WO2020178316A1

WO2020178316A1 - 5- or 7-azaindazoles as beta-lactamase inhibitors

Info

Publication number: WO2020178316A1
Application number: PCT/EP2020/055658
Authority: WO
Inventors: Rosella Ombrato; Barbara Garofalo; Federica PRATI; Gabriele Magaro'; Rosa BUONFIGLIO
Original assignee: Aziende Chimiche Riunite Angelini Francesco ACRAF SpA
Current assignee: Angelini Acraf SpA
Priority date: 2019-03-05
Filing date: 2020-03-04
Publication date: 2020-09-10
Anticipated expiration: 2021-09-05

Abstract

The present invention relates to β-lactamase inhibitors having the following general formula (I): wherein R1-R4 and X1-X2 are defined in the specification, pharmaceutical composition thereof, and use thereof for the treatment of a bacterial infection, alone or in combination with β-lactam antibiotics and/or other antibiotics and/or other β-lactamase inhibitors.

Description

5- OR 7-AZAINDAZOLES AS BETA-LACTAMASE INHIBITORS

FIELD OF THE INVENTION

The present invention relates to b-lactamase inhibitors and pharmaceutical compositions thereof. More in particular, the present invention relates to 5- and 7- azaindazole derivatives able to inhibit b-lactamases and pharmaceutical compositions comprising a combination of the b-lactamase inhibitors of the present invention and b- lactam antibiotics.

STATE OF THE ART

b-lactam antibiotics (beta-lactam antibiotics) are a class of broad-spectrum antibiotics containing a beta-lactam ring in their molecular structures. This class generally includes penicillin derivatives, cephalosporins, monobactams, and carbapenems. Most b-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics b-lactam antibiotics are widely employed, and it has been estimated that, when measured by sales, more than half of all commercially available antibiotics in use were b-lactam compounds.

The global increase in antibiotic-resistant Gram-negative bacteria has been realized for more than 40 years and has become a serious and growing threat to public health. In many cases, the mechanism underlying bacterial resistance involves the production of b- lactamase enzymes, which inactivate the antibiotic by hydrolyzing the b-lactam ring.

As of 2012, roughly 1 ,300 b-lactamases had been identified, including many that are not inhibited by established b-lactamase inhibitors such as tazobactam and clavulanic acid and several that hydrolyze carbapenems, which were previously regarded as“b-lactamase stable”. (Bush K. Proliferation and significance of clinically relevant b-lactamases. Ann N Y Acad Sci 2013; 1277: 84-90).

The most widely used classification of b-lactamases is the Ambler classification (Ambler R.P. The structure of beta-lactamases. Philos Trans R Soc B Biol Sci. 1980 May; 289 (1036):321— 31 ) that divides b-lactamases into four classes (A, B, C and D) based upon their amino acid sequences. Classes A, C and D include enzymes that hydrolyze their substrates by forming an acyl enzyme through an active site serine, for this reason they are also named as serine^-lactamases, whereas class B b-lactamases are metalloenzymes that utilize at least one active-site zinc ion to facilitate b-lactam hydrolysis.

The spread of extended-spectrum of serine^-lactamases has led the failure of cephalosporin-based therapies and the increase of clinical dependence on carbapenems, which represent the last line of antibacterial defense. As a result, there is an urgent medical need for new classes of antibiotics that are refractory to most common mechanisms of bacterial resistance or that may restrain or inhibit the mechanisms of resistance.

Different strategies could be followed to tackle antibiotic resistance, such as reducing antibiotic prescriptions, using antibiotic alternatives or developing new antibiotic inhibitors, particularly small organic molecules, that target directly the biochemical mechanisms of antibiotic resistance.

The combination of the penicillin analogue amoxicillin, and the b-lactamase inhibitor, clavulanic acid, provides a remarkable example of a combination therapy that permits extension of the pharmacodynamic spectrum of amoxicillin to bacteria that produce conventional or extended-spectrum b-lactamase.

Some other example of b-lactamase inhibitors used in combination with the most common antibiotics and similar to clavulanic acid are sulbactam and tazobactam, but unfortunately, they are not able to adequately inhibit one of the most important extended spectrum class-A b-lactamases such as K. pneumoniae carbapenemase (KPC).

