WO2019133666A1

WO2019133666A1 - Triazolophthalazine compounds, use as anti-human immunodeficiency virus inhibitors of hiv vif-dependent degradation of apobec3

Info

Publication number: WO2019133666A1
Application number: PCT/US2018/067609
Authority: WO
Inventors: Subramaniam Ananthan; Corinne E. Augelli-Szafran; Ryan P. BENNETT; Harold C. Smith; Phanindra Krishna Mohan VENUKADASULA
Original assignee: Southern Research Institute; Oyagen, Inc.
Priority date: 2017-12-28
Filing date: 2018-12-27
Publication date: 2019-07-04
Also published as: WO2019133666A8

Abstract

The present disclosure is concerned with triazolophthalazine compounds that are capable of inhibiting infection by the Human Immunodeficiency Virus (HIV) by inhibiting HIV Vif-dependent degradation of the APOBEC3 innate immune system. The present disclosure is also concerned with methods of using these compounds for the treatment of an HIV infection and control of viral loads in patients infected with HIV and in AIDS.

Description

TRIAZOLOPHTHALAZINE COMPOUNDS, USE AS ANTI- HUMAN IMMUNODEFICIENCY VIRUS INHIBITORS OF HIV VIF-DEPENDENT DEGRADATION OF APOBEC3, AND METHODS FOR PREPARATION THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Provisional Application Nos.

62/611,363, filed on December 28, 2017, and 62/644,872, filed on March 19, 2018, the contents of which are incorporated herein by reference in their entireties. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0001] This invention was made with government support under grant numbers HSN272201400010I and HHSN27200022 awarded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0002] Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS) and presently infects approximately 33 million people worldwide, with approximately 1.9 million infected people in North America alone. Recent studies have shown that HIV/AIDS has become a global epidemic that is not under control in developing nations. The rapid emergence of drug-resistant strains of HIV throughout the world has placed a priority on innovative approaches for the identification of novel drug targets that may lead to a new class of anti-retroviral therapies.

[0003] The virus contains a 10-kb single-stranded RNA genome that encodes three major classes of gene products that include structural proteins (Gag, Pol, and Env), essential trans-acting proteins (Tat and Rev), and“auxiliary” proteins that are not required for efficient virus replication in permissive cells (Vpr, Vif, Vpu, Nef) (reviewed in Frankel and Young (1998) Annu. Rev. Biochem.67: 1-25). There has been a heightened interest in Vif as an antiviral target due to the discovery that the primary function of Vif is to overcome the action of a cellular antiviral protein known as APOBEC3G or A3G expressed as part of innate immunity to retroviruses (Sheehy et al. (2002) Nature 418: 646-650).

[0004] Despite the discovery that peptides mimetics of Vif can disrupt Vif self- association (Yang et al. (2003) J. Biol. Chem.27(8): 6596-6602) and inhibit HIV infection in an A3G-dependent manner by preventing Vif-dependent degradation of A3G (Miller et al. (2007) Retrovirology 4: 81-91) anti-HIV therapeutic development of potent and selective small molecule inhibitors acting specifically targeting Vif have remained elusive. Thus, there remains a need for agents capable of targeting Vif that enable A3G innate immunity to HIV and methods of making and using same. SUMMARY

[0005] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compositions and methods for use in the prevention and treatment of HIV infection and control of viral loads in patients infected with HIVand in AIDS.

[0006] Disclosed are compounds that inhibits HIV infection by inhibitiing Vif multimerization and thereby enabling APOBEC3 innate immunity against HIV.

[0007] Also disclosed are pharmaceutical compositions comprising an effective amount of at least one compound that inhibits HIV infection by inhibiting Vif multimerization and thereby enabling APOBEC3 innate immunity against HIV.

[0008] Also disclosed are methods for the treatment of a viral infection in a subject having the viral infection, the method comprising the step of administering to the subject a therapeutically effective amount of at least one compound that inhibits HIV infection by inhibiting Vif multimerization and thereby enabling APOBEC3 innate immunity against HIV.

[0009] Also disclosed are compounds that inhibit HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV, wherein the compound has a structure represented by a formula:

, wherein each is an optional covalent bond; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is present and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1- C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,–NH2,– CN,–NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups

independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

provided that when is absent and each of Z¹, Z², and Z³ is CR⁵, then each of R¹ and R² is selected from hydrogen and–NH₂, and R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when either: (a) one or more of R¹ and R² is halogen,‒NO₂, or C1-C4 alkoxy; (b) R⁵ is halogen; or (c) R⁴ is C1-C4 alkyl, C1-C4 haloalkyl, or aryl, then R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when R⁴ is methyl and Z³ is N, then either at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen or at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof.

[0010] Also disclosed are compounds having a structure represented by a formula:

,

wherein each is an optional covalent bond; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is present and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, and –NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, C1-C4 alkyl, C1- C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),–NHSO2(C1-C4 alkyl), and– CO₂(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,– CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,– OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; provided that when is absent and each of Z¹, Z², and Z³ is CR⁵, then each of R¹ and R² is selected from hydrogen and–NH2, and R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when R⁴ is methyl and Z³ is N, then at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen, or that when R⁴ is methyl and Z³ is N, at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof.

[0011] Also disclosed are pharmaceutical compositions comprising an effective amount of at least one compound that inhibits HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV, wherein the compound has a structure represented by a formula:

,

wherein is a solid bond or is absent; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),–NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; provided that when R⁴ is aryl, then R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when R⁴ is methyl and Z³ is N, then at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen, or that when R⁴ is methyl and Z³ is N, at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] Also disclosed are compositions comprising a therapeutically effective amount of at least one compound having a structure represented by a formula:

,

wherein each is an optional covalent bond; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, and –NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen,–OH,–NH₂,–CN,– NO2,–CO2H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO2(C1-C4 alkyl), and–CO2(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups

independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

provided that when R⁴ is methyl and Z³ is N, then at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen, or that when R⁴ is methyl and Z³ is N, at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof.

[0013] The present invention also provides a method for the treatment of a viral infection in a subject having the viral infection, the method comprising the step of administering to the subject a therapeutically effective amount of at least one compound that inhibits HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV, wherein the compound has a structure represented by a formula:

,

wherein is a solid bond or is absent; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,–NH2,–CN,–NO2,–CO2H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),–NHSO2(C1-C4 alkyl), and–CO2(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0014] Also disclosed are methods of treating or preventing HIV infection or AIDS in a patient using anti-HIV agents identified herein. Specifically, that method comprises the step of administering to the subject a therapeutically effective amount of at least one compound having a structure represented by a formula:

wherein each is an optional covalent bond; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, and –NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen,–OH,–NH2,–CN,– NO2,–CO2H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO2(C1-C4 alkyl), and–CO2(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups

independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0015] Also disclosed are kits comprising at least one compound having a structure represented by a formula:

,

wherein each is an optional covalent bond; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, and –NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen,–OH,–NH2,–CN,– NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO2(C1-C4 alkyl), and–CO2(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups

independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; or a pharmaceutically acceptable salt thereof, and one or more of: (a) at least one antiviral agent; (b) a instructions for administering the at least one compound in connection with treating a viral infection; (c) instructions for administering the at least one compound in connection with reducing the risk of viral infection; or (d) instructions for treating a viral infection.

[0016] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. DETAILED DESCRIPTION

[0017] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0018] Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0019] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0020] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.

A. DEFINITIONS [0021] As used in the specification and the appended claims, the singular forms“a,” “an” and“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to“a functional group,”“an alkyl,” or“a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0022] As used in the specification and in the claims, the term“comprising” can include the aspects“consisting of” and“consisting essentially of.”

[0023] Ranges can be expressed herein as from“about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. For example, if the value“10” is disclosed, then“about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0024] As used herein, the terms“about” and“at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is“about” or“approximate” whether or not expressly stated to be such. It is understood that where“about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0025] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0026] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0027] As used herein,“IC50,” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an IC₅₀ can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein. In a further aspect, IC50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance.

[0028] As used herein,“EC50,” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein. In a further aspect, EC50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response.

[0029] As used herein, the terms“optional” or“optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0030] As used herein, the term“subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term“patient” includes human and veterinary subjects.

[0031] As used herein, the term“treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term“subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). [0032] As used herein, the term“prevent” or“preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0033] As used herein, the term“infectivity” means the ability of a virus to produce infected cells or the ability to propagate more virus in other cells. For example, HIV infectivity means the ability of HIV to produce infected cells or the ability to propagate more HIV in other cells.

[0034] As used herein, the term“inhibition of infectivity” means the lessening, weakening, diminishing, or otherwise hinderling the ability of a virus to produce infected cells or the ability to propagate more virus in other cells.

[0035] As used herein, the term“diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0036] As used herein, the terms“administering” and“administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0037] As used herein, the terms“effective amount” and“amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. 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 specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a“prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0038] As used herein,“dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative. [0039] As used herein,“kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0040] As used herein,“instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0041] As used herein, the terms“therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic,

immunogenic, and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14^th edition), the Physicians' Desk Reference (64^th edition), and The Pharmacological Basis of Therapeutics (12^th edition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term“therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; anti-HIV agents such as entry inhibitors, fusion inhibitors, non- nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, NCP7 inhibitors, protease inhibitors, and integrase inhibitors; analgesics and analgesic combinations, anorexics, anti- inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0042] The term“pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0043] As used herein, the term“derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0044] As used herein, the term“pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. 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 media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0045] As used herein, the term“innate immunity” means the body's non-specific mechanisms for resistance to pathogens that are not enhanced upon subsequent challenge with a particular antigen.

[0046] As used herein, the term“host defense factors” means natural protections that guard against infection such as, for example, physical barriers (e.g., skin, mucous membranes) and specific and non-specific immune response. For example, Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC) proteins provide antiviral innate immunity.

[0047] “Viral infectivity factor” and“Vif” means a protein found in HIV and other retroviruses having a primary role of disrupting the antiviral activity of the human enzyme APOBEC by targeting it for ubiquitination and cellular degradation.

[0048] As used herein, the term“protein degradation” means the directed digestion of proteins. Protein degradation can occur by, for example, enzymes (i.e., via proteolysis, which breaks the peptide bonds that link amino acids together in the polypeptide chain forming the protein), heat, and pH-value changes.

[0049] As used herein, the term“substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms“substitution” or“substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0050] In defining various terms,“A¹,”“A²,”“A³,” and“A⁴” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0051] The term“aliphatic” or“aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0052] The term“alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A“lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0053] Throughout the specification“alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term“halogenated alkyl” or“haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term“monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term“alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term“aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term“hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When“alkyl” is used in one instance and a specific term such as“hydroxyalkyl” is used in another, it is not meant to imply that the term“alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

[0054] This practice is also used for other groups described herein. That is, while a term such as“cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a“halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an“alkenylalcohol,” and the like. Again, the practice of using a general term, such as“cycloalkyl,” and a specific term, such as“alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0055] The term“cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term“heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term“cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0056] The term“polyalkylene group” as used herein is a group having two or more CH₂ groups linked to one another. The polyalkylene group can be represented by the formula— (CH₂)_a—, where“a” is an integer of from 2 to 500.

[0057] The terms“alkoxy” and“alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an“alkoxy” group can be defined as—OA¹ where A¹ is alkyl or cycloalkyl as defined above.“Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as—OA¹—OA² or—OA¹—(OA²)a—OA³, where“a” is an integer of from 1 to 200 and A¹, A², and A³ are alkyl and/or cycloalkyl groups.

[0058] The term“alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.

Asymmetric structures such as (A¹A²)C=C(A³A⁴) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0059] The term“cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,

cyclohexadienyl, norbornenyl, and the like. The term“heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0060] The term“alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0061] The term“cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term“heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0062] The term“aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled“Aromaticity,” pages 477-497, incorporated herein by reference. The term“aromatic group” is inclusive of both aryl and heteroaryl groups.

[0063] The term“aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde,─NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in the definition of“aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0064] The term“aldehyde” as used herein is represented by the formula—C(O)H. Throughout this specification“C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0065] The terms“amine” or“amino” as used herein are represented by the formula— NA¹A², where A¹ and A² can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is─NH2.

[0066] The term“alkylamino” as used herein is represented by the formula—NH(- alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0067] The term“dialkylamino” as used herein is represented by the formula—N(- alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group,

diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert- pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N- propylamino group, N-ethyl-N-propylamino group and the like. [0068] The term“carboxylic acid” as used herein is represented by the formula— C(O)OH.

[0069] The term“ester” as used herein is represented by the formula—OC(O)A¹ or— C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term“polyester” as used herein is represented by the formula—(A¹O(O)C-A²-C(O)O)_a— or—(A¹O(O)C-A²-OC(O))_a—, where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0070] The term“ether” as used herein is represented by the formula A¹OA², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term“polyether” as used herein is represented by the formula—(A¹O-A²O)a—, where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0071] The terms“halo,”“halogen,” or“halide,” as used herein can be used

interchangeably and refer to F, Cl, Br, or I.

[0072] The terms“pseudohalide,”“pseudohalogen,” or“pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0073] The term“heteroalkyl,” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0074] The term“heteroaryl,” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0075] The terms“heterocycle” or“heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to,“heterocycloalkyl”,“heteroaryl”,“bicyclic heterocycle” and“polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3- oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2- C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl,

tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring. [0076] The term“bicyclic heterocycle” or“bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.

[0077] The term“heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0078] The term“hydroxyl” or“hydroxyl” as used herein is represented by the formula —OH.

[0079] The term“ketone” as used herein is represented by the formula A¹C(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0080] The term“azide” or“azido” as used herein is represented by the formula—N₃.

[0081] The term“nitro” as used herein is represented by the formula—NO2.

[0082] The term“nitrile” or“cyano” as used herein is represented by the formula—CN.

[0083] The term“silyl” as used herein is represented by the formula—SiA¹A²A³, where A¹, A², and A³ can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0084] The term“sulfo-oxo” as used herein is represented by the formulas—S(O)A¹,— S(O)2A¹,—OS(O)2A¹, or—OS(O)2OA¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification“S(O)” is a short hand notation for S=O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula—S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term“sulfone” as used herein is represented by the formula A¹S(O)2A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term“sulfoxide” as used herein is represented by the formula

A¹S(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,

cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0085] The term“thiol” as used herein is represented by the formula—SH.

[0086] “R¹,”“R²,”“R³,”“Rⁿ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R¹ is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase“an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0087] As described herein, compounds of the invention may contain“optionally substituted” moieties. In general, the term“substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0088] The term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein. [0089] Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;–(CH₂)_0–4R °;–(CH₂)_0–4OR °; -O(CH₂)_0-4R^o,– O–(CH2)0–4C(O)OR°;–(CH2)0–4CH(OR °)2;–(CH2)0–4SR °;–(CH2)0–4Ph, which may be substituted with R°;–(CH2)0–4O(CH2)0–1Ph which may be substituted with R°;–CH=CHPh, which may be substituted with R°;–(CH₂)_0–4O(CH₂)_0–1-pyridyl which may be substituted with R°;–NO2;–CN;–N3; -(CH2)0–4N(R °)2;–(CH2)0–4N(R °)C(O)R °;–N(R °)C(S)R °;– (CH2)0–4N(R °)C(O)NR °2; -N(R °)C(S)NR °2;–(CH2)0–4N(R °)C(O)OR °;–N(R °)N(R °)C(O)R °; -N(R °)N(R °)C(O)NR °₂; -N(R °)N(R °)C(O)OR °;–(CH₂)_0–4C(O)R °;–C(S)R °;–(CH₂)_0– 4C(O)OR °;–(CH2)0–4C(O)SR °; -(CH2)0–4C(O)OSiR °3;–(CH2)0–4OC(O)R °;–OC(O)(CH2)0– 4SR–, SC(S)SR°;–(CH2)0–4SC(O)R °;–(CH2)0–4C(O)NR °2;–C(S)NR °2;–C(S)SR°; -(CH2)0– 4OC(O)NR °2; -C(O)N(OR °)R °;–C(O)C(O)R °;–C(O)CH2C(O)R °;–C(NOR °)R °; -(CH2)0– 4SSR °;–(CH₂)_0–4S(O)₂R °;–(CH₂)_0–4S(O)₂OR °;–(CH₂)_0–4OS(O)₂R °;–S(O)₂NR °₂; -(CH₂)_0– ₄S(O)R °; -N(R °)S(O)₂NR °₂;–N(R °)S(O)₂R °;–N(OR °)R °;–C(NH)NR °₂;–P(O)₂R °;

-P(O)R °2; -OP(O)R °2;–OP(O)(OR °)2; SiR °3;–(C1–4 straight or branched alkylene)O–N(R °)2; or–(C1–4 straight or branched alkylene)C(O)O–N(R °)2, wherein each R ° may be substituted as defined below and is independently hydrogen, C1–6 aliphatic,–CH2Ph,–O(CH2)0–1Ph, - CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R °, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0090] Suitable monovalent substituents on R ° (or the ring formed by taking two independent occurrences of R ° together with their intervening atoms), are independently halogen,–(CH2)0–2R^●,–(haloR^●),–(CH2)0–2OH,–(CH2)0–2OR^●,–(CH2)0–2CH(OR^●)2;

-C(O)SR^● _,–(C_1–4 straight or branched alkylene)C(O)OR^●, or–SSR^● wherein each R^● is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently selected from C_1–4 aliphatic,–CH₂Ph,–O(CH₂)_0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ° include =O and =S. [0091] Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: =O, =S, =NNR^* ₂, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)2R^*, =NR^*, =NOR^*,–O(C(R^*2))2–3O–, or–S(C(R^*2))2–3S–, wherein each independent occurrence of R^* is selected from hydrogen, C_1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include:–O(CR^* ₂)_2–3O–, wherein each independent occurrence of R^* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0092] Suitable substituents on the aliphatic group of R^* include halogen,–R^●,

-(haloR^●), -OH,–OR^●,–O(haloR^●),–CN,–C(O)OH,–C(O)OR^●,–NH₂,–NHR^●,–NR^● ₂, or– NO2, wherein each R^● is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic,–CH₂Ph,–O(CH₂)_0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0093] Suitable substituents on a substitutable nitrogen of an“optionally substituted” group include–R^†,–NR^† ₂,–C(O)R^†,–C(O)OR^†,–C(O)C(O)R^†,–C(O)CH₂C(O)R^†,– S(O)2R^†, -S(O)2NR^†2,–C(S)NR^†2,–C(NH)NR^†2, or–N(R^†)S(O)2R^†; wherein each R^† is independently hydrogen, C_1–6 aliphatic which may be substituted as defined below, unsubstituted–OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0094] Suitable substituents on the aliphatic group of R^† are independently halogen,–R^●, -(haloR^●),–OH,–OR^●,–O(haloR^●),–CN,–C(O)OH,–C(O)OR^●,–NH₂,–NHR^●,–NR^● ₂, or –NO2, wherein each R^● is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic,–CH2Ph,–O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0095] The term“leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0096] The terms“hydrolysable group” and“hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example,“Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0097] The term“organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0098] A very close synonym of the term“residue” is the term“radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure:

,

regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein. [0099] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[00100] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[00101] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and

pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. [00102] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[00103] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via

Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[00104] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the“R” forms of the compounds can be substantially free from the“S” forms of the compounds and are, thus, in enantiomeric excess of the“S” forms. Conversely,“S” forms of the compounds can be substantially free of“R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[00105] When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.

[00106] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem.1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p.30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[00107] “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof. The“combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates. Examples of radio- actively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like.

[00108] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[00109] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[00110] The term“co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g.“Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[00111] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.

[00112] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N¹-unsubstituted, 3-A³ and N¹-unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possible tautomers.

[00113] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[00114] In some aspects, a structure of a compound can be represented by a formula:

,

which is understood to be equivalent to a formula:

,

wherein n is typically an integer. That is, Rⁿ is understood to represent five independent substituents, R^n(a), R^n(b), R^n(c), R^n(d), R^n(e). By“independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R^n(a) is halogen, then R^n(b) is not necessarily halogen in that instance.

[00115] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[00116] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order.

Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[00117] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively

contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[00118] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

B. C^OMPOUNDS [00119] In one aspect, the invention relates to compounds useful in treating disorders associated with a viral infection, in particular, HIV.

[00120] In one aspect, the disclosed compounds exhibit antiviral activity against HIV.

[00121] In one aspect, the compounds of the invention are useful in inhibiting HIV infections in primates. In a further aspect, the compounds of the invention are useful in inhibiting HIV activity in at least one cell.

[00122] In one aspect, the compounds of the invention are useful in inhibiting Vif dimerization in a mammal. In a further aspect, the compounds of the invention are useful in inhibiting Vif dimerization in at least one cell. [00123] In one aspect, the compounds of the invention are useful in preventing Vif- dependent degradation of APOBEC3 in a mammal. In a further aspect, the compounds of the invention are useful in inhibiting Vif-dependent degradation of APOBEC3 in at least one cell.

[00124] In one aspect, the compounds of the invention are useful in enabling APOBEC3 hypermutation of the HIV genome in a mammal. In a further aspect, the compounds of the invention are useful in enabling APOBEC3 hyper mutation of the HIV genome in at least one cell.

[00125] In one aspect, the compounds of the invention are useful in the treatment of HIV infections, as further described herein.

[00126] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.

1. S^TRUCTURE [00127] In one aspect, disclosed are compounds that inhibit HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV, wherein the compound has a structure represented by a formula:

,

wherein each is an optional covalent bond; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is present and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1- C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,–NH₂,– CN,–NO2,–CO2H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO2(C1-C4 alkyl), and–CO2(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

provided that when is absent and each of Z¹, Z², and Z³ is CR⁵, then each of R¹ and R² is selected from hydrogen and–NH2, and R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when either: (a) one or more of R¹ and R² is halogen,‒NO2, or C1-C4 alkoxy; (b) R⁵ is halogen; or (c) R⁴ is C1-C4 alkyl, C1-C4 haloalkyl, or aryl, then R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when R⁴ is methyl and Z³ is N, then either at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen or at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof.

[00128] In one aspect, disclosed are compounds having a structure represented by a formula:

,

wherein each is an optional covalent bond; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is present and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, and –NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, C1-C4 alkyl, C1- C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),–NHSO₂(C1-C4 alkyl), and– CO2(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,– CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,– OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; provided that when is absent and each of Z¹, Z², and Z³ is CR⁵, then each of R¹ and R² is selected from hydrogen and–NH₂, and R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when R⁴ is methyl and Z³ is N, then at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen, or that when R⁴ is methyl and Z³ is N, at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof.

[00129] In a further aspect, the compound has a structure represented by a formula:

.

[00130] In a further aspect, the compound has a structure represented by a formula:

,

wherein each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, halogen,– CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

[00131] In a further aspect, the compound has a structure represented by a formula:

.

[00132] In a further aspect, the compound has a structure represented by a formula:

[00133] In a further aspect, the compound is:

.

[00134] In a further aspect, the compound is selected from:

,

[00135] In a further apsect, the compound is selected from:

[00136] In a further aspect, the compound is selected from:

[00137] In a further aspect, the compound is selected from:

[00138] In a further aspect, the compound is selected from:

[00139] In a further aspect, the compound is selected from:

,

[00140] In a further aspect, the compound is selected from:

[00141] In one aspect, each is an optional covalent bond. In a further aspect, each is a covalent bond. In a still further aspect, each is absent.

[00142] In one aspect, n is 0 or 1. In a further aspect, n is 0. In a still further aspect, n is 1.

a. Z G^ROUPS [00143] In one aspect, each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is present and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent. [00144] In a further aspect, each of Z¹, Z², and Z³ is N. In a still further aspect, each of Z¹, Z², and Z³ is CR⁵. In yet a further aspect, Z¹ is N and each of Z² and Z³ is CR⁵. In an even further aspect, Z¹ is CR⁵ and each of Z² and Z³ is N. In a still further aspect, Z² is N and each of Z¹ and Z³ is CR⁵. In yet a further aspect, Z² is CR⁵ and each of Z¹ and Z³ is N. In an even further aspect, Z³ is N and each of Z¹ and Z² is CR⁵. In a still further aspect, Z³ is CR⁵ and each of Z¹ and Z² is N.

[00145] In a further aspect, each of Z¹ and Z² is N. In a still further aspect, each of Z¹ and Z² is CR⁵.

[00146] In a further aspect, each of Z¹ and Z³ is N. In a still further aspect, each of Z¹ and Z³ is CR⁵.

[00147] In a further aspect, each of Z² and Z³ is N. In a still further aspect, each of Z² and Z³ is CR⁵.

[00148] In a further aspect, Z¹ is N. In a still further aspect, Z¹ is CR⁵.

[00149] In a further aspect, Z² is N. In a still further aspect, Z² is CR⁵.

[00150] In a further aspect, Z³ is N. In a still further aspect, Z³ is CR⁵.

[00151] In a further aspect, each of Z¹, Z², and Z³ is NH. In a still further aspect, each of Z¹, Z², and Z³ is CHR⁵. In yet a further aspect, Z¹ is NH and each of Z² and Z³ is CHR⁵. In an even further aspect, Z¹ is CHR⁵ and each of Z² and Z³ is NH. In a still further aspect, Z² is NH and each of Z¹ and Z³ is CHR⁵. In yet a further aspect, Z² is CHR⁵ and each of Z¹ and Z³ is NH. In an even further aspect, Z³ is NH and each of Z¹ and Z² is CHR⁵. In a still further aspect, Z³ is CHR⁵ and each of Z¹ and Z² is NH.

[00152] In a further aspect, each of Z¹ and Z² is NH. In a still further aspect, each of Z¹ and Z² is CHR⁵.

[00153] In a further aspect, each of Z¹ and Z³ is NH. In a still further aspect, each of Z¹ and Z³ is CHR⁵.

[00154] In a further aspect, each of Z² and Z³ is NH. In a still further aspect, each of Z² and Z³ is CHR⁵.

[00155] In a further aspect, Z¹ is NH. In a still further aspect, Z¹ is CHR⁵.

[00156] In a further aspect, Z² is NH. In a still further aspect, Z² is CHR⁵.

[00157] In a further aspect, Z³ is NH. In a still further aspect, Z³ is CHR⁵.

b. R^{1 AND} R² G^ROUPS [00158] In one aspect, each of R¹ and R² is independently selected from hydrogen, halogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, –NHC(O)(C1-C4 alkyl),–NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl). In a further aspect, each of R¹ and R² is independently selected from hydrogen,‒F,‒Cl,–OH,–NH2,–CN,– NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl).

[00159] In one aspect, each of R¹ and R² is independently selected from hydrogen,–OH, –NH₂,–CN,–NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,– NHC(O)(C1-C4 alkyl),–NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl).

[00160] In a further aspect, each of R¹ and R² is independently selected from hydrogen, halogen,–OH,–NH₂,–NO₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, provided that at least one of R¹ and R² is not hydrogen.

[00161] In a further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,– CO2H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4

hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO2(C1-C4 alkyl), and–CO2(C1-C4 alkyl). In a still further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, methyl, ethyl, n-propyl, i-propyl,–CH₂F,– CH2Cl,–CH2CH2F,–CH2CH2Cl,–CH2CH2CH2F,–CH2CH2CH2Cl,–CH(CH3)CH2F,– CH(CH₃)CH₂Cl,–OCH₃,–OCH₂CH₃,–OCH₂CH₂CH₃,–OCH(CH₃)CH₃,–NHCH₃,– NHCH2CH3,–NHCH2CH2CH3,–NHCH(CH3)CH3,–N(CH3)2,–N(CH2CH3)2,–

N(CH₂CH₂CH₃)₂,–N(CH(CH₃)CH₃)₂,–N(CH₃)(CH₂CH₃),–NHC(O)CH₃,–

NHC(O)CH2CH3,–NHC(O)CH2CH2CH3,–NHC(O)CH(CH3)CH3,–NHSO2CH3,–

NHSO₂CH₂CH₃,–NHSO₂CH₂CH₂CH₃,–NHSO₂CH(CH₃)CH₃,–CO₂CH₃,–CO₂CH₂CH₃,– CO2CH2CH2CH3, and–CO2CH(CH3)CH3. In a still further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, methyl, ethyl,–CH₂F,–CH₂Cl,–CH₂CH₂F,– CH2CH2Cl,–OCH3,–OCH2CH3,–NHCH3,–NHCH2CH3,–N(CH3)2,–N(CH2CH3)2,– N(CH₃)(CH₂CH₃),–NHC(O)CH₃,–NHC(O)CH₂CH₃,–NHSO₂CH₃,–NHSO₂CH₂CH₃,– CO2CH3, and–CO2CH2CH3. In yet a further aspect, R¹ is selected from hydrogen,–OH,– NH₂,–CN,–NO₂,–CO₂H, methyl,–CH₂F,–CH₂Cl,–OCH₃,–NHCH₃,–N(CH₃)₂,–

NHC(O)CH3,–NHSO2CH3, and–CO2CH3.

[00162] In a further aspect, R¹ is selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R¹ is selected from methyl, ethyl, n-propyl, i-propyl,–CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl,– CH2CH2CH2F,–CH2CH2CH2Cl,–CH(CH3)CH2F,–CH(CH3)CH2Cl,–OCH3,–OCH2CH3,– OCH₂CH₂CH₃,–OCH(CH₃)CH₃,–NHCH₃,–NHCH₂CH₃,–NHCH₂CH₂CH₃,–

NHCH(CH3)CH3,–N(CH3)2,–N(CH2CH3)2,–N(CH2CH2CH3)2,–N(CH(CH3)CH3)2, and– N(CH₃)(CH₂CH₃). In yet a further aspect, R¹ is selected from methyl, ethyl,–CH₂F,–CH₂Cl, –CH2CH2F,–CH2CH2Cl,–OCH3,–OCH2CH3,–NHCH3,–NHCH2CH3,–N(CH3)2,– N(CH₂CH₃)₂, and–N(CH₃)(CH₂CH₃). In an even further aspect, R¹ is selected from methyl, –CH2F,–CH2Cl,–OCH3,–NHCH3, and–N(CH3)2.

