR (300.0 MHz, MeOD) d 8.71 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 5.5 Hz, 1H), 4.07 (s, 2H), 2.13 (qn, J =1.5 Hz, H), 1.37- 1.33 (m, 2H) and 1.17 -1.11 (m,2H)ppm |
| 13 66 | A | A | 36 2.1 5 | 3.6 | Methano! d4 8.7 (d, 1H); 8.2 (d, 1H); 8.1 (s, 1H); 8.0 (d, 1 H); 7.65 (m, 1H);4.2(m, 2H); 2.0-1.6 (m, 6H) |
| 13 67 | A | A | 1HNMR (400MHz, DMSOd6): 12.30 (s, exchanged with D2O, 1H), 9.17 (d, J=2.4Hz, 1H), 8.26(d, J=2.4Hz, 1H), |
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| 8.22(d, J=4Hz, 1H), 8.17 (s,1 H), 7.32(s, exchanged with D2O, 1H), 3.32 (s,1H), 1 .77-1.61 (m,8H), 1.30-1.28 (m,2H) | |||||
| 13 68 | A | A | 1HNMR (400MHz, DMSOd6): 12.33(s, exchanged withD2O, 1H), 8,74 (d, J=2.4Hz, 1H), 8.29(d, J=2.4Hz, 1H), 8 .17(d, J=4Hz, 1H), 8.10(d, J=2Hz, 1H), 6.74(s,1H, partially exchanged with D2O), 4.60 (s, exchanged with D2O, 1H), 2.25(br s,2H), 2.12(br s, 5H), 1. | ||
| 13 69 | A | A | 1HNMR (400MHz, DMSOd6): 12.33(s, exchanged with D2O, 1H), 8.70 (s, 1H), 8.28 (s, 1H), 8.17(d, J=4.4Hz, 1 H), 6.99(s,1H), 4.3(s,1H), 2.20-1,75(m,13H), 1,55(d, J=12.8Hz,2H) | ||
| 13 70 | A | A | 36 0.4 2 | 3.7 8 | H NMR (300.0 MHz, DMSO) d 12.35 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.23-8.20 (m, 2H), 7.75 (d, J = 7,5 Hz, 1 H), 4.45 (d, J =9,4 Hz, 1H), 2.652.62 (m, 2H), 2.50 (t, J =1.8 Hz, H), 2.36 (dd, J = 12.2, 17.4 Hz, 1H), 2.26-2.20 (m, 3H), 2.07 -2.04 (m, 1H), 1.84 - 1.74 (m, 2H) and -0.00 (s, H) ppm |
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| 13 71 | A | A | (400MHz, DMSO-d6): 12.32(s, 1H), 8,78(brs, 1H), 8.28(br s,1H), 8.17(br s ,1H), 8,13(d, J=3.6Hz,1H), 7.40(d, J=8Hz, exchanged with D2O.1H), 4.85(br s, 1H), 2.31-2.25(m,1H), 1.871.82(m,1H), 1.68(br s,2H),1.47(brs,1H), 1.291.16(m,5H), 0.890.81(m,1H). | ||
| 13 72 | A | A | (400MHz, DMSO-d6): 12.33(s, 1H), 8.77(d, J=2Hz,1H), 8.27(d,J=2.4Hz,1H),8. 18(d, J=2Hz,1H), 8.13(d, J=4Hz,1 H),7.65(d, J=8.4Hz, 1H),4.85-4.77(m,1H), 2.64-2. 60(m,1H),2.36-2.34(m,1H), 2.22-2.19(m,1H),1.97(br s, 1H),1.85-1.84(m,1H),1.72-0. 83(m,13H) | ||
| 13 73 | A | A | (400MHz, DMSO-d6): 12.51 (s, exchanged with D2O ,1 H), 8.69 (s,1H), 8.32(d, J=2Hz,1H), 8.29(d, J=3.6Hz,1H), 8.23(s, 1H), 6.96(s, exchanged with D2O, 1H), 3.03 (s, 2H), 2.47 (d, J=12.8Hz,2H), 1.751.74(m,2H), 1.51(brs,5H), 1.35-1.33(m ,1H). |
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| 13 74 | A | A | (400MHz, DMSO-d6): 12.33(s, 1H), 8.77(d, J=2Hz, 1H), 8.27(d, J=2.4Hz, 1H), 8.18(d, J=3.2Hz,1H), 8.13(d, J=4Hz,1H), 7.65(d, J=8.4Hz, 1H), 4.83-4.79(m,1H), 2.642.19(m,3H), 1.97(brs,1H), 1.85-1.83(m,1H), 1 _72(dd,J1 =11.6,6.4Hz, 1 H), 1. 28 (s,9H),1.1(d, J=7,3H) | ||
| 13 75 | B | C | 36 0.4 | 3.8 2 | H NMR (300.0 MHz, DMSO) d 12.53 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.33 (dd, J = 2.7, 9.8 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J = 3.2 Hz, 1H), 2.65 (d, J = 10.3 Hz, 1H), 2.43- 2.37 (m, 4H), 2.24 (t, J = 9.1 Hz, 1H), 1.82 (t, J = 11.6 Hz, 2H) and -0.00 (s, H) ppm |
| 13 76 | C | C | (400MHz, DMSO-d6): 12.32 (s, exchanged with D2O, 1H), 8.76 (s, 1H), 8.29-8.11 (m, 3H), 6.64 (s, exchanged with D2O, 1H), 2.25-2.14 (m, 9H), 1.80-1.70 (m , 6H). | ||
| 13 77 | C | C | (400MHz, DMSO-d6): 12.35 (brs, 1H), 8.71(d,J=2.4Hz,1H).8.29(d,J= 2.4HZ.1H), 8.19-8.17(m,2H), 6.79(d,J=9.6Hz, partially exchanged with D2O,1H),5.01-4.99(m, 1H), 1.82-1.79(m,3H), 1.66- 1.27(m,6H), 0.88(s,9H). |
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| 13 78 | A | A | 400MHz, DMSO-d6): 12.32(s, 1H),,8.74(d,J=2Hz,1H),8.28(d ,J=2Hz,1H), 8.18(d ,J=2.8Hz, 1H), 8.11(d,J=3.6Hz,1H),7.46(d,J= 8.8Hz, 1H),4.19-4.16(m,1H), 1.99-1.91 (m,2H), 1.78- 1.48(m,5H), 1.15-1.07(m,2H), 0.91(d,J=6.8Hz,3H), 0.88(d,J=7.2Hz,3H) , 0.71(d,J=6.8Hz,3H). | ||
| 13 79 | A | A | 35 8.3 | 2.9 1 | (400MHz, DMSO-d6): 12.33 (br s,1H), 8.76 (d, J=2Hz,1H), 8.28 (d,J=2Hz,1H) , 8.18 (d, J=2Hz,1H), 8.14 (d, J=3.6Hz,1H), 7.6 (d, J=5.6Hz,1 H) 4.37-4.36 (br m, 1H), 3.16 (d, J=5.6Hz,1H), 2.69 (br s, 1H), 2.24 (brs, 1H), 1.99 (t, J=12,1H),1 .6- 1.2(m, 8H) |
| 13 80 | A | C | 40 3.3 4 | 3.1 | |
| 13 81 | A | C | 38 8.3 7 | 4.0 4 | |
| 13 82 | A | A | 38 8.3 7 | 4.0 2 | |
| 13 83 | A | 37 1.3 4 | 3.9 9 | ||
| 13 84 | C | 38 8.3 7 | 4.2 6 |
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| 13 85 | A | A | 38 8.3 7 | 4.2 6 | |
| 13 86 | C | C | 40 1.2 3 | 3.8 9 | |
| 13 87 | 42 4.5 4 | 3.5 3 | 1HNMR (300 MHz, DMSO) d 12.30 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 8.32-8.09 (m, J = 19.6, 9.0 Hz, 2H), 7.62 (d, J = 7.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.77-6.59 (m, 2H), 4.57 -4.33 (m, 1H), 3.71 (s, 3H), 3.21 -2.77 (m, 4H), 2.292.11 (m, J = 14.7 Hz, 1 H), 1.87 - 1.66 (m, J = 23.9, 12.0, 5.7 Hz, 1H). |
Table 5: IC50, ECS0, NMR and LCMS Data of Compounds of FIG. 8
| N 0 s | Cell Flu, MDCK protec tion, ATP (IC50: IC50: uM)(M ean (AH)) | Cell Influ enza HA(-) 30 hr A/PR /8 bDN A:bD NA EC50 uM( Mean (AU)) | LC M S_ PI us | LC MS _R T | NMR |
| 1 | 1H NMR (DMSO-d6): 1.53 (3H,m), | ||||
| 4 | 36 | 1.81 (2H, m), 1.98 (1H, m), 2.90 | |||
| 0 | 1.4 | (1H, m), 3.31 (1H, m), 3.43 (1 H, m), | |||
| 0 | B | 4 | 3.7 | 3.58 (2H, m), 7.85 (1H, s), 8.30 (2H, |
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| d), 8.36(1 H, s), 8.68(1 H, d), 8.84 (1H, s), 12.52 (1H, s) | |||||
| 1 4 0 1 | B | 36 1.4 4 | 3.5 9 | 1H NMR (DMSO-d6): 1.34 (1 H, m), 1.60 (1H, m), 1.92 (2H, m), 2.20 (1 H, m), 2.78 (2H, m), 3.24 (3H, m), 3.54 (1H, m), 7.99 (1H, s), 8.23 (1H, m), 8.30 (2H, d), 8.60 (1H, d), 8.70 (1H, s), 12.45 (1H, s) | |
| 1 4 Û 2 | D | 36 1.4 4 | 3.5 7 | 1H NMR (DMSO-d6): 1.41 (2H,m), 1.92 (2H, m), 2.08 (1H, m), 2.83 (2H, m), 3.29 (2H, m), 3.44 (2H, m), 7.97 (1H, s), 8.20 (1H, s), 8.25 (1H, s), 8.30 (1H, s), 8.48 (1H, d), 8.71 (1H, s), 12.43 (1H, s) | |
| 1 4 0 3 | B | 34 7.4 | 3.6 7 | 1H NMR (DMSO-d6): 1.94 (1H,m), 1.96 (2H, m), 2.14 (1H, m), 3.20 (2H, m), 3.71 (2H, m), 3.83 (1 H, m), 7.89 (1H, s), 8.30 (4H, m), 8.69 (1H, s), 8.91 (1H, s), 12.58 (1H, s) | |
| 1 4 0 4 | 34 7.4 | 3.5 4 | 1H NMR (DMSO-d6): 1.77 2.12 (1H, m), 2.77 (1H, m), 3.00 (1H, m), 3.17 (1H, m), 3.34 (2H, m), 3.60 (2H, m), 7.98 (1H, s), 8.23 (1H, d), 8.31 (2H, m), 8.71 (3H, m), 12.53 (1H,s) | ||
| 1 4 0 5 | D | 39 4.4 5 | 5.2 8 | 1H NMR (DMSO-d6): 2.04 (4H, m), 2.84 (2H, m), 3.33 (1H, s), 5.61 (1H, m), 7.18 (3H, m), 7.27 (1H, d), 8.00 (1H, d), 8.21 (1H, t), 8.23 (1H, s), 8.26 (1H, s), 8.68 (1H, s), 12.34 (1H, s) | |
| 1 4 0 6 | 33 3 | 3.5 4 | 1H NMR (CD3OD): 2.40-2.50 (2H, m), 2.6-2.7 (2H, m), 3.50-3.60 (3H, m), 3.7-3.8 (1H, m), 5.2-5.3 (1 H, m), 8.40 (1H, s), 8.50 (1H, m), 8.55 (1H. s), 8.75 (1H, s) |
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| 1 4 0 7 | 34 7 | 3.5 | 1H NMR (DMSO-d6): 1.80-1.90 (2H,m), 2.1-2.2 (2H, m), 3.05-3.15 (2H, m), 3.4-3.5 (2H, m), 4.30-4.40 (1H, m), 7.65-7.70 (1 H, m), 8.308.35 (2H, m), 8.40-8.50 (1 H, s), 8.60-8.70 (1H, s), 8.75-8.80 (1H, m), 12.0 (1H, s) | ||
| 1 4 0 8 | A | 34 7.4 7 | 3.6 8 | 1H NMR (DMSO-d6): 1.66 (1H.ni), 1.85 (1H, m), 1.98 (1H, m), 2.11 (1H, m), 2.90 (2H, m), 3.32 (1H, m), 3.47 (1H, m), 4.46 (1H, m), 7.57 (1H, d), 8.31 (3H, m), 8.66 (3H, m), 12.47 (1H, s) | |
| 1 4 0 9 | D | 34 8.4 4 | 4.4 2 | 1H NMR (DMSO-d6): 1.67 (2H,m), 1.96 (2H, d), 3.49 (2H, t), 3.96 (2H, d),4.30(1H, m), 7.62 (1H, d), 8.18 (1H, s), 8.22 (1H, s), 8.29 (1H, s), 8.72 (1H, s),12.36 (1H, s) | |
| 1 4 1 0 | A | 36 0.4 6 | 5.3 9 | 1H NMR (DMSO-d6): 1.17 (5H,m), 1.70 (6H, m), 2.67 (2H, d), 8.27 (1H, s), 8.42 (2H, s), 8.72 (1H, s), 12.57 (1H,s) | |
| 1 4 1 1 | 37 4.5 | 5.4 7 | 1H NMR (DMSO-d6): 1.15 (8H,m), 1.28 (2H, m), 1.72 (2H, m), 1.84 (2H, m), 4.23 (1H, m), 7.43 (1H, d), 8.12 (1H, s), 8.18 (1H, s), 8.27 (1H, s), 8.73 (1H, s),12.32 (1H, s) | ||
| 1 4 1 2 | A | 34 6.4 3 | 5.2 5 | 1H NMR (DMSO-d6): 0.85 (1 H, m), 1.48 (4H, m), 1.68 (1H, d), 1.81 (2H, m), 2.04 (2H, m), 4.03 (1H, m), 7.49 (1H, d), 8.13 (1H, s), 8.19 (1H, s), 8.29 (1H, s), 8.73 (1H, s), 12.21 (1H, s) | |
| 1 4 1 3 | 36 2 | 4.5 | (d6-DMSO, 400MHz) 1.23-1.33 (2H, m), 1.72 (2H, d), 1.99-2.04 (1H, m), 3.27 (2H, t), 3.41 (2H, t), 3.85- 3.89 (2H, m), 7.80 (1H,t), 8.14 (1H, d), 8.21 (1H, s), 8.28 (1 H, |
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| d), 8.74 (1H, d), 12.35 (1H, brs) | |||||
| 1 4 1 4 | 37 5 | 3.9 5 | (d6-DMSO, 400MHz) 1.14 - 1.24 (2H, m), 1.75- 1.80 (5H, m), 2.11 (3H, s), 2.75 (2H, d), 3.40 (2H, t), 7.80 (1H, t), 8.13 (1H, d), 8.20 (1H, s), 8.28 (1H,d), 8.73 (1H, d), 12.35 (1H,s) | ||
| 1 4 1 5 | D | 34 8 | 3.2 7 | (d6-DMSO, 400MHz) 1.66 - 1.74 (1H, m), 1.99-2.08 (1H, m), 2.67- 2.74 (1H, m), 3.49-3.51 (2H, m), 3.58-3.67 (2H, m), 3.73 (1H,t), 3.79-3.84 (1H, m), 7.88 (1H,t), 8.16 (1H, d), 8.22 (1H, s), 8.29 (1H, d), 8.74 (1H, d), 12.36 (1H, brs) | |
| 1 4 1 6 | B | 34 7.4 7 | 3.5 4 | 1H NMR (CDCI3 / MeOD): 0.83 (2H, m), 1.94 (1H, m), 2.32 (1 H, m), 3.00 (1 H, m), 3.30 (1H, m), 3.36 (2H, m), 3.46 (1H, m), 3.60 (1H,m), 3.87 (1H, m), 8.15 (1H, s), 8.24 (1H, s), 8.29 (1H, s), 8.68 (1H, s) | |
| 1 4 1 7 | D | 33 3.5 1 | 5 | 1H NMR (DMSO-d6): 2.15 (1 H, m), 2.30 (2H, m), 3.35 (2H, m), 3.58 (1H, m), 4.77 (1H, m), 7.87 (1H, s), 8.29 (3H, m), 8.81 (1 H, s), 8.94 (2H, br s), 12.45 (1H, s) | |
| 1 4 1 8 | D | 33 3.4 | 5 | 1H NMR (DMSO-d6): 2.17 (1H, m), 2.34 (1H, m), 3.34 (3H, m), 3.58 (1H, m), 4,79 (1 H, m), 7.87 (1H,d), 8.27 (3H, m), 8.68 (1H, s), 8.81 (2H, br s), 12.45 (1H, s) | |
| 1 4 1 9 | B | 40 3.4 8 | 3.1 8 | 1H NMR (DMSO-d6): 0.82 (2H, m), 1.11 (1H, m), 1.22 (1H, m). 1.85 (2H, t), 1.98 (3H, s), 2.07 (1H, brs), 3.00 (1H,t), 3.51 (1H,s), 3.83 (1H, m), 4.40 (1H,d), 8.40 (1H, s), 8.44 |
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| (1H, d), 8.65 (1H, s), 8.88 (1H,s), 9.20 (1H, brs), 12.91 (1H, s) |
In Vivo Assay
