Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
  • C07D487/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

• the present invention relates generally to compounds and pharmaceutical
• compositions useful as hepatitis virus replication inhibitors relate to tetracyclic pyridone compounds that are useful in treating viral infections such as hepatitis B virus (HBV).
• HBV hepatitis B virus
• the invention provides novel tetracyclic pyridone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions in the treatment and prevention of HBV infections.
• HBV hepatitis B virus
• HBV is a member of the Hepadnavirus family, and it is able to replicate through the reverse transcription of an RNA intermediate.
• the 3.2-kb HBV genome exists in a circular, partially doublestranded DNA conformation (rcDNA) that has four overlapping open reading frames (ORF). These encode for the core, polymerase, envelope, and X proteins of the virus.
• rcDNA must be converted into covalently closed circular DNA (cccDNA) in cells prior to the transcription of viral RNAs. As rcDNA is transcriptionally inert, cccDNA is the only template for HBV transcription, and its existence is required for infection.
• the HBV viral envelope contains a mixture of surface antigen proteins (HBsAg).
• the HBsAg coat contains three proteins that share a common region that includes the smallest of the three proteins (SHBsAg).
• the other two proteins, Medium HBsAg (MHBsAg) and Large HBsAg (LHBsAg) both contain a segment of SHBsAg with additional polypeptide segments.
• SHBsAg, MHBsAg, and LHBsAg can also assemble into a non-infectious subviral particle known as the 22-nm particle that contains the same proteins found around infectious viral particles.
• the 22-nm particles contain the same antigenic surface proteins that exist around the infectious HB V virion, they can be used as a vaccine to produce neutralizing antibodies.
• the non-infectious 22-nm particles are found in much greater abundance than the infectious virions.
• the 22-nm particles are thought to be able to protect the infectious virions from the infected host’s immune response. Not only can they serve as infectious decoys, but they also suppress normal functioning of immune cells thereby impairing the host’s immune response to HBV. Therefore, reducing the level of subviral particles is a feasible therapeutic approach to treating HBV infections. (Refer to W02015/13990).
• WO2016/128335 WO 2017/140821, WO2019097479, WO2019166951, WO2019123285, WO2018198079, WO2018073753, W02018047109, WO2019110352, WO2019129681, WO2018087345, WO2018083136, W02018083106, W02018083081, WO2017216391, W02018001952, W02018001944, WO2016107832, WO2016177655, W02017017042, W02017017043.
• the present invention relates to novel antiviral compounds, pharmaceutical compositions comprising such compounds, as well as methods to treat or prevent viral (particularly HBV) infection in a subject in need of such therapy with said compounds.
• HBV hepatitis B virus
• the present invention provides compounds represented by Formula (I),
• Qi, , Q 3 , and Q 4 are each independently selected from hydrogen, halo, NR 11 R 12 , optionally substituted -C 1 -C 6 alkyl, optionally substituted -C 1 -C 6 alkoxy, optionally substituted -C 3 -C 8 cycloalkyl; optionally substituted -C 3 -C 8 cycloalkenyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl;
• one of Qi and Q 2 and one of Q 3 and Q 4 are taken together with the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
• Qi and Q 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
• Q3 and Q4 are taken together with the carbon atom to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
• Yi is hydrogen, halo, or optionally substituted C 1 -C 6 alkyl
• Y 2 is O, NR 11 , N(ORii), or N(NRn);
• Y 3 is -COOR11, -C(0)NHS0 2 R I I , -C(0)NHS0 2 NR H R I2 , or l,2,4-oxadiazol-3- yl-5(4H)-one, or Y3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 5 -C 6 cycloalkyl, or optionally substituted 5- to 6-membered heterocycloalkyl;
• Y4 is hydrogen or optionally substituted methyl
• Y 2 and Y 3 are taken together to form an optionally substituted 5-12 membered heterocyclic ring containing 1, 2, or 3 double bonds;
• Zi is N or CRi
• Z 2 is N or CR 2
• Z 3 is N or CR 3 , provided that at least one of Zi, Z 2 and Z 3 is N;
• Ri, R 2 and R 3 are each independently selected from:
• Rn, R I2 , and R13 are each independently selected from hydrogen, optionally substituted -Ci-Cx alkyl, optionally substituted -C 2 -Cx alkenyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8- membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
• Rn and R I2 are taken together with the nitrogen atom to which they attached to form an optionally substituted 3-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds.
• Rn and R I2 are taken together with the nitrogen atom to which they attached to form an optionally substituted 3-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds.
• R 2 is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted bicyclic heterocycloalkyl, more preferably optionally substituted aryl or optionally substituted heteroaryl.
• Ri is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C3-C8 cycloalkyl or optionally substituted 3- to 12-membered heterocycloalkyl; and R 2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C3-C8 cycloalkyl or optionally substituted 3- to 12-membered heterocycloalky.
• Z3 is N, Zi is CRi and Z 2 is CR 2 , and R 2 is not hydrogen; halogen; cyano; optionally substituted -C1-C6 alkyl; optionally substituted -C3-C7 cycloalkyl; optionally substituted 3- to 7-membered heterocycloalkyl; -NH 2 ; -NHC1-C6 alkyl; -OH; or - OC1-C6 alkyl.
• R 2 is preferably optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl
• Ri is preferably optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, hydrogen or halogen.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Yi is hydrogen, F, Cl, -CFE or -CF 3 .
• Yi is H or F.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Y2 is O.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Y 3 is -COOH, or - C(0)NHS02NRiiRi2, or Y3 is triazolyl, wherein Rn and R12 are as previously defined.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Y4 is hydrogen or CFE.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein at least one of Ri, R 2 and R 3 , preferably R 2 , is optionally substituted aryl; optionally substituted arylalkyl; optionally substituted heteroaryl; or optionally substituted heteroarylalkyl.
• Z 3 is N, Z 2 is CR2, and Zi is CRi, wherein Ri and R2 are as defined above.
• Ri is hydrogen or halogen, preferably hydrogen.
• R2 is is optionally substituted aryl; optionally substituted arylalkyl; optionally substituted heteroaryl; or optionally substituted heteroarylalkyl.
• Z 3 is N, Zi is CRi, and Z 2 is CR 2 , wherein Ri is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 12-membered heterocycloalkyl; and R 2 is as previously defined.
• Ri is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 8-membered heterocycloalkyl; and R2 is as previously defined.
• Ri is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C3-C8 cycloalkyl, or optionally substituted 3- to 8- membered heterocycloalkyl; and R2 is hydrogen.
• Z 3 is N, Zi is CRi, and Z 2 is CR 2 , wherein R 2 is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 12-membered heterocycloalkyl; and Ri is as previously defined.