A further and valuable approach to restrain the activity of b-lactamase is the use of inhibitors which do not bear the b-lactam nucleus, like diazabicyclooctane derivatives (Avibactam, Relebactam, zidebactam, nacubactam, CB-618) and boronic acid derivatives (4,7-Dichloro-1 -benzothien-2-yl sulfonylaminomethyl boronic acid (aka DSABA), Vaborbactam, VNRX-5133).

Diazabicyclooctane derivatives are also described in US2014288051 A1 , US2014315876A1 , W02017109025A1 , and WO2017136254A1 , and boronic acid derivatives in W02017100537A1 , US2017065626A1 , US2017226135A1 and US2017107239A1.

The commercially available beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) were developed to address the beta-lactamases that were clinically relevant in the 1970s and 1980s (e.g. penicillinases). These enzyme inhibitors are available only as fixed combinations with penicillin derivatives. No combinations with cephalosporins (or carbapenems) are clinically available. This fact, combined with the increased use of newer generation cephalosporins and carbapenems, is driving the selection and spread of the new beta-lactamase variants (ESBLs, carbapenemases, chromosomal and plasmid-mediated Class C, Class D oxacillinases, etc.).

While maintaining good inhibitory activity against ESBLs, the legacy beta-lactamase inhibitors are largely ineffective against the new Class A and Class B carbapenemases, against the chromosomal and plasmid-mediated Class C cephalosporinases and against many of the Class D oxacillinases.

To address this growing therapeutic vulnerability, there is a continuous need in the art to develop new generation of beta-lactamase inhibitors having different spectrum functionality.

SUMMARY OF THE INVENTION

The Applicant has faced the problem of developing new b-lactamase inhibitors.

After extensive experimentation, the Applicant has surprisingly found that a group of azaindazole derivatives are able to inhibit clinically important carbapenem-hydrolyzing b- lactamases. In particular, the Applicant has surprisingly found that 5- and 7-azaindazole derivatives were able to inhibit OXA-48 b-lactamases.

Then, in a first aspect, the present invention relates to b-lactamase inhibitors having the following general formula (I):

wherein

Xi and X₂ are CH or N, at least one thereof being N and at least one thereof being CH, R¹ is selected from the group consisting of halogen, O-Ci-Ce alkyl, C₁-C6 alkyl-OH, COOH, Ci-Ce alkyl-COOH, COO-Ci-C₆ alkyl, Ci-Ce alkyl-COO- Ci-Ce alkyl, CONH₂, CONHOH, SO₂NH₂, NHSO₂-C₁-C6 alkyl, and Ci-Ce alkyl,

R² is selected from the group consisting of halogen, OH, C₂-C6 alkyl, C₁-C6 alkyl- phenyl, aliphatic carbocyclic ring having from 3 to 12 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, O-i-Ob haloalkyl, O-i-Ob haloalkoxy, O-i-Ob alkyl-OH, and O-i-Ob alkyl, aromatic carbocyclic ring having from 3 to 12 members substituted by one or more substituents selected from the group consisting of halogen, OH, O-i-Ob haloalkyl, O-i-Ob haloalkoxy, O-i-Ob alkyl-OH, and C₁-C₆ alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, other than pyridyl and thienyl, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, O-i-Ob haloalkyl, O-i-Ob haloalkoxy, O-C₁-C6 alkyl, O-i-Ob alkyl-OH, and Ci-Ce alkyl,

R³ is selected from the group consisting of COOH, C₁-C6 alkyl-COOH, COO-C₁-C6 alkyl, C₁-C6 alkyl-COO-alkyl, CONH₂, CONHOH, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, substituted by one or more substituents S_a selected from the group consisting of halogen, NO₂, COOH, C₁-C6 alkyl- COOH, COO-C1-C6 alkyl, S0₂N(R^llR^l11), NHS0₂-R^IV, S0₂CH₂-R^IV, CH₂S0₂-R^IV, S-R^v, S0₂-R^v, with the proviso that when the substituent S_a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substituent S_a, preferably selected from the group consisting of COOH and S0₂N(R^NR^IN), and that when R₂ is said aliphatic carbocyclic ring, then R₃ is said carbocyclic or heterocyclic ring substituted by S0₂N(R^NR^IN),

wherein R", R¹¹¹, R^IV, and R^v, are independently hydrogen, Ci-Ce alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, C₁-C6 alkyl, C3-C6 cycloalkyl, 0-Ci-Ce alkyl, Ci-Ce alkyl-OH, COOH, COO-Ci-C₆ alkyl, CONH₂, NHCOCHs, and

R⁴ is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, O-Ci-Ce alkyl, C-I-C6 alkyl-OH, and O-i-Ob alkyl.