For efficacy studies, Balb/c mice (4-5 weeks of âge) were challenged with 5x103TClD5Q in a total volume of 50 μΙ by intranasal by intranasal instillation (25 μΙ/nostril) under general anesthésia (Ketamine/Xylazine). Uninfected controls were challenged with tissue culture media (DMEM, 50 μΙ total volume). For the prophylaxis study (FIG. 1), the initial dose of Compound 514 (100 mg/kg) or vehicle only (0.5% Methylcellulose/0,5% Tween 80) were administered 2 hours prior to infection by oral gavage (10 mL/kg) and continued twice daily for 5 days. For the treatment study (FIG. 2), Compound 588 (200 mg/kg) or vehicle only (0.5% Methylcellulose/0.5% Tween 80) were administered by oral gavage 24 hours post infection and continued twice daily for 10 days. Animais were monitored for survival for 21 days and Kaplan Meier plots. As shown in FIGs. 1 and 2, Compound 514 and Compound 588 provided complété survival that was statistically significant from vehicle treated controls (P<0.0001).
Table 6. Influneza Therapeutic Mouse Model (Dosing @ 48 hours post infection with 30 mg/kg BID X 10 days)
| Compounds | Percent Survival | Percent Weight Loss (Day 8) |
| 895 | 100 | 12.8 |
| 936 | 100 | 20.9 |
| 933 | 100 | 28.0 |
| 706 | 75 | 27.0 |
| 967 | 75 | 30.9 |
| 866 | 62.5 | 29.5 |
| 968 | 37.5 | 32.7 |
Ail references provided herein are incorporated herein in its entirety by reference. As used herein, ail abbreviations, symbols and conventions are consistent with those used in the contemporary scientific literature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual forAuthors and Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997.
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit
-53716260 the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
Claims (51)
1. A compound represented by the following structural formula (I):
Z1
H N or a pharmaceutically acceptable sait thereof, for use in inhibiting the réplication of influenza viruses in a biological sample or patient, wherein:
Z1 is -R*, -F, -Cl, -CN, -OR*, -CO2R*, -NO2, or -CON(R*)2;
Z2 is -R*, -OR*, -CO2R*, -NR*21 or -CON(R*)2;
Z3 is -H, -OH, halogen, -NH2; -NH(C,-C4 alkyl); -N(C,-C4 alkyl)2. -O(C,-C4 alkyl), or C,-C6 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(C,-C4 alkyl);
R1 is -H or CrC6 alkyl;
R2 is -H; -F; -CH3; -CH20H; -NH2; -NH(C,-C4 alkyl); -N(C,-C4 alkyl)2; -C=N-OH; cyclopropyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -OCH3, and -CH3; or C,-C4 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(Ci-C4 alkyl); and
R3 is -H, -Cl, -F, -OH, -0(0,-04 alkyl), -NH2, -NH(C,-C 4 alkyl), -N(C,-C4 alkyl)2, -Br, CN, or C1-C4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)21 -000(0,-04 alkyl), -CO(C,-C4 alkyl), -CO2H, -C02(C,-C4 alkyl), and C,-C4 alkoxy;
R4 is:
or r5; and wherein:
539 ring A is a C3-C10 non-aromatic carbocycle optionally further substituted with one or more instances of JA or a 3-10 membered non-aromatic heterocycle optionally further substituted with one or more instances of JB;
rings B is a 4-10 membered non-aromatic heterocycle-optionally and independently
5 further substituted with one or more instances of JB; or ring A and R8 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each carbocycle is optionally further substituted with 10 one or more instances of JA, and wherein each heteroocycle is optionally further substituted with one or more instances of JB,
Q2 is independently a bond, ΠΟΟ, DSn, nNR’a, DC(O)a, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, aCO2n, ΠΟΟ(0)Π, nC(O)NR’D, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, □NRC(O)a, DNRCiOJNR’a, aNRCO2n, -0C(O)NR’a, -S(O)-, nSO20a-SO2NR’-, nNRSO2nn
15 or -NRSO2NR’-, -P(O)(OR)O-, -0P(O)(ORa)O-, -P(O)2O-, -CO2SO2-, or -(CReR7)pDY1n;
Q3 is independently a bond, 00(0)0, -C(=NR)-, -C(=NR)NR-, 0002Π, -C(O)NR’O, □ SO2Q-SO2NR'-, -C(O)NRC(O)O-, or-(CR6R7)pOY1DO optionally, each Q2 and Q3, together with R5, independently form a 5-7 membered ring optionally substituted with one or more instances of JE1;
20 Re and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-C6 alkyl, Ci-C6 haloalkyl, C-|-C6 cyanoalkyl, C2-C6 alkoxyalkyl, CrC6 aminoalkyl, Ο,-Οβ hydroxyalkyl, Ci-C6 carboxyalkyl, CrCealkoxy, CrCç haloalkoxy, CrC6aminoalkoxy, C^Cecyanoalkoxy, Cr C6 hydroxyalkoxy , or C2-C6 alkoxyalkoxy; or R0, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more
25 instances of JE1;
R11, R12, R13 and R14 are each independently OH, halogen, or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, C^Ce alkoxy, CrCB haloalkoxy, CrC6 aminoalkoxy, CrCe cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
30 optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl;
n and m are each independently 0, 1 or 2;
x and y are each independently 0;
35 each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q1 DR5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 4-8 membered ring that is optionally substituted with one or more instances of JE1;
540
Q1 is independently a bond, ΠΟΠ, OSn, lINR'lI, nC(O)O, -C(=NR)-, -C(=NR)NR-,
-NRC(=NR)NR-, nCO2n, 000(0)0, OC^NRO, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-,
0NRC(O)D, ONRC(O)NRO, ONRCOzO, -OC(O)NR’D, -S(0)-, OSOzOO -SO2NR’-, DNRSO2OD or -NRSOZNR’-, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(O)2O-, -CO2SO2-, or -(CR6R7)POY1O;
Y1 is independently a bond, ΠΟΟ, OSD, ONR’O, 00(0)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-„ OCOaQ, 000(0)0, 0C(O)NR'Ü, -C(O)NRC(O)O000-NRC(O)NRC(O)O-, 0NRC(O)0, □NRC(O)NR,O, 0NRCO20, 0OC(O)NR’D,-S(0)-, OSOzOD-SO2NR’-, ONRSOZOO -NRSOZNR'-, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(0)20-, or -CO2SO2-;
R5 is: i) -H; ii) a C^-Cg aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-Ci0 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1; or
R5, together with Q1, optionally forms a 4-8 membered, non-aromatic ring optionally substituted with one or more instances of JE1; and
R6 and R7 are each independently DH or Ci-C6 alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C^-Cg alkoxy, CrC6 haloalkoxy, CpCg aminoalkoxy, Ci-CBcyanoalkoxy, CrC6 hydroxyalkoxy and C2-C6 alkoxyalkoxy, or optionally R6 and R7, together with the carbon atom to which they are attached, form aDcyclopropane ring optionally substituted with one or more instances of methyl;
R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, CrCB alkyl, C-rCg haloalkyl, Ci-CB cyanoalkyl, C2-C6 alkoxyalkyl, C-,-CB aminoalkyl, Ci-C6 hydroxyalkyl, CrCB carboxyalkyl, Ci-Ce alkoxy, CrC6 haloalkoxy, CrC6 aminoalkoxy, CrCgcyanoalkoxy, C-|-CB hydroxyalkoxy and C2-C6 alkoxyalkoxy;
R and R' are each independently DH or CrC6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, CrCg alkoxy, CpCg haloalkoxy, CrC6 aminoalkoxy, CrCgcyanoalkoxy, CrCg hydroxyalkoxy and C2-C6 alkoxyalkoxy; or optionally R', together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered nonaromatic heterocycle optionally substituted with one or more instances of JD1;
R’ is independently: i) -H; ii) a CrCg alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C3-Ca non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 membered heteroaryl, -OfCj-Cg alkyl), and -C(O)(C1-C5-alkyl); wherein each of said alkyl groups in -OfC^-Cg alkyl), and -C(O)(Ci-C6-alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2) -NHfCi-Ci alkyl), alkyl)z, -OCO(CrC4 alkyl),
541
-00(0,-04 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; and wherein each of said carbocycle, heterocycle, phenyl, and heteroaryl is independently and optionally substituted with one or more instances of JE1; or iii) a C3-CB non-aromatic carbocycle, or a 4-8 membered nonaromatic heterocycle, each of which is independently and optionally substituted with one or more instances of JE1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, aORb, DSR15, -S(O)Ra, OSO2Ra, DNRbRc, □C(O)Rb, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, DC(O)ORb, □OCfOJR'5, aNRC(O)Rb, nC(O)NRbRc, □NRC(O)NRbRc, □ NRC(O)ORb, DOCONRhR', -C(O)NRCOaRb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),n-SO2NRcRb, -NRSO2Rb, -NRSO2NRcRb, -P(O)(ORa)2, -OP(O)(ORa)21 -P(O)2ORa and -CO2SO2Rb, or optionally, two JC1 and two JD1, respectively, together with the atom(s) to which they are attached, independently form a 4-8-membered ring that is optionally substituted with one or more instances of JE1;
each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, Ci-C6 alkyl, -O(Ci-C6 alkyl), and -CiOXC-i-Ce-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,C4 alkyl), and C,-C4 alkoxy; and
Ra is independently: i) a Ci-CB aliphatiç group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -O(C,-CB alkyl), -C(O)(C-f-CB-alkyl), C3-C8 non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and 6-10 membered carbocyclic aryl group; wherein each of said alkyl groups for the substituents of the CrC6 aliphatiç group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH21 -NH(Ci-C4 alkyl), -N(C1-C4 alkyl)2, -000(0,-04 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,C4 alkyl), and 0,-04 alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl and carbocyclic aryl groups for the substituents of the C,-C6 aliphatiç group represented by Ra is optionally and independently substituted with one or more instances of JE1;
ii) a C3-C8 non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is optionally and independently substituted with one or more instances of JE1; or iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclic aryl group, each of which is optionally and independently substituted with one or more instances of JE1; and
Rb and Rc are each independently Ra or -H; or optionally, Rb and Rc, together with the nitrogen atom(s) to which they are attached, each independently form a 5-7 membered nonaromatic heterocycle optionally substituted with one or more instances of JE1;
p is independently 1,2, 3 or 4.