[00163] In a further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,– CO2H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, methyl, ethyl, n-propyl, i-propyl,–OCH3,–OCH2CH3,–OCH2CH2CH3,–OCH(CH3)CH3,– NHCH₃,–NHCH₂CH₃,–NHCH₂CH₂CH₃,–NHCH(CH₃)CH₃,–N(CH₃)₂,–N(CH₂CH₃)₂,– N(CH2CH2CH3)2,–N(CH(CH3)CH3)2, and–N(CH3)(CH2CH3). In a still further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, methyl, ethyl,–OCH₃,–

OCH2CH3,–NHCH3,–NHCH2CH3,–N(CH3)2,–N(CH2CH3)2, and–N(CH3)(CH2CH3). In yet a further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, methyl, –OCH3,–NHCH3, and–N(CH3)2.

[00164] In a further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,– CO2H, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, methyl, ethyl, n-propyl, i-propyl,–OCH₃,– OCH2CH3,–OCH2CH2CH3, and–OCH(CH3)CH3. In a still further aspect, R¹ is selected from hydrogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, methyl, ethyl,–OCH₃, and–OCH₂CH₃. In yet a further aspect, R¹ is selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, methyl, and–OCH₃.

[00165] In a further aspect, R¹ is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In a still further aspect, R¹ is selected from methyl, ethyl, n-propyl, i-propyl,–CH₂F, –CH2Cl,–CH2CH2F,–CH2CH2Cl,–CH2CH2CH2F,–CH2CH2CH2Cl,–CH(CH3)CH2F,– CH(CH₃)CH₂Cl,–OCH₃,–OCH₂CH₃,–OCH₂CH₂CH₃, and–OCH(CH₃)CH₃. In yet a further aspect, R¹ is selected from methyl, ethyl,–CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl,–OCH3, and–OCH₂CH₃. In yet a further aspect, R¹ is selected from methyl,–CH₂F,–CH₂Cl, and– OCH3.

[00166] In a further aspect, R¹ is C1-C4 haloalkyl. In a still further aspect, R¹ is selected from–CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl,–CH2CH2CH2F,–CH2CH2CH2Cl,–

CH(CH3)CH2F, and–CH(CH3)CH2Cl. In yet a further aspect, R¹ is selected from–CH2F,– CH2Cl,–CH2CH2F, and–CH2CH2Cl. In yet a further aspect, R¹ is selected from–CH2F and –CH₂Cl.

[00167] In a further aspect, R¹ is C1-C4 alkyl. In a still further aspect, R¹ is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In yet a further aspect, R¹ is selected from methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, R¹ is selected from methyl and ethyl. In a still further aspect, R¹ is ethyl. In yet a further aspect, R¹ is methyl.

[00168] In a further aspect, R¹ is selected from–OH,–NH₂, and C1-C4 alkoxy. In a still further aspect, R¹ is selected from–OH,–NH2,–OCH3,–OCH2CH3,–OCH2CH2CH3, and– OCH(CH₃)CH₃. In yet a further aspect, R¹ is selected from–OH,–NH₂,–OCH₃, and– OCH2CH3. In an even further aspect, R¹ is selected from–OH,–NH2, and–OCH3.

[00169] In a further aspect, R¹ is–NH₂. In a further aspect, R¹ is–OH. In a still further aspect, R¹ is–CN. In yet a further aspect, R¹ is–NO2. In an even further aspect, R¹ is– CO₂H.

[00170] In a further aspect, R¹ is selected from–NHC(O)(C1-C4 alkyl),–NHSO2(C1-C4 alkyl), and–CO₂(C1-C4 alkyl). In a still further aspect, R¹ is selected from–NHC(O)CH₃,– NHC(O)CH2CH3,–NHC(O)CH2CH2CH3,–NHC(O)CH(CH3)CH3,–NHSO2CH3,–

NHSO₂CH₂CH₃,–NHSO₂CH₂CH₂CH₃,–NHSO₂CH(CH₃)CH₃,–CO₂CH₃,–CO₂CH₂CH₃,– CO2CH2CH2CH3, and–CO2CH(CH3)CH3. In yet a further aspect, R¹ is selected from– NHC(O)CH₃,–NHC(O)CH₂CH₃,–NHSO₂CH₃,–NHSO₂CH₂CH₃,–CO₂CH₃, and–

CO2CH2CH3. In an even further aspect, R¹ is selected from–NHC(O)CH3,–NHSO2CH3, and –CO₂CH₃.

[00171] In a further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,– CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4

hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl). In a still further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, methyl, ethyl, n-propyl, i-propyl,–CH2F,– CH₂Cl,–CH₂CH₂F,–CH₂CH₂Cl,–CH₂CH₂CH₂F,–CH₂CH₂CH₂Cl,–CH(CH₃)CH₂F,– CH(CH3)CH2Cl,–OCH3,–OCH2CH3,–OCH2CH2CH3,–OCH(CH3)CH3,–NHCH3,– NHCH₂CH₃,–NHCH₂CH₂CH₃,–NHCH(CH₃)CH₃,–N(CH₃)₂,–N(CH₂CH₃)₂,–

N(CH2CH2CH3)2,–N(CH(CH3)CH3)2,–N(CH3)(CH2CH3),–NHC(O)CH3,–

NHC(O)CH2CH3,–NHC(O)CH2CH2CH3,–NHC(O)CH(CH3)CH3,–NHSO2CH3,–

NHSO2CH2CH3,–NHSO2CH2CH2CH3,–NHSO2CH(CH3)CH3,–CO2CH3,–CO2CH2CH3,– CO2CH2CH2CH3, and–CO2CH(CH3)CH3. In a still further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, methyl, ethyl,–CH2F,–CH2Cl,–CH2CH2F,– CH₂CH₂Cl,–OCH₃,–OCH₂CH₃,–NHCH₃,–NHCH₂CH₃,–N(CH₃)₂,–N(CH₂CH₃)₂,– N(CH3)(CH2CH3),–NHC(O)CH3,–NHC(O)CH2CH3,–NHSO2CH3,–NHSO2CH2CH3,– CO₂CH₃, and–CO₂CH₂CH₃. In yet a further aspect, R² is selected from hydrogen,–OH,– NH2,–CN,–NO2,–CO2H, methyl,–CH2F,–CH2Cl,–OCH3,–NHCH3,–N(CH3)2,–

NHC(O)CH₃,–NHSO₂CH₃, and–CO₂CH₃.

[00172] In a further aspect, R² is selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R² is selected from methyl, ethyl, n-propyl, i-propyl,–CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl,– CH₂CH₂CH₂F,–CH₂CH₂CH₂Cl,–CH(CH₃)CH₂F,–CH(CH₃)CH₂Cl,–OCH₃,–OCH₂CH₃,– OCH2CH2CH3,–OCH(CH3)CH3,–NHCH3,–NHCH2CH3,–NHCH2CH2CH3,–

NHCH(CH₃)CH₃,–N(CH₃)₂,–N(CH₂CH₃)₂,–N(CH₂CH₂CH₃)₂,–N(CH(CH₃)CH₃)₂, and– N(CH3)(CH2CH3). In yet a further aspect, R² is selected from methyl, ethyl,–CH2F,–CH2Cl, –CH₂CH₂F,–CH₂CH₂Cl,–OCH₃,–OCH₂CH₃,–NHCH₃,–NHCH₂CH₃,–N(CH₃)₂,– N(CH2CH3)2, and–N(CH3)(CH2CH3). In an even further aspect, R² is selected from methyl, –CH₂F,–CH₂Cl,–OCH₃,–NHCH₃, and–N(CH₃)₂.

[00173] In a further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,– CO₂H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, methyl, ethyl, n-propyl, i-propyl,–OCH₃,–OCH₂CH₃,–OCH₂CH₂CH₃,–OCH(CH₃)CH₃,– NHCH3,–NHCH2CH3,–NHCH2CH2CH3,–NHCH(CH3)CH3,–N(CH3)2,–N(CH2CH3)2,– N(CH₂CH₂CH₃)₂,–N(CH(CH₃)CH₃)₂, and–N(CH₃)(CH₂CH₃). In a still further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, methyl, ethyl,–OCH3,–

OCH₂CH₃,–NHCH₃,–NHCH₂CH₃,–N(CH₃)₂,–N(CH₂CH₃)₂, and–N(CH₃)(CH₂CH₃). In yet a further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, methyl, –OCH₃,–NHCH₃, and–N(CH₃)₂.

[00174] In a further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,– CO₂H, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, methyl, ethyl, n-propyl, i-propyl,–OCH3,– OCH₂CH₃,–OCH₂CH₂CH₃, and–OCH(CH₃)CH₃. In a still further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, methyl, ethyl,–OCH3, and–OCH2CH3. In yet a further aspect, R² is selected from hydrogen,–OH,–NH2,–CN,–NO2,–CO2H, methyl, and–OCH3. [00175] In a further aspect, R² is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In a still further aspect, R² is selected from methyl, ethyl, n-propyl, i-propyl,–CH₂F, –CH2Cl,–CH2CH2F,–CH2CH2Cl,–CH2CH2CH2F,–CH2CH2CH2Cl,–CH(CH3)CH2F,– CH(CH₃)CH₂Cl,–OCH₃,–OCH₂CH₃,–OCH₂CH₂CH₃, and–OCH(CH₃)CH₃. In yet a further aspect, R² is selected from methyl, ethyl,–CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl,–OCH3, and–OCH₂CH₃. In yet a further aspect, R² is selected from methyl,–CH₂F,–CH₂Cl, and– OCH3.

[00176] In a further aspect, R² is C1-C4 haloalkyl. In a still further aspect, R¹ is selected from–CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl,–CH2CH2CH2F,–CH2CH2CH2Cl,–

CH(CH₃)CH₂F, and–CH(CH₃)CH₂Cl. In yet a further aspect, R² is selected from–CH₂F,– CH2Cl,–CH2CH2F, and–CH2CH2Cl. In yet a further aspect, R² is selected from–CH2F and –CH₂Cl.

[00177] In a further aspect, R² is C1-C4 alkyl. In a still further aspect, R² is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In yet a further aspect, R² is selected from methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, R² is selected from methyl and ethyl. In a still further aspect, R² is ethyl. In yet a further aspect, R² is methyl.

[00178] In a further aspect, R² is selected from–OH,–NH₂, and C1-C4 alkoxy. In a still further aspect, R² is selected from–OH,–NH2,–OCH3,–OCH2CH3,–OCH2CH2CH3, and– OCH(CH₃)CH₃. In yet a further aspect, R² is selected from–OH,–NH₂,–OCH₃, and– OCH2CH3. In an even further aspect, R² is selected from–OH,–NH2, and–OCH3.

[00179] In a further aspect, R² is–NH₂. In a further aspect, R² is–OH. In a still further aspect, R² is–CN. In yet a further aspect, R² is–NO2. In an even further aspect, R² is– CO₂H.

[00180] In a further aspect, R² is selected from–NHC(O)(C1-C4 alkyl),–NHSO2(C1-C4 alkyl), and–CO₂(C1-C4 alkyl). In a still further aspect, R² is selected from–NHC(O)CH₃,– NHC(O)CH2CH3,–NHC(O)CH2CH2CH3,–NHC(O)CH(CH3)CH3,–NHSO2CH3,–

NHSO₂CH₂CH₃,–NHSO₂CH₂CH₂CH₃,–NHSO₂CH(CH₃)CH₃,–CO₂CH₃,–CO₂CH₂CH₃,– CO2CH2CH2CH3, and–CO2CH(CH3)CH3. In yet a further aspect, R² is selected from– NHC(O)CH₃,–NHC(O)CH₂CH₃,–NHSO₂CH₃,–NHSO₂CH₂CH₃,–CO₂CH₃, and–

CO2CH2CH3. In an even further aspect, R² is selected from–NHC(O)CH3,–NHSO2CH3, and –CO2CH3.

[00181] In a further aspect, R² is selected from hydrogen,−OH, and C1-C4 haloalkyl. In a still further aspect, R¹ is selected from hydrogen,−OH,–CH2F,–CH2Cl,–CH2CH2F,– CH2CH2Cl,–CH2CH2CH2F,–CH2CH2CH2Cl,–CH(CH3)CH2F, and–CH(CH3)CH2Cl. In yet a further aspect, R² is selected from hydrogen,−OH,–CH₂F,–CH₂Cl,–CH₂CH₂F, and– CH2CH2Cl. In yet a further aspect, R² is selected from– hydrogen,−OH, CH2F, and–CH2Cl.

c. R^3A AND R^3B GROUPS [00182] In one aspect, each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl. In a further aspect, each of R^3a and R^3b is hydrogen.

[00183] In a further aspect, each of R^3a and R^3b is independently selected from hydrogen, −F,−Cl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In a still further aspedct, each of R^3a and R^3b is independently selected from hydrogen,−F,−Cl, methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, each of R^3a and R^3b is independently selected from hydrogen,−F,−Cl, methyl, and ethyl. In an even further aspect, each of R^3a and R^3b is independently selected from hydrogen,−F,−Cl, and ethyl. In a still further aspect, each of R^3a and R^3b is independently selected from hydrogen,−F,−Cl, and methyl.

[00184] In a further aspect, each of R^3a and R^3b is independently selected from hydrogen and halogen. In a still further aspect, each of R^3a and R^3b is independently selected from hydrogen and−F. In yet a further aspect, each of R^3a and R^3b is independently selected from hydrogen and−Cl.

[00185] In a further aspect, each of R^3a and R^3b is independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, each of R^3a and R^3b is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, each of R^3a and R^3b is independently selected from hydrogen, methyl, and ethyl. In an even further aspect, each of R^3a and R^3b is independently selected from hydrogen and ethyl. In a still further aspect, each of R^3a and R^3b is independently selected from hydrogen and methyl.

[00186] In a further aspect, R^3a is hydrogen and R^3b is selected from halogen and C1-C4 alkyl. In a still further aspect, R^3a is hydrogen and R^3b is selected from−F,−Cl, methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, R^3a is hydrogen and R^3b is selected from −F,−Cl, methyl, and ethyl. In an even further aspect, R^3a is hydrogen and R^3b is selected from−F,−Cl, and ethyl. In a still further aspect, R^3a is hydrogen and R^3b is selected from−F, −Cl, and methyl. d. R⁴ GROUPS [00187] In one aspect, R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹. In a further aspect, R⁴ is selected from C1-C4 alkyl, C1-C4 haloalkyl, and Cy¹. In a still further aspect, R⁴ is selected from methyl, ethyl, n-propyl, i-propyl,–CH2F,–CH2Cl,–CH2CH2F,– CH₂CH₂Cl,–CH₂CH₂CH₂F,–CH₂CH₂CH₂Cl,–CH(CH₃)CH₂F,–CH(CH₃)CH₂Cl, and Cy¹. In yet a further aspect, R⁴ is selected from methyl, ethyl,–CH2F,–CH2Cl,–CH2CH2F,– CH₂CH₂Cl, and Cy¹. In an even further aspect, R⁴ is selected from methyl,–CH₂F,–CH₂Cl, and Cy¹.

[00188] In a further aspect, R⁴ is selected from C1-C8 alkyl and Cy¹. In a still further aspect, R⁴ is selected from C1-C4 alkyl and Cy¹. In yet a further aspect, R⁴ is selected from methyl, ethyl, n-propyl, i-propyl, and Cy¹. In an even further aspect, R⁴ is selected from methyl, ethyl, and Cy¹. In a still further aspect, R⁴ is selected from ethyl and Cy¹. In yet a further aspect, R⁴ is selected from methyl and Cy¹.

[00189] In a further aspect, R⁴ is selected from C1-C8 haloalkyl and Cy¹. In a still further aspect, R⁴ is selected from C1-C4 haloalkyl and Cy¹. In yet a further aspect, R⁴ is selected from–CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl,–CH2CH2CH2F,–CH2CH2CH2Cl,–

CH(CH3)CH2F,–CH(CH3)CH2Cl, and Cy¹. In an even further aspect, R⁴ is selected from– CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl, and Cy¹. In a still further aspect, R⁴ is selected from–CH2F,–CH2Cl, and Cy¹.

[00190] In a further aspect, R⁴ is C1-C8 alkyl. In a still further aspect, R⁴ is C1-C4 alkyl. In yet a further aspect, R⁴ is selected from methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, R⁴ is selected from methyl and ethyl. In a still further aspect, R⁴ is ethyl. In yet a further aspect, R⁴ is methyl.

[00191] In a further aspect, R⁴ is C1-C8 haloalkyl. In a still further aspect, R⁴ is C1-C4 haloalkyl. In yet a further aspect, R⁴ is selected from–CH2F,–CH2Cl,–CH2CH2F,– CH₂CH₂Cl,–CH₂CH₂CH₂F,–CH₂CH₂CH₂Cl,–CH(CH₃)CH₂F, and–CH(CH₃)CH₂Cl. In an even further aspect, R⁴ is selected from–CH2F,–CH2Cl,–CH2CH2F, and–CH2CH2Cl. In a still further aspect, R⁴ is selected from–CH₂F and–CH₂Cl.

[00192] In a further aspect, R⁴ is Cy¹. In a still further aspect, R⁴ is cyclopropyl.

[00193] In a further aspect, R⁴ is selected from isopropyl, cyclopropyl, and–CH₂CF₃. e. R⁵ GROUPS [00194] In one aspect, each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b. In a further aspect, each occurrence of R⁵, when present, is independently selected from hydrogen,−F,−Cl, methyl, ethyl, n-propyl, isopropyl,–CH₂F,–CH₂Cl,–CH₂CH₂F,–CH₂CH₂Cl,–

CH2CH2CH2F,–CH2CH2CH2Cl,–CH(CH3)CH2F,–CH(CH3)CH2Cl, and–NR^10aR^10b. In a still further aspect, each occurrence of R⁵, when present, is independently selected from hydrogen,−F,−Cl, methyl, ethyl,–CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl, and–NR^10aR^10b. In yet a further aspect, each occurrence of R⁵, when present, is independently selected from hydrogen,−F,−Cl, methyl,–CH2F,–CH2Cl, and–NR^10aR^10b.

[00195] In one aspect, each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, and–NR^10aR^10b. In a further aspect, each occurrence of R⁵, when present, is independently selected from hydrogen and halogen. In a still further aspect, each occurrence of R⁵, when present, is independently selected from hydrogen and–NR^10aR^10b. In yet a further aspect, each occurrence of R⁵, when present, is independently selected from halogen and–NR^10aR^10b.

[00196] In a further aspect, each occurrence of R⁵, when present, is hydrogen. In a still further aspect, each occurrence of R⁵, when present, is–NR^10aR^10b.

[00197] In a further aspect, each occurrence of R⁵, when present, is independently selected from hydrogen,−F,−Cl, and–NR^10aR^10b.

[00198] In a further aspect, each occurrence of R⁵, when present, is halogen. In a still further aspect, each occurrence of R⁵, when present, is independently selected form–F and– Cl.

[00199] In a further aspect, R⁵ is–NR^10aR^10b.

f. R^10A AND R^10B GROUPS [00200] In one aspect, each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. [00201] In a further aspect, each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, each of R^10a and R^10b, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s- butyl, and t-butyl. In yet a further aspect, each of R^10a and R^10b, when present, is

independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, each of R^10a and R^10b, when present, is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R^10a and R^10b, when present, is independently selected from hydrogen and ethyl. In yet a further aspect, each of R^10a and R^10b, when present, is independently selected from hydrogen and methyl.

[00202] In a further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,– NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0 or 1 group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and monosubstituted with a group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered

heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and

unsubstituted.

[00203] In a further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,– OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0 or 1 group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5- membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and monosubstituted with a group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 5-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and unsubstituted.

[00204] In a further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,– OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0 or 1 group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 6- membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and unsubstituted.

[00205] In a further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a morpholine ring.

[00206] In a further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a morpholinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,– CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a morpholinyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a morpholinyl substituted with 0 or 1 group selected from halogen,–CN,–NH2,– OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^10a and R^10b, together with the intermediate atoms, comprise a morpholinyl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^10a and R^10b, together with the intermediate atoms, comprise an unsubstituted morpholinyl.

g. R^X AND R^Y GROUPS [00207] In one aspect, wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

[00208] In a further aspect, each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, each of R^x and R^y is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, each of R^x and R^y is independently selected from hydrogen, methyl, and ethyl. In an even further aspect, each of R^x and R^y is independently selected from hydrogen and ethyl. In a still further aspect, each of R^x and R^y is independently selected from hydrogen and methyl. [00209] In a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0 or 1 group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6- to 8- membered cycloalkyl or a monocyclic aryl, and are monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are unsubstituted.

[00210] In a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl substituted with 0 or 1 group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6- to 8- membered cycloalkyl monosubstituted with a group selected from halogen,–CN,–NH2,– OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise an unsubstituted 6- to 8-membered cycloalkyl. [00211] In a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6-membered cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6-membered cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In yet a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6-membered cycloalkyl substituted with 0 or 1 group selected from halogen,–CN, –NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^x and R^y, together with the intermediate atoms, comprise a 6-membered cycloalkyl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise an

unsubstituted 6-membered cycloalkyl.

[00212] In a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 7-membered cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise a 7-membered cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In yet a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 7-membered cycloalkyl substituted with 0 or 1 group selected from halogen,–CN, –NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^x and R^y, together with the intermediate atoms, comprise a 7-membered cycloalkyl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise an

unsubstituted 7-membered cycloalkyl.

[00213] In a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 8-membered cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise a 8-membered cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In yet a further aspect, R^x and R^y, together with the intermediate atoms, comprise a 8-membered cycloalkyl substituted with 0 or 1 group selected from halogen,–CN, –NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^x and R^y, together with the intermediate atoms, comprise a 8-membered cycloalkyl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise an

unsubstituted 8-membered cycloalkyl.

[00214] In a further aspect, R^x and R^y, together with the intermediate atoms, comprise a monocyclic aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen,– CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise a monocyclic aryl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R^x and R^y, together with the intermediate atoms, comprise a monocyclic aryl substituted with 0 or 1 group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1- C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^x and R^y, together with the intermediate atoms, comprise a monocyclic aryl monosubstituted with a group selected from halogen,–CN,– NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^x and R^y, together with the intermediate atoms, comprise an unsubstituted monocyclic aryl.

[00215] In a further aspect, R^x and R^y, together with the intermediate atoms, comprise a structure represented by a formula:

,

h. R^20A, R^20B, R^20C, R^20D GROUPS [00216] In one aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, each of R^20a, R^20b, R^20c, and R^20d is hydrogen.

[00217] In a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–OH,–NH2,–CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–OH,– NH₂,–CN, methyl, ethyl, n-propyl, i-propyl,–CH₂F,–CH₂Cl,–CH₂CH₂F,–CH₂CH₂Cl,– CH2CH2CH2F,–CH2CH2CH2Cl,–CH(CH3)CH2F,–CH(CH3)CH2Cl,–OCH3,–OCH2CH3,– OCH₂CH₂CH₃,–OCH(CH₃)CH₃,–NHCH₃,–NHCH₂CH₃,–NHCH₂CH₂CH₃,–

NHCH(CH3)CH3,–N(CH3)2,–N(CH2CH3)2,–N(CH2CH2CH3)2,–N(CH(CH3)CH3)2, and– N(CH₃)(CH₂CH₃). In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–OH,–NH2,–CN, methyl, ethyl,–CH2F,–CH2Cl,–CH2CH2F,– CH₂CH₂Cl,–OCH₃,–OCH₂CH₃,–NHCH₃,–NHCH₂CH₃,–N(CH₃)₂,–N(CH₂CH₃)₂, and– N(CH3)(CH2CH3). In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–OH,–NH2,–CN, methyl,–CH2F,–CH2Cl,–OCH3,–NHCH3, and– N(CH3)2.

[00218] In a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl,–CH2F,–CH2Cl,– CH2CH2F,–CH2CH2Cl,–CH2CH2CH2F,–CH2CH2CH2Cl,–CH(CH3)CH2F,–

CH(CH3)CH2Cl,–OCH3,–OCH2CH3,–OCH2CH2CH3,–OCH(CH3)CH3,–NHCH3,– NHCH2CH3,–NHCH2CH2CH3,–NHCH(CH3)CH3,–N(CH3)2,–N(CH2CH3)2,– N(CH2CH2CH3)2,–N(CH(CH3)CH3)2, and–N(CH3)(CH2CH3). In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, methyl, ethyl,–CH₂F,– CH2Cl,–CH2CH2F,–CH2CH2Cl,–OCH3,–OCH2CH3,–NHCH3,–NHCH2CH3,–N(CH3)2,– N(CH₂CH₃)₂, and–N(CH₃)(CH₂CH₃). In an even further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, methyl,–CH2F,–CH2Cl,–OCH3,–NHCH3, and–N(CH₃)₂.

[00219] In a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–F,–Cl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–F,–Cl, methyl, ethyl, n-propyl, i-propyl,–OCH₃,–OCH₂CH₃,– OCH2CH2CH3,–OCH(CH3)CH3,–NHCH3,–NHCH2CH3,–NHCH2CH2CH3,–

NHCH(CH₃)CH₃,–N(CH₃)₂,–N(CH₂CH₃)₂,–N(CH₂CH₂CH₃)₂,–N(CH(CH₃)CH₃)₂, and– N(CH3)(CH2CH3). In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–F,–Cl, methyl, ethyl,–OCH₃,–OCH₂CH₃,–NHCH₃,–

NHCH2CH3,–N(CH3)2,–N(CH2CH3)2, and–N(CH3)(CH2CH3). In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–F,–Cl, methyl,– OCH3,–NHCH3, and–N(CH3)2.

[00220] In a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–F,–Cl, methyl, ethyl, n- propyl, i-propyl,–OCH3,–OCH2CH3,–OCH2CH2CH3, and–OCH(CH3)CH3. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–F, –Cl, methyl, ethyl,–OCH3, and–OCH2CH3. In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–F,–Cl, methyl, and–OCH₃.

[00221] In a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, methyl, ethyl, n- propyl, i-propyl,–CH₂F,–CH₂Cl,–CH₂CH₂F,–CH₂CH₂Cl,–CH₂CH₂CH₂F,–

CH2CH2CH2Cl,–CH(CH3)CH2F,–CH(CH3)CH2Cl,–OCH3,–OCH2CH3,–OCH2CH2CH3, and–OCH(CH₃)CH₃. In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is

independently selected from hydrogen, methyl, ethyl,–CH2F,–CH2Cl,–CH2CH2F,– CH2CH2Cl,–OCH3, and–OCH2CH3. In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, methyl,–CH2F,–CH2Cl, and–OCH3. [00222] In a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen and C1-C4 haloalkyl. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–CH2F,–CH2Cl,–CH2CH2F,–CH2CH2Cl,– CH₂CH₂CH₂F,–CH₂CH₂CH₂Cl,–CH(CH₃)CH₂F, and–CH(CH₃)CH₂Cl. In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–CH2F,– CH₂Cl,–CH₂CH₂F, and–CH₂CH₂Cl. In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–CH2F, and–CH2Cl.

[00223] In a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s- butyl, and t-butyl. In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen and ethyl. In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen and methyl.

[00224] In a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–OH,–NH₂, and C1-C4 alkoxy. In a still further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–OH,–NH2,–OCH3,–OCH2CH3,– OCH₂CH₂CH₃, and–OCH(CH₃)CH₃. In yet a further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–OH,–NH2,–OCH3, and–OCH2CH3. In an even further aspect, each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen,–OH,–NH2, and–OCH3.

i. CY¹ GROUPS [00225] In one aspect, Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0 or 1 group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is monosubstituted with a group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is unsubstituted.

[00226] In a further aspect, Cy¹, when present, is selected from cycloalkyl and heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is selected from cycloalkyl and heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is selected from cycloalkyl and heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen,–CN,–NH₂,– OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is selected from cycloalkyl and heterocycloalkyl, and is monosubstituted with a group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is selected from cycloalkyl and heterocycloalkyl, and is unsubstituted.

[00227] In a further aspect, Cy¹, when present, is cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is cycloalkyl substituted with 0 or 1 group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is cycloalkyl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is unsubstituted cycloalkyl.

[00228] In a further aspect, Cy¹, when present, is cyclopropyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is cyclopropyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is cyclopropyl substituted with 0 or 1 group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is cyclopropyl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is unsubstituted cyclopropyl.

[00229] In a further aspect, Cy¹, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1- C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is heterocycloalkyl substituted with 0 or 1 group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is heterocycloalkyl monosubstituted with a group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is unsubstituted heterocycloalkyl.

[00230] In a further aspect, Cy¹, when present, is selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is selected from aryl and heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is selected from aryl and heteroaryl, and is substituted with 0 or 1 group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is selected from aryl and heteroaryl, and is monosubstituted with a group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is selected from aryl and heteroaryl, and is unsubstituted.

[00231] In a further aspect, Cy¹, when present, is aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is aryl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is aryl substituted with 0 or 1 group selected from halogen, –CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is aryl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1- C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is unsubstituted aryl.

[00232] In a further aspect, Cy¹, when present, is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is phenyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is phenyl substituted with 0 or 1 group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is phenyl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is unsubstituted phenyl. [00233] In a further aspect, Cy¹, when present, is heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is heteroaryl substituted with 0 or 1 group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is heteroaryl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is unsubstituted heteroaryl.

[00234] In a further aspect, Cy¹, when present, is furanyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is furanyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is furanyl substituted with 0 or 1 group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is furanyl monosubstituted with a group selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is unsubstituted furanyl.

[00235] In a further aspect, Cy¹, when present, is thiophenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is thiophenyl substituted with 0, 1, or 2 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present, is thiophenyl substituted with 0 or 1 group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, when present, is thiophenyl monosubstituted with a group selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, when present, is unsubstituted thiophenyl.

2. EXAMPLE COMPOUNDS [00236] In one aspect, a compound can be present as one or more of the following structures:

,

or a pharmaceutically acceptable salt thereof.

[00237] In one aspect, a compound can be present as one or more of the following structures:

[00238] In one aspect, a compound can be present as one or more of the following structures:

,

or a pharmaceutically acceptable salt thereof.

[00239] In one aspect, a compound can be present as one or more of the following structures:

or a pharmaceutically acceptable salt thereof.

[00240] In one aspect, a compound can be present as one or more of the following structures:

or a pharmaceutically acceptable salt thereof.

[00241] In one aspect, a compound can be present as one or more of the following structures:

or a pharmaceutically acceptable salt thereof.

3. PROPHETIC COMPOUND EXAMPLES [00242] The following compound examples are prophetic, and can be prepared using the synthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be active as inhibitors of a viral infection, and such activity can be determined using the assay methods described herein below.