The dotted line of formula (I) represents any one of the sequence of single and double bonds able to form for each meaning of Xi and X₂ an aromatic bicycle ring and allowing R⁴ to be linked either to the 1 -position or the 2-position of the bicycle ring, as illustrated in the formulae of the examples.

In a second aspect, the present invention relates to a pharmaceutical composition comprising at least one b-lactamase inhibitor of formula (I) as described above, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and at least one inert pharmaceutically acceptable excipient.

According to a preferred embodiment, the pharmaceutical composition of the invention further comprises a beta-lactam antibiotic.

In a further preferred embodiment, the pharmaceutical composition further comprises a beta-lactam antibiotic, wherein the beta-lactam antibiotic is a penicillin, cephalosporin, penem, carbapenem, clavam, monobactam, bridged monobactam, any other compound susceptible to serine beta-lactamases, or a combination thereof.

In a third aspect, the present invention relates to the combination of (i) at least one b- lactamase inhibitor of formula (I) as described above, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and (ii) a beta-lactam antibiotic, for use in the treatment of a bacterial infection.

A fourth aspect provides a method of treating a bacterial infection in a subject, comprising administering to the subject a b-lactamase inhibitor of formula (I) in combination with a therapeutically effective amount of beta-lactam antibiotic.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention is a b-lactamase inhibitor according to formula (I) as described above.

In a first embodiment of the invention, Xi is N, and X₂ is CH.

In a second embodiment of the invention, Xi is CH, and X₂ is N.

Accordingly, one aspect of the invention is a b-lactamase inhibitor according to any of the formulae (lc) to (1 f) described below:

As mentioned above, R¹ is selected from the group consisting of halogen, 0-Ci-Ce alkyl, Ci-C₆ alkyl-OH, COOH, Ci-C₆ alkyl-COOH, COO-Ci-Ce alkyl, Ci-C₆ alkyl-COO-Ci- Ce alkyl, CONH2, CONHOH, SO2NH2, NHS0₂-Ci-Ce alkyl, and Ci-Ce alkyl.

In a first embodiment of the invention, R¹ is selected from the group consisting of halogen, O-C₁-C₄ alkyl, Ci-C₄ alkyl-OH, COOH, Ci-C₄ alkyl-COOH, COO-C₁-C₄ alkyl, Ci- C₄ alkyl-COO-Ci-C₄ alkyl, CONH₂, CONHOH, SO2NH2, NHSO2-C1-C4 alkyl, and C1-C4 alkyl.

In a second embodiment of the invention, R¹ is selected from the group consisting of halogen, O-C₁-C₂ alkyl, Ci-C₂ alkyl-OH, COOH, Ci-C₂ alkyl-COOH, COO-C₁-C₂ alkyl, Ci- C₂ alkyl-COO-Ci-C₂ alkyl, CONH₂, CONHOH, SO2NH2, NHSO2-C1-C2 alkyl, and C1-C2 alkyl.

Preferably, R¹ is selected from the group consisting of halogen, O-C₁-C₂ alkyl, C₁-C₂ alkyl-OH, COOH, COO-C₁-C₂ alkyl, CONH₂, CONHOH, C₁-C₂ alkyl.

As mentioned above, R² is selected from the group consisting of halogen, OH, C₂-C₆ alkyl, C₁-C₆ alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 12 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, Ci-Ce haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-OH, and Ci-Ce alkyl, aromatic carbocyclic ring having from 3 to 12 members substituted by one or more substituents selected from the group consisting of halogen, OH, Ci-Ce haloalkyl, Ci-C₆ haloalkoxy, Ci- Ce alkyl-OH, and Ci-Ce alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, other than pyridyl and thienyl, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, C₁-C₆ haloalkyl, Ci-Ce haloalkoxy, O-Ci-Ce alkyl, C₁-C6 alkyl-OH, and Ci-Ce alkyl.