542
2. The compound for use of claim 1, represented by Structural Formula (I):
or a pharmaceutically acceptable sait thereof.
3. The compound for use according to any one of claims 1 - 2, wherein:
n and m are each independently 0 or 1 when rings A and B are 3-6 membered; or n and m are each independently 0, 1 or 2 when rings A and B are 7-10 membered;
provided that if Y1 is a bond, then R6 is neither H nor a aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither -H nor a aliphatic group.
4. The compound for use according to claim 3, wherein:
ring A is a C3-C8 non-aromatic carbocycle optionally and independently is further substituted with one or more instances of JA;
ring B is a 4-8 membered non-aromatic heterocycle-optionally and independently further substituted with one or more instances of JB;
Q1 is independently a bond, DOO, OSD, ONR’D, 00(0)0, ΠΟΟ2α, 000(0)0, 0C(O)NRO, -C(O)NRC(0)0- -NRC(O)NRC(O)O-, 0NRC(O)O, ONRCfOJNR’Q, 0NRC020, -00(0)NR’0, -S(0)-, OS0200 -S02NR’-, DNRS0200 or-NRSO2NR'-, or-{CR6R7)p0Y1O;
Q2is independently bond, 000, OSO, ONRO, 00(0)0, 0CO20, 000(0)0, OC(O)NRO, -C(0)NRC(0)0-, -NRC(O)NRC(O)O-, 0NRC(O)0, 0NRC(O)NR0, 0NRC020, OOC(0)NRO, -S(0)-, 0SO2OO ON(R)S020, 0S02NR'-, -NRSOïNR’-, or-(CR6R7)pOY1D;
Q3 is independently a bond, 00(0)0, 0C020, -C(0)NRO, OS02D,-S02NR’-, -C(O)NRC(O)O-, or -(CR6R7)PDY1OO optionally, each of Q2 and Q3, together with R5, independently forms a 5-7 membered ring optionally substituted with one or more instances of JE1;
Y1 is independently a bond, 000, OSO, ONR’D, 00(0)0, 00020, 000(0)0, 0C(O)NR'O, -C(O)NRC(O)OOOD-NRC(O)NRC(O)O-, 0NRC(O)0, 0NRC(O)NRO, 0NRCO20, 0OC(O)NR’Îl, -S(0)-, 0SO200 -SO2NR’-, 0NRSO20D or-NRSO2NR'~;
543 each of JA and JB is îndependently selected from the group consisting of halogen, cyano, oxo, and Q1DR5; or optionally two JA and two JB, respectîvely, together with the atom(s) to which they are attached, îndependently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1 and fused to the ring to which they are attached; and each of JC1 and JD1 is îndependently selected from the group consisting of halogen, cyano, oxo, Ra, 7lORb, nSRb, -S(O)Ra, DSOsR3, ONR^, ClC(O)Rb, aC(O)ORb, nOC(O)Rb, -|NRC(O)Rb, aCtOJNRhR0, □NRC(O)NRbRc, □NRC(O)ORb, □ OCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),a-SO2NRcRb, -NRSO2Rb, and -NRSO2NRcRb, or optionally, two JC1 and two JD1, respectîvely, together with the atoms to which they are attached, îndependently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
5. The cornpound for use according to any one of daims 1-4, wherein:
Z1 is -H, CrC6 alkyl, -O(CrCe alkyl), -F, -Cl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH(Ci-C6 alkyl), or -CON(CrC6 alkyl)2, wherein each of said alkyl groups is optionally and îndependently substituted with one or more substituents îndependently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NHiCrCi alkyl), -N(CrC4 alkyl)2, -OCO(C-|C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and CrC4 alkoxy; and
Z2 is -H, Ci-Ce alkyl, -O(Ci-C6 alkyl), -NH2, -NM/CpCe alkyl), or -N(C-|-CB alkyl)2, wherein each of said alkyl groups is optionally and îndependently substituted with one or more substituents îndependently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(CrC4 alkyl)2, -OCOiC,-^ alkyl), -CO(C1-C4 alkyl), -COZH, -CO2(Cr C4 alkyl), and Ci-C4 alkoxy.
6. The cornpound for use according to any one of daims 1-5, wherein:
Z1 is -H, -F, -Cl, -CF3, -CH3, or -CN;
Z2 is -H or Ci-C6 alkyl optionally substituted with one or more substituents îndependently selected from the group consisting of halogen, cyano, hydroxy, and -O(C!-C4 alkyl);
Z3 is -H or C-j-Cb alkyl optionally substituted with one or more substituents îndependently selected from the group consisting of halogen, cyano, hydroxy, and -O(CrC4 alkyl);
R1 is -H;
Rz is -H;
R3 is Independently -H, -Cl or -F;
R6 and R7 are each independently -H or -CH3) or together with the carbon atoms to which they are attached they form a cyclopropane ring;
each Re is independently -H, halogen, cyano, hydroxy, CVC4 alkyl, CrC4 haloalkyl, Cr C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -Ο(^-ϋ4alkyl), ΠΝΗ2, □NH(C1nC4 alkyl), or □N(C1nC4 alkyl)2;
544 each R9 is independently -H or-CH3; and R11 and R12 are each independently -H or-CH3.
7. The compound for use according to any one of daims 4-5, wherein the compound is represented by any one of the structural formulae below (II) and (III):
(H) (HI) or a pharmaceutically acceptable sait thereof, wherein:
R3 is-H, OF, CCI, OCFa, ΠΝΗ2, nNH(CH3), or ONfCH^;
each R and R’ are independently -H or C-i-C6 alkyl;
ring A is an optionally substituted, C4-C7 non-aromatic carbocycle;
ring B is an optionally substituted, 4-7 membered non-aromatic heterocycle;
Z1 is -H, -F, -Cl, -CF3, -CHs, or -CN; and ’
Z2 is -H or an optionally substituted C^Cg alkyl.
8. The compound for use according to claim 7, wherein the compound is represented by the following structural formula (XIA) or (XIB):
H or h (XIA), . (XIB), or a pharmaceutically acceptable sait thereof, wherein:
ring A is a 5-7 membered ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-Cealkyl, C2-Ce alkenyl, -NH21 -NH(CrC6 alkyl), -N(CrC6 alkyl)21 -OfC^Cg alkyl), -C(O)NH2, -C(O)NH(CrC6 alkyl), -C(O)N(CrCe alkyl)2, -CfOXC^Cg-alkyl), -OCfOJfCrCg alkyl), NHCfOXCrCg alkyl), -N(C-|-CB alkyl)C(O)(Ci-Ce alkyl), and -CO2Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2,
545
-NH(Ci-C4 alkyl), -NfC;-^ alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(C4-C4 alkyl), and CrC4 alkoxy.
9. The compound for use according to claim 8, wherein n is 0 or 1;
Q2 is ΊΟΞ1, ΙΝΗΊ, -N(CH3)-, ΠΟ(Ο)ΓΊ, ΊβΟζΠ, l]C(O)NHl1, □C(0)N(CH3)n, ΠΝΗ0(Ο)Π, □hffCHjJCfOn nNHC(O)NR’n, □N(CH3)C(0)NRO ΠΝΗΟΟ,α, nN(CH3)CO2a, □OC(O)NRO, -NHSO2D, -N(CH3)SO2nan-SO2NRO, or-(CR6R7)pOY1n;
Rs is independently i) -H; ii) a Ci-C6-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1;
each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, OORb, nSRb, -S(O)Ra, 0SO2Ra, DNHR0, 0C(O)Rb, nC(O)ORb, □OC(O)Rb, □ NHC(O)Rb, nC(O)NHRc, □NHC(O)NHRC, nNHC(O)ORb, aOCONHR0, -NHC(0)NHC(O)0Rb, HN(CH3)Rc, □NiCHaWOJR1’, □C(O)N(CH3)Rc, □N(CH3)C(O)NHRc, □NfCHaJCtCOOR'1, nOCON(CH3)Rc, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(O)NHC(O)ORb, -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb; and ring A is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C-i-C4 alkyl, -O(Ci-C4 alkylODDDNHz, □NH(C10C4 alkyl), ONîC^Cî alky1)2, -C(O)(CrC4 alkyln, -OCO(CrC4 alkyl), -CO2H, and -CO2(C!-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, alkyl), -N(CrC4 alkyl)2, -OCO(Cr
C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(C-|-C4 alkyl), and CrC4 alkoxy.
10. The compound for use according to any one of claims 8-9, wherein the group [C(R13R1',)]x-ringA-Q2-R5 is independently selected from:
546 wherein each of rings A1-A27 is independently and optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C2 alkyl), -NH(CrC2 alkyl)2, C)-C2 alkyl, CrC2 haloalkyl,
5 CrC2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, Ci-C2 hydroxyalkoxy, θ!-θ2 haloalkoxy, C2C4 alkoxyalkoxy, -CO2H, and -CO2(Ci-C4 alkyl); and
R6 is independently:
i) -H;
10 ii) a Ci-Ce-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(C1-C4 alkyl), ΊΝΗ2, nNH(CiDC4 alkyl), □N(C1nC4 alkyl)2, -C(O)(Ci-C4 alkyl), -00(0)(0(-0, alkyl), -C(O)O(Ci-C4 alkyl), -CO2H, C3-Ca non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl;
15 iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of
547 halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(C,-C4 alkyl), ΠΝΗ2, nNH(C5DC4 alkyl), nNfC^Ci alkyl)2, -0(0)(0,-0, alkyl), -00(0)(0,-0, alkyl), -C(O)O(C,-C4 alkyl), and -CO2H;
wherein each of said alkyl groups for the substituents of R5 rs independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -000(0,C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and Ci-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the Ci-Ce-aliphatic group represented by R5 is ndependently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -000(0,-0, alkyl), -00(0,C4 alkyl), -C02H, -C02(C,-C4 alkyl), and 0,-C, alkoxy.