[00243] In one aspect, a compound can be selected from:

[00244] In one aspect, a compound can be selected from:

[00245] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[00246] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[00247] It is understood that pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses. The pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like.

C. PHARMACEUTICAL COMPOSITIONS [00248] In one aspect, disclosed are pharmaceutical compositions comprising a disclosed compound, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[00249] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of at least one compound that inhibits HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV, wherein the compound has a structure represented by a formula:

,

wherein is a solid bond or is absent; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,–NH2,–CN,–NO2,–CO2H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),–NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; provided that when R⁴ is aryl, then R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when R⁴ is methyl and Z³ is N, then at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen, or that when R⁴ is methyl and Z³ is N, at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00250] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of at least one compound having a structure represented by a formula:

,

wherein is a solid bond or is absent; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, and– NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen,–OH,–NH₂,–CN,– NO2,–CO2H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO2(C1-C4 alkyl), and–CO2(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

provided that when R⁴ is methyl and Z³ is N, then at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen, or that when R⁴ is methyl and Z³ is N, at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00251] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., intravenous or oral administration.

[00252] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The compounds and compositions of the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for injection or for ingestion. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[00253] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous)

administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[00254] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[00255] In a further aspect, the pharmaceutical composition further comprises an antiviral agent. In a still further aspect, the pharmaceutical composition is administered with an antiviral agent. In yet a further aspect, the pharmaceutical composition is administered simultaneously with an antiviral agent. In an even further aspect, the composition is administered sequentially with an antiviral agent.

[00256] In a further aspect, the antiviral agent is selected from selected from acemannan, acyclovir, acyclovir sodium, adamantanamine, adefovir, adenine arabinoside, alovudine, alvircept sudotox, amantadine hydrochloride, aranotin, arildone, atevirdine mesylate, avridine, cidofovir, cipamfylline, cytarabine hydrochloride, BMS 806, C31G, carrageenan, cellulose sulfate, cyclodextrins, dapivirine, delavirdine mesylate, desciclovir, dextrin 2- sulfate, didanosine, disoxaril, dolutegravir, edoxudine, enviradene, envirozime, etravirine, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, foscarnet sodium, fosfonet sodium, FTC, ganciclovir, ganciclovir sodium, GSK 1265744, 9-2-hydroxy-ethoxy methylguanine, ibalizumab, idoxuridine, interferon, 5-iodo-2′-deoxyuridine, IQP-0528, kethoxal, lamivudine, lobucavir, maraviroc, memotine pirodavir, penciclovir, raltegravir, ribavirin, rimantadine hydrochloride, rilpivirine (TMC-278), saquinavir mesylate, SCH-C, SCH-D, somantadine hydrochloride, sorivudine, statolon, stavudine, T20, tilorone hydrochloride, TMC120, TMC125, trifluridine, trifluorothymidine, tenofovir, tenofovir alefenamide, tenofovir disoproxyl fumarate, prodrugs of tenofovir, UC-781, UK-427, UK- 857, valacyclovir, valacyclovir hydrochloride, vidarabine, vidarabine phosphate, vidarabine sodium phosphate, viroxime, zalcitabene, zidovudine, and zinviroxime. In a still further aspect, the antiviral agent is an anti-HIV agent.

[00257] In a further aspect, the anti-HIV agent selected from entry inhibitors, fusion inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, NCP7 inhibitors, protease inhibitors, and integrase inhibitors. In a still further aspect, the entry inhibitor and/or fusion inhibitor is selected from Enfuvirtide (Fuzeon, T-20), AMD11070, PRO542, SCH-C, T-1249, TNX-355, cyanovirin, grifithsen, maraviroc and enfuvirtide. In yet a further aspect the entry inhibitor is selected from the class of lectins. In yet a further aspect, the non- nucleoside reverse transcriptase inhibitor is selected from delavirdine (Rescriptor), efavirenz (Sustiva), nevirapine (Viramune), calanolide A, capravirine, epivir, hivid, TMC125, adefovir, etravirine, rilpivirine, dapivirine, and lersivirine, and mixtures thereof. In an even further aspect, the nucleoside reverse transcriptase inhibitor and/or nucleotide reverse transcriptase inhibitor is selected from abacavir (Ziagen), didanosine (Videx, ddl), emtricitabine (Emtriva, FTC), lamivudine (Epivir, eTC), stavudine (Zerit, d4t), tenofovir (({[(2R)-1-(6-amino-9H- purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid), tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, delavirdine (Rescriptor), zalcitabine (Hivid, ddc), zidovudine (Retrovir, AZT, ZDR), entecavir, and apricitabine, and mixtures thereof. In a still further aspect, the protease inhibitor is selected from amprenavir (Agenerase), atazanavir (Reyataz), fosamprenavir (Lexiva, 908), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), emtriva, saquinavir (Fortovase, Invirase), invirase, agenerase, lopinavir, tipranavir, and darunavir, and mixtures thereof. In yet a further aspect, the integrase inhibitor is selected from elvitegravir, raltegravir, GSK 1265744, GSK-572, and MK-2048, and mixtures thereof. Other anti-HIV agents include, for example, AMD-3100, BMS-806, BMS-793, C31G, carrageenan, CD4-IgG2, cellulose acetate phthalate, zinc salts, cellulose sulphate, cyclodextrins, dextrin-2-sulphate, mAb 2G12, mAb b12, Merck 167, plant lectins, poly naphthalene sulfate, poly sulfo-styrene, PRO2000, PSC-Rantes, SCH-C, SCH-D, T-20, TMC-125, UC-781, UK-427, UK-857, and Viramune, and mixtures thereof.

[00258] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[00259] In preparing the compositions for oral dosage form, any convenient

pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[00260] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[00261] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose.

Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[00262] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[00263] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[00264] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.

[00265] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient. [00266] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.

D. METHODS OF MAKING A COMPOUND [00267] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[00268] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I-III, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.

1. ROUTE I [00269] In one aspect, substituted triazolophthalazines can be prepared as shown below. S^CHEME 1A.

[00270] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 1B.

[00271] In one aspect, compounds of type 1.3, and similar compounds, can be prepared according to reaction Scheme 1B above. Thus, compounds of type 1.3 can be prepared by a cyclization reaction of an appropriate 2,5-dihalopyridine or 2,5-dihalopyridazine, e.g., 1.1 as shown above, and an appropriate hydrazide, e.g., 1.2 as shown above. Appropriate pyridines, appropriate pyridazines, and appropriate hydrazides are commercially available or prepared by methods known to one skilled in the art. The cyclization reaction is carried out in the presence of an appropriate protic solvent, e.g., butanol, at an appropriate temperature, e.g., 118 °C, for an appropriate period of time, e.g., 1-16 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.4 and 1.5), can be substituted in the reaction to provide substituted triazolophthalazines similar to Formula 1.6.

2. ROUTE II [00272] In one aspect, substituted triazolophthalazines can be prepared as shown below. SCHEME 2A.

[00273] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 2B.

[00274] In one aspect, compounds of type 1.3, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus, compounds of type 1.3 can be prepared by a cyclization reaction of an appropriate dihydrophthalazine or dihydroisoquinoline, e.g., 2.1 as shown above, and an appropriate carboxylic acid, e.g., 2.2 as shown above. Appropriate dihydrophthalazines, appropriate dihydroisoquinolines, and appropriate carboxylic acids are commercially available or prepared by methods known to one skilled in the art. The cyclization reaction is carried out at an appropriate temperature, e.g., 110 °C, for an appropriate period of time, e.g., about 4 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.3 and 2.4), can be substituted in the reaction to provide substituted triazolophthalazines similar to Formula 2.5.

3. R^OUTE III [00275] In one aspect, substituted triazolophthalazines can be prepared as shown below. SCHEME 3A.

.

[00276] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 3B.

[00277] In one aspect, compounds of type 3.2, and similar compounds, can be prepared according to reaction Scheme 3B above. Thus, compounds of type 2.3 can be prepared by a nucleophilic aromatic substitution of an appropriate amine, e.g., 3.1 as shown above, and an appropriate aryl halide, e.g., 1.3 as shown above. Appropriate amines are commercially available or prepared by methods known to one skilled in the art. The nucleophilic aromatic substitution is carried out in the presence of an appropriate base, e.g., potassium carbonate, in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 100 °C, for an appropriate period of time, e.g., between about 12 hours and 7 days. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.6 and 3.3), can be substituted in the reaction to provide substituted triazolophthalazines similar to Formula 3.4.

E. METHODS OF USING THE COMPOUNDS [00278] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with a viral infection, in particular, HIV.

[00279] Examples of viral infections for which the compounds and compositions can be useful in treating, include, but are not limited to, human immunodeficiency virus (HIV), human papillomavirus (HPV), influenza, chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2,

parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, chikungunya, Venezuelan equine encephalitis, dengue, influenza, and zika.

[00280] To treat or control the disorder, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non- human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of a viral infection, such as HIV.

[00281] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of a viral infection, such as HIV.

[00282] The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.

1. T^REATMENT M^ETHODS [00283] The compounds disclosed herein are useful for treating or controlling disorders associated with an HIV infection. Thus, provided is a method comprising administering a therapeutically effective amount of a composition comprising a disclosed compound to a subject. In a further aspect, the method can be a method for treating a viral infection.

a. TREATING A VIRAL INFECTION [00284] In one aspect, disclosed are methods of treating an HIV infection in a subject having the viral infection, the method comprising the step of administering to the subject a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[00285] In one aspect, disclosed are methods for the treatment of a viral infection in a subject having the viral infection, the method comprising the step of administering to the subject a therapeutically effective amount of at least one compound that inhibits HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV, wherein the compound has a structure represented by a formula:

,

[00286] In one aspect, disclosed are methods for the treatment of an HIVinfection in a subject having the viral infection, the method comprising the step of administering to the subject a therapeutically effective amount of at least one compound having a structure represented by a formula:

wherein is a solid bond or is absent; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, and– NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen,–OH,–NH2,–CN,– NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),– NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups

[00287] In a further aspect, the subject has been diagnosed with a need for treatment of the disorder prior to the administering step.

[00288] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human.

[00289] In a further aspect, the method further comprises the step of identifying a subject in need of treatment of the HIV infection.

[00290] In a further aspect, the method further comprises the step of co-administering with a therapeutically effective amount of at least one other antiviral agent. In a still further aspect, the at least one agent is selected from acemannan, acyclovir, acyclovir sodium, adamantanamine, adefovir, adenine arabinoside, alovudine, alvircept sudotox, amantadine hydrochloride, aranotin, arildone, atevirdine mesylate, avridine, cidofovir, cipamfylline, cytarabine hydrochloride, BMS 806, C31G, carrageenan, cellulose sulfate, cyclodextrins, dapivirine, delavirdine mesylate, desciclovir, dextrin 2-sulfate, didanosine, disoxaril, dolutegravir, edoxudine, enviradene, envirozime, etravirine, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, foscarnet sodium, fosfonet sodium, FTC, ganciclovir, ganciclovir sodium, GSK 1265744, 9-2-hydroxy-ethoxy methylguanine, ibalizumab, idoxuridine, interferon, 5-iodo-2′-deoxyuridine, IQP-0528, kethoxal, lamivudine, lobucavir, maraviroc, memotine pirodavir, penciclovir, raltegravir, ribavirin, rimantadine hydrochloride, rilpivirine (TMC-278), saquinavir mesylate, SCH-C, SCH-D, somantadine hydrochloride, sorivudine, statolon, stavudine, T20, tilorone hydrochloride, TMC120, TMC125, trifluridine, trifluorothymidine, tenofovir, tenofovir alefenamide, tenofovir disoproxyl fumarate, prodrugs of tenofovir, UC-781, UK-427, UK-857, valacyclovir, valacyclovir hydrochloride, vidarabine, vidarabine phosphate, vidarabine sodium phosphate, viroxime, zalcitabene, zidovudine, and zinviroxime.

[00291] In a further aspect, the method further comprises the step of co-administering a therapeutically effective amount of at least one anti-HIV agent. In a still further aspect, the at least one agent is selected from entry inhibitors, fusion inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, NCP7 inhibitors, protease inhibitors, and integrase inhibitors. In a still further aspect, the entry inhibitor and/or fusion inhibitor is selected from Enfuvirtide (Fuzeon, T-20), AMD11070, PRO542, SCH-C, T-1249, TNX-355, cyanovirin, grifithsen, maraviroc and enfuvirtide. In yet a further aspect the entry inhibitor is selected from the class of lectins. In yet a further aspect, the non-nucleoside reverse transcriptase inhibitor is selected from delavirdine (Rescriptor), efavirenz (Sustiva), nevirapine

(Viramune), calanolide A, capravirine, epivir, hivid, TMC125, adefovir, etravirine, rilpivirine, dapivirine, and lersivirine, and mixtures thereof. In an even further aspect, the nucleoside reverse transcriptase inhibitor and/or nucleotide reverse transcriptase inhibitor is selected from abacavir (Ziagen), didanosine (Videx, ddl), emtricitabine (Emtriva, FTC), lamivudine (Epivir, eTC), stavudine (Zerit, d4t), tenofovir (({[(2R)-1-(6-amino-9H-purin-9- yl)propan-2-yl]oxy}methyl)phosphonic acid), tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, delavirdine (Rescriptor), zalcitabine (Hivid, ddc), zidovudine

(Retrovir, AZT, ZDR), entecavir, and apricitabine, and mixtures thereof. In a still further aspect, the protease inhibitor is selected from amprenavir (Agenerase), atazanavir (Reyataz), fosamprenavir (Lexiva, 908), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), emtriva, saquinavir (Fortovase, Invirase), invirase, agenerase, lopinavir, tipranavir, and darunavir, and mixtures thereof. In yet a further aspect, the integrase inhibitor is selected from elvitegravir, raltegravir, GSK 1265744, GSK-572, and MK-2048, and mixtures thereof. Other anti-HIV agents include, for example, AMD-3100, BMS-806, BMS-793, C31G, carrageenan, CD4-IgG2, cellulose acetate phthalate, zinc salts, cellulose sulphate, cyclodextrins, dextrin-2-sulphate, mAb 2G12, mAb b12, Merck 167, plant lectins, poly naphthalene sulfate, poly sulfo-styrene, PRO2000, PSC-Rantes, SCH-C, SCH-D, T-20, TMC-125, UC-781, UK-427, UK-857, and Viramune, and mixtures thereof.

[00292] In a further aspect, the at least one compound and the at least one agent are administered sequentially. In a still further aspect, the at least one compound and the at least one agent are administered simultaneously.

[00293] In a further aspect, the at least one compound and the at least one agent are co- formulated. In a still further aspect, the at least one compound and the at least one agent are co-packaged.

2. METHODS OF INHIBITING A VIRAL INFECTION IN A MAMMAL [00294] In one aspect, disclosed are methods of inhibiting an HIV infection in a mammal, the method comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[00295] The APOBEC3 restriction factors are a family of deoxycytidine deaminases that are able to suppress replication of viruses with a single-stranded DNA intermediate by inducing mutagenesis and functional inactivation of the virus. The restriction of HIV-1 occurs most potently in the absence of HIV-1 Vif that induces polyubiquitination and degradation of APOBEC3 enzymes through the proteasome pathway. To restrict HIV-1, APOBEC3 enzymes must be encapsidated into budding virions. Upon infection of the target cell during reverse transcription of the HIV-1 RNA into (-)DNA, APOBEC3 enzymes deaminate cytosines to form uracils in single-stranded (-)DNA regions. Upon replication of the (-)DNA to (+)DNA, the HIV-1 reverse transcriptase incorporates adenines opposite to the uracils thereby inducing C/G to T/A mutations that can functionally inactivate HIV-1.

APOBEC3G is the most studied APOBEC3 enzyme and it is known that Vif attempts to thwart APOBEC3 function not only by inducing its proteasomal degradation but also by several degradation-independent mechanisms, such as inhibiting APOBEC3G virion encapsidation, mRNA translation, and for those APOBEC3G molecules that still become virion encapsidated, Vif can inhibit APOBEC3G mutagenic activity. For at least these reasons, Vif-mediated protein-protein interactions are excelent targets for antiretroviral therapeutics to combat AIDS.

[00296] In a further aspect, the compound exhibits inhibition of HIV-1 activity with an IC50 of less than about 30 µM. In a still further aspect, the compound exhibits inhibition of HIV-1 activity with an IC₅₀ of less than about 25 µM. In yet a further aspect, the compound exhibits inhibition of HIV-1 activity with an IC50 of less than about 20 µM. In an even further aspect, the compound exhibits inhibition of HIV-1 activity with an IC₅₀ of less than about 15 µM. In a still further aspect, the compound exhibits inhibition of HIV-1 activity with an IC₅₀ of less than about 10 µM. In yet a further aspect, the compound exhibits inhibition of HIV-1 activity with an IC50 of less than about 5 µM. In an even further aspect, the compound exhibits inhibition of HIV-1 activity with an IC₅₀ of less than about 1 µM. In a still further aspect, the compound exhibits inhibition of HIV-1 activity with an IC50 of less than about 0.5 µM.

[00297] In a further aspect, the compound exhibits inhibition of Vif dimerization with an IC₅₀ of less than about 30 µM. In a still further aspect, the compound exhibits inhibition of Vif dimerization with an IC50 of less than about 25 µM. In yet a further aspect, the compound exhibits inhibition of Vif dimerization with an IC₅₀ of less than about 20 µM. In an even further aspect, the compound exhibits inhibition of Vif dimerization with an IC50 of less than about 15 µM. In a still further aspect, the compound exhibits inhibition of Vif dimerization with an IC50 of less than about 10 µM. In yet a further aspect, the compound exhibits inhibition of Vif dimerization with an IC50 of less than about 5 µM. In an even further aspect, the compound exhibits inhibition of Vif dimerization with an IC50 of less than about 1 µM. In a still further aspect, the compound exhibits inhibition of Vif dimerization with an IC50 of less than about 0.5 µM.

[00298] In a further aspect, the subject is a mammal. In a still further aspect, the subject is a human.

[00299] In a further aspect, the subject has been diagnosed with a need for treatment of an infection infection prior to the administering step. In a still further aspect, the method further comprises the step of identifying a subject at risk of becoming infected with HIV prior to treatment of the disorder.

3. METHODS OF INHIBITING A VIRAL INFECTION IN AT LEAST ONE CELL [00300] In one aspect, disclosed are methods for inhibiting an HIV infection in at least one cell, the method comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[00301] In a further aspect, the cell is mammalian. In a still further aspect, the cell is human. In yet a further aspect, the cell has been isolated from a mammal prior to the contacting step.

[00302] In a further aspect, contacting is via administration to a mammal.

4. USE OF COMPOUNDS [00303] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for the treatment of a viral infection in a subject.

[00304] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[00305] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.

[00306] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[00307] In various aspects, the use relates to a treatment of a viral infection in a subject. Also disclosed is the use of a compound for antagonism of a viral infection. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the disorder is a viral infection.

[00308] In a further aspect, the use relates to the manufacture of a medicament for the treatment of a viral infection in a subject.

[00309] In a further aspect, the use relates to antagonism of a viral infection in a subject. In a further aspect, the use relates to modulating viral activity in a subject. In a still further aspect, the use relates to modulating viral activity in a cell. In yet a further aspect, the subject is a human.

[00310] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a viral infection in a mammal. In a further aspect, the viral infection is HIV.

5. M^{ANUFACTURE OF A} M^EDICAMENT [00311] In one aspect, the invention relates to a method for the manufacture of a medicament for treating a viral infection in a subject having the viral infection, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[00312] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the inhibition of a viral infection. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.

[00313] The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg/kg and about 1000 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[00314] The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

[00315] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.

6. K^ITS [00316] In one aspect, the invention relates to a kit comprising at least one compound that inhibits HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV, wherein the compound has a structure represented by a formula:

,

wherein is a solid bond or is absent; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,–NH₂,–CN,–NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,–NHC(O)(C1-C4 alkyl),–NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, and one or more of: (a) at least one antiviral agent; (b) a instructions for administering the at least one compound in connection with treating a viral infection; (c) instructions for administering the at least one compound in connection with reducing the risk of viral infection; and (d) instructions for treating a viral infection.

[00317] In one aspect, the invention relates to a kit comprising at least one compound having a structure represented by a formula:

hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; or a pharmaceutically acceptable salt thereof, and one or more of: (a) at least one antiviral agent; (b) a instructions for administering the at least one compound in connection with treating a viral infection; (c) instructions for administering the at least one compound in connection with reducing the risk of viral infection; and (d) instructions for treating a viral infection.

[00318] In a further aspect, the viral infection is selected from human immunodeficiency virus (HIV), human papillomavirus (HPV), influenza, chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, chikungunya, Venezuelan equine encephalitis, dengue, influenza, and zika. In a still further aspect, the viral infection is selected from chikungunya, Venezuelan equine encephalitis, dengue, influenza, and zika. In a further aspect, the viral infection is HIV. In a still further aspect, the viral infection is HIV-1.

[00319] In a further aspect, the antiviral agent is selected from selected from acemannan, acyclovir, acyclovir sodium, adamantanamine, adefovir, adenine arabinoside, alovudine, alvircept sudotox, amantadine hydrochloride, aranotin, arildone, atevirdine mesylate, avridine, cidofovir, cipamfylline, cytarabine hydrochloride, BMS 806, C31G, carrageenan, cellulose sulfate, cyclodextrins, dapivirine, delavirdine mesylate, desciclovir, dextrin 2- sulfate, didanosine, disoxaril, dolutegravir, edoxudine, enviradene, envirozime, etravirine, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, foscarnet sodium, fosfonet sodium, FTC, ganciclovir, ganciclovir sodium, GSK 1265744, 9-2-hydroxy-ethoxy methylguanine, ibalizumab, idoxuridine, interferon, 5-iodo-2′-deoxyuridine, IQP-0528, kethoxal, lamivudine, lobucavir, maraviroc, memotine pirodavir, penciclovir, raltegravir, ribavirin, rimantadine hydrochloride, rilpivirine (TMC-278), saquinavir mesylate, SCH-C, SCH-D, somantadine hydrochloride, sorivudine, statolon, stavudine, T20, tilorone hydrochloride, TMC120, TMC125, trifluridine, trifluorothymidine, tenofovir, tenofovir alefenamide, tenofovir disoproxyl fumarate, prodrugs of tenofovir, UC-781, UK-427, UK- 857, valacyclovir, valacyclovir hydrochloride, vidarabine, vidarabine phosphate, vidarabine sodium phosphate, viroxime, zalcitabene, zidovudine, and zinviroxime. In a still further aspect, the antiviral agent is an anti-HIV agent.

[00320] In a further aspect, the anti-HIV agent selected from entry inhibitors, fusion inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, NCP7 inhibitors, protease inhibitors, and integrase inhibitors. In a still further aspect, the entry inhibitor and/or fusion inhibitor is selected from Enfuvirtide (Fuzeon, T-20), AMD11070, PRO542, SCH-C, T-1249, TNX-355, cyanovirin, grifithsen, maraviroc and enfuvirtide. In yet a further aspect the entry inhibitor is selected from the class of lectins. In yet a further aspect, the non- nucleoside reverse transcriptase inhibitor is selected from delavirdine (Rescriptor), efavirenz (Sustiva), nevirapine (Viramune), calanolide A, capravirine, epivir, hivid, TMC125, adefovir, etravirine, rilpivirine, dapivirine, and lersivirine, and mixtures thereof. In an even further aspect, the nucleoside reverse transcriptase inhibitor and/or nucleotide reverse transcriptase inhibitor is selected from abacavir (Ziagen), didanosine (Videx, ddl), emtricitabine (Emtriva, FTC), lamivudine (Epivir, eTC), stavudine (Zerit, d4t), tenofovir (({[(2R)-1-(6-amino-9H- purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid), tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, delavirdine (Rescriptor), zalcitabine (Hivid, ddc), zidovudine (Retrovir, AZT, ZDR), entecavir, and apricitabine, and mixtures thereof. In a still further aspect, the protease inhibitor is selected from amprenavir (Agenerase), atazanavir (Reyataz), fosamprenavir (Lexiva, 908), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), emtriva, saquinavir (Fortovase, Invirase), invirase, agenerase, lopinavir, tipranavir, and darunavir, and mixtures thereof. In yet a further aspect, the integrase inhibitor is selected from elvitegravir, raltegravir, GSK 1265744, GSK-572, and MK-2048, and mixtures thereof. Other anti-HIV agents include, for example, AMD-3100, BMS-806, BMS-793, C31G, carrageenan, CD4-IgG2, cellulose acetate phthalate, zinc salts, cellulose sulphate, cyclodextrins, dextrin-2-sulphate, mAb 2G12, mAb b12, Merck 167, plant lectins, poly naphthalene sulfate, poly sulfo-styrene, PRO2000, PSC-Rantes, SCH-C, SCH-D, T-20, TMC-125, UC-781, UK-427, UK-857, and Viramune, and mixtures thereof.

[00321] In a further aspect, the at least one compound and the at least one agent are co- formulated. In a further aspect, the at least one compound and the at least one agent are co- packaged.

[00322] The kits can also comprise compounds and/or products co-packaged, co- formulated, and/or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient.

[00323] It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.

[00324] The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[00325] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls. F. EXAMPLES [00326] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[00327] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way.

1. CHEMISTRY EXPERIMENTALS a. G^ENERAL E^XPERIMENTAL [00328] All reactions were carried out in an oven- or flame-dried glassware under argon atmosphere using standard gas-tight syringe, cannula, and septa. The reaction temperatures were measured externally. Stirring was achieved with oven dried magnetic bars. All the reactions were done in anhydrous solvents (DMF, THF, CH2Cl2, 1,4-Dioxane, 1-Butanol, CHCl₃, DME) purchased from Sigma-Aldrich. Microwave reactions were performed in CEM discover Labmate System with Intelligent Technology for Focused Microwave Synthesizer (Explorer 48). All commercially purchased reagents were used without purification. The reactions were monitored by thin-layer chromatography (TLC) on a pre- coated silica gel (60 F254) glass plates from EMD Millipore and visualized using UV light (254 nm). Purification of the compounds was performed on Teledyne-ISCO Combiflash Rf 200 purification system. Used Redisep Rf® normal phase silica gel columns 230-400 mesh. Proton NMR spectra were recorded on a Varian Unity 400 NMR spectrometer operating at 400 MHz calibrated to the solvent peak and TMS peak. The chemical formula and Exact Mass for target compounds were determined from the (M+H)+ by high resolution mass spectroscopy using an Agilent 6210 Electrospray Time of Flight Spectrometer.

[00329] The purity of the final compounds were checked by HPLC using Agilent 1100 LC equipped with a diode array UV detector and monitored at multiple wavelengths on Bondclone 10 µ C18 column using Solvent A: H2O, Solvent B: CH3CN, 1.0 ml/min; 30 min linear gradient from 10-90% B, or on Waters HPLC equipped with a 3100 Mass Detector using Sunfire C18 column (5 µM, 4.6X150 mm) using ACN-H2) (both containing 0.1% formic acid) from 10-90% gradient in 15 min.

a. GENERAL SYNTHESIS OF 3-SUBSTITUTED TRIAZOLOPHTHALAZINES (i) PROCEDURE A

[00330] To 1,4-dichlorophthalazine (1 equiv.) dissolved in 1-BuOH (0.25 M) was added the corresponding hydrazide (2 equiv.) and refluxed for ~ 1-16 h. After reaction completion (as monitored by TLC and MS analysis) the solvents were evaporated off and the resulting solids were purified by silica gel column chromatography using 5% MeOH in CH2Cl2 as the gradient for 30 min. All the final compounds were isolated as white color solids in 50-90% yield.

1) 6-^CHLORO-3-^CYCLOPROPYL-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZINE

[00331] ¹H NMR (400 MHz, Chloroform-d) δ 8.66 (ddt, J = 8.0, 1.2, 0.7 Hz, 1H), 8.25 (ddd, J = 8.2, 1.2, 0.7 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.87 - 7.82 (m, 1H), 2.49 (tt, J = 8.5, 5.1 Hz, 1H), 1.42 - 1.36 (m, 2H), 1.25 - 1.20 (m, 2H). LRMS: (M+H)⁺ = 245.1 m/z. Yield: 73%.

2) 6-CHLORO-3-METHYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZINE

[00332] ¹H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 8.0, 1.3, 0.6 Hz, 1H), 8.30 - 8.27 (m, 1H), 8.13 (ddd, J = 8.0, 7.4, 1.2 Hz, 1H), 8.02 - 7.97 (m, 1H), 2.67 (s, 3H). LRMS:

(M+H)⁺ = 219.1 m/z. Yield: 87%.

3) 6-CHLORO-3,7,8-TRIMETHYL-[1,2,4]TRIAZOLO[4,3- B]^PYRIDAZINE

[00333] ¹H NMR (400 MHz, Chloroform-d) δ 2.78 (s, 3H), 2.72 (q, J = 0.8 Hz, 3H), 2.43 – 2.41 (m, 3H). LRMS: (M+H)⁺ = 197.1 m/z. Yield: 26%.

4) 6-CHLORO-3-METHYL-7,8,9,10-TETRAHYDRO-7,10- ETHANO[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE

[00334] ¹H NMR (400 MHz, Chloroform-d) δ 4.09-4.05 (m, 1H), 3.58-3.54 (m, 1H), 2.82 (s, 3H), 2.02 - 1.91 (m, 4H), 1.53 - 1.39 (m, 4H). LRMS: (M+H)⁺ = 249.1 m/z. Yield: 44%.

5) 6-CHLORO-3-ISOPROPYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZINE

[00335] ¹H NMR (400 MHz, Chloroform-d) δ 8.69 (ddt, J = 7.6, 1.3, 0.6 Hz, 1H), 8.27 - 8.24 (m, 1H), 8.01 - 7.96 (m, 1H), 7.88 - 7.83 (m, 1H), 3.65 (p, J = 7.0 Hz, 1H), 1.57 - 1.54 (m, 6H). LRMS: (M+H)⁺ = 247.1 m/z. Yield: 90%.

6) 6-CHLORO-3-METHYL-[1,2,4]TRIAZOLO[4,3-B]PYRIDAZINE

[00336] ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J = 9.7 Hz, 1H), 7.45 (d, J = 9.6 Hz, 1H), 2.67 (s, 3H). HRMS: C6H5ClN4 calculated (M+H)⁺ = 169.02755 m/z; found (M+H)⁺ = 169.02736 m/z. Yield: 47%.