In a first embodiment of the invention, R² is selected from the group consisting ofhalogen, OH, C₂-C₄ alkyl, C₁-C₄ alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 10 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkyl-OH, and C₁-C₄ alkyl, aromatic carbocyclic ring having from 4 to 10 members substituted by one or more substituents selected from the group consisting of halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkyl-OH, and C₁-C₄ alkyl, and heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, other than pyridyl and thienyl, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, C-i- C₄ haloalkyl, Ci-C₄ haloalkoxy, O-C₁-C₄ alkyl, Ci-C₄ alkyl-OH, and C₁-C₄ alkyl.

In a second embodiment of the invention, R² is selected from the group consisting ofhalogen, OH, C₂-C₄ alkyl, C₁-C₂ alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 6 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, Ci-C₂ alkyl-OH, and C₁-C₂ alkyl, aromatic carbocyclic ring having from 4 to 10 members substituted by one or more substituents selected from the group consisting of halogen, OH, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂ alkyl-OH, and C₁-C₂ alkyl, and heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, other than pyridyl and thienyl, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, C-i- C₂ haloalkyl, C₁-C₂ haloalkoxy, O-C₁-C₂ alkyl, C₁-C₂ alkyl-OH, and C₁-C₂ alkyl.

Preferably, R² is selected from the group consisting of halogen, OH, C3 alkyl, C1 -C2 alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 6 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, C1 -C2 haloalkyl, C1 -C2 haloalkoxy, C1 -C2 alkyl-OH, and C1 -C2 alkyl, aromatic carbocyclic ring having from 3 to 6 members substituted by one or more substituents selected from the group consisting of halogen, OH, C1 -C2 haloalkyl, C1 -C2 haloalkoxy, C1 -C2 alkyl-OH, and C1 -C2 alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 6 members, other than pyridyl and thienyl, substituted by one or more substituents selected from the group consisting of O-C1 -C2 alkyl, C1 -C2 alkyl-OH, and C1 -C2 alkyl. In an embodiment, the carbocyclic or heterocyclic ring of R² is selected from phenyl, pyridinyl, furanyl, cyclohexyl, cyclohexenyl, and cyclopropyl.

As mentioned above, R³ is selected from the group consisting of COOH, Ci-C₆ alkyl- COOH, COO-Ci-C₆ alkyl, Ci-C₆ alkyl-COO-alkyl, CONH₂, CONHOH, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, substituted by one or more substituents S_a selected from the group consisting of halogen, NO₂, COOH, Ci- Cealkyl-COOH, COO-Ci-C₆alkyl, S0₂N(R^llR^l11), NHS0₂-R^IV, S0₂CH₂-R^IV, CH₂S0₂-R^IV, S- R^v, S0₂-R^v, with the proviso that when the substituent S_a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substituent S_a, preferably selected from the group consisting of COOH and S0₂N(R^NR^IN), and that when R₂ is said aliphatic carbocyclic ring, then R₃ is said carbocyclic or heterocyclic ring substituted by S0₂N(R^NR^IN),

wherein R", R¹¹¹, R^IV, and R^v, are independently hydrogen, Ci-Ce alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, C₁-C6 alkyl, C3-C6 cycloalkyl, 0-Ci-Ce alkyl, Ci-Ce alkyl-OH, COOH, COO-Ci-C₆ alkyl, CONH₂,

NHCOCHs.

In a first embodiment of the invention, R³ is selected from the group consisting of COOH, Ci-C₄ alkyl-COOH, COO-C₁-C₄ alkyl, Ci-C₄ alkyl-COO-alkyl, CONH₂, CONHOH, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, substituted by one or more substituents S_a selected from the group consisting of halogen, NO2, COOH, Ci-C₄ alkyl-COOH, COO-Ci-C₄ alkyl, S0₂N(R^llR^l11), NHS0₂-R^IV, SO2CH2- R^IV, CH₂S0₂-R^iv, S-R^v, S0₂-R^v, with the proviso that when the substituent S_a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substituent S_a, preferably selected from the group consisting of COOH and S0₂N(R^NRⁱⁿ), and that when R₂ is said aliphatic carbocyclic ring, then R₃ is said carbocyclic or heterocyclic ring substituted by S0₂N(R^NR^IN),

wherein R", R^IN, R^IV, and R^v, are independently hydrogen, Ci-C₄ alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy, Ci-C₄ alkyl, C₃-C₆ cycloalkyl, 0-Ci-C₄ alkyl, Ci-C₄ alkyl-OH, COOH, COO-Ci-C₄ alkyl, CONH₂, NHCOCH3.

