JP2008546813A - [Pyrazolo [3,4-B] pyridin-2-yl] -benzoic acid derivatives as HIV integrase inhibitors - Google Patents

Abstract

The present invention provides compounds of formula (I) and their pharmaceutically acceptable salts. Where C _X , m, n, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R _a , R _b , R _{b ′} are as defined herein. It is.

Description

  The present invention relates to a series of novel [pyrazolo [3,4-B] pyridin-2-yl] -benzoic acid derivatives that inhibit HIV integrase and are characterized by unique structural and physicochemical properties. This inhibitory property can be advantageously used to provide compounds having antiviral properties against retroviruses such as HIV viruses (including HIV-1 and HIV-2 viruses). These [pyrazolo [3,4-B] pyridin-2-yl] -benzoic acid derivatives, including their pharmaceutical compositions, can be used to inhibit the activity of HIV integrase and thus HIV Can be used to reduce duplication.

HIV (human immunodeficiency virus) retrovirus is the causative agent of AIDS (acquired immune deficiency syndrome). HIV-1 retroviruses primarily use the CD4 receptor (a 58 kDa transmembrane protein), the viral envelope glycoprotein (gp 120), and in CD4 (+) helper-T lymphocytes and certain other cells It enters the cell by a high affinity interaction with a specific region of the CD4 (+) molecule found inside (Lasky LA et al., Cell vol. 50, p. 975-985 (1987)). HIV infection is characterized by a period that immediately follows an infection called “asymptomatic” that has no clinical symptoms in the patient. Progressive HIV-induced destruction of the immune system then increases the susceptibility of opportunistic infections, eventually called AIDS-related syndromes (ARC), such as persistent systemic lymphadenoma, fever, weight It causes a syndrome characterized by symptoms such as a decrease, followed by full-fledged AIDS symptoms. After retrovirus entry into the cell, the viral RNA is converted to DNA, which is then integrated into the host cell DNA. The reverse transcriptase encoded by the viral genome catalyzes the early stages of these reactions (Haseltine WA FASEB J. vol 5, p. 2349-2360 (1991)). At least three actions are due to reverse transcriptase: RNA-dependent DNA polymerase activity that catalyzes the synthesis of DNA minus strand from viral RNA, and ribonuclease H (RNase H) activity that cleaves RNA templates from RNA-DNA hybrids And DNA-dependent DNA polymerase activity that catalyzes the synthesis of the second DNA strand from the minus-strand DNA template (Goff SPJ Acq. Imm. Defic. Syndr. VoI 3, p. 817-831 (1990)). When reverse transcription is over, the viral genome, now in a DNA form (called provirus), is integrated into the host genomic DNA and serves as a template for viral gene expression by the host transcription system. (Roth et al., 1989). The preintegration complex consists of integrase, reverse transcriptase p17, and proviral DNA (Bukrinsky M. L, Proc.
Natn. Acad. Sci. USA vol. 89 p.6580-6584 (1992)). Phosphorylated p17 protein plays a central role in targeting the preintegration complex into the nucleus of the host cell (Gallay et al., 1995).

  The first RNA transcript produced by the provirus is synthesized by the host cell RNA polymerase II, which is regulated by two proteins encoded by the viruses called tat and rev. These viral proteins are formed as polyproteins.

  Post-transcriptional regulation of viral polyproteins includes Env (envelope) protein processing and glycosylation, and myristylation of the N-terminal residue of the p17 protein in Gag and Gag-Pol polyproteins. Viral proteases are involved in the processing of Gag and Gag-Pol polyproteins to mature proteins. This processing is an essential step in viral infection.

A number of synthetic antiviral agents have been designed to block various stages of the HIV replication cycle. These agents include compounds that interfere with the binding of viral CD4 (+) helper-T lymphocytes (eg, soluble CD4), compounds that inhibit viral reverse transcriptase (eg, didanosine and zidovudine (AZT)) , Compounds that inhibit budding of virions from cells (interferons), or compounds that inhibit viral proteases (eg, ritonavir and indinavir). Some of these drugs were ineffective in clinical trials. In addition, drugs targeted primarily at the early stages of viral replication had no effect on the production of infectious virions in chronically infected cells. Furthermore, administration of these agents in many therapeutically effective amounts results in cytotoxicity and unwanted side effects such as anemia, neurotoxicity, and myelosuppression. Anti-protease compounds are typically large and complex peptidic molecules in their presence, tend to have low bioavailability and are generally not compatible with oral administration. These compounds often show side effects such as nausea, diarrhea, liver abnormalities, and kidney stones.
Bukrinsky M. L, Proc. Natn. Acad. Sci. USA vol. 89 p.6580-6584 (1992)

None of the commercially known antiviral agents target HIV integrase.
There is a need for compounds that can effectively inhibit the action of HIV integrase and can be used to reduce HIV infection.
The present invention seeks to meet these and other needs.

  The present invention relates to a class of [pyrazolo [3,4-B] pyridin-2-yl] -benzoic acid compounds and their pharmaceutically acceptable derivatives (eg, salts).

  Accordingly, the present invention in its first aspect has the formula I:

And pharmaceutically acceptable derivatives thereof, including pharmaceutically acceptable salts or solvates thereof.
n may be, for example, 0 to 4 (0, 1, 2, 3, or 4), m may be, for example, 0 to 4 (0, 1, 2, 3, or 4), Of course, the sum of n and m must not exceed the number of available positions (ie 4),
C _X is —CHO, —CH═N—OR ₃ (eg, —CH═N—OH), —CH═N—NR ₃ R ₄ (eg, —CH═N—NH ₂ ), —CH═NR ₅ and may be selected from the group consisting of —CH (OR ₃ ) ₂ ,
R ₁ is, for example, -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, -F, -Cl, -Br, -I, -CN , And -OR (eg, -OH)
R ₂ may be selected, for example, from the group consisting of —H, —CO ₂ H, —CONR ₃ R ₄ , and —COR ₆ ;
R ₃ is, for example, -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, an allyl group, or a cycloalkyl group having 3 to 8 carbon atoms. , Piperidine, pyrrolidine, morpholine, and -R _a -COOH, where R _a may be a linear alkyl group of 1 to 6 carbon atoms;
R _b can be a cleavable unit (eg, a physiologically cleavable unit), and cleavage of this unit causes the compound to release an integrase inhibitor (HIV integrase inhibitor). For example, R _b may be an enzymatically or metabolically cleavable unit or a bond that can be hydrolyzed in intestinal and / or gastrointestinal conditions (pH) or other physiological conditions;
More specifically, R _b is, for example, —H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, an allyl group, or 3 to 8 carbon atoms. number of the cycloalkyl _{group, R b '-CO -, (} HO) 2 P (O), and (MO) from the group consisting of ₂ P (O) (independently) may be selected, where, M is It may be an alkali metal (eg Na, K, Cs etc.) or an alkaline earth metal (eg Ca, Mg etc.)
R _{b ′} is, for example, H, a linear or branched alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, tert- Butyl —CH ₂ — and the like), a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl, cyclohexyl, etc.), and 3 to 6 carbon atoms in its cycloalkyl moiety, May be selected from the group consisting of cycloalkylalkyl groups having 1 to 3 alkyl moieties in the alkyl portion (eg, cyclopropyl-CH2-, cyclohexyl-CH2-, etc.);
R ₄ is, for example, H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, -CH ₂ CH ₂ OH, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-(l, _{2,3,4-tetrahydroquinolyl), - CO 2 R 3,} -CONR 3 R 3, -COR 6, 2- Hydroxy-6-methylnicotinyl, formyl, substituted or unsubstituted benzyl (with a linear alkyl group of 1 to 6 carbon atoms, branched alkyl group of 3 to 6 carbon atoms), (non Substituted or phenyl, mono-, di-, or tri-hydroxy substituted) phenyl, linear alkyl group (1-6 carbon atoms) or branched (3-6 carbon atoms) May be selected from the group consisting of phenyl substituted at the o,-, m,-, p, -position with an alkyl group,
R ₅ may be selected from the group consisting of piperidine (1-, 2-, 3-piperidine) and morpholine (1-morpholine);
R ₆ is -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, -NH ₂ , Phenyl [unsubstituted or substituted phenyl, eg mono-, di-, or tri-hydroxy substituted phenyl, linear alkyl group (1-6 carbon atoms) or branched (3-6 carbon atoms) Phenyl substituted at the o,-, m,-, p, -position with an alkyl group], -CH ₂ CH ₂ OH, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5- (l, 2,3 , 4-Tetrahydroquinolyl), pyridyl substituted at the o,-, m,-, p, -position with a linear or branched alkyl group, substituted with a branched alkyl group of 3 to 6 carbon atoms Pyridyl, nicotinyl [(mono, di, tri) substituted nicotinyl such as hydroxy substituted nicotinyl, alkyl substituted nicotinyl such as 2-OH-6-Me nicotinyl, or non-substituted Nicotinyl], and it may be selected from the group consisting of -OR _7, and
R ₇ may be -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, or a cycloalkyl group having 3 to 8 carbon atoms. .

Exemplary embodiments of compounds of formula I as claimed in the present invention include:
C _X is a compound selected from the group consisting of, for example, —CHO, —CHNO—R _a —COOH, —CHNO—R ₃ , —CH═NR ₃ R ₄ , —CH═NR ₅ ,
R ₃ may more particularly be selected from the group consisting of —H and a linear alkyl group of 1 to 6 carbon atoms;
R ₄ is, for example, H, —COR ₆ , formyl, benzyl substituted with a linear alkyl group of 1 to 6 carbon atoms or a branched alkyl group of 3 to 6 carbon atoms, unsubstituted benzyl, May be selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, substituted or unsubstituted phenyl;
R ₅ may be selected from the group consisting of piperidine and morpholine,
R ₆ is more particularly —NH ₂ , unsubstituted phenyl, mono-, di-, or tri-hydroxy substituted phenyl, phenyl substituted with a linear alkyl group of 1 to 6 carbon atoms, carbon atoms 3 Phenyl, unsubstituted nicotinyl, nicotinyl (a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and / or substituted with 1 to 6 branched alkyl groups, and / or Or substituted with at least one hydroxy group), and -OR ₇ and
R ₇ is selected from the group consisting of —H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, and a cycloalkyl group having 3 to 8 carbon atoms. May be selected,
Compounds are included.

Exemplary embodiments of compounds of formula I as claimed herein are:
A compound wherein C _X is —CH═NR ₃ R ₄ and a compound wherein R ₃ is —H (eg, —CH═N—HR ₄ ),
R ₄ is more particularly H, 2-pyridyl, 3-pyridyl, 4-pyridyl, formyl, [(eg, a linear alkyl group of 1 to 6 carbon atoms or a branch of 3 to 6 carbon atoms Substituted with benzylic alkyl group) benzyl, (substituted or unsubstituted) phenyl, —COR ₆ ,
R ₆ is more particularly —NH ₂ , —OR ₇ , a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, 3 to 8 carbon atoms A cycloalkyl group, phenyl (substituted or unsubstituted; eg, mono-, di-, or tri-hydroxy substituted phenyl, o,-, m,-, p, -position substituted with a linear or branched alkyl group Selected from the group consisting of: (mono, di, tri) substituted nicotinyl, eg, hydroxy substituted nicotinyl, alkyl substituted nicotinyl, eg, 2-OH-6-Me nicotinyl, or unsubstituted nicotinyl] May be, and
R ₇ is as defined above,
Also included are compounds.

In accordance with the present invention, C _X more particularly includes, for example, —CHO, —CHNO—CH ₂ —COOH, —CHNO—Me, —CHNOEt, —CHNO-allyl, —CHNO-t-Bu, —CHNOH, — CHNNH _2, -CHN-1- piperidine, -CHN-1-morpholine, -CHN-NH- (CO-2 -OH-6-Me nicotinyl), - CHN-NH- (CO- hydroxyphenyl) [e.g., - CHN-NH- (CO-2-OH-phenyl)], -CHN-NH- (CO-di-hydroxyphenyl) [e.g., -CHN-NH- (CO-2,3-diOH-phenyl)], -CHN-NH- (CO-tri-hydroxyphenyl) [e.g., -CHN-NH- (CO-2,3,4-triOH-phenyl)], -CHN-NH-2-pyridine, -CHN-NH Selected from the group consisting of -formyl, -CHN-NH- (COOMe), -CHN-NH- (CONH ₂ ), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu Bz) Good.