• R 2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 8-membered heterocycloalkyl; and Ri is as previously defined.
• R2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 8- membered heterocycloalkyl; and Ri is hydrogen.
• Z 3 is N, Zi is CRi, and Z 2 is CR 2 , wherein Ri is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 12-membered heterocycloalkyl; and R2 is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 12-membered heterocycloalkyl.
• Ri is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 8- membered heterocycloalkyl; and R2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 8- membered heterocycloalkyl.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein at least one of Ri, R 2 and R 3 , preferably at least one of Ri and R 2 , is derived from one of the following by removal of a hydrogen atom:
• each of these groups is optionally substituted with one to four groups selected from halo, CN, -ORn, -NR 11 R 12 , optionally substituted C 1 -C 6 alkyl, and optionally substituted 3- to 8- membered heterocyclic.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein at least one of Ri, R 2 and R 3 , preferably at least one of Ri and R 2 , is selected from one of the following:
• each R 21 is independently selected from -CH 3 , -isopropyl, -t-butyl, or one of the following by removal of a hydrogen atom:
• each of these groups is optionally substituted with one to four groups selected from halo, CN, -OR 11 , -NRn R 12 , optionally substituted C 1 -C 6 alkyl, and optionally substituted 3- to 8- membered heterocyclic.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Qi is hydrogen, Cl or F; Q 2 is hydrogen, Cl or F, and Q 3 is hydrogen, Cl or F.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Q4 is -t-butyl or isopropyl.
• the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Q 4 is taken together with Qi or Q 2 , and with the carbon atoms on piperidinyl ring to which they are attached to form an optionally substituted ring selected from below:
• the compound of Formula (I) is represented by one of Formulae (II-l) ⁇ (P-7), or a pharmaceutically acceptable salt thereof:
• Yi, Y3, Y4, Ri, R2, R3, Qi, Q2, Q3, and Q4 are as previously defined.
• Q 3 and Q 4 are taken together with the carbon atom to which they are attached to form a spiro ring.
• Qi and Q 3 are both hydrogen, and Q 2 and Q 4 are taken together with the carbon atoms to which they are attached to form a cis-fused ring.
• the compound of Formula (I) is represented by Formula (HI- 1) or Formula (IP-2), or Formula (IP-3), or a pharmaceutically acceptable salt thereof:
• the compound of Formula (I) is represented by Formula (IV) or Formula (IV-1), or a pharmaceutically acceptable salt thereof:
• the compound of Formula (I) is represented by Formula (IV- a) or Formula (IV-la), or a pharmaceutically acceptable salt thereof:
• the compound of Formula (I) is represented by one of Formulae (V-l) ⁇ Formulae (V-8), or a pharmaceutically acceptable salt thereof:
• Ri is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocycloalkyl
• R2 IS optionally substituted aryl or optionally substituted heteroaryl, or R2 is optionally substituted -C3-C8 cycloalkyl, or optionally substituted 3- to 8-membered heterocycloalkyl.
• the present invention relates to compounds of Formulae (V- 1) ⁇ Formulae (V-8) prison and pharmaceutically acceptable salts thereof, wherein Ri and R2 are derived from one of the following by removal of a hydrogen atom:
• each of these groups is optionally substituted with one to four groups selected from halo, CN, -ORn, -NR 11 R 12 , optionally substituted C 1 -C 6 alkyl, and optionally substituted 3- to 8- membered heterocyclic.
• the present invention relates to compounds of Formulae (V- 1) ⁇ Formulae (V-8), and pharmaceutically acceptable salts thereof, wherein Ri and R 2 are selected from one of the following:
• each R 21 is independently selected from -CH 3 , -isopropyl, -t-butyl, or one of the following by removal of a hydrogen atom:
• each of these groups is optionally substituted with one to four groups selected from halo, CN, -OR 11 , -NR 11 R 12 , optionally substituted C 1 -C 6 alkyl, and optionally substituted 3- to 8- membered heterocyclic.
• the compound of Formula (I) is represented by Formula (VI), or a pharmaceutically acceptable salt thereof:
• each R 22 is independently hydrogen, optionally substituted -C 1 -C 6 alkyl, optionally substituted -C 2 - , alkenyl, optionally substituted -C 2 - , alkynyl, optionally substituted Ci- C 6 alkoxy; optionally substituted -C 3 -C 7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclic, optionally substituted aryl or optionally substituted heteroaryl; n is 0, 1, 2 or 3.
• two adjacent Vs are -C(R22)2-.
• two adjacent Vs are -C(R22)2-.
• two adjacent Vs are -C(R22)2-.
• the compound of Formula (I) is represented by Formula (VII-1) or Formula (VII-2),or a pharmaceutically acceptable salt thereof:
• the compound of Formula (I) is represented by one of Formulae (VIII-1) ⁇ (VIII-6), or a pharmaceutically acceptable salt thereof:
• the compound of Formula (I) is represented by one of Formulae (IX- 1) ⁇ (IX-6), or a pharmaceutically acceptable salt thereof:
• R 2 IS optionally substituted aryl or optionally substituted heteroaryl, or R 2 is optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 8-membered heterocycloalkyl.
• R 2 is derived from one of the following by removal of a hydrogen atom:
• each of these groups is optionally substituted with one to four groups selected from halo, CN, -OR 11 , -NR 11 R 12 , optionally substituted C 1 -C 6 alkyl, and optionally substituted 3- to 8- membered heterocyclic.
• the compound is represented by one of Formulae (IX-1) ⁇ (IX-6), or a pharmaceutically acceptable salt thereof, wherein R2 is independently selected from one of the following:
• each R21 is independently selected from -CH3 , -isopropyl, -t-butyl, or one of the following by removal of a hydrogen atom:
• each of these groups is optionally substituted with one to four groups selected from halo, CN, -OR 11 , -NRn R 12 , optionally substituted C 1 -C 6 alkyl, and optionally substituted 3- to 8- membered heterocyclic.
• the compound is represented by Formula (V-l), Formula (V- 5), Formula (IX-1), or Formula (IX -4), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from halogen, -CN, -CH 3 , -CF 3 , -CHF2,-C(0)CH3, -OCH 3 , -OCF 3 , - OCHF 2 , -OH, -OR 11 , -NH 2 , and -NHR 12 , wherein Rn and R 12 are each independently selected from one of the following by removal of a hydrogen atom:
• each of these groups is optionally substituted with one to four groups selected from halo, CN, -OR11, -NR11R12, optionally substituted C1-C6 alkyl, and optionally substituted 3- to 8- membered heterocyclic.