In a second embodiment of the invention, R³ is selected from the group consisting of COOH, C1-C2 alkyl-COOH, COO-C1-C2 alkyl, Ci-C₂ alkyl-COO-alkyl, CONH₂, CONHOH, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members, substituted by one or more substituents S_a selected from the group consisting of halogen, NO2, COOH, C1-C2 alkyl-COOH, COO-C1-C2 alkyl, S0₂N(R^llR^l11), NHS0₂-R^IV, SO2CH2- R^IV, CH₂S0₂-R^iv, S-R^v, S0₂-R^v, with the proviso that when the substituent S_a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substituent S_a, preferably selected from the group consisting of COOH and S0₂N(R^NRⁱⁿ), and that when R₂ is said aliphatic carbocyclic ring, then R₃ is said carbocyclic or heterocyclic ring substituted by S0₂N(R^NR^IN),

wherein R", R¹¹¹, R^IV, and R^v, are independently hydrogen, C₁-C₂ alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂ alkyl, C3-C6 cycloalkyl, O-C₁-C₂ alkyl, C₁-C₂ alkyl-OH, COOH, COO-C₁-C₂ alkyl, CONH₂, NHCOCH3.

Preferably, R³ is selected from the group consisting of COOH, C₁-C₂ alkyl-COOH, COO-C₁-C₂ alkyl, C₁-C₂ alkyl-COO-alkyl, CONH₂, CONHOH, and carbocyclic or heterocyclic ring, aromatic, having from 5 to 6 members substituted by one or more substituents S_a selected from the group consisting of halogen, NO₂, COOH, C₁-C₂ alkyl- COOH, COO-C1-C2 alkyl, S0₂N(R^llR^l11), NHS0₂-R^IV, S0₂CH₂-R^IV, CH₂S0₂-R^IV, S-R^v, S0₂-R^v, with the proviso that when the substituent S_a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substituent S_a, preferably selected from the group consisting of COOH and S0₂N(R^NR^IN), and that when R₂ is said aliphatic carbocyclic ring, then R₃ is said carbocyclic or heterocyclic ring substituted by S0₂N(R^NR^IN),

wherein R", R^IN, R^IV, and R^v, are independently hydrogen, C₁-C₂ alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members substituted by one or more substituents selected from the group consisting of halogen, OH, CN, C-i- C₂ haloalkyl, C₁-C₂ alkyl, C3-C6 cycloalkyl, O-C₁-C₂ alkyl, Ci-C₂ alkyl-OH, and CONH₂.

In an embodiment, the carbocyclic or heterocyclic ring of R³ is selected from phenyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, isoxazolyl, triazolyl, thiazolyl, pyrazolyl, and thiophenyl.

As mentioned above, R⁴ is selected from the group consisting of hydrogen, Ci-Ce alkyl, C₁-C6 alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, OH, 0-Ci-Ce alkyl, Ci-Ce alkyl-OH, and C₁-C₆ alkyl.

In a first embodiment of the invention, R⁴ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, OH, O-C₁-C₄ alkyl, Ci-C₄ alkyl-OH, and C₁-C₄ alkyl.

In a second embodiment of the invention, R⁴ is selected from the group consisting of hydrogen, C₁-C₂ alkyl, C₁-C₂ alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, OH, O-C₁-C₂ alkyl, Ci-C₂ alkyl-OH, and C₁-C₂ alkyl.

Preferably, R⁴ is selected from the group consisting of hydrogen, C₁-C₂ alkyl, C₁-C₂ alkyl-C3-C6 cycloalkyl, and aromatic carbocyclic or heterocyclic ring having 6 members substituted by one or more substituents selected from the group consisting of halogen, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, OH, O-C₁-C₂ alkyl, Ci-C₂ alkyl-OH, and C₁-C₂ alkyl. In an embodiment, the carbocyclic or heterocyclic ring of R⁴ is selected from phenyl and pyridinyl.