According to one embodiment of the invention, C _X is, for example, —CHO, —CHNO—CH ₂ —COOH, —CHNO-Me, —CHNOEt, —CHNO-allyl, —CHNO-t-Bu, —CHN— NH- (CO-2-OH-6-Me nicotinyl), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-Bz, And -CHN-NH- (4-t-Bu Bz).

Further, according to certain embodiments of the invention, C _X is —CHO, —CHNO—CH ₂ —COOH, —CHNOEt, —CHN—NH— (CO-2-OH-6-Me nicotinyl), and May be selected from the group consisting of -CHN-NH- (CO-hydroxyphenyl)

  -CHN-NH- (CO-hydroxyphenyl) groups are more particularly -CHN-NH- (CO-mono-hydroxyphenyl), -CHN-NH- (CO-di-hydroxyphenyl), -CHN-NH- (CO-tri-hydroxyphenyl) etc., for example, -CHN-NH- (CO-2-OH-phenyl), -CHN-NH- (CO-3-OH-phenyl), -CHN-NH- (CO- 4-OH-phenyl), -CHN-NH- (CO-5-OH-phenyl), -CHN-NH- (CO-2,3-di-OHphenyl), -CHN-NH- (CO-2, 4-di-OHphenyl), -CHN-NH- (CO-3,4-di-OHphenyl), -CHN-NH- (CO-2,3,4-tri-OH-phenyl), -CHN- It may be selected from the group consisting of NH- (CO-3,4,5-tri-OH-phenyl) and the like.

  In one embodiment of the invention, the compound of formula I includes, for example, a compound in which —COOH or —H is in the 3′-position.

Exemplary embodiments of the compounds encompassed herein include, for example,
The compound of formula I, wherein m may be 0, 1, or 2;
The compound of formula I, wherein n may be 0, 1, or 2;
A compound of formula I, wherein the -COOR _{b '} group may be in the 3',-position or 4 ',-position;
The compound of formula I, wherein R _{b ′} may be, for example, —H;
- R _b is, more particularly, -H, from the group consisting of (HO) (wherein, M is an alkali metal or alkaline earth metal) ₂ P (O), and (MO) ₂ P (O) A compound of formula I, which may be selected,
A compound of formula I in which C _X may be -CHO and / or a compound of formula I in which R ₁ and R ₂ are both -H or m and n may both be 0 included.

A further embodiment of the present invention includes compounds of formula I wherein R ₂ may be —H or —COOH. In another exemplary embodiment of the invention are compounds wherein n may be 0 or 1, for example.

Another embodiment of the present invention includes compounds of formula I, wherein R ₁ may be more particularly —H, —F, —Cl, —Br, and —OH. More particularly, Cl may be in the 2′-position, the 4′-position, and / or the 6′-position, for example. According to the invention, m may more particularly be 0, 1, or 2.

For example, Cx is -CHO, R ₁ and R ₂ are both -H or m and n are both 0, the -COOR _{b '} group is in the 4',-position, and R _{b '} A compound wherein is —H and R _b is —H is included.

The compounds of the present invention also include compounds wherein R ₁ may be —OH and compounds where R ₂ may be —CO ₂ H, more particularly compounds where R ₂ may be —CO ₂ H in the 4′-position.

の化合物および医薬品として許容できるこれらの誘導体（医薬品として許容できるこれらの塩または溶媒和物を含む）に関する。式中、C_X、m、n、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R_a、R_b、R_b’ は、本明細書において定義したとおりである。 In a further aspect, the invention provides a compound of formula IA:

And pharmaceutically acceptable derivatives thereof, including pharmaceutically acceptable salts or solvates thereof. In which C _X , m, n, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R _a , R _b , R _{b ′} are as defined herein. is there.

According to the present invention, C _X is more particularly —CHO, —CHNO—CH ₂ —COOH, —CHNO—Me, —CHNOEt, —CHNO-allyl, —CHNO-t-Bu, —CHNOH, —CHNNH _2. , -CHN-1-piperidine, -CHN-1-morpholine, -CHN-NH- (CO-2-OH-6-Menicotinyl), -CHN-NH- (CO-hydroxyphenyl), -CHN-NH- 2-pyridine, -CHN-NH-formyl, -CHN-NH- (COOMe), -CHN-NH- (CONH ₂ ), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu Bz ) May be selected.

More specifically, C _X is -CHO, -CHNO-CH ₂ -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, -CHNO-t-Bu, -CHN-NH- (CO-2- OH-6-Me nicotinyl), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN-NH- ( 4-t-Bu Bz) may be selected.

Even more particularly, C _X is —CHO, —CHNO—CH ₂ —COOH, —CHNOEt, —CHN—NH— (CO-2-OH-6-Me nicotinyl), and —CHN—NH— (CO -Hydroxyphenyl) may be selected.

  Compounds of certain embodiments of the present invention include compounds wherein Cz may be, for example, -CHO.

In one embodiment of the compounds of formula IA encompassed by the present invention, Cx may be —CHO, n may be 1, and R ₂ is —COOH in the 4′-position or the 5′-position. Possible compounds are included. Other embodiments of the present invention include compounds of formula IA where m may be 0 and R ₁ may be H. Also encompassed by the invention are compounds of Formula IA where R _b is, for example, H. Also encompassed by the invention are compounds of Formula IA where R _{b ′} is, for example, H.

A further embodiment of the present invention is that Cx may be -CHO, n may be 1, R ₂ may be, for example, -COOH in the 5'-position, m may be 1, Provided are compounds of formula IA, wherein R ₁ may be, for example, —OH in the 4′-position.

According to the present invention, a compound of formula IA may have, for example, Cx may be —CHO, m may meet ₁ , R ₁ may be, for example, —Cl at the 4′-position or the 6′-position, Good compounds may be included.

Other particularly exemplary embodiment of the compounds of the present invention, Cx may be -CHNO-CH ₂ -COOH, it includes compounds.

In a more specific embodiment of the invention, Cx may be —CHNO—CH ₂ —COOH, m may be 0, n may be 1, and R ₂ may be —COOH. Also included are compounds of formula IA. According to the invention, R ₂ may be in the 5, − position, for example.

In other exemplary embodiments of the invention, Cx may be —CHNO—CH ₂ —COOH, m may be 1, n may be 0, and R ₁ is, for example, —Cl. Included are compounds of formula IA, which may be present. According to the invention, R ₁ may be in the 4′-position, for example.

  In a further exemplary embodiment of the invention, Cx may be, for example, -CHN-NH- (CO-2-OH-6-Me nicotinyl).

More particularly, according to the present invention, Cx may be -CHN-NH- (CO-2-OH-6-Me nicotinyl), m may be 0, n may be 1, Also included are compounds of formula IA, wherein R ₂ may be —COOH. According to the invention, R ₂ may be in the 5, -position.

Also according to the invention, Cx may be -CHN-NH- (CO-2-OH-6-Me nicotinyl), m may be 1, n may be 0, and R ₁ is Also included are compounds of formula IA, which may be -Cl. According to the invention, R ₁ may more particularly be in the 4, -position.

In a further exemplary embodiment of the invention, Cx may be —CH═N—NHCOR ₆ and R ₆ is for example a phenyl group (substituted or unsubstituted; eg mono, di or trihydroxy substituted phenyl). It may be.

In other embodiments of the invention, Cx is, for example, -CHN-NH- (CO-2-OH-phenyl), -CHN-NH- (CO-2,3-di-OH-phenyl), or- It may be CHN-NH- (CO-2,3,4-tri-OH-phenyl) or other hydroxyphenyl. According to the present invention, m may be 0, n may be 1, and R ₂ may be —COOH. R ₂ may be, for example, in the 5, -position.

Further embodiments of the invention include, for example, Cx may be —CHNO-allyl, m may be 1, R ₁ may be —Cl, n may be 0, and R ₂ Included are compounds of formula IA, wherein may be -H.

Exemplary embodiments of compounds encompassed herein include, for example,
The compound of formula IA, wherein R ₂ may be more particularly -H or -COOH, or more particularly -COOH;
The compound of formula IA, wherein R ₁ may be more particularly selected from the group consisting of —H, —F, —Cl, —Br, and —OH, more particularly —Cl or —OH;
The compound of formula IA, wherein m may be 0, 1, or 2;
The compound of formula IA, wherein n may be 0, 1, or 2;
A compound of formula IA, wherein the -COOR _{b '} group may be in the 3', -position, 4 ',-position, or 5',-position;
The compound of formula IA, wherein R _{b ′} may be, for example, —H;
-R _b is selected from the group consisting of, for example, -H, (HO) ₂ P (O), and (MO) ₂ P (O), wherein M is an alkali metal or an alkaline earth metal A compound of formula IA, which may be
The compound of formula IA, wherein R ₂ may be -COOH in the 4 ',-position, or 5',-position;
- R ₁ is 4 '- position, or 6', - may be a -Cl or -OH in position, the compound of formula IA,
The compound of formula IA, wherein R _b and R _{b ′} may both be -H;
The compound of formula IA, wherein R ₂ may be -COOH in the 4 ',-position, or 5',-position, m is 0 or 1, and n is 1 or 2;
The formula IA, wherein R ₁ may be -Cl or -OH in the 4 ',-position, or 6',-position, m is 1, 2, or 3 and n is 0 or 1 A compound of
Is included.

Thus, examples of compounds of formula IA encompassed by the present invention include, but are not limited to,
The compound of formula IA, wherein Cx is -CHO, R _b and R _{b '} are both -H, R ₂ is -COOH in the 4',-position, and m is 0;
-Cx is -CHO, R _b and R _{b '} are both -H, R ₂ is -COOH in the 5',-position, and R ₁ is -OH in the 4 ',-position. A compound of formula IA,
The compound of formula IA, wherein Cx is -CHO, R _b and R _{b '} are both -H, R ₂ is H, and R ₁ is -Cl in the 4'-position;
The compound of formula IA, wherein Cx is -CHO, R _b and R _{b '} are both -H, R ₂ is H, and R ₁ is -Cl in the 6'-position;
- Cx is -CHNO-CH ₂ -COOH, R _b and R _{b 'both} are -H, R ₂ is 5', - is -COOH in position, m is 0, the formula IA A compound of
- Cx is -CHNO-CH ₂ -COOH, R _b and R _{b 'both} are -H, R ₁ is 4', - is -Cl in the position, n is 0, the formula IA A compound of
-Cx is -CHN-NH- (CO-2-OH-6-Me nicotinyl), R _b and R _{b '} are both -H, and R ₂ is in the 5',-position A compound of formula IA, wherein m is 0;
-Cx is -CHN-NH- (CO-2-OH-6-Me nicotinyl), R _b and R _{b '} are both -H, and R ₁ is -Cl in the 4'-position. A compound of formula IA, wherein n is 0;
-Cx is -CHN-NH- (CO-hydroxyphenyl), R _b and R _{b '} are both -H, R ₂ is -COOH in the 5'-position, m is 0 A compound of formula IA,
- Cx is _{-CH = N-OR 3, R} 3 is, -H, is selected from the group consisting of one to six straight chain alkyl group having a carbon atom, both R _b and R _{b 'are} - is H, R ₁ is 4 ', - is -Cl in the position, n is 0, compounds of formula IA,
The compound of formula IA, wherein Cx is -CHNO-allyl, R _b and R _{b '} are both -H, R ₁ is -Cl in the 4',-position, and n is 0;
The compound of formula IA, wherein Cx is -CHNO-alkyl, R _b and R _{b '} are both -H, R ₁ is -Cl in the 4',-position, and n is 0;
-Cx is -CHN-NH-Bz and the compound of formula IA
-Cx is -CHN-NH- (4-t-Bu Bz), R _b and R _{b '} are both -H, R ₁ is -Cl in the 4',-position, and n is A compound of formula IA, which is 0,
The formula wherein Cx is -CHN-NH- (COOMe), R _b and R _{b '} are both -H, R ₁ is -Cl in the 4'-position, n is 0, IA compounds,
- Cx is _{-CHN-NH- (CONH 2),} R b and R _{b 'both} are -H, R ₁ is 4', - is -Cl in the position, n is 0, A compound of formula IA,
Is included.