• the compound is represented by Formula (V-l), Formula (V- 5), Formula (IX-1), or Formula (IX -4), or a pharmaceutically acceptable salt thereof, wherein R 2 is derived from one of the following by removal of a hydrogen atom:
• each of these groups is optionally substituted with one to four groups selected from halo, CN, -OR 11 , -NR 11 R 12 , optionally substituted C 1 -C 6 alkyl, and optionally substituted 3- to 8- membered heterocyclic.
• the compound of Formula (I) is represented by one of Formulae (X-l) ⁇ (X-8), or a pharmaceutically acceptable salt thereof:
• R 2 and V are as previously defined.
• R 2 IS optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 8-membered heterocycloalkyl.
• the compound of Formula (I) is represented by one of Formulae (XI- 1) ⁇ (XI-8), or a pharmaceutically acceptable salt thereof:
• R2 is as previously defined.
• R2 is optionally substituted aryl
• optionally substituted heteroaryl optionally substituted -C 3 -C 8 cycloalkyl, or optionally substituted 3- to 8-membered heterocycloalkyl.
• the compound of Formula (I) is represented by one of
• Yi, Ri, R 2 , and R 3 are as previously defined.
• Yi is H or F; Ri, R 2 , and R 3 are each independently selected from hydrogen, halogen, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted -C 3 -C 8 cycloalkyl, and optionally substituted 3- to 8- membered heterocycloalkyl. More preferably, Yi is H; and Ri, R 2 , and R 3 are each independently selected from optionally substituted aryl and optionally substituted heteroaryl.
• the compound of Formula (I) is represented by one of
• Yi, Y 3 , Ri, R 2 , and R 3 are as previously defined.
• Yi is H or F;
• Y 3 is - COOH or triazolyl;
• Ri, R 2 , and R 3 are each independently selected from hydrogen, halogen, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted -C 3 -C 8 cycloalkyl, and optionally substituted 3- to 8-membered heterocycloalkyl.
• Yi is H; Y 3 is - COOH, and Ri, R 2 , and R 3 are each independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 3 -C 8 cycloalkyl, and optionally substituted 3- to 8-membered heterocycloalkyl.
• the compound of Formula (I) is represented by one of Formulae (XIV-1) ⁇ (XIV-4), or a pharmaceutically acceptable salt thereof:
• Yi, Y 3 , Ri, R 2 , R 3 and G4 are as previously defined.
• Yi is H or F;
• Y 3 is - COOH or triazolyl;
• G4 is t-butyl or isopropyl;
• Ri, R 2 , and R 3 are each independently selected from hydrogen, halogen, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted -C 3 -C 8 cycloalkyl, and optionally substituted 3- to 8-membered heterocycloalkyl.
• Yi is H; Y3 is -COOH or triazolyl; G4 is t-butyl or isopropyl; and Ri, R 2 , and R 3 are each independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C3-C8 cycloalkyl, and optionally substituted 3- to 8- membered heterocycloalkyl.
• the compound of Formula (I) is represented by one of Formulae (XV- 1) ⁇ (XV-6), or a pharmaceutically acceptable salt thereof:
• Yi, Y 3 , Ri, and R2 are as previously defined.
• Yi is H or F
• Y 3 is -COOH or triazolyl
• Ri, and R2 are each independently selected from optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted -C 3 -C 8 cycloalkyl, and optionally substituted 3- to 8- membered heterocycloalkyl.
• Yi is H; Y 3 is -COOH or triazolyl; and Ri and R2 are each independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 3 -C 8 cycloalkyl, and optionally substituted 3- to 8- membered heterocycloalkyl.
• the compound is represented by Formula (XII-1) ⁇ Formula (XII-6), or Formula (XIII-1) ⁇ Formula (XIII-6), or Formula (XIV- 1) ⁇ Formula (XIV-4), or Formula (XV-1) ⁇ Formula (XV-6), or a pharmaceutically acceptable salt thereof, wherein Ri, R 2 , and R 3 are each independently selected from one of the following by removal of a hydrogen atom:
• the compound is represented by Formula (XII-1) ⁇ Formula (XII-6), or Formula (XIII-1) ⁇ Formula (XIII-6), or Formula (XIV- 1) ⁇ Formula (XIV-4), or Formula (XV- 1) ⁇ Formula (XV-6), or a pharmaceutically acceptable salt thereof, wherein Ri, R 2 , and R 3 are each independently selected from one of the following by removal of a hydrogen atom:
• the compound of the invention is represented by Formula (XII-1) ⁇ Formula (XII-6), or Formula (XIII-1) ⁇ Formula (XIII-6), or Formula (XIV- 1) ⁇
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (X-l), and pharmaceutically acceptable salts thereof, where R2 and are defined for each compound in Table 1.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (X-2), and pharmaceutically acceptable salts thereof, where R2 and are defined for each compound in Table 2.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (X-3), and pharmaceutically acceptable salts thereof, where R2 and are defined for each compound in Table 3.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (X-4), and pharmaceutically acceptable salts thereof, where R2 and are defined for each compound in Table 4.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (X-5), and pharmaceutically acceptable salts thereof, where R2 and are defined for each compound in Table 5.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (X-6), and pharmaceutically acceptable salts thereof, where R2 and are defined for each compound in Table 6.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (X-7), and pharmaceutically acceptable salts thereof, where R2 and are defined for each compound in Table 7.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (X-8), and pharmaceutically acceptable salts thereof, where R2 and are defined for each compound in Table 8.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (XI-1), and pharmaceutically acceptable salts thereof, where R2 is defined for each compound in Table 9.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (XI-2), and pharmaceutically acceptable salts thereof, where R2 is defined for each compound in Table 10.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (XI-3), and pharmaceutically acceptable salts thereof, where R2 is defined for each compound in Table 11.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (XI-4), and pharmaceutically acceptable salts thereof, where R2 is defined for each compound in Table 12.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (XI-5), and pharmaceutically acceptable salts thereof, where R2 is defined for each compound in Table 13.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (XI-6), and pharmaceutically acceptable salts thereof, where R2 is defined for each compound in Table 14.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (XI-7), and pharmaceutically acceptable salts thereof, where R2 is defined for each compound in Table 15.
• Representative compounds of the invention include, but are not limited to, compounds according to Formula (XI-8), and pharmaceutically acceptable salts thereof, where R2 is defined for each compound in Table 16.
• the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
• the compounds described herein are suitable for monotherapy and are effective against natural or native HBV strains and against HBV strains resistant to currently known drugs. In another embodiment, the compounds described herein are suitable for use in combination therapy.