According to a preferred aspect of the present invention at least one of Ri and R₃ as described above comprises at least one acidic hydrogen containing group or substituent.

According to a more preferred aspect of the present invention both Ri and R₃ as described above comprise at least one acidic hydrogen containing group or substituent.

The expression "acidic hydrogen containing group or substituent" herein means a group or substituent having an acid dissociation constant (pKa) of not more than 7, preferably not more than 6.5, more preferably not more than 6, and advantageously not more than 5.

Useful examples of acidic hydrogen containing groups or substituents are -COOH, - OH (especially when linked to an aromatic or heteroaromatic ring), -SO3H, -SO2NH-, - NHSO2-, -CONH2, -CONH-, -NHCO-, -CONHOH, -SO2NH2, and -NHS0₂-Ci-Ce alkyl.

In the present description and in the following claims, the term halogen atom includes iodide, bromide, chloride and fluoride, preferably bromide, chloride and fluoride, more preferably chloride and fluoride.

In the present description and in the following claims, the term "C1-C6 alkyl" means a linear or branched alkyl chain comprising from 1 to 6 carbon atoms, such as for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, sec-pentyl, 3- pentyl, n-hexyl, isohexyl, neo-hexyl, 3-methyl-pentyl, 2,3-dimethylbutyl.

In the present description and in the following claims, the term "C1-C4 alkyl" means a linear or branched alkyl chain comprising from 1 to 4 carbon atoms, such as for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

In the present description and in the following claims, the term "C1-C2 alkyl" means a linear alkyl chain comprising from 1 to 2 carbon atoms, such as methyl and ethyl.

In the present description and in the following claims, the term "C3-C6 cycloalkyl" means a saturated or unsaturated ring comprising from 3 to 6 carbon atoms, such as for example cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl.

In the present description and in the following claims, the terms "Ci-Ce alkyl-OH”, "Ci- C4 alkyl-OH”, and "C1-C2 alkyl-OH” have the meaning of a“C1-C6 alkyl”, "C1-C4 alkyl" and "C1-C2 alkyl" group, respectively, wherein one or more hydrogen atom of the alkyl chain is substituted by a hydroxyl group (OH), such as for example, -CH2OH, -(CH₂)₂0H, - (CH₂)₃OH, and (CH₃)2CHOHCH₂-.

In the present description and in the following claims, the terms "O-C1-C6 alkyl”, "O-C1- C4 alkyl”, and "O-C1-C2 alkyl” have the meaning of a“C1-C6 alkyl”, "C1-C4 alkyl" and "Ci- C2 alkyl" group, respectively, wherein the alkyl chain is linked by a oxy group (O), such as for example, CH3O-, CH3CH2O-, CH₃(CH₂)20-, and (0H₃)₃00-.

In the present description and in the following claims, the terms "C1-C6 haloalkyl”, "Ci- C4 haloalkyl”, and "C1-C2 haloalkyl” have the meaning of a“C1-C6 alkyl”, "C1-C4 alkyl" and "C1-C2 alkyl" group, respectively, wherein one or more hydrogen atom of the alkyl chain is substituted by a halogen atom (F, Cl, Br, I), such as for example, halomethyl, haloethyl, halopropyl, haloisopropyl, n-halobutyl, haloisobutyl, sec-halobutyl, tert-halobutyl, n- halopentyl, haloisopentyl, haloneopentyl, tert-halopentyl, sec-halopentyl, 3-halopentyl, n- halohexyl, haloisohexyl, neo-halohexyl, 3-methyl-halopentyl, 2,3-dimethylhalobutyl. In a preferred embodiment, the term haloalkyl refers to an alkyl group substituted with 1 to 3 halogens, preferably chloride, bromide, and fluoride, more preferably fluoride.

Representative examples of haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2- difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 1 , 1 -difluoroethyl, pentafluoroethyl, 1 -fluoro-1-methylethyl, 2-fluoro-1 ,1-dimethylethyl, 2-fluoro-1 - fluoromethyl-1-methylethyl, 2-fluoro-1 ,1 -di(fluoromethyl)-ethyl, 1 -chlorobutyl and 2- chloro-3-fluoropentyl.