11. The compound for use according to claim 10, wherein the group -[C(R13R14)]x-ringA-Q2R5 is selected from one of the structures depicted below:
or 1 h ; and wherein:
each of rings A6, A8, A11, A14 and A15 is optionally and independently further substituted;
each Rs independently is halogen, cyano, hydroxy, 0,-04 alkyl, 0,-04 haloalkyl, 0,-04 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C,-C4 alkyl), 0NH2, ΠΝΗίΟ,ΟΟ, alkyl), or ΠΝίΟ,ΠΟ, alkyl)2; and
R6 is: i) -H; ii) an optionally substituted C,-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle;
wherein said alkyl group represented by R6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC, alkyl), -N(C,-C, alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C, alkyl), -CO2H, -CO2(C,C, alkyl), C-|-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the C,-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C-i-C4alkyl), ΠΝΗ2, □NH(C1DC4 alkyl), □N(C1QC4
54g alkyl)2, -0(0)(0,-04 alkyl), -00(0)(0,-04 alkyl), -0(0)0(0,-04 alkyl) and -CO2H, each of said alkyl groups being optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2,
-NH(C,-C4 alkyl), -Ν(0,-04 alkyl)2, -000(0,-04 alkyl), -00(0,-0, alkyl), -C02H, -CO2(C,-C4 alkyl), and 0,-04 alkoxy.
12. The compound for use according to claim 7, wherein the compound is represented by the following structural formula (XIIA) or (XIIB):
(XIIA) (XIIB), or a pharmaceutically acceptable sait thereof; wherein:
ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6 alkyl, C2-C6 alkenyl, -NHZ, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -O(C,.Ce alkyl), -C(O)NHZ, -C(O)NH(C,-C6 alkyl), C(O)N(C,-C6 alkyl)2, -C(O)(C,-C6-alkyl), -OC(O)(C,-Ce alkyl), -NHC(O)(C,-C6 alkyl), -N(C,-C6 alkyOCiOXCrCe alkyl), and -COzRb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2K, -ΟΟ^Ο,-Ο, alkyl), and 0,-04 alkoxy;
Q3 is independently Π0(Ο)Π, α002Π, Π0(Ο)ΝΗθ, ΠΟ(0)Ν(ΟΗ3)Π, -C(O)NHC(O)O-, -C(O)N(CH3)C(O)O-, -S02-, -SOzNH-QD -S02N(CH3)-Dor -(CR^p-Y1-;
R5 is independently i) -H; ii) a Ci-C6-alipahtic group optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, □0Ri>, OSRb, -S(O)Ra, nSO2Ra, nNHRc, nC(0)Rb, □CiOJOR”, L10C(0)Rb, □NHC(O)Rb, ElC(O)NHRc, □NHC(O)NHRc, □NHCfCOOR11, lIOCONHR0, -NHC(O)NHC(O)ORb, □hKCHaiR0, □N(CH3)C(O)Rb, DCfOiNiCHaJR0, nN(CH3)C(O)NHRc, DN(CH3)C(O)ORb,
549 □OCON(CH3)Rc, -C(0)NHC02Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(0)NHC(0)ORb, -NHSO2Rb,
-S02NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb
13. The compound for use according to claim 12, wherein ring B is independently selected
5 from one of the structures depicted below:
wherein each of rings B1-B9 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C,-C2 alkyl), -NH(C,-C2 alkyl)2, C,-C2 alkyl, Ci-C2 haloalkyl,
10 Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C,-C2 alkoxy, C,-C2 hydroxyalkoxy, C,-C2 haloalkoxy, C2C4 alkoxyalkoxy, -CO2H, and -002(0,-04 alkyl); and
R5 is independently:
i)-H;
15 ii) a Ci-C6-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4alkyl), ΠΝΗΖ, ΠΝΗ(Ο,ΠΟ4 alkyl), ΠΝ(Ο,ΠΟ4 alkyl)2, -C(O)(C,-C4 alkyl), -OC(O)(C,-C4 alkyl), -C(O)O(C,-C4 alkyl), -CO2H, C3-C0 non-aromatic carbocycle, 4-8 membered nonaromatic heterocycle, phenyl, and 5-6 membered heteroaryl;
20 iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4 alkyl), ΠΝΗ2, □NH(CiDC4 alkyl), ΠΝ(0,α04 alkyl)21 -C(O)(C,-C4 alkyl), -OC(O)(C,-C4 alkyl), -C(O)O(C,-C4 alkyl), and -CO2H;
25 wherein each of said alkyl groups for the substituents of R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)Z1 -000(0,C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents
30 of the CrC6-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NHZ, -NH(C,-C4 alkyl), -N(CrC4 alkyl)2, -OCO(C,-C4 alkyl), -00(0,C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
550
14. The compound for use according to any one of claims 1-3, wherein r11 R12 , wherein:
ring E is a C4-C10 non-aromatic carbocycle optionally further substituted with one or more instances of JA;
rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1;
R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, CrC6 alkyl, CrC6 haloalkyl, CrC6 cyanoalkyl, C2-C6 alkoxyalkyl, CrC6 aminoalkyl, CrC6 hydroxyalkyl, CrC6 carboxyalkyl, CrCe alkoxy, CrC6 haloalkoxy, CrC6 aminoalkoxy, Ci-CBcyanoalkoxy, CrC6 hydroxyalkoxy, or C2-Ce alkoxyalkoxy;
R11, R12, R13 and R14 are each independently ΠΗ, halogen, or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrCe alkoxy, CrC6 haloalkoxy, CrC6 aminoalkoxy, CrCecyanoalkoxy, CrC6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl;
s is 0, 1 or 2; and x is 0.
15. The compound for use according to claim 14, wherein ring F is selected from any one of rings F1-F6:
O each of rings F1-F6 optionally and independently substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, CrC4 alkoxy, and CrC4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(CrC4 alkyl).; and each Rf is independently ΠΗ or C-i-Ce alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, CrC6 haloalkoxy, CrC6aminoalkoxy, CrCe cyanoalkoxy, CrC6 hydroxyalkoxy and C2-C6 alkoxyalkoxy.
551
16. The compound for use according to any one of daims 14-15, wherein:
R9 is independently -H, halogen, cyano, hydroxy, C!-C4 alkyl, Ci-C4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C!-C4 alkyl), ΠΝΗ2, □NH(C1nC4 alkyl), or nN(CiOC4 alkyl)2;
ring E is a C4-C8 non-aromatic carbocycle optionally further substituted with one or more instances of JA; and ring F is selected from any one of rings F1-F5:
o wherein each of rings F1-F5 optionally and independently substituted.
17. The compound for use according to any one of daims 1-5, wherein R4 is:
each of rings G1-G4 is independently a 5-ÏO membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 5-10 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB;
X is -O-, -S-, or -NR9-;
Rb and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-CB alkyl, CrC6 haloalkyl, Ci-CB cyanoalkyl, C2-Ce alkoxyalkyl, Ci-CB aminoalkyl, CrCs hydroxyalkyl, C-i-Ce carboxyalkyl, C-i-C6 alkoxy, Ο,-Ο6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-C6cyanoalkoxy, Cr
Ce hydroxyalkoxy, or C2-C6 alkoxyalkoxy;
R21, R22, R23, R24, and R25 are each independently ΠΗ, halogen, -OH, CrC6alkoxy, or
Ci-CB alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-CB alkoxy, Ci-CB
552 haloalkoxy, CrCeaminoalkoxy, Ci-C6 cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
R9 is -H or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consîsting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ο,-Οβ alkoxy, Ci-C6 haloalkoxy, Ο,-Οβ aminoalkoxy, CrC6 cyanoalkoxy, CrC6 hydroxyalkoxy, and C2C6 alkoxyalkoxy;
q is 0, 1 or 2;
x is 0; and r is 1 or 2.
18. The compound for use according to claim 17, wherein R4 is:
each of R8 and R9 is independently -H, halogen, cyano, hydroxy, Cj-C4 alkyl, C!-C4 haloalky), CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(Ci-C4alkyl), ONH2) □ΝΗίΟιϋΚλι alkyl), or alkyl)z; and
R19 * 21, R22, R23, and R24 are each independently DH, halogen, -OH, or Ci-Cs alkyl optionally substituted with one or more substituents independently selected from the group consîsting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Οί-Οθ alkoxy, CrC6 haloalkoxy, Ci-C6aminoalkoxy, Ο,-Οβ cyanoalkoxy, C-j-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
Q2is independently a bond, ΠΟΠ, HSD, DNR.O, DC(O)n, -C(=NR)-, 00020, OOC(0)n, nC(O)NRn, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, □NRC(O)D, nNRC(O)NRQ, ONRCOza, □OC(O)NRH, -S(O)-, nso2an □N(R)SO2O, aSOzNR’-, -NRSO2NR’-, or -(CR6R7)pDY1n, -CO2SO2-, or -P(O)2O-.
19. The compound for use according to any one of ciaims 14-18, wherein:
Q1 is independently a bond, ΠΟΠ, DSO, ONRD, 00(0)0, -C(=NR)-, .000213,
1OC(O)O, nC(O)NRO, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, DNRC(O)0, ONRC(O)NRO, lNRCOzO, OOC(O)NRO, -S(O)-, OSO2OO 0N(R)S020, OSO2NR’-, -NRSO2NR'-, or
-(CR6R7)POY1O; and
553
Y1 is independently a bond, 000, DSD, lINRO, nC(O)O, -C(=NR)-, nCOzO, 000(0)0,
0C(O)NRO, -C(O)NRC(O)Onn0-NRC(O)NRC(0)O-, nNRC(O)D, 0NRC(O)NRO,
ONRCOaO, OOC(O)NR’O, -S(0)-, 0SO200 -SO2NR’-, ONRSO2OD or-NRSO2NR’-.
20. The compound for use according to any one of claims 14-19, wherein:
a) R5 is independently i) -H; ii) a Ci-CB-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-CB non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, QORb, aSRb, -S(O)Ra, DSO2Ra, ONHRC, nC(O)Rb, ElC(O)ORb, □OC(O)Rb, □NHC(O)Rb, nC(O)NHRc, nNHC(O)NHRc, □NHC(O)ORb, DOCONHR0, -NHC(O)NHC(O)ORb, nN(CH3)Rc, □N(CH3)C(O)Rb, nC(O)N(CH3)Rc, 0N(CH3)C(O)NHRc, □N(CH3)C(O)ORb, □ OCON(CH3)RC, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(O)NHC(O)ORb, -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb; for example, wherein:
R1 is -H;
R2 is -H, -CH3, -CH2OH, or -NH2;
R3 ts -H, OF, CCI, Cm alkyl, or Ci.4 haloalkyI;
Z1 is -H, -F, or -Cl;
Z2 is -H or C-t-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(CrC4 alkyl);
Z3 is -H or Cj-Cs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(C-j-C4 alkyl);
R5 is: i) -H; ii) an optionally substituted C^Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(CrC4 alkyl), C,-C4 alkoxy, -NRCOIC,-^ alkyl), -CONR(C4-C4 alkyl), -NRCO2(CrC4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7
554 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1;
and a phenyl optionally substituted with one or more instances of JE1; and wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C, alkyl, -0(0,-0, alkyl), aNH2, □ NH(C,nC, alkyl), DN^QC, alkyl)2, -0(0)(0,-0, alkyl), -00(0)(0,-0, alkyl), -0(0)0(0,-0, alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy;
b) R6 is: i) -H; ii) an optionally substituted C,-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C, alkyl), -N(C,-C, alkyl)2, -000(0,-0, alkyl), -00(0,-0, alkyl), -CO2H, -002(0,-0, alkyl), C,-C4 alkoxy, an optionally substituted C3-C7 non-aromatic carbocycle, and an optionally substituted 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the C,-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -O(C,-C,alkyl), DNH2, DNHiCiDC, alkyl), nN(C,nC4 alkyl)z, -C(O)(C,-C4 alkyl), -00(0)(0,-0, alkyl), -C(O)O(C,-C, alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C, alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C, alkyl), -CO(C,-C, alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; or
c) R1 is -H;
R2 is -H or-CH2OH;
R3 is-H, DF, or OCI;
Z1 is-H,-F, or -Cl;
Z2 is -H;
Z3 is -H;
R5 is independently: i) -H or ii) a Ci-C6-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy,
555 oxo, CvC, alkyl, -O(Ci-C4alkyl), ΠΝΗ2, ΠΝΗ(0ιΠ04 alkyl), □N(CiDC4 alkyl)2, -0(0)(0^ alkyl), -OC(O)(Ci-C4 alkyl), -0(0)0(0,-0.1 alkyl), -CO2H, C3-Ca non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl;
wherein each of said alkyl groups referred to in the substituents of the Ci-C6-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -ΝίΟ,-Ο, alkyl)2, -000(0,-04 alkyl), -CO(C,-C4 alkyl), -COZH, -002(0,-04 alkyl), and CrC4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the C,-CB-alkyl group represented by RE is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(CrC4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -C0(CrC4 alkyl), -C02H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy.
