HK1173994A

HK1173994A - Novel antiviral compounds

Info

Publication number: HK1173994A
Application number: HK13101024.3A
Authority: HK
Inventors: Gunter Carlens; Patrick Chaltin; Frauke Christ; Zeger Debyser; Arnaud Marchand; Damien Marchand; Arnout Voet; Marc De Maeyer
Original assignee: 勒芬天主教大学
Priority date: 2009-12-23
Filing date: 2010-12-20
Publication date: 2013-05-31

Description

Novel antiviral compounds

Technical Field

The present invention relates to a series of novel compounds having antiviral activity, more specifically HIV (human immunodeficiency virus) replication inhibiting activity. The invention also relates to methods of making such compounds and to novel intermediates useful in one or more steps of such syntheses. The invention also relates to pharmaceutical compositions comprising an effective amount of such compounds as active ingredients. The invention also relates to compounds for use as medicaments and to the use of such compounds for the preparation of a medicament, in particular for the prophylaxis or treatment of a subject suffering from a viral infection, in particular an HIV infection. The invention also relates to methods of preventing or treating viral infections in animals by administering therapeutically effective amounts of such compounds, optionally in combination with one or more agents having antiviral activity.

Background

Retroviruses, known as Human Immunodeficiency Virus (HIV), are the etiological agents of complex diseases including progressive destruction of the immune system (acquired immunodeficiency syndrome, hereinafter AIDS) and degeneration of the central and peripheral nervous systems. There are two types of HIV, HIV-1 and HIV-2, the latter producing less severe disease than the former. As a retrovirus, its genetic material is in the form of RNA (ribonucleic acid) consisting of two single RNA strands. Coexisting with RNA are reverse transcriptase (having polymerase and ribonuclease activities), integrase, protease, and other proteins.

Some antiviral compounds that are inhibitors of HIV replication are known in the art as effective agents for the treatment of AIDS and similar diseases. Pharmaceutical terms known and approved for the treatment of HIV infected patients are one of the following categories:

nucleoside Reverse Transcriptase (RT) inhibitors such as but not limited to Azidothymidine (AZT) and lamivudine (3TC),

nucleotide reverse transcriptase inhibitors, such as but not limited to tenofovir (R-PMPA),

non-nucleotide reverse transcriptase inhibitors such as but not limited to nevirapine, efavirenz, etravirine and lavivirin,

-protease inhibitors such as, but not limited to, nelfinavir, saquinavir, ritonavir, atazanavir, darunavir and amprenavir,

fusion inhibitors, such as enfuvirdine,

-CCR5 antagonists such as maraviroc, and

integrase inhibitors such as raltegravir or eltamivir.

Replication of human immunodeficiency virus type 1 (hereinafter HIV-1) can be significantly reduced by combining potent antiviral drugs that target multiple viral targets, as described by Vandamme et al in antiviral Chem. Chemother (1998)9: 187-.

The multi-drug combination regimen can reduce viral load below the detection limit of the most sensitive assay. However, according to Perelson et al, Nature (1997)387:123-124, it has been shown that low levels of ongoing replication may occur at cryptic sites (sanctuary sites), leading to the emergence of resistant strains. In addition, many antiviral agents are relatively low selective, which may cause side effects and toxicity. Furthermore, according to Schmit et al, J.Infect.Dis. (1996)174: 962-. The ability of HIV to rapidly develop resistance and toxicity problems caused by known drugs has been well documented requiring the development of other classes of antiviral drugs.

Thus, there remains an urgent need in the art for effective HIV inhibitors. It is therefore an object of the present invention to meet this urgent need by identifying effective pharmaceutical active ingredients which are active against HIV, less toxic, more stable (i.e. chemically stable, metabolically stable), effective against viruses resistant to currently available drugs, and/or which are more resistant to viral mutations than existing antiviral drugs, and which can be used, alone or in combination with other active ingredients, for the treatment of retroviral infections, in particular lentiviral infections, more particularly HIV infections, in mammals and more particularly in humans. It is known to the person skilled in the art that the physicochemical properties of the known drugs and their ADME-Tox (administration, distribution, metabolism, excretion and toxicology) properties may limit or prevent their use in the treatment of diseases. Thus, problems with existing drugs that can be overcome with the compounds of the invention can be selected from poor or inappropriate physicochemical or ADME-Tox properties such as solubility, LogP, CYP inhibition, hepatic stability, plasma stability, and other properties that have been considered in the synthesis and design of the compounds of the invention. Furthermore, it is another object of the present invention to supplement existing antiviral drugs in such a way that the resulting drug combination has an improved activity or an improved resistance against viral mutations compared to each individual compound.

Disclosure of Invention

The present invention is based on the unexpected discovery that at least one of the above problems can be solved by a novel class of compounds.

The present invention provides novel antiviral agents, particularly antiretroviral agents, and more particularly anti-HIV compounds. These are of the structure as further described herein, and we show that they have antiviral activity, more specifically anti-HIV activity. The present invention demonstrates that these compounds are effective in inhibiting HIV replication. Thus, these compounds constitute a new class of potent antiviral compounds useful for the treatment and/or prevention of viral infections in animals, mammals and humans, more particularly for the treatment and/or prevention of HIV in humans.

The invention also relates to the use of such compounds as a pharmaceutical, more particularly as an antiviral agent, and to their use in the manufacture of a medicament for the treatment and/or prophylaxis of viral infections, in particular retroviral infections (such as but not limited to HIV) in a subject such as a human. The invention also relates to a process for the preparation of all such compounds and to pharmaceutical compositions comprising an antiviral effective amount of such compounds.

The invention also relates to methods of treating or preventing viral infections, particularly retroviral infections such as but not limited to HIV, in a human or animal comprising administering to a patient in need thereof one or more such compounds optionally in combination with one or more other antiviral agents.

One aspect of the present invention is to provide novel compounds, and pharmaceutically acceptable salts thereof, having a structure according to formula (a):

wherein the content of the first and second substances,

-each dotted line represents an optional double bond, whereby two dotted lines of the 5 dotted lines each constitute a double bond and 2 double bonds are non-adjacent;

-each of X and Y is independently selected from C or N, whereby at least one of X and Y is N;

-R¹independently selected from cycloalkyl; a cycloalkenyl group; a cycloalkynyl group; an aryl group; a heterocycle; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl or heterocycle-heteroalkynyl;

and wherein said cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heteroaryl is provided,The heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl is unsubstituted or substituted with one or more R¹⁰Substitution;

-R^2aand R^2bEach of which is independently selected from hydrogen; a cyano group; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; a heterocycle; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl; or R ^2aAnd R^2bCan together form a vinyl or a vinyl alkyl;

and wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl is unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

-R³independently selected from hydrogen; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; a heterocycle; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl;

wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl The radicals being unsubstituted or substituted by one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

-R⁴independently selected from hydrogen; an alkyl group; alkenyl or alkynyl;

wherein the alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

-R⁵is absent; or is selected from hydrogen; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; and heteroalkynyl;

wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl; unsubstituted or substituted by one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

-R⁶selected from hydrogen; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; a heterocycle; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl;

Wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl is unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynylAlkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

-R⁷is absent; or is selected from hydrogen; halogen; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; a heterocycle; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl;

wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl is unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF ₃Cyano, nitro, -C (O) OH or NH₂Substitution;

each R¹⁰Independently selected from halogen; -OR¹¹；=O；-SR¹¹；=S；-S(O)R¹²；-S(O)₂R¹²；-S(O)₂NR¹³R¹⁴(ii) a A trifluoromethyl group; a nitro group; -NR¹³R¹⁴；-NR¹¹S(O)₂R¹²(ii) a A cyano group; -C (O) OR¹¹；-C(O)NR¹³R¹⁴；-C(O)R¹²(ii) a An alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; a heterocycle; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl;

and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylateThe alkyl, alkenyl, alkynyl, heteroaryl, or heteroaryl group is unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroaryl, or heteroaryl groups₃Cyano, nitro, -C (O) OH or NH₂Substitution;

each R¹¹Independently selected from hydrogen; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; a heterocycle; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; and heterocycle-heteroalkynyl;

Wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl and heterocycle-heteroalkynyl are unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

each R¹²Independently selected from hydrogen; a hydroxyl group; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; a heterocycle; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; and heterocycle-heteroalkynyl;

wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle -alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl and heterocycle-heteroalkynyl unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

-R¹³and R¹⁴Each of which is independently selected from hydrogen; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; a heterocycle; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; and heterocycle-heteroalkynyl;

and wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl and heterocycle-heteroalkynyl are unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF ₃Cyano, nitro, -C (O) OH or NH₂Substitution;

and wherein R¹³And R¹⁴Taken together with N to form a 5-, 6-or 7-membered heterocyclic ring which is unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂And (4) substitution.

In a particular embodiment, R¹Is selected from aryl or heterocycle, and in yet a more particular embodiment is selected from phenyl or heteroaryl, wherein said aryl, heterocycle, heteroaryl or phenyl is unsubstituted or substituted, and in a particular embodiment is substituted with one or more R¹⁰And (4) substitution.

In yet another embodiment, R^2aAnd R^2bOne of which is not hydrogen. In another embodiment, R^2aAnd R^2bOne is hydrogen and R is^2aAnd R^2bIs selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl. In still more particular embodiments, R^2aAnd R^2bOne is hydrogen and R is^2aAnd R^2bThe other of which is selected from alkyl and heteroalkyl.

In yet another embodiment, R³Is H.

In yet another embodiment, R⁴Selected from hydrogen and alkyl, more particularly, it is methyl.

In yet another embodiment, R⁵Absent, or selected from hydrogen and methyl.

In yet another embodiment, R⁶Selected from the group consisting of hydrogen, alkyl, aryl, and heterocycle, wherein the alkyl, aryl, and heterocycle are unsubstituted or substituted.

In yet another embodiment, R⁷Absent, or selected from hydrogen, halogen, alkyl, aryl and heterocycle, wherein said alkyl, aryl and heterocycle are unsubstituted or substituted.

In another embodiment, the compounds of the invention have a structure according to formula (B),

wherein X, Y, dotted line, R¹、R^2a、R^2b、R⁴、R⁵、R⁶And R⁷Each as in formula (a) and the embodiments described herein.

In another embodiment, the compounds of the invention have a structure according to formula (C-I) or (C-II),

wherein X, Y, dotted line, R¹、R^2a、R^2b、R³、R⁵、R⁶And R⁷Each as in formula (a) and the embodiments described herein.

In another embodiment, the compounds of the invention have a structure according to formula (D),

wherein X, Y, dotted line, R¹、R^2b、R⁵、R⁶And R⁷Each as in formula (a) and the embodiments described herein.

In another embodiment, the compounds of the invention have a structure according to formula (E), consisting of formula (E-I), (E-II), (E-III) or (E-IV),

Wherein R is¹、R^2a、R^2b、R³、R⁴、R⁵、R⁶And R⁷Each as in formula (a) and the embodiments described herein.

Specific embodiments of this aspect are described in the claims and relate to subclasses of compounds of the invention (subtypes). In particular embodiments, the term alkyl, alkenyl or alkynyl may be limited to refer to cyclic or acyclic subgroups thereof (such as, for alkyl, may refer to acyclic alkyl or cycloalkyl).

In a specific embodiment, the compounds of the invention are selected from the following list:

ethyl 2- (7- ((R) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

ethyl 2- (7- ((S) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

ethyl 2- (7- ((R) -3- (4-chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

ethyl 2- (7- ((S) -3- (4-chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

2- (5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

methyl 2- (5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

2- (2-tert-butyl-5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

Methyl 2- (2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

methyl 2- (5-methyl-2-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

2- (2-tert-butyl-7- (3-hydroxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (2-naphthyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (1H-indol-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (1H-indol-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (1-benzofuran-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (1-benzothien-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (2, 3-dihydrobenzofuran-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (4-chlorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (3, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (4-ethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (3, 4-dihydro-2H-benzo [ b ] [1,4] dioxacyclohepta-7-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (2- (7- (4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

ethyl 2- (3-bromo-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

ethyl 2- (5-methyl-3-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

ethyl 2- (5-methyl-3, 7-di-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

methyl 2- (3-bromo-2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

methyl 2- (2-tert-butyl-5-methyl-3, 7-di-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

methyl 2- (5-methyl-2-propyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

methyl 2- (2- (furan-2-yl) -5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

methyl 2- (2-tert-butyl-7- (4-chloro-2-fluorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

2- (2-tert-butyl-7- (2-fluoro-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -6,6, 6-trifluorohexanoic acid methyl ester;

2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionic acid methyl ester;

2- (2-tert-butyl-7- (1-methylindol-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionic acid methyl ester;

2- (2-tert-butyl-5-methyl-7- (1-methyldihydroindol-5-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-5-methyl-7- (1-methyl-1H-indol-6-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (chroman-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-methylpentanoic acid methyl ester;

methyl 2- (2-tert-butyl-3-chloro-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -4-methoxybutanoic acid methyl ester;

methyl 2- (2-tert-butyl-5-methyl-7- (4-isopropylphenyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

2- (2-tert-butyl-5-methyl-7- (4-trifluoromethylphenyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

methyl 2- (2-tert-butyl-7- (2, 4-difluorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

2- (2-tert-butyl-7- (2-chloro-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (7- (2-amino-4-methylphenyl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (2-methoxy-4-chlorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-7- (2-fluoro-4-methoxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-5-methyl-7- (5-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

2- (2-tert-butyl-5-methyl-7- (8-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid methyl ester;

methyl 2- (2-tert-butyl-7- (2, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

methyl 2- (2-tert-butyl-3, 5-dimethyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

methyl 2- (2-tert-butyl-5-methyl-3-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

methyl 2- (2,3, 5-trimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) acetate;

methyl 2- (2,3, 5-trimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate;

ethyl 2- (1,2, 5-trimethyl-7-p-tolyl-1H-imidazo [4,5-b ] pyridin-6-yl) pentanoate;

ethyl 2- (3, 5-dimethyl-2-propyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate;

Ethyl 2- (3, 5-dimethyl-2-isopropyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate;

2- (7- ((R) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (7- ((S) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (7- ((R) -3- (4-chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (7- ((S) -3- (4-chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (3-bromo-2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (5-methyl-2-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (3-hydroxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-5-methyl-7- (2-naphthyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (1H-indol-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (1H-indol-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (7- (benzofuran-5-yl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (7- (benzo [ b ] thiophen-5-yl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (2, 3-dihydrobenzofuran-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (4-chlorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (3, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (4-ethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (3, 4-dihydro-2H-benzo [ b ] [1,4] dioxacyclohepta-7-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (5-methyl-3-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (3, 7-di-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-3, 7-di-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (5-methyl-2-propyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2- (furan-2-yl) -5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (4-chloro-2-fluorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (2-fluoro-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -6,6, 6-trifluorohexanoic acid;

2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionic acid;

2- (2-tert-butyl-5-methyl-7- (1-methylindolin-5-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-5-methyl-7- (1-methyl-1H-indol-6-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (chroman-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-methylpentanoic acid;

2- (2-tert-butyl-3-chloro-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -4-methoxybutanoic acid;

2- (2-tert-butyl-5-methyl-7- (4-isopropylphenyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-5-methyl-7- (4-trifluoromethylphenyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (2, 4-difluorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (2-chloro-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (7- (2-amino-4-methylphenyl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (2-methoxy-4-chlorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (2-fluoro-4-methoxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-5-methyl-7- (5-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-5-methyl-7- (8-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-7- (2, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-3, 5-dimethyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2-tert-butyl-5-methyl-3-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

2- (2,3, 5-trimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoic acid;

2- (1,2, 5-trimethyl-7-p-tolyl-1H-imidazo [4,5-b ] pyridin-6-yl) pentanoic acid;

2- (2-propyl-3, 5-dimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoic acid;

2- (2-isopropyl-3, 5-dimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate;

methyl 2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) acetate;

2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) acetic acid;

methyl 2- [ 2-tert-butyl-7- (1, 2-dihydroacenaphthen-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetate;

2- [ 2-tert-butyl-7- (1, 2-dihydroacenaphthen-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetic acid;

2- [ 2-tert-butyl-7- (2-methoxy-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetic acid methyl ester;

2- [ 2-tert-butyl-7- (2-methoxy-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetic acid;

2- [ 2-tert-butyl-7- (2-hydroxy-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetic acid;

methyl 2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid;

ethyl 2- (2-benzyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate; and

ethyl 2- (2-benzyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate;

and pharmaceutically acceptable salts thereof.

According to a second aspect, the present invention relates to the use of a compound as described herein (more particularly, formulae (a), (B), (C), (D) and (E), embodiments thereof and claims herein) as a medicament or pharmaceutical product, more particularly as an antiviral medicament, and for the prevention or treatment of a viral infection in a subject (animal, mammal or human).

The invention also relates to the use of compounds of formulae (a), (B), (C), (D) and (E), embodiments thereof and claims as antiviral compounds, more particularly as compounds active against retroviruses, still more particularly as compounds active against HIV. The invention also relates to the use of the compounds of the invention for the preparation of medicaments or as pharmaceutically active ingredients, in particular as inhibitors of viral replication, for example for the preparation of medicaments or pharmaceutical compositions having antiviral activity, which are customarily used for the prophylaxis and/or treatment of viral infections in humans, mammals and animals. The present invention also relates to a method for the prophylaxis or treatment of viral infections, preferably retroviral infections, in animals, including mammals, including humans, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention as an active ingredient, preferably in admixture with at least one pharmaceutically acceptable carrier.

In another aspect, the invention relates to a process for preparing the compounds of the general formula and claims herein. In addition, intermediates used in the preparation methods described herein are also aspects of the invention.

One embodiment relates to a process for the preparation of a compound according to the invention, comprising the steps of:

-preparing a substituted or unsubstituted alkyl 2- (7-hydroxypyrazolo [1,5-a ] pyrimidin-6-yl) acetate derivative or a substituted or unsubstituted alkyl 2- (7-hydroxy [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) acetate derivative from a substituted or unsubstituted 3-aminopyrazole or 3-amino 1,2, 4-triazole and a 2-substituted succinate derivative;

-conversion of the 7-hydroxy group from the previous intermediate with a halogen such as chlorine, bromine or iodine;

-optionally reacting the compound obtained in the previous step with a compound having the structure of formula R2 a-and/or R2 b-leaving group via nucleophilic substitution;

-substitution of the 7-halogen atom from the previously obtained compound with a suitable chemical reagent in a specific manner (amination, alkylation, arylation) to obtain the desired compound;

-hydrolyzing the ester compound obtained in the previous step to obtain the desired free carboxylic acid derivative.

Alternatively, the method of preparing the compound comprises the steps of:

-converting a substituted or unsubstituted 5-amino-1H-imidazole-4-carbonitrile or 4-amino-1H-imidazole-5-carbonitrile derivative into a substituted or unsubstituted 1- (5-amino-1H-imidazol-4-yl) ketone or 1- (4-amino-1H-imidazol-5-yl) ketone;

-reacting the previously obtained intermediate with formula R⁴C(O)CH₂CH₂COOR³Or R⁴C(O)CH₂CR^2aR^2bCOOR³In the presence of trimethylsilyl chloride in a polar aprotic solvent at a temperature between 50 ℃ and 200 ℃;

-optionally, reacting the compound obtained in the preceding step with a compound having formula R^2a-a leaving group and/or R^2b-reacting a compound of leaving group structure by nucleophilic substitution;

A further aspect of the present invention relates to pharmaceutical compositions comprising the compounds of the invention described herein, embodiments thereof and claims, the active ingredient preferably being in the concentration range of about 0.1 to 100% by weight, in admixture with at least a pharmaceutically acceptable carrier, and to the use of these derivatives, i.e. as medicaments for the treatment of subjects suffering from viral infections, in particular retroviral infections.

The invention also relates to the use of a composition comprising as biologically active agents (a) one or more compounds of the invention (compounds of the formulae and claims herein), and (b) one or more viral inhibitors, in respective proportions, for example to provide a synergistic effect against a viral infection in a subject, e.g. in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of a viral infection. Within the framework of this embodiment of the invention, the viral enzyme inhibitors used as therapeutically active ingredient (b) may belong to the class known in the art. In particular embodiments, the compounds of the present invention may be combined with:

fusion inhibitors, such as enfuvirdine,

-CCR5 antagonists such as maraviroc, and

integrase inhibitors such as raltegravir or eltamivir.

More generally, the present invention relates to the use of compounds of general formula (la), embodiments herein and claims as agents with biological activity or as diagnostic agents. Any of the applications described in relation to the present invention may be limited to non-medical applications, non-therapeutic applications, non-diagnostic applications or simply in vitro applications, or applications related to cells detached from an animal.

Detailed Description

The present invention is described with respect to specific embodiments, but the present invention is not limited thereto.

It is to be noticed that the term 'comprising', used in the claims, should not be interpreted as being restricted to the meanings listed thereafter; it does not exclude other elements or steps.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments as would be apparent to one of ordinary skill in the art upon reading this disclosure. Where an indefinite or definite article is used, when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated.

Similarly, it should be appreciated that in describing exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, feature, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects.

In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms most suitably present in a substituent or linker in general; it is to be understood that, unless otherwise specified herein, the number of carbon atoms represents the most suitable maximum number of carbon atoms for that particular substituent or linker.

As used herein, the term "leaving group" or "LG" refers to a chemical group that is readily displaced by a nucleophile or removed or hydrolyzed under basic or acidic conditions. In particular embodiments, the leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate).

The term "protecting group" refers to a moiety of a compound that masks or alters the nature of a functional group or the nature of the compound as a whole. The chemical structure of the protecting group varies widely. One function of the protecting group is to act as an intermediate in the synthesis of the parent drug. Chemical protecting groups and protecting/deprotecting strategies are well known in the art. See: "Protective Groups in organic chemistry", Theodora W.Greene (John Wiley & Sons, Inc., New York, 1991. protecting Groups are often used to mask the reactivity of certain functional Groups to aid in the efficiency of the desired chemical reaction, e.g., to form and open chemical bonds in an orderly and planned manner. Thereby releasing the parent drug in vivo after prodrug conversion. Because an active prodrug may be more efficiently absorbed than the parent drug, the prodrug may have greater efficacy in vivo than the parent drug. In the case of chemical intermediates, the protecting group is removed in vitro, or in the case of prodrugs, the protecting group is removed in vivo. In the case of chemical intermediates, it is not particularly important whether the resulting product after deprotection, e.g. an alcohol, is physiologically acceptable, although in general it is more desirable that the product is pharmacologically non-toxic.

As used herein, the terms "hydrocarbyl", "C", and "C" are used interchangeably_1-18Hydrocarbyl "," hydrocarbyl group "or" C_1-18The "hydrocarbyl radical" means C₁-C₁₈Normal, secondary, tertiary, unsaturated or saturated, non-aromatic, acyclic or cyclic hydrocarbons and combinations thereof. The term thus includes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl.

As used herein, the terms "heterohydrocarbyl", "heteroC", and "heterohydrocarbyl", optionally including one or more heteroatoms (said heteroatoms being selected from O, S and N)_1-18Alkyl group, heteroalkyl group and heteroC_1-18Hydrocarbyl group "or" hydrocarbyl group "refers to a group in which one or more carbon atoms are replaced by oxygenHydrocarbyl substituted with an atom, nitrogen atom or sulfur atom and thus includes heteroalkyl, heteroalkenyl, heteroalkynyl and non-aromatic heterocycles. The term thus includes alkoxy, alkenyloxy, C as examples_walkyl-O-C_18-wAlkyl radical, C_walkenyl-O-alkyl, C_walkyl-NH-C_18-wAlkenyl, and others, wherein w is selected from any number between 1 and 18.

As used herein, the term "alkyl" or "C_1-18Alkyl "means C containing no unsaturation₁-C₁₈Normal, secondary or tertiary, straight or branched chain hydrocarbons. Examples are methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl (i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, cyclopropylethylene, methylcyclopropylidene, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a particular embodiment, the term alkyl refers to C _1-12Hydrocarbon, however more specifically C as further defined herein above_1-6A hydrocarbon.

As used herein, the term "acyclic alkyl" refers to a C that does not contain a site of unsaturation₁-C₁₈Normal, secondary or tertiary, linear, branched or straight chain hydrocarbons. Examples are methyl, ethyl, 1-propyl, 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl (i-Bu), 2-butyl (s-Bu), 2-methyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-Pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl and n-eicosyl.

As used herein and unless otherwise specified, the term "cycloalkyl" or "C_3-18Cycloalkyl "refers to a saturated hydrocarbon monovalent radical having 3 to 18 carbon atoms, consisting of C_3-10Monocyclic ring or C_7-18Polycyclic saturated hydrocarbons consist of or include, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene (cyclopropropylene), methylcyclopropylidene (methylcyclopropylene), cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene (cyclooctylmethylene), norbornyl, fenchyl, trimethyltricycloheptyl, decahydronaphthyl, adamantyl, and the like.

As used herein, the term "alkenyl" or "C_2-18Alkenyl "means a C having at least one (typically 1-3, preferably 1) site of unsaturation (i.e., a carbon-carbon sp2 double bond)₂-C₁₈Normal, secondary or tertiary, linear or cyclic, branched or straight chain hydrocarbons. Examples include, but are not limited to: ethylene or vinyl (-CH = CH)₂) Allyl (-CH)₂CH=CH₂) Cyclopentenyl (-C)₅H₇) Cyclohexenyl (-C)₆H₉) Cyclopentenylpropylene (cyclopropenylpropylene), methylcyclohexylene (methylcyclohexylene), and 5-hexenyl (-CH)₂CH₂CH₂CH₂CH=CH₂). The double bond may be in the cis or trans configuration. In a particular embodiment, the term alkenyl refers to C_1-12A hydrocarbon, yet more specifically C as further defined herein above_1-6A hydrocarbon.

As used herein, the term "cycloalkenyl-free" refers to a C having at least one (typically 1-3, preferably 1) unsaturated position (i.e., a carbon-carbon sp2 double bond)₂-C₁₈Normal, secondary or tertiary, linear, branched or straight chainA hydrocarbon. Examples include, but are not limited to: ethylene or vinyl (-CH = CH)₂) Allyl (-CH)₂CH=CH₂) And 5-hexenyl (-CH)₂CH₂CH₂CH₂CH=CH₂). The double bond may be in the cis or trans configuration.