• the compounds of the invention can be used in methods of modulating (e.g., inhibit, disrupt or accelerate) the activity of HBV cccDNA. In yet another embodiment, the compounds of the invention can be used in methods of diminishing or preventing the formation of HBV cccDNA.
• the additional therapeutic agent is selected from core inhibitor, which includes GLS4, GLS4JHS, JNJ-379, ABI-H0731, ABI-H2158, AB-423, AB-506, WX-066, and QL-0A6A; immune modulator or immune stimulator therapies, which includes T-cell response activator AIC649 and biological agents belonging to the interferon class, such as interferon alpha 2a or 2b or modified interferons such as pegylated interferon, alpha 2a, alpha 2b, lamda; or STING (stimulator of interferon genes) modulator; or TLR modulators such as TLR-7 agonists, TLR-8 agonists or TLR-9 agonists; or therapeutic vaccines to stimulate an HBV-specific immune response such as virus-like particles composed of HBcAg and HBsAg, immune complexes of HBsAg and HBsAb, or recombinant proteins comprising HBx, HBsAg
• the reverse transcriptase inhibitor is at least one of Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Aba-cavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.
• the TLR-7 agonist is selected from the group consisting of SM360320 (12-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)ad- enine), AZD 8848 (methyl [3-( ⁇ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-12- yl)propyl][3-(4-morpholinyl) propyl] amino Imethyl)phenyl] acetate), GS-9620 (4-Amino-2- butoxy-8-[3-(2-pyrrolidinylmethyl)benzyl]-7,8-dihydro-6(5H)-pteridinone), AL-034 (TQ- A3334), and RO6864018.
• SM360320 (12-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)ad- enine)
• AZD 8848 methyl [3-( ⁇ [3-(6-amino-2
• the TLR-8 agonist is GS-9688.
• the compound and the additional therapeutic agent are co-formulated. In another embodiment, the compound and the additional therapeutic agent are co-administered.
• administering the compound of the invention allows for administering of the additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.
• the individual before administering the therapeutically effective amount of the compound of the invention, is known to be refractory to a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
• administering the compound of the invention reduces viral load in the individual to a greater extent compared to the
• administering of the compound of the invention causes a lower incidence of viral mutation and/or viral resistance than the administering of a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
• aryl refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
• a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
• Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
• heteroaryl refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
• Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl.
• a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
• aromatic groups can be substituted or unsubstituted.
• alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
• C2-C4 alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
• C2-C4 alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
• C 2. C 6 alkyl “C 2. C 8 alkyl,”“C 2.
• Ci 2 alkyl refers to alkyl groups containing from one to four, one to six, one to eight, one to twelve, 2 to 4 and 3 to 6 carbon atoms respectively. Examples of C 2.
• C alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, «-butyl, /er/-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
• alkenyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
• C 2 -C 8 alkenyl “C 2 -Ci 2 alkenyl,”“C 2 -C 4 alkenyl,”“C 3 -C 4 alkenyl,” or“C 3 -C 6 alkenyl,” refer to alkenyl groups containing from two to eight, two to twelve, two to four, three to four or three to six carbon atoms respectively.
• Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like.
• alkynyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
• C 2 -C 8 alkynyl refers to alkynyl groups containing from two to eight, two to twelve, two to four, three to four or three to six carbon atoms respectively.
• Representative alkynyl groups include, but are not limited to, for example, ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, and the like.
• cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo- substituted or optionally substituted with exocyclic olefmic double bond.
• Preferred cycloalkyl groups include C3-C12 cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl.
• C3-C12 cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene- cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3- methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.
• cycloalkenyl refers to monocyclic or polycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo- substituted or optionally substituted with exocyclic olefmic double bond.
• Preferred cycloalkenyl groups include C3-C12 cycloalkenyl, C3-C8 cycloalkenyl or C5-C7 cycloalkenyl groups.
• C3-C12 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2- enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-2-enyl, bicyclo[4.2.1]non-3-en-12-yl, and the like.
• arylalkyl means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CEhCEh-phenyl.
• substituted arylalkyl means an arylalkyl functional group in which the aryl group is substituted.
• heteroarylalkyl means a functional group wherein an alkylene chain is attached to a heteroaryl group.
• substituted heteroarylalkyl means a heteroarylalkyl functional group in which the heteroaryl group is substituted.
• alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 2-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• Preferred alkoxy are (C2-C3) alkoxy.
• any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
• An“aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds.
• aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH 2 , C(0), S(0) 2 , C(0)0, C(0)NH, 0C(0)0, OC(0)NH, OC(0)NH 2 , S(0) 2 NH, S(0) 2 NH 2 , NHC(0)NH 2 , NHC(0)C(0)NH, NHS(0) 2 NH, NHS(0) 2 NH 2 , C(0)NHS(0) 2, C(0)NHS(0) 2 NH or C(0)NHS(0) 2 NH 2 , and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group.
• functional groups such as alkyl, alkenyl, alkynyl, O, OH, NH, NH 2 , C(0), S(0) 2 , C(0)0, C(0)NH, 0C
• Carbon atoms of an aliphatic group can be optionally oxo- substituted.
• An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
• aliphatic groups expressly include, for example, alkoxyalkyls, poly alkoxy alkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.
• heterocyclic or“heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo- substituted or optionally substituted with exocyclic olefmic double bond.
• each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen
• each ring system can be saturated or unsaturated
• the nitrogen and sulfur heteroatoms may optionally be oxidized
• the nitrogen heteroatom may optionally be
• heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 2- oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups can be C-attached or N-
• any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s).
• One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
• substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C 2 -Ci 2 -alkyl; C 2 -Ci 2 -alkenyl, C 2 -Ci 2 -alkynyl, -C 3 -Ci 2 -cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-C2-Ci2-alkyl, -NH-C2-C8- alkenyl, -NH-C 2 -C 8 -alkynyl, -NH-C 3 -C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH- heterocycloalkyl, -dialkylamino
• the substituents are independently selected from halo, preferably Cl and F; Ci-C 4 -alkyl, preferably methyl and ethyl; halo-Ci-C 4 -alkyl, such as fluorom ethyl, difluorom ethyl, and trifluorom ethyl; C 2 -C 4 -alkenyl; halo-C 2 -C 4 -alkenyl; C 3 -C 6 - cycloalkyl, such as cyclopropyl; Ci-C 4 -alkoxy, such as methoxy and ethoxy; halo-CiXri- alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy, -CN; -OH; NH 2 ; Ci- C 4 -alkylamino; di(Ci-C 4 -alkyl)amino; and N0 2 .
• each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from Ci-C 4 -alkyl; -CF 3 , -OCH 3 , -OCF 3 , -F, -Cl, -Br, -I, -OH, -NO 2 , - CN, and -NH 2 .