21. The compound for use according to any one of daims 14-20, wherein each of JA and JB is selected from the group consisting of halogen, cyano, hydroxy, CrC6alkyl, -NH2, -NH(C,-Ce alkyl), -N(C,-CS alkyl)2, -O(C,.C6 alkyl), -C(O)NH2, -C(O)NH(C,-C6 alkyl), -C(O)N(C,-Ce alkyl)2, -C(O)(Ci-C6-alkyl), -OC(O)(C,-C6 alkyl), -NHC(O)(C,-Ce alkyl), -N(C,-C6 alkyl)C(O)(CrC6 alkyl), and -CO2Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CtC4 alkyl), -N(CrC4 alkyl)2, -OCO(C1-C4 alkyl), -C0(C1-C4 alkyl), -CO2H, -COz(CrC4 alkyl), and CrC4 alkoxy; for example, wherein each of JA and JB is selected from the group consisting of halogen, cyano, hydroxy, -NH21 -NH(C,-C4 alkyl), -N(CVC4 alkyl)2, TOCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), C-i-C4 alkoxy, and Ci-C4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -O(Ci-C4 alkyl).
22. The compound for use according to daims 1-2, wherein:
ring A is a non-aromatic, 5-10 membered, bridged carbocylce or heterocycle, or ring A and R8 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each of said carbocycle is independently and optionally substituted with one or more instances of JA and wherein each carbocycle is independently and optionally substituted with one or more instances of JB;
R1 is -H;
R2 is -H, -CH31 -CH2OH, or -NH2;
R3 is-H, OF, DCI, Cm alkyl, orCV4 haloalkyl;
Z1 is -H, -F, or -Cl;
Z2 is -H or Ο,-Ο6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(0,-04 alkyl);
Z3 is -H or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(0,-04 alkyl);
Q2 is independently ΠΟΠ, Π002Π, ΠΟΟ(0)Π, □CiOJNR’EJ, -C(O)NRC(O)O.□NRC(O)Fl, nNRC(O)NRO, LlNRCO2n, -OC(O)NR’lI, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(O)2O-, -CO2SO2-, or-(CRsR7)pDY1D;
Y1 is non, □co2n, noc(O)n, nc(0)NRO,-C(0)NRC(0)0-,aNRC(0)o, □NRC(O)NRO, nNRCO2n, -OC(O)NR'D, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(O)2O-, or -CO2SO2-;
R5 is: i) -H; ii) an optionally substituted 0,-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by RE is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -CO2(CrC4 alkyl), C,-C4 alkoxy, -NRCO(CrC4 alkyl), -CONR(C,-C4 alkyl), -NRCO^C,^ alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1;
wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R6 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -0(0,-04 alkyl), ΠΝΗΖ] ΊΝΗ(0,Π04 alkyl), ΠΝ(Ο,ΠΟ4 alkyl)2, -0(0)(0,-04 alkyl), -00(0)(0,-04 alkyl), -C(O)O(C,-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -000(0-|-04 alkyl), -CO(C,-C4 alkyl), -CO2H, -002(0,-04 alkyl), and C,-C4 alkoxy;
557 each of Rs and R9 is independently -H, halogen, cyano, hydroxy, Ο,-Ο4 alkyl, CrC4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -Ο(Ο,-Ο4 alkyl), 0NH2, □ΝΗίΟ,ΓΚΙ, alkyl), or □N(C1DC4 alkyl)2;
R11, R12, R13, and R14 are each independently ΠΗ, halogen, or 0,-06 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and 0γ06 alkoxy; and each of JA and JB is independently selected from the group consisting of halogen, cyano, hydroxy, Ο,-ΟΒalkyl, -NH2, -NH(CrCB alkyl), -N(CrCB alkyl)2, -Ο(ΟηΌ6 alkyl), -C(O)NH2, -C(O)NH(C-i-CB alkyl), -CfOJNfCrCe alkyl)2, -CiOXCrCe-alkyl), -OC(O)(CrC6 alkyl), -NHC(O)(Ci-CB alkyl), -N(CrCB alkyl)C(O)(CrC6 alkyl), and -CO2Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -0C0(CrC4 alkyl), -00(0,-04 alkyl), -CO2H, -CO2(CrC4 alkyl), and CrC4 alkoxy; and n is 0 or 1 ;
x is 0.
23. The compound for use according to claim 22, wherein:
R23 each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 5-10 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB;
X is -O-, -S-, or -NR9-;
R21, R22, R23, R24, and R25 are each independently ΠΗ, halogen, -OH, C-t-Ce alkoxy, or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-CB alkyl, -NH2, -NHiCX-Ce alkyl), -N(Ci-C6 alkyl)2, -OÎC^Ce alkyl), -C(O)NH2, -C(O)NH(CrC6 alkyl), -C(O)N(CrCB alkyl)2, -C(O)(CrC6alkyl), -00(0)(0,-06 alkyl), -NHCiOXCrCe alkyl), -NiCrCe alkyl)C(OXCrCB alkyl);
558
R9 is -H or CtCg alkyl ptîonally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, C^Ce haloalkoxy, CrCB aminoalkoxy, CrC6 cyanoalkoxy, C]-C6 hydroxyalkoxy, and C2C6 alkoxyalkoxy; and q is 0, 1 or 2; and r is 1 or 2; for example, wherein:
R1 rs -H;
R2 is -H;
R3 is -H, DF, or CCI;
Z1 is -H, -F, or -Cl;
Z2 is -H;
Z3 is -H;
X is -O-;
Rs is -H, an optionally substituted Ci-C6 alkyl, or optionally substituted phenyl;
each Rs is independently-H, halogen, hydroxy, Ci-C4 alkyl, CVC4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, or-O(C1-C4 alkyl);
each of R9, R13, and R14is independently -H or CrC4 alkyl;
R21, R22, R23, R24, and R25are each independently DH, halogen, -OH, C^Ce alkoxy, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C^Cg alkyl, and -O(CVC6 alkyl); and each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NHfCrCe alkyl), -N(Ci-C6 alkyl)?, -O(Ci.C6 alkyl), CrC4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and CrC4 alkoxy.
24. A compound represented by structural formula (IA):
559 or a pharmaceutically acceptable sait thereof, wherein:
Z1 is -R*, -F, -Cl, -CN, -OR*, -CO2R*. -NO2, or -CON(R*)2;
Z2 is -R*, -OR*, -CO2R*, -NR*2, or -CON(R*)2;
Z3 is -H, -OH, halogen, -NH2; -NH^-C^ alkyl); -NiC,-^ alkyl)2, -0(0,-04 alkyl), or 0,-06 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(CrC4 alkyl);
R1 is -H, C,-Ce alkyl, -S(O)2-R”, or-C(0)OR;
R2 is -H; -F; -CH3; -CH2OH; -NH2; -NH(CrC4 alkyl); -N(C,-C4 alkyl)2; -C=N-0H; cyclopropyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -OCH3, and -CH3; or CrC4 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(C,-C4 alkyl); and
R3 is -H, -Cl, -F, -Br, -OH, -O(C,-C4 alkyl), -NH2, -NH(CrC4 alkyl), -N(C,-C4 alkyl)2, CN, or C,-C4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy;
R4 is:
ring A is a C3-C10 non-aromatic carbocycle optionally further substituted with one or more instances of JA or a 3-10 membered non-aromatic heterocycle optionally further substituted with one or more instances of JB;
ring B is a 4-10 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB;
ring A and R8 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each carbocycle is optionally further substituted with
560 one or more instances of JA, and wherein each heteroocycle is optionally further substituted with one or more instances of JB;
each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q1OR5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 4-8 membered ring that is optionally substituted with one or more instances of JE1;
Q1 is independently a bond, 000, OSD, ONR’D, DC(0)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, 0CO2O, 000(0)0, OC(O)NR’O, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, 0NRC(0)0, DNRC(O)NR’O, 0NRCO2D, -OC(O)NRO, -S(0)-, OS0200 -SO2NR’-, DNRSO20D or-NRSO2NR'-, -P(O)(OR)Û-, -0P(0)(ORa)0-, -P(0)20-, -C02S02-, or-(CR6R7)pOY10;
Q2is independently a bond, 000, DSO, ONRO, DC(O)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, 0C020, 000(0)0, 0C(O)NRD,-C(0)NRC(0)0-, -NRC(O)NRC(0)0-, 0NRC(O)n, ONRC(0)NRO, 0NRCO20, 0OC(O)NR0, -S(0)-, 0SO200 ON(R)SO2D, □SO2N(R)-, -NRSO2NR-, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(0)20-, -CO2SO2-, or -(CR6R7)POY1D; and
Q3 is independently a bond, 00(0)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, 0C020, -C(O)NR0, 0SO20. -SO2N(R)-, -C(O)NRC(O)O- or -(CR6R7)POY’OO each Y1 is independently a bond, 000, OSO, ONRO, 00(0)0, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, OC020, 000(0)0, 0C(0)NRD, -C(0)NRC(O)O-, -NRC(O)NRC(O)O-, 1NRC(0)0, ONRC(0)NRO, ONRCO/l, 10C(0)NRO, -S(0)-, 0SO200 DN(R)SO20, OSO2N(R)-, -NRSO2NR-, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(0)20-, or -CO2SO2-;
R5 is: i) -H; ii) a Ci-Ce aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C 1Q non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1; or
R5, together with each of Q1, Q2 and Q3, optionally and independently forms a 4-8 membered, non-aromatic ring optionally substituted with one or more instances of JE1; and
R6 and R7 are each independently OH or CrC6 alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, CrC6 haloalkoxy, C-i-Ceaminoalkoxy, Ci-C6 cyano alkoxy, CrC6 hydroxyalkoxy, and C2-C6alkoxyalkoxy, or optionally R6 and R7, together with the carbon atom to which they are attached, form aOcyclopropane ring optionally substituted with one or more instances of methyl;
R8 and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, CrCe alkyl, CrC6 haloalkyl, Ci-C6 cyanoalkyl, C2-C6 alkoxyalkyl, Ci-C6 aminoalkyl, CrCe hydroxyalkyl, CrCB carboxyalkyl, CrC6alkoxy, CrC6 haloalkoxy, 0,-06 aminoalkoxy, CrCecyanoalkoxy, Cr C6 hydroxyalkoxy, or C2-C6 alkoxyalkoxy; or R8, together with Q2 and R5, optionally and
551 independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1; or
R10 is independently -H or a Ci-C6 alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, CpCe haloalkoxy, CrCe aminoalkoxy, CrCe cyanoalkoxy, CrC0 hydroxyalkoxy, C2-C6 alkoxyalkoxy, C3-C8 non-aromatic carbocycle, phenyl, 4-8 membered nonaromatic heterocycle, and 5-6 membered heteroaryl group, wherein each of said carbocycle, phenyl, heterocycle and heteroaryl group is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, CrC6 alkyl, CrC6 haloalkyl, CrC6 cyanoalkyl, C2-C6 alkoxyalkyl, CrCB aminoalkyl, CrC6 hydroxyalkyl, Ci-CB alkoxy, CrC6 haloalkoxy, CrC6 aminoalkoxy, CrC6 cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-Cs alkoxyalkoxy;
R11 and R12, are each independently DH, halogen, or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, CrC6 alkoxy, CrC6 haloalkoxy, Ci-CB aminoalkoxy, CrC6 cyanoalkoxy, CrCe hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
R and R’ are each independently DH or CrC6alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, CrC6 haloalkoxy, Ci-C6 aminoalkoxy, C^Ce cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or optionally R’, together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered nonaromatic heterocycle optionally substituted with one or more instances of JD1;
R is independently: i) a CrCs-alkyl optionally substituted with one or more substituents selected independently from the group consisting of halogen, cyano, hydroxyl, ΠΝΗ2, □NHiC-iC6 alkyl), nN(Ci-Ce alkyl)2, CrCBalkoxy, CrC6 haloalkoxy, CrC6 aminoalkoxy, CrCe cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or ii) a C3-C6 carbocyclîc group, a 56 membered heteroaryl group, or a phenyl group, each optionally and independently being substituted with one ore more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, nitro, ONH2, nNH(CrCB alkyl), nN(CrCe a1kyl)2, CrC6 alkyl, Cr C6 haloalkyl, Ci-CB cyanoalkyl, CrC6-hydroxyalkyl, C2-C6-alkoxyalkyl, CrC6-aminoalkyl, CrC6 alkoxy, CrCB haloalkoxy, CrCB aminoalkoxy, CrC6 cyanoalkoxy, CrC6-hydroxyalkoxy, and C2Ce alkoxyalkoxy;
R* is independently: i) -H; ii) a CrC6 alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C3-Ce non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 membered heteroaryl, -O(C-|-C6 alkyl), and -C(O)(C1-C6-alkyl); wherein each of said alkyl groups in -O(CrC6 alkyl), and -CCOXCT-Ce-alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -000(0,-0., alkyl), -CO(C-|-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; and wherein each of said carbocycle, heterocycle, phenyl, and heteroaryl is independently and optionally substituted with one or more instances of JE1; or iii) a C3-Ce non-aromatic carbocycle, or a 4-8 membered nonaromatic heterocycle, each of which is independently and optionally substituted with one or more instances of JE1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, DORb, nSRb, -S(O)Ra, DSO2Ra, DNRbRc, □C(O)Rb, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, □ C(O)ORb, nOC(O)Rb, □NRCfOJR1’, □ C(O)NRbRc, DNRCfOJNRhR0, □NRC(O)OR6, DOCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),O-SO2NRcRb, -NRSO2Rb, -NRSO2NRcRb, -P(O)(ORa)2, -OP(O)(ORa)2, -P(O)2(ORa), and -CO2SO2Rb, or optionally, two JC1 and two JD1, respectively, together with the atom(s) to which they are attached, independently form a 4-8-membered ring that is optionally substituted with one or more instances of JE1;
each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C,-C6 alkyl, -O(CrC6 alkyl), and -C(O)(C-i-C6-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH21 -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -00(0,-0, alkyl), -CO2H, -CO2(C,C4 alkyl), and 0,-04 alkoxy; and each Ra is independently: i) a C,-Ce aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -0(0,-06 alkyl), -C(O)(Ci-C6-alkyl), C3-Ce non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and 610 membered carbocyclic aryl group; wherein each of said alkyl groups for the substituents of the C,-C5 aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl, and carbocyclic aryl groups for the substituents of the Ci-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more instances of JE1;
ii) a C3-C0 non-aromatrc carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is optionally and independently substituted with one or more instances of JE1;
iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclic aryl group, each of which is optionally and independently substituted with one or more instances of JE1; and
Rb and Rc are each independently Ra or -H; or optionally, Rb and R°, together with the nitrogen atom(s) to which they are attached, each independently form a 5-7 membered nonaromatic heterocycle optionally substituted with one or more instances of JE1;
563 p is independently 1, 2, 3 or 4;
n and m are each independently 0 or 1 when rings A and B are 3-6-membered; or n and m are each independently 0, 1 or 2 when rings A and B are 7-10-membered; and k is 0, 1 or 2;
x and y are each independently 0;
z is 1 or 2; and provided that if Y1 is a bond, then R6 is neither-H nor a C-|-Ce aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither-H nor a Cf-Ce aliphatic group.