7) 6-CHLORO-3-(THIOPHEN-2-YL)-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZINE

[00337] ¹H NMR (400 MHz, DMSO-d6) δ 8.62 (ddt, J = 8.0, 1.4, 0.7 Hz, 1H), 8.37 - 8.33 (m, 1H), 8.20 - 8.14 (m, 2H), 8.07 - 8.01 (m, 1H), 7.89 (dt, J = 5.1, 1.0 Hz, 1H), 7.35 (ddd, J = 5.1, 3.7, 0.8 Hz, 1H). LRMS: (M+H)⁺ = 287.0 m/z. Yield: 60%.

8) 6-^CHLORO-3-(^FURAN-2-^YL)-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZINE

[00338] LRMS: (M+H)⁺ = 271.0 m/z. Yield: 33%.

9) 6-CHLORO-3-(THIOPHEN-3-YL)-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZINE

[00339] ¹H NMR (400 MHz, Chloroform-d) δ 8.76 (ddd, J = 8.0, 1.3, 0.6 Hz, 1H), 8.59 (dd, J = 3.0, 1.2 Hz, 1H), 8.30 (ddd, J = 8.2, 1.2, 0.6 Hz, 1H), 8.10 (dd, J = 5.1, 1.2 Hz, 1H), 8.06 - 8.01 (m, 1H), 7.92 - 7.87 (m, 1H), 7.51 (dd, J = 5.1, 3.0 Hz, 1H). LRMS: (M+H)⁺ = 287.0 m/z. Yield: 49%.

10) 4-(6-^CHLORO-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZIN-3- YL)THIAZOLE

[00340] LRMS: (M+H)⁺ = 288.0 m/z. Yield: 56%.

11) 6-^CHLORO-3-(3-^{METHOXYPHENYL})-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZINE

[00341] ¹H NMR (400 MHz, Chloroform-d) δ 8.79– 8.75 (m, 1H), 8.31– 8.28 (m, 1H), 8.07 (ddd, J = 7.7, 1.6, 0.9 Hz, 1H), 8.04– 8.01 (m, 2H), 7.93– 7.89 (m, 1H), 7.52– 7.46 (m, 1H), 7.09 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 3.94 (s, 3H). LRMS: (M+H)⁺ = 311.1 m/z. Yield: 22%.

12) 6-CHLORO-3-PHENYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN

[00342] ¹H NMR (400 MHz, Chloroform-d) δ 8.84 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.06– 8.02 (m, 1H), 7.95– 7.90 (m, 1H), 7.64– 7.44 (m, 5H). LRMS: (M+H)⁺ = 281.1 m/z. Yield: 89%.

[00343] To a reaction flask was added 1-chloro-4-hydrazinylphthalazine (1 equiv) and the corresponding carboxylic acid (10 equiv.) and the combined reaction mixture was heated to 110 ^oC for 4 h. After reaction completion as monitored by TLC and MS, the solvents were evaporated off by diluting with ethanol. The resulting crude product was then purified by silica gel column chromatography using 5% MeOH in CH2Cl2 as the gradient for 30 min. All the final compounds were isolated as white color solids in 50-90% yield.

1) 6-CHLORO-3-(TRIFLUOROMETHYL)-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZINE

[00344] ¹H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 7.9 Hz, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.25 (t, J = 7.7 Hz, 1H), 8.14 (t, J = 7.8 Hz, 1H). LRMS: (M+H)⁺ = 273.0 m/z. Yield: 64%.

2) 6-CHLORO-3-(2,2,2-TRIFLUOROETHYL)- [1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE

[00345] ¹H NMR (400 MHz, Chloroform-d) δ 8.74 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.06 (t, J = 7.7 Hz, 1H), 7.93 (t, J = 8.5 Hz, 1H), 4.14 (q, J = 9.8 Hz, 2H). LRMS: (M+H)⁺ = 287.0 m/z. Yield: 41%.

3) 6-CHLORO-3-(DIFLUOROMETHYL)-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZINE

[00346] ¹H NMR (400 MHz, Chloroform-d) δ 8.78 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.10 (t, J = 7.7 Hz, 1H), 7.98 (t, J = 8.4 Hz, 1H), 7.23 (t, J = 51.8 Hz, 1H). LRMS: (M+H)⁺ = 255.0 m/z. Yield: 86%.

b. GENERAL SYNTHESIS OF FINAL COMPOUNDS

[00347] All the reactions were done in a pressure tube. To the starting substituted tetrahydroisoquinoline (1 equiv) dissolved in 1,4-dioxane (0.2 M) was added the corresponding triazolophthalazine (1.05 equiv) and potassium carbonate (3 equiv.) and the combined reaction mixture was heated to 100 °C for between 12 h and 7 days. After the reaction completion as monitored by TLC and MS analysis, the reaction mixture was cooled to room temperature, quenched with aq. NH₄Cl (sat), and extracted with methylene chloride (3X). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuuo. The resulting crude product was then purified by silica gel column chromatography using 0-10% MeOH in CH2Cl2 as the gradient for 30 min. All the final compounds were isolated as powdered or crystalline solids in 10-50% yield.

(i) 6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3-METHYL- [1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (1)

[00348] ¹H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 7.9, 1.3 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.99 (ddd, J = 8.2, 7.3, 1.1 Hz, 1H), 7.87 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.27 - 7.18 (m, 4H), 4.59 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.19 (t, J = 5.9 Hz, 2H), 2.66 (s, 3H). HRMS: C₁₉H₁₇N₅ calculated (M+H)⁺ = 316.15567 m/z; found (M+H)⁺ = 316.15540 m/z. Yield: 44%.

(ii) 6-(6,7-DIMETHOXY-3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3- METHYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (2)

[00349] ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (dd, J = 8.0, 1.3 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.02 - 7.97 (m, 1H), 7.88 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 6.83 (d, J = 10.9 Hz, 2H), 4.51 (s, 2H), 3.76 (s, 3H), 3.74 (s, 3H), 3.63 (t, J = 5.8 Hz, 2H), 3.14 - 3.07 (m, 2H), 2.66 (s, 3H). HRMS: C21H21N5O2 calculated (M+H)⁺ = 376.17680 m/z; found (M+H)⁺ = 376.17654 m/z. Yield: 38%.

(iii) 2-(3-^METHYL-[1,2,4]^TRIAZOLO[4,3-^B]^PYRIDAZIN-6-^YL)- 1,2,3,4-TETRAHYDROISOQUINOLINE (3)

[00350] ¹H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 10.1 Hz, 1H), 7.42 (d, J = 10.1 Hz, 1H), 7.30 - 7.19 (m, 4H), 4.75 (s, 2H), 3.85 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.59 (s, 3H). HRMS: C₁₅H₁₅N₅ calculated (M+H)⁺ = 266.14002 m/z; found (M+H)⁺ = 266.13982 m/z. Yield: 46%.

(iv) 3-(DIFLUOROMETHYL)-6-(3,4-DIHYDROISOQUINOLIN-2(1H)- YL)-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (4)

[00351] ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (ddd, J = 7.9, 1.4, 0.6 Hz, 1H), 8.23 - 8.20 (m, 1H), 8.06 (ddd, J = 8.1, 7.4, 1.1 Hz, 1H), 7.97 (ddd, J = 8.3, 7.3, 1.4 Hz, 1H), 7.71 (t, J = 51.6 Hz, 1H), 7.28 - 7.19 (m, 4H), 4.63 (s, 2H), 3.73 (t, J = 5.9 Hz, 2H), 3.21 (t, J = 5.9 Hz, 2H). HRMS: C19H15F2N5 calculated (M+H)⁺ = 352.13683 m/z; found (M+H)⁺ = 352.13649 m/z. Yield: 89%.

(v) 2-(3,7,8-^TRIMETHYL-[1,2,4]^TRIAZOLO[4,3-^B]^PYRIDAZIN-6- YL)-1,2,3,4-TETRAHYDROISOQUINOLINE (5)

[00352] ¹H NMR (400 MHz, DMSO-d6) δ 7.24-7.26 (m, 4H), 4.40 (s, 2H), 3.41 (t, J = 5.8 Hz, 2H), 3.05 (t, J = 5.9 Hz, 2H), 2.62 (s, 3H), 2.52 (s, 3H), 2.31 (s, 3H). HRMS: C₁₇H₁₉N₅ calculated (M+H)⁺ = 294.17132 m/z; found (M+H)⁺ = 394.17105 m/z. Yield: 13%.

(vi) 3-METHYL-6-(OCTAHYDROISOQUINOLIN-2(1H)-YL)- [1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE (8)

[00353] ¹H NMR (400 MHz, Chloroform-d) δ 8.75 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1H), 3.82 (dd, J = 12.7, 3.3 Hz, 1H), 3.63 (dt, J = 12.7, 2.7 Hz, 1H), 3.00 (td, J = 12.6, 2.6 Hz, 1H), 2.78 (s, 3H), 2.67 (t, J = 11.8 Hz, 1H), 1.85 - 1.72 (m, 4H), 1.67-1.58 (m, 2H), 1.58 - 1.49 (m, 1H), 1.36-1.31 (m, 2H), 1.27 - 1.14 (m, 2H), 1.13-1.00 (m, 1H). HRMS: C₁₉H₂₃N₅ calculated (M+H)⁺ = 322.20262 m/z; found (M+H)⁺ = 322.20270 m/z. Yield: 29%. (vii) 3-(DIFLUOROMETHYL)-6-(6,7-DIMETHOXY-3,4- D^{IHYDROISOQUINOLIN}-2(1H)-^YL)-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZINE (9)

[00354] ¹H NMR (400 MHz, DMSO-d6) δ 8.56 (dd, J = 8.0, 1.3 Hz, 1H), 8.21 (dd, J = 8.2, 0.9 Hz, 1H), 8.06 (td, J = 7.6, 1.1 Hz, 1H), 7.97 (ddd, J = 8.6, 7.3, 1.4 Hz, 1H), 7.63 (t, J = 51.3 Hz, 1H), 6.82 (s, 2H), 4.56 (s, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.70 (t, J = 5.8 Hz, 2H), 3.12 (t, J = 5.8 Hz, 2H). HRMS: C₂₁H₁₉F₂N₅O₂ calculated (M+H)⁺ = 412.15796 m/z; found (M+H)⁺ = 412.15744 m/z. Yield: 65%.

(viii) 6-(6-METHOXY-3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3- M^ETHYL-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE (10)

[00355] ¹H NMR (400 MHz, Chloroform-d) δ 8.77 (d, J = 8.0 Hz, 1H), 8.09 (ddd, J = 8.2, 1.2, 0.6 Hz, 1H), 7.90 (ddd, J = 7.9, 7.3, 1.2 Hz, 1H), 7.79 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.83 - 6.76 (m, 2H), 4.58 (s, 2H), 3.83 (s, 3H), 3.73 (t, J = 6.2 Hz, 2H), 3.20 (t, J = 5.9 Hz, 2H), 2.81 (s, 3H). HRMS: C20H19N5O calculated (M+H)⁺ =

346.16624 m/z; found (M+H)⁺ = 346.16626 m/z. Yield: 33%.

(ix) 6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3-ISOPROPYL- [1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (11)

[00356] ¹H NMR (400 MHz, Chloroform-d) δ 8.84 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.90 (t, J = 7.5 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.27 - 7.22 (m, 3H), 7.22 - 7.16 (m, 1H), 4.63 (s, 2H), 3.76 (t, J = 5.9 Hz, 2H), 3.64 (p, J = 7.0 Hz, 1H), 3.21 (t, J = 5.9 Hz, 2H), 1.55 (d, J = 7.1 Hz, 6H). HRMS: C₂₁H₂₁N₅ calculated (M+H)⁺ = 346.16624 m/z; found (M+H)⁺ = 346.16626 m/z. Yield: 32%.

(x) 6-(7-METHOXY-3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3- M^ETHYL-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE (12)

[00357] ¹H NMR (400 MHz, Chloroform-d) δ 8.68 (d, J = 7.9 Hz, 1H), 8.07 (ddd, J = 8.2, 1.2, 0.6 Hz, 1H), 7.87 (ddd, J = 8.1, 7.3, 1.2 Hz, 1H), 7.75 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.81 (dd, J = 8.4, 2.7 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 4.58 (s, 2H), 3.81 (s, 3H), 3.70 (t, J = 5.9 Hz, 2H), 3.15 (t, J = 5.9 Hz, 2H), 2.78 (s, 3H). HRMS:

C₂₀H₁₉N₅O calculated (M+H)⁺ = 346.16624 m/z; found (M+H)⁺ = 346.16587 m/z. Yield: 17%.

(xi) 6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3- (TRIFLUOROMETHYL)-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (13)

[00358] ¹H NMR (400 MHz, Chloroform-d) δ 8.75 (dd, J = 7.9, 1.3 Hz, 1H), 8.14 (dt, J = 8.2, 0.9 Hz, 1H), 7.98 - 7.93 (m, 1H), 7.86 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.26 - 7.17 (m, 4H), 4.68 (s, 2H), 3.81 (t, J = 5.9 Hz, 2H), 3.25 (t, J = 5.9 Hz, 2H). HRMS: C₁₉H₁₄F₃N₅ calculated (M+H)⁺ = 370.12741 m/z; found (M+H)⁺ = 370.12744 m/z. Yield: 89%.

(xii) 6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3-PHENYL- [1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (14)

[00359] ¹H NMR (400 MHz, Chloroform-d) δ 8.84 (d, J = 8.0 Hz, 1H), 8.48 - 8.44 (m, 2H), 8.14 (dt, J = 8.1, 0.9 Hz, 1H), 7.93 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H), 7.81 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.58 - 7.49 (m, 3H), 7.28 - 7.20 (m, 4H), 4.70 (s, 2H), 3.83 (t, J = 5.9 Hz, 2H), 3.20 (t, J = 5.9 Hz, 2H). HRMS: C24H19N5 calculated (M+H)⁺ = 378.17132 m/z; found (M+H)⁺ = 378.17183 m/z. Yield: 48%.

(xiii) 6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3-(THIOPHEN-2-YL)- [1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE (15)

[00360] ¹H NMR (400 MHz, Chloroform-d) δ 8.77 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 3.7 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.91(t, J = 7.6 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.57 (dd, J = 5.0, 1.3 Hz, 1H), 7.29-7.23 (m, 5H), 4.75 (s, 2H), 3.84 (t, J = 5.9 Hz, 2H), 3.26 (t, J = 6.0 Hz, 2H). HRMS: C22H17N5S calculated (M+H)⁺ = 384.12774 m/z; found (M+H)⁺ =

384.12731 m/z. Yield: 45%.

(xiv) 3-^CYCLOPROPYL-6-(3,4-^{DIHYDROISOQUINOLIN}-2(1H)-^YL)- [1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (17)

[00361] ¹H NMR (400 MHz, Chloroform-d) δ 8.77 (d, J = 7.9 Hz, 1H), 8.09 (dd, J = 8.2, 1.1 Hz, 1H), 7.89 (td, J = 7.7, 1.2 Hz, 1H), 7.78 (td, J = 7.8, 7.2, 1.4 Hz, 1H), 7.26 - 7.17 (m, 4H), 4.65 (s, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.23 (t, J = 5.9 Hz, 2H), 2.54 (tt, J = 8.5, 5.1 Hz, 1H), 1.45 (dt, J = 6.5, 3.3 Hz, 2H), 1.25 - 1.21 (m, 2H). HRMS: C21H19N5 calculated (M+H)⁺ = 342.17132 m/z; found (M+H)⁺ = 342.17099 m/z. Yield: 28%.

(xv) 6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3-(2,2,2- TRIFLUOROETHYL)-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (18)

[00362] ¹H NMR (400 MHz, Chloroform-d) δ 8.81 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.93 (td, J = 7.7, 1.2 Hz, 1H), 7.82 (td, J = 7.7, 7.3, 1.4 Hz, 1H), 7.27-7.22 (m, 3H), 7.22-7.17 (m, 1H), 4.65 (s, 2H), 4.09 (q, J = 9.8 Hz, 2H), 3.78 (t, J = 5.9 Hz, 2H), 3.22 (t, J = 5.9 Hz, 2H). HRMS: C20H16F3N5 calculated (M+H)⁺ = 384.14306 m/z; found (M+H)⁺ = 384.14272 m/z. Yield: 27%.

(xvi) 2-(3-METHYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZIN-6-YL)- 1,2,3,4-^{TETRAHYDROISOQUINOLINE}-7-^CARBONITRILE (19)

[00363] ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 8.15 (dt, J = 8.0, 1.0 Hz, 1H), 8.00 (ddd, J = 8.0, 7.3, 1.1 Hz, 1H), 7.88 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.68 (dd, J = 7.9, 1.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 4.64 (s, 2H), 3.69 (t, J = 5.9 Hz, 2H), 3.26 (t, J = 5.8 Hz, 2H), 2.65 (s, 3H). HRMS: C20H16N6 calculated (M+H)⁺ = 341.15092 m/z; found (M+H)⁺ = 341.15020 m/z. Yield: 20%.

(xvii) 3-^CYCLOPROPYL-6-(7-^NITRO-3,4-^{DIHYDROISOQUINOLIN}- 2(1H)-YL)-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (42)

[00364] ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (dd, J = 7.9, 1.3 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.16 (dt, J = 8.1, 1.0 Hz, 1H), 8.09 (dd, J = 8.4, 2.5 Hz, 1H), 7.98 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 7.87 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 4.74 (s, 2H), 3.73 (t, J = 5.9 Hz, 2H), 3.32 - 3.26 (m, 2H), 2.49-2.42 (m, 1H), 1.24 - 1.11 (m, 4H). HRMS: C₂₁H₁₈N₆O₂ calculated (M+H)⁺ = 387.15640 m/z; found (M+H)⁺ = 387.15630 m/z. Yield: 50%.

(xviii) 3-ISOPROPYL-6-(7-METHOXY-3,4-DIHYDROISOQUINOLIN- 2(1H)-^YL)-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE (22)

[00365] ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (dd, J = 8.0, 1.2 Hz, 1H), 8.15 (dd, J = 8.1, 1.1 Hz, 1H), 7.98 (ddd, J = 8.0, 7.3, 1.1 Hz, 1H), 7.88 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.84 - 6.77 (m, 2H), 4.57 (s, 2H), 3.75 (s, 3H), 3.66 (t, J = 5.9 Hz, 2H), 3.51 (p, J = 7.0 Hz, 1H), 3.08 (t, J = 5.8 Hz, 2H), 1.44 (d, J = 7.0 Hz, 6H). HRMS: C22H23N5O calculated (M+H)⁺ = 374.19754 m/z; found (M+H)⁺ = 374.19724 m/z. Yield: 35%.

(xix) 3-(DIFLUOROMETHYL)-6-(7-NITRO-3,4- DIHYDROISOQUINOLIN-2(1H)-YL)-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZINE (44)

[00366] ¹H NMR (400 MHz, DMSO-d6) δ 8.58 (dd, J = 8.0, 1.3 Hz, 1H), 8.26 - 8.22 (m, 1H), 8.19 (d, J = 2.5 Hz, 1H), 8.11 - 8.05 (m, 2H), 7.98 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.62 (t, J = 51.7 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 4.79 (s, 2H), 3.79 (t, J = 5.8 Hz, 2H).2.50 (m, 2H). HRMS: C₁₉H₁₄F₂N₆O₂ calculated (M+H)⁺ = 397.12191 m/z; found (M+H)⁺ = 397.12174 m/z. Yield: 66%.

(xx) 6-(5-FLUORO-3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3- M^ETHYL-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE (24)

[00367] ¹H NMR (400 MHz, Chloroform-d) δ 8.72 - 8.66 (m, 1H), 8.07 (dd, J = 8.1, 1.1 Hz, 1H), 7.89 (ddd, J = 8.1, 7.3, 1.2 Hz, 1H), 7.76 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.21 (td, J = 7.9, 5.6 Hz, 1H), 7.01 - 6.94 (m, 2H), 4.62 (s, 2H), 3.72 (t, J = 6.0 Hz, 2H), 3.18 (t, J = 6.0 Hz, 2H), 2.78 (s, 3H). HRMS: C₁₉H₁₆FN₅ calculated (M+H)⁺ = 334.14625 m/z; found (M+H)⁺ = 334.14662 m/z. Yield: 7%.

(xxi) 6-(7-METHOXY-3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3- (THIOPHEN-2-YL)-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (25)

[00368] ¹H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.69 (m, 1H), 8.20 (dd, J = 3.7, 1.2 Hz, 1H), 8.12 (ddd, J = 8.2, 1.2, 0.6 Hz, 1H), 7.92 - 7.86 (m, 1H), 7.77 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.55 (dd, J = 5.0, 1.2 Hz, 1H), 7.24 (dd, J = 5.0, 3.7 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 8.4, 2.7 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.70 (s, 2H), 3.84 (s, 3H), 3.80 (t, J = 5.9 Hz, 2H), 3.16 (t, J = 5.9 Hz, 2H). HRMS: C23H19N5OS calculated (M+H)⁺ = 414.13831 m/z; found (M+H)⁺ = 414.13844 m/z. Yield: 26%.

(xxii) 6-(4,4-DIMETHYL-3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3- METHYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (26)

[00369] ¹H NMR (400 MHz, Chloroform-d) δ 8.68 (d, J = 8.0 Hz, 1H), 8.23 (ddt, J = 8.2, 1.3, 0.6 Hz, 1H), 7.87 (dddd, J = 7.9, 7.2, 1.2, 0.6 Hz, 1H), 7.73 (dddd, J = 8.0, 7.3, 1.3, 0.6 Hz, 1H), 7.44 (dd, J = 7.9, 1.3 Hz, 1H), 7.31 (dddd, J = 7.9, 7.2, 1.5, 0.7 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.16 - 7.12 (m, 1H), 4.54 (s, 2H), 3.46 (s, 2H), 2.80 (d, J = 0.6 Hz, 3H), 1.51 (s, 6H). HRMS: C21H21N5 calculated (M+H)⁺ = 344.18697 m/z; found (M+H)⁺ = 344.18764 m/z. Yield: 16%.

(xxiii) 6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3-METHYL-7,8,9,10- T^ETRAHYDRO-7,10-^ETHANO[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZINE (27)

[00370] ¹H NMR (400 MHz, DMSO-d₆) δ 7.26 - 7.15 (m, 4H), 4.46 (s, 2H), 3.65 (br.s, 1H), 3.50 (t, J = 5.9 Hz, 2H), 3.26 (br.s, 1H), 3.08 (t, J = 5.9 Hz, 2H), 2.62 (s, 3H), 1.89 (br.d, J = 9.0 Hz, 4H)1.49 - 1.32 (m, 4H). HRMS: C₂₁H₂₃N₅ calculated (M+H)⁺ = 346.20262 m/z; found (M+H)⁺ = 346.20231 m/z. Yied: 30%.

(xxiv) 6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3-(FURAN-2-YL)- [1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE (28)

[00371] ¹H NMR (400 MHz, DMSO-d6) δ 8.58 - 8.53 (m, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.07 - 8.01 (m, 2H), 7.94 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.47 (dd, J = 3.5, 0.8 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.27 - 7.21 (m, 3H), 6.83 (dd, J = 3.4, 1.8 Hz, 1H), 4.70 (s, 2H), 3.77 (t, J = 5.9 Hz, 2H), 3.18 (t, J = 5.9 Hz, 2H). HRMS: C22H17N5O calculated (M+H)⁺ = 368.15059 m/z; found (M+H)⁺ = 368.15042 m/z. Yield: 34%.

(xxv) 4-(6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)- [1,2,4]TRIAZOLO[3,4-A]PHTHALAZIN-3-YL)THIAZOLE (29)

[00372] ¹H NMR (400 MHz, DMSO-d⁶) δ 9.36 (d, J = 1.9 Hz, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.59 (dd, J = 7.9, 1.2 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.09 - 8.04 (m, 1H), 7.98 - 7.92 (m, 1H), 7.36 (d, J = 5.6 Hz, 1H), 7.24 (d, J = 3.2 Hz, 3H), 4.71 (s, 2H), 3.79 (t, J = 5.8 Hz, 2H), 3.19 - 3.14 (m, 2H). HRMS: C21H16N6S calculated (M+H)⁺ = 385.12299 m/z; found (M+H)⁺ = 385.12218 m/z. Yield: 46%.

(xxvi) 6-(7,8-^DIHYDRO-1,6-^NAPHTHYRIDIN-6(5H)-^YL)-3-^METHYL- [1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (30)

[00373] ¹H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.46 (m, 1H), 8.44 (dd, J = 4.8, 1.7 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.89 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.28 - 7.23 (m, 1H), 4.63 (s, 2H), 3.76 (t, J = 5.9 Hz, 2H), 3.28 (t, J = 5.9 Hz, 2H). HRMS: C₁₈H₁₆N₆ calculated (M+H)⁺ = 317.15092 m/z; found (M+H)⁺ = 317.15034 m/z. Yield: 23%.

(xxvii) METHYL 2-(3-METHYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZIN- 6-YL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-CARBOXYLATE (31)

[00374] ¹H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.44 (m, 1H), 8.19 - 8.14 (m, 1H), 8.00 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.81 (dd, J = 8.0, 1.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 4.68 (s, 2H), 3.85 (s, 3H),3.70 (t, J = 5.8 Hz, 2H), 3.26 (t, J = 5.9 Hz, 2H), 2.66 (s, 3H). HRMS: C21H19N5O2 calculated (M+H)⁺ = 374.16115 m/z; found (M+H)⁺ = 374.16085 m/z. Yield: 45%.

(xxviii) 6-(3,4-^{DIHYDROISOQUINOLIN}-2(1H)-^YL)-3-(^THIOPHEN-3-^YL)- [1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (33)

[00375] ¹H NMR (400 MHz, Chloroform-d) δ 8.72 (ddd, J = 8.0, 1.4, 0.7 Hz, 1H), 8.43 (dd, J = 3.0, 1.2 Hz, 1H), 8.13 (ddd, J = 8.2, 1.2, 0.7 Hz, 1H), 8.09 (dd, J = 5.1, 1.2 Hz, 1H), 7.90 (ddd, J = 8.0, 7.3, 1.2 Hz, 1H), 7.77 (ddd, J = 8.2, 7.3, 1.3 Hz, 1H), 7.47 (dd, J = 5.1, 3.0 Hz, 1H), 7.29 - 7.23 (m, 4H), 4.70 (s, 2H), 3.82 (t, J = 5.9 Hz, 2H), 3.20 (t, J = 5.9 Hz, 2H). HRMS: C22H17N5S calculated (M+H)⁺ = 384.12774 m/z; found (M+H)⁺ = 384.12750 m/z. Yield: 65%.

(xxix) 6-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-3-(3- METHOXYPHENYL)-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (34)

[00376] ¹H NMR (400 MHz, DMSO-d6) δ 8.57 (dd, J = 7.9, 1.2 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.13 (dd, J = 2.6, 1.5 Hz, 1H), 8.04 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.93 (ddd, J = 8.3, 7.3, 1.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.23 (qd, J = 4.7, 2.9 Hz, 4H), 7.12 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 4.69 (s, 2H), 3.94 (s, 3H), 3.76 (t, J = 5.8 Hz, 2H), 3.18 (t, J = 5.8 Hz, 2H). HRMS: C25H21N5O calculated (M+H)⁺ = 408.18189 m/z; found (M+H)⁺ = 408.18166 m/z. Yield: 58%.

(xxx) 6-(5,8-^DIHYDRO-1,7-^NAPHTHYRIDIN-7(6H)-^YL)-3-^METHYL- [1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (35)

[00377] ¹H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.46 (m, 1H), 8.42 (dd, J = 4.7, 1.7 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.03 - 7.97 (m, 1H), 7.92 - 7.86 (m, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.28 (dd, J = 7.7, 4.7 Hz, 1H), 4.62 (s, 2H), 3.71 (t, J = 5.8 Hz, 2H), 3.21 (t, J = 5.9 Hz, 2H), 2.65 (s, 3H). HRMS: C₁₈H₁₆N₆ calculated (M+H)⁺ = 317.15092 m/z; found (M+H)⁺ = 317.15059 m/z. Yield: 10%.

(xxxi) 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZIN-6- Y^L)-1,2,3,4-^{TETRAHYDROISOQUINOLINE}-7-^CARBONITRILE (38)

[00378] ¹H NMR (400 MHz, DMSO-d6) δ 8.44 - 8.41 (m, 1H), 8.14 - 8.11 (m, 1H), 7.98 - 7.94 (m, 1H), 7.85 (ddt, J = 8.4, 7.2, 1.5 Hz, 1H), 7.77 - 7.75 (m, 1H), 7.66 (dd, J = 8.0, 1.7 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 4.62 (s, 2H), 3.68 (t, J = 5.9 Hz, 2H), 3.23 (t, J = 5.9 Hz, 2H), 2.42 (ddd, J = 8.2, 5.5, 2.9 Hz, 1H), 1.19 - 1.14 (m, 4H). HRMS: C₂₂H₁₈N₆ calculated (M+H)⁺ = 367.16657 m/z; found (M+H)⁺ = 367.16599 m/z. Yield: 77%.

(xxxii) 3-CYCLOPROPYL-6-(3-NITRO-7,8-DIHYDRO-1,6- NAPHTHYRIDIN-6(5H)-YL)-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZINE (45)

[00379] ¹H NMR (400 MHz, Chloroform-d) δ 9.33 (dd, J = 2.5, 0.8 Hz, 1H), 8.73– 8.69 (m, 1H), 8.37– 8.34 (m, 1H), 8.07– 8.03 (m, 1H), 7.94– 7.88 (m, 1H), 7.79 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 4.76 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 2.45 (tt, J = 8.5, 5.1 Hz, 1H), 1.42– 1.37 (m, 2H), 1.22– 1.16 (m, 2H). HRMS: C20H17N7O2 calculated (M+H)⁺ = 388.15165 m/z; found (M+H)⁺ = 388.15128 m/z. Yield: 4%.