の化合物および医薬品として許容できるこれらの誘導体（医薬品として許容できるこれらの塩または溶媒和物を含む）に関する。式中、C_X、m、n、R₁、R₃、R₄、R₅、R₆、R₇、R_a、R_b、R_b’ は、本明細書において定義したとおりである。 In an additional aspect, the present invention provides compounds of formula IA ′:

And pharmaceutically acceptable derivatives thereof, including pharmaceutically acceptable salts or solvates thereof. In the formula, C _X , m, n, R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R _a , R _b , and R _{b ′} are as defined in this specification.

According to the present invention, C _X is more particularly —CHO, —CHNO—CH ₂ —COOH, —CHNO—Me, —CHNOEt, —CHNO-allyl, —CHNO-t-Bu, —CHNOH, —CHNNH _2. , -CHN-1-piperidine, -CHN-1-morpholine, -CHN-NH- (CO-2-OH-6-Menicotinyl), -CHN-NH- (CO-hydroxyphenyl), -CHN-NH- 2-pyridine, -CHN-NH-formyl, -CHN-NH- (COOMe), -CHN-NH- (CONH ₂ ), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu Bz ) May be selected.

More specifically, C _X is -CHO, -CHNO-CH ₂ -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, -CHNO-t-Bu, -CHN-NH- (CO-2- OH-6-Me nicotinyl), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN-NH- ( 4-t-Bu Bz) may be selected.

Even more particularly, C _X is —CHO, —CHNO—CH ₂ —COOH, —CHNOEt, —CHN—NH— (CO-2-OH-6-Me nicotinyl), and —CHN—NH— (CO -Hydroxyphenyl) (for example, -CHN-NH- (CO-mono-hydroxyphenyl), -CHN-NH- (CO-di-hydroxyphenyl), -CHN-NH- (CO-tri-hydroxyphenyl), etc.) May be selected from the group consisting of

In an exemplary embodiment of the invention, Cx may be, for example, —CH═N—OR ₃ . According to the invention, R ₃ is selected from the group consisting of —H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and an allyl group. Good.

In other exemplary embodiments of the invention of formula IA ′, compounds of formula IA ′, wherein Cx may be —CHNNH ₂ , and Cx are —CHN-1-piperidine, —CHN-1-morpholine, — Also included are compounds of formula IA ′, which may be CHN—NH-2-pyridine, or —CHN—NH-formyl.

According to the present invention, compounds of formula IA ′ include, for example, compounds wherein m is 0 and R ₁ is —H. A compound in which R _b is, for example, H and R _{b ′} is, for example, H is also encompassed in the present invention.

Exemplary embodiments of compounds encompassed herein include, for example,
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H,
- R ₁ is, -H, -OH, -F, -Cl , selected from the group consisting of -Br, and -I, more particularly, R ₁ is -Cl or -OH, the compound of formula IA ',
The compound of formula IA, wherein m is 0, 1, or 2;
Is included.

Thus, examples of compounds of formula IA encompassed by the present invention include, but are not limited to,
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHO, and m is 0;
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHNOMe, and m is 0;
- R _b and R _{b 'both} are -H, Cx is -CHNOEt, m is 0, formula IA' compound of
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHNO-allyl, and m is 0;
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHNO-t-butyl, and m is 0;
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHNOH, and m is 0;
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHNNH ₂ , and m is 0;
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHN-1-piperidine, and m is 0;
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHN-1-morpholine, and m is 0;
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHN—NH-2-pyridine, and m is 0;
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHN—NH-formyl, and m is 0;
The compound of formula IA ′, wherein R _b and R _{b ′} are both —H, Cx is —CHN—NH— (CO-hydroxyphenyl), and m is 0;
Is included.

  Accordingly, in a further aspect, the present invention provides compounds of formula IB:

の化合物および医薬品として許容できるこれらの誘導体（医薬品として許容できるこれらの塩または溶媒和物を含む）に関する。式中、C_X、n、R₂、R₃、R₄、R₅、R₆、R₇、R_a、R_b、R_b’ は、本明細書において定義したとおりである。

And pharmaceutically acceptable derivatives thereof, including pharmaceutically acceptable salts or solvates thereof. In the formula, C _X , n, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R _a , R _b and R _{b ′} are as defined in the present specification.

According to the present invention, C _X is —CHO, —CHNO—CH ₂ —COOH, —CHNOEt, —CHN—NH— (CO-2-OH-6-Me nicotinyl), and —CHN—NH— (CO -Hydroxyphenyl) may be selected.

According to the present invention, exemplary compounds of formula IB include, for example, compounds where n is 0 and R ₂ is H. Also encompassed by the invention are compounds of formula IB where R _b is, for example, H and R _{b ′} is, for example, H.

According to the present invention, R ₁ may be, for example, one of —OH, —Cl, —F, —Br, —I, and the like.

Further according to the invention, C _X may be, for example, —CH═N—NR ₃ R ₄ , such as —CHN—NH— (COOMe), —CHN—NH— (CONH ₂ ). According to the present invention, R ₃ and R ₄ may be as defined herein, eg R ₃ may be H and R ₄ is benzyl (substituted or unsubstituted), eg- It may be CHN-NH-Bz, -CHN-NH- (4-t-Bu Bz), or the like.

の化合物および医薬品として許容できるこれらの誘導体（医薬品として許容できるこれらの塩または溶媒和物を含む）に関する。式中、C_X、m、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R_a、R_b、R_b’ は、本明細書において定義したとおりである。 In yet another aspect, the present invention provides compounds of formula IC:

And pharmaceutically acceptable derivatives thereof, including pharmaceutically acceptable salts or solvates thereof. In the formula, C _X , m, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R _a , R _b and R _{b ′} are as defined in the present specification.

According to the present invention, C _X is more particularly —CHO, —CHNO—CH ₂ —COOH, —CHNO—Me, —CHNOEt, —CHNO-allyl, —CHNO-t-Bu, —CHN—NH— ( CO-2-OH-6-Me nicotinyl), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN It may be selected from the group consisting of -NH- (4-t-Bu Bz).

More specifically, C _X is -CHO, -CHNO-CH ₂ -COOH, -CHNOEt, -CHN-NH- (CO-2-OH-6-Me nicotinyl), and -CHN-NH- (CO -Hydroxyphenyl) may be selected.

According to the invention, R ₁ may also be selected from the group consisting of H, —F, —Cl, —Br, —I and —OH, more particularly the group consisting of —H, —Cl and —OH. May be selected.

Further according to the invention, R ₂ may be as defined herein, in particular H or —COOH, for example.

  The present invention also relates to a pharmaceutical composition comprising at least one compound of formula I, IA, IA ', IB and / or IC and a pharmaceutically acceptable carrier. The pharmaceutical composition may comprise, for example, a pharmaceutically acceptable amount of one or more such compounds of the invention. The pharmaceutical composition can be used to inhibit integrase (including HIV integrase) and thus provide protection against HIV infection.

  The present invention relates to the use of at least one compound of formula I, IA, IA ', IB and / or IC for preparing a pharmaceutical composition, pharmaceutical product or medicament. Compounds of formula I, IA, IA ′, IB and / or IC may be used for the treatment and / or prevention of HIV infection and / or for the prevention of the appearance of acquired immune deficiency syndrome (AIDS) and / or It can be used in the preparation of a medicament to reduce HIV replication and / or its cytopathic effect and / or to inhibit the HIV integrase enzyme.

  The present invention further relates to the replication of HIV and / or its use for the treatment and / or prevention of HIV infection and / or AIDS of at least one compound of the formula I, IA, IA ′, IB and / or IC. It relates to the use for reducing the cytopathic effect and / or inhibiting the HIV integrase enzyme.

  The present invention relates to a method for the treatment and / or prevention of HIV infection and / or AIDS (eg, a method for slowing the emergence of AIDS) of an individual in need thereof, and replication of HIV and / or its The present invention relates to a method for reducing cytopathic action and / or inhibiting HIV integrase enzyme. According to the present invention, the method comprises administering a compound of formula I, IA, IA ', IB, and / or IC (or pharmaceutical composition, agent, etc.) to an individual in need thereof.

  The present invention is more particularly a method for reducing HIV replication (eg, integration) comprising a compound of formula I, IA, IA ′, IB, and / or IC (or pharmaceutical composition, drug, etc.) Or a method comprising administering such a compound to an individual in need thereof.

  The invention also relates to processes or methods for preparing compounds of formula I, IA, IA ', IB, and / or IC, and the use of intermediate compounds to prepare these compounds.

  The compounds of the present invention may include pharmaceutically acceptable derivatives of compounds of formula I, IA, IA ', IB, and / or IC as defined above. “Pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt (Na, K, Cs, etc.), acetal (ie, dimethyl acetal, diethyl acetal, etc.) oxime, or ester (eg, Non-limiting examples include methyl, ethyl, propyl, isopropyl ester, and the like.

  Furthermore, the expression “pharmaceutically acceptable derivative” gives (directly or indirectly) a compound of the invention or an antivirally active metabolite or residue of a compound of the invention when administered to a recipient. It should be understood to refer to any other compound having such a structure. Accordingly, the compounds of the present invention can be modified by adding appropriate functionalities to enhance selective biological properties. Such variants are well known in the art, and variants that enhance biological permeability to a given biological system (eg, blood, lymphatic system, central nervous system), oral bioavailability Variations that enhance performance, variations that increase solubility to allow administration by infusion, variations that alter metabolism, and variations that change excretion rates are included.

  The compounds of the present invention, if appropriate, including these pharmaceutically acceptable derivatives, have an affinity for integrases such as, in particular, HIV integrase. Thus, these compounds may be useful as inhibitors of such integrase. That is, they are particularly useful as HIV integrase inhibitors. These compounds can be used alone or to treat or prevent viral infections, to reduce the likelihood of infection, or to reduce the likelihood of expression of ARC and / or AIDS, It can be used in combination with other therapeutic or prophylactic agents (eg, antiviral agents, antibiotics, immunomodulators, vaccines, etc.).

  In accordance with the present invention, the compounds of the present invention provide for the replication of HIV virus in human CD4 + T-cells, and the double-stranded DNA for HIV replication by the host cell machinery subsequent to host integrase. It can be inhibited by inhibiting the activity that integrates into (Sakai H., J. Virol. Vol. 67 p. 1169-1174 (1993)). These novel compounds can therefore inhibit infection of the initial or subsequent host cells. Thus, these compounds may result in asymptomatic HIV-1 infection, AIDS-related syndrome (ARC), acquired immune deficiency syndrome (AIDS), AIDS-related dementia, or similar diseases of the immune system, It is useful as a therapeutic and prophylactic agent for treating or preventing infection by HIV (eg, HIV-1) and related viruses. As used herein, the terms “HIV integrase” and “integrase” are used interchangeably with and refer to integrase enzymes encoded by type 1 and type 2 human immunodeficiency viruses. In particular, the term includes human immunodeficiency virus type 1 integrase.

  The term “pharmaceutically effective amount” is effective in treating or preventing a patient's HIV infection (eg, reducing HIV replication, appearance of AIDS, reducing the likelihood of infection, reducing the likelihood of progression of AIDS, etc.). Means quantity. Also, as used herein, “pharmaceutically effective amount” refers to ingestion, alone or in combination with other therapeutic agents, whether single or multiple doses or ingestion by any dose or route. Even in cases, it can be interpreted as an amount that provides the desired therapeutic effect. In the case of the present invention, a “pharmaceutically effective amount” refers to the infection cycle of HIV [not only HIV-1 and HIV-2 but also related viruses (eg, HTLV-I and HTLV-II, and simian immunodeficiency virus)]. For example, replication, reinfection, maturation, inhibition of germination, etc.) and an amount that has an inhibitory effect on any organism that is dependent on integrase in its life cycle.

  The term “prophylactically effective amount” refers to an amount effective for preventing HIV infection or AIDS in a patient (eg, delaying the appearance of AIDS, reducing the likelihood of infection, reducing the likelihood of progression of AIDS, etc.). means. As used herein, “patient” means mammals including humans.