As used herein, the term "cycloalkenyl" refers to a non-aromatic hydrocarbon having from 4 to 18 carbon atoms and containing at least one (typically 1 to 3, preferably 1) site of unsaturation (i.e., a carbon-carbon sp2 double bond), consisting of C _4-10Monocyclic hydrocarbon or C_7-18Polycyclic hydrocarbons make up or include them. Examples include, but are not limited to: cyclopentenyl (-C)₅H₇) Cyclopentenylpropylene, methylcyclohexenyl and cyclohexenyl (-C)₆H₉). The double bond may be in the cis or trans configuration.

As used herein, the term "alkynyl" or "C_2-18Alkynyl "means a C having at least one (usually 1-3, preferably 1) site of unsaturation (i.e., a carbon-carbon sp triple bond)₂-C₁₈Normal, secondary, tertiary, linear or cyclic, branched or straight chain hydrocarbons. Examples include, but are not limited to: ethynyl (-C.ident.CH), 3-ethyl-cyclohepten-1-ynyl, 4-cyclohepten-1-ynyl-methylene and 1-propynyl (propargyl, -CH₂C ≡ CH). In a specific embodiment, the term alkynyl refers to C_1-12A hydrocarbon, yet more specifically C as further defined herein above_1-6A hydrocarbon.

As used herein, the term "acyclic alkynyl" refers to a C having at least one (typically 1-3, preferably 1) site of unsaturation (i.e., a carbon-carbon sp triple bond)₂-C₁₈Normal, secondary, tertiary, linear, branched or straight chain hydrocarbons. Examples include, but are not limited to: ethynyl (-C ≡ CH) and 1-propynyl (propargyl, -CH)₂C≡CH)。

As used herein, the term "cycloalkynyl" refers to a non-aromatic hydrocarbon having 5 to 18 carbon atoms and containing at least one (typically 1 to 3, preferably 1) site of unsaturation (i.e., a carbon-carbon sp triple bond) formed from C _5-10Monocyclic hydrocarbon or C_7-18Polycyclic hydrocarbons make up or include them. Examples of the inventionIncluding but not limited to: cyclohept-1-ynyl, 3-ethyl-cyclohepten-1-ynyl, 4-cyclohepten-1-ynyl-methylene, and ethylene-cyclohepten-1-ynyl.

As used herein, the term "alkylene" refers to a group having 1 to 18 carbon atoms (more specifically C)_1-12Or C_1-6Carbon atoms) and has two monovalent radical centers derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane. Typical alkylene groups include, but are not limited to: methylene (-CH)₂-), 1, 2-Ethyl (-CH)₂CH₂-), 1, 3-propyl (-CH)₂CH₂CH₂-), 1, 4-butyl (-CH)₂CH₂CH₂CH₂-) and the like.

As used herein, the term "alkenylene" refers to a compound having 2-18 carbon atoms (more specifically C)_2-12Or C_2-6Carbon atoms) and having at least one site of unsaturation (typically 1 to 3, preferably 1) (i.e., a carbon-carbon sp2 double bond), which has two monovalent radical centers resulting from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent olefin.

As used herein, the term "alkynylene" each refers to a compound having 2-18 carbon atoms (more specifically C)_2-12Or C_2-6Carbon atoms) and having at least one site of unsaturation (typically 1 to 3, preferably 1) (i.e., a carbon-carbon sp triple bond), which has two monovalent radical centers resulting from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkyne.

As used herein, the term "heteroalkyl" refers to an acyclic alkyl group in which one or more carbon atoms are replaced with an oxygen, nitrogen, or sulfur atom.

As used herein, the term "heteroalkenyl" refers to an acyclic alkenyl group in which one or more carbon atoms are replaced with an oxygen, nitrogen, or sulfur atom.

As used herein, the term "heteroalkynyl" refers to an acyclic alkynyl group in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom.

As used herein, the term "heteroalkylene" refers to an alkylene group in which one or more carbon atoms are replaced with an oxygen, nitrogen, or sulfur atom.

As used herein, the term "heteroalkenylene" refers to an alkenylene group in which one or more carbon atoms are replaced with an oxygen, nitrogen or sulfur atom.

As used herein, the term "heteroalkynylene" refers to an alkynylene group in which one or more carbon atoms are replaced with an oxygen, nitrogen, or sulfur atom.

As used herein, the term "aryl" refers to an aromatic hydrocarbon group of 6 to 20 carbon atoms obtained by the removal of carbon atoms from a parent aromatic ring system. "parent aromatic ring system" refers to a monocyclic aromatic ring system or a bicyclic or tricyclic ring system in which at least one ring is aromatic. Typical aryl groups include, but are not limited to, 1 ring or 2 or 3 rings fused together and include groups derived from benzene, naphthalene, anthracene, biphenyl, 2, 3-dihydro-1H-indene, and the like. Phenyl is a specific example of aryl.

As used herein, the term "arylalkyl" or "arylalkyl-" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenethyl-1-yl, 2-styryl-1-yl, naphthylmethyl, 2-naphthylethyl, and the like. Arylalkyl groups contain from 6 to 20 carbon atoms, e.g., the alkyl portion of an arylalkyl group is from 1 to 6 carbon atoms and the aryl portion is from 6 to 14 carbon atoms.

As used herein, the term "arylalkenyl" or "arylalkenyl-" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group. Arylalkenyl contains 6 to 20 carbon atoms, e.g., the alkenyl portion of arylalkenyl is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

As used herein, the term "arylalkynyl" or "arylalkynyl-" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group. Arylalkynyl contains 6 to 20 carbon atoms, e.g., the alkynyl portion of an arylalkynyl group is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

As used herein, the term "arylheteroalkyl" or "arylheteroalkyl-" refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl. The arylheteroalkyl group contains from 6 to 20 carbon atoms, e.g., the heteroalkyl portion of the arylheteroalkyl group is from 1 to 6 carbon atoms and the aryl portion is from 6 to 14 carbon atoms.

As used herein, the term "arylheteroalkenyl" or "arylheteroalkenyl-" refers to a heteroalkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group. The arylheteroalkenyl group contains 6 to 20 carbon atoms, e.g., the heteroalkenyl moiety of the arylheteroalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

As used herein, the term "arylheteroalkynyl" or "arylheteroalkynyl-" refers to a heteroalkynyl group in which one of the hydrogen atoms bonded to the carbon atom is replaced by an aryl group. Arylheteroalkynyl contains 6 to 20 carbon atoms, e.g., the heteroalkynyl portion of the arylheteroalkynyl is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

As used herein, the term "heterocycle" refers to a saturated, unsaturated, or aromatic ring system of 3-18 atoms that includes at least one N, O, S or P. Heterocycles thus include heteroaryl groups. Heterocycles as used herein include (by way of example and without limitation) those described in the following references: pattertte, Leo a. "Principles of Modern Heterocyclic Chemistry" (w.a. benjamin, New York,1968), specifically chapters 1, 3, 4, 6, 7 and 9; "The chemistry company, A series of monograms" (John Wiley & Sons, New York,1950 to date), specifically chapters Vol 13, 14, 16,19 and 28; katritzky, Alan R., Rees, C.W. and Scripten, E. "Comprehensive heterocyclic chemistry" (Pergamon Press, 1996); and j.am.chem.soc. (1960)82: 5566. In particular embodiments, the term refers to pyridyl, dihydropyridinyl, tetrahydropyridinyl (piperidinyl), thiazolyl, tetrahydrothiophenyl, thiooxidised tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, hydrazono, imidazolyl, tetrazolyl, benzofuranyl, thionaphthyl (thianaphtalenyl), indolyl, indolylenyl, quinolinyl, isoquinolinyl, benzimidazolyl and piperidinyl, 4-piperidinonyl, pyrrolidinyl, 2-pyrrolidinonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2, 5-thiadiazinyl, 2H,6H-1,5, 2-dithiazinyl, thianthrenyl, pyranyl, thionylphenyl, isoquinolinyl, furanyl, isoquinolinyl, 4-piperidinonyl, pyrrolidinyl, 2-pyrrolidinonyl, 2H-1, 5, 2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenothiazinyl (phenoxathinyl), 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, 2, 3-naphthyridinyl, 1, 5-dihydroheteronaphthalene, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4 aH-carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, isoindolyl, and the like, Oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl and isatinoyl.

The term "heteroaryl" refers to an aromatic ring system of 5 to 18 atoms including at least one N, O, S or P, thus referring to aromatic heterocycles. Examples of heterocycles include, but are not limited to, pyridyl, dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thienyl, and pyrrolyl.

As used herein, the term "non-aromatic heterocyclic ring" refers to a saturated or unsaturated non-aromatic ring system of 3-18 atoms of at least one N, O, S or P.

As used herein, the term "heterocycle-alkyl" or "heterocycle-alkyl-" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is substituted with a heterocyclic group. An example of a heterocycle-alkyl is 2-pyridine-methylene. Heterocycle-alkyl contains from 6 to 20 atoms, e.g., the alkyl portion of heterocycle-alkyl is from 1 to 6 carbon atoms and the heterocycle portion is from 3 to 14 atoms.

As used herein, the term "heterocycle-alkenyl" or "heterocycle-alkenyl-" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclic group. Heterocycle-alkenyl contains 6 to 20 atoms, e.g., the alkenyl portion of heterocycle-alkenyl is 1 to 6 carbon atoms and the heterocycle portion is 3 to 14 atoms.

As used herein, the term "heterocycle-alkynyl" or "heterocycle-alkynyl-" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl group. Heterocycle-alkynyl contains 6 to 20 atoms, e.g., the alkynyl portion of heterocycle-alkynyl is 1 to 6 carbon atoms and the heterocycle portion is 3 to 14 atoms.

As used herein, the term "heterocycle-heteroalkyl" or "heterocycle-heteroalkyl-" refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom (typically the terminal or sp3 carbon atom) is replaced with a heterocyclyl. Heterocycle-heteroalkyl contains from 6 to 20 atoms, e.g., the heteroalkyl portion of heterocycle-heteroalkyl is from 1 to 6 carbon atoms and the heterocycle portion is from 3 to 14 atoms.

As used herein, the term "heterocycle-heteroalkenyl" or "heterocycle-heteroalkenyl-" refers to a heteroalkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl group. Heterocycle-heteroalkenyl contains 6 to 20 atoms, e.g., the heteroalkenyl moiety of a heterocycle-heteroalkenyl is 1 to 6 carbon atoms and the heterocycle moiety is 3 to 14 atoms.

As used herein, the term "heterocycle-heteroalkynyl" or "heterocycle-heteroalkynyl-" refers to a heteroalkynyl group in which one of the hydrogen atoms bonded to the carbon atom is replaced by a heterocyclyl group. Heterocycle-heteroalkynyl contains 6 to 20 atoms, e.g., the heteroalkynyl portion of heterocycle-heteroalkynyl is 1 to 6 carbon atoms and the heterocycle portion is 3 to 14 atoms.

As used herein, the term "heteroaryl-alkyl" or "heteroaryl-alkyl-" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is substituted with a heteroaryl group. An example of heteroaryl-alkyl is 2-pyridine-methylene. Heteroaryl-alkyl groups contain 6 to 20 atoms, e.g., the alkyl portion of the heteroaryl-alkyl group is 1 to 6 carbon atoms and the heteroaryl portion is 5 to 14 atoms.

As used herein, the term "heteroaryl-alkenyl" or "heteroaryl-alkenyl-" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. Heteroaryl-alkenyl contains 6 to 20 atoms, e.g., the alkenyl portion of heteroaryl-alkenyl is 1 to 6 carbon atoms and the heteroaryl portion is 5 to 14 atoms.

As used herein, the term "heteroaryl-alkynyl" or "heteroaryl-alkynyl-" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. Heteroaryl-alkynyl contains 6 to 20 atoms, e.g., the alkynyl moiety of heteroaryl-alkynyl is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.

As used herein, the term "heteroaryl-heteroalkyl" or "heteroaryl-heteroalkyl-" refers to a heteroaryl group in which one of the hydrogen atoms bonded to a carbon atom (typically the terminal or sp3 carbon atom) is substituted with a heterocyclyl group. Heteroaryl-heteroalkyl groups contain from 6 to 20 atoms, e.g., the heteroalkyl portion of the heteroaryl-heteroalkyl group is from 1 to 6 carbon atoms and the heteroaryl portion is from 5 to 14 atoms.

As used herein, the term "heteroaryl-heteroalkenyl" or "heteroaryl-heteroalkenyl-" refers to a heteroalkenyl group in which one of the hydrogen atoms bonded to the carbon atom is replaced with a heteroaryl group. Heteroaryl-heteroalkenyl contains 6 to 20 atoms, e.g., the heteroalkenyl moiety of a heteroaryl-heteroalkenyl is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.

As used herein, the term "heteroaryl-heteroalkynyl" or "heteroaryl-heteroalkynyl-" refers to a heteroalkynyl group in which one of the hydrogen atoms bonded to the carbon atom is replaced with a heteroaryl group. Heteroaryl-heteroalkynyl contains 6 to 20 atoms, e.g., the heteroalkynyl portion of heteroaryl-heteroalkynyl is 1 to 6 carbon atoms and the heteroaryl portion is 5 to 14 atoms.

As used herein, the term "non-heteroaromatic-alkyl" or "non-heteroaromatic-alkyl-" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is substituted with a non-aromatic heterocyclic group. Non-aromatic heterocyclic-alkyl groups contain 6 to 20 atoms, e.g., the alkyl portion of the non-aromatic heterocyclic-alkyl group is 1 to 6 carbon atoms, and the non-aromatic heterocyclic portion is 3 to 14 atoms.

As used herein, the term "non-aromatic heterocyclic-alkenyl" or "non-aromatic heterocyclic-alkenyl-" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is substituted with a non-aromatic heterocyclic group. Non-aromatic heterocyclic-alkenyl groups contain 6 to 20 atoms, e.g., the alkenyl portion of a non-aromatic heterocyclic-alkenyl group is 1 to 6 carbon atoms and the non-aromatic heterocyclic portion is 3 to 14 atoms.

As used herein, the term "non-aromatic heterocyclic-alkynyl" or "non-aromatic heterocyclic-alkynyl-" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a non-aromatic heterocyclic group. Non-aromatic heterocyclic-alkynyl contains 6 to 20 atoms, e.g., the alkynyl moiety of non-aromatic heterocyclic-alkynyl is 1 to 6 carbon atoms and the non-aromatic heterocyclic moiety is 3 to 14 atoms.

As used herein, the term "non-heteroaromatic-heteroalkyl" or "non-heteroaromatic-heteroalkyl-" as used herein refers to a heteroalkyl group wherein one of the hydrogen atoms bonded to a carbon atom (typically the terminal or sp3 carbon atom) is replaced with a heterocyclic group. The non-heteroaromatic-heteroalkyl group contains from 6 to 20 atoms, e.g., the heteroalkyl portion of the non-heteroaromatic-heteroalkyl group is from 1 to 6 carbon atoms and the non-heteroaromatic portion is from 3 to 14 atoms.

As used herein, the term "non-aromatic heterocyclic-heteroalkenyl" or "non-aromatic heterocyclic-heteroalkenyl-" as used herein refers to a heteroalkenyl group in which one of the hydrogen atoms bonded to a carbon atom is substituted with a non-aromatic heterocyclic group. The non-heteroaromatic-heteroalkenyl group contains 6 to 20 atoms, e.g., the heteroalkenyl moiety of the non-heteroaromatic-heteroalkenyl group is 1 to 6 carbon atoms and the non-heteroaromatic moiety is 3 to 14 atoms.

As used herein, the term "non-aromatic heterocyclic-heteroalkynyl" or "non-aromatic heterocyclic-heteroalkynyl-" as used herein refers to a heteroalkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a non-aromatic heterocyclic group. Non-aromatic heterocyclic-heteroalkynyl contains 6 to 20 atoms, e.g., the heteroalkynyl portion of the non-aromatic heterocyclic-heteroalkynyl is 1 to 6 carbon atoms and the non-aromatic heterocyclic portion is 3 to 14 atoms.

By way of example, a carbon-binding heterocycle is bound at the 2, 3, 4, 5, or 6 position of pyridine, at the 3, 4, 5, or 6 position of pyridazine, at the 2, 4, 5, or 6 position of pyrimidine, at the 2, 3, 5, or 6 position of pyrazine, at the 2, 3, 4, or 5 position of furan, tetrahydrofuran, thiophene, pyrrole, or tetrahydropyrrole, at the 2, 4, or 5 position of oxazole, imidazole, or thiazole, at the 3, 4, or 5 position of isoxazole, pyrazole, or isothiazole, at the 2 or 3 position of aziridine, at the 2, 3, or 4 position of azetidine, at the 2, 3, 4, 5, 6, 7, or 8 position of quinoline, or at the 1, 3, 4, 5, 6, 7, or 8 position of isoquinoline. Still more typically, carbon-binding heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example, a nitrogen-binding heterocycle is bound at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole; binding at the 2-position of isoindoline or isoindoline; binding at the 4-position of morpholine; and binding at the 9-position of carbazole or β -carboline. Still more typically, nitrogen-binding heterocycles include 1-aziridinyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl.

As used herein and unless otherwise specified, the terms "alkoxy", "cyclo-alkoxy", "aryloxy", "arylalkoxy", "heterocyclooxy", "alkylthio", "cycloalkylthio", "arylthio", "arylalkylthio" and "heterocyclylthio" refer to substituents wherein the alkyl, cycloalkyl, aryl, arylalkyl or heterocycle (each of which is as defined herein) is attached to the oxygen or sulfur atom, respectively, via a single bond, such as, but not limited to, methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenoxy, benzyloxy, mercaptobenzyl, and the like. The same definitions apply for alkenyl and alkynyl groups instead of alkyl groups.

As used herein and unless otherwise specified, the term "halogen" refers to any atom selected from fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

As used herein, the term "optionally including one or more heteroatoms selected from O, S and N" with respect to a chemical group refers to a group in which one or more carbon atoms is replaced with an oxygen atom, a nitrogen atom, or a sulfur atom, and thus includes heteroalkyl, heteroalkenyl, heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, arylheterocyclenyl, heteroarylalkenyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, arylheteroalkynyl, heteroarylalkynyl, and the like, depending on the group referred to. Depending on the radicals mentioned, the term therefore includes, by way of example, alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy Benzyloxy, heterocycle-heteroalkyl, heterocycle-alkoxy, and the like. As an example, the term "alkyl group optionally including one or more heteroatoms selected from O, S and N" thus refers to heteroalkyl groups, meaning alkyl groups that include one or more heteroatoms in the hydrocarbon chain, which heteroatoms may be located at the beginning of the hydrocarbon chain, in the hydrocarbon chain, or at the end of the hydrocarbon chain. Examples of heteroalkyl groups include methoxy, methylthio, ethoxy, propoxy, CH₃-O-CH₂-、CH₃-S-CH₂-、CH₃-CH₂-O-CH₂-、CH₃-NH-、(CH₃)₂-N-、(CH₃)₂-CH₂-NH-CH₂-CH₂-and many other examples. As an example, the term "arylalkylene optionally comprising one or more heteroatoms in the alkylene chain, said heteroatoms being selected from O, S and N" thus refers to arylheteroalkylene (arylheteroalkylene), meaning arylalkylene comprising one or more heteroatoms in the hydrocarbon chain, which heteroatoms may be located at the beginning of the hydrocarbon chain, in the hydrocarbon chain or at the end of the hydrocarbon chain. "Arylheteroalkylene" thus includes aryloxy, arylalkoxy, aryl-alkyl-NH-, and the like, and examples are phenoxy, benzyloxy, aryl-CH₂-S-CH₂-, aryl-CH₂-O-CH₂-, aryl-NH-CH₂-and many other examples. References to "which optionally includes one or more heteroatoms selected from O, S and N" may likewise be interpreted as references to "heteroalkenylene," "heteroalkynylene," and other terms used herein.

As used herein, with respect to a chemical group "where optionally two or more hydrogen atoms on a carbon atom or heteroatom of the group may be joined together to form the term = O or = S", it is meant that two or more hydrogen atoms on a carbon atom or heteroatom of the group together form = O or = S. As an example, the term refers to "alkyl, wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl may be combined together to form = O or = S", and which includes CH₃-C(O)-CH₂-、CH₃-C(O)-、CH₃-C(S)-CH₂-、CH₃-S(O)₂-CH₂-and (CH)₃)₂-CH₂-C(O)-CH₂-CH₂-and other examples.

A group "which optionally includes one or more heteroatoms selected from O, S and N" and "wherein optionally, a combination in which two or more hydrogen atoms on a carbon atom or heteroatom of the group may be combined together to form = O or = S" may combine both aspects described hereinbefore and includes (if the group referred to is alkyl) CH₃-C(O)O-、CH₃-C(O)O-CH₂-、CH₃-NH-C(O)-、CH₃-C(O)-NH-CH₃-NH-C(O)-CH₂-、CH₃-NH-C(S)-CH₂-、CH₃-NH-C(S)-NH-CH₂-、CH₃-NH-S(O)₂-and CH₃-NH-S(O)₂-NH-CH₂-and other examples.

With respect to substituents, as used herein and unless otherwise specified, the term "substituted", such as in "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted aryl", "substituted heterocycle", "substituted arylalkyl", "substituted heterocycle-alkyl", and the like, refers to the chemical structure defined herein, and wherein the hydrocarbyl, heterohydrocarbyl group and/or the aryl or heterocycle is optionally substituted with one or more substituents (preferably 1, 2, 3, 4, 5 or 6), meaning that one or more hydrogen atoms are each independently substituted with a substituent. Typical substituents include, but are not limited to, and in specific embodiments are selected from the group consisting of halogen, amino, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, and heterocycle-alkynyl, -X, -Z, -O ^-、-OZ、=O、-SZ、-S^-、=S、-NZ₂、-N⁺Z₃、=NZ、=N-OZ、-CX₃(e.g., trifluoromethyl), -CN, -OCN, -SCN, -N = C = O, -N = C = S, -NO₂、=N₂、-N₃、-NZC(O)Z、-NZC(S)Z、-NZC(O)O^-、-NZC(O)OZ、-NZC(S)OZ、-NZC(O)NZZ、NZC(NZ)Z、NZC(NZ)NZZ、-C(O)NZZ、-C(NZ)Z、-S(O)₂O^-、-S(O)₂OZ、-S(O)₂Z、-OS(O)₂OZ、-OS(O)₂Z、-OS(O)₂O^-、-S(O)₂NZ、-S(O)Z、-OP(O)(OZ)₂、-P(O)(OZ)₂、-P(O)(O^-)₂、-P(O)(OZ)(O^-)、-P(O)(OH)₂、-C(O)Z、-C(O)X、-C(S)Z、-C(O)OZ、-C(O)O^-、-C(S)OZ、-C(O)SZ、-C(S)SZ、-C(O)NZZ、-C(S)NZZ、-C(NZ)NZZ、-OC(O)Z、-OC(S)Z、-OC(O)O^--OC (O) OZ, -OC (S) OZ, wherein each X is independently a halogen selected from F, Cl, Br or I; and each Z independently represents-H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, a heterocycle, a protecting group, or a prodrug moiety, and two Z's bound to a nitrogen atom may be bound together with the nitrogen atom to which they are bound to form a heterocycle. Alkyl (alkylene), alkenyl (alkenylene), and alkynyl (alkynylene) groups may also be similarly substituted.

Any substituent found in more than one position of a compound of the invention indicates that it should be independently selected.

Substituents are optionally indicated to include or exclude bonds. Whether or not indicated by a bond, if a substituent is multivalent (based on its position in the structure referred to), it is intended to include any and all possible orientations of that substituent.

References herein to compounds of the present invention are also intended to include solvates of such compounds. As used herein and unless otherwise specified, the term "solvate" includes any combination that may be formed from the derivatives of the present invention with a suitable inorganic solvent (e.g., hydrate) or organic solvent such as, but not limited to, an alcohol, ketone, ester, ether, nitrile, and the like.

The compounds of the invention are optionally covalently bound to an insoluble matrix and used for affinity chromatography separation, depending on the nature of the compound group, e.g. compounds with pendant aryl groups are used for hydrophobic affinity separations.

The compounds of the invention are useful for the treatment or prevention of viral infections, more particularly retroviral infections, especially HIV infections. When one or more compounds of the invention are used, together with compounds of the general formula as defined herein:

the compound may be administered to an animal or mammal (including a human) to be treated by any method well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intraarterially, parenterally or by catheterization.

A therapeutically effective amount of a compound preparation, in particular for the treatment of viral infections in humans and other mammals, preferably a retroviral replication inhibiting amount of a formula as defined herein, and corresponding to an amount ensuring a plasma level between 1 μ g/ml and 100mg/ml, optionally 10 mg/ml.

The invention also relates to methods of preventing or treating a viral infection in a subject or patient by administering to a patient in need thereof a therapeutically effective amount of a compound of the invention. Particularly for use in treating viral infections in humans and other mammals, a therapeutically effective amount of the compound is preferably an amount that inhibits retroviral replication. Such suitable doses will generally range from 0.001mg to 60mg, optionally from 0.01mg to 10mg, optionally from 0.1mg to 1mg per kg of body weight per day. Depending on the pathological condition to be treated and the condition of the patient, the effective amount may be divided into several subunits per day, or may be administered at intervals of more than one day.

As is conventional in the art, the synergistic effect in a drug combination formulation can be assessed by analysing the quantification of the interaction between the individual drugs using the principle of intermediate effect described by Chou et al in adv. enzyme Reg, (1984)22: 27. In short, the principle describes that the interaction (synergy, additivity, antagonism) between two drugs can be quantified using a combination coefficient (hereinafter referred to as CI) defined by the following equation:

wherein ED_xIs the dose (1a, 2a) of the first or second drug, respectively, used alone or in combination with the second drug or, respectively, the first drug (1c,2c), which is necessary to produce a specific effect. The first and second drugs are dependent on CI<1. CI =1 or CI>1 have a synergistic or additive or antagonistic effect, respectively.