(xxxiii) 3-^CYCLOPROPYL-6-(^ISOINDOLIN-2-^YL)-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZINE (46)

[00380] ¹H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.3 Hz, 1H), 8.46 (dd, J = 8.0, 1.4 Hz, 1H), 7.97 (td, J = 7.6, 1.1 Hz, 1H), 7.86 (ddd, J = 8.7, 7.2, 1.5 Hz, 1H), 7.45 (dt, J = 7.3, 3.5 Hz, 2H), 7.35 (dd, J = 5.6, 3.1 Hz, 2H), 5.24 (s, 4H), 2.48-2.41 (m, 1H), 1.26 - 1.10 (m, 4H). HRMS: C₂₀H₁₇N₅ calculated (M+H)⁺ = 325.15567 m/z; found (M+H)⁺ = 325.15586 m/z. Yield: 35%.

(xxxiv) 3-CYCLOPROPYL-6-(7-NITRO-3,4-DIHYDROISOQUINOLIN- 2(1H)-^YL)-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE (48)

[00381] ¹H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, J = 7.9, 1.3 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.16 (dt, J = 8.1, 1.0 Hz, 1H), 8.09 (dd, J = 8.4, 2.5 Hz, 1H), 7.98 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 7.87 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 4.74 (s, 2H), 3.73 (t, J = 5.9 Hz, 2H), 3.32 - 3.26 (m, 2H), 2.49-2.42 (m, 1H), 1.24 -1.11 (m, 4H). HRMS:

C₂₁H₁₈N₆O₂ calculated (M+H)⁺ = 387.15640 m/z; found (M+H)⁺ = 387.15630. Yield: 50%.

(xxxv) 3-CYCLOPROPYL-6-(7,8-DIHYDRO-1,6-NAPHTHYRIDIN-6(5H)- YL)-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (51)

[00382] ¹H NMR (400 MHz, DMSO-d6) δ 8.46– 8.42 (m, 2H), 8.17 (ddd, J = 8.2, 1.3, 0.6 Hz, 1H), 7.98 (ddd, J = 7.8, 7.3, 1.1 Hz, 1H), 7.87 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.67 (dd, J = 7.8, 1.6 Hz, 1H), 7.25 (dd, J = 7.7, 4.7 Hz, 1H), 4.63 (s, 2H), 3.77 (t, J = 5.9 Hz, 2H), 3.27 (t, J = 6.0 Hz, 2H), 2.48– 2.42 (m, 1H), 1.25– 1.12 (m, 4H). HRMS: C₂₀H₁₈N₆ calculated (M+H)⁺ = 343.16657 m/z; found (M+H)⁺ = 343.16610. Yield: 22%.

(xxxvi) 3-CYCLOPROPYL-6-(6-METHYL-3,4-DIHYDROISOQUINOLIN- 2(1H)-^YL)-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZINE (57)

[00383] ¹H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J = 7.9, 1.3 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.95 (td, J = 7.6, 1.2 Hz, 1H), 7.84 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.04 (s, 1H), 6.99 (dd, J = 7.8, 1.7 Hz, 1H), 4.52 (s, 2H), 3.63 (t, J = 5.9 Hz, 2H), 3.12 (t, J = 5.8 Hz, 2H), 2.43 (tdd, J = 9.2, 5.6, 3.6 Hz, 1H), 2.27 (s, 3H), 1.22– 1.11 (m, 4H). HRMS: C22H21N5; Calculated (M+H)⁺ = 356.18697 m/z, found (M+H)⁺ = 356.18685 m/z.

(xxxvii) 3-^CYCLOPROPYL-6-(1,4,6,7-^TETRAHYDRO-5H-^PYRROLO[3,2- C]PYRIDIN-5-YL)-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (58)

[00384] ¹H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.40 (dd, J = 7.9, 1.3 Hz, 1H), 8.11 (dd, J = 8.0, 1.1 Hz, 1H), 7.93 (td, J = 7.6, 1.1 Hz, 1H), 7.83 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 6.60 (t, J = 2.6 Hz, 1H), 5.86 (t, J = 2.5 Hz, 1H), 4.38 (s, 2H), 3.64 (t, J = 5.7 Hz, 2H), 2.98 (t, J = 5.7 Hz, 2H), 2.46– 2.39 (m, 1H), 1.23– 1.10 (m, 4H). HRMS: C19H18N6; Calculated (M+H)⁺ = 331.16657 m/z, found (M+H)⁺ = 331.16683 m/z. Yield: 22%.

(xxxviii) 3-CYCLOPROPYL-6-(3-METHYL-5,6-DIHYDRO- [1,2,4]^TRIAZOLO[4,3-^A]^PYRAZIN-7(8H)-^YL)- [1,2,4]TRIAZOLO[3,4-A]PHTHALAZINE (59)

[00385] ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (dd, J = 8.0, 1.2 Hz, 1H), 8.16 (dt, J = 8.2, 0.9 Hz, 1H), 8.00 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 7.87 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 4.70 (s, 2H), 4.24 (t, J = 5.5 Hz, 2H), 3.86 (t, J = 5.5 Hz, 2H), 2.44 (tt, J = 8.3, 5.1 Hz, 1H), 2.36 (s, 3H), 1.25– 1.11 (m, 4H). HRMS: C18H18N8; Calculated (M+H)⁺ = 347.17272 m/z, found (M+H)⁺ = 347.17273 m/z. Yield: 14%.

(xxxix) 7-FLUORO-2-(3-METHYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-6- A^MINE (69)

[00386] ¹H NMR (400 MHz, DMSO-d6) δ 8.43 (ddd, J = 7.9, 1.4, 0.5 Hz, 1H), 8.10 (dt, J = 8.1, 1.0 Hz, 1H), 7.96 (ddd, J = 8.0, 7.3, 1.1 Hz, 1H), 7.85 (ddd, J = 8.5, 7.4, 1.4 Hz, 1H), 6.87 (d, J = 12.1 Hz, 1H), 6.60 (d, J = 9.1 Hz, 1H), 4.98 (s, 2H), 4.40 (s, 2H), 3.57 (t, J = 5.8 Hz, 2H), 3.01 (t, J = 5.8 Hz, 2H), 2.63 (s, 3H). HRMS: C19H17FN6; Calculated (M+H)⁺ = 349.15715 m/z, found (M+H)⁺ = 349.15822 m/z. Yield: 61%.

(xl) 7-FLUORO-2-(3-ISOPROPYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-1,2,3,4-^{TETRAHYDROISOQUINOLIN}-6- AMINE (70)

[00387] ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (ddd, J = 7.9, 1.4, 0.5 Hz, 1H), 8.10 (dt, J = 8.0, 1.0 Hz, 1H), 7.99– 7.92 (m, 1H), 7.85 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 6.86 (d, J = 12.0 Hz, 1H), 6.59 (d, J = 9.1 Hz, 1H), 4.97 (s, 2H), 4.40 (s, 2H), 3.59 (t, J = 5.9 Hz, 2H), 3.49 (hept, J = 7.0 Hz, 1H), 2.99 (t, J = 5.8 Hz, 2H), 1.42 (d, J = 7.0 Hz, 6H). HRMS:

C21H21FN6; Calculated (M+H)⁺ = 377.18845 m/z, found (M+H)⁺ = 377.18960 m/z. Yield: 61%.

(xli) 6-FLUORO-2-(3-METHYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7- AMINE (71)

[00388] ¹H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, J = 8.0, 1.3 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.98 (td, J = 7.6, 1.1 Hz, 1H), 7.87 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 6.87 (d, J = 12.0 Hz, 1H), 6.59 (d, J = 9.1 Hz, 1H), 4.98 (s, 2H), 4.41 (s, 2H), 3.59 (t, J = 5.8 Hz, 2H), 3.01 (t, J = 5.8 Hz, 2H), 2.65 (s, 3H). HRMS: C19H17FN6; Calculated (M+H)⁺ = 349.15715 m/z, found (M+H)⁺ = 349.15804 m/z. Yield: 55%. (xlii) 6-FLUORO-2-(3-ISOPROPYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-1,2,3,4-^{TETRAHYDROISOQUINOLIN}-7- AMINE (72)

[00389] ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J = 8.1, 1.3 Hz, 1H), 8.11 (dt, J = 8.1, 1.0 Hz, 1H), 7.96 (ddd, J = 8.0, 7.3, 1.1 Hz, 1H), 7.85 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 6.85 (d, J = 12.0 Hz, 1H), 6.57 (d, J = 9.1 Hz, 1H), 4.95 (s, 2H), 4.40 (s, 2H), 3.59 (t, J = 5.9 Hz, 2H), 3.49 (p, J = 7.0 Hz, 1H), 2.98 (t, J = 5.8 Hz, 2H), 1.45– 1.36 (m, 6H). HRMS: C21H21FN6; Calculated (M+H)⁺ = 377.18845 m/z, found (M+H)⁺ = 377.18932 m/z. Yield: 52%.

(xliii) 2-(3-METHYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZIN-6-YL)-5- (TRIFLUOROMETHYL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7- AMINE (73)

[00390] ¹H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 7.4 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.98 (t, J = 7.4 Hz, 1H), 7.87 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6.64 (s, 1H), 5.41 (s, 2H), 4.49 (s, 2H), 3.61 (t, J = 5.9 Hz, 2H), 3.10 (s, 2H), 2.65 (s, 3H). HRMS:

C20H17F3N6; Calculated (M+H)⁺ = 399.15396 m/z, found (M+H)⁺ = 399.15491 m/z. Yield: 18%.

(xliv) 2-(3-^ISOPROPYL-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZIN-6-^YL)- 5-(TRIFLUOROMETHYL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7- AMINE (74)

[00391] ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (dd, J = 8.2, 1.4 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.97 (td, J = 7.7, 1.1 Hz, 1H), 7.87 (ddd, J = 8.6, 7.3, 1.3 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.64 (s, 1H), 5.39 (s, 2H), 4.49 (s, 2H), 3.63 (t, J = 5.9 Hz, 2H), 3.08 (s, 2H), 2.32- 2.30 (m, 1H), 1.42 (d, J = 7.0 Hz, 6H). HRMS: C22H21F3N6; Calculated (M+H)⁺ = 427.18526 m/z, found (M+H)⁺ = 427.18647 m/z. Yield: 35%.

(xlv) 2-(3-^CYCLOPROPYL-9-^METHYL-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-7-FLUORO-1,2,3,4- T^{ETRAHYDROISOQUINOLIN}-6-^AMINE (79)

[00392] ¹H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.65 (ddd, J = 8.4, 1.9, 0.7 Hz, 1H), 6.85 (d, J = 12.0 Hz, 1H), 6.59 (d, J = 9.2 Hz, 1H), 4.98 (s, 2H), 4.39 (s, 2H), 3.56 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 5.9 Hz, 2H), 2.55 (s, 3H), 2.42 (tt, J = 8.2, 5.2 Hz, 1H), 1.23– 1.08 (m, 4H). HRMS: C22H21FN6; Calculated (M+H)⁺ =

389.18845 m/z, found (M+H)⁺ = 389.18939 m/z. Yield: 21%.

(xlvi) 2-(3-CYCLOPROPYL-8-METHYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-7-^FLUORO-1,2,3,4- TETRAHYDROISOQUINOLIN-6-AMINE (80)

[00393] ¹H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.9, 1H), 7.87 (s, 1H), 7.79 (dd, J = 8.3, 1.6 Hz, 1H), 6.88 (d, J = 12.0 Hz, 1H), 6.62 (d, J = 9.1 Hz, 1H), 5.00 (s, 2H), 4.41 (s, 2H), 3.58 (t, J = 5.9 Hz, 2H), 3.02 (t, J = 5.8 Hz, 2H), 2.55 (s, 3H), 2.43 (tt, J = 8.2, 5.2 Hz, 1H), 1.22– 1.12 (m, 4H). HRMS: C22H21FN6; Calculated (M+H)⁺ = 389.18845 m/z, found (M+H)⁺ = 389.18957 m/z. Yield: 21%.

c. SYNTHESIS OF 2-(3-METHYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZIN-6- Y^L)-1,2,3,4-^{TETRAHYDROISOQUINOLIN}-7-^AMINE (6)

[00394] Followed synthetic procedure described in“General Synthesis of Final

Compounds." ¹H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.09 (dd, J = 8.6, 2.3 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 4.74 (s, 2H), 3.72 (t, J = 5.9 Hz, 2H), 2.97 (t, J = 5.9 Hz, 2H), 2.66 (s, 3H). LRMS: (M+H)⁺ = 361.1 m/z. Yield: 35%.

(ii) S^TEP 2 (6) [00395] To a solution of 3-methyl-6-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)- [1,2,4]triazolo[3,4-a]phthalazine (260 mg, 0.721 mmol) dissolved in Acetic Acid (7215 µl), Iron (201 mg, 3.61 mmol) powder was added and the combined reaction mixture continued to stirr at 50 ˚C for 6 h. After reaction completion, as monitored by TLC and MS analysis, filtered through a celite pad washing with ethanol to remove Iron. The solvents were then evaporated off and the crude is purified by silica gel column chromatography (eluting with 5% MeOH in DCM) to obtain the desired product as a light brick color crystalline solid in 21% yield.¹H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 7.9, 1.3 Hz, 1H), 8.13 (dt, J = 8.2, 0.9 Hz, 1H), 7.98 (ddd, J = 8.0, 7.3, 1.1 Hz, 1H), 7.87 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.47 (dd, J = 8.1, 2.4 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 4.90 (s, 2H), 4.43 (s, 2H), 3.60 (t, J = 5.8 Hz, 2H), 3.00 (t, J = 5.9 Hz, 2H), 2.66 (s, 3H). HRMS: C19H18N6 calculated (M+H)⁺ = 331.16657 m/z; found (M+H)⁺ = 331.16627 m/z. Yield: 21%. d. SYNTHESIS OF 2-(3-METHYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZIN-6- Y^L)-1,2,3,4-^{TETRAHYDROISOQUINOLINE}-6,7-^DIOL (7)

[00396] To a solution of 6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl- [1,2,4]triazolo[3,4-a]phthalazine (0.511 mmol, 192 mg) in methylene chloride (5 mL) cooled to 0 ˚C, BBr3 (5.112 mmmol, 5 mL) was added and allowed to stir for 1 h at 0 ˚C followed by stirring at room temperature for 24 h. After reaction completion as monitored by TLC and MS analysis reaction mixture was quenched with aq. NaHCO3 (sat.) (15 mL) and extracted with chloroform (3 X 25 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuuo. The resulting crude is purified by silica gel column chromatography (5% MeOH in DCM solvent gradient) to obtain the desired product as a yellow color solid in 7% yield (12 mg).¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (s, 2H), 8.45 (dd, J = 7.9, 1.3 Hz, 1H), 8.12 (dt, J = 8.2, 1.0 Hz, 1H), 7.98 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 7.87 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 6.58 (d, J = 13.2 Hz, 2H), 4.40 (s, 2H), 3.58 (t, J = 5.9 Hz, 2H), 3.00 (t, J = 5.8 Hz, 2H), 2.66 (s, 3H). HRMS: C19H17N5O2 calculated (M+H)⁺ = 348.14550 m/z; found (M+H)⁺ = 348.14518 m/z. Yield: 7%.

e. SYNTHESIS OF N-(2-(3-METHYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7- YL)ACETAMIDE (16)

[00397] To a solution of 2-(3-methyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-1,2,3,4- tetrahydroisoquinolin-7-amine (20 mg, 0.061 mmol) in DCM (3 mL), triethylamine (25.3 µl, 0.182 mmol) followed by Acetyl chloride (5.17 µl, 0.073 mmol) were added at room temperature and stirred for 5 h. Upon reaction completion, as monitored by TLC and MS analysis, the solvents were evaporated off and the crude is purified by silica gel column chromatography (eluting with 5% MeOH in DCM). The desired product was obtained as a white color solid in 71% yield (16 mg).¹H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.02 - 7.96 (m, 1H), 7.91 - 7.85 (m, 1H), 7.55 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.55 (s, 2H), 3.65 (t, J = 5.8 Hz, 2H), 3.13 (t, J = 5.8 Hz, 2H), 2.67 (s, 3H), 2.04 (s, 3H). HRMS: C₂₁H₂₀N₆O calculated (M+H)⁺ = 373.17714 m/z; found (M+H)⁺ = 377.17652 m/z. Yield: 71%.

f. SYNTHESIS OF 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-1,2,3,4-^{TETRAHYDROISOQUINOLIN}-7-^AMINE (20)

[00398] To a solution of 3-cyclopropyl-6-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)- [1,2,4]triazolo[3,4-a]phthalazine (64 mg, 0.166 mmol) in Acetic Acid (3 mL), Iron (92 mg, 1.656 mmol) powder was added and stirred at 50 °C for 5 h. After reaction completion, as monitored by TLC and MS analysis, filtered through a celite pad washing with ethanol to remove Iron. The solvents were then evaporated off and the crude is purified by silica gel column chromatography (eluting with gradient of 5% MeOH in DCM for 30 min). The desired product was obtained as a light orange color solid in 35% yield (21 mg).¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (ddd, J = 7.9, 1.4, 0.6 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.96 (ddd, J = 8.0, 7.3, 1.2 Hz, 1H), 7.86 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.47 (dd, J = 8.2, 2.3 Hz, 1H), 6.39 (d, J = 2.2 Hz, 1H), 4.90 (s, 2H), 4.43 (s, 2H), 3.60 (t, J = 5.8 Hz, 2H), 3.00 (t, J = 5.9 Hz, 2H), 2.48 - 2.42 (m, 1H), 1.27 - 1.13 (m, 4H). HRMS:

C₂₁H₂₀N₆ calculated (M+H)⁺ = 357.18222 m/z; found (M+H)⁺ = 357.18127 m/z. Yield: 35%.

g. SYNTHESIS OF 2-(3-ISOPROPYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZIN- 6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7-AMINE (21)

(i) STEP 1 [00399] Followed synthetic procedure described in“General Synthesis of Final

Compounds." ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 8.49 - 8.45 (m, 1H), 7.99 (tdd, J = 8.0, 2.3, 1.2 Hz, 2H), 7.88 (ddd, J = 8.5, 7.3, 1.3 Hz, 2H), 7.51 (d, J = 8.5 Hz, 1H), 4.73 (s, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.28 - 3.23 (m, 2H), 2.41 (dt, J = 13.7, 6.8 Hz, 1H), 1.40 (d, J = 6.9 Hz, 6H). LRMS: (M+H)⁺ = 389.1 m/z. Yield: 43%.

(ii) STEP 2 (21) [00400] To a solution of 3-isopropyl-6-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)- [1,2,4]triazolo[3,4-a]phthalazine (120 mg, 0.309 mmol) in Acetic Acid (6 mL), Iron (173 mg, 3.09 mmol) was added and stirred at 50 ˚C for 5 h. After reaction completion, crude is filtered through a celite pad washing with ethanol to remove Iron. The solvents were then evaporated off and the crude is purified by silica gel column chromatography (eluting with gradient of 5% MeOH in DCM for 30 min). The desired product was obtained as a brick color solid in 13% yield (14 mg).¹H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 8.0, 1.3 Hz, 1H), 8.13 (dd, J = 8.1, 1.1 Hz, 1H), 7.98 (ddd, J = 8.0, 7.3, 1.2 Hz, 1H), 7.87 (ddd, J = 8.3, 7.2, 1.4 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.46 (dd, J = 8.1, 2.3 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 4.89 (s, 2H), 4.43 (s, 2H), 3.61 (t, J = 5.8 Hz, 2H), 3.52 (p, J = 7.0 Hz, 1H), 2.99 (t, J = 5.9 Hz, 2H), 1.45 (d, J = 6.9 Hz, 6H). HRMS: C21H22N6 calculated (M+H)⁺ = 359.19787 m/z; found (M+H)⁺ = 359.19666 m/z. Yield: 13%.

h. S^{YNTHESIS OF} 2-(3-(^{DIFLUOROMETHYL})-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7-AMINE (23)

[00401] To a solution of 3-(difluoromethyl)-6-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)- [1,2,4]triazolo[3,4-a]phthalazine (430 mg, 1.085 mmol) in Acetic Acid (7 mL), Iron (606 mg, 10.85 mmol) powder was added and stirred at 50 °C for 5 h. After reaction completion the crude is filtered through a celite pad washing with ethanol. The solvents were then evaporated off and the resulting crude is purified by silica gel column chromatography. The desired product is obtained as an yellow color solid in 37% yield (145 mg). ¹H NMR (400 MHz, DMSO-d6) δ 8.58 - 8.54 (m, 1H), 8.22 - 8.17 (m, 1H), 8.06 (td, J = 7.6, 1.1 Hz, 1H), 7.96 (ddd, J = 8.6, 7.4, 1.4 Hz, 1H), 7.64 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.47 (dd, J = 8.2, 2.3 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 4.91 (s, 2H), 4.47 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.03 (t, J = 5.9 Hz, 2H). HRMS: C₁₉H₁₆F₂N₆ calculated (M+H)⁺ = 367.14773 m/z; found (M+H)⁺ = 367.14816 m/z. Yield: 37%.

i. SYNTHESIS OF 2-(3-(THIOPHEN-2-YL)-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-1,2,3,4-^{TETRAHYDROISOQUINOLIN}-7-^AMINE (32)

(i) STEP 1 [00402] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (ddd, J = 8.0, 1.3, 0.5 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.23 (dt, J = 8.2, 0.9 Hz, 1H), 8.12 (dd, J = 3.7, 1.2 Hz, 1H), 8.09 (dd, J = 8.5, 2.6 Hz, 1H), 8.06– 8.03 (m, 1H), 7.96– 7.92 (m, 1H), 7.83 (dd, J = 5.1, 1.2 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.28– 7.25 (m, 1H), 4.85 (s, 2H), 3.84 (t, J = 5.8 Hz, 2H), 3.31– 3.26 (m, 2H). LRMS: (M+H)⁺ = 429.1 m/z. Yield: 78%.

(ii) S^TEP 2 (32) [00403] To a solution of 6-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-3-(thiophen-2-yl)- [1,2,4]triazolo[3,4-a]phthalazine (120 mg, 0.280 mmol) in Methanol (3 mL), Tin(II)chloride (159 mg, 0.840 mmol) was added and stirred for 24 h at 65 °C. After reaction completion, cooled to room temperature, evaporated off the solvents, diluted with chloroform and quenched with aq. Sodium bicarbonate (Sat.). The aqueous layer extracted with chloroform (3 X 25 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuuo. Purification of the resulting crude by silica gel column chromatography provided the desired product as an off white color solid in 26% yield.¹H NMR (400 MHz, DMSO-d6) δ 8.56 - 8.52 (m, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.16 (dd, J = 3.7, 1.2 Hz, 1H), 8.05 - 8.00 (m, 1H), 7.92 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 7.86 (dd, J = 5.1, 1.2 Hz, 1H), 7.35 (dd, J = 5.1, 3.7 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.49 - 6.45 (m, 2H), 4.95 (s, 2H), 4.55 (s, 2H), 3.72 (t, J = 5.7 Hz, 2H), 3.00 (t, J = 5.8 Hz, 2H). HRMS: C₂₂H₁₈N₆S calculated (M+H)⁺ = 399.13864 m/z; found (M+H)⁺ = 399.13829 m/z. Yield: 26%.

j. SYNTHESIS OF N-(2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-1,2,3,4-^{TETRAHYDROISOQUINOLIN}-7- YL)METHANESULFONAMIDE (36)

[00404] Combined solution of 2-(3-cyclopropyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)- 1,2,3,4-tetrahydroisoquinolin-7-amine (12 mg, 0.034 mmol), Methanesulfonylchloride (3.94 µl, 0.051 mmol), and Et₃N (9.39 µl, 0.067 mmol) in DCM (1.5 mL) stirred at room temperature for 72 h. After reaction completion evaporated off the solvents and the crude is purified by silica gel column chromatography to obtain the desired product as a white solid in 36% yield.¹H NMR (400 MHz, Chloroform-d) δ 8.73 (d, J = 7.9 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.88 - 7.81 (m, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.03 (dd, J = 8.2, 2.3 Hz, 1H), 6.71 (s, 1H), 4.58 (s, 2H), 3.68 (t, J = 5.9 Hz, 2H), 3.12 (t, J = 5.8 Hz, 2H), 2.96 (s, 3H), 2.47 (tt, J = 8.5, 5.1 Hz, 1H), 1.38 (tt, J = 6.9, 3.7 Hz, 2H), 1.21 - 1.16 (m, 2H). HRMS: C₂₂H₂₂N₆O₂S calculated (M+H)⁺ = 435.15977 m/z; found (M+H)⁺ = 435.16017 m/z. Yield: 36%.

k. SYNTHESIS OF N-(2-(3-ISOPROPYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7- YL)METHANESULFONAMIDE (37)

[00405] Combined solution of 2-(3-isopropyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)- 1,2,3,4-tetrahydroisoquinolin-7-amine (16 mg, 0.045 mmol), Methanesulfonylchloride (5.22 µl, 0.067 mmol), and Et₃N (12.44 µl, 0.089 mmol) in DCM (1.5 mL) stirred at room temperature for 72 h. After reaction completion evaporated off the solvents and the crude is purified by silica gel column chromatography to obtain the desired product as a white solid in 60% yield.¹H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 8.2, 2.3 Hz, 1H), 6.58 (s, 1H), 4.58 (s, 2H), 3.70 (t, J = 5.9 Hz, 2H), 3.59 (p, J = 7.0 Hz, 1H), 3.13 (t, J = 5.9 Hz, 2H), 2.96 (s, 3H), 1.49 (d, J = 7.0 Hz, 6H). HRMS:

C22H24N6O2S calculated (M+H)⁺ = 437.17542 m/z; found (M+H)⁺ = 437.17456 m/z. Yield: 60%.

l. S^{YNTHESIS OF} 2-(3-^METHYL-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZIN-6- YL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-CARBOXYLIC ACID (39)

[00406] To a solution of methyl 2-(3-methyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)- 1,2,3,4-tetrahydroisoquinoline-7-carboxylate (52 mg, 0.140 mmol) in MeOH/Water (2 mL/0.5 mL), Lithium hydroxide monohydrate (28 mg, 0.667 mmol) was added and stirred for 72 h at room temperature. After reaction completion, solvents were evaporated off, diluted with water and quenched with 1 N HCl. The aqueous layer was then extracted with chloroform (3 X 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuuo. Purification of the crude by silica gel column chromatography provided the desired product as a white solid in 20% yield.¹H NMR (400 MHz, DMSO-d₆) δ 12.91 (s, 1H), 8.47 (dd, J = 7.9, 1.0 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.00 (ddd, J = 8.0, 7.3, 1.1 Hz, 1H), 7.88 (ddd, J = 8.5, 7.4, 1.4 Hz, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.79 (dd, J = 7.9, 1.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.66 (s, 2H), 3.69 (t, J = 5.8 Hz, 2H), 3.25 (t, J = 5.8 Hz, 2H), 2.66 (s, 3H). HRMS: C₂₀H₁₇N₅O₂ calculated (M+H)⁺ = 360.14550 m/z; found (M+H)⁺ = 360.14494 m/z. Yield: 20%.

m. SYNTHESIS OF N-(2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-1,2,3,4-^{TETRAHYDROISOQUINOLIN}-7- YL)ACETAMIDE (40)

(i) STEP 1– BOC PROTECTION [00407] Combined solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline (1.0 g, 5.61 mmol), Boc2O (2 mL, 8.42 mmol) and Et3N (1.5 mL, 11.22 mmol) dissolved in THF (12 mL) was stirred at room temperature for 2 h. After reaction completion, quenched with water, extracted with chloroform (3 X 50 mL). Evaporation of the solvent and purification of the resulting crude by silica gel column chromatography provided the desired product as a colorless viscous oil in 87% yield.¹H NMR (400 MHz, Chloroform-d) δ 8.04 - 7.98 (m, 2H), 7.29 (d, J = 8.2 Hz, 1H), 4.66 (s, 2H), 3.69 (t, J = 5.9 Hz, 2H), 2.93 (t, J = 5.9 Hz, 2H), 1.50 (s, 9H). Yield: 87%.

(ii) STEP 2– NITRO REDUCTION [00408] To an argon purged reaction flask was added tert-butyl 7-nitro-3,4- dihydroisoquinoline-2(1H)-carboxylate (1.36 g, 4.89 mmol) and methanol (25 mL) at room temperature. To this 10% Pd/C (0.52 g, 0.489 mmol) was added and the combined reaction mixture was purged with Hydrogen gas three times and left to stir under hydrogen atmosphere (at atmospheric pressure) for 3 h. After reaction completion, the reaction mixture was filtered through a celite pad washing with methanol. Solvent evaporation followed by purification by silica gel column chromatography provided the desired product as a white powder in 64% yield (780 mg).¹H NMR (400 MHz, DMSO-d₆) δ 6.78 (d, J = 8.1 Hz, 1H), 6.39 (dd, J = 8.1, 2.4 Hz, 1H), 6.30 (s, 1H), 4.87 (s, 2H), 4.32 (s, 2H), 3.47 (t, J = 5.9 Hz, 2H), 2.57 (t, J = 5.9 Hz, 2H), 1.42 (s, 9H).

(iii) STEP 3– ACYLATION OF AMINE [00409] To a solution of tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (270 mg, 1.087 mmol), triethylamine (303 µl, 2.175 mmol) dissolved in DCM (6 mL) was added AcCl (85 µl, 1.196 mmol) and continued to stir for 30 min. After reaction completion added few drops of water to quench acetyl chloride, and the solvents were then evaporated off under reduced pressure. The resulting crude is purified by silica gel column

chromatography to obtain the desired product as an yellow color gummy solid in 97% yield (307 mg). ¹H NMR (400 MHz, Chloroform-d) δ 7.55 - 7.42 (m, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.10 - 7.04 (m, 1H), 4.55 (s, 2H), 3.6-3.58 (m, 2H), 2.78 (t, J = 6.0 Hz, 2H), 2.17 (s, 3H), 1.49 (s, 9H). (Amide NH proton signal not seen).

(iv) S^TEP 4– B^{OC DEPROTECTION} [00410] To a solution of tert-butyl 7-acetamido-3,4-dihydroisoquinoline-2(1H)- carboxylate (307 mg, 1.057 mmol) in DCM (10.600 ml) was added TFA (0.815 ml, 10.57 mmol) and stirred at room temperature for 30 min. After reaction completion the reaction mixture diluted with chloroform and evaporated off the solvents. The resulting crude is purified by silica gel column chromatography to obtain the desired product as an off white solid in quantitative yields (230 mg).¹H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.35 (dd, J = 8.3, 2.2 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 4.25 (s, 2H), 3.40- 3.32 (m, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.03 (s, 3H). (NH peak of THIQ is not seen). LRMS: (M+H)+ = 191.1 m/z. Yield: Quantitative (100%).