  The terms “pharmaceutically acceptable carrier”, “pharmaceutically acceptable adjuvant”, and “physiologically acceptable vehicle” can be administered to a patient together with one or more compounds of the present invention and the pharmacological By non-toxic carrier or adjuvant that does not impair activity.

  In the present specification, the “linear alkyl group having 1 to 6 carbon atoms” includes, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl.

  As used herein, “branched alkyl group of 3 to 6 carbon atoms” includes, but is not limited to, for example, isobutyl, tert-butyl, 2-pentyl, 3-pentyl, and the like.

As used herein, “a cycloalkyl group having 3 to 6 carbon atoms” includes, but is not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (ie, C ₆ H ₁₁ ).

Salts derived from appropriate bases include alkali metal (eg, sodium), alkaline earth metal (eg, magnesium), ammonium, and N— (C _1-4 alkyl) ₄ ⁺ salts.

  The only combinations of substituents and variables envisioned by this invention are those that achieve stable compound formation. As used herein, the term “stable” means a compound that has sufficient stability to allow for production and administration to a mammal in a manner known in the art.

In this specification, when a “range” or “group of substances” is described in terms of specific features of the present invention (eg, temperature, concentration, time, etc.), Whatever individual configurations and combinations are relevant to the present invention and expressly incorporated herein. Thus, any specified range or group is not only an abbreviation for individually describing each and every configuration of a range or group, but also each and every possible inclusion in it. It should be understood as an abbreviation for listing subranges or subgroups. The same is true for any subrange or subgroup within it. So, for example,
-With respect to the number of carbon atoms, the description of the range of 1 to 6 carbon atoms is used herein not only for the number of each and every individual carbon atom, but also for the subranges (e.g. 1 carbon atom, carbon Including 3 atoms, 4-6 carbon atoms, etc.)
-For reaction times, times of 1 minute or longer are used herein not only for each and every individual time, but also for subranges exceeding 1 minute (e.g. 1 minute, 3-15 minutes, 1 minute- 20 hours, 1-3 hours, 16 hours, 3-20 hours, etc.)
-Furthermore, with respect to other parameters (eg concentration, components etc.) as well,
Should be understood.

  In particular, not only each and every individual compound described thereby, but also each and every possible class, subgroup, or subclass of compound are represented by such formulas, respectively. It should be understood that a class or subclass includes whether it is positively defined to include a particular compound or whether it is defined to exclude a particular compound or combination. For example, an example of an exclusive definition of a chemical formula (eg, I) can be read as follows: “However, when one of A and B is —COOH and the other is H, —COOH is X ′ -I can't occupy the place. "

  The compounds of the present invention can be readily synthesized using conventional techniques from readily available inexpensive starting materials. In general, the derivatives of the present invention can be easily obtained from pyridoxal by a series of sequences recognized as straightforward by knowledge in the field, using inexpensive reagents and simple techniques that are readily available. The approach shown below allows pyridoxal to be converted to the desired HIV integrase inhibitor using standard techniques.

  Scheme 1 shows a general example of the coupling of aminoarylcarboxylic acid 1 with pyridoxal.

By treatment with NaNO ₂ and HCl, suitable aminoaryl carboxylic acid 1 (i.e., ortho, meta, or para form) when diazotizing the corresponding diazonium salt intermediate ^{_{(1-N 2 + Cl -}} ) are obtained This is immediately added to the basic solution of pyridoxal. From the obtained reaction product, Compound 2 was obtained with an average yield of 65%. Compound 2 was then treated with acid in a suitable polar solvent such as water or acetic acid to give title compound 3 in 65-95% yield.

  The title compound 3 is further converted into suitable O-substituted oximes, N′-substituted hydrazines, N′-substituted hydrazides, N ′, N′-disubstituted hydrazines, N ′, N′-disubstituted hydrazides. Can be modified by reaction with to give the title compound 4 or 5.

  As will be appreciated by those skilled in the art, the synthetic schemes described above are not intended as a comprehensive list of all the means by which the compounds described herein and which are included in the claims can be synthesized. Absent. Further methods will be apparent to those skilled in the art.

  The novel compounds of the present invention are excellent ligands for integrases, particularly HIV-1, most preferably HIV-2 and HTLV-1 integrase. Thus, these compounds can target and inhibit events in the early stages of replication (ie, integration of viral DNA into the human genome), thereby preventing viral replication.

  In addition to use in the prevention or treatment of HIV infection or AIDS, the compounds of the present invention may be inhibitors of other viruses whose essential events in their life cycle depend on integrase (an integrase similar to HIV integrase) or It can also be used as a blocking agent. Such compounds inhibit the viral replication cycle by inhibiting integrase. Since integrase is essential for the production of mature virions, inhibiting this process effectively blocks viral transmission by inhibiting the production and replication of infectious virions. The compounds of the present invention advantageously inhibit the enzymatic activity of integrase and inhibit the ability of integrase to catalyze the integration of the virus into the genome of human cells.

  The compounds of the present invention can be used in conventional methods for the treatment or prevention of infection by HIV and other viruses, viruses whose life cycle essential events depend on integrase. Such treatment methods, dosage levels, and requirements can be selected from available methods and techniques by conventional techniques in the art. For example, a compound of the present invention is administered in a pharmaceutically acceptable adjuvant and pharmaceutically acceptable method for administration to a virally infected patient and in an amount effective to reduce the severity of the viral infection. Can be combined. In addition, the compounds of the present invention can be combined with pharmaceutically acceptable adjuvants conventionally used in vaccines to administer a prophylactically effective amount to protect individuals from viral infections such as HIV infection over time. be able to. For this reason, the novel integrase inhibitors of the present invention are administered as drugs for treating or preventing viral infections (including HIV infection) in mammals (based on the cleavage of physiologically cleavable units). can do. The compounds of the present invention can be administered to healthy or HIV-infected patients as a single agent or in combination with other antiviral agents that interfere with the HIV replication cycle. Administration of the compounds of the present invention with other antiviral agents that target different events in the viral life cycle enhances the therapeutic effects of these compounds. For example, a co-administered antiviral agent may be an agent that targets early events in the viral life cycle, such as cell entry, reverse transcription, and incorporation of viral DNA into cellular DNA. Antiviral agents that target these early life cycle events include didanosine (ddI), sarcitabine (ddC), stavudine (d4T), zidovudine (AZT), and polysulphated polysaccharide sT4 (soluble) CD4) (which inhibits attachment and absorption of the virus to the host cell), other compounds that prevent the virus from binding to the CD4 receptor on T4 lymphocytes with CD4. Other retroviral reverse transcriptase inhibitors (such as derivatives of AZT, etc.) of the present invention to provide therapeutic treatment to substantially reduce or eliminate viral infection and symptoms associated with infection. It may be co-administered with the compound. Examples of other antiviral agents include ganciclovir, dideoxycytidine, trisodium phosphonoformate, eflornithine, ribavirin, acyclovir, alpha interferon, and trimethotrexate. In addition, for example, non-ribonucleoside inhibitors of reverse transcriptase (eg, TIBO, nevirapine, delavirdine, etc.) may be used to enhance the effects of the compounds of the invention. Similarly, viral decoating inhibitors, transactivating proteins (eg, Tat or Rev), or viral protease inhibitors may be used to enhance the effectiveness of the compounds of the invention. These compounds may be co-administered with other HIV integrase inhibitors.

  The combination therapy of the present invention exerts a synergistic effect on inhibition of HIV replication because each component of the combination acts on different sites of HIV replication. Using such a combination, the dosage required for a desired therapeutic or prophylactic effect of a given conventional antiretroviral agent is compared to when the drug is administered as a monotherapy. Can be advantageously reduced. These combinations can reduce or eliminate the side effects of conventional single agent antiretroviral therapy without inhibiting the antiretroviral activity of those agents. These combinations reduce the potential for resistance to monotherapy while minimizing any associated toxicity. These combinations also increase the effectiveness of conventional drugs without increasing the associated toxicity. A preferred combination therapy comprises administering a compound of the invention together with AZT, 3TC, ddI, ddC, d4T, Combivir, Ziagen, Sastiva, nevirapine, and delavirdine.

  Alternatively, the compounds of the present invention may also be co-administered with other HIV protease inhibitors such as saquinavir, indinavir, nelfinavir, ritonavir, and amprenavir to produce various viral mutants or other HIV analogs. The therapeutic or preventive effect on the constituent species of can be increased.

  Administration of the compounds of the present invention can be carried out, for example, as a single agent or in combination with a retrovirus reverse transcriptase inhibitor (eg, AZT derivative etc.) or an HIV aspartyl protease inhibitor. Co-administration of a compound of the invention with a retroviral reverse transcriptase inhibitor or HIV integrase inhibitor can exert a substantial synergistic effect, thereby preventing viral infectivity and its associated symptoms, It can be substantially alleviated or completely eliminated.

  The compounds of the present invention include immunomodulators (eg, bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone, and rEPO), antibiotics (Eg, pentamidine isethionate) or in combination with vaccines can also be used to prevent or treat infections and diseases associated with HIV infection (eg, AIDS and ARC, etc.).

  When the compound of the present invention is administered in combination therapy with other drugs, it may be administered to the patient sequentially or simultaneously. Alternatively, the pharmaceutical or prophylactic agent composition of the present invention may consist of a combination of the integrase inhibitor of the present invention and another therapeutic agent or prophylactic agent.

  Although the present invention focuses on the use of the compounds disclosed herein for the prevention and treatment of HIV infection, these compounds of the present invention are also similar because of essential events in their life cycle. It can also be used as an inhibitor against other viruses that depend on other integrases. These viruses include, but are not limited to, retroviruses that cause other diseases, such as simian immunodeficiency virus, HTLV-I, and HILV-II.

  The pharmaceutical composition of the present invention includes any of the compounds of the present invention and pharmaceutically acceptable salts thereof, together with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human Serum albumin etc.), buffer substances (eg phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of vegetable saturated fatty acids, water, salts or electrolytes (eg protamine sulfate, disodium hydrogen phosphate, Potassium hydrogen phosphate, sodium chloride, zinc salt, etc.), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, waxes, polyethylene-polio Shi propylene block copolymer, polyethylene glycol and wool fat.

  The pharmaceutical composition of the present invention can be administered orally, parenterally by inhalation spray, topically, rectally, nasally, buccally, vaginally or in an implantable reservoir. Thus, it can be seen herein that oral administration or administration by infusion is encompassed by the present invention. The pharmaceutical compositions of the present invention may comprise any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. As used herein, the term “parenteral” refers to subcutaneous, intradermal, intravenous, intramuscular, intraarticular, bursa, intrasternal, intrathecal, intralesional, And intracranial infusion or injection techniques.

  The pharmaceutical composition may be in the form of a sterile injectable dosage form, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known to those skilled in the art using suitable dispersing or wetting agents (such as, for example, Tween 80). The sterile injectable preparation may also be a sterile injectable solution or oily suspension in a nontoxic parenterally acceptable diluent or solvent (eg, 1,3-butanediol solution) . Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, and pharmaceutically acceptable natural oils such as olive oil or castor oil, especially those that are polyoxyethylenated are useful. . These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. HeIv. Or a similar alcohol.

  The pharmaceutical composition of the present invention can be orally administered in any orally acceptable dosage form. Orally acceptable dosage forms include, but are not limited to, capsules, tablets, and aqueous suspensions and solutions. For tablets to be used orally, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are usually added. Diluents useful for oral administration in a capsule form include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and dispersing agents. If desired, certain sweetening and / or flavoring and / or coloring agents can be added.

  The pharmaceutical composition of the present invention can also be administered in the form of suppositories for rectal administration. These compositions mix the compounds of this invention with suitable nonirritating excipients that are solid at room temperature but liquid at rectal temperature and therefore dissolve in the rectum to release the active ingredient. To prepare. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

  Topical administration of the pharmaceutical composition of the invention is particularly useful when the desired treatment involves a region or organ that can be readily applied by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active component dissolved or suspended in a carrier. Carriers for topical administration of the compositions of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene compound or polyoxypropylene compound, emulsifying wax, and water. Is mentioned. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active ingredient dissolved or suspended in a carrier. Preferred carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present invention may also be topically applied to the lower gastrointestinal tract by rectal suppository or in a suitable neat formulation. Topically transdermal patches are also included in the present invention.