• a substituted alkyl group is substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms.
• halo or halogen alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.
• the term“optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.
• hydrogen includes hydrogen and deuterium.
• recitation of an atom includes other isotopes of that atom so long as the resulting compound is
• hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
• hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate and the like.
• activated hydroxyl refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate groups, for example.
• hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis 3rd edition, John Wiley & Sons, New York (1999).
• hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy- carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2 -trimethyl silyl ethyl, allyl, benzyl, triphenyl- methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)- ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
• protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
• hydroxy prodrug group refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs. Topical and Ocular Drug Delivery
• amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
• Amino protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, m ethoxy carbonyl, t-butoxy carbonyl, 12-fluorenyl- methoxycarbonyl, benzyloxycarbonyl, and the like.
• protected amino refers to an amino group protected with an amino protecting group as defined above.
• leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
• representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
• aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
• examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
• protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
• solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick et a/. , Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.
• the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
• a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
• further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
• Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations. 2 nd Ed. Wiley- VCH (1999); T.W. Greene and P.G.M.
• subject refers to an animal.
• the animal is a mammal. More preferably, the mammal is a human.
• a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
• the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
• modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
• the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
• the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
• Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
• any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans , or a mixture of the two in any proportion.
• Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
• the present invention includes each conformational isomer of these compounds and mixtures thereof.
• the term "pharmaceutically acceptable salt,” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic 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 al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 2-19 (1977).
• salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
• suitable organic acid examples include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic 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.
• salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate
• pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
• ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
• Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
• esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
• compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
• the term "pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
• materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium
• compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
• the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
• the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
• parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• 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,
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectable.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• the rate of drug release can be controlled.
• biodegradable polymers include poly(orthoesters) and poly(anhydrides).
• Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
• compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature 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.
• 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 g
• 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 preferentially, 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 of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
• the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
• Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
• Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
• 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.
• a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
• Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No.
• Drug resistance most typically occurs by mutation of a gene that encodes for a protein such as an enzyme used in viral replication, and most typically in the case of HIV, reverse transcriptase, protease, or DNA polymerase, and in the case of HBV, DNA polymerase, or in the case of HCV, RNA polymerase, protease, or helicase.
• the compounds can be used for combination are selected from the group consisting of a HBV polymerase inhibitor, interferon, TLR modulators such as TLR-7 agonists or TLR-9 agonists, therapeutic vaccines, immune activator of certain cellular viral RNA sensors, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
• TLR modulators such as TLR-7 agonists or TLR-9 agonists
• therapeutic vaccines immune activator of certain cellular viral RNA sensors
• viral entry inhibitor viral maturation inhibitor
• distinct capsid assembly modulator distinct capsid assembly modulator
• antiviral compounds of distinct or unknown mechanism and combination thereof.
• the pharmacokinetics, biodistribution, or other parameter of the drug can be altered by such combination or alternation therapy.
• combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
• Preferred compounds for combination or alternation therapy for the treatment of HBV include 3TC, FTC, L-FMAU, interferon, adefovir dipivoxil, entecavir, telbivudine (L-dT), valtorcitabine (3'-valinyl L-dC), b-D-dioxolanyl-guanine (DXG), P-D-dioxolanyl-2,6- diaminopurine (DAPD), and P-D-dioxolanyl-6-chloropurine (ACP), famciclovir, penciclovir, lobucavir, ganciclovir, and ribavirin.
• An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
• viral infections, conditions are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
• a “therapeutically effective amount” of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
• the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
• An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific
• therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
• the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
• Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
• treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
• the compounds of the present invention described herein can, for example, be administered by injection, intravenously, intra-arterial, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
• compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
• amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations may contain from about 20% to about 80% active compound.
• a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
• the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level.
• Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
• compositions of this invention comprise a combination of a compound of the Formula described herein and one or more additional therapeutic or prophylactic agents
• both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
• the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
• The“additional therapeutic or prophylactic agents” include but are not limited to, immune therapies (eg. interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti -oxidants (e.g. N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (e.g. ribavirin and amantidine).
• the compositions according to the invention may also be used in combination with gene replacement therapy.
• Intermediate 1 can be reacted in a carbon-nitrogen bond forming reaction with sulfamidate 2, typically mediated by a base (denoted as [Base]) including, but not limited to: K 2 CO 3 , CS 2 CO 3 , KOAc, NaOtBu, NaOH, KOH, NaH, Et 3 N, or DBU.
• Base a base
• Carbamate 3 can be reacted in an deprotection step (denoted as [Deprotection]) using reagents including, but not limited to: TFA, HC1, or ⁇ SC o produce amine 4.
• Intermediate 1 can be reacted in a carbon-nitrogen bond forming reaction with ketone 2 (X 2 defined as halogen, -OTf, -OMs, -OAc or -OTs) typically mediated by a base (denoted as [Base]) including, but not limited to: K 2 CO 3 , CS 2 CO 3 , KOAc, NaOtBu, NaOH, KOH, Et 3 N, or DBU.
• Base a base
• Intermediate 3 can be reacted in an amination step (denoted as [Animation]) using reagents including, but not limited to: NaBEECN and NEEOAc to produce amine 4.
• Intermediate 3 can be reacted in a ring closing step (denoted as [Ring Closure]) typically mediated by a metal-containing reagent including, but not limited to: Pd(OAc) 2 , PdBr 2 , or Pd-SPhos G3 and a base, including, but not limited to: KOAc, K 2 CO 3 , CS 2 CO 3 , Et 3 N, or K 3 PO 4 to produce heterocycle 4.
• a metal-containing reagent including, but not limited to: Pd(OAc) 2 , PdBr 2 , or Pd-SPhos G3 and a base, including, but not limited to: KOAc, K 2 CO 3 , CS 2 CO 3 , Et 3 N, or K 3 PO 4 to produce heterocycle 4.
• Compound 1 (X defined as halogen, -B(OH) 2 , -BF 3 K, -B(pin), -OTf, or -OMs) can be reacted in a coupling reaction with 2 (M defined as halogen, -B(OH) 2 , -BF 3 K, -B(pin), -OTf, or -OMs) that is mediated by a metal-containing reagent (denoted as [Metal]) including, but not limited to reagents that contain: Pd, Cu, Zn, Fe, Ir, Ru, Rh, or Ni, and a base (denoted as [Base]) including, but not limited to: KOAc, K2CO 3 , CS2CO 3 , Et3N, or K 3 PO4 to produce 3.