(v) S^TEP 5 (40) [00411] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 8.44 (dd, J = 7.9, 0.9 Hz, 1H), 8.14 (d, J = 8.0, 1H), 8.01 - 7.94 (m, 1H), 7.87 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.3, 2.2 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4.54 (s, 2H), 3.65 (t, J = 5.8 Hz, 2H), 3.17 (d, J = 5.3 Hz, 1H), 3.12 (t, J = 5.9 Hz, 2H), 2.01 (s, 3H), 1.25 - 1.13 (m, 4H). HRMS: C₂₃H₂₂N₆O calculated (M+H)⁺ = 399.19279 m/z; found (M+H)⁺ = 399.19280 m/z. Yield: 10%. n. SYNTHESIS OF 3-CYCLOPROPYL-6-(6-METHOXY-7-NITRO-3,4- D^{IHYDROISOQUINOLIN}-2(1H)-^YL)-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZINE (41)

(i) S^TEP 1– T^{RIFLUOROACETYL} P^ROTECTION [00412] To a solution of 6-methoxy-1,2,3,4-tetrahydroisoquinoline (1.08 g, 6.62 mmol) dissolved DCM (16 mL) was added Pyridine 1.6 mL, 19.85 mL) and

Trifluoroaceticanhydride (2.8 ml, 19.85 mmol) and allowed to react overnight at room temperature. After reaction completion, quenched with water (25 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuuo. Purification of the resulting crude by silica gel column chromatography provided the desired product as a colorless viscous oil in 98% yield (1.68 mg).¹H NMR (400 MHz, Chloroform-d) δ 7.09– 7.01 (m, 1H), 6.79 (dt, J = 8.5, 3.0 Hz, 1H), 6.70 (dd, J = 10.3, 2.7 Hz, 1H), 4.71 (d, J = 18.6 Hz, 2H), 3.89– 3.80 (m, 2H), 3.80 (d, J = 1.5 Hz, 3H), 2.96– 2.90 (m, 2H). Yield: 98%.

(ii) STEP 2– NITRATION [00413] Reaction flask containing 2,2,2-trifluoro-1-(6-methoxy-3,4-dihydroisoquinolin- 2(1H)-yl)ethanone (448 mg, 1.728 mmol), Acetic acid (6.5 mL, 112 mmol), and Ac2O (652 µl, 6.91 mmol) was cooled to 0 °C to which Nitric acid (172 µl, 3.46 mmol) dissolved in Acetic acid (6.5 mL µl, 112 mmol) and Ac2O (652 µl, 6.91 mmol) was added dropwise over 10 min. Stirred for an additional 15 min at 0 °C then removed the ice bath and allowed the reaction to continue at room temperature for 2 h. After 2 h ice cold water was added and extracted with methylene chloride. Organic layer was then washed with water, aq. NaHCO₃ (Sat.), and brine. The separated organic layer was then dried over anhyd. Na2SO4, filtered and concentrated in vacuuo. Purification of the resulting crude provided exclusively one regio-isomer as specified as a white color solid in 38% yield (200 mg).¹H NMR (400 MHz, DMSO-d6) δ 7.99 - 7.85 (m, 1H), 7.24 (d, J = 2.7 Hz, 1H), 4.75 (d, J = 18.2 Hz, 2H), 3.90 (d, J = 1.6 Hz, 3H), 3.82 (q, J = 6.2 Hz, 2H), 3.00 (q, J = 7.2, 6.7 Hz, 2H). Yield: 38%.

(iii) STEP 3– TRIFLUOROACETYL DEPROTECTION [00414] To a solution of 2,2,2-trifluoro-1-(6-methoxy-7-nitro-3,4-dihydroisoquinolin- 2(1H)-yl)ethanone (200 mg, 0.657 mmol) in MeOH (5 mL)/Water (2 mL) was added potassium carbonate (909 mg, 6.57 mmol) and allowed to react at room temperature for 6 h. After reaction completion, evaporated off the solvents and the crude is separated between H₂O and methylene chloride. The organic layer washed with brine, dried over anhyd.

Na2SO4 and concentrated in vacuuo. The resulting crude is then absorbed onto silica gel for purification. The desired product was obtained as a yellow solid in 60% yield (83 mg).¹H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 0.9 Hz, 1H), 7.05 (s, 1H), 3.87 (s, 3H), 3.79 (s, 2H), 2.92 (t, J = 5.9 Hz, 2H), 2.74 (t, J = 5.9 Hz, 2H). (NH Proton not seen). LRMS:

(M+H)⁺ = 209.1 m/z. Yield: 60%.

(iv) STEP 4 (41) [00415] Followed synthetic procedure described in“General Synthesis of Final Compounds.” ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (ddd, J = 7.9, 1.3, 0.5 Hz, 1H), 8.17 - 8.12 (m, 1H), 8.04 - 7.95 (m, 1H), 7.88 - 7.85 (m, 2H), 7.26 (s, 1H), 4.60 (s, 2H), 3.93 (s, 3H), 3.70 (t, J = 5.9 Hz, 2H), 3.24 (t, J = 5.9 Hz, 2H), 2.47 - 2.40 (m, 1H), 1.22 - 1.13 (m, 4H). HRMS: C22H20N6O3 calculated (M+H)⁺ = 417.16697 m/z; found (M+H)⁺ = 417.16642 m/z. Yield: 57%.

o. S^{YNTHESIS OF} N-(2-(3-^CYCLOPROPYL-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-6-(TRIFLUOROMETHOXY)-1,2,3,4- T^{ETRAHYDROISOQUINOLIN}-7-^YL)^ACETAMIDE (43)

(i) STEP 1– HYDROXYLAMINE SYNTHESIS [00416] To a reaction flask flushed with argon, THF (6803 µl) followed by tert-butyl 7- nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (568 mg, 2.041 mmol), and rhodium (12.60 mg, 6.12 µmol) (5% Rh on Carbon) were added at room temperature. The suspension was then cooled to 0 °C and hydrazine hydrate (119 µl, 2.449 mmol) was added dropwise. The reaction continued at 0 °C for 1 h and then removed the ice bath and continued for 4 h at room temperature. After reaction completion, filtered the crude through a celite pad to remove the catalyst washing with methylene chloride. Evaporation of the solvents under reduced pressure and overnight drying under high vacuum provided the crude as a white color solid in quantitative yields (522 mg). The crude is carried through next step without purification.¹H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.65 (dd, J = 8.2, 2.2 Hz, 1H), 6.60 (s, 1H), 4.40 (s, 2H), 3.51 (t, J = 5.9 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 1.42 (s, 9H). Yield: 97%.

(ii) STEP 2– N-ACYLATION [00417] The solution of tert-butyl 7-(hydroxyamino)-3,4-dihydroisoquinoline-2(1H)- carboxylate (520 mg, 1.967 mmol) and sodium bicarbonate (198 mg, 2.361 mmol) dissolved in diethylether (10 ml) was cooled to 0 °C under argon, and to this Acetylchloride (0.168 mL, 2.361 mmol) (dissolved in 10 ml diethyl ether) was added via syringe pump with the flow rate of 10 ml/h. After complete addition stirred for additional 15 minutes at 0 °C.

Afterwards, removed ice bath, warmed to room temperature and the crude is filtered through celite pad washing with methylene chloride. After evaporation off the solvents, the resulting crude oil was absorbed onto silica gel for purification. The desired compound was obtained as an orange color gummy oil in 68% yield (409 mg).¹H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.43-7.36 (m, 2H), 7.14 (d, J = 8.2 Hz, 1H), 4.47 (s, 2H), 3.54 (t, J = 5.9 Hz, 2H), 2.74 (t, J = 5.9 Hz, 2H), 2.18 (s, 3H), 1.42 (s, 9H). Yield: 68%.

(iii) STEP 3– TRIFLUOROMETHYLATION [00418] To a solution of tert-butyl 7-(N-hydroxyacetamido)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (403 mg, 1.315 mmol), cesium carbonate (42.9 mg, 0.132 mmol) dissolved in Chloroform (13 mL) was added 1-(trifluoromethyl)-1l3-benzo[d][1,2]iodaoxol- 3(1H)-one (499 mg, 1.579 mmol) (Togni Reagent II) and allowed to react for 18 h at room temperature. The crude reaction mixture was then filtered through celite pad and the solvents were evaporated off in vacuuo. Further purification by flash chromatography over silica gel provided the desired product as an orange color viscous oil in quantitative yields (540 mg). The isolated compound contained impurities which carried through next step without further purification. LRMS: (M-Boc)⁺ = 275.1 m/z.

(iv) STEP 4– TRIFLUOROMETHOXY MIGRATION [00419] Combined solution of tert-butyl 7-(N-(trifluoromethoxy)acetamido)-3,4- dihydroisoquinoline-2(1H)-carboxylate (540 mg, 1.442 mmol) and Nitromethane (1.5 mL) was heated to 80 °C in a pressure tube for 24 h. The solvents were then evaporated off and the crude is purified by silica gel flash chromatography. The desired product was obtained as a brown color gummy solid in 8% yield (38 mg). Compound was analyzed after removal of the Boc group in next step. Additionally, the other regio-isomer tert-butyl 7-acetamido-8- (trifluoromethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate also obtained as a brown color gummy solid in 10% yield (54 mg).

(v) S^TEP 5– B^{OC DEPROTECTION} [00420] Combined solution of tert-butyl 7-acetamido-6-(trifluoromethoxy)-3,4- dihydroisoquinoline-2(1H)-carboxylate (38 mg, 0.102 mmol), TFA (78 µl, 1.015 mmol) in DCM (1 mL) stirred at room temperature for 30 min. After reaction completion diluted with chloroform and evaporated off the solvents. The resulting crude is absorbed onto silica gel for purification. The desired prod uct obtained as brown color gummy solid in 72% yield. ¹H NMR (400 MHz, Methanol-d₄) δ 7.79 (s, 1H), 7.27 (s, 1H), 4.35 (s, 2H), 3.50 (t, J = 6.4 Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H), 2.17 (s, 3H). (NH protons not observed). LRMS: (M+H)⁺ = 275.1 m/z. Yield: 72%. (vi) STEP 6 (43) [00421] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, Chloroform-d) δ 8.65 (dd, J = 7.9, 1.2 Hz, 1H), 8.27 (s, 1H), 8.02 (dt, J = 8.0, 0.9 Hz, 1H), 7.85 (ddd, J = 8.1, 7.3, 1.2 Hz, 1H), 7.73 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.40 (s, 1H), 7.12 (d, J = 1.8 Hz, 1H), 4.61 (s, 2H), 3.71 (t, J = 5.9 Hz, 2H), 3.16 (t, J = 5.9 Hz, 2H), 2.54 - 2.46 (m, 1H), 2.24 (s, 4H), 1.44 - 1.36 (m, 2H), 1.23 - 1.17 (m, 2H). HRMS: C₂₄H₂₁F₃N₆O₂ calculated (M+H)⁺ = 483.17509 m/z; found (M+H)⁺ = 483.17452 m/z. Yield: 14%.

p. SYNTHESIS OF 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-6-^METHOXY-1,2,3,4- TETRAHYDROISOQUINOLIN-7-AMINE (47)

[00422] Combined solution of 3-cyclopropyl-6-(6-methoxy-7-nitro-3,4- dihydroisoquinolin-2(1H)-yl)-[1,2,4]triazolo[3,4-a]phthalazine (100 mg, 0.241 mmol) and Iron (134 mg, 2.41 mmol) in Acetic Acid (5 mL) stirred at 50 °C for 5 h. After reaction completion, stopped heating, and filtered the crude product through a Celite pad, washing with ethanol. Evaporated off the solvents and the resulting crude was absorbed onto silica gel for purification. The desired product was obtained as a yellow color powdered solid in 47% yield (44 mg).¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (ddd, J = 7.9, 1.3, 0.5 Hz, 1H), 8.11 (dt, J = 8.0, 1.0 Hz, 1H), 7.99– 7.93 (m, 1H), 7.86 (ddd, J = 8.5, 7.4, 1.4 Hz, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 4.58 (br.s, 2H), 4.39 (s, 2H), 3.77 (s, 3H), 3.60 (t, J = 5.8 Hz, 2H), 3.03 (t, J = 5.8 Hz, 2H), 2.49– 2.42 (m, 1H), 1.26– 1.12 (m, 4H). HRMS: C22H22N6O calculated (M+H)⁺ = 387.19279 m/z; found (M+H)⁺ = 387.19214 m/z. Yield: 48%.

q. SYNTHESIS OF 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLINE-6,7-DIOL (49)

(i) STEP 1 [00423] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” LRMS: (M+H)⁺ = 402.2 m/z. Yield: 60%.

(ii) S^TEP 2 - M^{ETHYL DEPROTECTION} [00424] 3-cyclopropyl-6-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)- [1,2,4]triazolo[3,4-a]phthalazine (210 mg, 0.52 mmol) dissolved in DCM (10 mL) was cooled to -78 °C and was added Boron tribromide solution (5.23 mL, 5.23 mmol) (1.0 M solution in DCM) solution drop wise. After complete addition, stirred for an addition 10 min at -78 °C and then removed the dry ice bath and continued reaction at room temperature. After overnight stirring, the crude was quenched with aq. NaHCO₃ (sat), extracted with methylene chloride (2 X 50 mL). The combined organic extract was then dried over anhyd. Na₂SO₄, filtered and concentrated under reduced pressure. Purification of the crude by silica gel column chromatography provided 12 mg of the final compound in 6% yield as a light orange color solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.95-8.56 (br.s, 2H), 8.43 (ddd, J = 7.9, 1.4, 0.5 Hz, 1H), 8.11 (dt, J = 7.9, 1.0 Hz, 1H), 7.96 (ddd, J = 8.0, 7.3, 1.2 Hz, 1H), 7.86 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 6.59 (s, 1H), 6.55 (s, 1H), 4.40 (s, 2H), 3.58 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 5.9 Hz, 2H), 2.48– 2.43 (m, 1H), 1.27– 1.12 (m, 4H). HRMS: C21H19N5O2 calculated (M+H)⁺ = 374.16115 m/z; found (M+H)⁺ = 374.16079. Yield: 6%.

r. SYNTHESIS OF 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-6-OL (50)

(i) STEP 1 [00425] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” LRMS: (M+H)⁺ = 372.2 m/z. Yield: 49%.

(ii) S^TEP 2 - M^{ETHYL DEPROTECTION} [00426] 3-cyclopropyl-6-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)- [1,2,4]triazolo[3,4-a]phthalazine (270 mg, 0.7300mmol) dissolved in DCM (9 mL) was cooled to -78 °C and was added Boron tribromide solution (3.6 mL, 3.63 mmol) (1.0 M in DCM) dropwise. The combined solution stirred for an additional 10 min at -78 °C followed by overnight stirring at room temperature. After reaction completion, quenched with aq. NaHCO3 (sat), extracted with methylene chloride (2 X 50 mL). The combined organic extract was dried over anhyd. Na2SO4, filtered and concentrated in vacuuo and purified by silica gel column chromatography. The desired product was obtained as a white color solid in 14% yield (36 mg). ¹H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.43 (ddd, J = 7.9, 1.4, 0.5 Hz, 1H), 8.14– 8.08 (m, 1H), 7.97 (ddd, J = 8.0, 7.3, 1.1 Hz, 1H), 7.86 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.02 (dd, J = 7.8, 1.0 Hz, 1H), 6.62 (d, J = 7.7 Hz, 2H), 4.47 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 3.10 (t, J = 5.9 Hz, 2H), 2.48– 2.42 (m, 1H), 1.26– 1.12 (m, 4H). HRMS: C21H19N5O calculated (M+H)⁺ = 358.16624 m/z; found (M+H)⁺ = 358.16637. Yield: 14%.

s. SYNTHESIS OF 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7-OL (52)

(i) STEP 1 [00427] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (ddd, J = 7.9, 1.4, 0.5 Hz, 1H), 8.16– 8.11 (m, 1H), 8.00– 7.93 (m, 1H), 7.86 (ddd, J = 8.1, 7.3, 1.3 Hz, 1H), 7.17– 7.13 (m, 1H), 6.84– 6.78 (m, 2H), 4.57 (s, 2H), 3.74 (s, 3H), 3.65 (t, J = 5.9 Hz, 2H), 3.10 (t, J = 5.9 Hz, 2H), 2.49– 2.40 (m, 1H), 1.23– 1.14 (m, 4H). LRMS: (M+H)⁺ = 372.2 m/z. Yield: 72%. (ii) STEP 2 - METHYL DEPROTECTION [00428] 3-cyclopropyl-6-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)- [1,2,4]triazolo[3,4-a]phthalazine (280 mg, 0.7500mmol) dissolved in DCM (4 mL) was cooled to -78 °C and was added Boron tribromide solution (3.8 mL, 3.77 mmol) drop wise (1.0 M in DCM). After 3 h at -78 ˚C, the reaction mixture was quenched with aq. NaHCO₃ (sat), extracted with methylene chloride (2 X 50 mL). The combined organic extract was over anhyd. Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography provided the final product as a white color solid in 32% yield (86 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.43 (ddd, J = 7.9, 1.4, 0.5 Hz, 1H), 8.12 (ddd, J = 8.1, 1.2, 0.6 Hz, 1H), 7.96 (ddd, J = 7.9, 7.3, 1.1 Hz, 1H), 7.86 (ddd, J = 8.1, 7.3, 1.4 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.64 (dd, J = 8.2, 2.6 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 4.49 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 3.05 (t, J = 5.8 Hz, 2H), 2.49– 2.43 (m, 1H), 1.23 – 1.13 (m, 4H). HRMS: C₂₁H₁₉N₅O calculated (M+H)⁺ = 358.16624 m/z; found (M+H)⁺ = 358.16595. Yield: 32%.

t. SYNTHESIS OF 6-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-5,6,7,8-^TETRAHYDRO-1,6-^NAPHTHYRIDIN-3- AMINE (53)

[00429] 3-cyclopropyl-6-(3-nitro-7,8-dihydro-5H-1,6-naphthyridin-6-yl)- [1,2,4]triazolo[3,4-a]phthalazine (50 mg, 0.13 mmol) dissolved in Acetone (5mL)/Water (1mL) was added Zinc powder (84 mg, 1.29 mmol) followed by ammonia hydrochloride (104 mg, 1.94 mmol) and stirred at room temperature for 1 h. After reaction completion the reaction mixture was filtered through a Celite pad washing with acetone. The resulting solvents were then evaporated off and the crude is purified by silica gel column

chromatography. The final compound was obtained as a white color solid in 82% yield (38 mg). ¹H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J = 8.0, 1.3 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.96 (td, J = 8.1, 7.7,1.2 Hz, 1H), 7.89– 7.83 (m, 2H), 6.77 (d, J = 2.6 Hz, 1H), 5.17 (s, 2H), 4.47 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 3.08 (t, J = 5.9 Hz, 2H), 2.44 (dt, J = 8.2, 5.0 Hz, 1H), 1.24– 1.10 (m, 4H). HRMS: C21H19N7 calculated (M+H)⁺ = 358.17747 m/z; found (M+H)⁺ = 358.17701. Yield: 82%.

u. SYNTHESIS OF 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-5-MORPHOLINO-1,2,3,4- T^{ETRAHYDROISOQUINOLIN}-7-^AMINE (54)

Example 54 (i) STEP 1 - IODINATION [00430] 7-nitro-1,2,3,4-tetrahydroisoquinoline (1 g, 5.61 mmol), N-Iodosuccinimide (1.64 g, 7.3 mmol) dissolved in Trifluoromethanesulfonic acid (5.5 mL, 61.73 mmol) allowed to react at room temperature overnight. After reaction completion crude reaction mixture was carefully transferred onto sat. NaHCO3 (aq) solution. After complete addition the aqueous layer was extracted with methylene chloride (2 X 75 mL). The combined organic extracts were then washed with aq. Sodium Thiosulfate (sat), dried over Na2SO4 (anhyd) and concentrated under reduced pressure to obtain providing 1.6 g of the crude as a purple color solid in 94% yield. This crude was then carried through next step without purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 3.88 (s, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.56 (t, J = 6.0 Hz, 2H). LRMS: (M+H)⁺ = 305.0 m/z. Yield: 94%.

(ii) STEP 2 - BOC PROTECTION [00431] 5-iodo-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.6 g, 5.26mmol), N,N- diethylethanamine (1.5 mL, 10.52 mmol), dissolved in DCM (20 mL) was added di-tert-butyl dicarbonate (1.73 g, 7.89 mmol) at room temperature and stirred for 2 h. After the reaction completion evaporated off the solvents under reduced pressure and the resulting crude was purified by silica gel column chromatography. The desired product was obtained as a white color solid in 37% yield (780 mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.57– 8.55 (m, 1H), 8.13 (dd, J = 2.0, 1.0 Hz, 1H), 7.99 (dt, J = 2.0, 0.8 Hz, 1H), 7.92 (dt, J = 2.0, 0.8 Hz, 1H), 4.67 (s, 3H), 4.64 (s, 2H), 3.69 (tt, J = 10.6, 6.0 Hz, 5H), 2.94 (t, J = 6.1 Hz, 2H), 2.85 (t, J = 6.1 Hz, 2H), 1.51– 1.49 (m, 23H). LRMS: [(M-Boc)+H]⁺ = 305.0 m/z. Yield: 37%.

(iii) S^TEP 3 - B^UCKWALD-H^ARTWIG C-N ^COUPLING [00432] A pressure tube charged with argon was added tert-butyl 5-iodo-7-nitro-3,4- dihydro-1H-isoquinoline-2-carboxylate (700 mg, 1.73 mmol), Morpholine (0.230 mL, 2.6 mmol), Cesium Carbonate (1.2 g, 3.46 mmol), XPhos (83 mg, 0.17 mmol) followed by 1,4- Dioxane (9 mL) at room temperature. After flushing with argon again

Tris(dibenzylideneacetone)dipalladium(0), (79 mg, 0.09 mmol) was added at once and re- flushed the tube with argon. The resulting reaction mixture continued to stir at 100 °C overnight. After reaction completion as monitored by LCMS analysis (~ 16 h) stopped heating and the reaction mixture was filtered through a short plug of Celite to remove the solid residues washing chloroform. The filtrate was then partitioned between water and chloroform. The separated aqueous layer then washed with chloroform (2 X 50 mL). The combined organic extracts were then dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting crude was then purified by silica gel to retrieve the desired product as an orange color viscous oil in 84% yield (528 mg). ¹H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 4.61 (s, 2H), 3.79– 3.72 (m, 4H), 3.50 (t, J = 5.5 Hz, 2H), 2.92 (dd, J = 5.6, 3.5 Hz, 4H), 2.86 (t, J = 5.7 Hz, 2H), 1.44 (s, 9H). LRMS: (M+H)⁺ = 364.2 m/z. Yield: 84%.

(iv) STEP 4 - BOC DEPROTECTION [00433] Combined solutions of tert-butyl 5-morpholino-7-nitro-3,4-dihydroisoquinoline- 2(1H)-carboxylate (520 mg, 1.431 mmol) and TFA (1.096 mL, 14.31 mmol) in DCM (8 mL) was stirred at room temperature for 1 h. After reaction completion, evaporated off the solvents under reduced pressure, diluted the crude with chloroform and evaporated off the solvents again. Repeated this process three times. The resulting crude obtained in quantitative yields was carried through to the next step without purification. ¹H NMR (400 MHz, DMSO- d₆) δ 7.95 (d, J=2.3 Hz, 1H), 7.78 (d, J=2.3 Hz, 1H), 4.41 (t, J=3.4 Hz, 2H), 3.80-3.73 (m, 4H), 3.41-3.33 (m, 3H), 3.01 (t, J=6.1 Hz, 2H), 2.95-2.89 (m, 4H). LRMS: C13H17N3O3; (M+H)⁺ = 264.1 m/z. Yield: 100%.

(v) STEP 5 [00434] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.46-8.42 (m, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.01-7.95 (m, 1H), 7.93 (d, J=2.3Hz, 1H), 7.87 (td, J=7.8, 7.3, 1.3 Hz, 1H), 7.72 (d, J=2.3 Hz, 1H), 4.73 (s, 2H), 3.78 (t, J=4.4 Hz, 4H), 3.65 (t, J=5.5 Hz, 2H), 3.24 (d, J=5.3 Hz, 2H), 3.00 (t, J=4.4 Hz, 4H), 2.46-2.43 (m, 1H), 1.23-1.09 (m, 4H). LRMS: C25H25N7O3; (M+H)⁺ = 472.2 m/z. Yield: 14%.

(vi) STEP 6 (54) [00435] Followed similar synthetic procedure as described in Example 53. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44-8.40 (m, 1H), 8.18-8.13 (m, 1H), 7.95 (ddd, J=8.0, 7.3, 1.1 Hz, 1H), 7.85 (ddd, J=8.5, 7.3, 1.4 Hz, 1H), 6.25 (d, J=2.1 Hz, 1H), 6.15 (d, J=2.1 Hz, 1H), 4.89 (s, 2H), 4.41 (s, 2H), 3.73 (t, J=4.5 Hz, 4H), 3.53 (t, J=5.6 Hz, 2H), 2.97 (t, J=5.6 Hz, 2H), 2.82 (t, J=4.5 Hz, 4H), 2.47-2.41 (m, 1H), 1.24-1.11 (m, 4H). HRMS: C25H27N7O; Calculated (M+H)⁺ = 442.23498 m/z, found (M+H)⁺ = 442.23451 m/z. Yield: 34%.

v. S^{YNTHESIS OF} 2-(3-^CYCLOPROPYL-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-5-(4-METHYLPIPERAZIN-1-YL)-1,2,3,4- T^{ETRAHYDROISOQUINOLIN}-7-^AMINE (55)

(i) STEP 1 - BUCKWALD-HARTWIG C-N COUPLING [00436] Followed similar synthetic procedure as described in STEP 3 en route to

Example 54. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 4.60 (s, 2H), 3.49 (t, J = 5.7 Hz, 2H), 2.93 (t, J = 4.7 Hz, 4H), 2.83 (t, J = 5.7 Hz, 2H), 2.55-2.50 (m 4H), 2.26 (s, 3H), 1.44 (s, 9H). LRMS: C19H28N4O4; (M+H)⁺ = 377.2 m/z. Yield: 88%.

(ii) STEP 2 - BOC DEPROTECTION [00437] Followed similar synthetic procedure as described in STEP 4 en route to

Example 54. ¹H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 4.42 (s, 2H), 3.59-3.45 (m, 4H), 3.31– 3.18 (m, 4H), 3.01 (t, J = 6.1 Hz, 2H), 2.89 (s, 3H), 2.58– 2.51 (m, 2H). LRMS: C14H20N4O2; (M+H)⁺ = 277.2 m/z. Yield: 100%.

(iii) STEP 3 - SNAR [00438] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (dd, J = 8.0, 1.3 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.02– 7.96 (m, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.88 (ddd, J = 8.5, 7.3, 1.5 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 4.74 (s, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.21 (t, J = 5.6 Hz, 2H), 3.01 (t, J = 4.7 Hz, 4H), 2.69– 2.52 (m, 4H), 2.48– 2.45 (m, 1H), 2.28 (s, 3H), 1.21– 1.12 (m, 4H). LRMS: C26H28N8O2; (M+H)⁺ = 485.2 m/z. Yield: 21%.

(iv) S^TEP 4 (55) [00439] Followed similar synthetic procedure as described in Example 53. ¹H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J = 8.0, 1.3 Hz, 1H), 8.18– 8.10 (m, 1H), 7.96 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 7.85 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.36 (s, 1H), 7.24 (s, 1H), 7.15– 7.07 (m, 1H), 6.36– 6.22 (m, 2H), 4.43 (s, 2H), 3.54 (t, J = 5.6 Hz, 2H), 3.46 (d, J = 11.3 Hz, 2H), 3.22– 3.14 (m, 4H), 3.06 (d, J = 12.3 Hz, 2H), 2.98 (s, 2H), 2.80 (s, 3H), 2.47-2.41 (m, 1H), 1.24– 1.10 (m, 4H). HRMS: C26H30N8; Calculated (M+H)⁺ = 455.26662 m/z, found (M+H)⁺ = 455.26548 m/z. Yield: 57%.

w. S^{YNTHESIS OF} 2-(3-(^{METHOXYMETHYL})-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7-AMINE (56)

(i) STEP 1 - CYCLIZATION [00440] 1,4-Dichlorophthalazine (500 mg, 2.51 mmol), 2-methoxyacetohydrazide (523.0607 mg, 5.02 mmol) dissolved in 1-Butanol (8 mL) allowed to stir at 118 °C under argon atmosphere for 1 h. The solvents were then evaporated off under reduced pressure and purified by silica gel column chromatography. The desired product was obtained as a white color solid in 79% yield (493 mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.73 (ddd, J = 8.0, 1.3, 0.6 Hz, 1H), 8.30 (ddd, J = 8.2, 1.2, 0.6 Hz, 1H), 8.03 (ddd, J = 7.9, 7.3, 1.2 Hz, 1H), 7.93– 7.88 (m, 1H), 5.03 (s, 2H), 3.52 (s, 3H). LRMS: C26H28N8O2; (M+H)⁺ = 485.2 m/z. Yield: 79%.

(ii) S^TEP 2 - S^NA^R [00441] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 8.0, 1.4, 0.6 Hz, 1H), 8.20 (dd, J = 3.9, 1.7 Hz, 1H), 8.07 (dd, J = 8.5, 2.5 Hz, 1H), 8.03 (tdd, J = 8.0, 4.3, 1.2 Hz, 2H), 7.91 (ddd, J = 8.5, 7.4, 1.4 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 4.85 (s, 2H), 4.75 (s, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.36 (s, 3H), 3.31– 3.25 (m, 2H). LRMS: C20H18N6O3; (M+H)⁺ = 391.1 m/z. Yield: 70%.