  The pharmaceutical composition of the present invention can be administered by nasal aerosol or inhalation. Such compositions can be prepared by techniques well known to those skilled in the pharmaceutical formulation arts, including benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, And / or other solubilizers or dispersants known to those skilled in the art can be prepared as a saline solution.

  Prevention of viral infections (including HIV infection) at dosage levels between about 0.01 and about 25 mg / kg body weight / day, for example, dosages between about 0.5 and about 25 mg / kg body weight of active ingredient compound And useful in therapy. Typically, the pharmaceutical composition of the invention is administered about 1 to 5 times per day, or alternatively by continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient being treated and the particular mode of administration. A typical preparation may contain from about 5% to about 95% active compound (w / w). For example, such formulations may contain from about 20% to about 80% active compound.

  As the patient's condition improves, maintenance doses of the compounds, compositions, or combinations of the invention can be administered if necessary. Thereafter, the amount or frequency of administration, or both, can be reduced to a level that maintains an improved condition, depending on the symptoms. Treatment is terminated when symptoms are relieved to the desired level. However, patients may require long-term intermittent treatment for any recurrence of any disease symptom (especially AIDS).

  As can be appreciated by those skilled in the art, lower or higher doses than those listed above may be desired. The specific dose and treatment regimen for a specific patient depends on the activity, age, weight, general health status, sex, diet, time of administration, excretion rate, drug combination, severity of infection and the particular compound employed. It depends on a variety of factors, including the course, the patient's susceptibility to infection, and the judgment of the treating physician.

  The compounds of the present invention are also useful as commercial reagents that bind efficiently to integrase (especially HIV integrase). As commercially available reagents, the compounds of the present invention and their derivatives can be used to inhibit the incorporation of targeted DNA molecules by integrase, or they can be derivatized and stable as a constrained substrate for affinity chromatography. Can be combined. These and other uses that characterize commercially available integrase inhibitors will be apparent to those skilled in the art.

In the description herein, the following abbreviations are used:

  This section describes the synthesis of some of the compounds described herein. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way. This section provides details of the synthesis of the compounds of the present invention.

[Materials and methods]
Analytical thin layer chromatography (TLC) was performed on 0.25 mm silica gel E. Merck 60 F ₂₅₄ plates, eluting with the indicated solvent system. Preparative chromatography was performed using silica gel 60 (EM Science) and flash chromatography at the positive air pressure allowing the indicated solvent system and appropriate elution rate. Compound detection is accomplished by exposing the eluted plate (analytical or preparative) to iodine, UV light and / or the analytical plate in ethanol containing 3% sulfuric acid and 1% acetic acid. This was performed by heating with a 2% solution of p-anisaldehyde. Alternatively, the analytical plate was prepared by using 20% (NH ₄ ) ₆ Mo ₇ O ₂₄ in 0.3% ninhydrin solution in ethanol containing 3% acetic acid and / or water (750 mL) containing concentrated sulfuric acid (90 mL). and Ce (SO ₄₎ made from a _second poly hydrate 8.3 g, may be treated with CAM solution.

  Unless otherwise indicated, all starting materials were purchased from commercial sources such as Aldrich or Sigma.

  The melting point (mp) is measured in a capillary tube using a melting point measuring apparatus Buchi 530 and is uncorrected.

  Mass spectra were recorded on a Hewlett Packard LC / MSD 1100 system using APCI in either negative or positive mode.

Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AMX-II-500 equipped with a reverse or QNP probe. Samples were dissolved in deuterated chloroform (CDCl ₃ ), deuterated water (CD ₂ O), or deuterated dimethyl sulfoxide (DMSO-d ₆ ), and tetramethylsilane was used as an internal standard for data acquisition. Chemical shift ( ^* ) is expressed in parts per million (ppm), coupling constant (J) is expressed in hertz (Hz), multiplicity is s for single line, d for double line, 2d for double line. The double line is represented as dd, the triple line as t, the quadruple line as q, the quintet line as quint., The multiple line as m, and the broad single line as br s.

[General synthesis method]
A. General Method for Coupling Pyridoxal to Diazobenzoic Acid Method A:
1 mmol of aminobenzoic acid was dissolved in 5 ml of 2N HCl (with ethanol to aid dissolution if necessary) and cooled to 0-5 ° C. in an ice / salt bath. When 1 mmol of NaNO ₂ was added in small portions, a diazonium salt was formed in 5 minutes. 1 mmol (263 mg) of pyridoxal was then dissolved in 10 mL of ice water to which 0.5 mL of saturated NaOH was added. The diazonium salt was added in small portions over 1 minute and the resulting orange solution was left for 15 minutes. The solution was then allowed to return to room temperature in 1 to 4 hours. The red solution was cooled in an ice bath and 6N HCl was added dropwise to form a red precipitate. The precipitate was removed by filtration, washed with ice water and dried. The yield of this reaction varied between 20 and 99%.
Method B:
1 mmol of aminobenzoic acid was dissolved in 2 ml of 2N HCl (with 5 ml of ethanol to aid dissolution if necessary) and cooled to 0-5 ° C. in an ice / salt bath. When 1 mmol of NaNO ₂ was added in small portions, a diazonium salt was formed in 5 minutes. 1 mmol (263 mg) of pyridoxal was then dissolved in 2 mL of ice water to which 0.5 mL of saturated NaOH was added. The diazonium salt was added in small portions over 1 minute and the resulting orange solution was left for 15 minutes. The solution was then allowed to return to room temperature in 1 to 4 hours. The red solution was cooled in an ice bath until a yellow precipitate was obtained. The precipitate was filtered and dried. The yield of this reaction varied between 20 and 80%.

B. General method for pyrazolo formation To a suspension of pyridoxal derivative (5 mmol) in 5 mL acetic acid was added 2 mL 12N HCl and heated to 80 ° C. This solution became reddish brown as the product was formed. The solution was then filtered hot and the filtrate was poured onto crushed ice. The tan precipitate was filtered and dried (yield higher than 90%).

C. General methods of oxime formation
[Pyrazolo [3,4-B] pyridin-2-yl] -benzoic acid derivative (0.01 mmol) is added to a 20% solution of hydroxylamine hydrochloride in 2-5 mL of water buffered to pH 6, Stir for 20 minutes. The pH was adjusted with hydrochloric acid until product precipitation was complete. The precipitate was filtered and dried (about 65-95% yield).

D. General methods of hydrazone formation
[Pyrazolo [3,4-B] pyridin-2-yl] -benzoic acid derivative (0.01 mmol) is added to a 20% solution of hydrazine hydrochloride in 2-5 mL of water buffered to pH 6. Stir for minutes. The pH was adjusted with hydrochloric acid until product precipitation was complete. The precipitate was filtered and dried (approximately 65% yield).

[Specific examples of preparation of derivatives of general formula I]
The following compounds were all prepared from the pyridoxal form using the methods summarized in Schemes 1, 2, and 3.

Example 1. Preparation of 5- (4-formyl-5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl) -isophthalic acid This product is commercially available 3 , 5-amino-isophthalic acid and pyridoxal were obtained according to general method A, methods A and B. The final product was obtained in 85% yield.
LC / MS M + 1 = 342.1 95%
¹ H NMR (DMSO-d ₆ ) δ: 2.59 s 3H, 8.43 s 1H, 8.72 s 2H, 9.25 s 1H, 10.6 s 1H

Example 2. Preparation of 2-chloro-5- (4-formyl-5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl) -benzoic acid This product is commercially available Obtained according to general method A, methods A and B from available 2-chloro-5-amino-benzoic acid and pyridoxal. The final product was obtained in 70% yield.
LC / MS M + 1 = 332.1
¹ H NMR (D ₂ O / NaOD) δ: 2.10 s 3H, 8.0 d (J = 7.4 Hz) 1H, 8.32 d (J = 7.4 Hz) 1H, 8.47 s 1H, 9.28 s 1H, 10.6 s 1H

Example 3. Preparation of 4-chloro-3- (4-formyl-5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl) -benzoic acid This product is commercially available Obtained according to general method A, methods A and B from the available 4-chloro-5-amino-benzoic acid and pyridoxal. The final product was obtained in 88% yield.
LC / MS M + 1 = 332.1
_{^{1 H NMR (DMSO-d 6}} ) δ: 2.65 s 3H, 7.89 d (8 Hz) 1H, 8.09 d (8 Hz) 1H, 9.20 s 1H, 10.59 s 1H

Example 4. Preparation of 4- (4-formyl-5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl) -benzoic acid This product is commercially available 4 Obtained according to general method A, method A and B from 2-amino-benzoic acid and pyridoxal. The final product was obtained in 95% yield.
LC / MS M + 1 = 298.1
¹ H NMR (DMSO-d ₆ ) δ: 2.65 s 3H, 8.11 d (J = 8Hz) 1H, 8.25 d (J = 8Hz) lH, 9.20 s 1H, 10.59 s

Example 5. Preparation of 4- (4-formyl-5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl) -phthalic acid This product is commercially available 3 -Obtained according to general method A, method A and B from amino-phthalic acid and pyridoxal. The final product was obtained in 85% yield.
LC / MS M + 1 = 342.1
¹ H NMR (DMSO-d ₆ ) δ: 2.65 s 3H, 8.00 d (J = 7.4) 1H, 8.32 d (J = 7.4) 1H, 8.47 s 1H, 9.28 s 1H, 10.6 s 1H

Example 6. Preparation of 5- (4-formyl-5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl) -2-hydroxy-isophthalic acid This product is commercially available Obtained according to general method A, methods A and B from available 2-hydroxy-5-amino-isophthalic acid and pyridoxal. The final product was obtained with a yield of 65%.
LC / MS M + 1 = 358.2
¹ H NMR (D ₂ O / NaOD) δ: 2.33 s 3H, 7.33 s 2H, 8.26 s 2H, 9.92 s 2H

Example 7. Preparation of 5- [4- (carboxymethoxyimino-methyl) -5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid Obtained according to general method A, method A and B (Example 1) from commercially available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with carboxymethoxylamine by general method C to give the product in 80% yield.
LC / MS M + 1 = 415.1
¹ H NMR (DMSO-d ₆ ) δ: 2.58 s 3H, 4.90 s 2H, 8.46 s 1H, 8.67 s 2H, 8.84 s 1H, 9.05 s 1H

Example 8. Preparation of 5- [5-hydroxy-4- (methoxyimino-methyl) -6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid And obtained according to general method A, method A and B (Example 1) from 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with methoxylamine by general method C to give the product in 80% yield.
LC / MS M + 1 = 371.1
¹ H NMR (DMSO-d ₆ ) δ: 2.51 s 3H, 4.13, 3H, 8.45 s 1H, 8.70 s 2H, 8.76 s 1H, 9.10 s 1H, 10.0 s 1H

Example 9. Preparation of 5- [4- (ethoxyimino-methyl) -5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid And obtained according to general method A, method A and B (Example 1) from 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with exoylamine by general method C to give the product in 80% yield.
LC / MS M + 1 = 385.1
¹ H NMR (DMSO-d ₆ ) δ: 1.35 t (6Hz) 3H, 2.60 s 3H, 4.45 q (J = 6Hz) 2H, 8.70 s 2H, 8.80 s 1H, 9.1 s 1H, 10.0 s 1H

Example 10. Preparation of 5- [4- (allyloximino-methyl) -5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid This product is commercially available Obtained according to general method A, method A and B (Example 1) from available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with exoylamine by general method C to give the product in 80% yield.
LC / MS M + 1 = 397.1
¹ H NMR (DMSO-d ₆ ) δ: 2.55 s 3H, 4.77 d (J = 6Hz) 2H, 5.31 d (J = 6Hz) 1H, 5.40 d (J = I 5hz) 1H, 5.98-6.10m 1H, 8.36 s 1H, 8.65 s 2H, 8.71 s lH, 9.01 s 1H, 10.01 s 1H

Example 11 Preparation of 5- [4- (tert-Butoxyimino-methyl) -5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid Obtained according to General Method A, Method A and B (Example 1) from commercially available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with t-butoxylamine by general method C to give the product in 80% yield.
LC / MS M + 1 = 413.1
¹ H NMR (DMSO-d ₆ ) δ: 1.41 s 9H, 2.56 s 3H, 8.45 s 1H, 8.67 s 2H, 8.78 s 1H, 9.09 s 1H.10.05 s 1H