The synergistic activity of the pharmaceutical composition or combination formulation of the present invention against viral infections can also be readily determined by one or more assays including, but not limited to: isobologram, as previously described by Elion et al in J.biol.chem. (1954)208:477-488 and by Baba et al in anti. Agents Chemother (1984)25:515-517, the method utilizes EC ₅₀To calculate the fractional inhibitory concentration (hereinafter referred to as FIC). When corresponding to the FIC of a combination compound (e.g., FIC)_x+FIC_y) Is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as sub-synergistic, and when it is below 0.5, the combination is defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as sub-antagonistic (sub)antagnostic), and when it is higher than 2.0, the combination is defined as antagonistic.

This principle can be applied to a combined preparation of different antiviral drugs of the present invention or a combined preparation of an antiviral drug of the present invention in combination with other drugs exhibiting anti-HIV activity.

The invention therefore relates to a pharmaceutical composition or a combined preparation having a synergistic effect on viral infections and comprising:

A)

(a) combinations of two or more compounds of the invention, and

(b) optionally, one or more pharmaceutical excipients or a pharmaceutically acceptable carrier,

for simultaneous, separate or sequential use in the treatment or prevention of a retroviral infection,

or

B)

(c) One or more antiviral agents, and

(d) at least one compound of the invention, and ═

(e) Optionally, one or more pharmaceutical excipients or a pharmaceutically acceptable carrier,

For simultaneous, separate or sequential use in the treatment or prevention of a retroviral infection.

Agents that may be used in combination with the compounds of the present invention include, but are not limited to, those that act as HIV protease inhibitors, HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, CCR5 inhibitors, HIV fusion inhibitors or other HIV entry inhibitors, maturation inhibitors, agents that act to disrupt HIV capsid polymerization or viral nuclear stability, compounds that target host proteins required for viral replication or immune evasion (such as, but not limited to, PSIP1), compounds that act as immunomodulators, compounds that inhibit the HIV virus by unknown mechanisms, compounds for treating herpes viruses, compounds that act as anti-infectives, and other compounds as described below.

Compounds useful as HIV protease inhibitors that may be used in combination with the compounds of the present invention include, but are not limited to, 141W94 (amprenavir), CGP-73547, CGP-61755, DMP-450(mozenavir), nelfinavir, ritonavir, saquinavir (inverase), lopinavir, TMC-126, atazanavir, palinavir, GS-3333, KN I-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, MK-478, 944-944, indinavir, tipranavir, TMC-114 (darunavir), DPC-681, DPC-684, calcium fosamprenavir (Lexiva), benzenesulfonamide derivatives disclosed in WO 03053435, R-944, Ro-34649, and so-D-61755, VX-385(brecanavir), GS-224338, OPT-TL3, PL-100, SM-309515, AG-148, DG-35-VIII, DMP-850, GW-5950X, KNI-1039, L-756423, LB-71262, LP-130, RS-344, SE-063, UIC-94-003, Vb-19038, A-77003, BMS-182193, BMS-186318, SM-309515, JE-2147, GS-9005, tipinavir (SC-52151), BILA-2185BS, DG-17, PPL-100, GS-80987, GS-8374, DMP-323, U-103017, CGP-57813 and CGP-53437.

Useful HIV reverse transcriptase inhibitors and compounds that may be used in combination with the compounds of the present invention include, but are not limited to, abacavir, emtricitabine (FTC), GS-840 (adefovir), lamivudine, adefovir dipivoxil, β -fluoro-ddA, zolmitabine, didanosine, stavudine, zidovudine, tenofovir disoproxil fumarate, amdoxovir, SPD-754 (aprevibine), SPD-756, racivir, revertset (DPC-817), MIV-210(FLG), β -L-Fd4C (ACH-126443, elvucitabine), MIV-310 (alovudine, FLT), dOTC, DAPD, entecavir, GS-7340, stampidine, D-D4FC (dexvuvundine), spazidine, phofovir dipivoxil and saxidol.

Compounds useful as non-nucleoside inhibitors of HIV reverse transcriptase that may be used in combination with the compounds of the present invention include, but are not limited to, efavirenz, HBY-097, nevirapine, dapivirine (TMC-120), TMC-125, etravirine, delavirdine, DPC-083, DPC-961, TMC-120, cappivirin, GW-678248, GW-695634, calanolide, rilpivirine (TMC-278), lovirmine, ethimevirine (MKC-442), DPC-963, MIV-150, BILR 355BS, VRX-840773, lersivirine (UK-453061), RDEA806, and tricyclic pyrimidinone derivatives as disclosed in WO 03062238.

Compounds useful as CCR5 inhibitors that may be used in combination with the compounds of the present invention include, but are not limited to, TAK-779, SC-351125, SCH-D, UK-427857 (Malavirromic), PRO-140, and GW-873140(aplaviroc, Ono-4128, AK-602), SCH-417690(viciviroc, SCH-D), INCB-9471, INCB-15050, TBR-220(TAK-220), CCR5mAb 004. Other compounds useful as inhibitors of CCR5 that can be used in combination with the compounds of the present invention include, but are not limited to, (N- { (1S) -3- [ 3-isopropyl-5-methyl-4H-1, 2, 4-triazol-4-yl ] -exo-8-azabicyclo [3.2.1] oct-8-yl } -1-phenylpropyl) -4, 4-difluorocyclohexanecarboxamide), 1-endo- {8- [ (3S) -3- (acetylamino) -3- (3-fluorophenyl) propyl ] -8-azabicyclo [3.2.1] oct-3-yl } -2-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-5-carboxylic acid methyl ester and N- { (1S) -3- [ 3-endo- (5-isobutyryl-2-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl ] -1- (3-fluorophenyl) propyl } acetamide).

Compounds useful as integrase inhibitors that may be used in combination with the compounds of the present invention include, but are not limited to, raltegravir, eltoprevir (GS-9137, JTK-303), GSK-364735, MK-2048, BMS-707035, S-1360(GW-810781), L-870810, L-870812, AR-177, BA-011, the 1, 5-naphthyridine-3-carboxamide derivative disclosed in WO 03062204, the compound disclosed in WO 03047564, the compound disclosed in WO 03049690, the 5-hydroxypyrimidine-4-carboxamide derivative disclosed in WO 03035076, and L-000810810.

Fusion inhibitors useful in the treatment of HIV that may be used in combination with the compounds of the present invention include, but are not limited to, enfuvirdine (T-20), T-1249, AMD-3100, the cidofovir peptide, FB-006M, TRI-1144, PRO-2000, and the fused tricyclic compounds disclosed in JP 2003171381.

Maturation inhibitors useful in the treatment of HIV that may be used in combination with the compounds of the present invention include, but are not limited to, bevirimat and vivocon.

HIV fixed drug combinations useful in the treatment of HIV with which the compounds of the present invention may be used include, but are not limited to, cobivir, atripla, sanxiawei, Teluvada, kaletra, and epzicom.

CXCR4 inhibitors useful in the treatment of HIV that may be used in combination with the compounds of the present invention include, but are not limited to, AMD-070.

Infusion inhibitors useful in the treatment of HIV that may be used in combination with the compounds of the present invention include, but are not limited to, SP-01A.

Gp 120 inhibitors useful in the treatment of HIV that can be used in combination with the compounds of the present invention include, but are not limited to, BMS-488043 and BMS-378806.

G6PD and NADH-oxidase inhibitors useful in the treatment of HIV that can be used in combination with the compounds of the present invention include, but are not limited to, immutin.

Other compounds useful as HIV inhibitors that may be used in combination with the compounds of the present invention include, but are not limited to, soluble CD4, PRO-542, ibalizumab (TNX-355), and the compounds disclosed in JP 2003119137.

Compounds that may be used in combination with the compounds of the present invention for treating or controlling infection from a non-HIV virus include, but are not limited to, aciclovir, fomivirsen, penciclovir, HPMPC, nucleoside analogs G, AL-721, cidofovir, cytomegalovirus immunoglobulin, symmetivol, fomivganciclovir, famciclovir, foscarnet, Isis 2922, KNI-272, valacyclovir, ribavirin, valganciclovir, ME-609, PCL-016, DES6, ODN-93, ODN-112, VGV1, polyinosinic cells, HRG-214, cytolin, VGX-410, KD-247, AMZ-0026, CYT-99007A-221, DEBIO-025, BAY 50-4798, MDX-010(ipilimumab), PBS-119, ALG-889, PA-1050040(PA-040) and filbvir (PF-00868554).

Compounds that act AS immunomodulators and that can be used in combination with the compounds of the present invention include, but are not limited to, AD-439, AD-519, interferon-alpha, AS-101, bromoprimine, acetylmorphinan, CL246,738, EL10, FP-21399, interferon-gamma, granulocyte macrophage colony stimulating factor, IL-2, intravenous immunoglobulin (immunoglobulin intracerebrovenous), IMREG-1, IMREG-2, ethidium dimercaptocarbamate, interferon-alpha-2, methionine enkephalin, MTP-PE, granulocyte colony stimulating factor, remunene, rCD4, recombinant soluble human CD 106 4, interferon-alpha-2, SK & F528, soluble T4 ymopentin, Tumor Necrosis Factor (TNF), tocarol, recombinant human gamma, and interferon alpha n-3.

Anti-infectives that may be used in combination with the compounds of the present invention include, but are not limited to, atovaquone, azithromycin, methylerythromycin, trimethoprim, trovafloxacin, pyrimethamine, daunorubicin, clindamycin and primaquine, pastill, eflornithine hydrochloride injection, enoximiramide, rifabutin, acetylspiramycin, intraconazole-R51211, trimetrexate, daunorubicin, chloroquine, recombinant human erythropoietin, recombinant human growth hormone, megestrol acetate, testerone, and total gastrointestinal nutrition.

Antifungal agents that may be used in combination with the compounds of the present invention include, but are not limited to, alpha, C31G, alpha, DB-289, fluconazole, itraconazole, ketoconazole, micafungin, posaconazole and voriconazole.

Other compounds that may be used in combination with the compounds of the present invention include, but are not limited to, acetylmorphinan, ansamycin, LM 427, AR177, BMS-232623, BMS-234475, CI-1012, curdlan sulfate, dextran sulfate, STOCRINE EL10, hypericin, lobecavir, Norwalk, the peptide T ocabpeptide sequence, trisodium phosphate formate, probucol, and RBC-CD 4.

In addition, the compounds of the present invention may be used in combination with antiproliferative agents for the treatment of conditions such as Kaposi's sarcoma. Such agents include, but are not limited to, metallo-matriptase inhibitors, A-007, bevacizumab, BMS-275291, bromocloperaquine, interleukin-12, rituximab, paclitaxel, porfimer sodium, rebimastat, and COL-3.

According to a particular embodiment of the invention, the compounds of the invention may be used in combination with other therapeutic agents for the treatment or prevention of retroviral infections, more preferably HIV. The present invention therefore relates to the use of a composition comprising:

(a) one or more compounds of the formulae herein, and

(b) one or more retroviral enzyme inhibitors in respective proportions as a biologically active agent to provide a synergistic effect against viral infections, particularly retroviral infections, in mammals, for example in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of viral infections such as HIV.

More generally, the present invention relates to compounds of formula (a), (B), (C), (D), (E), (F) and embodiments thereof for use as medicaments having biological activity, in particular antiviral activity, or as diagnostic agents. Any use mentioned in relation to the present invention may be limited to non-medical use, non-therapeutic use or use exclusively to in vitro use or use in relation to cells detached from an animal.

It will also be appreciated by those skilled in the art that the compounds of the invention may exist in many different protonation states, depending on the pH of their environment and other factors. Although the structural formulae provided herein describe the compounds in only one of several possible protonation states, it should be understood that these structures are merely illustrative and that the present invention is not limited to any particular protonation state-any and all protonated forms of the compounds are intended to fall within the scope of the present invention.

As used herein, the term "pharmaceutically acceptable salt" as used herein refers to therapeutically active non-toxic salt forms that the compounds of the general formula herein are capable of forming. Thus, the compounds of the invention optionally comprise salts of the compounds described herein, in particular containing, for example, Na⁺、Li⁺、K⁺、Ca²⁺And Mg²⁺Pharmaceutically acceptable non-toxic salts thereof. Such salts may include those obtained by combining an appropriate cation such as an alkali metal ion and an alkaline earth metal ion or ammonium with a quaternary ammonium ion and the anionic portion of an acid, typically a carboxylic acid. The compounds of the present invention may have multiple positive or negative charges. The net charge of the compounds of the invention may be positive or negative. Any relevant counterions are generally dictated by the synthetic and/or isolation method from which the compound is obtained. Typical counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, and the like, and mixtures thereof. It is to be understood that the identification of any relevant counterion is not a critical feature of the invention, and that the invention encompasses compounds associated with any type of counterion. Furthermore, because the compounds can exist in a variety of different forms, the present invention is intended to include not only the compound form associated with the counterion (e.g., a dry salt), but also forms not associated with the counterion (e.g., an aqueous or organic solution). The metal salts are typically prepared by reacting a metal hydroxide with a compound of the present invention. Examples of metal salts prepared in this way are those containing Li ⁺、Na⁺And K⁺A salt. The less soluble metal salt can be precipitated from the more soluble salt solution by adding a suitable metal compound. In addition, salts can be formed by the acid addition of certain organic and inorganic acids to a basic center (typically an amine) or to an acidic group. Examples of such suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid such as, for example, acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid (i.e., 2-hydroxybenzoic acid), p-aminosalicylic acid, and the like. In addition, the term also includes solvates that the compounds of the general formula herein and salts thereof can form, such as hydrates, alcoholates and the like. Finally, it is understood that the compositions herein compriseIonized and zwitterionic forms of the compounds of the invention, and combinations with stoichiometric amounts of water, such as in hydrates.

Also included within the scope of the invention are salts of the parent compounds with one or more amino acids, particularly naturally occurring amino acids found as protein components. The amino acid is typically an amino acid having a side chain with a basic or acidic group (e.g., lysine, arginine, or glutamic acid) or a neutral group (such as glycine, serine, threonine, alanine, isoleucine, or lysine).

The compounds of the present invention also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the present invention include salts derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX₄ ⁺(wherein X is C₁-C₄Alkyl groups). Physiologically acceptable salts of hydrogen atoms or amino groups include: salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid and succinic acid; salts of organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and salts of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid. Physiologically acceptable salts of hydroxyl-containing compounds include anions of the compounds with suitable cations such as Na ⁺And NX₄ ⁺(wherein X is typically independently selected from H or C₁-C₄Alkyl) groups. However, salts of acids or bases which are not physiologically acceptable may also find application, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of the invention.

As used herein and unless otherwise specified, the term "enantiomer" refers to each individual optically active form of a compound of the present invention having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

As used herein, the term "isomer" as used herein refers to all possible isomeric forms, including tautomeric and stereochemical forms that the compounds of the general formula herein may possess, but does not include positional isomers. Generally, the structures shown herein illustrate only one tautomeric or resonant form of the compound, but corresponding alternative configurations are also contemplated. Unless otherwise indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures comprising all diastereomers and enantiomers of the basic molecular structure (since the compounds of the general formula herein may have at least one chiral center) as well as stereochemically pure or enriched compounds. More specifically, the stereocenter may have an R-configuration or an S-configuration, and the multiple bonds may have a cis-configuration or a trans-configuration.

The compounds of the present invention may have a chiral center adjacent to the carboxyl group. Thus, compounds that also do not exhibit rotameric enantiomers (described in detail below) may exist as two stereoisomers (i.e., enantiomers). For example:

rotamase phenomena may also occur when the 4-substituent asymmetrically surrounds the bond plane at the 4-position. This is because the aromatic ring at the 4-position and the pyridine/pyrimidine moiety of the fused bicyclic ring are more or less orthogonal to each other and rotation around the bond at the 4-position of the 2,3, 4-substituted bicyclic compounds of the present invention may be limited. Such compounds may thus exist as four stereoisomers (i.e., diastereomers). For example:

pure isomeric forms of the compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term "stereoisomerically pure" or "chirally pure" relates to compounds having a stereoisomeric excess of at least about 80% (i.e., at least 90% of one isomer and up to 10% of the other possible isomer), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms "enantiomerically pure" and "diastereomerically pure" are to be understood in a similar manner with respect to the enantiomeric excess in the mixture in question, or the corresponding diastereomeric excess.

The separation of stereoisomers is accomplished by standard methods known to those skilled in the art. One enantiomer of a compound of the invention may be separated from being substantially free of its opposite enantiomer by methods such as diastereomer formation using optical resolving agents ("Stereochemistry of carbon compounds," (1962) by E.L.Eliel, McGraw Hill; Lochmuller, C.H., (1975) J.Chromatoger., 113 (3) 283-. Separation of isomers in a mixture may be accomplished by any suitable method, including: (1) the use of chiral compounds to form ionic diastereomeric salts and separation by fractional crystallization or other means, (2) the use of chiral derivatizing reagents to form diastereomeric compounds, separation of the diastereomers and conversion to the pure enantiomers, or (3) the enantiomers can be separated directly under chiral conditions. In process (1), diastereomeric salts can be formed by reaction of an enantiomerically pure chiral base such as strychnine, quinine, ephedrine, brucine, a-methyl-b-phenylethylamine (amphetamine) equivalent to an asymmetric compound having an acidic functionality such as carboxylic and sulfonic acids. Diastereomeric salts can be separated by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can lead to the formation of diastereomeric salts. Alternatively, by method (2), the substrate to be resolved can be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (diasteromeric pair) (Eliel, E.and Wilen, S. (1994) stereoschemistry of Organic Comp ounds,John Wiley&Sons, inc., p.322). Diastereomeric compounds may be formed by: asymmetric compounds are reacted with an enantiomerically pure chiral derivatizing reagent such as a menthyl derivative, followed by separation of diastereomers and hydrolysis to yield free enantiomerically enriched xanthenes (xanthenes). The method of determining optical purity involves preparing the chiral ester menthyl or Mosher (Mosher) ester a-methoxy-a- (trifluoromethyl) phenylacetate (Jacob III, (1982) j.org.chem.47:4165) of the racemic mixture and analyzing the NMR spectrum to determine the presence of the two atropisomeric diastereomers. The separation of the rotameric naphthyl-isoquinoline is a procedure, and the stable diastereomers can be separated and separated by normal and reverse phase chromatography (Hoye, t., WO 96/15111). Under method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral fixatives are, for example, polysaccharides, in particular cellulose or starch derivatives. The commercially available polysaccharide, i.e. the chiral stationary phase, is ChiralCeI^TMCA. OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak^TMAD. AS, OP (+) and OT (+). Suitable eluents or mobile phases for use in conjunction with the polysaccharide chiral stationary phase are hexane and the like, which is modified with alcohols such as ethanol, isopropanol and the like. (for "chiral liquid Chromatography" (1989) W.J.Lough, Ed.Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of two nucleotide molecules High-performance Chromatography using phenyl carbamates of polysaccharides as a phase stability phase", J.of chromatography.513: 375-.

The terms cis and trans are used herein in accordance with the chemical abstracts nomenclature and include references to substituent positions on the ring portion. The absolute stereochemical configuration of the compounds of formula (1) can be readily determined by those skilled in the art using well known methods such as, for example, X-ray diffraction.

The compounds of the invention may be formulated with conventional carriers and excipients selected in accordance with standard practice. Tablets contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery by means other than oral administration. The formulations optionally contain excipients such as those described in the Handbook of pharmaceutical excipients (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, sugars such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid and the like.

Thereafter, as used herein, the term "pharmaceutically acceptable carrier" refers to any material or substance by which the active ingredient is formulated so as to facilitate its administration or dissemination to the site to be treated, e.g., by dissolving, dispersing or diffusing the composition, and/or to facilitate its storage, transport or handling without compromising its efficacy. The pharmaceutically acceptable salt may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the composition of the invention may suitably be used as a concentrate, emulsion, solution, granule, dust, spray, aerosol, suspension, ointment, salve, tablet, pill or powder.

Suitable pharmaceutical carriers for use in the pharmaceutical compositions and formulations thereof are well known to those skilled in the art and there is no particular limitation on the choice thereof within the present invention. It may also include additives such as wetting agents, dispersing agents, sticking agents, binding agents, emulsifying agents, solvents, coating agents, antibacterial and antifungal agents (e.g., phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride), and the like, as long as the additives are consistent with pharmaceutical practice, i.e., the carriers and additives do not cause permanent damage to the mammal. The pharmaceutical compositions of the invention can be prepared in any known manner, for example by homogeneously mixing, coating and/or grinding the active ingredient together with the selected carrier substances in a one-step or multi-step process, and where appropriate also by micronisation of other additives such as surfactants, for example in order to obtain them with a diameter of typically about 1 to 10gm, i.e. to produce microcapsules for controlled or sustained release of the active ingredient.

Used in the pharmaceutical composition of the present inventionSuitable surfactants, also known as emulsifiers (emulgents or emulsiifiers), are nonionic, cationic and/or anionic substances having excellent emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include water-soluble fatty acid salts and water-soluble synthetic surfactants. Suitable fatty acid salts are alkali metal salts or alkaline earth metal salts, higher fatty acids (C) ₁₀-C₂₂) For example, sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures derived from coconut oil or animal oils. Synthetic surfactants include sodium or potassium salts of polyacrylic acids; fatty sulfonates and phosphates; sulfonated benzimidazole derivatives and alkyl aryl sulfonates. The fatty sulfonates or phosphates are typically in the form: an alkali metal salt or an alkaline earth metal salt; unsubstituted ammonium salts or ammonium salts substituted with alkyl or acyl groups having from 8 to 22 carbon atoms, for example the sodium or potassium salts of lignosulfonic acid or dodecylsulfonic acid or of fatty alcohol sulfate mixtures derived from natural fatty acids; alkali metal or alkaline earth metal salts of sulfuric acid and sulfonic acid esters (such as sodium lauryl sulfate); and sulfonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulfonated benzimidazole derivatives preferably contain from 8 to 22 carbon atoms. Examples of alkylaryl sulfonates are the sodium, calcium or alkanolamine salts (alkylolamines) of dodecylbenzenesulfonic acid or dibutyl-naphthalenesulfonic acid or naphthalenesulfonic acid/formaldehyde condensation products. Also suitable are the corresponding phosphates, for example, phosphate esters and salts of adducts of nonylphenol with ethylene oxide and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are phospholipids of the cephalin or lecithin type, natural (of animal or plant origin) or synthetic, such as, for example, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, lysolecithin, cardiolipin, dioctylphosphatidylcholine, dipalmitoylphosphatidylcholine and mixtures thereof.

Suitable nonionic surfactants include polyethoxylated and polypropoxylated alkyl phenols, fatty alcohols, fatty acids, aliphatic amines or amides having at least 12 carbon atoms in the molecule, alkylarenesulfonates and dialkylsulfosuccinates, such as polyethylene glycol derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkyl phenols, preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkyl phenol. Other suitable nonionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediamine polypropylene glycol having from 1 to 10 carbon atoms in the alkyl chain, which adducts contain from 20 to 250 ethylene glycol ether groups and/or from 10 to 100 propylene glycol ether groups. The compound contains 1-5 ethylene glycol units/propylene glycol units. Representative examples of nonionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyethoxyethanol ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyoxyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable nonionic surfactants.

Suitable cationic surfactants include: quaternary ammonium salts, in particular halides, having four hydrocarbon groups optionally substituted with halogen, phenyl, substituted phenyl or hydroxy; e.g. containing at least one C₈-C₂₂Alkyl groups (e.g., cetyl, lauryl, palmityl, myristyl, oleyl, etc.) as the N-substituent and quaternary ammonium salts containing unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl as other substituents.

A more detailed description of Surfactants suitable for this purpose can be found, for example, in "McCutcheon's Detergents and Emulsifiers annular" (MC publishing Crop., Ridgewood, New Jersey,1981), "Tensid-Taschenbucw', 2d ed. (Hanser Verlag, Vienna,1981) and" encyclopedia of Surfactants "(chemical publishing Co., New York, 1981).

The compounds of the present invention and their physiologically acceptable salts (hereinafter collectively referred to as active ingredients) may be administered by any route suitable for the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ophthalmic, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intrathecal and epidural). The preferred route of administration may vary depending, for example, on the condition of the recipient.

Although the active ingredient may be administered alone, it is preferably presented as a pharmaceutical formulation. The formulations of the invention for veterinary and human use comprise at least one active ingredient as described above together with one or more pharmaceutically acceptable carriers thereof and optionally other therapeutic ingredients. The carrier is optionally "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, rectal, nasal, topical (including ophthalmic and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more of the essential ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be presented as follows: discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; powder or granules; a solution or suspension in an aqueous liquid or a non-aqueous liquid; or an oil-in-water liquid emulsion and/or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Tablets may be prepared by compression or molding, optionally with one or more of the necessary ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored (coded) and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues such as the oral cavity and the skin, the formulation is optionally applied as a topical ointment or cream containing an active ingredient in an amount of, for example, 0.075-20% w/w (including active ingredients ranging between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredient may be used with either a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an ointment-in-water base. If desired, the aqueous phase of the paste base may comprise, for example, at least 30% w/w of a polyol, i.e. an alcohol having two or more hydroxyl groups, such as propylene glycol, 1, 3-diol, mannitol, sorbitol, glycerol and polypropylene glycols (including PEG400) and mixtures thereof. Topical formulations may include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas, as desired. Such transdermal penetration enhancers include dimethylsulfoxide and related analogues.

The oil phase of the emulsions of the invention may be constituted from known ingredients in known manner. Although this phase may comprise only emulsifiers (otherwise referred to as emulsions), it desirably comprises a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier may be included with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oil and fat. Emulsifiers with or without stabilizers together constitute the so-called emulsifying wax, and the wax together with oils and fats constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of the ointment formulation.

The selection of a suitable formulation oil or fat is based on achieving the desired cosmetic properties, since the solubility of the active compound in the oil, which is most likely to be used in pharmaceutical emulsion formulations, is very low. Thus, the paste should optionally be a non-greasy, non-staining washable product and have a suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono-or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the desired properties. Alternatively, high melting point lipids such as soft white wax and/or liquid paraffin or other mineral oils may be used.