Most preferred examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl.

In the present description and in the following claims, the terms“C1-C6 haloalkoxy”, "C1-C4 haloalkoxy" and "C1-C2 haloalkoxy" have the meaning of a "C1-C6 haloalkyl”, "Ci- C4 haloalkyl”, and "C1-C2 haloalkyl” group, respectively, wherein the haloalkyl chain is linked by a oxy group (O), such as for example, halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, n-halobutoxy, haloisobutoxy, sec-halobutoxy, tert-halobutoxy, n- halopentoxy, haloisopentoxy, haloneopentoxy, tert-halopentoxy, sec-halopentoxy, 3- halopentoxy, n-halohexoxy, haloisohexoxy, neo-halo hexoxy, 3-methyl-halopentoxy, 2,3- dimethylhalobutoxy.

In a preferred embodiment, the term haloalkoxy refers to an alkoxy group substituted with 1 to 3 halogens, preferably chloride, bromide, and fluoride, more preferably fluoride. Representative example of haloalkyl include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and 2-chloro-3-fluoropentoxy.

In the present description and in the following claims, the terms "C1-C6 alkyl-COOH”, "Ci-C₄alkyl-COOH”, and "C1-C2 alkyl-COOH” have the meaning of a“Ci-C₆ alkyl”, "C1-C4 alkyl" and "C1-C2 alkyl" group, respectively, wherein one or more hydrogen atom of the alkyl chain is substituted by a carboxyl group (COOH), such as for example, -CH2COOH, -(CH₂)₂COOH, -(CH₂)₃COOH, and (CH₃)₂CCOOH.

In the present description and in the following claims, the terms "COO-C1-C6 alkyl”, "COO-C1-C4 alkyl”, and "COO-C1-C2 alkyl” have the meaning of a“C1-C6 alkyl”, "C1-C4 alkyl" and "C1-C2 alkyl" group, respectively, substituting the hydrogen atom of the carboxyl group (COOH), such as for example, -COOCH3, -COOCH2CH3, -COO(CH₂)₂CH3, and - C00C(CH₂)₃.

Similarly, in the present description and in the following claims, the terms "Ci-C₆ alkyl- COO-Ci-C₆ alkyl”, "Ci-C₄alkyl-COO-Ci-C4 alkyl”, and "Ci-C₂alkyl-COO-Ci-C₂ alkyl” have the meaning of a "Ci-Ce alkyl-COOH”, "C1-C4 alkyl-COOH”, and "C1-C2 alkyl-COOH” group, respectively, wherein the hydrogen atom of the carboxyl group (COOH) is substituted by a“C₁-C6 alkyl”, "C₁-C₄ alkyl" and "C₁-C₂ alkyl" group, respectively, such as for example, - CH2COOCH2CH3,

In an embodiment, the aliphatic or aromatic carbocyclic ring as defined in the above described formula (I) can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cyclobutenyl, cyclopentenyl cyclohexenyl, decalinyl, phenyl, and naphthalenyl.

In an embodiment, the aliphatic or aromatic heterocyclic ring as defined in the above described formula (I) can be selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, imidazolyl, morpholinyl, thiazolyl, thiazolidinyl, thiadiazolyl, thiadiazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, triazolyl, and pyrazolyl.

In a preferred embodiment, the aliphatic or aromatic carbocyclic ring as defined in the above described formula (I) can be selected from the group consisting of phenyl, cyclopropyl, cyclohexenyl, and cyclohexyl.

In a preferred embodiment, the aliphatic or aromatic heterocyclic ring as defined in the above described formula (I) can be selected from the group consisting of pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, furanyl, thiophenyl, pyrrolyl, isoxazolyl, triazolyl, thiazolyl, and pyrazolyl.

To the best knowledge of the named inventors and applicant of the present application, none of the 5- and 7-azaindazole derivatives falling within the above described general formula (I) is known in the art before the priority of the present application. However, any 5- and 7-azaindazole derivative known in the art before the priority date of the present application falling within the above described general formula (I) is herein properly disclaimed.