• a metal-containing reagent including, but not limited to reagents that contain: Pd, Cu, Zn, Fe, Ir, Ru, Rh, or Ni
• Base denotes a base
• Compound 1 (X defined as halogen, -B(OH) 2 , -BF 3 K, -B(pin), -OTf, or -OMs) can be reacted in a coupling reaction with 2 (M defined as halogen, -B(OH) 2 , -BF 3 K, -B(pin), -OTf, or -OMs) that is mediated by a metal-containing reagent (denoted as [Metal]) including, but not limited to reagents that contain: Pd, Cu, Zn, Fe, Ir, Ru, Rh, or Ni, and a base (denoted as [Base]) including, but not limited to: KOAc, K2CO 3 , CS2CO 3 , Et3N, or K 3 PO4 to produce 3.
• a metal-containing reagent including, but not limited to reagents that contain: Pd, Cu, Zn, Fe, Ir, Ru, Rh, or Ni
• Base denotes a base
• Compound 1 (X defined as halogen, -B(OH) 2 , -BF 3 K, -B(pin), -OTf, or -OMs) can be reacted in a coupling reaction with 2 (M defined as halogen, -B(OH) 2 , -BF 3 K, -B(pin), -OTf, or -OMs) that is mediated by a metal-containing reagent (denoted as [Metal]) including, but not limited to reagents that contain: Pd, Cu, Zn, Fe, Ir, Ru, Rh, or Ni, and a base (denoted as [Base]) including, but not limited to: KOAc, K2CO 3 , CS2CO 3 , Et3N, or K 3 PO4 to produce 3.
• a metal-containing reagent including, but not limited to reagents that contain: Pd, Cu, Zn, Fe, Ir, Ru, Rh, or Ni
• Base denotes a base
• Halide 1 can be reacted in a borylation reaction, typically mediated by a Pd-containing reagent (denoted as [Pd source]) including, but not limited to: Pd(OAc) 2 , PdCl2(dppf), or Pd(PPh3)4, and a base (denoted as [Base]) including, but not limited to: KOAc, K2CO3, or Et3N to produce 2.
• Pd source a Pd-containing reagent
• base denoted(Ac) including, but not limited to: KOAc, K2CO3, or Et3N to produce 2.
• Boron-containing intermediate 1 (each Q5 independently defined as hydrogen or optionally substituted alkyl; alternatively, R groups can be combined to form an optionally substituted heterocyclic ring) can be reacted in a coupling reaction with halide 2 (X defined as halogen), typically mediated by a Pd-containing reagent (denoted as [Pd source]) including, but not limited to: Pd(OAc) 2 , PdCb(dppf), or Pd(PPh3)4, and a base (denoted as [Base]) including, but not limited to: KOAc, K 2 CO 3 , or Et 3 N to produce 3.
• Pd-containing reagent including, but not limited to: Pd(OAc) 2 , PdCb(dppf), or Pd(PPh3)4
• Base denotes a base
• Halide 1 (X defined as halogen) can be reacted in a coupling reaction with 2 (M defined as a functional group containing an atom including, but not limited to: B, Sn, Al, Si, Zn, or Mg), typically mediated by a Pd-containing reagent (denoted as [Pd source]) including, but not limited to: Pd(OAc)2, PdCl2(dppf), or Pd(PPh3)4, and a base (denoted as [Base]) including, but not limited to: KOAc, K2CO3, or Et3N to produce 3.
• Pd source including, but not limited to: Pd(OAc)2, PdCl2(dppf), or Pd(PPh3)4
• Base denotes a base
• each R independently defined as optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl can be prepared according to the illustrated synthetic methods herein, or by similar methods known to those skilled in the art.
• Ester 1 (Wi defined as optionally substituted alkyl) can be reacted in a substitution reaction with 2 (M defined as a functional group containing an atom including, but not limited to: B, Sn, Al, Si, Zn, or Mg), typically mediated by a Cu-containing reagent including, but not limited to: Cul or CuBr to produce 3 and/or 4.
• Intermediate 1 can be reacted in a carbon-nitrogen bond forming reaction with sulfamidate 2, typically mediated by a base (denoted as [Base]) including, but not limited to: K2CO3, CS2CO3, KOAc, NaOtBu, NaOH, KOH, NaH, Et3N, or DBU.
• Amine 3 can be reacted in an deprotection step (denoted as [Deprotection]) using reagents including, but not limited to: TFA, HC1, or EbSC o produce amine 4.
• Mass spectra were run on LC-MS systems using electrospray ionization. These were Agilent 1290 Infinity II systems with an Agilent 6120 Quadrupole detector. Spectra were obtained using a ZORBAX Eclipse XDB-C18 column (4.6 x 30 mm, 1.8 micron). Spectra were obtained at 298K using a mobile phase of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Spectra were obtained with the following solvent gradient: 5% (B) from 0-1.5 min, 5-95% (B) from 1.5-4.5 min, and 95% (B) from 4.5-6 min. The solvent flowrate was 1.2 mL/min. Compounds were detected at 210 nm and 254 nm wavelengths. [M+H] + refers to mono-isotopic molecular weights.
• Compounds were purified via reverse-phase high-performance liquid chromatography (RPHPLC) using a Gilson GX-281 automated liquid handling system. Compounds were purified on a Phenomenex Kinetex EVO C18 column (250 x 21.2 mm, 5 micron), unless otherwise specified. Compounds were purified at 298K using a mobile phase of water (A) and acetonitrile (B) using gradient elution between 0% and 100% (B), unless otherwise specified. The solvent flowrate was 20 mL/min and compounds were detected at 254 nm wavelength.
• RPHPLC reverse-phase high-performance liquid chromatography
• NPLC normal-phase liquid chromatography
• Teledyne ISCO Combiflash purification system a Teledyne ISCO Combiflash purification system.
• Compounds were purified on a REDISEP silica gel cartridge.
• Compounds were purified at 298K and detected at 254 nm wavelength.
• Step 1 An oven-dried flask was charged with 3,5-dibromo-lH-pyrazole (3 g, 13.28 mmol) and THF (30 mL). The reaction mixture was cooled in an ice bath and to this was added sodium hydride (584 mg, 14.61 mmol). After stirring at this temperarure for 20 minutes, a solution of tert-butyl (R)-4-(tert-butyl)-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4.45 g, 15.94 mmol) was added as a solution in THF (20 mL). The reaction mixture was then warmed to rt.
• Step 2 The material from the previous step was dissolved in 2: 1 EtOH:AcOH (25 mL). To this was added a solution of ethyl 4-oxo-4H-pyran-3-carboxylate (3.34 g, 19.84 mmol) as a solution in EtOH (10 mL). The reaction mixture was heated to reflux for 18 h, then allowed to reach rt.