Formulations for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is optionally present in such formulations at a concentration of 0.5-20%, advantageously 0.5-10%, in particular about 1.5% w/w. Formulations suitable for topical application in the oral cavity include: lozenges comprising the active ingredient in a flavour base (usually sucrose or acacia or tragacanth); candy lozenges comprising the active ingredient in an inert matrix such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for nasal administration in which the carrier is a solid include a coarse powder having a particle size, for example in the range 20 to 500 microns (including particle sizes in the range between 20 and 500 microns, increments of 5 microns such as 30 microns, 35 microns etc.), which is administered in an olfactory dose, i.e. by rapid inhalation through the nasal orifice from a powder container held close up to the nose. Wherein the liquid carrier, suitable formulation for administration, e.g., as a nasal spray or as nasal drops, comprises an aqueous or oily solution of the active ingredient. Formulations suitable for aerosol administration may be prepared in conventional manner and may be delivered with other therapeutic agents.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are suitable in the art.

Formulations suitable for parenteral administration include: aqueous and non-aqueous sterile injection formulations containing antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose solutions, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injections and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose of the active ingredient, as described herein, or a suitable fraction thereof.

It will be appreciated that in addition to the ingredients specifically mentioned above, the formulations of the invention may include other materials conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include taste enhancers.

The compounds of the present invention are useful in enhanced controlled release pharmaceutical compositions containing, as the active ingredient, one or more compounds of the present invention ("controlled release formulations"), wherein the release of the active ingredient can be controlled and modulated to allow less frequent dosing or to modify the pharmacokinetic or toxicity profile of the particular inventive compound. Controlled release formulations suitable for oral administration may be prepared according to conventional methods wherein the discrete units comprise one or more compounds of the invention.

Other ingredients may be included in order to control the duration of action of the active ingredients in the composition. Controlled release group numbers are thus obtained by selecting suitable polymeric carriers such as, for example, polyesters, polyamino acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymer, methylcellulose, carboxymethylcellulose, protamine sulfate, and the like. Drug release rates and duration of action can also be controlled by incorporating the active ingredient into particles of polymers (e.g., microcapsules) such as hydrogels, polylactic acids, hydroxymethylcellulose, polymethylmethacrylate, and other polymers described above. Such methods include colloidal drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules, and the like. Depending on the route of administration, the pharmaceutical composition may require a protective coating. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, and the like, and mixtures thereof.

In view of the fact that when several active ingredients are used in combination, they do not necessarily show their combined therapeutic effect in the mammal to be treated at the same time, the corresponding composition may also be in the form of a pharmaceutical kit or pack containing two components located in separate but adjacent compartments or compartments. In the latter case, each active principle may therefore be formulated in a manner suitable for a route of administration different from that of the other, for example, one of them may be in the form of an oral or parenteral preparation, while the other is in the form of an intravenous ampoule or in the form of an aerosol.

Another embodiment of the invention relates to various precursors or "prodrug" forms of the compounds of the invention. It may be desirable to formulate the compounds of the invention in the form of a chemical species which is not itself significantly biologically active, but which, when delivered to an animal, will undergo a chemical reaction catalysed by the normal bodily functions of that animal, particularly the enzymes present in the stomach or serum, which chemical reaction has the effect of releasing a compound as defined herein. The term "prodrug" thus relates to these species which are converted in vivo to the active pharmaceutical ingredient.

The prodrugs of the invention may be in any form suitable to the formulator, for example, esters are non-limiting common prodrug forms. In the present case, however, the prodrug must be present in a form in which the covalent bond is cleaved by the action of an enzyme present at the target locus. For example, the C-C covalent bond may be selectively cleaved by one or more enzymes located at the target locus, and therefore prodrugs in forms other than readily hydrolysable precursors, particularly esters, amides, and the like, may be used. The equivalent of the active pharmaceutical ingredient in a prodrug may have different structures such as amino acid or peptide structures, alkyl chains, sugar moieties, and other structures as are known in the art.

For the purposes of this invention, the term "therapeutically suitable prodrug" is defined herein as "a compound that is modified in vivo by being converted to a therapeutically active form, whether by a single or multiple biotransformation, without undue toxicity, irritation, or allergic response and to achieve the desired therapeutic result" when contacted with an animal, mammal, or human to which the prodrug has been administered.

More specifically, as used herein, the term "prodrug" relates to inactive or significantly less active derivatives of a compound such as represented by structural formula (I), which undergo spontaneous or enzymatic conversion in vivo in order to release the pharmaceutically active form of the compound. For a general review, reference is made to Rauto J. et al ("Prodrugs: design and clinical applications" NatureReviews Drug Discovery,2008, doi:10.1038/nrd 2468).

The compounds of the invention may be prepared using a series of compounds well known to those skilled in the art and using (make up) methods for preparing the compounds described and further exemplified. The further described method is only by way of example and is in no way meant to limit the scope of the invention.

The compounds of the invention can be prepared according to the following outlined procedure as shown below:

scheme 1: all R¹、R^2a、R^2b、R³、R⁴、R⁶、R⁷And LG are the same as described for the compounds of the invention and embodiments of the general formulae thereof.

The condensation of 3-aminopyrazoles of formula II (either commercially available or synthesized by methods known to those skilled in the art) with intermediates of formula III, wherein R is an ester protecting group (e.g., methyl, ethyl, etc.), in the presence of a non-polar aprotic solvent (e.g., benzene, toluene, xylene, etc.) at temperatures ranging from 80 ℃ to-140 ℃ affords the desired intermediates of formula IV. Intermediate IV is then converted to an intermediate of formula V, wherein LG is a leaving group selected only from halogens, by methods known to those skilled in the art or as described in the examples below. The intermediate of formula V is alkylated by methods known to those skilled in the art or as described in the examples below to give compounds of formula VI. The intermediate of formula VI is reacted with the appropriate R by methods known to those skilled in the art or as described in the following ¹The precursor is coupled to give an intermediate of formula VII, which can be converted to the desired compound of formula I using standard hydrolysis conditions.

Alternatively, the compounds of formula I may be prepared as outlined in scheme 2 below.

Scheme 2:

scheme 2: all R¹、R^2a、R^2b、R⁴、R⁶、R⁷And LG are the same as described for the compounds of the invention and embodiments of the general formulae thereof.

3-aminopyrazoles of formula II (commercially available or synthesized by methods known to those skilled in the art) are synthesized with intermediates of formula VIII (commercially available or synthesized by methods known to those skilled in the art) wherein R is an ester protecting group (e.g., methyl, ethyl, etc.) in a non-polar aprotic solvent (e.g., benzene, toluene, xylene, etc.)) Condensation in the presence of water at a temperature of from 80 to-140 ℃ gives the desired intermediate of formula IX. Intermediate IX is then converted to an intermediate of formula VI, wherein LG is a leaving group selected only from halogens, by methods known to those skilled in the art or as described in the examples below. The intermediate of formula VI is reacted with the appropriate R by methods known to those skilled in the art or as described in the examples below¹The precursor is coupled to give an intermediate of formula VII, which can be converted to the desired compound of formula I using standard hydrolysis conditions.

In another embodiment, compounds of formula Ia may be prepared as outlined in scheme 3 below.

Scheme 3:

scheme 3: all R¹、R^2a、R^2b、R⁴、R⁶And LG are the same as described for the compounds of the invention and embodiments of the general formulae thereof.

The condensation of 3-amino-1, 2, 4-triazoles of general formula X (commercially available or synthesized by methods known to those skilled in the art) with an intermediate of formula III, wherein R is an ester protecting group (e.g., methyl, ethyl, etc.), in the presence of a non-polar aprotic solvent (e.g., benzene, toluene, xylene, etc.) at temperatures ranging from 80 ℃ to-140 ℃ affords the desired intermediate of formula XI. Intermediate XI is then converted to an intermediate of formula XII, wherein LG is a leaving group selected only from halogens, by methods known to those skilled in the art or as described in the examples below. The intermediate of formula XII is coupled with the appropriate R by methods known to those skilled in the art (amination, Suzuki coupling, Negishi coupling, Stille coupling, etc.) or as described below¹The precursor is coupled to give an intermediate of formula XIII. Alkylation of the intermediate of formula XIII by methods known to those skilled in the art or as described in the examples below gives compounds of formula XIV,it can be converted to the desired compound of formula Ia using standard hydrolysis conditions.

In another embodiment, compounds of formula Ia may be prepared as outlined in scheme 4 below.

Scheme 4:

scheme 4: all R¹、R^2a、R^2b、R⁴、R⁶、R⁷And LG are the same as described for the compounds of the invention and embodiments of the general formulae thereof.

Condensation of a primary amine of formula XV with an orthoester of formula XVI, wherein R is alkyl (methyl or ethyl), and an amino malonyl butyronitrile, in the presence of a strong base (e.g., triethylamine, diisopropylethylamine, etc.) in a polar solvent (e.g., acetonitrile, THF, etc.) at a temperature ranging from 0 ℃ to 80 ℃ affords the desired intermediate of formula XVII. More details can be found in the following references (US 2006/0094706a 1). The intermediate of formula XVII is then reacted with a grignard reagent to give an intermediate of formula XVIII, which can be condensed with an intermediate of formula III in the presence of trimethylsilyl chloride to give an intermediate of formula XIX. Alkylation of the intermediate of formula XIX by methods known to those skilled in the art or as described in the examples below gives the compound of formula XX, which can be converted to the desired compound of formula Ib using standard hydrolysis conditions. Alternatively, the intermediate of formula XX may also result from condensation of an intermediate of formula XVIII with an intermediate of formula VIII, wherein R is an ester protecting group (e.g., methyl, ethyl, etc.).

In another embodiment, compounds of formula Ia may be prepared as outlined in scheme 5 below.

Scheme 5:

scheme 5: all R¹、R^2a、R^2b、R⁴、R⁵、R⁶And LG are the same as described for the compounds of the invention and embodiments of the general formulae thereof.

Condensation of an intermediate of formula XXI (either commercially available or synthesized by methods known to those skilled in the art or as described in the examples below) with a grignard reagent affords an intermediate of formula XXII which is condensed with an intermediate of formula III in the presence of trimethylsilyl chloride to afford an intermediate of formula XXIII. The intermediates of formula XXIII are alkylated by methods known to those skilled in the art or as described in the examples below to give compounds of formula XXIV, which can be converted to the desired compounds of formula Ic using standard hydrolysis conditions. Alternatively, intermediates of formula XXIV can also be obtained from the condensation of an intermediate of formula XXII with an intermediate of formula VIII, wherein R is an ester protecting group (e.g., methyl, ethyl, etc.).

Examples

The following examples are provided for the purpose of illustrating the invention and should in no way be construed as limiting the invention.

Part a represents the preparation of the compounds (intermediates and final compounds) while part B describes the antiviral activity of the compounds of the invention.

TABLE 1: the structures of the compounds of the examples of the present invention and their respective codes.

TABLE 2: the structures of the compounds of the examples of the present invention and their respective codes.

Table 3: the structures of the compounds of the examples of the present invention and their respective codes.

Compound code

R¹

R^2a

R^2b

R³

R⁴

R⁶

CPD-118

P-tolyl radical

H

Me

iPr

CPD-119

P-tolyl radical

H

Me

iPr

CPD-120

P-tolyl radical

N-propyl radical

H

Me

iPr

CPD-121

P-tolyl radical

N-propyl radical

H

Me

iPr

CPD-122

P-tolyl radical

N-propyl radical

H

Et

Me

Benzyl radical

CPD-123

P-tolyl radical

N-propyl radical

H

Me

Benzyl radical

The examples describe the materials used, the general methods of preparation and the synthesis of intermediates

All preparative HPLC purifications mentioned in this experimental section were performed using the following system: waters 2489UV/Visible Detector, Waters 2545Binary Gradient Module, Waters Fraction Collector III and Waters Dual Flex Injector.

The separation was carried out using a SunFire Prep C18ODB column (5 μm; 19X 100mm) equipped with a SunFire C18 guard column (5 μm; 19X 10 mm). Elution was performed using the method described in the table below, and the detection wavelengths were fixed at 210 and 254 nm.

HPLC method 1

Solvent A0.1% formic acid LC-MS grade in MilliQ grade water

Solvent B acetonitrile HPLC grade.

HPLC method 2

Solvent A0.1% formic acid LC-MS grade in MilliQ grade water

Solvent B: acetonitrile HPLC grade.

Summarizing step A:

a mixture of 3-aminopyrazole (1 equivalent) and dialkyl acetyl succinate (1.1 equivalents) in toluene (1mL/mmol of default reagent) was heated to reflux using a Dean Stark system until the theoretical volume of water distilled out in the trap. The precipitate was filtered off and washed with toluene and diethyl ether to give the desired alkyl 2- (7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate, which was used in the next step without any further purification.

Summarizing step B:

alkyl 2- (7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate was suspended in phosphorus oxychloride (1mL/mmol) and dimethylaniline (0.2 to 0.25mL/mmol) was added under a nitrogen atmosphere. The well stirred reaction mixture (temperature from 30 to 60 ℃) was heated until the disappearance of the starting material. Excess phosphorus oxychloride was removed under reduced pressure and the remaining oil was placed in an ice bath. A cold saturated sodium bicarbonate solution was carefully added until neutralization. The aqueous layer was extracted with ethyl acetate, the organics combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the desired alkyl 2- (7-chloropyrazolo [1,5-a ] pyrimidin-6-yl) acetate.

Summarizing step C:

to a solution of alkyl 2- (7-chloropyrazolo [1,5-a ] pyrimidin-6-yl) acetate (1 eq) in dry DMF at-10 ℃ was slowly added a 1N solution of LHMDS in tetrahydrofuran (1.1 to 2 eq). Then, the halide derivative (1.5 to 2 equivalents) is added and the reaction mixture is stirred at room temperature until the default compound disappears. The reaction mixture was quenched by addition of saturated ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the expected product.

Summarizing step D:

to a sonicated solution of alkyl 2- (7-chloropyrazolo [1,5-a ] pyrimidin-6-yl) -2-alkyl-acetate (1 equivalent) and aryl boronic acid (1.5 to 3 equivalents) in a water/DME (1/3) mixture was added tetrakis (triphenyl) phosphine palladium (0.1 to 0.2 equivalents) and diisopropylethylamine (2 to 4 equivalents). The solution was stirred at 140 ℃ for 20 minutes under microwave irradiation. Ethyl acetate was added to the reaction mixture and washed with 1N hydrochloric acid solution, 1N sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the expected product.

Summarizing step E:

to a sonicated solution of alkyl 2- (7-chloropyrazolo [1,5-a ] pyrimidin-6-yl) -2-alkyl-acetate (1 equivalent) and aryl boronic acid (1.5 to 3 equivalents) in a water/DME (1/3) mixture was added tetrakis (triphenylphosphine) palladium (0.1 to 0.2 equivalents) and diisopropylethylamine (3 to 4 equivalents). The reaction mixture is heated at a temperature between 80 and 140 ℃ under an inert atmosphere until the default compound disappears. Ethyl acetate was added to the reaction mixture and the solution was washed with 1N hydrochloric acid solution, 1N sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the expected product.

Intermediate 1: preparation of methyl 2- (7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step A from dimethyl acetylsuccinate (4.1 g; 22mmol) and 3-aminopyrazole (1.66 g; 20mmol) in toluene (20mL) for 18 h. 4.2g of the title compound (95%) were obtained as a white solid. ESI/APCI (+):222(M + H).

Intermediate 2: 2- (7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetic acid ethyl ester

This intermediate was prepared according to step A from diethyl acetylsuccinate (22 mL; 110mmol) and 3-aminopyrazole (8.3 g; 100mmol) in toluene (100mL) for 18 h. 20.2g of the title compound (86%) were obtained as a white solid. ESI/APCI (+):236(M + H).

Intermediate 3: preparation of methyl 2- (2-tert-butyl-7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step A from dimethyl acetylsuccinate (3 g; 15.9mmol) and 3-amino-5-tert-butyl-1H-pyrazole (2.01 g; 14.4mmol) in toluene (25mL) for 18H. 3.32g of the title compound (83%) was obtained as a white solid. ESI/APCI (+):278(M + H).¹H-NMR(DMSO-d₆)12.08(1H,bs)；5.96(1H,s)；3.60(3H,s)；3.52(2H,s)；2.28(3H,s)；1.30(9H,s)。

Intermediate 4: preparation of methyl 2- (7-hydroxy-5-methyl-2-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step A from dimethyl acetylsuccinate (3.92 g; 20.8mmol) and 3-amino-5-phenyl-1H-pyrazole (3 g; 18.9mmol) in toluene (40mL) for 18H. 5.33g of the title compound (95%) was obtained as a white solid. ESI/APCI (+):298(M + H). ESI/APCI (-):296 (M-H).¹H-NMR(DMSO-d₆)(ppm)δ12.38(1H,bs)；7.98(2H,d,J＝6.82Hz)；7.41-7.50(3H,M)；6.58(1H,s)；3.62(3H,s)；3.57(2H,s),2.32(3H,s)。

Intermediate 5: preparation of methyl 2- (7-hydroxy-5-methyl-2-propylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step A from dimethyl acetylsuccinate (1.65 g; 8.8mmol) and 3-amino-5-n-propyl l-1H-pyrazole (1 g; 8mmol) in toluene (8mL) for 20H. 1.79g of the title compound (85%) was obtained as a white solid. ESI/APCI (+):264(M + H).

Intermediate 6: preparation of methyl 2- (2- (furan-2-yl) -7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step A from dimethyl acetylsuccinate (1.4 g; 7.4mmol) and 5- (furan-2-yl) -1H-pyrazol-3-amine (1 g; 6.7mmol) in toluene (7mL) for 20H. 1.76g of the title compound (92%) was obtained as a white solid. ESI/APCI (+):287(M + H).

Intermediate 7: preparation of methyl 2- (7-hydroxy-2-isopropyl-5-methyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) acetate

A mixture of 3-amino-5-isopropyl-1H-1, 2, 4-triazole (1.00 g; 7.93mmol) and dimethyl acetyl succinate (1.85 g; 9.83mmol) in toluene (35mL) was heated to reflux in a Dean Stark system for 24 hours. After cooling, the volatiles were removed under reduced pressure and the remaining oily residue was co-evaporated several times with methanol and then crystallized from methanol. The white solid was filtered and washed with methanol to give 0.396 g. The filtrate was evaporated under reduced pressure, acetic acid (3mL) was added, and the second layer of the solution was crystallized to give 0.187g of a white solid. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (10-100%) gave another 0.72g of a white solid. The overall yield of this step was 62%.¹H-NMR(400MHz,DMSO-d₆)(ppm)δ13.11(1H,bs)；3.61(3H,s)；3.55(2H,s)；3.05(1H,h,J=6.9Hz)；2.31(3H,s)；1.28(6H,d,J=6.9Hz)。

Intermediate 8: preparation of methyl 2- (7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step B from methyl 2- (7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (4.4 g; 20mmol), phosphorus oxychloride (20mL) and dimethylaniline (4mL) for 3 days. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (5-40%) to give 2.4g (50%) of the title compound as a white solid.

ESI/APCI(+):240(M+H)。

Intermediate 9: 2- (7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetic acid ethyl ester

This intermediate was prepared according to step B from ethyl 2- (7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (11.75 g; 50mmol), phosphorus oxychloride (50mL) and dimethylaniline (10mL) for 3 days. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (5-40%) to give 8.2g (64%) of the title compound as a white solid. ESI/APCI (+):240(M + H).

Intermediate 10: preparation of methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step B from methyl 2- (2-tert-butyl-7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (2.00 g; 7.21mmol), phosphorus oxychloride (8mL), and dimethylaniline (1.6mL) for 3 days. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-15%) to give 1.45g (68%) of the title compound as a yellow solid. ESI/APCI (+). 296-298(M + H).

Intermediate 11: preparation of methyl 2- (7-chloro-5-methyl-2-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step B from methyl 2- (7-hydroxy-5-methyl-2-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (3.00 g; 10.09mmol), phosphorus oxychloride (12mL) and dimethylaniline (3mL) for 3 days. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-25%) to give 2.07g (65%) of the title compound as a white solid. ESI/APCI (+): 317-.

Intermediate 12: preparation of methyl 2- (7-chloro-5-methyl-2-propylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step B from methyl 2- (7-hydroxy-5-methyl-2-propylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (1.79 g; 6.8mmol), phosphorus oxychloride (6.8mL), and dimethylaniline (1.4mL) for 3 days. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (1-20%) to give 0.573g (30%) of the title compound as a solid. ESI/APCI (+):282(M + H).

Intermediate 13: preparation of methyl 2- (7-chloro-2- (furan-2-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate

This intermediate was prepared according to step B from methyl 2- (2- (furan-2-yl) -7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (2.75 g; 9.61mmol), phosphorus oxychloride (10mL) and dimethylaniline (2mL) for 3 days. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (1-20%) to give 2.12g (73%) of the title compound as a pale yellow solid. ESI/APCI (+):305(M + H).

Intermediate 14: preparation of methyl 2- (7-chloro-2-isopropyl-5-methyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) acetate

A solution of methyl 2- (7-hydroxy-2-isopropyl-5-methyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) acetate (0.58 g; 2.19mmol) in phosphorus oxychloride (5mL) was heated at 100 ℃ for 24 hours. The phosphorus oxychloride was removed under reduced pressure and the remaining oil was placed in an ice bath. Saturated sodium bicarbonate solution was carefully added until neutralization. The aqueous layer was extracted with ethyl acetate, the organics combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (10-60%) gave 0.403g (65%) of the title compound as a yellow solid. ESI/APCI (+): 283-.

Intermediate 15: preparation of methyl 2- (7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate

This intermediate was prepared according to step C from methyl 2- (7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (1.8 g; 7.8mmol), LHMDS (8.3 mL; 8.3mmol), 1-iodopropane (1.1 mL; 11.25mmol) in DMF (22mL) for 3 hours. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (5-20%) to give 1.8g (85%) of the title compound as a brown oil. ESI/APCI (+). 282-284(M + H).

Intermediate 16: preparation of ethyl 2- (7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate

This intermediate was prepared according to step C from ethyl 2- (7-hydroxy-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (2.53 g; 10mmol), LHMDS (11 mL; 11mmol), 1-iodopropane (1.45 mL; 15mmol) in DMF (30mL) for 3 h. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (5-20%) to give 2.4g (81%) of the title compound as a brown oil. ESI/APCI (+). 296-298(M + H).

Intermediate 17: preparation of methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate

This intermediate was prepared according to step C from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (1 g; 3.38mmol), LHMDS (4 mL; 4mmol), 1-iodopropane (0.50 mL; 5.12mmol) in DMF (10mL) for 3.5 h. Purification by flash chromatography on silica gel using an acetone gradient (0-10%) in heptane yielded 0.90g (79%) of the title compound as a yellow oil. ESI/APCI (+). 338-340(M + H).

Intermediate 18: preparation of methyl 2- (7-chloro-5-methyl-2-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step C from methyl 2- (7-chloro-5-methyl-2-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (1.50 g; 4.75mmol), LHMDS (5.25 mL; 5.25mmol), 1-iodopropane (0.70 mL; 7.17mmol) in DMF (15mL) for 3.5 h. Purification was performed by flash chromatography on silica gel using an acetone gradient in heptane (0-20%) to give 0.90g (41%) of the title compound as an orange oil. ESI/APCI (+). 358- & ltSUB & gt 360(M + H).

Intermediate 19: preparation of methyl 2- (7-chloro-5-methyl-2-propylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step C from methyl 2- (7-chloro-5-methyl-2-propylpyrazolo [1,5-a ] pyrimidin-6-yl) acetate (0.281 g; 1mmol), LHMDS (1.1 mL; 1.1mmol), 1-iodopropane (0.146 mL; 1.5mmol) in DMF (4mL) for 20 hours. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-20%) to give 0.229g (70%) of the title compound as an orange oil. ESI/APCI (+):324-326(M + H).

Intermediate 20: preparation of methyl 2- (7-chloro-5-methyl-2- (furan-2-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step C from methyl 2- (7-chloro-5-methyl-2- (furan-2-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) acetate (0.305 g; 1mmol), LHMDS (1.1 mL; 1.1mmol), 1-iodopropane (0.146 mL; 1.5mmol) in DMF (4mL) for 20 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-20%) gave 0.229g (52%) of the title compound as an oil. ESI/APCI (+). 348- & 350(M + H).

Intermediate 21: preparation of methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -6,6, 6-trifluorohexanoate

This intermediate was prepared according to step C from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrimidino [1,2-b ] indazol-3-yl) acetate (0.303 g; 1.02mmol), LHMDS (1.1 mL; 1.1mmol), 1,1, 1-trifluoro-4-iodobutane (0.210 mL; 1.62mmol) in DMF (3mL) for 20 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-25%) gave 0.175g (42%) of the title compound as an oil. ESI/APCI (+) > 406-408(M + H).

Intermediate 22: preparation of methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionate

This intermediate was prepared according to step C from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrimidino [1,2-b ] indazol-3-yl) acetate (0.504 g; 1.70mmol), LHMDS (2 mL; 2mmol), benzyl bromide (0.300 mL; 2.53mmol) in DMF (5mL) for 20 h. After the addition of benzyl bromide, potassium iodide (0.420 g; 2.53mmol) was added to the mixture. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-25%) to give 0.551g (84%) of the title compound as an orange solid. ESI/APCI (+). 368-370(M + H). ESI/APCI (-): 366-.

Intermediate 23: preparation of methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-methylpentanoate

This intermediate was prepared according to step C from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrimidino [1,2-b ] indazol-3-yl) acetate (0.401 g; 1.36mmol), LHMDS (1.5 mL; 1.5mmol), 2-iodobutane (0.250 mL; 2.17mmol) in DMF (4mL) for 20 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-15%) gave 0.057g (12%) of the title compound as an orange solid. ESI/APCI (+). 338-340(M + H).

Intermediate 24: preparation of methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -4-methoxybutyrate

This intermediate was prepared according to step C from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrimidino [1,2-b ] indazol-3-yl) acetate (0.500 g; 1.70mmol), LHMDS (2 mL; 2mmol), bromoethyl methyl ether (0.300 mL; 2.53mmol) in DMF (5mL) for 20 h. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-35%) to give 0.220g (36%) of the title compound as an orange solid. ESI/APCI (+):354-356(M + H).