(iii) STEP 3 - NITRO REDUCTION (56) [00442] Followed similar synthetic procedure as described in Example 53. ¹H NMR (400 MHz, DMSO-d6) δ 8.53– 8.47 (m, 1H), 8.18– 8.13 (m, 1H), 8.01 (td, J = 7.5, 1.1 Hz, 1H), 7.90 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.46 (dd, J = 8.1, 2.3 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 4.90 (s, 2H), 4.87 (s, 2H), 4.44 (s, 2H), 3.63 (t, J = 5.9 Hz, 2H), 3.39 (s, 3H), 3.00 (t, J = 5.8 Hz, 2H). HRMS: C20H20N6O; Calculated (M+H)⁺ = 361.17714 m/z, found (M+H)⁺ = 361.17719 m/z. Yield: 35%.

x. SYNTHESIS OF 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-N,N-DIMETHYL-1,2,3,4- T^{ETRAHYDROISOQUINOLIN}-7-^AMINE (60)

Example 60

(i) STEP 1 - BOC PROTECTION [00443] 7-Nitro-1,2,3,4-tetrahydroisoquinoline (750 mg, 4.21 mmol) dissolved in DCM (20 mL) was added di-tert-butyl dicarbonate (1.4 g, 6.31 mmol) followed by trimethylamine (1.2 mL, 8.42 mmol) at room temperature. After 2 h, the reaction mixture was quenched with water, extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were then dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by silica gel column chromatography providing the desired product as a colorless viscous oil in 89% yield (1.04 g). ¹H NMR (400 MHz, Chloroform-d) δ 8.05– 7.98 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 4.66 (s, 2H), 3.69 (t, J = 5.9 Hz, 2H), 2.93 (t, J = 5.9 Hz, 2H), 1.50 (t, J = 1.1 Hz, 9H). LRMS: [(M-Boc)+H]⁺ = 179.1 m/z. Yield: 89%.

(ii) STEP 2 - NITRO REDUCTION [00444] tert-Butyl 7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (1 g, 3.59 mmol) dissolved in Acetone (25 mL)/Water (5 mL) mixture was added Zinc powder (2.4 g, 35.93 mmol) followed by NH₄Cl (2.9 g, 53.9 mmol) at room temperature and stirred overnight. After reaction completion, the crude was filtered through Celite pad washing with acetone. The solvents were then evaporated off under reduced pressure and the crude was purified by silica gel column chromatography. The desired product was obtained as an orange color gummy solid in 82% yield (727 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 6.76 (d, J = 8.1 Hz, 1H), 6.37 (dd, J = 8.1, 2.4 Hz, 1H), 6.28 (s, 1H), 4.85 (s, 2H), 4.30 (s, 2H), 3.45 (t, J = 5.9 Hz, 2H), 2.55 (t, J = 5.9 Hz, 2H), 1.40 (s, 9H). LRMS: [(M-tBu)+H]⁺ = 193.1 m/z. Yield: 89%.

(iii) STEP 3 - N-METHYLATION [00445] tert-Butyl 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate (403 mg, 1.62 mmol) dissolved in THF (8 mL) cooled to 0 °C and was added sodium hydride (143 mg, 3.57 mmol) and continued to stir for 20 min at same temperature. Afterwards, Iodomethane (0.26 mL, 4.06 mmol) was added and stirred for an additional 20 min at 0 °C followed by removal of ice bath and continued to react at room temperature. After 24 h, the reaction mixture was quenched with aq. NH₄Cl (saturated) and extracted with ethyl acetate (2 X 50 mL). The combined organic extracts were then dried with anhyd. Na2SO4, filtered and concentrated under reduced pressure. The crude is then purified by silica gel column chromatography providing the desired product as an off white color viscous oil in 30% yield (130 mg). ¹H NMR (400 MHz, Chloroform-d) δ 7.00 (d, J = 8.4 Hz, 1H), 6.62 (dd, J = 8.4, 2.7 Hz, 1H), 6.47 (s, 1H), 4.53 (s, 2H), 3.62 (s, 2H), 2.91 (s, 6H), 2.76– 2.70 (m, 2H), 1.49 (s, 9H).

LRMS: (M+H)⁺ = 277.2 m/z. Yield: 30%.

(iv) S^TEP 4 - B^{OC DEPROTECTION} [00446] tert-Butyl 7-(dimethylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylate (130 mg, 0.4700 mmol) dissolved in DCM (4.7038 mL) was added Trifluoroacetic acid (0.3602 mL, 4.7 mmol) and stirred for 2 h at room temperature. After reaction completion, diluted the crude with chloroform and evaporated off the solvents. Repeated this three times. The desired product was obtained as a dark orange color viscous oil in quantitative yields (198 mg – bistriflate salt). ¹H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 2H), 7.03 (d, J = 8.5 Hz, 1H), 6.70 (dd, J = 8.5, 2.7 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 4.22– 4.17 (m, 2H), 3.34 (h, J = 5.8 Hz, 2H), 2.89-2.83 (m, 2H), 2.86 (s, 6H). LRMS: (M+H)⁺ = 177.1 m/z. Yield: 100%.

(v) STEP 5– SNAR (60) [00447] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J = 7.9, 1.3 Hz, 1H), 8.15– 8.11 (m, 1H), 7.97 (td, J = 7.6, 1.1 Hz, 1H), 7.86 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.66 (dd, J = 8.5, 2.7 Hz, 1H), 6.58 (d, J = 2.6 Hz, 1H), 4.53 (s, 2H), 3.63 (t, J = 5.8 Hz, 2H), 3.06 (t, J = 5.8 Hz, 2H), 2.86 (s, 6H), 2.48– 2.44 (m, 1H), 1.22– 1.15 (m, 4H). HRMS: C23H24N6; Calculated (M+H)⁺ = 385.21352 m/z, found (M+H)⁺ = 385.21319 m/z. Yield: 11%.

y. S^{YNTHESIS OF} 3-^CYCLOPROPYL-6-(7-^FLUORO-3,4- DIHYDROISOQUINOLIN-2(1H)-YL)-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZINE (61)

(i) STEP 1 - TRIFLUOROACETYLATION [00448] 2-(4-Fluorophenyl)ethanamine (4.7 mL, 35.93 mmol) dissolved in DCM (100 mL) was added N,N-diethylethanamine (10 mL, 71.85 mmol) and cooled to -5 °C.

Trifluoroacetic anhydride (6.1 mL, 43.11 mmol) was added drop-wise to above solution and continued stirring at -5 °C for an additional 30 minutes, followed by stirring at 0 °C for 2 h. After reaction completion the reaction mixture was quenched with water and the separated aqueous layer was extracted with methylene chloride. The combined organic extracts were then dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure.

Purification of the crude by silica gel column chromatography provided the desired product as a white crystalline solid in quantitative yields (8.76 g). ¹H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.27– 7.21 (m, 2H), 7.15– 7.08 (m, 2H), 3.44– 3.37 (m, 2H), 2.79 (t, J = 7.2 Hz, 2H). Yield: 100%.

(ii) STEP 2 - MODIFIED BICHLER-NAPIERALSKI REACTION [00449] To a mixture of acetic acid (9.5 mL, 165.83 mmol), sulfuric acid (6.4 mL, 204.1 mmol) was added 2,2,2-trifluoro-N-[2-(4-fluorophenyl)ethyl]acetamide (3 g, 12.76 mmol) followed by Paraformaldehyde (0.64 g, 12.76 mmol) at room temperature under argon. The resulting viscous cloudy reaction mixture allowed to stir for ~20 h at room temperature. The reaction mixture was then poured onto 100 mL of cold water, extracted with ethyl acetate (2 X 100 mL). The organic extracts were then combined, washed with saturated aq. NaHCO₃ (2 X 100 mL), brine (2X100 mL), dried over anhydrous sodium sulfate, filtered and

concentrated under reduced pressure. The residue is then absorbed onto silica gel for purification. The desired product was obtained as a colorless viscous oil in 88% yield (2.77 g). ¹H NMR (400 MHz, Chloroform-d) δ 7.17– 7.09 (m, 1H), 6.99– 6.81 (m, 2H), 4.79– 4.70 (m, 2H), 3.91– 3.81 (m, 2H), 2.92 (h, J = 5.4 Hz, 2H). Yield: 88%.

(iii) STEP 3 - TRIFLUOROACETYL DEPROTECTION [00450] 2,2,2-Trifluoro-1-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (500 mg, 2.02 mmol) dissolved in Methanol (10 mL)/Water (4 mL) was added K₂CO₃ (2.9 g, 20.23 mmol) and continued to stir at room temperature for 5 h. After reaction completion, evaporated off the solvents and the solid was re-diluted with water (50 mL) and extracted with chloroform (3 X 50 mL). The combined organic extracts were then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. A colorless viscous oil was obtained in 71% yield (217 mg) which was used in next step without purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.08 (dd, J = 8.4, 6.0 Hz, 1H), 6.91 (td, J = 8.7, 2.8 Hz, 1H), 6.84 (dd, J = 9.8, 2.8 Hz, 1H), 3.81 (s, 2H), 3.07 (br.s, 1H), 2.90 (t, J = 5.9 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H). LRMS: (M+H)⁺ = 152.1 m/z. Yield: 71%.

(iv) S^TEP 4– S^NA^R (61) [00451] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.43– 8.39 (m, 1H), 8.13– 8.09 (m, 1H), 7.95 (ddd, J = 8.1, 7.4, 1.2 Hz, 1H), 7.84 (ddd, J = 8.3, 7.3, 1.4 Hz, 1H), 7.26 (dd, J = 8.5, 5.8 Hz, 1H), 7.10 (dd, J = 9.8, 2.7 Hz, 1H), 7.04 (td, J = 8.7, 2.8 Hz, 1H), 4.57 (s, 2H), 3.64 (t, J = 5.9 Hz, 2H), 3.14– 3.09 (m, 2H), 2.42 (tt, J = 8.3, 5.2 Hz, 1H), 1.22– 1.09 (m, 4H).

HRMS: C21H18FN5; Calculated (M+H)⁺ = 360.16190 m/z, found (M+H)⁺ = 360.16230 m/z. Yield: 41%.

z. S^{YNTHESIS OF} 3-^CYCLOPROPYL-6-(6-^FLUORO-3,4- DIHYDROISOQUINOLIN-2(1H)-YL)-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZINE (62)

(i) S^TEP 1 - T^{RIFLUOROACETYLATION} [00452] Followed similar synthetic procedure as described in Step 1 en route to Example 61. ¹H NMR (400 MHz, Chloroform-d) δ 7.34– 7.27 (m, 1H), 7.00– 6.94 (m, 2H), 6.93– 6.88 (m, 1H), 6.33 (s, 1H), 3.62 (q, J = 6.7 Hz, 2H), 2.90 (t, J = 7.0 Hz, 2H). Yield: 98%.

(ii) STEP 2 - MODIFIED BICHLER-NAPIERALSKI REACTION [00453] Followed similar synthetic procedure as described in Step 2 en route to Example 61. ¹H NMR (400 MHz, Chloroform-d) δ 7.10 (ddd, J = 13.8, 8.5, 5.5 Hz, 1H), 6.98– 6.84 (m, 2H), 4.73 (d, J = 19.8 Hz, 2H), 3.91– 3.80 (m, 2H), 2.94 (q, J = 5.8 Hz, 2H). Yield: 94%.

(iii) S^TEP 3 - T^{RIFLUOROACETYL DEPROTECTION} [00454] Followed similar synthetic procedure as described in Step 3 en route to Example 61. ¹H NMR (400 MHz, DMSO-d6) δ 7.03 (dd, J = 8.1, 6.1 Hz, 1H), 6.94– 6.85 (m, 2H), 3.79 (s, 2H), 3.15 (s, 1H), 2.90 (t, J = 6.0 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H). LRMS: (M+H)⁺ = 152.1 m/z. Yield: 58%.

(iv) STEP 4– SNAR (62) [00455] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 8.13 (ddd, J = 8.2, 1.2, 0.6 Hz, 1H), 7.97 (ddd, J = 8.0, 7.3, 1.2 Hz, 1H), 7.86 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.29 (dd, J = 8.5, 5.8 Hz, 1H), 7.10 (dd, J = 9.8, 2.8 Hz, 1H), 7.04 (td, J = 8.7, 2.8 Hz, 1H), 4.57 (s, 2H), 3.65 (t, J = 5.9 Hz, 2H), 3.18 (t, J = 5.9 Hz, 2H), 2.49– 2.42 (m, 1H), 1.25– 1.13 (m, 4H). HRMS: C21H18FN5; Calculated (M+H)⁺ = 360.16190 m/z, found (M+H)⁺ = 360.16136 m/z. Yield: 38%.

aa. SYNTHESIS OF 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-5-(PYRROLIDIN-1-YL)-1,2,3,4- T^{ETRAHYDROISOQUINOLIN}-7-^AMINE (63)

(i) STEP 1 - BUCKWALD-HARTWIG C-N COUPLING [00456] Followed similar synthetic procedure as described in STEP 3 en route to Example 54. LRMS: C18H25N3O4; (M+H)⁺ = 348.1 m/z. Yield: 100%.

(ii) STEP 2 - BOC DEPROTECTION [00457] Followed similar synthetic procedure as described in STEP 4 en route to Example 54. LRMS: C13H17N3O2; (M+H)⁺ = 248.2 m/z. Yield: 100%.

(iii) S^TEP 3– S^NA^R [00458] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J = 7.8, 1.3 Hz, 1H), 8.40– 8.36 (m, 1H), 8.16– 8.12 (m, 1H), 8.01– 7.94 (m, 2H), 7.87– 7.84 (m, 1H), 4.71 (d, J = 7.2 Hz, 2H), 4.49 (t, J = 6.4 Hz, 1H), 3.71 (t, J = 6.2 Hz, 1H), 3.60 (t, J = 5.6 Hz, 1H), 3.17 (s, 1H), 2.46– 2.36 (m, 1H), 1.90-1.80 (m, 2H), 1.53 (h, J = 7.3 Hz, 1H), 1.23– 1.09 (m, 9H).

LRMS: C25H25N7O2; (M+H)⁺ = 456.2 m/z. Yield: 33%.

(iv) STEP 4 - NITRO REDUCTION (63) [00459] Combined solution of 3-cyclopropyl-6-(7-nitro-5-(pyrrolidin-1-yl)-3,4- dihydroisoquinolin-2(1H)-yl)-[1,2,4]triazolo[3,4-a]phthalazine (120 mg, 0.2634 mmol), zinc powder (172 mg, 2.634 mmol), and NH4Cl (211 mg, 3.952 mmol) in acetone (5 mL)/water (1 mL) were allowed to react at room temperature for 30 minutes. After reaction completion as monitored by LCMS analysis, the reaction mixture was filtered washing with acetone to remove zinc powder and other solid residues. The solvents were then evaporated off and the resulting crude was purified under silica gel column chromatography. The desired product was isolated in 15% yield (17 mg) as a brown color gummy solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.41 (dd, J = 8.0, 1.3 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.95 (td, J = 7.6, 1.1 Hz, 1H), 7.85 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 6.20 (d, J = 2.1 Hz, 1H), 6.11– 6.07 (m, 1H), 4.43 (s, 2H), 3.51 (t, J = 5.6 Hz, 2H), 3.14 (s, 2H), 3.13– 3.07 (m, 4H), 2.97– 2.91 (m, 2H), 2.44 (dt, J = 8.3, 3.2 Hz, 1H), 1.90– 1.83 (m, 4H), 1.23– 1.12 (m, 4H). HRMS: C25H27N7; Calculated (M+H)⁺ = 426.24007 m/z, found (M+H)⁺ = 426.23928 m/z. Yield: 17%.

bb. SYNTHESIS OF 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-7-^FLUORO-1,2,3,4-^{TETRAHYDROISOQUINOLIN}- 6-AMINE (64)

[00460] 2,2,2-Trifluoro-1-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (2.27 g, 9.18 mmol) was added slowly to an ice-cold concentrated sulfurinc acid (10 mL). The resulting yellow solution was then cooled to 0 °C and to this an ice cold solution of NaNO₃ (0.82 g, 9.64 mmol) dissolved in concentrated sulfuric acid (12 mL) was added drop wise over 1 h via an additional funnel keeping the temperature between 0-2 °C. After complete addition the reaction mixture continued to stir at 0-4 °C for an additional 45 min. After reaction completion, the crude was transferred onto an ice-cold water (~ 350 mL), extracted with ethyl acetate (2 X 250 mL). The combined organics were washed with water (1 X 150 mL), brine (1 X 150), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the crude by silica gel column chromatography provided the desired compound as an off white color solid in 72% yield (1.93 g). ¹H NMR (400 MHz, DMSO-d6) δ 8.07 (dd, J = 7.6, 2.9 Hz, 1H), 7.68– 7.57 (m, 1H), 4.91– 4.83 (m, 2H), 3.86– 3.81 (m, 2H), 3.00 (t, J = 5.5 Hz, 2H). Yield: 72%.

(ii) S^TEP 2 - N^ITRO R^EDUCTION [00461] 2,2,2-Trifluoro-1-(7-fluoro-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (150 mg, 0.51 mmol) dissolved in Acetone (10 mL)/Water (2 mL) was added Zinc powder (336 mg, 5.13 mmol) followed by NH₄Cl (412 mg, 7.7 mmol) at room temperature and stirred for 30 min. After reaction completion, filtered the crude through Celite pad washing with methanol. The filtrate was then evaporated off under reduced pressure and the crude is then directly absorbed onto silica gel for purification. Desired product was obtained as a beige color solid in 65% yield (88 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 6.98– 6.89 (m, 1H), 6.55 (dd, J = 9.1, 3.1 Hz, 1H), 5.07 (d, J = 9.0 Hz, 2H), 4.56 (t, J = 7.6 Hz, 2H), 3.73 (q, J = 6.2 Hz, 2H), 2.73 (dt, J = 11.2, 6.0 Hz, 2H). Yield: 65%.

(iii) S^TEP 3 - T^{RIFLUOROACETYL DEPROTECTION} [00462] 1-(6-Amino-7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (88 mg, 0.34 mmol) dissolved in Water (4 mL)/Methanol (10 mL) was added K2CO3 (471 mg, 3.36 mmol) and combined reaction mixture allowed to stir at room temperature under argon for 5 h. After reaction completion, evaporated off the solvent under reduced pressure and the resulting crude solid was partitioned between aq. NH₄Cl and methylene chloride. The separated aqueous layer was extracted with methylene chloride (2 X 50 mL). The combined organic extracts were then washed with bring, separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. An off white color solid was obtained in quantitative yield (62 mg). This material was used in next step without purification. ¹H NMR (400 MHz, DMSO-d6) δ 6.60 (d, J = 12.0 Hz, 1H), 6.42 (d, J = 9.2 Hz, 1H), 4.77 (s, 2H), 3.65 (s, 2H), 2.84 (t, J = 5.9 Hz, 2H), 2.48 (t, J = 1.8 Hz, 3H). LRMS: C9H11FN2; (M+H)⁺ = 167.1 m/z. Yield: 100%.

(iv) STEP 4– SNAR (64) [00463] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d₆) δ 8.44– 8.41 (m, 1H), 8.13– 8.09 (m, 1H), 7.99– 7.94 (m, 1H), 7.88– 7.83 (m, 1H), 6.88 (d, J = 12.0 Hz, 1H), 6.62 (d, J = 9.2 Hz, 1H), 4.99 (s, 2H), 4.42 (s, 2H), 3.59 (t, J = 5.7 Hz, 2H), 3.02 (t, J = 5.8 Hz, 2H), 2.48– 2.40 (m, 1H), 1.22– 1.15 (m, 4H). HRMS: C21H19FN6; Calculated (M+H)⁺ = 375.17280 m/z, found (M+H)⁺ = 375.17276 m/z. Yield: 25%.

cc. S^{YNTHESIS OF} 3-^CYCLOPROPYL-6-(7-(^{TRIFLUOROMETHYL})-3,4- DIHYDROISOQUINOLIN-2(1H)-YL)-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZINE (65)

(i) STEP 1– TRIFLUOROACETYLATION [00464] Followed similar synthetic procedure described in Step 1 en route to Example 61. ¹H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 6.29 (s, 1H), 3.65 (q, J = 6.8 Hz, 2H), 2.97 (t, J = 7.1 Hz, 2H). Yield: 86% (3.9 g).

(ii) STEP 2 - MODIFIED BICHLER-NAPIERALSKI REACTION [00465] Followed similar synthetic procedure described in Step 2 en route to Example 61. ¹H NMR (400 MHz, Chloroform-d) δ 7.52– 7.45 (m, 1H), 7.41 (d, J = 11.5 Hz, 1H), 7.30 (dd, J = 10.8, 7.3 Hz, 1H), 4.82 (d, J = 18.5 Hz, 2H), 3.95– 3.85 (m, 2H), 3.02 (q, J = 6.2 Hz, 2H). Yield: 40% (1.61 g).

(iii) S^TEP 3 - T^{RIFLUOROACETYL DEPROTECTION} [00466] Followed similar synthetic procedure described in Step 3 en route to Example 61. ¹H NMR (400 MHz, DMSO-d₆) δ 7.47– 7.32 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 3.89 (s, 2H), 2.94 (t, J = 5.9 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H). LCMS: (M+H)⁺ = 202.1 m/z. Yield: 71% (235 mg). (iv) STEP 4– SNAR (65) [00467] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d₆) δ 8.44– 8.41 (m, 1H), 8.14 (dt, J = 8.2, 0.9 Hz, 1H), 7.99– 7.94 (m, 1H), 7.85 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.55 (dd, J = 8.1, 2.0 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 4.67 (s, 2H), 3.70 (t, J = 5.9 Hz, 2H), 3.23 (t, J = 6.0 Hz, 2H), 2.43 (tt, J = 8.3, 5.1 Hz, 1H), 1.22– 1.09 (m, 4H). HRMS:

C22H18F3N5; Calculated (M+H)⁺ = 410.15871 m/z, found (M+H)⁺ = 410.15846 m/z. Yield: 25%.

dd. SYNTHESIS OF 3-CYCLOPROPYL-6-(5-(TRIFLUOROMETHYL)-3,4- D^{IHYDROISOQUINOLIN}-2(1H)-^YL)-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZINE (66)

(i) STEP 1– TRIFLUOROACETYLATION [00468] Followed similar synthetic procedure described in Step 1 en route to Example 61. ¹H NMR (400 MHz, Chloroform-d) δ 7.67 (dt, J = 7.9, 0.9 Hz, 1H), 7.53 (td, J = 7.6, 1.3 Hz, 1H), 7.41– 7.33 (m, 2H), 6.39 (s, 1H), 3.64 (q, J = 6.8 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H). Yield: 99%.

(ii) S^TEP 2 - M^ODIFIED B^ICHLER-N^APIERALSKI R^EACTION [00469] Followed similar synthetic procedure described in Step 2 en route to Example 61. ¹H NMR (400 MHz, Chloroform-d) δ 7.63– 7.56 (m, 1H), 7.38– 7.30 (m, 2H), 4.82 (d, J = 18.5 Hz, 2H), 3.93– 3.83 (m, 2H), 3.17– 3.09 (m, 2H). Yield: 66%.

(iii) S^TEP 3 - T^{RIFLUOROACETYL DEPROTECTION} [00470] Followed similar synthetic procedure described in Step 3 en route to Example 61. ¹H NMR (400 MHz, DMSO-d₆) δ 7.55– 7.46 (m, 1H), 7.35– 7.27 (m, 2H), 3.91 (s, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.81– 2.75 (m, 2H). LCMS: (M+H)⁺ = 202.1 m/z. Yield: 54% (235 mg).

(iv) S^TEP 4– S^NA^R (66) [00471] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J = 7.9, 1.3 Hz, 1H), 8.18 (dt, J = 8.1, 1.0 Hz, 1H), 7.98 (td, J = 7.7, 1.2 Hz, 1H), 7.88 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.62 (dd, J = 23.6, 7.7 Hz, 2H), 7.44 (t, J = 7.8 Hz, 1H), 4.69 (s, 2H), 3.72 (t, J = 5.9 Hz, 2H), 3.32 (d, J = 5.7 Hz, 2H), 2.49– 2.43 (m, 1H), 1.24– 1.13 (m, 4H). HRMS: C22H18F3N5; alculated (M+H)⁺ = 410.15871 m/z, found (M+H)⁺ = 410.15887 m/z. Yield: 20%.

ee. 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4-A]PHTHALAZIN-6-YL)-6- F^LUORO-1,2,3,4-^{TETRAHYDROISOQUINOLIN}-7-^AMINE (67)

(i) STEP 1– NITRATION [00472] Followed similar synthetic procedure described in Step 1 en route to Example 64. ¹H NMR (400 MHz, Chloroform-d) δ 7.91 (t, J = 6.6 Hz, 1H), 7.14 (t, J = 10.0 Hz, 1H), 4.81 (d, J = 19.1 Hz, 2H), 3.98– 3.83 (m, 2H), 3.04 (q, J = 6.1 Hz, 2H). Yield: 48%.

(ii) STEP 2 - NITRO REDUCTION [00473] Followed similar synthetic procedure described in Step 2 en route to Example 64. ¹H NMR (400 MHz, DMSO-d6) δ 6.82 (dd, J = 11.9, 3.8 Hz, 1H), 6.56 (dd, J = 9.0, 3.2 Hz, 1H), 5.03 (s, 2H), 4.55 (s, 2H), 3.72 (td, J = 6.2, 4.0 Hz, 2H), 2.71 (dt, J = 9.4, 6.1 Hz, 2H). LRMS: (M+H)⁺ = 263.1 m/z. Yield: 84%.

(iii) STEP 3 - TRIFLUOROACETYL DEPROTECTION [00474] Followed similar synthetic procedure described in Step 3 en route to Example 64. ¹H NMR (400 MHz, DMSO-d₆) δ 6.67 (d, J = 12.1 Hz, 1H), 6.39 (d, J = 9.3 Hz, 1H), 4.83 (s, 2H), 3.70 (s, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.53 (t, J = 5.9 Hz, 2H). LRMS: (M+H)⁺ = 167.1 m/z. Yield: 53%.

(iv) S^TEP 4– S^NA^R (67) [00475] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.41 (ddd, J = 7.9, 1.3, 0.5 Hz, 1H), 8.10– 8.06 (m, 1H), 7.94 (ddd, J = 8.1, 7.4, 1.1 Hz, 1H), 7.83 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 6.86 (d, J = 12.0 Hz, 1H), 6.56 (d, J = 9.1 Hz, 1H), 4.96 (s, 2H), 4.39 (s, 2H), 3.57 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 5.8 Hz, 2H), 2.47– 2.40 (m, 1H), 1.23– 1.11 (m, 4H). HRMS:

C21H19FN6; Calculated (M+H)⁺ = 375.17280 m/z, found (M+H)⁺ = 375.17258 m/z. Yield: 58%.

ff. S^{YNTHESIS OF} 2-(3-^CYCLOPROPYL-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-5-(TRIFLUOROMETHYL)-1,2,3,4- T^{ETRAHYDROISOQUINOLIN}-7-^AMINE (68)

(i) STEP 1– NITRATION [00476] 2,2,2-trifluoro-1-[5-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (2.06 g, 6.93 mmol) dissolved in Nitric Acid (7.2309 mL, 173.28 mmol) (90% Nitric acid) was cooled to 0 °C and was added sulfuric acid (7.5812 mL, 242.6 mmol) drop-wise over 20 minutes. After complete addition the reaction was stirred for an additional 20 min at 0 °C followed by overnight stirring at room temperature. The Reaction mixture was poured into an ice-water mixture and the solution was then made alkaline to pH >10 with addition of solid LiOH.H2O at 0 °C with vigorous stirring. Once the solution became alkaline, the aqueous solution was extracted with ethyl acetate (3 X 100 mL). The combined organic extract was then washed with aq. sodium bicarbonate (100 mL), brine (100 mL). The organic extract was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the crude silica gel column chromatography provided the desired product as a white shiny crystalline solid in 73% yield (1.74 g). ¹H NMR (400 MHz, Chloroform-d) δ 8.49– 8.43 (m, 1H), 8.27– 8.22 (m, 1H), 4.94 (d, J = 18.0 Hz, 2H), 3.99– 3.90 (m, 2H), 3.23 (q, J = 5.6 Hz, 2H). Yield: 73%.

(ii) STEP 2 - TRIFLUOROACETYL DEPROTECTION [00477] Followed similar synthetic procedure described in Step 3 en route to Example 64. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 4.03 (s, 2H), 2.99 (t, J = 5.9 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.74 (s, 1H). LRMS: (M+H)⁺ = 247.1 m/z. Yield: 95%.

(iii) S^TEP 3– S^NA^R [00478] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” LRMS: (M+H)⁺ = 455.1 m/z. Yield: 30%.

(iv) STEP 4 - NITRO REDUCTION (68) [00479] Followed similar synthetic procedure described in Step 2 en route to Example 64. ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J = 7.9, 1.3 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.97 (ddd, J = 8.0, 7.3, 1.2 Hz, 1H), 7.87 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.65 (d, J = 2.2 Hz, 1H), 5.43 (s, 2H), 4.50 (s, 2H), 3.63 (t, J = 5.8 Hz, 2H), 3.14-3.07 (m, 2H), 2.46-2.44 (m, 1H), 1.25– 1.14 (m, 4H). HRMS: C22H19F3N6; Calculated (M+H)⁺ = 425.16961 m/z, found (M+H)⁺ = 425.16866 m/z. Yield: 26%.

gg. SYNTHESIS OF TWO REGIOISOMERS: 5-FLUORO-1,2,3,4- TETRAHYDROISOQUINOLIN-8-AMINE AND 5-FLUORO-1,2,3,4- TETRAHYDROISOQUINOLIN-6-AMINE (SCHEME 1)

(i) STEP 1– TRIFLUOROACETYLATION [00480] Followed similar synthetic procedure as described in Step 1 en route to Example 61. ¹H NMR (400 MHz, Chloroform-d) δ 7.29– 7.23 (m, 1H), 7.21– 7.16 (m, 1H), 7.12 (dd, J = 7.4, 1.2 Hz, 1H), 7.10– 7.03 (m, 1H), 6.34 (s, 1H), 3.63 (q, J = 6.7 Hz, 2H), 2.95 (t, J = 6.9 Hz,, 2H). Yield: 92%.