• Step 3 An oven-dried vial was charged with ethyl (R)-2-(2-(3,5-dibromo-lH-pyrazol-2-yl)- 3,3-dimethylbutan-2-yl)-4-oxo-l,4-dihydropyridine-3-carboxylate (3 g, 6.31 mmol), PdBr2 (168 mg, 0.631 mmol), KOAc (929 mg, 9.47 mmol), and DMF (25 mL). The reaction mixture was stirred at 90 °C for 14 h.
• Step 4 An oven-dried vial was charged with ethyl (R)-2-bromo-6-(tert-butyl)-10-oxo-5,6- dihydro-10H-pyrazolo[l,5-a]pyrido[2,2-c]pyrazine-12-carboxylate (25 mg, 0.063 mmol), (4- fluorophenyl)boronic acid (9 mg, 0.063 mmol), CS2CO3 (62 mg, 0.19 mmol), and Pd-XPhos- G3 (7 mg, 0.006 mmol). The vial was purged with nitrogen gas, then 1,4-dioxane (2 mL) and water (1 mL) were added.
• Step 1 An oven-dried flask was charged with 3, 5-dibromo-lH-l, 2, 4-triazole (5 g, 22.04 mmol) and THF (100 mL). The reaction mixture was cooled in an ice bath and to this was added sodium hydride (582 mg, 24.24 mmol). After stirring at this temperarure for 20 minutes, a solution of tert-butyl (R)-4-(tert-butyl)-l,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide (7.39 g, 26.4 mmol) was added as a solution in THF (50 mL). The reaction mixture was then warmed to rt.
• Step 2 The material from the previous step was dissolved in 2: 1 EtOH:AcOH (25 mL). To this was added a solution of ethyl 4-oxo-4H-pyran-3-carboxylate (3.09 g, 18.4 mmol) as a solution in EtOH (10 mL). The reaction mixture was heated to reflux for 18 h, then allowed to reach rt.
• Step 3 An oven-dried vial was charged with ethyl (R)-2-(2-(3,5-dibromo-lH-l,2,4-triazol-2- yl)-3,3-dimethylbutan-2-yl)-4-oxo-l,4-dihydropyridine-3-carboxylate (530 mg, 1.11 mmol), PdBr2 (59 mg, 0.223 mmol), KOAc (328 mg, 3.34 mmol), and DMF (25 mL). The reaction mixture was stirred at 90 °C for 14 h.
• Step 4 An oven-dried vial was charged with ethyl (R)-2-bromo-6-(tert-butyl)-10-oxo-5,6- dihydro-10H-pyrido[l,2-a][l,2,4]triazolo[5,2-c]pyrazine-12-carboxylate (6 mg, 0.015 mmol), (2-ethoxyphenyl)boronic acid (4 mg, 0.023 mmol), CS2CO3 (15 mg, 0.046 mmol), and Pd- XPhos-G3 (1.2 mg, 0.002 mmol). The vial was purged with nitrogen gas, then 1,4-dioxane (2 mL) and water (1 mL) were added.
• Step 1 To a solution of 4-chloro-lH-pyrazole (80.0 g) and NaOH (125.5 g) in water (1.5 L) was added Br2 (100.0 mL) drop-wise at 0 °C. After addition, the mixture was stirred at room temperature overnight, then made acidic with 2N aq. HC1. The solids were filtered and washed with water (500 mL x 3). The filter cake was triturated with PE/EA(10: 1) several times and filtered. The white solid was dried in vacuo to afford 3,5-dibromo-4-chloro-lH-pyrazole (101 g, 50% yield). 3 ⁇ 4 NMR (400 MHz, DMSO- ⁇ e) d 14.14 (s, 1H). 13 C NMR (100 MHz, DMSO- de) d 119.70, 110.95.
• Step 2 A solution of 3,5-dibromo-4-chloro-lH-pyrazole (5.0 g) in THF (100 mL) was cooled to 0 °C under nitrogen. 60 wt% sodium hydride (0.845 g) was added portionwise. The mixture was allowed to stir at 0 °C until bubbling ceased. Tert-butyl (R)-4-(tert-butyl)-l,2,3- oxathiazolidine-3-carboxylate 2,2-dioxide (6.44 g) was added portionwise at 0 °C. The mixture was stirred for 5 min, then allowed to reach room temperature. The reaction mixture was stirred for an additional 30 min, then opened to air and quenched with a small amount of methanol. The volatiles were removed and the residue was dissolved in DCM (100 mL).
• Step 3 A microwave vial was charged with ethyl (R)-l-(l-(3,5-dibromo-4-chloro-lH- pyrazol-l-yl)-3,3-dimethylbutan-2-yl)-4-oxo-l,4-dihydropyridine-3-carboxylate (500 mg), cesium pivalate (690 mg), palladium(II) bromide (250 mg) and DMF (20 mL) under nitrogen. Nitrogen was bubbled through the resulting solution for 10 min. The resulting solution was heated in the microwave at 120 °C for 60 min. The resulting solution was filtered,
• Step 4 A solution of 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (16 mg), ethyl (R)-2-bromo-6-(tert-butyl)- 1 -chloro- 10-oxo-5, 6-dihydro- 10H-pyrazolo[ 1,5- a]pyrido[2,l-c]pyrazine-9-carboxylate (27 mg), cesium carbonate (61 mg) and Pd(PPli3)4 (7 mg) in 1,4-dioxane (1.4 mL) and water (0.7 mL) was heated at 100 °C with stirring in a sealed vial for 16 h.
• Step 1 A solution of 2,4-dibromo-lH-imidazole (5.0 g) in THF (100 mL) was cooled to 0 °C under nitrogen. 60 wt% sodium hydride (0.975 g) was added portionwise. The mixture was allowed to stir at 0 °C until bubbling ceased. Tert-butyl (R)-4-(tert-butyl)-l,2,3- oxathiazolidine-3-carboxylate 2,2-dioxide (7.42 g) was added portionwise at 0 °C. The mixture was stirred for 5 min, then allowed to reach room temperature.
• Step 2 A microwave vial was charged with ethyl (R)-l-(l-(2,4-dibromo-lH-imidazol-l-yl)-
• Step 3 A solution of 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (15 mg), ethyl (R)-2-bromo-6-(tert-butyl)- 10-oxo-5, 6-dihydro- 10H-imidazo[ 1 ,2-a]pyrido[2, 1 - c]pyrazine-9-carboxylate (22 mg), cesium carbonate (55 mg) and XPhos-Pd G3 (5 mg) in
• Step 1 A solution of 3,5-dibromo-lH-pyrazole (5.0 g) and Selectfluor (23.5 g) in MeCN (110 mL) was heated to 100 °C for 16 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried, filtered and concentrated to provide 3,5-dibromo-4-fluoro-lH-pyrazole (5.4 g, 99% yield), which was used directly without any additional purification.