Intermediate 25: preparation of ethyl 2- (3-bromo-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate

To 2- (7-chloro-5-methylpyrazolo [1,5-a ]]Pyrimidin-6-yl) pentanoic acid ethyl ester (0.100 g; 0.338mmol) in dichloromethane (1.3mL) was added N-bromosuccinimide (0.085 g; 0.478mmol) and the reaction mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate (10mL) and the resulting solution was washed with saturated sodium hydrogen sulfate solution (10mL), 1M sodium bicarbonate solution (10mL) and (10mL), dried MgSO ₄Filtered and concentrated under reduced pressure. 0.127g of the crude residue (98%) was used in the next step without further purificationAny further purification. ESI/APCI (+): 374-.

Intermediate 26: preparation of methyl 2- (3-bromo-2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ]]Pyrimidin-6-yl) pentanoic acid methyl ester (0.162 g; 0.480mmol) in dichloromethane (2mL) was added N-bromosuccinimide (0.122 g; 0.685mmol), and the reaction mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate (10mL) and the resulting solution was washed with saturated sodium hydrogen sulfate solution (2X 10mL), 1M sodium bicarbonate solution (10mL) and brine (10mL), dried MgSO₄Filtered and concentrated under reduced pressure. 0.182g of crude remaining orange oil (91%) was used in the next step without any further purification. ESI/APCI (+): 416-.

Intermediate 27: preparation of ethyl 3- (2-methyl-1, 3-dioxolan-2-yl) propionate

In a flask equipped with a water trap, a mixture of ethyl levulinate (28.83 g; 200mmol), ethylene glycol (37.24 g; 600mmol) and a catalytic amount of pyridine p-toluenesulfonate in toluene (200mL) was heated to reflux. The trap was purged 3 times until the desired volume of water was distilled. After cooling, the mixture was washed with saturated sodium bicarbonate solution. The basic layer was extracted with ether and the organics were combined and then washed with brine and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a colorless oil. ESI/APCI (+):189(M + H).

Intermediate 28: preparation of ethyl 2- ((2-methyl-1, 3-dioxolan-2-yl) methyl) pentanoate

To a solution of lithium diisopropylamide 2N in tetrahydrofuran (30mL,60mmol) in THF (8mL) cooled (-78 ℃ C.) was added hexamethylphosphoramide (12mL) and the solution was stirred for 30 min. A solution of ethyl 3- (2-methyl-1, 3-dioxolan-2-yl) propionate (9.4 g; 50mmol) in tetrahydrofuran (9mL) was added over 30 minutes and stirring was continued for 1 hour. Propyl iodide (6.84 mL; 70mmol) was added slowly and the solution was allowed to warm to room temperature for 4 hours. The reaction was quenched by the addition of saturated ammonium chloride solution and water. The phases were separated, the aqueous layer was extracted with ethyl acetate (50mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The remaining orange oil was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-40%) to give 9.8g (85%) of oil. ESI/APCI (+):231(M + H).

Intermediate 29: preparation of ethyl 4-oxo-2-propylvalerate

To a solution of ethyl 2- ((2-methyl-1, 3-dioxolan-2-yl) methyl) pentanoate (9.8 g; 42.55mmol) in hexane (106mL) at-78 ℃ under nitrogen was added boron tribromide (1M in dichloromethane) (55 mL; 55mmol) and the reaction mixture was stirred at-20 ℃ for 2 h. Water (50mL) and ethyl acetate (50mL) were added to the reaction mixture and the two phases were separated. The aqueous layer was extracted with ethyl acetate, the organics combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (1-40%) to give 6.41g (81%) of the title compound as a pale yellow oil. ESI/APCI (+):187(M + H).

Intermediate 30: preparation of 5-amino-1, 2-dimethyl-1H-imidazole-4-carbonitrile

To a suspension of aminomalonbutyronitrile p-toluenesulfonate (0.5 g; 1.974mmol) in acetonitrile (9mL) was added a 0.5M aqueous ammonia solution (4 mL; 2mmol) in tetrahydrofuran. The reaction mixture was stirred at room temperature for 2.5 hours. The solid was filtered and washed with tetrahydrofuran. The filtrate was concentrated to a volume of 10 mL. Triethylorthoacetate (Triethyltartoacetate) (0.361 mL; 1.969mmol) was added and the reaction mixture was refluxed for 1 h. After cooling to 0 ℃ a solution of triethylamine (0.330 mL; 2.368mmol) and 2M methylamine in tetrahydrofuran (1.2 mL; 2.400mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (5-10%) to yield 0.090g (33%) of the title compound as a yellow solid. ESI/APCI (+):137(M + H). ESI/APCI (-):135 (M-H).

Intermediate 31: preparation of (5-amino-1, 2-dimethyl-1H-imidazol-4-yl) (p-tolyl) methanone

To a solution of 5-amino-1, 2-dimethyl-1H-imidazole-4-carbonitrile (0.090 g; 0.661mmol) in tetrahydrofuran (27mL) was added a solution of 1 Mp-methylphenylmagnesium bromide in tetrahydrofuran (3.3 mL; 3.300 mmol). After stirring at room temperature for 2h, 3M hydrochloric acid solution (27mL) was added and the reaction mixture was stirred at room temperature for 18h and at 80 ℃ for an additional 1 h. The reaction mixture was then cooled to 0 ℃, basified with 6M sodium hydroxide solution (pH =9) and extracted twice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The remaining residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (2-30%) to give 0.077mg (51%) of the title compound as a yellow solid. ESI/APCI (+):230(M + H); 252(M + Na); 481(2M + Na).

Intermediate 32: n-cyanoacetimidate

To a solution of 1,1, 1-triethoxyethane (3.66 mL; 20mmol) in acetonitrile (40mL) was added cyanamide (0.882 g; 21mmol), and the reaction mixture was stirred at room temperature for 21 hours. There was no reaction, so the mixture was heated to reflux for 18 hours. Volatiles were removed under reduced pressure and 2.24g (100%) of the crude white solid was dried and used without further purification. ESI/APCI (+):113(M + H). NMR (C)¹H):DMSO-d64.24(q,2H,CH₂),2.37(s,3H,CH₃),1.27(t,3H,CH₃)。

Intermediate 33: n' -cyano-N- (cyanomethyl) -N-methyletheneimide

To a solution of ethyl N-cyanoethylidene (1.12 g; 10mmol) in ethanol (20mL) was added 2- (methylamino) acetonitrile (0.736 g; 10.5mmol), and the reaction mixture was stirred at room temperature for 24 hours. Volatiles were removed under reduced pressure and 1.36g (100%) of the crude white solid was dried and used without further purification. ESI/APCI (+):137(M + H).

Intermediate 34: preparation of 4-amino-1, 2-dimethyl-1H-imidazole-5-carbonitrile

To a solution of N' -cyano-N- (cyanomethyl) -N-methylethanamide (1.36 g; 10mmol) in dry ethanol (50mL) under nitrogen was added sodium ethoxide (4.85 mL; 13mmol) and the reaction mixture was stirred at room temperature for 18h after cooling, the volatiles were removed under reduced pressure and the remaining crude was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-20%) to give 1.23g (61%) of the title compound as a pale beige solid. ESI/APCI (+):137(M + H).

Intermediate 35: preparation of (4-amino-1, 2-dimethyl-1H-imidazol-5-yl) (p-tolyl) methanone

To a solution of 4-amino-1, 2-dimethyl-1H-imidazole-5-carbonitrile (0.272 g; 2mmol) in dry tetrahydrofuran (60mL) under a nitrogen atmosphere was slowly added a solution of 1M magnesium p-tolyl bromide in tetrahydrofuran (10 mL; 10 mmol). The resulting solution was stirred at room temperature for 21 hours. A 3N hydrochloric acid solution (40mL) was added to hydrolyze the intermediate imine and the reaction mixture was heated to reflux for 2 hours. The volatiles were removed under reduced pressure and the crude residue was dissolved in ethyl acetate. The well stirred mixture was basified by the addition of 3N sodium hydroxide solution. Purification by flash chromatography on silica gel using a gradient of methanol in dichloromethane (1-20%) gave 0.172g (37%) of the title compound as a dark yellow oil. ESI/APCI (+):230(M + H).

Intermediate 36: preparation of 5-amino-1-methyl-2-propyl-1H-imidazole-4-carbonitrile

To a suspension of aminomalonbutyronitrile p-toluenesulfonate (1.26 g; 5mmol) in acetonitrile was added a solution of 0.5M aqueous ammonia in tetrahydrofuran (12 mL; 6mmol), and the reaction mixture was stirred at room temperature for 2.5 hours. The suspension was filtered, washed with acetonitrile, and the filtrate was concentrated until about 20 mL. Trimethyltributyrate was added and the reaction mixture was heated to reflux for 5 hours.

After cooling at 0 ℃ triethylamine (1.69 mL; 6mmol) and methylamine (2M in tetrahydrofuran) (3 mL; 6mmol) were added. The solution was stirred at room temperature for 21 hours. The volatiles were removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (1-20%) to give 0.351g (42%) of the title compound as a pale brown solid. ESI/APCI (+):164(M + H).

Intermediate 37: preparation of (5-amino-1-methyl-2-propyl-1H-imidazol-4-yl) (p-tolyl) methanone

To a solution of 5-amino-1-methyl-2-n-propyl-1H-imidazole-4-carbonitrile (0.328 g; 2mmol) in dry tetrahydrofuran (20mL) was slowly added a solution of 1M p-tolylmagnesium bromide in tetrahydrofuran (10 mL; 10mmol) under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 hours. A 3N hydrochloric acid solution (20mL) was added to hydrolyze the intermediate imine and the reaction mixture was heated to reflux for 1h and at room temperature for 18 h. After cooling at 0 ℃, the reaction mixture was basified with 6N sodium hydroxide solution. The product was extracted with ethyl acetate (80mL) and the organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol in dichloromethane (1-20%) gave 0.180g (35%) of the title compound as a dark yellow oil. ESI/APCI (+):258(M + H).

Intermediate 38: preparation of 5-amino-1-methyl-2-isopropyl-1H-imidazole-4-carbonitrile

To a suspension of aminomalonbutyronitrile p-toluenesulfonate (2.53 g; 10mmol) in acetonitrile (40mL) was added a 0.5M solution of aqueous ammonia in tetrahydrofuran (24 mL; 12mmol), and the reaction mixture was stirred at room temperature for 2.5 hours. The suspension was filtered, washed with acetonitrile and tetrahydrofuran, and the filtrate was concentrated until about 40 mL. Trimethyltributyrate was added and the reaction mixture was heated to reflux for 21 hours. After cooling at 0 ℃ triethylamine (3.4 mL; 12mmol) and methylamine (2M in tetrahydrofuran) (6 mL; 12mmol) were added. The solution was stirred at room temperature for 21 hours. The volatiles were removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (1-20%) to give 0.901g (55%) of the title compound as a brown solid. ESI/APCI (+):164(M + H).

Intermediate 39: preparation of (5-amino-1-methyl-2-isopropyl-1H-imidazol-4-yl) (p-tolyl) methanone

To a solution of 5-amino-1-methyl-2-isopropyl-1H-imidazole-4-carbonitrile (0.328 g; 2mmol) in dry tetrahydrofuran (20mL) was slowly added a solution of 1M p-tolylmagnesium bromide in tetrahydrofuran (10 mL; 10mmol) under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 hours. A 3N hydrochloric acid solution (20mL) was added to hydrolyze the intermediate imine and the reaction mixture was heated to reflux for 1h and at room temperature for 18 h. After cooling at 0 ℃, the reaction mixture was basified with 6N sodium hydroxide solution. The product was extracted with ethyl acetate (80mL) and the organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol in dichloromethane (1-20%) gave 0.304g (59%) of the title compound as a dark yellow oil. ESI/APCI (+):258(M + H).

Intermediate 40: preparation of methyl 2- (7-hydroxy-2-isopropyl-5-methyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) acetate

A mixture of 3-amino-5-isopropyl-1H-1, 2, 4-triazole (1 g; 7.93mmol) and dimethyl acetyl succinate (1.85 g; 9.83mmol) in toluene (35mL) was heated at reflux in a flask equipped with a Dean-Stark apparatus for 24 hours. The solvent was evaporated under reduced pressure and the remaining residue was co-evaporated in methanol before crystallization in methanol to give 0.396g of the title compound as a white solid. The filtrate was evaporated, acetic acid (3mL) was added, and the solution was crystallized a second time to give 0.187g of the title compound. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (20-100%) to give 0.72g of the title compound as a white solid (62% overall yield).¹H-NMR(400MHz,DMSO-d₆)(ppm)δ13.11(bs,1H,OH)；3.61(s,3H,OCH₃)；3.55(s,2H,CH₂)；3.05(m,1H,CH(CH₃)₂)；2.31(s,3H,CH₃)；1.28(d,J=6.9Hz,6H,CH(CH₃)₂)。

Intermediate 41: preparation of methyl 2- (7-chloro-2-isopropyl-5-methyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) acetate

A stirred solution of methyl 2- (7-hydroxy-2-isopropyl-5-methyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) acetate (0.50 g; 1.89mmol) in phosphorus oxychloride (5 mL; 53.6mmol) was heated at 105 ℃ for 18 hours. Dimethylaniline (1 mL; 7.89mmol) was then added and the solution was stirred at 105 ℃ for 3 hours. After cooling, the volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane (15 mL). The solution was washed successively with 1N sodium hydroxide solution (2X 10mL), 1N hydrochloric acid solution (10mL) and brine (2X 15 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (10-60%) gave 0.325g (61%) of the title compound as a light brown solid. ESI/APCI (+): 283-.

Intermediate 42: preparation of 2-methoxy-4-methylaniline

To a solution of 2-methoxy-4-methyl-1-nitrobenzene (5 g; 29.9mmol) in methanol (200mL) was added tin (II) chloride dihydrate (33.7 g; 150mmol) and the mixture was heated at reflux for 3 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and a saturated solution of sodium bicarbonate was added until a basic pH was reached. The suspension was filtered through a celite plug, the organic phase was separated, washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is thus used in the next reaction.

Intermediate 43: preparation of 1-bromo-2-methoxy-4-toluene

To a solution of copper (II) bromide (6.35 g; 28.4mmol) in acetonitrile (25mL) was added tert-butyl nitrite (2.85 mL; 24.06mmol) and the mixture was heated at 65 ℃ under nitrogen. A solution of 2-methoxy-4-methylaniline (3g,21,87mmol) in 25ml acetonitrile was added carefully and the mixture was stirred at 65 ℃ for 20 min. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and washed with 5% aqueous ammonia solution, water, EDTA solution, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification was carried out by flash chromatography on silica gel, Using a gradient of ethyl acetate in heptane (2-50%) 2.32g (53%) of the title compound are obtained.¹H-NMR(300MHz,CDCl₃)(ppm)δ6.63-6.60(m,3H,3×Harom.)；3.82(s,3H,OCH₃)；2.26(s,3H,CH₃)。

Intermediate 44: preparation of 2-methoxy-4-methylphenylboronic acid

To a cold (-78 ℃ C.) solution of 1-bromo-2-methoxy-4-toluene (1.67 g; 8.31mmol) in dry THF (40mL) under a nitrogen atmosphere was added dropwise a 1.5M solution of tert-butyllithium in pentane (12.18 mL; 18,27 mmol). After 10 min, trimethyl borate (1.415 mL; 12.46mmol) was added dropwise as a neat liquid and the reaction was stirred at-78 ℃ for 1 h. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1 hour. The mixture was quenched with a saturated solution of ammonium chloride and the organic layer was removed under reduced pressure. The residue was acidified with 2N hydrochloric acid solution and the mixture was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was precipitated from DCM/heptane, washed with heptane and dried under high vacuum to give 0.2g (14.5%) of the title compound as an off-white solid.¹H-NMR(300MHz,CDCl₃)(ppm)δ7.57(d,J=8.1Hz,1H,H⁶)；6.86(s,1H,H³)；6.79(d,J=8.1Hz,1H,H⁵)；3.99(s,3H,OCH₃)；2.40(s,3H,CH₃)。

Intermediate 45: preparation of methyl 2- (7-hydroxy-2-isopropyl-5-methyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate

A mixture of diethyl 2-acetyl-3-propylsuccinate (1.50 g; 5.81mmol) and 3-amino-5-isopropyl-1, 2, 4-triazole (0.50 g; 3.96mmol) in toluene (20mL) was heated at reflux in a flask equipped with a Dean-Stark apparatus for 4 days. After cooling, the solvent was evaporated, diethyl ether (5mL) was added and the solution was cooled at 4 ℃ for several hours. The white precipitate formed was filtered and then dissolved in THF (3.75 mL). 5% sodium hydroxide solution (1.25 mL; 1.56mmol) was added and the reaction mixture was stirred at room temperature for 24 h. Solid sodium hydroxide (0.100 g; 2.50mmol) was added and the reaction mixture was heated to 75 ℃ for 18 h. The solvent was evaporated and a 1N hydrochloric acid solution was added to the residue. The aqueous solution was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was dissolved in methanol (2mL) and thionyl chloride (thionyl chloride) (0.050 mL; 0.685mmol) was added. The solution was stirred at room temperature for 40 hours. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid solution and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.133g (11%) of the title compound as an off-white oil. ESI/APCI (+):307(M + H). ESI/APCI (-):305 (M-H).

Intermediate 46: preparation of methyl 2- (7-chloro-2-isopropyl-5-methyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To a solution of methyl 2- (7-hydroxy-2-isopropyl-5-methyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.133 g; 0.434mmol) in phosphorus oxychloride (2mL) was added dimethylaniline (0.050 mL; 0.394mmol), and the solution was stirred at 45 ℃ for 3 days and at 110 ℃ for another 24 hours. After cooling, the solvent was evaporated and 1N sodium hydroxide solution was added to the residue. The product was extracted with ethyl acetate and the combined organics were washed with 1N hydrochloric acid solution, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The title compound (0.122g,87%) was isolated as a brown oil. ESI/APCI (+):325-327(M + H).

Intermediate 47: preparation of ethyl 2- (2-benzyl-7-hydroxy-5-methyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate

3-amino-5-benzyl-1H-1, 2, 4-triazole (0.700 g; 4.02mmol) and diethyl 2-acetyl-3-propylsuccinate (1.50 g; 5.81mmol) were dissolved in toluene (20mL) and the solution was heated at reflux in a flask equipped with a Dean-Stark apparatus for 4 days. The solvent was evaporated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-3%) to give 0.571g (39%) of the title compound as a white foam. ESI/APCI (+):369(M + H).

Intermediate 48: preparation of ethyl 2- (2-benzyl-7-chloro-5-methyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To a solution of ethyl 2- (-2-benzyl-7-hydroxy-5-methyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.571 g; 1.55mmol) in phosphorus oxychloride (7mL) was added dimethylaniline (0.200 mL; 1.58mmol), and the solution was stirred at 110 ℃ for 5 hours. After cooling, the excess phosphorus oxychloride was removed and ethyl acetate was added to the residue. Solution 1N sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with 1N hydrochloric acid solution, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-50%) to give 0.390g (65%) of the title compound as a colorless oil. ESI/APCI (+). 387-389(M + H).

Example 1: preparation of ethyl 2- (7- ((R) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To a suspension of ethyl 2- (7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.295 g; 1mmol) in anhydrous toluene (1mL) were added (R) -3-aminopiperidine (0.4 g; 2mmol), diisopropylethylamine (0.331 mL; 2mmol), and the reaction mixture was heated at 90 ℃ in a sealed tube for 18 hours. After cooling, the volatiles were removed under reduced pressure and the residue left was purified by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-50%) to yield 0.413g (93%) of ethyl 2- (7- ((R) -3- (tert-butoxycarbonylamino) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate as a yellow oil. ESI/APCI (+):460(M + H).

The final ethyl 2- (7- ((R) -3- (tert-butoxycarbonylamino) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.378g,0.82mmol) was dissolved in dichloromethane (4mL) and trifluoroacetic acid (1mL) was added dropwise. After stirring for 30 minutes, toluene (5ml) was added and volatiles were removed under reduced pressure. The remaining residue was dissolved in a dichloromethane-triethylamine mixture (1:1,6mL), and p-chlorobenzenesulfonyl chloride (0.211 g; 1mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by addition of saturated ammonium chloride solution and the aqueous layer was extracted with dichloromethane. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (2-50%) to give 0.380g (87%) of the title compound as an oil. ESI/APCI (+):534-536(M + H).

Example 2: preparation of ethyl 2- (7- ((S) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To a suspension of ethyl 2- (7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.295 g; 1mmol) in dry toluene (1mL) was added (S) -3-Boc aminopiperidine (0.4 g; 2mmol), diisopropylethylamine (0.331 mL; 2mmol), and the reaction mixture was heated in a sealed tube at 90 ℃ for 3 hours. After cooling, the volatiles were removed under reduced pressure and the residue left was purified by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-50%) to yield 0.401g (87%) of ethyl 2- (7- ((S) -3- (tert-butoxycarbonylamino) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate as a yellow oil. ESI/APCI (+):460(M + H).

The final ethyl 2- (7- ((S) -3- (tert-butoxycarbonylamino) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.368g,0.80mmol) was dissolved in dichloromethane (4mL) and trifluoroacetic acid (1mL) was added dropwise. After stirring for 30 minutes, toluene (5ml) was added and volatiles were removed under reduced pressure. The remaining residue was dissolved in a dichloromethane-triethylamine mixture (1:1,6mL), and p-chlorobenzenesulfonyl chloride (0.211 g; 1mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by addition of saturated ammonium chloride solution and the aqueous layer was extracted with dichloromethane. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (2-50%) to give 0.280g (65%) of the title compound as an oil. ESI/APCI (+):534-536(M + H).

Example 3: 2- (7- ((R) -3- (4-Chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid ethyl ester

To a suspension of ethyl 2- (7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.281 g; 1mmol) in dry toluene (1mL) was added (R) -3-Boc aminopyrrolidine (0.370 g; 2mmol), diisopropylethylamine (0.414 mL; 2.5mmol), and the reaction mixture was heated at 90 ℃ for 3 hours in a sealed tube. After cooling, the volatiles were removed under reduced pressure and the residue left was purified by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-50%) to yield 0.394g (92%) of ethyl 2- (7- ((R) -3- (tert-butoxycarbonylamino) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate as a yellow oil. ESI/APCI (+):446(M + H).

The final ethyl 2- (7- ((R) -3- (tert-butoxycarbonylamino) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.394g,0.92mmol) was dissolved in dichloromethane (4mL) and trifluoroacetic acid (1mL) was added dropwise. After stirring for 30 minutes, toluene (5ml) was added and volatiles were removed under reduced pressure. The remaining residue was dissolved in a dichloromethane-triethylamine mixture (1:1,6mL), and p-chlorobenzenesulfonyl chloride (0.211 g; 1mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by addition of saturated ammonium chloride solution and the aqueous layer was extracted with dichloromethane. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (2-50%) to give 0.316g (67%) of the title compound as an oil. ESI/APCI (+). 520-522(M + H).

Example 4: 2- (7- ((S) -3- (4-Chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid ethyl ester

To a suspension of ethyl 2- (7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.281 g; 1mmol) in dry toluene (1mL) was added (S) -3-Boc aminopyrrolidine (0.370 g; 2mmol), diisopropylethylamine (0.414 mL; 2.5mmol), and the reaction mixture was heated at 90 ℃ for 3 hours in a sealed tube. After cooling, the volatiles were removed under reduced pressure and the residue left was purified by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-50%) to yield 0.402g (93%) of ethyl 2- (7- ((S) -3- (tert-butoxycarbonylamino) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate as a yellow oil. ESI/APCI (+):446(M + H).

The final ethyl 2- (7- ((S) -3- (tert-butoxycarbonylamino) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.394g,0.92mmol) was dissolved in dichloromethane (4mL) and trifluoroacetic acid (1mL) was added dropwise. After stirring for 30 minutes, toluene (5ml) was added and volatiles were removed under reduced pressure. The remaining residue was dissolved in a dichloromethane-triethylamine mixture (1:1,6mL), and p-chlorobenzenesulfonyl chloride (0.211 g; 1mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by addition of saturated ammonium chloride solution and the aqueous layer was extracted with dichloromethane. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (2-50%) to give 0.300g (64%) of the title compound as an oil. ESI/APCI (+). 520-522(M + H).

Example 5: preparation of methyl 2- (5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate

This intermediate was prepared according to step D from methyl 2- (7-chloro-5-methyl-2-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.281 g; 1mmol), phenylboronic acid (0.366 mg; 3mmol), tetrakis (triphenylphosphine) palladium (0.231 mg; 0.2mmol) and diisopropylethylamine (0.663 mL; 4mmol) in DME-water (3: 1; 4mL) at 130 ℃ for 20 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-50%) gave 0.266g (82%) of the title compound as an oil contaminated with impurities. ESI/APCI (+):324(M + H).

Example 6: preparation of methyl 2- (5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (7-chloro-5-methyl-2-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.281 g; 1mmol), p-tolylboronic acid (0,268 g; 2mmol), tetrakis (triphenylphosphine) palladium (0.231 mg; 0.2mmol) and diisopropylethylamine (0.414 mL; 2.5mmol) in DME-water (3: 1; 4mL) at 140 ℃ for 40 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-50%) gave 0.337g (82%) of the title compound as an oil contaminated with impurities. ESI/APCI (+):338(M + H).

Example 7: preparation of methyl 2- (2-tert-butyl-5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.202 g; 0.598mmol), phenylboronic acid (0.146 g; 1.20mmol), tetrakis (triphenylphosphine) palladium (0.092 g; 0.079mmol) and diisopropylethylamine (0.350 mL; 2mmol) in DME-water (3: 1; 2.5mL) at 80 ℃ for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (2-50%) gave 0.141g (62%) of the title compound as an oil contaminated with impurities. ESI/APCI (+):380(M + H).

Example 8: preparation of methyl 2- (2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.152 g; 0.450mmol), p-tolylboronic acid (0.120 g; 0.833mmol), tetrakis (triphenylphosphine) palladium (0.080 g; 0.069mmol) and diisopropylethylamine (0.250 mL; 1.44mmol) in DME-water (3: 1; 1.7mL) at 140 ℃ for 40 hr. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-40%) gave 0.126g (71%) of the title compound as an oil contaminated with impurities. ESI/APCI (+):394(M + H).