Example 12 FIG. Preparation of PL-402 This product was obtained according to General Method A, Method A and B (Example 2) from commercially available 2-chloro-5-amino-benzoic acid and pyridoxal. The filtered product was then reacted with allyloxyamine by general method C to give the product in 80% yield.
LC / MS M + 1 = 387.1
¹ H NMR (DMSO-d ₆ ) δ: 2.54 s 3H, 4.76 brs 2H, 5.31 d (J = 6Hz) 1H, 5.49 q (J = 6Hz) 6.01 m 1H, 7.7 d (J = 8Hz) 1H, 8.22 d (J = 8Hz) 1H, 8.42 s 1H, 8.78 s 1H, 8.99 s 1H

Example 13. Preparation of 3- [4- (carboxymethoxyimino-methyl) -5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -4-chloro-benzoic acid The product was obtained according to General Method A, Method A and B (Example 2) from commercially available 2-chloro-5-amino-benzoic acid and pyridoxal. The filtered product was then reacted with carboxymethoxylamine by general method C to give the product in 80% yield.
LC / MS M + 1 = 405.0
¹ H NMR (DMSO-d ₆ ) δ: 2.61 s 3H, 4.95 s 2H, 7.76 d (J = 8Hz) 1H, 8.22 d (J = 8Hz) 1H, 8.46 s 1H, 8.73 s 1H, 9.00 s 1H

Example 14. Preparation of 5- [5-hydroxy-4- (hydroxyimino-methyl) -6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid And obtained according to general method A, method A and B (Example 1) from 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with hydroxylamine by general method C to give the product in 70% yield.
LC / MS M + 1 = 357
¹ H NMR (DMSO-d ₆ ) δ: 2.55 s 3H, 8.61 s 2H, 8.74 s 1H, 9.15 s 1H, 10.18 s 1H, 12.01 s 1H

Example 15. Preparation of 5- (4-hydrazonomethyl-5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl) -isophthalic acid This product is commercially available Obtained from general 5-amino-isophthalic acid and pyridoxal according to General Method A, Method A and B (Example 1). The filtered product was then reacted with hydrazine by general method D to give the product in 80% yield.
LC / MS M + 1 = 356.1
¹ H NMR (D ₂ O) δ: 2.25 s 3H, 8.12 s 1H, 8.17 s 2H, 8.25 s 1H, 8.37 s 1H

Example 16. Preparation of 5- [5-hydroxy-6-methyl-4- (piperidin-1-yliminomethyl) -pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid Obtained according to general method A, method A and B (Example 1) from commercially available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with 1-aminopiperidine by general method D to give the product in 69% yield.
LC / MS M + 1 = 424.2

Example 17. Preparation of 5- [5-hydroxy-6-methyl-4- (morpholin-4-yliminomethyl) -pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid Obtained according to general method A, method A and B (Example 1) from commercially available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with 4-aminomorpholine by general method D to give the product in 69% yield.
LC / MS M + 1 = 426
¹ H NMR (DMSO-d ₆ ) δ: 2.43 br s 4H, 2.55 s 3H, 3.66 br s 4 H, 3.80 br s 4H, 8.20 s 1H, 8.41 s 1H 8.66 s 2H, 9.34 s 1H

Example 18. 5- {5-hydroxy-4-[(2-hydroxy-6-methyl-pyridine-3-carbonyl) -hydrazonomethyl] -6-methyl-pyrazolo [3,4-b] pyridine-2 Preparation of -yl} -isophthalic acid This product was obtained according to general method A, method A and B (Example 1) from commercially available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with 2-hydroxy-6-methylnicotinyl hydrazide by general method D to give the product in 79% yield.
LC / MS M + 1 = 491
¹ H NMR (DMSO-d ₆ ) δ: 2.33 s 3H, 2.62 s 3H, 6.43 d 1H J = 7, 8.32 d 1H J = 7, 8.41 s 1H, 8.72 s 2H, 9.00 s 1H, 9.40 s 1H, 11.5 s 1H, 12.7 s 1H, 13.3 s 1H

Example 19. 5- {4-[(2,3-dihydroxy-benzoyl) -hydrazonomethyl] -5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl} -isophthalic acid This product was obtained according to general method A, method A and B (Example 1) from commercially available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with 2,3-dihydroxy-benzoic hydrazide by general method D to give the product in 77% yield.
LC / MS M + 1 = 492
_{^{1 H NMR (DMSO-d 6}} ) δ: 2.55 s 3H, 6.71 tj = 6, 7.03 d 1H J = 6, 7.48 d 1H J = 6, 8.4 s 1H, 8.7 s 2H, 9.1 s 1H, 9.3 s 1H, 12.55 s 1H

Example 20. 5- {5-hydroxy-6-methyl-4-[(2,3,4-trihydroxy-benzoyl) -hydrazonomethyl] -pyrazolo [3,4-b] pyridin-2-yl} -Preparation of isophthalic acid This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal according to General Method A, Method A and B (Example 1). The filtered product was then reacted with 2,3,4-trihydroxy-benzoic hydrazide by general method D to give the product in 77% yield.
LC / MS M + 1 = 508
¹ H NMR (DMSO-d ₆ ) δ: 2.61 s 3H, 6.45 d 1H J = 7, 7.45 d 1H J = 7, 8.45 s 1H, 8.70 s 2H, 9.00 s 1H, 9.31 s 1H, 12.41 s 1H

Example 21. Preparation of 5- [5-hydroxy-6-methyl-4- (pyridin-2-yl-hydrazonomethyl) -pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid The product was obtained according to General Method A, Method A and B (Example 1) from commercially available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with 2-pyridylhydrazine by general method D to give the product in 65% yield.
LC / MS M + 1 = 433.1
¹ H NMR (DMSO-d ₆ ) δ: 2.64 s 3H, 7.11 s 1H, 7.40 t (J = 7Hz) 1H, 8.02-8.18 m 2H, 8.80 s 2H, 8.91 s 1H, 9.55 s 1H

Example 22. Preparation of 5- [4- (formyl-hydrazonomethyl) -5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -isophthalic acid Obtained according to general method A, method A and B (Example 1) from commercially available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with formyl hydrazide by general method D to give the product in 85% yield.
LC / MS M + 1 = 384.1

Example 23. Preparation of 5- {5-hydroxy-4-[(2-hydroxy-benzoyl) -hydrazonomethyl] -6-methyl-pyrazolo [3,4-b] pyridin-2-yl} -isophthalic acid This product was obtained according to general method A, method A and B (Example 1) from commercially available 5-amino-isophthalic acid and pyridoxal. The filtered product was then reacted with salicylic hydrazide by general method D to give the product in 88% yield.
LC / MS M + 1 = 476.1
¹ H NMR (DMSO-d ₆ ) δ: 2.62 s 3H, 6.92-7.03 m 2H, 7.46 brs 1H, 7.93 d (J = 6.8 Hz) 1H, 8.44 s 1H, 8.71 s 2H, 9.00 s 1H, 9.32 s 1H , 11.3 brs 1H, 11.67 brs 1H, 12.30 s 1H

Example 24. Preparation of 2-chloro-5- [5-hydroxy-4- (methoxycarbonyl-hydrazonomethyl) -6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -benzoic acid The product was obtained according to General Method A, Method A and B (Example 2) from commercially available 2-chloro-5-amino-benzoic acid and pyridoxal. The filtered product was then reacted with NH ₂ NHCOOMe by general method D to give the product in 80% yield.
Pl-423
LC / MS M + 1 = 404.8

Example 25. Preparation of 2-chloro-5- [5-hydroxy-4- (aminocarbonyl-hydrazonomethyl) -6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -benzoic acid The product was obtained according to General Method A, Method A and B (Example 2) from commercially available 2-chloro-5-amino-benzoic acid and pyridoxal. The filtered product was then reacted with semicarbazide by general method D to give the product in 80% yield.
LC / MS M + 1 = 389.1

Example 26. Preparation of 5- [4- (Benzoyl-hydrazonomethyl) -5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl] -2-chloro-benzoic acid This formation The product was obtained according to General Method A, Method A and B (Example 2) from commercially available 2-chloro-5-amino-benzoic acid and pyridoxal. The filtered product was then reacted with benzoyl hydrazide by general method D to give the product in 80% yield.
LC / MS M + 1 = 450.8

Example 27. 5- {4-[(4-tert-Butyl-benzoyl) -hydrazonomethyl] -5-hydroxy-6-methyl-pyrazolo [3,4-b] pyridin-2-yl} -2- Preparation of chloro-benzoic acid This product was obtained from commercially available 2-chloro-5-amino-benzoic acid and pyridoxal according to General Method A, Method A and B (Example 2). . The filtered product was then reacted with 4-tert-butylbenzoyl hydrazide by general method D to give the product in 80% yield.
LC / MS M + 1 = 506.2

Example 28. 2-Chloro-5- {5-hydroxy-4-[(2-hydroxy-6-methyl-pyridine-3-carbonyl) -hydrazonomethyl] -6-methyl-pyrazolo [3,4-b Preparation of Pyridin-2-yl} -benzoic acid This product was prepared from the commercially available 2-chloro-5-amino-benzoic acid and pyridoxal by general methods D, A and B (Example 2). ). The filtered product was then reacted with 2-hydroxy-6-methyl-nicotinyl hydrazide by general method D to give the product in 80% yield.
LC / MS M + 1 = 481.8

[Biological evaluation]
[In vitro integrase inhibition assay]
For Table 1, an HIV-1 inhibition assay is performed according to known procedures (IGEN International, Inc. 2002; ORIGEN® HIV Integrase assay, A highly Sensitive and Rapid method to measure Integrase Activity and to Identify Inhibitors). M8 Electroluminescence analyzer (IGEN International) was used.

In vitro antiviral and cytotoxicity assays
-To assess the EC ₅₀ of the compound, various drug concentrations were incubated with infected cells for 6 days, and then the metabolic activity of the cells was monitored by MTT assay. (See AJ Japour et al., Antimicrobial Agents and Chemotherapy, 37, 1095-1101, 1993, and R. Pauwels et al., Journal of Virological Methods, 20, 309-321.)
-Virus laboratory strain NL4.3 was used as wild-type virus. Furthermore, the cell line used was MT-4, a T-cell line highly sensitive to HIV-1. WT clinical strains were also used. To overcome the resistance problem, we assayed the inhibitor with the NL4.3 variant designed to be resistant to certain commercially available inhibitors.
- except excluding viruses the same MTT assay was used to evaluate the CCLC ₅₀ of the present compounds.

The compounds listed in Table 1 were prepared according to Schemes 1, 2, 3 as described in more detail in the examples listed above. The compound numbers (Ex. No.) listed in Table 1 correspond to the example numbers shown above. The activities showing the potential utility of these compounds are also listed in the same table. Table 1 shows formulas in which the 2′-position, 3′-position, 4′-position, 5′-position, and in one case the 6′-position carbon is substituted as shown in Table 1. Compounds of I are shown. Also shown in Table 1 are the IC ₅₀ , EC ₅₀ , and CClC ₅₀ results of the compounds of Formulas I and Ib, which show the potential utility of these compounds.