(ii) STEP 2 - MODIFIED BICHLER-NAPIERALSKI REACTION [00481] Followed similar synthetic procedure as described in Step 2 en route to Example 61. ¹H NMR (400 MHz, Chloroform-d) δ 7.21 (td, J = 7.9, 5.6 Hz, 1H), 7.00– 6.89 (m, 2H), 4.78 (dd, J = 23.0, 1.3 Hz, 2H), 3.95– 3.83 (m, 2H), 2.94 (q, J = 6.6 Hz, 2H). Yield: 39%.

(iii) STEP 3– NITRATION [00482] Followed similar synthetic procedure as described in Step 1 en route to Example 68. ¹H NMR (400 MHz, Chloroform-d) δ 8.19– 8.10 (m, 1H), 7.21– 7.12 (m, 1H), 5.18 (d, J = 14.6 Hz, 2H), 4.00– 3.89 (m, 2H), 3.02 (q, J = 7.2, 6.8 Hz, 2H). (Para Isomer) ¹H NMR (400 MHz, Chloroform-d) δ 7.98– 7.91 (m, 1H), 7.14– 7.09 (m, 1H), 4.85 (d, J = 24.2 Hz, 2H), 3.99– 3.88 (m, 2H), 3.08– 3.01 (m, 2H). (Ortho Isomer) Yield: 63% (para-isomer); 15% (ortho-isomer).

(iv) S^TEP 4 - N^ITRO R^EDUCTION [00483] Followed similar synthetic procedure as described in Step 2 en route to Example 67. Para Isomer: ¹H NMR (400 MHz, Chloroform-d) δ 6.81 (tt, J = 8.8, 0.8 Hz, 1H), 6.57– 6.52 (m, 1H), 4.54 (d, J = 13.0 Hz, 2H), 3.92– 3.80 (m, 2H), 3.43 (d, J = 38.8 Hz, 2H), 2.95 – 2.85 (m, 2H). LRMS: (M+H)⁺ = 263.1 m/z. Yield: 83%. Ortho Isomer: ¹H NMR (400 MHz, Chloroform-d) δ 6.76– 6.64 (m, 2H), 4.67 (d, J = 23.0 Hz, 2H), 3.91– 3.77 (m, 2H), 3.69 (br.S, 2H), 2.91 (q, J = 6.1 Hz, 2H). LRMS: (M+H)⁺ = 263.1 m/z. Yield: 62%.

(v) S^TEP 5 - T^{RIFLUOROMETHYL} D^EPROTECTION [00484] Followed similar synthetic procedure as described in Step 3 en route to Example 67. Para Isomer: ¹H NMR (400 MHz, DMSO-d6) δ 6.66 (t, J = 9.0 Hz, 1H), 6.40 (dd, J = 8.7, 5.0 Hz, 1H), 4.54 (s, 2H), 3.54 (d, J = 1.1 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H), 2.53-2.51 (m, 2H), 2.39 (s, 1H). LRMS: (M+H)⁺ = 167.1 m/z. Yield: 96%. Ortho Isomer: ¹H NMR (400 MHz, DMSO-d₆) δ 6.55– 6.50 (m, 2H), 4.76 (s, 2H), 3.67 (s, 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.55-2.51 (m, 2H), 2.37 (s, 1H). LRMS: (M+H)⁺ = 167.1 m/z. Yield: 86%.

hh. SYNTHESIS OF TWO REGIOISOMERS: 5-FLUORO-1,2,3,4- T^{ETRAHYDROISOQUINOLIN}-8-^{AMINE AND} 5-^FLUORO-1,2,3,4- TETRAHYDROISOQUINOLIN-6-AMINE (SCHEME 2)

[00485] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 7.9, 1.2 Hz, 1H), 8.17– 8.12 (m, 1H), 7.99 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 7.88 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 6.82 (t, J = 9.0 Hz, 1H), 6.55 (dd, J = 8.7, 4.9 Hz, 1H), 4.82 (s, 2H), 4.32 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 3.05 (t, J = 5.8 Hz, 2H), 2.69 (s, 3H). HRMS: C19H17FN6; Calculated (M+H)⁺ = 349.15715 m/z, found (M+H)⁺ = 349.15817 m/z. Yield: 43%.

(ii) 5-^FLUORO-2-(3-^ISOPROPYL-[1,2,4]^TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-1,2,3,4-TETRAHYDROISOQUINOLIN-8- A^MINE (76)

[00486] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.47 (ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 8.16 (ddd, J = 8.2, 1.2, 0.6 Hz, 1H), 8.02– 7.95 (m, 1H), 7.88 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 6.81 (t, J = 9.0 Hz, 1H), 6.55 (dd, J = 8.7, 4.9 Hz, 1H), 4.78 (s, 2H), 4.33 (s, 2H), 3.64 (t, J = 5.8 Hz, 2H), 3.57 (h, J = 7.0 Hz, 1H), 3.02 (t, J = 5.7 Hz, 2H), 1.43 (d, J = 7.0 Hz, 6H). HRMS: C21H21FN6; Calculated (M+H)⁺ = 377.18845 m/z, found (M+H)⁺ = 377.18971 m/z. Yield: 52%.

(iii) 2-(3-^CYCLOPROPYL-[1,2,4]^TRIAZOLO[3,4-^A]^PHTHALAZIN-6- YL)-5-FLUORO-1,2,3,4-TETRAHYDROISOQUINOLIN-8-AMINE (77)

[00487] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J = 8.0, 1.2 Hz, 1H), 8.16– 8.12 (m, 1H), 7.98 (td, J = 7.7, 1.1 Hz, 1H), 7.87 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 6.82 (t, J = 9.0 Hz, 1H), 6.55 (dd, J = 8.7, 4.9 Hz, 1H), 4.81 (s, 2H), 4.33 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 3.05 (t, J = 5.7 Hz, 2H), 2.59 (tt, J = 8.4, 5.3 Hz, 1H), 1.25– 1.13 (m, 4H). HRMS: C21H19FN6; Calculated (M+H)⁺ = 375.17280 m/z, found (M+H)⁺ = 375.17382 m/z. Yield: 28%.

ii. SYNTHESIS OF TWO REGIOISOMERS: 5-FLUORO-1,2,3,4- TETRAHYDROISOQUINOLIN-8-AMINE AND 5-FLUORO-1,2,3,4- T^{ETRAHYDROISOQUINOLIN}-6-^AMINE (S^CHEME 3)

[00488] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J = 8.0, 1.2 Hz, 1H), 8.12 (dt, J = 8.2, 0.9 Hz, 1H), 7.96 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 7.86 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.65 (t, J = 8.6 Hz, 1H), 4.98 (s, 2H), 4.44 (s, 2H), 3.62 (t, J = 5.9 Hz, 2H), 3.07 (t, J = 6.0 Hz, 2H), 2.48– 2.40 (m, 1H), 1.26– 1.12 (m, 4H). HRMS:

C21H19FN6; Calculated (M+H)⁺ = 375.17280 m/z, found (M+H)⁺ = 375.17331 m/z. Yield: 47%.

jj. SYNTHESIS OF PHENYL SUBSTITUTED ANALOGS

(i) STEP 1 - DIHYROPHTHALAZINE SYNTHESIS [00489] A mixture of 4-methylphthalic anhydride (5.g, 30.84 mmol), hydrazine hydrate (1.6454 mL, 33.92 mmol) and Acetic acid (54.934 mL) was allowed to reflux under argon (118 °C) for 1 h. Evaporation off the solvents under reduced pressure provided the desired product as a yellow color solids in quantitative yields (6.65 g). Carried this through to the next step without purification. Heating started @ 1:45 PM on 9/14/18. ¹H NMR (400 MHz, DMSO-d₆) δ 11.46 (s, 2H), 7.96 (d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.69 (ddd, J = 8.1, 1.8, 0.7 Hz, 1H), 2.50 (S, 3H). LRMS: (M+H)⁺ = 177.0 m/z. Yield: 100%.

(ii) STEP 2 - DICHLOROPHTHALAZINE SYNTHESIS [00490] 6-methyl-2,3-dihydrophthalazine-1,4-dione (6.65 g, 37.75 mmol) dissolved in phosphorus oxychloride (52.9376 mL, 566.21 mmol) was allowed to stir under reflux temperature (106 °C) for 4 h. Afterwards the solvents were evaporated under reduced pressure to obtain a red color residue. This residue was re-dissolved in dichloromethane (50 mL) and stirred vigorously for 15 min. The solution was then neutralized by careful addition of solid and aq. NaHCO₃. When effervescence has ceased, the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 X 50 mL). The combined organic extracts were then dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain desired product as a yellow color solid in 75% yield (6.02 g). ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J = 8.4 Hz, 1H), 8.15 (dq, J = 1.7, 0.9 Hz, 1H), 8.10 (ddd, J = 8.4, 1.7, 0.5 Hz, 1H), 2.67 (s, 3H). LRMS: (M+2H)⁺ = 215.0 m/z. Yield: 75%.

(iii) STEP 3 - TRIAZOLOPHTHALAZINE SYNTHESIS [00491] 1,4-dichloro-6-methyl-phthalazine (500 mg, 2.35 mmol), cyclopropanecarboxylic acid hydrazide (469.9146 mg, 4.69 mmol) dissolved in 1-Butanol (7.8225 mL) heated to 118 °C for 1 h. After reaction completion solvents were evaporated off and the resulting crude was purified by column chromatography providing two region isomers which has disctinct Rf values on TLC. Isomer 1: ¹H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 8.1 Hz, 1H), 8.02 (s, 1H), 7.79 (dddd, J = 8.1, 2.2, 1.1, 0.5 Hz, 1H), 2.47 (ttd, J = 8.4, 5.0, 0.4 Hz, 1H), 1.41– 1.34 (m, 2H), 1.25– 1.17 (m, 2H). LRMS: (M+H)⁺ = 259.1 m/z. Yield: 21%. Isomer 2: ¹H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.64 (ddt, J = 8.3, 1.8, 0.6 Hz, 1H), 2.52– 2.44 (m, 1H), 1.41– 1.35 (m, 2H), 1.25– 1.18 (m, 2H). LRMS: (M+H)⁺ = 259.1 m/z. Yield: 24%.

kk. S^{YNTHESIS OF} C^OMPOUNDS 81-83

(i) STEP 1 - SYNTHESIS OF ETHYL 2-CYANO-2-(2-METHYL-4- N^ITROPHENYL)^ACETATE [00492] Combined reaction mixture of 1-fluoro-2-methyl-4-nitrobenzene (5 g, 32.23 mmol), K2CO3 (7.45 g, 53.5 mmol), KI (0.27 g, 1.611 mmol), and ethyl 2-cyanoacetate (4.56 mL, 42.87 mmol) in DMF (14.65 mL) was allowed to stir at 100 °C overnight. The reaction mixture was then diluted with water (200 mL) and cooled to 0 °C. To this HCl (12 N) was added dropwise with vigorous stirring until the reaction mixture turned acidic. The resulting solution was then extracted with ethyl acetate (2x150 mL). The combined organic layer was washed with H₂O, dried over anhydrous MgSO₄, filtered and concentrated under reduced pressure. The desired product was obtained as a red color gummy solid in 81% yield (6.5 g).The resulting crude was used as is in the next step without purification. ¹H NMR (400 MHz, chloroform-d) δ 8.15-8.09 (m, 2H), 7.70-7.65 (m, 1H), 4.96 (s, 1H), 4.29 (qd, J=7.1, 2.4 Hz, 2H), 2.52 (s, 3H), 1.31 (t, J=7.1 Hz, 3H). Yield: 81%. (ii) STEP 2 - SYNTHESIS OF 3-(2-METHYL-4- N^ITROPHENYL)^{PROPANENITRILE} [00493] Solution of ethyl 2-cyano-2-(2-methyl-4-nitrophenyl)acetate (6.5 g, 26.19 mmol) dissolved in H2O (31.6 mL) was added acetic acid (9.71 mL, 170.2 mmol) and 12 N HCl (4.4 mL, 52.4 mmol) at room temperature. The combined reaction mixture was allowed to reflux. After 2 days reaction was cooled and then poured onto 100 mL of H2O and allowed to stir for 15 minutes, then extracted with ethyl acetate (2x100 mL). The combined organic extracts were then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Final compound was obtained as a dark red color solid in quantitative yields (4.7 g). The crude was then used as is in the next step without purification. ¹H NMR (400 MHz, DMSO- d₆) δ 8.13-8.07(m, 2H), 7.62 (d, J=8.3 Hz, 1H), 4.16 (s, 2H), 2.39 (s, 3H). Yield: 100%.

(iii) S^TEP 3 - S^{YNTHESIS OF} 2-(2-^METHYL-4- NITROPHENYL)ETHAN-1-AMINE [00494] To the solution of 2-(2-methyl-4-nitrophenyl)acetonitrile (4.78 g, 27.13 mmol) in THF (55 mL) was added BH3THF (40 mL, 1.0 M in THF) slowly via additional funnel. After complete addition, the reaction was allowed to reflux at 70 °C for 4 h. The reaction was then diluted with 50 mL of MeOH and the solvents were evaporated off under reduced pressure. The resulting crude was diluted with 50 mL of 1 N HCl and stirred for 30 minutes at 50°C. The reaction was then cooled to RT, bacified via slow addition of aqueous NH4OH, and extracted with DCM (2x150 mL). The combined organic extracts were then dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The isolated crude was used as is in the next step without purification. Yield: 100%.

(iv) STEP 4 - TRIFLUOROACETYLATION OF AMINE [00495] Followed similar synthetic procedure as described in Step 1 en route to Example 61. ¹H NMR (400 MHz, chloroform-d) δ 8.09-8.05 (m, 1H), 8.01 (dd, J=8.4, 2.5 Hz, 1H), 7.29-7.26 (m, 1H), 6.41 (s, 1H), 3.66-3.58 (m, 2H), 3.04-2.98 (m, 2H), 2.46 (s, 3H). Yield: 48%.

(v) STEP 5 - MODIFIED BICHLER-NAPIERALSKI REACTION [00496] Followed similar synthetic procedure as described in Step 2 en route to Example 61. ¹H NMR (400 MHz, chloroform-d) δ 8.00-7.94 (m, 1H), 7.92-7.86 (m, 1H), 4.90-4.81 (m, 2H), 4.00-3.90 (m, 2H), 2.95-2.89 (m, 2H), 2.37 (d, J=2.6 Hz, 3H). Yield: 58%.

(vi) STEP 6 - NITRO REDUCTION [00497] Followed similar synthetic procedure described in Step 2 en route to Example 64. ¹H NMR (400 MHz, chloroform-d) δ 6.49-6.44 (m, 1H), 6.34-6.27 (m, 1H), 4.66 (d, J=25.6 Hz, 2H), 3.91-3.80 (m, 2H), 2.73 (q, J=6.0 Hz, 2H), 2.17 (d, J=2.4 Hz, 3H). LRMS:

(M+H)+ = 259.1 m/z. Yield: 80%.

(vii) S^TEP 7 - T^{RIFLUOROACETYL DEPROTECTION} [00498] Followed similar synthetic procedure described in Step 3 en route to Example 64. ¹H NMR (400 MHz, DMSO-d6) δ 6.28-6.22 (m, 1H), 6.06 (s, 1H), 4.67 (d, J=26.3 Hz, 2H), 3.76 (s, 1H), 3.43 (s, 1H), 3.09-2.97 (m, 2H), 2.70 (t, J=6.0 Hz, 1H), 2.43 (s, 1H), 2.01 (s, 3H). Yield: 72%.

(viii) STEP 8 - 5-METHYL-2-(3-METHYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-1,2,3,4-^{TETRAHYDROISOQUINOLIN}-7- AMINE (81)

[00499] Followed synthetic procedure described in“General Synthesis of Final

Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 8.0, 1.3 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.98 (ddd, J = 8.1, 7.4, 1.1 Hz, 1H), 7.87 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 6.24 (d, J = 2.2 Hz, 1H), 4.81 (s, 2H), 4.40 (s, 2H), 3.62 (t, J = 5.9 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.66 (s, 3H), 2.13 (s, 3H). HRMS: C20H20N6; Calculated (M+H)⁺ = 345.18222 m/z, found (M+H)⁺ = 345.18316 m/z. Yield: 27%.

(ix) STEP 8 - 2-(3-ISOPROPYL-[1,2,4]TRIAZOLO[3,4- A]PHTHALAZIN-6-YL)-5-METHYL-1,2,3,4- TETRAHYDROISOQUINOLIN-7-AMINE (82)

[00500] Followed synthetic procedure described in“General Synthesis of Final Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.48– 8.44 (m, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.98 (td, J = 7.7, 1.2 Hz, 1H), 7.90– 7.84 (m, 1H), 6.35 (d, J = 2.2 Hz, 1H), 6.24 (d, J = 2.2 Hz, 1H), 4.83– 4.77 (m, 2H), 4.40 (s, 2H), 3.63 (t, J = 5.8 Hz, 2H), 3.54– 3.50 (m, 1H), 2.88 (t, J = 5.9 Hz, 2H), 2.12 (s, 3H), 1.44 (dd, J = 7.0 Hz, 6H). HRMS: C22H24N6;

Calculated (M+H)⁺ = 373.21352 m/z, found (M+H)⁺ = 373.21435 m/z. Yield: 46%.

(x) STEP 8 - 2-(3-CYCLOPROPYL-[1,2,4]TRIAZOLO[3,4- A]^PHTHALAZIN-6-^YL)-5-^METHYL-1,2,3,4- TETRAHYDROISOQUINOLIN-7-AMINE (83)

[00501] Followed synthetic procedure described in“General Synthesis of Final Compounds.” ¹H NMR (400 MHz, DMSO-d6) δ 8.45– 8.41 (m, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.96 (td, J = 7.5, 1.2 Hz, 1H), 7.86 (ddd, J = 8.3, 7.3, 1.4 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 6.24 (d, J = 2.2 Hz, 1H), 4.81 (s, 2H), 4.40 (s, 2H), 3.62 (t, J = 6.0 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.48– 2.41 (m, 1H), 2.13 (s, 3H), 1.19 (ddtd, J = 15.9, 7.6, 5.1, 3.1 Hz, 4H). HRMS: C22H22N6; Calculated (M+H)⁺ = 371.19787 m/z, found (M+H)⁺ = 371.19846 m/z. Yield: 64%.

2. C^{HARACTERIZATION OF} A^NTI-HIV A^GENTS [00502] A list of compounds evaluated for anti-HIV activity is shown in Table 1 below. TABLE 1.

3. VIF-DEPENDENT APOBEC3G DEGRADATION (VIF-DEP A3G-DEG) ASSAY [00503] APOBEC3G-V5-mCherry was stably expressed from the pIRES-P vector in 293T cells under puromycin selection. Fifty ng of plasmid expressing Vif-HA (accession no. AB573087) was transfected into the cells in 384-well format with Turbofect or Genejuice transfection reagent on a liquid handling robot. Four hours after transfection the compounds were added to cells in a range from 0-15 μM. Twenty-four hours after compound addition mCherry fluorescence was read on a BioTek Synergy4 plate reader (ex = 587 nm, em = 610 nm). Relative fluorescence units (RFU) from compound treated wells were quantified using thresholds set by the–Vif (positive control) and +Vif (negative control).50% effective concentrations (EC₅₀) for the assay are listed in column 1 of Table 2.

4. PBMC ACUTE INFECTION [00504] PHA-stimulated cells from at least two normal donors were pooled (i.e. mixed together), diluted in fresh medium to a final concentration of 1 x 10⁶ cells/mL, and plated in the interior wells of a 96-well round bottom microplate at 50 μL/well (5 x 10⁴ cells/well). Pooling of mononuclear cells from more than one donor was used to minimize the variability observed between individual donors in quantitative and qualitative differences in HIV infection and overall response to the PHA and IL-2 of primary lymphocyte populations. Each plate contained virus control wells (cells plus virus) and experimental wells (drug plus cells plus virus) of either 00KE_KER2008 (Subtype A), IIIB (Subtype B), or 98US_MSC5016 (Subtype C). Test drug dilutions were prepared at a 2X concentration and 100 μL of each concentration was placed in appropriate wells. Fifty μL of a predetermined dilution of virus stock was placed in each test well (final MOI≅ 0.1). After this period, cell- free supernatant samples were collected for analysis of reverse transcriptase (RT) activity with an RT assay. Table 2 below shows the results of this Assay for the disclosed compounds. In the Table below the labels are for: 50% and 90% toxicity concentration (TC₅₀ and TC90); 50% and 90% inhibitory concentration (IC50 and IC90); Therapuetic Index 50% (TI₅₀=TC₅₀/IC₅₀) and 90% (TI₉₀=TC₉₀/IC₉₀).

5. E^{VALUATION OF} A^NTI-HIV A^GENTS [00505] Table 2 below summarizes various properties of exemplary compounds.

Attorney Docket No.19044.0407P1

_M 00KE_K 98US_M # 016 ER2008 IIIB IC90 SC 5016 µM) IC90 (µM) IC90 (µM) (µM) ¹ 0.91 0.31 -- ² 9 0.85 0.94 0.86 ³ 7 25.9 58.3 48.9 ⁴ 5 0.88 0.98 1.61 ⁵ 8 76.7 94.3 86.1 ⁶ 8 1.21 3.15 1.88 ⁷ 7 2.78 2.86 2.83 ⁸ 3 58.2 31 31.1 ⁹ 1 2.46 2.77 2.54 ¹⁰ 6 3.68 7.65 6.23

Attorney Docket No.19044.0407P1 _M 00KE_K 98US_M 016 ER2008 IIIB IC90 SC 5016 µM) IC₉₀ (µM) IC₉₀ (µM) (µM) 1 0.27 0.57 0.49 1 0.71 1.16 0.74 7 1.51 10.5 24.3 15 >100 >100 >100 A >100 >100 >100 4 20 65.1 24.1 2 5.64 2.68 4.04 1 2.54 2.58 2.75 5 -- -- -- 3 -- -- --

Attorney Docket No.19044.0407P1 S_M 00KE_K 98US_M 016 ER2008 IIIB IC90 SC 5016 (µM) IC₉₀ (µM) IC₉₀

(µM) (µM) 5 -- -- -- .5 -- -- -- 1.8 -- -- -- .6 8.5 12 19.4 .95 96.1 75.2 >100 17 57.4 68.5 70.3 .3 9.27 19.4 9.75 24 0.92 1.17 1.55 32 2.73 3.26 2.92 68 2.63 11.5 3.06 .9 8.36 8.03 1.17

Attorney Docket No.19044.0407P1 S_M 00KE_K 98US_M 5016 ER2008 IIIB IC90 SC 5016 (µM) IC₉₀ (µM) IC₉₀

(µM) (µM) 1 7.75 12.5 8.51 .24 29.6 >100 61.4 /A 98.6 >100 >100 .46 2.82 8.37 3.11 .40 1.28 1.77 2.08 .83 2.48 2.47 2.77 .44 2.99 3 3.55 .08 28.2 94.5 71.6 .45 0.3 0.3 0.41 .62 74.9 78.8 83.6 /A >100 >100 >100

Attorney Docket No.19044.0407P1 00KE_K 98US_M 6 ER2008 IIIB IC90 SC 5016 ) IC₉₀ (µM) IC₉₀ (µM) (µM) 0.96 0.95 1.15 14.5 15.4 20.3 46.5 36 58.5 >100 >100 >100 8.88 9.25 9.83 14.5 15.4 20.3 -- -- -- 3.19 3.83 3.28 -- -- -- 2.22 2.7 3.65 -- -- -- 51.3 85.2 57.8 -- -- --

Attorney Docket No.19044.0407P1 00KE_K 98US_M ER2008 IIIB IC90 SC 5016 ) IC₉₀ (µM) IC₉₀ (µM) (µM) -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 2.25 3.1 2.57 6.62 5.02 7.95 62.3 49.6 46.5 -- -- -- -- -- -- -- -- --

Attorney Docket No.19044.0407P1 00KE_K 98US_M # ER2008 IIIB IC90 SC 5016

IC₉₀ (µM) IC₉₀ (µM) (µM) 70 -- -- -- 71 -- -- -- 72 -- -- -- 73 -- -- -- 74 -- -- -- 75 -- -- -- 76 -- -- -- 77 -- -- -- 78 -- -- -- 79 -- -- -- 80 -- -- -- 81 -- -- -- 82 -- -- -- 83

6. EVALUATION OF ANTI-HIV AGENTS

[00506] Table 3 below summarizes additional properties of exemplary compounds.

TABLE 3.

[00507] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

What is claimed is: 1. A compound that inhibits HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV. 2. The compound of claim 1, wherein the compound has a structure represented by a formula:

, wherein each is an optional covalent bond; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is present and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from O, N, and S and substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,– NH₂,–CN,–NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,– NHC(O)(C1-C4 alkyl),–NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8- membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1,

2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; provided that when is absent and each of Z¹, Z², and Z³ is CR⁵, then each of R¹ and R² is selected from hydrogen and–NH2, and R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when either: (a) one or more of R¹ and R² is halogen,‒NO2, or C1-C4 alkoxy; (b) R⁵ is halogen; or (c) R⁴ is C1-C4 alkyl, C1-C4 haloalkyl, or aryl, then R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when R⁴ is methyl and Z³ is N, then either at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen or at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound has a structure represented by a formula:

.

4. The compound of claim 3, wherein n is 0.

5. The compound of claim 3, wherein n is 1.

6. The compound of claim 3, wherein each of Z¹ and Z² is CR⁵.

7. The compound of claim 6, wherein R⁵ is–NR^10aR^10b.

8. The compound of claim 7, wherein R^10a and R^10b, together with the intermediate atoms, comprise a morpholine ring.

9. The compound of claim 3, wherein Z² is N.

10. The compound of claim 3, wherein Z³ is N.

11. The compound of claim 3, wherein R¹ is selected from‒OH,‒NH2, and C1-C4 alkoxy.

12. The compound of claim 11, wherein R¹ is‒NH₂.

13. The compound of claim 3, wherein R² is selected from hydrogen,‒OH, and C1-C4 haloalkyl.

14. The compound of claim 3, wherein each of R^3a and R^3b is hydrogen.

15. The compound of claim 3, wherein R⁴ is selected from isopropyl, cyclopropyl, and ‒CH₂CF₃.

16. The compound of claim 3, wherein R^x and R^y, together with the intermediate atoms, comprise a structure represented by a formula:

, wherein each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

17. The compound of claim 3, wherein the compound has a structure represented by a formula:

18. The compound of claim 17, wherein the compound has a structure represented by a formula:

.

19. The compound of claim 17, wherein the compound has a structure represented by a formula:

.

20. The compound of claim 2, wherein each of Z¹ and Z² is CR⁵.

21. The compound of claim 2, wherein Z³ is N.

22. The compound of claim 2, wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,–NH2,–NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, provided that at least one of R¹ and R² is not hydrogen.

23. The compound of claim 2, wherein R¹ is–NH₂.

24. The compound of claim 2, wherein R² is selected from hydrogen,−OH, and C1-C4 haloalkyl.

25. The compound of claim 2, wherein R⁴ is selected from isopropyl, cyclopropyl, and– CH2CF3.

26. The compound of claim 2, wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

27. The compound of claim 2, wherein R^x and R^y, together with the intermediate atoms, comprise a structure represented by a formula:

28. The compound of claim 2, wherein the compound has a structure represented by a formula:

29. The compound of claim 2, wherein the compound has a structure represented by a formula:

wherein each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

30. The compound of claim 2, wherein the compound is:

.

31. The compound of claim 2, wherein the compound is selected from:

32. The compound of claim 2, wherein the compound is selected from:

33. The compound of claim 2, wherein the compound is selected from:

34. The compound of claim 2, wherein the compound is selected from:

35. A pharmaceutical composition comprising an effective amount of at least one compound that inhibits HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV. 36. The pharmaceutical composition of claim 35, wherein the compound has a structure represented by a formula:

, wherein is a solid bond or is absent; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,– NH2,–CN,–NO2,–CO2H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,– NHC(O)(C1-C4 alkyl),–NHSO2(C1-C4 alkyl), and–CO2(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8- membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; provided that when R⁴ is aryl, then R^x and R^y, together with the intermediate atoms, comprise a 6- to 8-membered cycloalkyl or a monocyclic aryl; and provided that when R⁴ is methyl and Z³ is N, then at least one of R¹, R², R^3a, R^3b, and R⁵ is not hydrogen, or that when R⁴ is methyl and Z³ is N, at least one of Z¹ and Z² is N, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 37. The pharmaceutical composition of claim 35, wherein the compound has a structure represented by a formula:

wherein each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 38. A method for the treatment of a viral infection in a subject having the viral infection, the method comprising the step of administering to the subject a therapeutically effective amount of at least one compound that inhibits HIV infection by inhibiting Vif and thereby enabling APOBEC3 innate immunity against HIV. 39. The method of claim 38, wherein the compound has a structure represented by a formula:

, wherein is a solid bond or is absent; wherein n is 0 or 1; wherein each of Z¹, Z², and Z³ is independently selected from N and CR⁵ when is a solid bond and wherein each of Z¹, Z², and Z³ is independently selected from NH and CHR⁵ when is absent; wherein each occurrence of R⁵, when present, is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and–NR^10aR^10b; wherein each of R^10a and R^10b, when present, is independently selected from hydrogen and C1-C4 alkyl; or wherein R^10a and R^10b, together with the intermediate atoms, comprise a 5- or 6-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R¹ and R² is independently selected from hydrogen, halogen,–OH,– NH₂,–CN,–NO₂,–CO₂H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,– NHC(O)(C1-C4 alkyl),–NHSO₂(C1-C4 alkyl), and–CO₂(C1-C4 alkyl); wherein each of R^3a and R^3b is independently selected from hydrogen, halogen, and C1-C4 alkyl; wherein R⁴ is selected from C1-C8 alkyl, C1-C8 haloalkyl, and Cy¹; wherein Cy¹, when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R^x and R^y is independently selected from hydrogen and C1-C4 alkyl; or wherein R^x and R^y, together with the intermediate atoms, comprise a 6- to 8- membered cycloalkyl or a monocyclic aryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen,–CN,–NH₂,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof. 40. The method of claim 38, wherein the compound has a structure represented by a formula:

,

wherein each of R^20a, R^20b, R^20c, and R^20d is independently selected from hydrogen, halogen,–CN,–NH2,–OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 41. The method of claim 38, wherein the viral infection is due to the human immunodeficiency virus (HIV). 42. The method of claim 38, wherein the subject is a mammal. 43. The method of claim 42, wherein the mammal is a human.