Example 9: preparation of methyl 2- (5-methyl-2-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (7-chloro-5-methyl-2-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.100 g; 0.279mmol), p-tolylboronic acid (0.075 g; 0.552mmol), tetrakis (triphenylphosphine) palladium (0.069 g; 0.059mmol) and diisopropylethylamine (0.200 mL; 1.15mmol) in DME-water (3: 1; 1mL) at 140 ℃ for 40 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-40%) gave 0.109g (94%) of the title compound as an oil contaminated with impurities. ESI/APCI (+):414(M + H).

Example 10: preparation of methyl 2- (2-tert-butyl-7- (3-hydroxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.171 g; 0.506mmol), p-tolylboronic acid (0.075 g; 0.552mmol), tetrakis (triphenylphosphine) palladium (0.067 g; 0.058mmol) and diisopropylethylamine (0.300 mL; 1.72mmol) in DME-water (3: 1; 2mL) at 80 ℃ for 4 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-40%) gave 0.172g (86%) of the title compound as an oil contaminated with impurities. ESI/APCI (+):396(M + H).

Example 11: preparation of methyl 2- (2-tert-butyl-7- (2-naphthyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.111 g; 0.328mmol), 2-naphthylboronic acid (0.106 g; 0.616mmol), tetrakis (triphenylphosphine) palladium (0.042 g; 0.039mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-20%) gave 0.143g (100%) of the title compound as an oil contaminated with impurities. ESI/APCI (+):430(M + H).

Example 12: preparation of methyl 2- (2-tert-butyl-7- (1H-indol-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.106 g; 0.313mmol), 1H-indol-5-ylboronic acid (0.106 g; 0.659mmol), tetrakis (triphenylphosphine) palladium (0.039 g; 0.033mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 48H. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-35%) to give 0.129g (98%) of the title compound as a yellow foam contaminated with impurities. ESI/APCI (+):419(M + H).

Example 13: preparation of methyl 2- (2-tert-butyl-7- (1H-indol-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.100 g; 0.295mmol), 1H-indol-6-ylboronic acid (0.102 g; 0.634mmol), tetrakis (triphenylphosphine) palladium (0.041 g; 0.035mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 48H. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-35%) to give 0.104g (84%) of the title compound as a yellow foam contaminated with impurities. ESI/APCI (+):419(M + H).

Example 14: preparation of methyl 2- (2-tert-butyl-7- (1-benzofuran-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.100 g; 0.296mmol),5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-benzofuran (0.152 g; 0.623mmol), tetrakis (triphenylphosphine) palladium (0.039 g; 0.034mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2mL) at 90 ℃ for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-15%) gave 0.114g (92%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):420(M + H).

Example 15: preparation of methyl 2- (2-tert-butyl-7- (1-benzothien-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.83 g; 0.244mmol), 2- (1-benzothien-5-yl) -4,4,5, 5-tetra-methyl-1, 3, 2-dioxaborolane (dioxaborolane) (0.120 g; 0.461mmol), tetrakis (triphenylphosphine) palladium (0.039 g; 0.034mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2mL) at 90 ℃ for 48 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-15%) gave 0.102g (96%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):436(M + H).

Example 16: preparation of methyl 2- (2-tert-butyl-7- (2, 3-dihydrobenzofuran-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.097 g; 0.287mmol),2, 3-dihydroxybenzofuran-5-ylboronic acid (0.096 g; 0.585mmol), tetrakis (triphenylphosphine) palladium (0.042 g; 0.036mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-35%) gave 0.096g (79%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):422(M + H).

Example 17: preparation of methyl 2- (2-tert-butyl-7- (4-chlorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.104 g; 0.302mmol), 4-chlorophenylboronic acid (0.105 g; 0.671mmol), tetrakis (triphenylphosphine) palladium (0.066 g; 0.057mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 18 hours. The crude was used in the next step without any further purification. ESI/APCI (+):414-416(M + H).

Example 18: preparation of methyl 2- (2-tert-butyl-7- (3, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.104 g; 0.308mmol), 3, 4-dimethylphenylboronic acid (0.087 g; 0.580mmol), tetrakis (triphenylphosphine) palladium (0.057 g; 0.049mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 18 hours. The crude was used in the next step without any further purification. ESI/APCI (+):408(M + H).

Example 19: preparation of methyl 2- (2-tert-butyl-7- (4-ethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.108 g; 0.320mmol), 4-ethylphenylboronic acid (0.090 g; 0.600mmol), tetrakis (triphenylphosphine) palladium (0.066 g; 0.057mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 18 hours. The crude was used in the next step without any further purification. ESI/APCI (+):408(M + H).

Example 20: preparation of methyl 2- (2-tert-butyl-7- (3, 4-dihydro-2H-benzo [ b ] [1,4] dioxacyclohepta-7-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.098 g; 0.290mmol), 3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-7-yl-boronic acid (0.121 g; 0.624mmol), tetrakis (triphenylphosphine) palladium (0.034 g; 0.029mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 48 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-15%) gave 0.114g (87%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):452(M + H).

Example 21: preparation of methyl 2- (2-tert-butyl-7- (2- (7- (4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.068 g; 0.201mmol), 4-methyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, dihydro-2H-benzo [ b ] [1,4] oxazine (0.112 g; 0.407mmol), tetrakis (triphenylphosphine) palladium (0.034 g; 0.030mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2mL) at 90 ℃ for 48H. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (0-35%) gave 0.071g (78%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):451(M + H).

Example 22: 2- (3-bromo-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid ethyl ester

To a solution of ethyl 2- (3-bromo-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.509 g; 1.36mmol) in dry tetrahydrofuran (15mL) was added p-tolylmagnesium bromide (3.2 mL; 2.36 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The organic solution was poured with saturated ammonium chloride solution (50mL), water (5mL) was added to the mixture, and the product was extracted with ethyl acetate (45 mL). The organic phase was washed with brine (40mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-15%) to give 0.381g (65%) of the title compound as a pale yellow oil contaminated with impurities. ESI/APCI (+). 430-432(M + H).

Example 23: preparation of ethyl 2- (5-methyl-3-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from ethyl 2 (3-bromo-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.070 g; 0.163mmol), phenylboronic acid (0.045 g; 0.372mmol), tetrakis (triphenylphosphine) palladium (0.023 g; 0.020mmol) and diisopropylethylamine (0.100 mL; 0.574mmol) in DME-water (3: 1; 1.5mL) at 90 ℃ for 18 hours. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-10%) to give 0.050g (72%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):428(M + H).

Example 24: preparation of ethyl 2- (5-methyl-3, 7-di-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from ethyl 2- (3-bromo-7-chloro-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.123 g; 0.328mmol), p-tolylboronic acid (0.100 g; 0.736mmol), tetrakis (triphenylphosphine) palladium (0.029 g; 0.025mmol) and diisopropylethylamine (0.240 mL; 1.38mmol) in DME-water (3: 1; 1.5mL) at 80 ℃ for 24 hours. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-20%) to give 0.086g (61%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):442(M + H).

Example 25: preparation of methyl 2- (3-bromo-2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ]]Pyrimidin-6-yl) pentanoic acid methyl ester (0.312 g; 0.793mmol) of dichloromethane (5mL) was added N-bromosuccinimide (0.214 g; 1.2mmol) and the reaction mixture was stirred at room temperature for 1.5 hours. The solution was diluted with ethyl acetate (20mL) and the resulting solution was washed with saturated sodium hydrogen sulfate solution (2X 20mL), 1M sodium bicarbonate solution (20mL) and brine (20mL), over MgSO ₄Dried, filtered and concentrated under reduced pressure. 0.369g of crude (99%) remaining as a viscous solid was used in the next step without any further purification. ESI/APCI (+). 472-474(M + H).¹H-NMR(400MHz,DMSO-d₆)(ppm)δ7.36(4H,m)；3.72(1H,t,J=6.6Hz)；3.64(3H,s)；2.48(3H,s)；2.42(3H,s)；2.01(1H,m)；1.60(1H,m)；1.33(9H,s)；1.01(2H,m),0.63(3H,t,J=7.2Hz)。

Example 26: preparation of methyl 2- (2-tert-butyl-5-methyl-3, 7-di-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (3-bromo-2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.047 g; 0.112mmol), p-tolylboronic acid (0.065 g; 0.479mmol), tetrakis (triphenylphosphine) palladium (0.017 g; 0.016mmol) and diisopropylethylamine (0.120 mL; 0.689mmol) in DME-water (3: 1; 1mL) at 120 ℃ for 24 h. Purification by flash chromatography on silica gel with a gradient of ethyl acetate in heptane (0-12%) gave 0.014g (25%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):484(M + H).

Example 27: preparation of methyl 2- (5-methyl-2-propyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (7-chloro-5-methyl-2-propylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.229 g; 0.7mmol), 4-methylphenylboronic acid (0.192 mg; 1.41mmol), tetrakis (triphenylphosphine) palladium (0.122 mg; 0.106mmol) and diisopropylethylamine (0.351 mL; 2.12mmol) in DME-water (3: 1; 2.8mL) at 140 ℃ for 20 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (1-30%) gave 0.105g (39%) of the title compound as an oil contaminated with impurities. ESI/APCI (+):380(M + H).

Example 28: preparation of methyl 2- (2- (furan-2-yl) -5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (7-chloro-2- (furan-2-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.182 g; 0.52mmol), 4-methylphenylboronic acid (0.142 mg; 1.04mmol), tetrakis (triphenylphosphine) palladium (0.090 mg; 0.078mmol) and diisopropylethylamine (0.260 mL; 1.57mmol) in DME-water (3: 1; 2.1mL) at 140 ℃ for 20 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in dichloromethane (1-40%) gave 0.123g (58%) of the title compound as an oil. ESI/APCI (+):404(M + H).

Example 29: preparation of methyl 2- (2-tert-butyl-7- (4-chloro-2-fluorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.097 g; 0.287mmol), 4-chloro-2-fluorophenylboronic acid (0.096 g; 0.551mmol), tetrakis (triphenylphosphine) palladium (0.033 g; 0.029mmol) and diisopropylethylamine (0.200 mL; 1.15mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) gave 0.101g (81%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+). 432-434(M + H).

Example 30: preparation of methyl 2- (2-tert-butyl-7- (2-fluoro-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.100 g; 0.296mmol), 2-fluoro-4-methylphenylboronic acid (0.086 g; 0.559mmol), tetrakis (triphenylphosphine) palladium (0.031 g; 0.027mmol) and diisopropylethylamine (0.200 mL; 1.15mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) gave 0.122g (87%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):412(M + H).

Example 31: preparation of methyl 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -6,6, 6-trifluorohexanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -6,6, 6-trifluorohexanoate (0.175 g; 0.431mmol), p-tolylboronic acid (0.120 mg; 0.883mmol), tetrakis (triphenylphosphine) palladium (0.050 g; 0.043mmol) and diisopropylethylamine (0.300 mL; 1.72mmol) in DME-water (3: 1; 4mL) at 140 ℃ for 20 min. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) to give 0.135g (68%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):462(M + H).

Example 32: preparation of methyl 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionate (0.150 g; 0.287mmol), p-tolylboronic acid (0.100 mg; 0.500mmol), tetrakis (triphenylphosphine) palladium (0.045 g; 0.039mmol) and diisopropylethylamine (0.270 mL; 1.55mmol) in DME-water (3: 1; 3.5mL) at 120 ℃ for 20 min. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) to give 0.118g (69%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):442(M + H).

Example 33: preparation of methyl 2- (2-tert-butyl-7- (1-methylindol-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.099 g; 0.292mmol), 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole (0.143 g; 0.556mmol), tetrakis (triphenylphosphine) palladium (0.038 g; 0.033mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2.5mL) at 90 ℃ for 21 hours. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-20%) to give 0.097g (77%) of the title compound as a yellow foam. ESI/APCI (+):433(M + H).

Example 34: preparation of methyl 2- (2-tert-butyl-5-methyl-7- (1-methyldiinoindol-5-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.079 g; 0.234mmol), 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline (0.099 mg; 0.382mmol), tetrakis (triphenylphosphine) palladium (0.025 g; 0.022mmol) and diisopropylethylamine (0.160 mL; 0.919mmol) in DME-water (3: 1; 2mL) at 90 ℃ for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-35%) gave 0.170g (73%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):435(M + H).

Example 35: preparation of methyl 2- (2-tert-butyl-5-methyl-7- (1-methyl-1H-indol-6-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.077 g; 0.227mmol), 1-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-H-indole (0.102 mg; 0.397mmol), tetrakis (triphenylphosphine) palladium (0.028 g; 0.024mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2mL) at 90 ℃ for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-20%) gave 0.079g (80%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):433(M + H).

Example 36: preparation of methyl 2- (2-tert-butyl-7- (chroman-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.075 g; 0.222mmol), 2- (chroman-6-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaboropentane (0.120 mg; 0.461mmol), tetrakis (triphenylphosphine) palladium (0.035 g; 0.030mmol) and diisopropylethylamine (0.220 mL; 1.26mmol) in DME-water (3: 1; 2mL) at 90 ℃ for 2 days. Purification by flash chromatography on silica gel using an ethyl acetate gradient in heptane (0-15%) gave 0.095g (98%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):436(M + H).

Example 37: preparation of methyl 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-methylpentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -6,6, 6-trifluorohexanoate (0.057 g; 0.162mmol), p-tolylboronic acid (0.045 mg; 0.883mmol), tetrakis (triphenylphosphine) palladium (0.020 g; 0.017mmol) and diisopropylethylamine (0.120 mL; 0.070mmol) in DME-water (3: 1; 1mL) at 140 ℃ for 20 min. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) to give 0.051g (77%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):408(M + H).

Example 38: preparation of methyl 2- (2-tert-butyl-3-chloro-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To a solution of methyl 2 (2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.097 g; 0.246mmol) in dichloromethane (1.5mL) was added N-chlorosuccinimide (0.050 g; 0.374mmol), and the solution was stirred at room temperature for 4 hours. Ethyl acetate (10mL) was added to the reaction mixture, and the solution was washed with 5% sodium bisulfate solution (10mL), 1N sodium bicarbonate solution (10mL), and brine (10 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) to give 0.070g (66%) of the title compound as a pale yellow oil. ESI/APCI (+):428-430(M + H).

Example 39: preparation of methyl 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -4-methoxybutyrate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -4-methoxybutyrate (0.220 g; 0.622mmol), p-tolylboronic acid (0.186 mg; 1.67mmol), tetrakis (triphenylphosphine) palladium (0.061 g; 0.053mmol) and diisopropylethylamine (0.450 mL; 2.58mmol) in DME-water (3: 1; 4mL) at 140 ℃ for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) gave 0.211g (83%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):408(M + H).

Example 40: preparation of methyl 2- (2-tert-butyl-5-methyl-7- (4-isopropylphenyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.205 g; 0.607mmol), 4-isopropylphenylboronic acid (0.186 g; 1.13mmol), tetrakis (triphenylphosphine) palladium (0.063 g; 0.055mmol) and diisopropylethylamine (0.410 mL; 2.35mmol) in DME-water (3: 1; 4mL) at 140 ℃ for 30 min. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) to give 0.180g (70%) of the title compound as a yellow solid. ESI/APCI (+):422(M + H).

Example 41: preparation of methyl 2- (2-tert-butyl-5-methyl-7- (4-trifluoromethylphenyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.209 g; 0.619mmol), 4- (trifluoromethyl) phenylboronic acid (0.170 g; 0.964mmol), tetrakis (triphenylphosphine) palladium (0.079 g; 0.069mmol) and diisopropylethylamine (0.410 mL; 2.35mmol) in DME-water (3: 1; 4mL) at 140 ℃ for 40 min. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) to give 0.220g (79%) of the title compound as a yellow solid. ESI/APCI (+):448(M + H).

Example 42: preparation of methyl 2- (2-tert-butyl-7- (2, 4-difluorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.152 g; 0.450mmol), 2, 4-difluorophenylboronic acid (114 mg; 0.722mmol), tetrakis (triphenylphosphine) palladium (0.052 g; 0.045mmol) and diisopropylethylamine (0.320 mL; 1.84mmol) in DME-water (3: 1; 3.5mL) at 140 ℃ for 40 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-20%) gave 0.188g (100%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):416(M + H).

Example 43: preparation of methyl 2- (2-tert-butyl-7- (2-chloro-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.152 g; 0.450mmol), 2-chloro-4-methylphenylboronic acid (110 mg; 0.646mmol), tetrakis (triphenylphosphine) palladium (0.052 g; 0.045mmol) and diisopropylethylamine (0.320 mL; 1.84mmol) in DME-water (3: 1; 3.5mL) at 140 ℃ for 40 min. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-20%) to give 0.188g (93%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):428-430(M + H).

Example 44: preparation of methyl 2- (7- (2-amino-4-methylphenyl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.100 g; 0.296mmol), 5-methyl- (2-4,4,5, 5-tetramethyl-1, 3, 2-dioxocyclopentylboran-2-yl) aniline (100 mg; 0.429mmol), tetrakis (triphenylphosphine) palladium (0.040 g; 0.035mmol) and diisopropylethylamine (0.210 mL; 1.21mmol) in DME-water (3: 1; 2mL) at 140 ℃ for 40 min. Purification by flash chromatography on silica gel using an ethyl acetate gradient in heptane (0-30%) gave 0.041g (34%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):409(M + H).

Example 45: preparation of methyl 2- (2-tert-butyl-7- (2-methoxy-4-chlorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.100 g; 0.296mmol), 4-chloro-2-methoxyphenylboronic acid (0.100 g; 0.429mmol), tetrakis (triphenylphosphine) palladium (0.040 g; 0.035mmol) and diisopropylethylamine (0.210 mL; 1.21mmol) in DME-water (3: 1; 2mL) at 140 ℃ for 40 min. Purification by flash chromatography on silica gel using an ethyl acetate gradient in heptane (0-20%) gave 0.075g (40%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+). 444-446(M + H).

Example 46: preparation of methyl 2- (2-tert-butyl-7- (2-fluoro-4-methoxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.142 g; 0.420mmol), 2-fluoro-4-methoxyphenylboronic acid (0.103 g; 0.606mmol), tetrakis (triphenylphosphine) palladium (0.040 g; 0.035mmol) and diisopropylethylamine (0.320 mL; 1.84mmol) in DME-water (3: 1; 3mL) at 140 ℃ for 40 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-25%) gave 0.174g (97%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):428(M + H).

Example 47: preparation of methyl 2- (2-tert-butyl-5-methyl-7- (5-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.149 g; 0.449mmol), quinoline-5-boronic acid (0.115 g; 0.655mmol), tetrakis (triphenylphosphine) palladium (0.040 g; 0.035mmol) and diisopropylethylamine (0.320 mL; 1.84mmol) in DME-water (3: 1; 3mL) at 140 ℃ for 40 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-50%) gave 0.144g (76%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):431(M + H).

Example 48: preparation of methyl 2- (2-tert-butyl-5-methyl-7- (8-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.139 g; 0.411mmol), quinoline-8-boronic acid (0.110 g; 0.636mmol), tetrakis (triphenylphosphine) palladium (0.043 g; 0.038mmol) and diisopropylethylamine (0.320 mL; 1.84mmol) in DME-water (3: 1; 3mL) at 140 ℃ for 40 min. Purification by flash chromatography on silica gel using an ethyl acetate gradient in heptane (0-40%) gave 0.065g (32%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):431(M + H).

Example 49: preparation of methyl 2- (2-tert-butyl-7- (2, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step D from methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.144 g; 0.426mmol), 2, 4-dimethylbenzeneboronic acid (0.105 g; 0.700mmol), tetrakis (triphenylphosphine) palladium (0.042 g; 0.037mmol) and diisopropylethylamine (0.320 mL; 1.84mmol) in DME-water (3: 1; 3mL) at 140 ℃ for 40 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-30%) gave 0.138g (79%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):408(M + H).

Example 50: preparation of methyl 2- (2-tert-butyl-3, 5-dimethyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

Methyl 2- (3-bromo-2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.050 g; 0,106mmol), potassium carbonate (0.0449 g; 0,318mmol), trimethylboroxine (0.080 g; 0,635mmol) and a complex of (1,1' -bis (diphenylphosphino) ferrocene) -palladium (II) dichloride with dichloromethane (0.008 g; 0.011mmol) and dimethylformamide (0.550mL) were placed in a sealed tube. The reaction mixture was purged with nitrogen, sealed and stirred under microwave irradiation at 150 ℃ for 45 minutes. The reaction mixture was partitioned between dichloromethane and saturated sodium chloride solution, filtered over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (5-30%) gave 0.025g (58%) of the title compound as a yellow oil. ESI/APCI (+):408(M + H).

Example 51: preparation of methyl 2- (2-tert-butyl-5-methyl-3-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate

This intermediate was prepared according to step E from methyl 2- (3-bromo-2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.057 g; 0.121mmol), phenylboronic acid (0.036 g; 0.300mmol), tetrakis (triphenylphosphine) palladium (0.014 g; 0.013mmol) and diisopropylethylamine (0.075 mL; 0.431mmol) in DME-water (3: 1; 1mL) at 140 ℃ for 40 min. Purification by flash chromatography on silica gel using an ethyl acetate gradient in heptane (0-15%) gave 0.041g (73%) of the title compound as a yellow oil contaminated with impurities. ESI/APCI (+):470(M + H).

Example 52: preparation of methyl 2- (2,3, 5-trimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) acetate

To a solution of (5-amino-1, 2-dimethyl-1H-imidazol-4-yl) (p-tolyl) methanone (0.077 g; 0.336mmol) and methyl levulinate (0.080 mL; 0.646mmol) in DMF (2mL) placed in a safety pressure tube was slowly added trimethylchlorosilane (0.340 mL; 2.679 mmol). The tube was sealed and heated to 110 ℃ for 24 hours. An additional volume of methyl levulinate (0.040 mL; 0.323mmol) trimethylchlorosilane (0.170 mL; 1.339mmol) was added and stirring was maintained at 110 ℃ for 23 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-10%) to give 0.047g (43%) of the title compound as a brown solid. ESI/APCI (+):324(M + H).

Example 53: preparation of methyl 2- (2,3, 5-trimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate

To a solution of methyl 2- (2,3, 5-trimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) acetate (0.051 g; 0.158mmol) in dry DMF (2.6mL) at-10 ℃ was slowly added a 1N solution of LHMDS in THF (0.187 mL; 0.187 mmol). After 35 minutes at-15 ℃ 1-iodopropane (0.027 mL; 0.277mmol) was added and the reaction mixture was stirred at room temperature for 6.5 hours. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (2-10%) to give 0.037g (64%) of the title compound as a yellow oil. ESI/APCI (+):366(M + H); 388(M + Na).

Example 54: preparation of ethyl 2- (1,2, 5-trimethyl-7-p-tolyl-1H-imidazo [4,5-b ] pyridin-6-yl) pentanoate

To a solution of (4-amino-1, 2-dimethyl-1H-imidazol-5-yl) (p-tolyl) methanone (0.172 g; 0.750mmol) and ethyl 4-oxo-2-propylvalerate (0.279 g; 1.5mmol) in dry DMF (3mL) under a nitrogen atmosphere was added trimethylsilylchloride (1.15 mL; 9 mmol). The mixture was stirred in a sealed tube and heated to 100 ℃ for 72 hours. After cooling, water was poured into the mixture and the heterogeneous mixture was stirred vigorously for 10 minutes. The aqueous layer was extracted twice with ethyl acetate, the organics were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-20%) as eluent gave 0.270g (94%) of the expected compound as a brown oil. ESI/APCI (+):380(M + H).

Example 55: preparation of ethyl 2- (3, 5-dimethyl-2-propyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate

To a solution of (5-amino-2-propyl-1-methyl-1H-imidazol-4-yl) (p-tolyl) methanone (0.180 g; 0.700mmol) and ethyl 4-oxo-2-propylvalerate (0.260 g; 1.4mmol) in dry DMF (2.8mL) under a nitrogen atmosphere was added trimethylchlorosilane (1.07 mL; 8.4 mmol). The mixture was stirred in a sealed tube and heated to 100 ℃ for 72 hours. After cooling, water was poured into the mixture and the heterogeneous mixture was stirred vigorously for 10 minutes. The aqueous layer was extracted twice with ethyl acetate, the organics were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient (0-20%) in dichloromethane as eluent gave 0.190g (66%) of the expected cyclic compound as a brown oil. ESI/APCI (+):408(M + H).

Example 56: preparation of ethyl 2- (3, 5-dimethyl-2-isopropyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate

To a solution of (5-amino-2-isopropyl-1-methyl-1H-imidazol-4-yl) (p-tolyl) methanone (0.296 g; 1.15mmol) and ethyl 4-oxo-2-propylpentanoate (0.429 g; 2.3mmol) in dry DMF (4.5mL) under a nitrogen atmosphere was added trimethylchlorosilane (1.76 mL; 13.80 mmol). The mixture was stirred in a sealed tube and heated to 100 ℃ for 72 hours. After cooling, water was poured into the mixture and the heterogeneous mixture was stirred vigorously for 10 minutes. The aqueous layer was extracted twice with ethyl acetate, the organics were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-20%) as eluent gave 0.367g (78%) of the expected compound as a brown oil. ESI/APCI (+):408(M + H).

Example 57: preparation of 2- (7- ((R) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of ethyl 2- (7- ((R) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.380 g; 0.7mmol) in ethanol (7mL) was added a 2N sodium hydroxide solution (7mL), and the reaction mixture was stirred at room temperature for 18 hours. An additional volume of 6N sodium hydroxide solution (1ml) was added and the mixture was stirred for a further 3 hours. Volatiles were removed under reduced pressure and the pH was adjusted to 2 by addition of 2N hydrochloric acid solution. And the precipitate was filtered. Purification was performed by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0.5-8%) to give 0.067g (18%) of the title compound as a white solid. ESI/APCI (+). 506-508(M + H).