25. The cornpound of claim 24, represented by structural formula (I):
or a pharmaceutically acceptable sait thereof, wherein:
R2 is -H; -CH3, -NH2, -NH(C1-C4 alkyl), -N^-C, alkyl)2;
ring A is a C3-Ce non-aromatic carbocycle or heterocycle, the carbocycle and heterocylce ptionally further substituted with one or more instances of JA and JB, respectîvely;
ring B is a 4-8 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB;
Q1 is independently a bond, OOO, OSO, ONR’O, 00(0)0, -C(=NR)-, 0CO20, □00(0)0, 0C(O)NRO, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, ONRC(O)O, nNRC(O)NR’O, 1NRC020, -00(0)NR'0, -S(O)-, ÜS0200 -SO2NR’-, ONRS0200 or -NRSOZNR’-, or(CR6R7)POY1O;
Q2is independently a bond, 000, OSO, ONRO, 00(0)0, -C(=NR)-, 0C020, 000(0)0, 0C(0)NR0, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, 0NRC(0)0, ONRC(O)NRn, ONRCOîO, -|OC(O)NRl, -S(O)-, nS0200 ON(R)S020, 0SOzN(R)-, -NRSOZNR-, or-(CR6R7)POY1O; and
Q3 is independently a bond, 00(0)0, -C(=NR)-, OCOzO, -C(O)NRl, 0SO20. -SO2N(R)-, -C(O)NRC(O)O- or -(CR6R7)pnY1no each of Q2 and Q3, together with R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1;
each Y1 is independently a bond, 000, OSO, ONRO, 00(0)0, OCOzO, 000(0)0, 0C(O)NR0, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, nNRC(0)0, 0NRC(O)NRn, ONRC020, □OC(O)NRO, -S(0)-, 0SO200 0N(R)SO20, 0SO2N(R)-, or -NRSO2NR-;
554
R5 is: i) -H; ii) a CpCe aliphatiç group optionally substituted with one or more instances of JC1; iii) a C3-C0 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1; or
R5, together with Q2 and Rs, optionally and independently forms a 5-7 membered, nonaromatic ring optionally substituted with one or more instances of JE1;
Rs and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, CrC6 alkyl, CrC6 haloalkyl, 0ή-06 cyanoalkyl, C2-C6 alkoxyalkyl, CrC6 aminoalkyl, Ci-C6 hydroxyalkyl, Ch-Ce alkoxy, C,-C6 haloalkoxy, Ο,-Ceaminoalkoxy, Ο,-Οβ cyanoalkoxy, Ο,-Ο6 hydroxyalkoxy, or C2-Ce alkoxyalkoxy; or R8, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1; and
R11 and R12 are each independently DH, halogen, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, C-|-C6 alkoxy, Ci-Ce haloalkoxy, CrCeaminoalkoxy, 0,-Ce cyanoalkoxy, hydroxyalkoxy, and C2-C0 alkoxyalkoxy;
each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, □OR1’, DSRb, -S(O)Ra, nSO2Ra, DNRbRc, aC(O)Rb, nC(O)ORb, nOC(O)Rb, □ NRC(O)Rb, □C(O)NRbRc, □NRC(O)NRbRc, □NRC(O)ORb, LlOCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),n-SO2NRcRb, -NRSOzRb, -NRSO2NRcRb, and -P(O)2(ORa), or optionally, two JC1 and two JD1, respectively, together with the atom(s) to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1 and fused to the respective ring to which they are attached; and n and m are each independently 0 or 1 when rings A and B are 3-6-membered; or n and m are each independently 0, 1 or 2 when rings A and B are 7-8-membered; for example, wherein:
ring A is a C3-C8 non-aromatic carbocycle optionally and independently further substituted with one or more instances of JA;
ring B is a 4-8 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB;
each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, and Q1DR5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1 and fused to the ring to which they are attached; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, nORb, nSRb, -S(O)Ra, üSO2Ra, □ NRhR0, DC(O)Rb, Π0(Ο)ΟΡ6, □OC(O)Rb, lNRC(O)Rb, □C(O)NRbRc, HNRC(O)NRbRc, nNRC(O)ORb, nOCONRbRc, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),n-SO2NRcRb, -NRSO2Rb, and -NRSO2NRcRb, or
555 optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached;
Q1 is independently a bond, DOD, OSO, L1NRD, 00(0)0, 0CO20, 000(0)0, 0C(O)NR0, -C(O)NRC(O)O- -NRC(0)NRC(0)0-, 0NRC(O)0, 0NRC(O)NR0, ONRC020, □OC(O)NRO, -S(0)-, 0S0200 DN(R)SO2O, 0SO2N(R)-, -NRSO2NR-, or-(CR6R7)pnY1nnn
Q2is independently a bond, Π00, OSO, ONRO, 00(0)0, 0CO20, 000(0)0, □ C(O)NRO, -C(O)NRC(O)O-, -NRC(0)NRC(0)0-, 0NRC(O)0, 0NRC(O)NRa, 0NRCO20, 0OC(O)NR0, -S(0)-, 0SO200 0N(R)SO2D, 0SO2N(R)-, -NRSO2NR-, or -(CR^pOY’O; and
Q3 is independently a bond, 00(0)0, 0CO2O, -C(0)NR0, 0S020.-SO2N(R)-, -C(O)NRC(O)O- or -(CR6R7)pnY1OO or each of Q2 and Q3, together with R®, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1;
each Y1 is independently a bond, 000, OSO, ONRO, 00(0)0, 00020, 000(0)0, 0C(0)NR0, -C(O)NRC(0)O-, -NRC(O)NRC(O)O-, DNRC(0)0, 0NRC(O)NR0, 0NRC020, 0OC(O)NRD, -S(O)-, 0SO2DD 0N(R)SO2D, 0SO2N(R)-, or-NRSO2NR-;
R5 is; i) -H; ii) a Ci-Cs aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-Ce non-aromatic carbocycle, or 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1; and
Ra and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, CrCe alkyl, Ci-C6 haloalkyl, Ci-C6 cyanoalkyl, C2-C6 alkoxyalkyl, CrC6 aminoalkyl, CrCe hydroxyalkyl, CrCe alkoxy, CrC6 haloalkoxy, C^Ce aminoalkoxy, Ci-C6 cyanoalkoxy, C^Cb hydroxyalkoxy, or C2-C6 alkoxyalkoxy.
26. The compound of any one of daims 24-25, wherein R3 is -H, -Cl, -F, -Br, -CN, -CF31 O(Ci-C4 alkyl), -OH, -NHZ, -NH(C-|-C4 alkyl), or-N(Ci-C4 alkyl)2, -CH3, -C2H5, nNH(CH3), or □N(CH3)Z.
27. The compound of any one of daims 24-26, wherein the compound is represented by the following structural formula (VI):
566 or a pharmaceutically acceptable sait thereof; wherein:
Z1 is -H, CrC6 alkyl, -O(C,-C6 alkyl), -F, -Cl, -CN, -CO2H, -CC^CrCe alkyl), -CONH2, -CONH(C-rC6 alkyl), or -CONfCrCe alkyl)z, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NHfCrC^ alkyl), -N(C1-C4 alkyl)2, -OCO(Cr C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), and CrC4 alkoxy; and
Z2 is -H, CtCs alkyl, -O(C5-CB alkyl), -NHZ, -NHfCrCe alkyl), or -N(Ci-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)2, -OCC^C,-^ alkyl), -CO(CrC4 alkyl), -CO2H, -COz(Cr C4 alkyl), and CrC4 alkoxy; for example, wherein:
Z1 is -H, -F, -Cl, -CF3, -CH3, or -CN;
Z2 is -H or CtCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(C1-C4 alkyl);
Z3 is -H or C-i-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(CrC4 alkyl);
R1 is -H;
R2 is -H;
R3 is independently -H, -Cl or -F;
R6 and R7 are each independently -H or-CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring;
each R8 is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, CrC4 haloalkyl, Cr C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C3—C4alkyl), F1NH2, ONH(CinC4 alkyl), or alkyl)2.
each R9 is independently -H or-CH3;
R11 and R12 are each independently -H or -CH3.
28. The compound of any one of claims 24-27, wherein the compound is represented by any one of structural formulae (II) and (III:
557 or a pharmaceutically acceptable sait thereof, wherein:
R3 is -H, DF, nCI, 0CF3, ONH2, □NHiCHg), or ONiCH^;
Z1 is-H, -F, -Cl, -CFs, CVC4 alkyl,-CH2NH2, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -O(Ci-C4 alkyl), or -CN;
each R and R' are independently -H or C4-Ce alkyl;
ring A is an optionally substituted, C4-C7 non-aromatic carbocycle;
ring B is an optionally substituted 4-7 membered non-aromatic heterocycle;
each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, andQ10R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1 and fused to the ring to which they are attached;
each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, nORb, OSRb, -S(O)Ra, 0SO2Ra, nNRbRc, 0C(O)Rb, □C(O)ORb, □OC(O)Rb, lNRC(O)Rb, □C(O)NRbRc, nNRC(O)NRbRc, □NRC(O)ORb, DOCONRhR0, -C(O)NRCO2Rb, -NRC(O)NRC(O)ORb, -C(O)NR(ORb),n-SO2NRcRb, -NRSO2Rb, and -NRSO2NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached;
Q1 is independently a bond, 000, OSO, ONR’O, 00(0)0, OCO2n, 000(0)0, nC(O)NR%, -C(O)NRC(O)O-, -NRC(O)NRC(0)0-, ElNRC(O)D, □NRC(O)NR’O, ONRCO2n, -OC(O)NR’O, -S(O)-, nS0200 -SO2NR’-, 0NRSO2ü0 or-NRSO2NR’-, or-(CR^pOY’O;
Q2is independently bond, ΟΟΠ, OSO, ONRO, 00(0)0, ΠΟΟ2Π, 000(0)0, DC(O)NR0, -C(O)NRC(O)O-, —NRC(O)NRC(O)O-, 0NRC(O)0, 0NRC(O)NR0, nNRCO2n, 0OC(O)NR0, -S(O)-, 0SO200 ON(R)SO2O, OSO2NR’-, -NRSO2NR'-, or-(CR6R7)pOY1O; and
Q3 is independently a bond, 00(0)0, 0C020, -C(0)NR’0, 0SO20-SO2NR’~, -C(O)NRC(O)O-, or-(CR6R7)pnY1OD provided that if Q2-R6 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H; and provided that if Q3 is -C(0)-, then R5 is a substituted Ci-C6 aliphatic group; an optionally substituted Ο3-Οβ non-aromatic carbocycle; an optionally substituted, 6-10-membered
563 carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group.