Claims (128)

Formula I:

And pharmaceutically acceptable salts or solvates thereof, comprising:
Where
n is 0, 1, 2, 3, or 4;
m is 0, 1, 2, 3, or 4;
C _X is selected from the group consisting of -CHO, -CH = N-OR ₃ , -CH = N-NR ₃ R ₄ , -CH = NR ₅ , and -CH (OR ₃ ) ₂ ;
R ₁ is -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, -F, -Cl, -Br, -I, -CN, and -Selected from the group consisting of OR ₃ ,
R ₂ is selected from the group consisting of -H, -CO ₂ H, -CONR ₃ R ₄ , and -COR ₆ ;
R ₃ is -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, an allyl group, a cycloalkyl group having 3 to 8 carbon atoms, or piperidine Selected from the group consisting of pyrrolidine, morpholine, and -R _a -COOH;
R _a is a linear alkyl group of 1 to 6 carbon atoms,
R _b is -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, an allyl group, a cycloalkyl group having 3 to 8 carbon atoms, R _{b '-CO} -, is selected from the group consisting of _{(HO) 2 P (O)} , and _{(MO) 2 P (O)} ,
M is an alkali metal or alkaline earth metal,
R _{b 'are,} H, 1 -6 carbon atoms, straight-chain or branched alkyl group, 3 carbon atoms to six cycloalkyl group, and its cycloalkyl moiety 3 to 6 carbon atoms And is selected from the group consisting of cycloalkylalkyl groups having 1 to 3 carbon atoms in the alkyl portion thereof,
R ₄ is H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, —CH ₂ CH ₂ OH, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-(l, _{2,3,4-tetrahydroquinolyl), - CO 2 R 3,} -CONR 3 R 3, -COR 6, 2- hydroxy - 6-methylnicotinyl, formyl, benzyl, unsubstituted benzyl, unsubstituted phenyl, mono-substituted with a linear alkyl group of 1 to 6 carbon atoms or a branched alkyl group of 3 to 6 carbon atoms , Di- or tri-hydroxy substituted phenyl, phenyl substituted with a linear alkyl group of 1 to 6 carbon atoms, and phenyl substituted with a branched alkyl group of 3 to 6 carbon atoms Selected from the group,
R ₅ is selected from the group consisting of piperidine and morpholine;
R ₆ is -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, -NH ₂ , Unsubstituted phenyl, mono-, di-, or tri-hydroxy substituted phenyl, phenyl substituted with a linear alkyl group of 1 to 6 carbon atoms, substituted with a branched alkyl group of 3 to 6 carbon atoms Phenyl, —CH ₂ CH ₂ OH, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5- (l, 2,3,4-tetrahydroquinolyl), unsubstituted pyridyl, 1 to 6 carbon atoms Pyridyl substituted with a linear alkyl group, pyridyl substituted with a branched alkyl group of 3 to 6 carbon atoms, unsubstituted nicotinyl, nicotinyl (a linear alkyl group of 1 to 6 carbon atoms, carbon atoms 3 to six branched alkyl group, and / or those substituted with at least one hydroxy group), and -OR ₇ It is selected from Ranaru group, and,
R ₇ is selected from the group consisting of —H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, and a cycloalkyl group having 3 to 8 carbon atoms. Selected,
Compounds and pharmaceutically acceptable salts or solvates thereof. C _X is selected from the group consisting of -CHO, -CHNO-R _a -COOH, -CHNO-R ₃ , -CH = NR ₃ R ₄ , -CH = NR ₅ ;
R ₃ is selected from the group consisting of —H and a linear alkyl group of 1 to 6 carbon atoms;
R ₄ is, H, -COR _6, formyl, benzyl substituted with 1 -6 carbon atoms straight-chain alkyl group or a carbon atom 3 to six branched alkyl group, unsubstituted benzyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, unsubstituted phenyl, mono-, di-, or tri-hydroxy substituted phenyl, phenyl substituted with a linear alkyl group of 1 to 6 carbon atoms, and 3 carbon atoms Selected from the group consisting of phenyl substituted with from 6 to 6 branched alkyl groups;
R ₅ is selected from the group consisting of piperidine and morpholine;
R ₆ is —NH ₂ , unsubstituted phenyl, mono-, di-, or tri-hydroxy substituted phenyl, phenyl substituted with a linear alkyl group of 1 to 6 carbon atoms, 3 to 6 carbon atoms Phenyl, unsubstituted nicotinyl, nicotinyl (a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and / or at least 1 substituted with 1 branched alkyl group Selected from the group consisting of -OR ₇ and
R ₇ is selected from the group consisting of —H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, and a cycloalkyl group having 3 to 8 carbon atoms. Selected,
2. The compound of claim 1. C _{X is, -CHO, -CHNO-CH 2 -COOH} , -CHNO-Me, -CHNOEt, -CHNO- allyl, -CHNO-t-Bu, -CHNOH , -CHNNH 2, -CHN-1- piperidine, - CHN-1-morpholine, -CHN-NH- (CO-2-OH-6-Me nicotinyl), -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-2-pyridine, -CHN-NH- Selected from the group consisting of formyl, -CHN-NH- (COOMe), -CHN-NH- (CONH ₂ ), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu Bz), 3. A compound according to claim 2. C _X is -CHO, -CHNO-CH ₂ -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, -CHNO-t-Bu, -CHN-NH- (CO-2-OH-6-Me Nicotinyl), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu 4. The compound of claim 3, selected from the group consisting of Bz). C _X consists _{-CHO, -CHNO-CH 2 -COOH,} -CHNOEt, from -CHN-NH- (CO-2- OH-6-Me nicotinyl), and -CHN-NH- (CO- hydroxyphenyl) 5. The compound of claim 4, selected from the group. 6. The compound of claim 5, wherein _CX is -CHN-NH- (CO-mono-hydroxyphenyl). 6. The compound of claim 5, wherein _CX is -CHN-NH- (CO-di-hydroxyphenyl). 6. The compound of claim 5, wherein _CX is -CHN-NH- (CO-tri-hydroxyphenyl). 7. The compound of claim 6, wherein _CX is -CHN-NH- (CO-2-OH-phenyl). 8. The compound of claim 7, wherein _CX is -CHN-NH- (CO-2,3-di-OH-phenyl). 9. The compound of claim 8, wherein _CX is -CHN-NH- (CO-2,3,4-tri-OH-phenyl). C _X is -CH = NR ₃ R ₄ and
R ₃ is -H;
R ₄ is H, 2-pyridyl, 3-pyridyl, 4-pyridyl, a benzyl substituted with a linear alkyl group of 1 to 6 carbon atoms or a branched alkyl group of 3 to 6 carbon atoms, Unsubstituted phenyl, mono-, di-, or tri-hydroxy substituted phenyl, phenyl substituted with a linear alkyl group of 1 to 6 carbon atoms, substituted with a branched alkyl group of 3 to 6 carbon atoms Selected from the group consisting of phenyl, and -COR ₆
R ₆ is —NH ₂ , —OR ₇ , a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, or a cycloalkyl group having 3 to 8 carbon atoms. An unsubstituted phenyl, mono-, di-, or tri-hydroxy substituted phenyl, a phenyl substituted with a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms Substituted phenyl, unsubstituted nicotinyl, nicotinyl (substituted with a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and / or at least one hydroxy group) Selected from the group consisting of:
R ₇ is as defined in claim 1, compound of claim 1. R ₁ is, -H, -F, -Cl, -Br , and is selected from the group consisting of -OH, A compound according to any one of claims 1 to 12.   14. A compound according to any one of claims 1 to 13, wherein m is 0, 1, or 2.   15. A compound according to any one of claims 1 to 14, wherein n is 0, 1, or 2. 16. A compound according to any one of claims 1 to 15, wherein the -COOR _{b '} group is in the 3',-position or 4 ',-position. The compound according to any one of claims 1 to 16, wherein R _{b '} is -H. R _b is selected from the group consisting of —H, (HO) ₂ P (O), and (MO) ₂ P (O), where M is an alkali metal or alkaline earth metal; 18. A compound according to any one of claims 1 to 17. 6. The compound of claim 5, wherein _CX is -CHO. R ₁ and or m and n R ₂ is -H both are both 0, a compound of claim 19. 21. The compound of claim 20, wherein the -COOR _{b '} group is in the 4',-position. 24. The compound of claim 21, wherein R _{b ′} is —H. 23. A compound according to any one of claims 19 to 22 wherein _Rb is -H. Formula IA:

And pharmaceutically acceptable salts or solvates thereof, comprising:
Where
n is 0, 1, 2, 3, or 4;
m is 0, 1, 2, 3, or 4;
C _X is selected from the group consisting of -CHO, -CH = N-OR ₃ , -CH = N-NR ₃ R ₄ , -CH = NR ₅ , and -CH (OR ₃ ) ₂ ;
R ₁ is -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, -F, -Cl, -Br, -I, -CN, and -Selected from the group consisting of OR ₃ ,
R ₂ is selected from the group consisting of -H, -CO ₂ H, -CONR ₃ R ₄ , and -COR ₆ ;
R ₃ is -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, an allyl group, a cycloalkyl group having 3 to 8 carbon atoms, or piperidine Selected from the group consisting of pyrrolidine, morpholine, and -R _a -COOH;
R _a is a linear alkyl group of 1 to 6 carbon atoms,
R _b is -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, an allyl group, a cycloalkyl group having 3 to 8 carbon atoms, R _{b '-CO} -, is selected from the group consisting of _{(HO) 2 P (O)} , and _{(MO) 2 P (O)} ,
M is an alkali metal or alkaline earth metal,
R _{b ′} is H, a linear or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, and a cycloalkyl moiety having 3 to 6 carbon atoms And is selected from the group consisting of cycloalkylalkyl groups having 1 to 3 carbon atoms in the alkyl portion thereof,
R ₄ is H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, —CH ₂ CH ₂ OH, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-(l, _{2,3,4-tetrahydroquinolyl), - CO 2 R 3,} -CONR 3 R 3, -COR 6, 2- hydroxy - 6-methylnicotinyl, formyl, benzyl, unsubstituted benzyl, unsubstituted phenyl, mono-substituted with a linear alkyl group of 1 to 6 carbon atoms or a branched alkyl group of 3 to 6 carbon atoms , Di- or tri-hydroxy substituted phenyl, phenyl substituted with a linear alkyl group of 1 to 6 carbon atoms, and phenyl substituted with a branched alkyl group of 3 to 6 carbon atoms Selected from the group,
R ₅ is selected from the group consisting of piperidine and morpholine;
R ₆ is -H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, -NH ₂ , Unsubstituted phenyl, mono-, di-, or tri-hydroxy substituted phenyl, phenyl substituted with a linear alkyl group of 1 to 6 carbon atoms, substituted with a branched alkyl group of 3 to 6 carbon atoms Phenyl, —CH ₂ CH ₂ OH, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5- (l, 2,3,4-tetrahydroquinolyl), unsubstituted pyridyl, 1 to 6 carbon atoms Pyridyl substituted with a linear alkyl group, pyridyl substituted with a branched alkyl group of 3 to 6 carbon atoms, unsubstituted nicotinyl, nicotinyl (a linear alkyl group of 1 to 6 carbon atoms, carbon atoms 3 to six branched alkyl group, and / or those substituted with at least one hydroxy group), and -OR ₇ It is selected from Ranaru group, and,
R ₇ is selected from the group consisting of —H, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, and a cycloalkyl group having 3 to 8 carbon atoms. Selected,
Compounds and pharmaceutically acceptable salts or solvates thereof. C _X is selected from the group consisting of -CHO, -CHNO-R _a -COOH, -CHNO-R ₃ , -CH = NR ₃ R ₄ , -CH = NR ₅ ;
R ₃ is selected from the group consisting of —H and a linear alkyl group of 1 to 6 carbon atoms;
R ₄ is H, —COR ₆ , formyl, benzyl substituted with a linear alkyl group of 1 to 6 carbon atoms or a branched alkyl group of 3 to 6 carbon atoms, unsubstituted benzyl, 2- Selected from the group consisting of pyridyl, 3-pyridyl, 4-pyridyl,
R ₅ is selected from the group consisting of piperidine and morpholine;
R ₆ represents —NH ₂ , unsubstituted phenyl, mono-, di-, or tri-hydroxy substituted phenyl, unsubstituted nicotinyl, nicotinyl (a linear alkyl group having 1 to 6 carbon atoms, 3 to Selected from the group consisting of 6 branched alkyl groups and / or substituted with at least one hydroxy group), and -OR ₇ ;
R ₇ is selected from the group consisting of -H, a linear alkyl group of 1 to 6 carbon atoms,
25. The compound of claim 24. C _{X is, -CHO, -CHNO-CH 2 -COOH} , -CHNO-Me, -CHNOEt, -CHNO- allyl, -CHNO-t-Bu, -CHNOH , -CHNNH 2, -CHN-1- piperidine, - CHN-1-morpholine, -CHN-NH- (CO-2-OH-6-Me nicotinyl), -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-2-pyridine, -CHN-NH- Selected from the group consisting of formyl, -CHN-NH- (COOMe), -CHN-NH- (CONH ₂ ), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu Bz), 26. The compound of claim 25. C _X is -CHO, -CHNO-CH ₂ -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, -CHNO-t-Bu, -CHN-NH- (CO-2-OH-6-Me Nicotinyl), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu 27. The compound of claim 26, selected from the group consisting of Bz). C _X consists _{-CHO, -CHNO-CH 2 -COOH,} -CHNOEt, from -CHN-NH- (CO-2- OH-6-Me nicotinyl), and -CHN-NH- (CO- hydroxyphenyl) 30. The compound of claim 28, selected from the group. C _X is selected from the group consisting of -CHN-NH- (CO-mono-hydroxyphenyl), -CHN-NH- (CO-dihydroxyphenyl), and -CHN-NH- (CO-trihydroxyphenyl) 29. The compound of claim 28. R ₂ is H or -COOH, a compound according to any one of claims 24 29. R ₁ is, -H, -F, -Cl, -Br , and is selected from the group consisting of -OH, A compound according to any one of claims 24 30. R ₁ is -Cl or -OH, A compound according to claim 31.   35. The compound of claim 32, wherein m is 0, 1, or 2.   34. A compound according to any one of claims 30 to 33, wherein n is 0, 1, or 2. 35. A compound according to any one of claims 24 to 34, wherein the -COOR _{b '} group is in the 3', -position, 4 ',-position, or 5, -position. 36. The compound according to any one of claims 24 to 35, wherein _{Rb '} is -H. R _b is selected from the group consisting of —H, (HO) ₂ P (O), and (MO) ₂ P (O), where M is an alkali metal or alkaline earth metal; 37. A compound according to any one of claims 24 to 36. R ₂ is -CO ₂ H, The compound of claim 24. R ₂ is 4 '- position, or 5, - in position, compound of claim 38. R ₁ is -Cl or -OH, A compound according to claim 24 or 39. R ₁ is 4 '- position, or 6, - in position, compound of claim 40. 42. The compound according to any one of claims 38 to 41, wherein _Rb and _{Rb '} are both -H. 28. The compound of claim 26 or 27, wherein R ₂ is 4 ',-position or 5, -position -COOH and m is 0 or 1. R ₁ is 4 '- position or 6, - a position of -Cl or -OH, n is 0 or 1, compound of claim 26 or 27. R _b is —H, (HO) ₂ P (O), or (MO) ₂ P (O) (wherein M is an alkali metal or alkaline earth metal), and R _{b ′} is − 45. A compound according to claim 43 or 44 which is H. 28. The compound of claim 27, wherein _CX is -CHO. 48. The compound of claim 46, wherein R _b and R _{b ′} are both —H. R ₂ is -H or -CO ₂ H, The compound of claim 47. R ₂ is 4 ', - a position of -COOH, m is 0, compound of claim 48. R ₂ is 5 ', - a position of -COOH, R ₁ is -OH, the compound of claim 48. R ₁ is 4 ', - in position, compound of claim 50. R ₂ is -H, compound of claim 48. R ₁ is -Cl, compounds of claim 52. R ₁ is 4 ', - in position, compound of claim 53. R ₁ is 6 ', - in position, compound of claim 54. C _X is -CHNO-CH ₂ -COOH, the compound of claim 26 or 27. 57. The compound of claim 56, wherein _Rb and _{Rb '} are both -H. R ₂ is -COOH, m is 0, compound of claim 57. R ₂ is 5 ', - in position, compound of claim 58. R ₁ is -Cl, n is 0, compounds of claim 57. R ₁ is 4 ', - in position, compound of claim 60. 28. The compound of claim 26 or 27, wherein _CX is -CHN-NH- (CO-2-OH-6-Me nicotinyl). 64. The compound of claim 62, wherein _Rb and _{Rb '} are both -H. R ₂ is -COOH, m is 0, compound of claim 63. R ₂ is 5 ', - in position, compound of claim 64. R ₁ is -Cl, n is 0, compounds of claim 63. R ₁ is 4 ', - in position, compound of claim 66. 28. The compound of claim 27, wherein _CX is -CHN-NH- (CO-hydroxyphenyl). 69. The compound of claim 68, wherein _Rb and _{Rb '} are both -H. R ₂ is -COOH, m is 0, compound of claim 69. R ₂ is 5 ', - in position, compound of claim 70. 72. The compound of claim 71, wherein _CX is -CHN-NH- (CO-2-OH-phenyl). 72. The compound of claim 71, wherein _CX is -CHN-NH- (CO-2,3-di-OH-phenyl). 72. The compound of claim 71, wherein _CX is -CHN-NH- (CO-2,3,4-tri-OH-phenyl). C _X is -CHNO-R _3, R ₃ is, -H, is selected from the group consisting of one to six straight chain alkyl group having a carbon atom, a compound of claim 25. 76. The compound of claim 75, wherein _Rb and _{Rb '} are both -H. R ₁ is -Cl, n is 0, compounds of claim 76. R ₁ is 4 ', - in position, compound of claim 77. 79. The compound of claim 78, wherein _CX is -CHNO-allyl. 28. The compound of claim 27, wherein _CX is -CHN-NH-Bz or -CHN-NH- (4-t-Bu Bz). 81. The compound of claim 80, wherein _Rb and _{Rb '} are both -H. R ₁ is -Cl, n is 0, compounds of claim 81. R ₁ is 4 ', - in position, compound of claim 82. C _X is selected from -CHN-NH- (COOMe) and -CHN-NH- group consisting (CONH _2), compound of claim 26. 84. The compound of claim 84, wherein _Rb and _{Rb '} are both -H. R ₁ is -Cl, n is 0, 85 compound of claim. R ₁ is 4 ', - in position 85 compound of claim. Formula IA ':

(Wherein C _X , m, R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R _a , R _b , R _{b ′} are as defined in claim 1)
And pharmaceutically acceptable salts or solvates thereof. C _{X is, -CHO, -CHNO-CH 2 -COOH} , -CHNO-Me, -CHNOEt, -CHNO- allyl, -CHNO-t-Bu, -CHNOH , -CHNNH 2, -CHN-1- piperidine, - CHN-1-morpholine, -CHN-NH- (CO-2-OH-6-Me nicotinyl), -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-2-pyridine, -CHN-NH- Selected from the group consisting of formyl, -CHN-NH- (COOMe), -CHN-NH- (CONH ₂ ), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu Bz), 90. The compound of claim 88. C _X is -CHO, -CHNO-CH ₂ -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, -CHNO-t-Bu, -CHN-NH- (CO-2-OH-6-Me Nicotinyl), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu 90. The compound of claim 89, selected from the group consisting of Bz). C _X consists _{-CHO, -CHNO-CH 2 -COOH,} -CHNOEt, from -CHN-NH- (CO-2- OH-6-Me nicotinyl), and -CHN-NH- (CO- hydroxyphenyl) 92. The compound of claim 90, selected from the group. C _X is selected from the group consisting of -CHN-NH- (CO-mono-hydroxyphenyl), -CHN-NH- (CO-dihydroxyphenyl), and -CHN-NH- (CO-trihydroxyphenyl) 92. The compound of claim 91. 90. The compound of claim 88, wherein _Rb and _{Rb '} are both -H. R ₁ is, -H, -OH, -F, -Cl , is selected from the group consisting of -Br, and -I, compound of claim 93. R ₁ is -Cl or -OH, the compound of claim 94.   96. The compound of claim 95, wherein m is 0, 1, or 2. 99. The compound of claim 96, wherein _CX is -CHO and m is 0. 99. The compound of claim 96, wherein _CX is -CHNO-Me and m is 0. 99. The compound of claim 96, wherein _CX is -CHNOEt and m is 0. 99. The compound of claim 96, wherein _CX is -CHNO-allyl and m is 0. 99. The compound of claim 96, wherein _CX is CHNO-t-butyl and m is 0. 99. The compound of claim 96, wherein _CX is -CHNOH and m is 0. C _X is -CHNNH _2, m is 0, compound of claim 96. C _X is -CHN-1-piperidine, m is 0, compound of claim 96. C _X is -CHN-1-morpholine, m is 0, compound of claim 96. 99. The compound of claim 96, wherein _CX is -CHN-NH-2-pyridine and m is 0. C _X is -CHN-NH- formyl, m is 0, compound of claim 96. 99. The compound of claim 96, wherein _CX is -CHN-NH- (CO-hydroxyphenyl) and m is 0. Formula IB:

(Wherein C _X , n, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R _a , R _b , R _{b ′} are as defined in claim 1)
And pharmaceutically acceptable salts or solvates thereof. C _{X is, -CHO, -CHNO-CH 2 -COOH} , -CHNO-Me, -CHNOEt, -CHNO- allyl, -CHNO-t-Bu, -CHNOH , -CHNNH 2, -CHN-1- piperidine, - CHN-1-morpholine, -CHN-NH- (CO-2-OH-6-Me nicotinyl), -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-2-pyridine, -CHN-NH- Selected from the group consisting of formyl, -CHN-NH- (COOMe), -CHN-NH- (CONH ₂ ), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu Bz), 110. The compound of claim 109. C _X is -CHO, -CHNO-CH ₂ -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, -CHNO-t-Bu, -CHN-NH- (CO-2-OH-6-Me Nicotinyl), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu 111. The compound of claim 110, selected from the group consisting of Bz). C _X consists _{-CHO, -CHNO-CH 2 -COOH,} -CHNOEt, from -CHN-NH- (CO-2- OH-6-Me nicotinyl), and -CHN-NH- (CO- hydroxyphenyl) 112. The compound of claim 111, selected from the group. 113. A compound according to any one of claims 109 to 112, wherein n is 0 and R < ₁ > is -H. R _b is —H, (HO) ₂ P (O), or (MO) ₂ P (O) (wherein M is an alkali metal or alkaline earth metal), and R _{b ′} is − 114. The compound of claim 113, which is H. R ₁ is, -Cl, -F, -Br, -I , and is selected from the group consisting of -OH, A compound according to any one of claims 109 114. R ₁ is -OH or -Cl, compounds of claim 115. Formula IC:

(Wherein C _X , m, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R _a , R _b , R _{b ′} are as defined in claim 1) )
And pharmaceutically acceptable salts or solvates thereof. C _{X is, -CHO, -CHNO-CH 2 -COOH} , -CHNO-Me, -CHNOEt, -CHNO- allyl, -CHNO-t-Bu, -CHNOH , -CHNNH 2, -CHN-1- piperidine, - CHN-1-morpholine, -CHN-NH- (CO-2-OH-6-Me nicotinyl), -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-2-pyridine, -CHN-NH- Selected from the group consisting of formyl, -CHN-NH- (COOMe), -CHN-NH- (CONH ₂ ), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu Bz), 118. The compound of claim 117. C _X is -CHO, -CHNO-CH ₂ -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, -CHNO-t-Bu, -CHN-NH- (CO-2-OH-6-Me Nicotinyl), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH- (CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN-NH- (4-t-Bu 119. The compound of claim 118, selected from the group consisting of Bz). C _X consists _{-CHO, -CHNO-CH 2 -COOH,} -CHNOEt, from -CHN-NH- (CO-2- OH-6-Me nicotinyl), and -CHN-NH- (CO- hydroxyphenyl) 120. The compound of claim 119, selected from the group. R _b is —H, (HO) ₂ P (O), or (MO) ₂ P (O) (wherein M is an alkali metal or alkaline earth metal), and R _{b ′} is − 121. The compound according to any one of claims 117 to 120, which is H. R ₁ is, -Cl, -F, -Br, -I , and is selected from the group consisting of -OH, A compound according to any one of claims 117 121. R ₁ is -H, -OH or -Cl,, compound of Claim 122. R ₂ is -H or -COOH, compound of Claim 123.   125. A pharmaceutical composition comprising the compound according to any one of claims 1-124 and a pharmaceutically acceptable carrier.   125. A compound according to any one of claims 1-124 for the treatment or prevention of HIV infection, the treatment or prevention of AIDS, or the manufacture of a pharmaceutical composition for reducing HIV replication. use.   125. Use of at least one compound according to any one of claims 1-124 for preventing or treating HIV infection or AIDS, or for reducing HIV replication. 125. A method for preventing or treating HIV infection or AIDS, or reducing HIV replication, comprising the step of administering at least one compound according to any one of claims 1-124.