Example 58: preparation of 2- (7- ((S) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of ethyl 2- (7- ((S) -3- (4-chlorophenylsulfonamido) piperidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.280 g; 0.52mmol) in ethanol (5.2mL) was added a 2N sodium hydroxide solution (5.2mL), and the reaction mixture was stirred at room temperature for 18 hours. An additional volume of 6N sodium hydroxide solution (0.8ml) was added and the mixture was stirred for a further 3 hours. Volatiles were removed under reduced pressure and the pH was adjusted to 2 by addition of 2N hydrochloric acid solution. And the precipitate was filtered. Purification by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0.5-8%) gave 0.011g (4%) of the title compound as a white solid. ESI/APCI (+). 506-508(M + H).

Example 59: preparation of 2- (7- ((R) -3- (4-chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of ethyl 2- (7- ((R) -3- (4-chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.316 g; 0.61mmol) in ethanol (6.1mL) was added 2N sodium hydroxide solution (6.1mL), and the reaction mixture was stirred at room temperature for 18 hours. An additional volume of 6N sodium hydroxide solution (0.9ml) was added and the mixture was stirred for a further 3 hours. Volatiles were removed under reduced pressure and the pH was adjusted to 2 by addition of 2N hydrochloric acid solution. And the precipitate was filtered. Purification was performed by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0.5-8%) to give 0.019g (7%) of the title compound as a white solid. ESI/APCI (+):492-494(M + H).

Example 60: preparation of 2- (7- ((S) -3- (4-chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of ethyl 2- (7- ((S) -3- (4-chlorophenylsulfonamido) pyrrolidin-1-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.300 g; 0.57mmol) in ethanol (5.7mL) was added 2N sodium hydroxide solution (5.7mL), and the reaction mixture was stirred at room temperature for 18 hours. An additional volume of 6N sodium hydroxide solution (0.8ml) was added and the mixture was stirred for a further 3 hours. Volatiles were removed under reduced pressure and the pH was adjusted to 2 by addition of 2N hydrochloric acid solution. And the precipitate was filtered. Purification was performed by flash chromatography on silica gel using a methanol gradient in dichloromethane (0.5-8%) to give 0.040g (14%) of the title compound as a white solid. ESI/APCI (+):492-494(M + H).

Example 61: preparation of 2- (5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.266 g; 0.8mmol) in a DMSO/water mixture (8mL/0.8mL) was added a 10N sodium hydroxide solution (0.8mL) and the mixture was stirred at 65 ℃ for 1 hour. Water (12mL)6N hydrochloric acid solution was added to adjust the pH to 1 and the aqueous phase was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure until dried, and water was added to the crude. The white precipitate was filtered, washed with cold water and dried under reduced pressure to give the title compound 0.042g (17%) as a white solid. ESI/APCI (+):310(M + H).

Example 62: preparation of 2- (5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

A solution of methyl 2- (5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.33 g; 0.98mmol) in methanol (10mL) was added 10N sodium hydroxide solution (1mL) and the mixture was heated to 80 ℃ for 18 hours. An additional volume of base (0.5mL) was added and the reaction mixture was stirred for an additional 24 hours. After cooling, the volatiles were removed under reduced pressure, the pH was adjusted by addition of cold 2N hydrochloric acid solution, and the acid layer was extracted with ethyl acetate. The organics were collected, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Crystallization from a crude solid ethyl acetate-heptane mixture yielded 0.106g (33%) of the title compound. ESI/APCI (+):324(M + H).

Example 63: preparation of 2- (2-tert-butyl-5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-5-methyl-7-phenylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate (0.141g,0.372mmol) in a methanol/water mixture (8mL/0.4mL) was added a 10N sodium hydroxide solution (0.400 mL; 4.00mmol) and the solution was stirred at 65 ℃ for 18 h. The volatiles were evaporated, a 5% citric acid solution (15mL) was added to the residue and the product was extracted with ethyl acetate (15 mL). The organic layer was washed with brine (15mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient (0-7%) in dichloromethane afforded 0.036g (27%) of the title compound as a yellow oil which solidified slowly. ESI/APCI (+):366(M + H). ESI/APCI (-):364 (M-H).

Example 64: 2- (2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.126g,0.372mmol) in a methanol/water mixture (6mL/0.3mL) was added a 10N sodium hydroxide solution (0.32 mL; 3.2mmol), and the solution was stirred at 65 ℃ for 18 hours. The volatiles were evaporated, a 5% citric acid solution (15mL) was added to the residue and the product was extracted with ethyl acetate (15 mL). The organic layer was washed with brine (15mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient (0-7%) in dichloromethane afforded 0.067g (55%) of the title compound as a yellow oil which solidified slowly. ESI/APCI (+):380(M + H). ESI/APCI (-):378 (M-H).

Example 65: preparation of 2- (3-bromo-2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (3-bromo-2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.052g,0.110mmol) in methanol (5mL) was added a 1N lithium hydroxide solution (0.15 mL; 0.15mmol), and the solution was stirred at room temperature for 18 hours. An additional volume of base (0.250 mL; 0.250mmol) was added and stirring was continued for 24 hours. An additional volume of base (0.400 mL; 0.400mmol) was added and stirring was continued for 48 hours. The volatiles were evaporated, 1N hydrochloric acid solution (10mL) was added to the residue, and the product was extracted with ethyl acetate (10 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel with a methanol gradient (0-20%) in dichloromethane afforded 0.041g (81%) of the title compound as a yellow oil which solidified slowly. ESI/APCI (+). 458-460(M + H).

Example 66: preparation of 2- (5-methyl-2-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (5-methyl-2-phenyl-7-p-tolylpyrazolo [1,5-a ]]A solution of pyrimidin-6-yl) pentanoic acid methyl ester (0.109g,0.264mmol) in a mixture methanol/water (5mL/0.25mL) was added 10N sodium hydroxide solution (0.25 mL; 2.50mmol) and the solution was stirred at 65 ℃ for 18 h. The volatiles were evaporated, a 5% citric acid solution (15mL) was added to the residue and the product was extracted with ethyl acetate (15 mL). The organic layer was washed with brine (15mL) over MgSO₄Dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-7%) gave 0.041g (39%) of the title compound as a white solid. ESI/APCI (+):400(M + H). ESI/APCI (-):398 (M-H).

Example 67: preparation of 2- (2-tert-butyl-7- (3-hydroxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (3-hydroxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate (0.176g,0.445mmol) in the mixture methanol/water (9mL/0.5mL) was added 10N sodium hydroxide solution (0.450 mL; 4.50mmol), and the solution was stirred at 65 ℃ for 18 hours. The volatiles were evaporated, 5% citric acid solution (15mL) was added to the residue, the product was extracted with ethyl acetate (3 × 15 mL.) the organic layer was washed with brine (15mL), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel with a methanol gradient (0-10%) in dichloromethane afforded 0.065g (40%) of the title compound as a yellow oil which solidified slowly. ESI/APCI (+):382(M + H). ESI/APCI (-):380 (M-H).

Example 68: preparation of 2- (2-tert-butyl-5-methyl-7- (2-naphthyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-5-methyl-7- (2-naphthyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.143g,0.333mmol) in methanol (7mL) was added a 5N sodium hydroxide solution (0.700 mL; 3.50mmol), and the solution was stirred at 50 ℃ for 18 hours. The volatiles were evaporated, a 5% citric acid solution (15mL) was added to the residue and the product was extracted with ethyl acetate (3 × 15 mL). The organic layer was washed with brine (15mL), dried over MgSO4 and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-20%) to give 0.114g (82%) of the title compound as a pale yellow foam. ESI/APCI (+):416(M + H). ESI/APCI (-):414 (M-H); 370 (M-COOH).

Example 69: preparation of 2- (2-tert-butyl-7- (1H-indol-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (2-tert-butyl-7- (1H-indol-5-yl) -5-methylpyrazolo [1, 5-a)]A solution of methyl pyrimidin-6-yl) pentanoate (0.129g,0.308mmol) in methanol (7mL) was added 5N sodium hydroxide solution (0.700 mL; 3.50mmol) and the solution stirred at 50 ℃ for 18 h. The volatiles were evaporated, a 5% citric acid solution (10mL) was added to the residue and the product was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10mL) over MgSO ₄Dried and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-20%) to give 0.101g (75%) of the title compound as a brown foam. ESI/APCI (+):405(M + H). ESI/APCI (-):403 (M-H); 359 (M-COOH).

Example 70: preparation of 2- (2-tert-butyl-7- (1H-indol-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (2-tert-butyl-7- (1H-indol-6-yl) -5-methylpyrazolo [1, 5-a)]A solution of methyl pyrimidin-6-yl) pentanoate (0.104g,0.248mmol) in methanol (5mL) was added 5N sodium hydroxide solution (0.500 mL; 2.50mmol) and the solution stirred at 50 ℃ for 18 h. The volatiles were evaporated, a 5% citric acid solution (10mL) was added to the residue and the product was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10mL) over MgSO₄Dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-20%) gave 0.058g (58%) of the title compound as a white solid. ESI/APCI (+):405(M + H). ESI/APCI (-):403 (M-H); 359 (M-COOH).

Example 71: preparation of 2- (7- (benzofuran-5-yl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (7- (benzofuran-5-yl) -2-tert-butyl-5-methylpyrazolo [1, 5-a)]A solution of pyrimidin-6-yl) pentanoic acid methyl ester (0.114g,0.272mmol) in a mixture methanol/water (5.5mL/0.55mL) was added 5N sodium hydroxide solution (0.550 mL; 2.50mmol) and the solution stirred at 50 ℃ for 18 h. The volatiles were evaporated, a 5% citric acid solution (10mL) was added to the residue and the product was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10mL) over MgSO₄Dried and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-20%) to give 0.084g (76%) of the title compound as a white solid. ESI/APCI (+):406(M + H). ESI/APCI (-):404 (M-H); 360 (M-COOH).

Example 72: preparation of 2- (7- (benzo [ b ] thiophen-5-yl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (7- (benzo [ b ])]Thien-5-yl) -2-tert-butyl-5-methylpyrazolo [1,5-a]A solution of methyl pyrimidin-6-yl) pentanoate (0.102g,0.234mmol) in a methanol/water mixture (5mL/0.5mL) was added 5N sodium hydroxide solution (0.5 mL; 2.50mmol) and the solution stirred at 50 ℃ for 18 h. The volatiles were evaporated, a 5% citric acid solution (10mL) was added to the residue and the product was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10mL) over MgSO ₄Dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient in dichloromethane (0-20%) gave 0.078g (79%) of the title compound as a yellow oil which solidified slowly. ESI/APCI (+):422(M + H). ESI/APCI (-):420 (M-H); 346 (M-COOH).

Example 73: preparation of 2- (2-tert-butyl-7- (2, 3-dihydrobenzofuran-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (2-tert-butyl-7- (2, 3-dihydrobenzofuran-5-yl) -5-methylpyrazolo [1, 5-a)]A solution of methyl pyrimidin-6-yl) pentanoate (0.096g,0.228mmol) in a methanol/water mixture (5mL/0.5mL) was added 5N sodium hydroxide solution (0.5 mL;2.50mmol) and the solution stirred at 50 ℃ for 18 h. The volatiles were evaporated, a 5% citric acid solution (10mL) was added to the residue and the product was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10mL) over MgSO₄Dried and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-20%) to give 0.076g (82%) of the title compound as a white solid. ESI/APCI (+):408(M + H). ESI/APCI (-):406 (M-H); 362 (M-COOH).

Example 74: preparation of 2- (2-tert-butyl-7- (4-chlorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (2-tert-butyl-7- (4-chlorophenyl) -5-methylpyrazolo [1,5-a ]]A solution of methyl pyrimidin-6-yl) pentanoate (0.125g,0.302mmol) in methanol (10mL) was added 1N lithium hydroxide solution (0.6 mL; 0.6mmol), the solution was stirred at room temperature for 24 hours. An additional volume of base (0.900 mL; 0.900mmol) was added and stirring continued for 24 hours. An additional volume of 5N sodium hydroxide solution (0.300 mL; 1.5mmol) was added and the reaction mixture was heated at 70 ℃ for 24 hours. The volatiles were evaporated, 1N hydrochloric acid solution (18mL) was added to the residue, and the product was extracted with ethyl acetate (25 mL). The organic layer was washed with brine (10mL) over MgSO₄Dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient (0-20%) in dichloromethane and by preparative HPLC as described in method 1 gave 0.062g (51%) of the title compound as a white solid. ESI/APCI (+):400-402(M + H). ESI/APCI (-):398-400 (M-H); 354-356 (M-COOH).

Example 75: preparation of 2- (2-tert-butyl-7- (3, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (3, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate (0.125g,0.302mmol) in methanol (10mL) was added a 1N lithium hydroxide solution (0.6 mL; 0.6mmol), and the solution was stirred at room temperature for 24 hours. An additional volume of base (0.900 mL; 0.900mmol) was added and stirring continued for 24 hours. An additional volume of 5N sodium hydroxide solution (0.300 mL; 1.5mmol) was added and the reaction mixture was heated at 70 ℃ for 24 hours. The volatiles were evaporated, 1N hydrochloric acid solution (10mL) was added to the residue, the product was extracted with ethyl acetate (2 × 10 mL.) the organic layer was washed with brine (10mL), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient in dichloromethane (0-20%) and by preparative HPLC as described in method 2 gave 0.057g (48%) of the title compound as a white solid. ESI/APCI (+):394(M + H). ESI/APCI (-):392 (M-H); 348 (M-COOH).

Example 76: preparation of 2- (2-tert-butyl-7- (4-ethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (4-ethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate (0.130g,0.319mmol) in methanol (10mL) was added a 1N lithium hydroxide solution (0.65 mL; 0.65mmol), and the solution was stirred at room temperature for 24 hours. An additional volume of base (1 mL; 1mmol) was added and stirring continued for 24 hours. An additional volume of 5N sodium hydroxide solution (0.300 mL; 1.5mmol) was added and the reaction mixture was heated at 70 ℃ for 24 hours. The volatiles were evaporated, 1N hydrochloric acid solution (10mL) was added to the residue, and the product was extracted with ethyl acetate (2X 10 mL). The organic layer was washed with brine (10mL), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient in dichloromethane (0-20%) and by preparative HPLC as described in method 2 gave 0.057g (45%) of the title compound as a white solid. ESI/APCI (+):394(M + H). ESI/APCI (-):392 (M-H); 348 (M-COOH).

Example 77: preparation of 2- (2-tert-butyl-7- (3, 4-dihydro-2H-benzo [ b ] [1,4] dioxacyclohepta-7-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (3, 4-dihydro-2H-benzo [ b ] [1,4] dioxacyclohepta-7-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.114g,0.252mmol) in the mixture methanol/water (5.5mL/0.55mL) was added 5N sodium hydroxide solution (0.55 mL; 2.75mmol) and the solution was stirred at 50 ℃ for 18 hours. The volatiles were evaporated, a 5% citric acid solution (10mL) was added to the residue, and the product was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10mL), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0-20%) gave 0.056g (50%) of the title compound as a white solid. ESI/APCI (+):438(M + H). ESI/APCI (-):436 (M-H).

Example 78: preparation of 2- (2-tert-butyl-7- (4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (2-tert-butyl-7- (3, 4-dihydro-2H-benzo [ b ]][1,4]Dioxacycloheptatrien-7-yl) -5-methylpyrazolo [1,5-a]A solution of pyrimidin-6-yl) pentanoic acid methyl ester (0.097g,0.224mmol) in methanol/water mixture (3.5mL/0.35mL) was added 5N sodium hydroxide solution (0.35 mL; 1.75mmol) and the solution was stirred at 50 ℃ for 18 h. The volatiles were evaporated, a 5% citric acid solution (10mL) was added to the residue and the product was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10mL) over MgSO ₄Dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient (0-20%) in dichloromethane and by preparative HPLC as described in method 2 gave 21mg (21%) of a bright yellow solid. ESI/APCI (+):437(M + H). ESI/APCI (-):435 (M-H); 391 (M-COOH).

Example 79: preparation of 2- (5-methyl-3-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (5-methyl-3-phenyl-7-p-tolylpyrazolo [1,5-a ]]To a solution of pyrimidin-6-yl) pentanoic acid ethyl ester (0.050g,0.117mmol) in methanol (2.5mL) was added 5N sodium hydroxide solution (0.25 mL; 1.25mmol) and the solution was stirred at 70 ℃ for 3 days. The volatiles were evaporated, a 5% citric acid solution (10mL) was added to the residue and the product was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10mL) over MgSO₄Dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient in dichloromethane (0-7%) and by preparative HPLC as described in method 2 gave 6.5mg (14%) of a white solid. ESI/APCI (+):400(M + H). ESI/APCI (-):398 (M-H).

Example 80: preparation of 2- (3, 7-di-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (3, 7-di-p-tolyl-5-methylpyrazolo [1,5-a ]]Pyrimidin-6-yl) pentanoic acid ethyl ester (0.086 mg; 0.195mmol) in a methanol/water mixture (4mL/0.2mL) was added 5N sodium hydroxide solution (0.4 mL; 2.0mmol), the resulting mixture was stirred at room temperature. After stirring for 24h, the solution was heated at 70 ℃ for 3 days. Volatiles were removed under reduced pressure and ethyl acetate (10mL) was added to the remaining residue. The solution was washed with 1N hydrochloric acid solution (2X 10mL) and brine (10mL), over MgSO₄Dried, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel with a methanol gradient (0-4%) in dichloromethane gave 0.048g (60%) of the title compound as a bright yellow oil which solidified slowly. ESI/APCI (+):414(M + H). ESI/APCI (-):412 (M-H).

Example 81: preparation of 2- (2-tert-butyl-3, 7-di-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (2-tert-butyl-3, 7-di-p-tolyl-5-methylpyrazolo [1,5-a ]]To a solution of methyl pyrimidin-6-yl) valerate (0.014g,0.029mmol) in methanol (1mL) was added 5N sodium hydroxide solution (0.1 mL; 0.5mmol), the solution was stirred at 60 ℃ for 3 days. The volatiles were evaporated, 1N hydrochloric acid solution (10mL) was added to the residue, and the product was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10mL) over MgSO ₄Drying and concentration under reduced pressure gave 14mg (96%) of a pale yellow solid. ESI/APCI (+):470(M + H). ESI/APCI (-):368 (M-H).

Example 82: preparation of 2- (5-methyl-2-propyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (5-methyl-2-propyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.105 g; 0.277mmol) in a methanol/water mixture (2:1) (9mL) was added 5% sodium hydroxide solution (6.6 mL; 8.3mmol) and the reaction mixture was heated to 60 ℃ for 18 h. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 6N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient in dichloromethane (1-20%) and by preparative HPLC as described in method 2 gave 0.021g (21%) of the title compound.

ESI/APCI(+):366(M+H)。ESI/APCI(-):364(M-H)。

Example 83: preparation of 2- (2- (furan-2-yl) -5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2- (furan-2-yl) -5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.123 g; 0.3mmol) in a methanol/water mixture (2:1) (9mL) was added 5% sodium hydroxide solution (7.3 mL; 9.1mmol) and the reaction mixture was heated to 60 ℃ for 18 h. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 6N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a methanol gradient (1-20%) in dichloromethane and by preparative HPLC as described in method 2 gave 0.014g (12%) of the title compound. ESI/APCI (+):390(M + H). ESI/APCI (-):389 (M-H).

Example 84: preparation of 2- (2-tert-butyl-7- (4-chloro-2-fluorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (2-tert-butyl-7- (4-chloro-2-fluorophenyl) -5-methylpyrazolo [1, 5-a)]Pyrimidin-6-yl) pentanoic acid methyl ester (0.101 g; 0.234mmol) in methanol (10mL) was added 5N sodium hydroxide solution (0.5 mL; 2.5mmol) and the reaction mixture was heated to 70 ℃ for 3 days. Ethyl acetate (10mL) was added to the reaction mixture, and the solution was washed with 1N hydrochloric acid solution (10mL) and brine (10 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Crystallization from ethyl acetate/heptane (twice) gave 0.034g (35%) of the title compound as a white solid. ESI/APCI (+):418(M + H). ESI/APCI (-):416 (M-H).¹H-NMR(400MHz,DMSO-d₆)(ppm)δ12.9(1H,bs)；7.76(1H,d,J=9.66Hz)；7.51(2H,m)；6.54(1H,s)；3.54(1H,t,J=5.63Hz)2.51(3H,s)；2.00(1H,m)；1.65(1H,m)；1.33(9H,s)；0.97(2H,m),0.66(3H,t,J=7.12Hz)。

Example 85: preparation of 2- (2-tert-butyl-7- (2-fluoro-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To 2- (2-tert-butyl-7- (2-fluoro-4-methylphenyl) -5-methylpyrazolo [1, 5-a)]Pyrimidin-6-yl) pentanoic acid methyl ester (0.106 g; 0.258mmol) in methanol (10mL) was added 5N sodium hydroxide solution (0.5 mL; 2.5mmol) and the reaction mixture was heated to 70 ℃ for 3 days. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Crystallization from ethyl acetate/heptane (twice) gave 0.061g (60%) of the title compound as a white solid. ESI/APCI (+):398(M + H). ESI/APCI (-):396 (M-H). ¹H-NMR(400MHz,DMSO-d₆)(ppm)δ12.9(1H,bs)；7.30(3H,m)；6.51(1H,s)；3.54(1H,t,J=5.7Hz)；2.48(3H,s)；2.44(3H,s)；1.99(1H,m)；1.64(1H,m)；1.33(9H,s)；0.95(2H,m),0.63(3H,t,J=7.3Hz)。

Example 86: preparation of 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -6,6, 6-trifluorohexanoic acid

To 2- (2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1, 5-a)]Pyrimidin-6-yl) -6,6, 6-trifluorohexanoic acid methyl ester (0.135 g; 0.293mmol) in methanol (12mL) was added 5N sodium hydroxide solution (0.6 mL; 3mmol) and the reaction mixture was heated to 70 ℃ for 3 days. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to the method 2 described gave 0.063g (46%) of a white solid. ESI/APCI (+):448(M + H). ESI/APCI (-):446 (M-H).¹H-NMR(400MHz,DMSO-d₆)(ppm)δ12.9(1H,bs)；7.37(4H,m)；6.49(1H,s)；3.57(1H,t,J=7.0Hz)；2.47(3H,s)；2.45(3H,s)；2.03(3H,M)；1.68(1H,m)；1.23(9H,s)；1.18(2H,m)。

Example 87: 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionic acid

To a solution of methyl 2- (2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionate (0.118 g; 0.293mmol) in methanol (6mL) was added a 5N sodium hydroxide solution (0.6 mL; 3mmol) and the reaction mixture was heated to 95 ℃ for 16 h. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Crystallization from ethyl acetate/heptane yielded 0.069g (60%) of the title compound as a white solid. ESI/APCI (+):428(M + H). ESI/APCI (-):426 (M-H).

Example 88: preparation of 2- (2-tert-butyl-7- (1H-indol-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (1H-indol-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-phenylpropionate (0.097 g; 0.224mmol) in methanol (5mL) was added a 5N sodium hydroxide solution (0.5 mL; 2.5mmol) and the reaction mixture was heated to 50 ℃ for 7 days. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate, brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to the method 2 gave 0.010g (11%) of the title compound as a white solid. ESI/APCI (+):418(M + H).

Example 89: preparation of 2- (2-tert-butyl-5-methyl-7- (1-methylindoline-5-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-5-methyl-7- (1-methylindolin-5-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.074 g; 0.170mmol) in methanol (8mL) was added a 5N sodium hydroxide solution (0.35 mL; 1.75mmol) and the reaction mixture was heated to 70 ℃ for 3 days. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to the method 2 gave 0.012g (17%) of the title compound as a yellow solid. ESI/APCI (+):421(M + H). ESI/APCI (-):419 (M-H).

Example 90: preparation of 2- (2-tert-butyl-5-methyl-7- (1-methyl-1H-indol-6-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-5-methyl-7- (1-methyl-1H-indol-6-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.079 g; 0.183mmol) in methanol (4mL) was added 5N sodium hydroxide solution (0.4 mL; 2mmol) and the reaction mixture was heated to 50 ℃ for 7 days. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to the method 2 gave 0.010g (13%) of the title compound as a yellow solid. ESI/APCI (+):419(M + H). ESI/APCI (-):417 (M-H).

Example 91: preparation of 2- (2-tert-butyl-7- (chroman-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (chroman-6-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.095 g; 0.218mmol) in methanol (5mL) was added a 5N sodium hydroxide solution (0.5 mL; 2.5mmol) and the reaction mixture was heated to 50 ℃ for 7 days. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel with a methanol gradient (0-20%) in dichloromethane yielded the expected compound, which was contaminated with impurities. Purification by preparative HPLC according to the method 2 described gave 0.054g (58%) of the title compound as a yellow solid. ESI/APCI (+):422(M + H). ESI/APCI (-):420 (M-H).

Example 92: preparation of 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-methylpentanoic acid

To a solution of methyl 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-methylpentanoate (0.055 g; 0.135mmol) in ethanol (6mL) and water (1mL) was added a 5N sodium hydroxide solution (0.6 mL; 3.0mmol), and the solution was heated under microwave irradiation at 140 ℃ for 2 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel with a methanol gradient (0-20%) in dichloromethane yielded the expected compound, which was contaminated with impurities. Crystallization from heptane yielded 0.028g (52%) of the title compound as a white solid. ESI/APCI (+):394(M + H). ESI/APCI (-):392 (M-H).

Example 93: preparation of 2- (2-tert-butyl-3-chloro-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-3-chloro-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.070 g; 0.164mmol) in methanol (6mL) was added a 5N sodium hydroxide solution (0.3 mL; 1.5mmol) and the solution was heated at 75 ℃ for 18 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. The remaining bright yellow oil slowly crystallized, yielding 0.066g (98%) of the title compound. ESI/APCI (+):414-416(M + H).

Example 94: preparation of 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -4-methoxybutanoic acid

To a solution of methyl 2- (2-tert-butyl-7-p-tolyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -3-methyl-4-methoxybutyrate (0.211 g; 0.515mmol) in methanol (11mL) was added a 5N sodium hydroxide solution (1.1 mL; 5.5mmol), and the solution was heated at 70 ℃ for 24 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to the method 2 gave 0.111g (55%) of the title compound as a yellow solid. ESI/APCI (+):396(M + H). ESI/APCI (-):394 (M-H).