• Step 2 A solution of 3,5-dibromo-4-fluoro-lH-pyrazole (540 mg) in THF (11 mL) was cooled to 0 °C under nitrogen. 60 wt% sodium hydride (97 mg) was added. The mixture was allowed to stir at 0 °C until bubbling ceased. Tert-butyl (R)-4-(tert-butyl)-l,2,3- oxathiazolidine-3-carboxylate 2,2-dioxide (740 mg) was added portionwise at 0 °C. The mixture was stirred for 5 min, then allowed to reach room temperature. The reaction mixture was stirred for an additional 30 min, then opened to air and quenched with a small amount of methanol.
• Step 3 A microwave vial was charged with ethyl (R)-l-(l-(3,5-dibromo-4-fluoro-lH- pyrazol - 1 -yl)-3 , 3 -dimethylbutan-2-yl)-4-oxo- 1 ,4-dihy dropyridine-3 -carboxylate (30 mg), cesium pivalate (40 mg), PCy3-Pd G4 (3 mg) and DMF (2 mL) under nitrogen. Nitrogen was bubbled through the resulting solution for 10 min. The resulting solution was heated in the microwave at 120 °C for 30 min.
• Step 4 A solution of (2-ethoxyphenyl)boronic acid (24 mg), ethyl (R)-2-bromo-6-(tert- butyl)- 1 -fluoro- 10-oxo-5, 6-dihydro- 10H-pyrazolo[ 1 , 5-a]pyrido[2, 1 -c]pyrazine-9-carboxylate (50 mg), cesium carbonate (120 mg) and Pd(Ph3P)4 (14 mg) in 1,4-dioxane (3 mL) and water (1.5 mL) was heated at 100 °C with stirring in a sealed vial for 16 h. After cooling to room temperature, methylene chloride and 1 N HC1 were added.
• Step 1 A solution of ethyl (R)-2-bromo-6-(tert-butyl)-l-chloro-10-oxo-5,6-dihydro-10H- pyrazolo[l,5-a]pyrido[2, l-c]pyrazine-9-carboxylate (50 mg), cesium carbonate (120 mg) and Pd(PPh3)4 (15 mg) in 1,4-dioxane (3 mL) and water (1 mL) was heated at 80°C with stirring in a sealed vial for 8 h. After cooling to room temperature, methylene chloride and 1 N HC1 were added. The reaction mixture was extracted with methylene chloride and the organic layers were concentrated.
• Step 1 A solution of (R)-6-(tert-butyl)-l-chloro-10-oxo-5,6-dihydro-10H-pyrazolo[l,5- a]pyrido[2, l-c]pyrazine-9-carboxylic acid (50 mg), (2,4-difluorophenyl)boronic acid (62 mg), cesium carbonate (120 mg) and Pd-XPhos-G3 (12 mg) in DMF (3 mL) and water (1 mL) was heated at 120°C with stirring in a sealed vial for 11 h. After cooling to room temperature, 1 N HC1 was added. The reaction mixture was filtered through a phase separator and concentrated.
• Step 1 To a stirred solution of 3,5-dibromo-4-chloro-lH-pyrazole (48 g, 184.62 mmol, 1.00 equiv) in THF was added NaH (14.8 g, 369.24 mmol, 2.00 equiv, 60%) in portions at 0 degrees C. To the above mixture was added tert-butyl (R)-4-isopropyl-l,2,3-oxathiazolidine- 3-carboxylate 2,2-dioxide (48.9 g, 184.62 mmol, 1.00 equiv) at 0 degrees C. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with water at room temperature.
• Step 2 To a stirred solution of tert-butyl N-[(2R)-l-(3,5-dibromo-4-chloropyrazol-l-yl)-3- methylbutan-2-yl]carbamate (85 g, 188.34 mmol, 1.00 equiv) in THF was added
• Step 4 A solution of (R)-2-bromo-3-chloro-6-isopropyl-6,7-dihydropyrazolo[l,5-a]pyrazine (5.5 g, 19.78 mmol, 1.00 equiv) and ethyl (Z)-2-(ethoxymethylene)-3-oxobutanoate (11.0 g, 59.35 mmol, 3.00 equiv) in EtOH was stirred overnight at reflux.
• Step 5 A solution of ethyl (6R)-2-bromo-l-chloro-6-isopropyl-10-oxo-5,6,l 1,1 la-tetrahydro- 10H-pyrazolo[l,5-a]pyrido[2,l-c]pyrazine-9-carboxylate (3.5 g, 8.39 mmol, 1.00 equiv) and p- chloranil (4.10 g) in DME was stirred for 3 h at 70 °C.
• Step 6 A mixture of (A)-ethyl 2-bromo- l -chloro-6-isopropyl- l 0-oxo-6, l O-dihydro-5//- pyrazolo[l,5-a] pyrido[2,l-c]pyrazine-9-carboxylate (500 mg, 1.20 mmol, 1.00 equiv.), cyclopropylboronic acid (258 mg, 3.00 mmol, 2.5 equiv.), Pd(PPli3)4 ( 139 mg, 0.12 mmol,
• Step 7 To a solution of (R)-l-chloro-2-cyclopropyl-6-isopropyl-10-oxo-5,6-dihydro-10H- pyrazolo[l,5-a]pyrido[2,l-c]pyrazine-9-carboxylic acid (50.00 mg, 0.144 mmol, 1.00 equiv) and thiophen-3-ylboronic acid (91.97 mg, 0.719 mmol, 5.00 equiv) in DMF (2.00 mL) and H2O (0.20 mL) were added CS2CO3 (140.52 mg, 0.431 mmol, 3.00 equiv) and Xphos Pd G3 (24.34 mg, 0.029 mmol, 0.20 equiv). After stirring for overnight at 120 °C under a nitrogen atmosphere, the mixture was diluted with H2O (10 ml), extracted with EtOAc (3 x 20 ml).
• Step 1 A solution of phenylboronic acid (16 mg), (R)-6-(tert-butyl)-l-chloro-2-(4- fluorophenyl)- 10-oxo-5, 6-dihydro- 10H-pyrazolo[ 1 , 5-a]pyrido[2, 1 -c]pyrazine-9-carboxylic acid (Example 87, 27 mg), cesium carbonate (61 mg) and Pd-tBuXPhos G3 (7 mg) in DMF (5 mL) was heated at 100 °C with stirring in a sealed vial for 18 h.

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