29. The compound of claim 28, wherein:
Z1 is -H, -F, -Cl, -CF3, -CH3i or -CN; and
Z2 is -H or an optionally substituted CrCB alkyl;
R3 is -H, -Cl or-F; and
R® and R7 are each independently -H or -CH3. or together with the carbon atoms to which they are attached they form a cyclopropane ring;
each R® is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, C-i-C, haloalkyl, 0,C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O(C,-C4 alkyl), ΠΝΗ2, ΟΝΗίΟ,ΠΟ, alkyl), or “1N(C,üC4 alkyl)2.
each R9 is independently -H or-CH3;
R11 and R12 are each independently -H or -CH3; and
R13 and R14 are each independently -H or -CH3, or optionally R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring.
30. The compound of any one of claims 28-29, wherein the compound is represented by structural formula (XIA) or (XIB):
or a pharmaceutically acceptable sait thereof, wherein:
ring A is a 5-7 membered non-aromatic carbocycle optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6 alkyl, C2-C6 alkenyl, -NH2, -NH(C-)-C6 alkyl), -N(C,-C6 alkyl)2, -O(Ci.C6 alkyl), -C(O)NH2, -C(O)NH(C,-C6 alkyl), -C(O)N(C,-CB alkyl)2, -C(O)(C,-C6-alkyl), -OC(O)(CrCB alkyl), -NHC(O)(Ci-Cb alkyl), -N(C,-Cb alkyl)C(O)(Ci-C6 alkyl), and -CO2Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -000(0,-0, alkyl), -00(0,-0, alkyl), -CO2H, -CO2(C,C4 alkyl), and 0,-0, alkoxy;
56S x is 0;
n is 0 or 1;
q2 is non, nNHo, -n(CH3)-, nc(O)n, nco2n, nC(O)NHn, □c(O)N(CH3)d1 oNHC^m, nN(CH3)C(O)n, nNHC(O)NR’Q, □ N(CH3)C(O)NR'î1, □ NHCO2D, nN(CH3)CO2n, nOC(O)NR’n, -NHSO2n. -N(CH3)SO2nnn-SO2NR’-nnor -(CR6R7)pOY1n;
R5 is independently i) -H; ii) a C,-C6-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-CB non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1; and each of JC1 and JD1 is independently selected from the group consisting of hhalogen, cyano, oxo, Ra, ElORb, üSR11, -S(O)Ra, nSO.R3, DNHRC, nC(O)Rb, aC(O)ORb, 300(0)^, □NHC(O)Rb, nC(O)NHRc, nNHC(O)NHRc, DNHC(O)ORb, □OCONHRC, -NHC(0)NHC(O)ORb, □ N(CH3)Rc, nN(CH3)C(O)Rb, □C(O)N(CH3)RC, □ N(CH3)C(O)NHRC, 061(0^)0(0)(^, nOCON(CH3)Rc, -C(O)NHC02Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(0)NHC(O)0Rb, -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb; and ring A is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -Ο(0,Ό4 alkylülODDNH2, □NH(C1OC4 alkyl), □N(C1nC4 alkyl)21 -0(0)(0,-04 alkylD, -00(0)(0,-04 alkylo, -CO2H, and -002(0,-04 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -Ν(0,-04 alkyl)2, -OCO(CiC4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and Ο,-Ο4 alkoxy.
31. The compound of claim 30, wherein the group -[C(R13R14)]x-ringA-Q2-R5 is independently selected from one of the depicted below:
570 wherein each of rings A1-A27 is independently and optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C2 alkyl), -NH(Ci-C2 alkyl)2, C-i-C2 alkyl, 0,-02 haloalkyl,
5 C,-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C,-C2 alkoxy, Ci-C2 hydroxyalkoxy, CrC2 haloalkoxy, C2C4 alkoxyalkoxy, -002Η, and -CO2(C,-C4 alkyl).
32. The compound of claim 31, wherein the group -[C(R13R14)]x-ringA-Q2-R5 is independently selected from one of the depicted below:
R0 _,R5 N H
R8
IJJH
10 R5 or wherein the group -[C(R13R14)]x-ringA-Q2-R5 is
571 wherein:
each of rings A5-A7, A21, A24 and A26; and each of rings A6, A8, A11, A14 and A15 is independently and optionally further substituted; and each R8 independently is halogen, cyano, hydroxy, CrC4 alkyl, C,-C4 haloalkyl, C,-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(0,-04 alkyl), ΠΝΗ2, □ΝΗ^αί^ alkyl) or □N(C1DC4 alkyl)2.
33, The compound of claim 32, wherein:
R5 is: i) -H; fi) an optionally substituted C,-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle;
wherein said alkyl group represented by RE is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NHtC^Ci alkyl), -N(Ci-C4 alkyl)2, -000(0,-0, alkyl), -CO(C,-C4 alkyl), -C02H, -COZ(C,C4 alkyl), and Ci-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by R5 and referred to for the substituents ofthe 0,-06 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(Ci-C4 alkyl), ΠΝΗ2, ΠΝΗ(0,Π04 alkyl), ΠΝ(0ιΠ04 alkyl)z, -C(0)(C,-C4 alkyl), -OC(O)(C1-C4 alkyl), -C(O)O(C,-C4 alkyl), and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)z, -OCO(CrC4 alkyl), -00(0,-04 alkyl), -COZH, -COZ(C,-C4 alkyl), and C,-C4 alkoxy.
34. The compound of any one of claims 28-29, wherein the compound is represented by structural formula (XIIA) or (XIIB):
572 (ΧΙΙΑ) (XIIB), or a pharmaceutically acceptable sait thereof; wherein:
ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrCe alkyl, C2-C6alkenyl, -NH2, -NH(CrC6 alkyl), -NfCrCe alkyl)2, -O(CvC6 alkyl), -C(O)NH2, -CiOJNHiCrCe alkyl), CiOJNiCrCe alkyl)2, -CiOJfCrCs-alkyl), -00(0)(0^06 alkyl), -ΝΗΟίΟχΟ,-Οε alkyl), -N(CrC6 alkyl)C(O)(CrC6 alkyl), and -CO2Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -002(0ν04 alkyl), and Οή-Ο4 alkoxy;
y is 0;
Q3 is independently 00(0)0, Π0020, 0C(0)NH0, Π0(Ο)Ν(ΟΗ3)Π, -C(0)NHC(0)0-, -C(O)N(CH3)C(O)O-, -S02-, -S02NH-, -SO2(CH3)-, or -(CReR7)p-Y1-; and
Rs is independently i) -H; ii) a CrC5-alkyl optionally substituted with one or more instances of JC1; iii) a C3-Ce non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 orvi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, nORb, HSRb, -S(O)Ra, 0SO2Ra, ONHRC, nC(O)Rb, nC(O)ORb, nOC(O)Rb, nNHC(O)Rb, nC(O)NHRc, r]NHC(O)NHRc, nNHC(O)ORb, nOCONHR0, -NHC(O)NHC(O)ORb, nN(CH3)Rc, nN(CH3)C(O)Rb, nC(O)N(CH3)Rc, nN(CH3)C(O)NHRc, □ N(CH3)C(O)ORb, □ OCON(CH3)Rc, -C(O)NHCO2Rb, -C(O)N(CH3)CO2Rb, -N(CH3)C(O)NHC(O)ORb, -NHSO2Rb, -SO2NHRb, -SO2N(CH3)Rb, and -N(CH3)SO2Rb
35. The compound of claim 34, wherein ring B is independently selected from:
573 wherein each of rings B1, B2 and B4-B9 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), -Ν(Οι-Ο2 alkyl)2, C,-C2 alkyl, C,-C2 haloalkyl, C4C2 hydroxyalkyl, C2-C4 alkoxyalkyI, CrC2 alkoxy, Ci-C2 hydroxyalkoxy, C1-C2 haloalkoxy, CO2H, and —CO2(C,-C4 alkyl).
36. The compound of claim 35, wherein R5 is independently:
i) -H;
ii) a C,-C5-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(C,-C4 alkyl), ΟΝΗζ, 0ΝΗ(0ιΠ04 alkyl), ΠΝ^ΠΟ* alkyl)2, -C(O)(C,-C4 alkyl), -OC(O)(C,-C4 alkyl), -0(0)0(0,-04 alkyl), -CO2H, C3-C8 non-aromatic carbocycle, phenyl, 4-8 membered nonaromatic heterocycle, and 5-6 membered heteroaryl;
iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, 0,-04 alkyl, -O(C-|-C4 alkyl), QNH2, □ΝΗ(ΟιΠΟ4 alkyl), ΠΝ(0,004 alkyl)2, -0(0)(0,-04 alkyl), -00(0)(0,-04 alkyl), -0(0)0(0,-04 alkyl), and -CO2H;
wherein each of said alkyl groups for the substituents of Rs is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(0,-04 alkyl), -N(C,-C4 alkyl)2, -000(0,C4 alkyl), -00(0,-04 alkyl), -CO2H, -002(0,-04 alkyl), and C,-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the 0,-06-aliphatic group represented by R6 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(C,-C4 alkyl), -Ν(0,-04 alkyl)2, -000(0,-04 alkyl), -00(0,C4 alkyl), -C02H, -002(0,-04 alkyl), and C,-C4 alkoxy; for example, wherein the group (ring B )-Q3-R5 is
574 wherein:
ring B2 is optionally and independently further substituted; and
R5 is: i) -H; ii) an optionally substituted C,-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle;
wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consîsting of halogen, cyano, hydroxy, oxo, -NH2i -NH(C,-C4 alkyl), -N(C,-C4 alkyl)21 -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,C4 alkyl), C,-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the C,-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consîsting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -O(C-|-C4alkyl), ΠΝΗ2, □ NH(CiDC4 alkyl), □ NfCiOC,, alkyl)2, -C(O)(C,-C4 alkyl), -OC(O)(C,-C4 alkyl), -C(O)O(C,-C4 alkyl), and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consîsting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -C0(C,-C4 alkyl), -CO2H, -002(0,-04 alkyl), and C,-C4 alkoxy.
37. The compound of any one of ciaims 24-27, wherein R4 is:
ring E is a C4-C10 non-aromatic carbocycle optionally further substituted with one or more instances of JA;
rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1;
R® is independently -H, halogen, cyano, hydroxy, amino, carboxy, C,-C6 alkyl, C,-C6 haloalkyl, CrC6 cyanoalkyl, C2-C6 alkoxyalkyl, C,-C6 aminoalkyl, C,-C6 hydroxyalkyl, C,-C6 carboxyalkyl, C,-C6 alkoxy, C,-C6 haloalkoxy, C,-C6 aminoalkoxy, C,-C6 cyanoalkoxy, C,-C6 hydroxyalkoxy, or C2-C6 alkoxyalkoxy;
R11, R12, R13 and R14 are each independently ΠΗ, halogen, or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consîsting of
575 halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, Ci-C6 haloalkoxy, Ci-Ce aminoalkoxy, C^Ce cyanoalkoxy, C4-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl;
s is 0, 1 or 2; and x is 0; for example, wherein ring F is selected from any one of rings F1-F6:
o i--X R'nA °V'NRf NRf ^NR’ ^-0 | F2 N 1F3)=0 [f4Y=O |F5)c=O [f6^=O i‘2£7^O/ <î{7k“O andVNRf »
each of rings F1-F6 optionally and independently substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, CrC4 alkoxy, and CrC4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -O(Ci-C4 alkyl); and each Rf is independently ΏΗ or Ο,-Οβalkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C4-Ce alkoxy, CrC6 haloalkoxy, Ci-C6 aminoalkoxy, CrC6 cyanoalkoxy, Ci-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy.
38. The compound of any one of claims 24-27, wherein R4 is:
each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 5-10 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB;
X is -O-, -S-, or -NR9-;
576
R8 and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, CrCe alkyl, CrC6 haloalkyl, CrC6 cyanoalkyl, C2-C6 alkoxyalkyl, Ci-C6 aminoalkyl, CrC6 hydroxyalkyl,
CrC6 carboxyalkyl, Ci-C6 alkoxy, Ci-C8 haloalkoxy, CrC6 aminoalkoxy, C,-Ce cyanoalkoxy, Cr
Cs hydroxyalkoxy, or C2-C6 alkoxyalkoxy;
R13 and R14 are each independently ΠΗ, halogen, or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrCe alkoxy, Ci-C6 haloalkoxy, CrC6aminoalkoxy, CrCe cyanoalkoxy, CrC6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl;
R21, R22, R23, R24, and R25 are each independently DH, halogen, -OH, CrC6 alkoxy, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C-i-C6 alkoxy, CrCe haloalkoxy, CrC6aminoalkoxy, CrC6 cyanoalkoxy, CrCe hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
R9 is -H or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, CrCe alkoxy, CrC6 haloalkoxy, CrC6aminoalkoxy, CrC6 cyanoalkoxy, CrC6 hydroxyalkoxy, and C2C6 alkoxyalkoxy;
q is 0, 1 or 2;
x is 0; and r is 1 or 2.