Example 95: preparation of 2- (2-tert-butyl-5-methyl-7- (4-isopropylphenyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (4-isopropylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.180 g; 0.427mmol) in methanol (5mL) was added a 5N sodium hydroxide solution (0.43 mL; 2.15mmol) and the solution was heated at 75 ℃ for 24 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography using an ethyl acetate gradient in heptane (0-25%) gave 0.069g (40%) of the title compound as a white solid. ESI/APCI (+):408(M + H). ESI/APCI (-):406 (M-H).

Example 96: preparation of 2- (2-tert-butyl-5-methyl-7- (4-trifluoromethylphenyl) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-5-methyl-7- (4-trifluorophenyl) pyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.220 g; 0.427mmol) in methanol (5mL) was added a 5N sodium hydroxide solution (0.5 mL; 2.5mmol), and the solution was heated at 75 ℃ for 24 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography using an ethyl acetate gradient in heptane (0-25%) gave 0.151g (71%) of the title compound as a pale yellow solid. ESI/APCI (+):434(M + H). ESI/APCI (-):432 (M-H).

Example 97: preparation of 2- (2-tert-butyl-7- (2, 4-difluorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (2, 4-difluorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.188 g; 0.433mmol) in methanol (5mL) was added a 5N sodium hydroxide solution (0.5 mL; 2.5mmol), and the solution was heated at 75 ℃ for 24 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure to give 0.161g (89%) of the title compound as a pale yellow solid. ESI/APCI (+):402(M + H). ESI/APCI (-):400 (M-H).

Example 98: preparation of 2- (2-tert-butyl-7- (2-chloro-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (2-chloro-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.180 g; 0.450mmol) in methanol (5mL) was added a 5N sodium hydroxide solution (0.5 mL; 2.5mmol), and the solution was heated at 75 ℃ for 24 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure to give 0.163g (93%) of the title compound as a pale yellow solid. ESI/APCI (+):413-415(M + H).

Example 99: preparation of 2- (7- (2-amino-4-methylphenyl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid and corresponding lactams

To a solution of methyl 2- (7- (2-amino-4-methylphenyl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.041 g; 0.010mmol) in methanol (2mL) was added a 5N sodium hydroxide solution (0.2 mL; 1mmol) and the solution was heated at 75 ℃ for 20 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to described method 2 gave 0.003g (7%) of 2- (7- (2-amino-4-methylphenyl) -2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid as a white solid. ESI/APCI (+):395(M + H).

Example 100: preparation of 2- (2-tert-butyl-7- (2-methoxy-4-chlorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (2-methoxy-4-chlorophenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.075 g; 0.17mmol) in methanol (3.5mL) was added a 5N sodium hydroxide solution (0.350 mL; 1.75mmol), and the solution was heated at 75 ℃ for 24 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography using an acetic acid-dichloromethane mixture (2-98) as eluent gave a yellow oil. Purification by preparative HPLC according to the method 2 gave 0.034g (47%) of the title compound as a yellow solid. ESI/APCI (+). 430-432(M + H).

Example 101: preparation of 2- (2-tert-butyl-7- (2-fluoro-4-methoxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (2-fluoro-4-methoxyphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate (0.174 g; 0.407mmol) in methanol (4mL) was added a 5N sodium hydroxide solution (0.410 mL; 2.05mmol), and the solution was heated at 75 ℃ for 18 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure to give 0.148g (88%) of the title compound as an off-white powder. ESI/APCI (+):414(M + H).

Example 102: preparation of 2- (2-tert-butyl-5-methyl-7- (5-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-5-methyl-7- (5-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.141 g; 0.327mmol) in methanol (3.5mL) was added a 5N sodium hydroxide solution (0.350 mL; 1.75mmol) and the solution was heated at 75 ℃ for 48 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure to give 0.118g (87%) of the title compound as an off-white solid. ESI/APCI (+):417(M + H).

Example 103: preparation of 2- (2-tert-butyl-5-methyl-7- (8-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-5-methyl-7- (8-quinoline) pyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.059 g; 0.137mmol) in methanol (2mL) was added a 5N sodium hydroxide solution (0.150 mL; 0.75mmol) and the solution was heated at 75 ℃ for 48 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure to give 0.047g (82%) of the title compound as an off-white solid. ESI/APCI (+):417(M + H).

Example 104: preparation of 2- (2-tert-butyl-7- (2, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-7- (2, 4-dimethylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate (0.138 g; 0.339mmol) in methanol (3.5mL) was added a 5N sodium hydroxide solution (0.350 mL; 1.75mmol) and the solution was heated at 75 ℃ for 48 hours. The organic volatiles were removed under reduced pressure, the remaining base solution was acidified with 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography using a methanol gradient in dichloromethane (0-7%) as eluent gave 0.064g (48%) of the title compound as a white solid. ESI/APCI (+):394(M + H). ESI/APCI (-):392 (M-H).

Example 105: preparation of 2- (2-tert-butyl-3, 5-dimethyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-tert-butyl-3, 5-dimethyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.025 g; 0.061mmol) in methanol (1mL) was added a 10N sodium hydroxide solution (0.100 mL; 1mmol), and the mixture was heated to 60 ℃ in a sealed tube for 20 hours. After cooling, the volatiles were removed under reduced pressure, the residue was dissolved in water and the mixture was acidified by addition of 2N hydrochloric acid solution until pH 2. The precipitate was filtered, washed with water and dried under reduced pressure. 0.014g (56%) of the title compound are obtained as a pale yellow solid. ESI/APCI (+):394(M + H).

Example 106: preparation of 2- (2-tert-butyl-5-methyl-3-phenyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (3-bromo-2-tert-butyl-5-methyl-7-p-tolylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.041 g; 0.087mmol) in methanol (4mL) was added a 5N sodium hydroxide solution (0.200 mL; 1mmol) and the mixture was heated to 70 ℃ for 72 h. After cooling, the volatiles were removed under reduced pressure and the residue was dissolved in water. The mixture was then acidified by addition of 1N hydrochloric acid solution until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to the method 2 gave 0.023g (58%) of the title compound as a pale yellow solid. ESI/APCI (+):456(M + H). ESI/APCI (-):454 (M-H).

Example 107: preparation of 2- (2,3, 5-trimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoic acid

To the 2- (2,3, 5-trimethyl-7-p-tolyl-3H-imidazo [4,5-b ]]Pyridin-6-yl) pentanoic acid methyl ester (0.037 g; 0.101mmol) in a mixture of methanol-ethanol (2:1,3mL) 5% sodium hydroxide solution (2.7 mL; 3.375 mmol). The reaction mixture was heated to reflux for 4 hrs Then (c) is performed. The solvent was evaporated, the residue was dissolved in water, acidified with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (3-20%) to give 0.019g (53%) of the title compound as a beige solid. ESI/APCI (+):352(M + H); 374(M + Na). ESI/APCI (-):350(M + H). 1H NMR (dmso-d)₆)δ0.58(3H,t)；0.87(2H,m)；1.52(1H,m)；1.96(1H,m)；2.39(3H,s)；2.46(3H,s)；2.50(3H,s)；3.70(3H,s)；3.85(1H,m)；7.26(4H,m)。

Example 108: preparation of 2- (1,2, 5-trimethyl-7-p-tolyl-1H-imidazo [4,5-b ] pyridin-6-yl) pentanoic acid

To a suspension of ethyl 2- (1,2, 5-trimethyl-7-p-tolyl-1H-imidazo [4,5-b ] pyridin-6-yl) pentanoate (0.270 g; 0.711mmol) in the mixture methanol-ethanol (2:1) (24mL) was added 5% sodium hydroxide solution (21.34 mmol; 17mL) and the reaction mixture was heated to 60 ℃ for 18 hours. The organic volatiles were removed under reduced pressure and the remaining base solution was acidified with hydrochloric acid solution (1N) until pH 2 and extracted twice with ethyl acetate. The organics were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to the method 1 described gave 0.021g (8%) of the title compound as an off-white solid. ESI/APCI (+):352(M + H).

Example 109: preparation of 2- (2-propyl-3, 5-dimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoic acid

To a suspension of ethyl 2- (2-propyl-3, 5-dimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate (0.190 g; 0.466mmol) in the mixture methanol-ethanol (2:1) (15mL) was added 5% sodium hydroxide solution (14 mmol; 11.2mL) and the reaction mixture was heated to 60 ℃ for 18H. The organic volatiles were removed under reduced pressure and the remaining base solution was acidified with hydrochloric acid solution (1N) until pH 2 and extracted twice with ethyl acetate. The organics were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to the method 1 gave 0.014g (8%) of the title compound as a beige solid. ESI/APCI (+):380(M + H).

Example 110: preparation of 2- (2-isopropyl-3, 5-dimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate

To a suspension of ethyl 2- (2-isopropyl-3, 5-dimethyl-7-p-tolyl-3H-imidazo [4,5-b ] pyridin-6-yl) pentanoate (0.367 g; 0.900mmol) in the mixture methanol-ethanol (2:1) (30mL) was added 5% sodium hydroxide solution (27.02 mmol; 21.6mL) and the reaction mixture was heated to 60 ℃ for 18H. The organic volatiles were removed under reduced pressure and the remaining base solution was acidified with hydrochloric acid solution (1N) until pH 2 and extracted twice with ethyl acetate. The organics were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC according to the method 1 gave 0.030g (9%) of the title compound as a beige solid. ESI/APCI (+):380(M + H).

Example 111: preparation of methyl 2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) acetate

To a sonicated solution of methyl 2- (7-chloro-2-isopropyl-5-methyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -acetate (0.150 g; 0.531mmol) and 4-tolylboronic acid (0.114 g; 0.839mmol) in a water/DME mixture (1/3) (4mL) was added tetrakis (triphenylphosphine) palladium (0.056 g; 0.049mmol) and diisopropylethylamine (0.500 mL; 1.84 mmol). The solution was stirred for 40 minutes under microwave irradiation at 140 ℃. Ethyl acetate (20mL) was added to the reaction mixture and the solution was washed with 1N hydrochloric acid solution, 1N sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (20-70%) to give 0.089g (50%) of the title compound as a white solid. ESI/APCI (+):339(M + H).

Example 112: 2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) acetic acid

To a solution of methyl 2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) acetate (0.089 g; 0.263mmol) in methanol (5mL) was added a 5N sodium hydroxide solution (0.550 mL; 2.75mmol) and the reaction mixture was stirred at 75 ℃ for 6 hours. After cooling, a 1N hydrochloric acid solution was added to the reaction mixture and the organics were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Crystallization from an ethyl acetate-heptane mixture gave 0.044g (52%) of the title compound as a white solid. ESI/APCI (+):325(M + H). ESI/APCI (-):323 (M-H).

Example 113: preparation of methyl 2- [ 2-tert-butyl-7- (1, 2-dihydroacenaphthen-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetate

To a solution of methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.080 g; 0.237mmol) and 2- (1, 2-dihydroacenaphthen-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.095 g; 0.339mmol) in a water/DME mixture (1/3) (1.5mL) was added tetrakis (triphenylphosphine) palladium (0.015 g; 0.013mmol) and diisopropylethylamine (0.170 mL; 0.976 mmol). The solution was stirred for 40 minutes under microwave irradiation at 140 ℃. Ethyl acetate was added to the reaction mixture, and the solution was washed successively with 1N hydrochloric acid solution, 1N sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-20%) gave 0.092g (85%) of the title compound as a bright yellow solid. ESI/APCI (+):408(M + H).

Example 114: preparation of 2- [ 2-tert-butyl-7- (1, 2-dihydroacenaphthen-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetic acid

To a solution of methyl 2- (2-tert-butyl-7- (1, 2-dihydroacenaphthen-5-yl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.092 mg; 0.202mmol) in methanol (3mL) was added a 5N sodium hydroxide solution (0.200 mL; 1.00mmol), and the solution was heated at 75 ℃ for 5 days. The volatiles were evaporated and a 1N hydrochloric acid solution was added to the residue. The precipitate was filtered and washed with water. Purification by preparative HPLC according to method 2 described gave 2 peaks with the same mass. The first peak eluted at Rt =8.20 min (0.0079g,9%), while the second peak eluted at Rt =8.58 min (0.0187g, 21%).

ESI/APCI(+):442(M+H)。

Example 115: preparation of methyl 2- [ 2-tert-butyl-7- (2-methoxy-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetate

To a solution of methyl 2- (2-tert-butyl-7-chloro-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.120 g; 0.355mmol) and 2-methoxy-4-methylphenylboronic acid (0.085 g; 0.512mmol) in a water/DME mixture (1/3) (3mL) was added tetrakis (triphenylphosphine) palladium (0.043 g; 0.038mmol) and diisopropylethylamine (0.3 mL; 1.72 mmol). The solution was stirred under microwave irradiation at 140 ℃ for 1 hour. Ethyl acetate was added to the reaction mixture, and the solution was washed successively with 1N hydrochloric acid solution, 1N sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using an ethyl acetate gradient in heptane (0-20%) gave 0.168g of the title compound as a bright yellow oil contaminated with methyl 2- (2-tert-butyl-5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) valerate. ESI/APCI (+):423(M + H).

Example 116: preparation of 2- [ 2-tert-butyl-7- (2-methoxy-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetic acid

To a solution of methyl 2- (2-tert-butyl-7- (2-methoxy-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.128 g; 0.3mmol) in methanol (3mL) was added a 5N sodium hydroxide solution (0.300 mL; 1.50mmol) and the reaction mixture was heated at 75 ℃ for 24 hours. The mixture was acidified with 1N hydrochloric acid solution and the product was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC according to method 2 described gave 2 peaks with the same mass. The first peak eluted at Rt =6.37 min (0.0207g,17%) and the second peak eluted at Rt =6.80 min (0.0074g, 6%). ESI/APCI (+):410(M + H).

Example 117: preparation of 2- [ 2-tert-butyl-7- (2-hydroxy-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl ] acetic acid

To a solution of 2- (2-tert-butyl-7- (2-methoxy-4-methylphenyl) -5-methylpyrazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid (0.080 g; 0.195mmol) in pyridine (0.75mL) was added lithium iodide (0.135 g; 1.01mmol), and the solution was heated under microwave radiation at 170 ℃ for 90 minutes. Ethyl acetate was added to the reaction mixture and washed with 1N hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC according to the method 2 gave 0.018g (23%) of the title compound as a white solid. ESI/APCI (+):396(M + H).

Example 118: preparation of methyl 2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To a solution of methyl 2- (7-chloro-2-isopropyl-5-methyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.122 g; 0.376mmol) in water/DME (1/3,3mL) were added 4-tolylboronic acid (0.100 g; 0.736mmol), tetrakis (triphenylphosphine) palladium (0.045 g; 0.039mmol) and diisopropylethylamine (0.265 mL; 1.52 mmol). The solution was heated under microwave irradiation at 140 ℃ for 40 minutes. To the reaction mixture was added a 1N hydrochloric acid solution and the product was extracted with ethyl acetate. The organic layer was washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-40%) to give 0.103g (72%) of the title compound as a pale yellow oil. ESI/APCI (+):381(M + H).

Example 119: preparation of 2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoic acid

To a solution of methyl 2- (2-isopropyl-5-methyl-7-p-tolyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) pentanoate (0.103 g; 0.271mmol) in methanol (5mL) was added a 5N sodium hydroxide solution (0.300 mL; 1.50mmol), and the solution was heated under reflux for 3 hours. The solvent was evaporated and a 1N hydrochloric acid solution was added to the residue. The mixture was sonicated for 5 minutes, the precipitate filtered, washed with water and dried under high vacuum to give 0.082g (83%) of the title compound as a white solid. ESI/APCI (+):367(M + H). ESI/APCI (-):365 (M-H).

Example 120: preparation of ethyl 2- (2-benzyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To a solution of ethyl 2- (2-benzyl-7-chloro-5-methyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.134 g; 0.346mmol) and 4-tolylboronic acid (0.091 g; 0.669mmol) in a water/DME mixture (1/3) (3mL) was added tetrakis (triphenylphosphine) palladium (0.038 g; 0.033mmol) and diisopropylethylamine (0.250 mL; 1.44 mmol). The solution was heated under microwave irradiation at 140 ℃ for 40 minutes. To the reaction mixture was added a 1N hydrochloric acid solution and the product was extracted with ethyl acetate. The organic layer was washed with 1N sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel using a gradient of ethyl acetate in heptane (0-50%) to give 0.152g (99%) of the title compound as a viscous white solid. ESI/APCI (+):443(M + H).

Example 121: preparation of ethyl 2- (2-benzyl-5-methyl-7-p-tolyl- [1,2,4] -triazolo [1,5-a ] pyrimidin-6-yl) pentanoate

To a solution of ethyl 2- (2-benzyl-5-methyl-7-p-tolyl- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -pentanoate (0.152 mg; 0.344mmol) in methanol (7mL) was added a 5N sodium hydroxide solution (0.350 mL; 1.75mmol), and the solution was heated under reflux for 24 hours. The volatiles were evaporated and a 1N hydrochloric acid solution was added to the residue. The product was extracted with ethyl acetate and the combined organic portions were washed with 1N hydrochloric acid solution, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC according to the method 1 gave 0.077g (54%) of the title compound as a white solid. ESI/APCI (+):415(M + H). ESI/APCI (-):413 (M-H).

And part B: antiviral activity of the compound

Example 122: evaluation of anti-HIV Activity of Compounds of the invention

anti-HIV agents are evaluated in vitro using rapid and automated assay methods. HTLV-1 transformed T4-cell line MT-4 (which previously showed to be very sensitive to and permissive for HIV infection) was used as the target cell line. Inhibition of HIV-induced cytopathic effects was used as an endpoint. Viability of HIV-infected and mock-infected cells was evaluated spectrophotometrically by reducing 3- (4,5-dimethylthiazol-2-yl) -2, 5-biphenyltetrazolium bromide (3- (4, 5-dimethylthizol-2-yl) -2,5-diphenyltetrazolium bromide, MTT) in situ. 50% Cytotoxic Concentration (CC) ₅₀μ g/ml) was defined as the concentration of compound that reduced the absorbance of the mock-infected control sample by 50%. The percent protection achieved by the compounds in HIV-infected cells was calculated by the following formula:

expressed in%

Wherein (ODT) HIV is the optical density measured at a given concentration of test compound in HIV-infected cells; (ODC) HIV is the optical density measured against an untreated HIV-infected cell control; (ODC) MOCK is the optical density measured against untreated MOCK-infected cell controls; all optical density values were measured at 540 nm. The dose to achieve 50% protection according to the above formula is defined as the 50% inhibitory concentration (EC)₅₀In μ g/ml or μ M). CC (challenge collapsar)₅₀And EC₅₀The ratio of (A) to (B) is defined as the Selectivity Index (SI). EC for inhibiting HIV proliferation with respect to specific compounds of the invention₅₀、CC₅₀And examples of SI values are listed in table 3 herein below.

By observing the respective CCs in the MT-4 cell line₅₀Examples of inhibition of cell proliferation by particular compounds of the invention may be found.

Cell: MT-4 cells (Miyoshi et al, 1982) in serum supplemented with 10% heat-inactivated fetal bovine serum, 2mM l-glutamine, 0.1% sodium bicarbonate andgentamicin/ml RPMI1640 medium.

Virus: the HIV-1(NL4.3) strain (Adachi et al, 1986) is a molecular clone obtained from the National Institutes of Health (Bethesda, Md.). Stock HIV-2(ROD) (Barr, -Sinoussi et al, 1983) was obtained from culture supernatants of HIV-2 infected cell lines.

Reference documents:

Adachi,A.,Gendelman,H.,Koenig,S.,Folks,T.,Willey，R.,Rabson,A.and Martin,M(1986)Production of acquired immunodeficiencysyndrome-associated retrovirus in human and nonhuman cells transfectedwith an infectious molecular clone,J.Virol.,59,284-291.Barr-Sinoussi,F.,Chermann,J.C.,Rey,F.,Nugeyre,M.T.,Chamaret,S.,Gruest,J.,Dauguet,C.,Axler-Blin,C.,V，zinet-Brun,F.,Rouzioux,C.,Rozenbaum,W.,Montagnier,L.(1983)Isolation of a T-lymphotropicretrovirus from patient at risk for AIDS,Science(Wash DC)220,868-871.Miyoshi,I.,Taguchi,H.,Kobonishi,I.,Yoshimoto,S.,Ohtsuki,Y.,Shiraishi,Y.andAkagi,T.(1982)Type C virus-producing cell lines derivedfrom adult T cell leukemia,Gann mongr,28,219-228.

example 123: ALPHASCREEN assay for measuring the LEDGF-integrase interaction inhibitory activity of the compounds of the invention

The AlphaScreen test (Perkin Elmer, Benelux) was performed according to the manufacturer's protocol. The reaction is carried out in 384-well Optiwell^TMMicrotiter plates (Perkin Elmer) were run at 25. mu.l final volume. The reaction buffer contained 25mM Tris-HCl (pH 7.4), 150mM NaCl, 1mM MgCl₂0.01% (v/v) Tween-20 and 0.1% (w/v) bovine serum albumin. His was treated at 4 ℃₆Labeled integrase (300nM final concentration) was incubated for 30 min with the compound. The compounds were added at different concentrations spanning a wide range from 0.1 up to 100 μ M. Thereafter, 100nM flag-LEDGF/p75 was added and the incubation was extended for another hour at 4 ℃. Subsequently, 5. mu.l of Ni chelate was addedCompound-coated acceptor beads (acceptor beads) and 5. mu.l anti-flag donor beads (donor beads) to a final concentration of 20. mu.g/ml for both beads. The protein and beads were incubated at 30 ℃ for 1 hour for association to occur. The reaction was left out of exposure to direct light as much as possible, and the light emission from the acceptor beads was measured in an EnVision plate reader (Perkin Elmer, Benelux) and analyzed using EnVision management software. Using His in similar devices ₆Labeled integrase (1 μ M final concentration) and oligodeoxynucleotide mimicking the IN ELISA oligonucleotide substrate (30nM final concentration) for IN/DNA binding. The reverse filtration screening (Counterscreens) using JPO2 or PogZ, respectively, was performed essentially as described previously.

Expression and purification of recombinant proteins: purification of His as described previously₆Labelled HIV-1 integrase, 3 xflag-labelled LEDGF/p75, MBP-JPO2 and MBP-PogZ for AlphaScreen applications.

Reference documents:

Bartholomeeusen,K.,et al.Differential interaction of HIV-1integrase andJPO2 with the C terminus of LEDGF/p75.J.Mol.Biol.372,407-421(2007).

Bartholomeeusen,K.,et al.Lens Epithelium Derived Growth Factor/p75interacts with the transposase derived DDE domain of pogZ.J.Biol.Chem.(2009).

Busschots,K.,et al.The interaction of LEDGF/p75 with integrase islentivirus-specific and promotes DNA binding.J.Biol.Chem.280,17841-17847(2005).

the compounds of the present invention show anti-HIV activity and examples thereof are listed in table 4.

TABLE 4

All publications and patent applications cited herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The chapters or pages of the above-cited documents specifically cited are specifically incorporated by reference. The invention has been described in sufficient detail to enable those skilled in the art to make and use the subject matter of the described embodiments. Many modifications to the described embodiments are possible without departing from the teachings thereof. All such modifications are intended to be included within the scope of the present claims.

Claims

1. A compound according to formula (A), and pharmaceutically acceptable salts thereof:

wherein the content of the first and second substances,

and wherein said cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl is unsubstituted or substituted with one or more R¹⁰Substitution;

and wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl or heterocycle-heteroalkynyl is unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

-R³independently selected from hydrogen; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; a heterocycle; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocyclic-heteroalkenyl or heterocycle-heteroalkynyl;

-R⁴independently selected from hydrogen; an alkyl group; alkenyl or alkynyl;

Wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-Alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

and wherein said alkyl, alkenyl, alkynyl,Heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heteroalkynyl Cyclo-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl and heterocycle-heteroalkynyl unsubstituted or substituted with one or more independently selected alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxy, = O, halogen, -SH, = S, trifluoromethyl, -OCF₃Cyano, nitro, -C (O) OH or NH₂Substitution;

2. The compound of claim 1, wherein R³Is H.

3. The compound of claim 1 or 2, wherein R¹Selected from aryl or heterocycle, wherein said aryl or heterocycle is unsubstituted or substituted with one or more R¹⁰And (4) substitution.

4. A compound according to claims 1 to 3, wherein R^2aAnd R^2bOne is hydrogen, and R^2aAnd R^2bWherein the other is selected from hydrogen; a cyano group; an alkyl group; an alkenyl group; an alkynyl group; a heteroalkyl group; a heteroalkenyl group; a heteroalkynyl group; an aryl group; an arylalkyl group; an arylalkenyl group; an aryl alkynyl group; an aryl-heteroalkyl group; (ii) an aryl-heteroalkenyl group; (ii) an aryl heteroalkynyl group; a heterocycle; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl; or R^2aAnd R^2bCan together form a vinyl or a vinyl alkyl;

and wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl is unsubstituted or substituted.

5. The compound according to claims 1 to 4, wherein the compound has the structure of formula (C-I) or (C-II)

Wherein X, Y, dotted line, R¹、R^2a、R^2b、R⁵、R⁶And R⁷Each as claimed in claims 1 to 4.

6. A compound according to claims 1 to 5, wherein the compound has a structure according to formula (E) consisting of (E-I), (E-II), (E-III) or (E-IV),

wherein R is¹、R^2a、R^2b、R³、R⁴、R⁵、R⁶And R⁷Each as claimed in claims 1 to 4.

7. A compound according to claims 1 to 6 for use as a medicament.

8. A compound according to claim 7 for use as a medicament for the prevention or treatment of a viral infection in an animal.

9. The compound of claim 8, wherein the viral infection is an HIV infection.

10. Use of a compound according to claims 1 to 6 for the manufacture of a medicament for the prevention or treatment of a viral infection in an animal.

11. The use according to claim 10, wherein the viral infection is an HIV infection.

12. A pharmaceutical composition comprising a compound according to claims 1 to 6 as active ingredient in admixture with at least one pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 further comprising at least one additional compound having antiviral activity.

14. A method of preventing or treating a viral infection in an animal or mammal, the method comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 6.