39. The compound of claim 38, wherein R4 is:
wherein:
each of R8 and R9 is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, CrC4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -OfC,-^ alkyl), 0NH2, DNH(CinC4 alkyl), or RN(C1OC4 alkyl)2; and
R21, R22, R23, and R24 are each independently DH, halogen, -OH, or CrCs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6alkoxy, CrC6
577 haloalkoxy, CrC6 aminoalkoxy, C,-C5cyanoalkoxy, C,-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;
Qzis independently a bond, ΠΟα, aSD, HNRn, αθ(0)Π, -C(=NR)-, nCO2n, aOC(O)a, □C(O)NRD, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, ONRC(O)Q, ONRC(O)NRn, nNRCO2ü, □ OC(O)NRD, -S(O)-, □SO2nn 01^)50^, nSO2NR’-, -NRSOZNR’-, or -(CR6R7)pnY1a; or -CO2SO2-, or -P(O)2O-.
40, The compound of any one of claims 37-39, wherein:
Q1 is independently a bond, □<)□, OSO, DNRn, nC(O)0, -C(=NR)-, Π0Ο2α, □OC(O)D, OC(O)NRa, -C(O)NRC(O)O-, -NRC(O)NRC(O)O-, nNRC(O)D, l3NRC(O)NR0, □ NRCO20, nOC(O)NRn, -S(O)-, DSOsOD nN(R)SO2D, DSOzNR’-, -NRSO2NR’-, or -(CR6R7)pDY1a; and
Y1 is independently a bond, DOD, nSD, nNR'O, 00(0)0, -C(=NR)-, 00020, 000(0)0, 0C(O)NR’n, -C(O)NRC(O)O000-NRC(O)NRC(O)O-, 0NRC(O)0, 0NRC(O)NRO, ONRCOjO, LlOC(O)NR’n, -S(O)-, OSOzOO -SO2NR'-, ONRS02OD or-NRSO2NR’-,
41. The compound of any one of claims 37-39, wherein:
a) R1 is -H;
R2 is -H, -CH3, -CH2OH, or -NH2;
R3 is -H, OF, HCI, Ci_4 alkyl, or C,.4 haloalkyl;
Z1 is -H, -F, or -Cl;
Z2 is -H or C,-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(Ci-C4 alkyl);
Z3 is -H or C,-Cs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(C,-C4 alkyl);
R5 is: i) -H; ii) an optionally substituted C,-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -000(0,-04 alkyl), -00(0,-04 alkyl), -CO2H, -002(0,-04 alkyl), C,-C4 alkoxy, a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1; and wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the C,-C6 alkyl group represented by R5 is independently and optionally
57b substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -0(0,-04 alkyl), DNH2, □NH(Cil]C4 alkyl), DN(CiQC4 alkyl)2, -C(O)(C,-C4 alkyl), -OC(O)(C,-C4 alkyl), -C(O)O(C,-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents
5 independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -Ν(0,-04 alkyl)2] -OCO(CrC4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and C,-C4 alkoxy; or
b) R1 is -H;
10 R2 is-H or-CH2OH;
R3 is —H, QF, or ΠΟΙ;
Z1 is-H,-F, or-Cl;
Z2 is -H;
Z3 is -H;
15 Rs is independently: i) -H or ii) a Ci-C6-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -O(C,-C4alkyl), DNHs, □ΝΗ(0,Π04 alkyl), □ N(C,nC4 alkyl)2, -C(O)(C,-C4 alkyl), -OC(O)(C,-C4 alkyl), -C(0)O(C,-C4 alkyl), -CO2H, C3-C8 non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl;
20 wherein each of said alkyl groups referred to in the substituents of the Ci-C6-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(Ci-C4 alkyl), and C,-C4 alkoxy; and
25 wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the Ο,-Ce-alkyl group represented by R6 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -00:(0,-04 alkyl), and 0,-04 alkoxy.
42. The compound of any one of daims 37-41, wherein each of JA and J8 is selected from the group consisting of halogen, cyano, hydroxy, C,-C6 alkyl, -NH2, -NH(C,-C6 alkyl), -Ν(0,-06 alkyl)2, -0(C,.C6 alkyl), -C(O)NH2, -C(O)NH(C,-C6 alkyl), -C(O)N(C,-C6 alkyl)2, -C(O)(C,-C6alkyl), -OC(O)(C,-C6 alkyl), -NHC(O)(C,-C6 alkyl), -N(C,-C6 alkyl)C(O)(C,-C6 alkyl), and
35 -CO2Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)z, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -CO2(C,-C4 alkyl), and CrC4 alkoxy; for example, wherein each of JA and JB is selected from the group consisting of halogen, cyano, hydroxy,
-NH2, -NH(CrC4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -CO2H, -C02(Cr
C4 alkyl), CrC4 alkoxy, and Ci-C4 alkyl optionally substituted with one or more substituents
5 selected from the group consisting of halogen, cyano, hydroxy, and -O(CrC4 alkyl),
43, The compound of any one of daims 24-29, wherein:
ring A is a non-aromatic, 5-10 membered, bridged carbocylce or heterocycle, or ring A
10 and R8 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each of said carbocycle is independently and optionally substituted with one or more instances of JA and wherein each carbocycle is independently and
15 optionally substituted with one or more instances of JB;
R1 is -H;
R3 is -H, -CH3, -CHzOH, or -NH2;
R3 is -H, CF, DCI, C-j.4 alkyl, or CM haloalkyl;
Z1 is -H, -F, or -Cl;
20 Z2 is -H or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(CrC4 alkyl);
Z3 is -H or Ci-Cs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O(Ci-C4 alkyl);
Q2 is independently DOD, rjCOZLl, 000(0)0, □C(O)NR’D, -C(O)NRC(O)O25 ,0NRC(0)0, ONRC(O)NR'O, 0NRC02D, -OC(O)NRO, -P(O)(OR)O-, -OP(O)(ORa)0-,
-P(O)2O-, -CO2SO2-, or-(CR6R7)pOY1O;
Y1 is 000, 0C020, 000(0)0, OC(O)NR’O, -C(O)NRC(0)0-,DNRC(0)0, 0NRC(O)NR'0, 0NRC020, -OC(O)NRO, -P(O)(OR)O-, -OP(O)(ORa)O-, -P(0)z0-, or -CO2SOZ-;
30 R5 is: i) -H; ii) an optionally substituted C^Ce alkyl group; iii) an optionally substituted,
C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by Rs is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -NiC-t-C, alkyl)2, -OCOfCr^ alkyl), -CO(C1-C4 alkyl), -CO2H, -CO2(CrC4 alkyl), CrC4 alkoxy, -NRCO(CrC4 alkyl), -CONR(CrC4 alkyl), -NRCO2(C1-C4 alkyl), a C3-C7 5 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1;
wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected 10 from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -O(C-|-C4 alkyl), ΠΝΚ2, ΠΝΗ(ΟιΠΟ4 alkyl), ΠΝ(0,α04 alkyl)2, -0(0)(0^ alkyl), -OC(0)(C,-C4 alkyl), -C(O)O(Ci-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -C0(CrC4
15 alkyl), -CO2H, -CO^Cr^ alkyl), and ΟτΟ4 alkoxy;
each of R0 and R9 is independently -H, halogen, cyano, hydroxy, CrC4 alkyl, CrC4 haloalkyl, hydroxyalkyl, C2-C4 alkoxyalkyl, -0(^-04 alkyl), ΠΝΗ2, □NH(C1DC4 alkyl), or □N(c1ac4 alky1)2;
R11, R12, R13, and R14 are each independently ΠΗ, halogen, or C-|-Ce alkyl optionally
20 substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and Ci-C6 alkoxy; and each of JA and JB is independently selected from the group consisting of halogen, cyano, hydroxy, CrC6 alkyl, -NH2, -NH(CrC6 alkyl), -N^-Ce alky1)2, -0(0^ alkyl), -C(O)NH2, -CfOJNHiCrCe alkyl), -C(O)N(CrC6 alkyl)2, -C(O)(CrC6-alkyl), -OC(O)(Ci-C6 alkyl),
25 -NHCiOXCrCij alkyl), -N(CrCB alkylJCiOXCrCe alkyl), and -CO2Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHZ, -NHfOrC., alkyl), -N(CrC4 alkyl)2, -OCO^-Cî alkyl), -CO(CrC4 alkyl), -CO2K, -CO2(CrC4 alkyl), and CrC4 alkoxy; and
30 nisOorl;
x is 0.
44. The compound of claim 43, wherein:
R23 each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 5-10 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB;
X is -O-, -S-, or -NR9-;
R21, R22, R23, R24, and R2Sare each independently ΠΗ, halogen, -OH, CtC6alkoxy, or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C6 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(CrC6 alky1)2, -O(C5.C6 alkyl), -C(O)NHZ, -C(O)NH(CrC6 alkyl), -C(O)N(CrC6 alkyl)21 -C(O)(CrC6alkyl), -00(0)(0^6 alkyl), -NHCtOXCrCe alkyl), -ΝίΟ,-Οβ alkyOCtOXCrCe alkyl);
R9 is -H or Ci-C6 alkyl ptionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, Ο-,-Οβ haloalkoxy, Ο,-CBaminoalkoxy, Ci-Cecyanoalkoxy, CrC6 hydroxyalkoxy, and C2C6alkoxyalkoxy; and q is 0, 1 or 2; and r is 1 or 2; for example wherein:
R1 is -H;
R2 is -H;
R3 is-H, OF, orHCI;
Z1 is -H, -F, or -Cl;
Z2 is -H;
Z3 is -H;
X is -O-;
R5 is -H, an optionally substituted Cî-Cb alkyl, or optionally substituted phenyl;
each R0 is independently -H, halogen, hydroxy, CrC4 alkyl, C^C., haloalkyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or -O(Ci-C4 alkyl);
362 each of R9, R13, and R14 is independently -H or CrC4 alkyl;
R21, R22, R23, R24, and R26are each independently OH, halogen, -OH, CrC8alkoxy, or
Ci-C8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, CrC6 alkyl, and -OfCi.Ce alkyl); and each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NHÎCtCb alkyl), -N(Ci-Ce alkyl)2, -O(Ci_C6 alkyl), C-i-C4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and CrC4 alkoxy.
45. The compound of claim 24, wherein the compound is selected from any of the structures depicted in FIG. 3, FIG. 4, FIG. 5, FIG. 6, and FIG. 7, or a pharmaceutically acceptable sait thereof.
46. A pharmaceutical composition, comprising an effective amount of a compound according to any one of daims 24 to 45, or a pharmaceutically acceptable sait of the same, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
47. The pharmaceutical composition of claim 46, additionally comprising a therapeutic agent selected from an antiviral agent or a vaccine.
48. The compound for use according to any one of daims 1-5,or the compound according to any one of daims 24-27, wherein R3 is methyl or ethyl
49. The compound for use according to daim 1, wherein the compound is selected from the compounds depicted in FIG. 3, FIG. 4, FIG. 5, FIG. 6, FIG. 7, and FIG. 8, or a pharmaceutically acceptable sait thereof.
50. A compound as described in any one of daims 1-23 and 48-49, or a combination of said compounds thereof, for use in reducing the amount of influenza viruses in a biological sample or in a patient, or for use in treating influenza in a patient.
51. A method preparing a compound represented by Structural Formula (IA):
583 or a pharmaceutically acceptable sait thereof, for example, wherein R1 of Structural Formula (IA) is -H comprising the step of:
5 A)
i) reacting compound A:
Cl
H N.
R (A) with compound B :
to form a compound represented by Structural Formula (XX);
ii) deprotecting the Ts group of the compound of Structural Formula (XX) to form the compound of Structural Formula (IA),wherein:
the variables of Structural Formulae (IA) and (XX), and compounds (A) and (B) are independently as defîned in any one of claims 24-45; and
15 Tsistosyl;or
534
i) reacting compound C1 or C2:
NH2R4 to form a compound represented by Structural Formula (XX):
ii) deprotecting the Ts group of the compound of Structural Formula (XX) to form the
5 compound of Structural Formula (IA),wherein:
the variables of Structural Formulae (IA) and (XX), and compounds (C1) and (C2) are independently as defined in any one of claims 24-45; and
Ts is tosyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/187,713 | 2009-06-17 | ||
| US61/287,781 | 2009-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA16260A true OA16260A (en) | 2015-04-10 |
Family
ID=
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