In the present description and in the following claims, the wording "optionally substituted" indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, the appropriate number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valence of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound. In one aspect, when a particular group is designated as being optionally substituted with one or more substituents, the particular group may be unsubstituted. In another aspect, the particular group may bear one substituent. In another aspect, the particular substituent may bear two substituents. In still another aspect, the particular group may bear three substituents. In yet another aspect, the particular group may bear four substituents. In a further aspect, the particular group may bear one or two substituents. In still a further aspect, the particular group may be unsubstituted, or may bear one or two substituents. The terms "pharmaceutically acceptable" and "physiologically acceptable" are intended to define, without any particular limitation, any material suitable for preparing a pharmaceutical composition to be administered to a living being.

In an embodiment of the present invention, R¹ is selected from halogen, O-Ci-Ce alkyl, Ci-C₆ alkyl-OH, COOH, COO-Ci-Ce alkyl, CONH₂, CONHOH, Ci-Ce alkyl.

In an embodiment of the present invention, R² is selected fromhalogen, OH, C₂-C₆ alkyl, C₁-C₆ alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 6 members optionally substituted by one or more substituents selected from the group consisting of halogen, and Ci-Ce alkyl, aromatic carbocyclic ring having from 3 to 6 members substituted by one or more substituents selected from the group consisting of halogen, and Ci-Ce alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 6 members, other than pyridyl and thienyl, substituted by one or more substituents selected from the group consisting of O-C₁-C₂ alkyl, Ci-C₂ alkyl-OH, and C₁-C₂ alkyl.

In an embodiment of the present invention, R³ is represented by the following general formula (a):

-Rng1 -L-Rng2-S1 (a)

wherein

Rng1 is selected from the group consisting of carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members,

L is a divalent linking group selected from the group consisting of -SO₂NH-, -NHSO₂-, -SO2CH2-, -CH2SO2-, -S-, and -SO2-,

Rng2 is selected from the group consisting of carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members,

S1 is one or more substituents selected from the group consisting of halogen, OH, CN, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, Ci-Ce alkyl, C3-C6 cycloalkyl, O-Ci-Ce alkyl, C-i-Cealkyl- OH, COOH, COO-Ci-Ce alkyl, CONH₂, and NHCOCH3.

According to a preferred embodiment of the present invention, when R³ is represented by the above general formula (a),

R¹ is selected from the group consisting of hydrogen, halogen, C₁-C₆ haloalkyl, O-C₁- Ce alkyl, C1-C6 alkyl-OH, COOH, Ci-Ce alkyl-COOH, COO-Ci-Ce alkyl, Ci-Ce alkyl-COO- Ci-Ce alkyl, CONH₂, CONHOH, SO2NH2, NHS0₂-Ci-Ce alkyl, Ci-Ce alkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, OH, O-Ci-Ce alkyl, C₁-C6 alkyl-OH, COOH, and COO-C₁-C₆ alkyl, and

R² is selected from the group consisting of hydrogen, halogen, OH, Ci-Ce alkyl, C₁-C6 alkyl-phenyl, C₁-C6 alkyl-OH, C-i-Ce haloalkyl, O-C-i-Ce alkyl, O-phenyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, C-i-Ce haloalkyl, Ci-C₆ haloalkoxy, O-Ci-Ce alkyl, Ci-Ce alkyl-OH, and Oi-Ob alkyl.

In an embodiment of the present invention, R³ is represented by the following general formula (b):

-Rng1 -S2 (b)

wherein

Rng1 is selected from the group consisting of carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, and

S2 is one or more substituents selected from the group consisting of halogen, NO2, COOH, C1-C6 alkyl-COOH, COO-Ci-Ce alkyl, SO2NH2, S0₂NHCi-Ce alkyl, NHS0₂Ci-C₆ alkyl, S-C1-C6 alkyl, and SO2-C1-C6 alkyl, with the proviso that when S2 is halogen, Rng1 comprises a second S2 substituent, preferably selected from the group consisting of COOH and S0₂N(R^llR^l11).

In a further embodiment, in the above described formulae (a) and (b), Rng1 is a carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, preferably a carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members.

In a preferred embodiment of the above described formulae (a) and (b), Rng1 is selected from phenyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, isoxazolyl, triazolyl, pyrazolyl, thiazolyl, and thiophenyl.

In a further embodiment, in the above described formulae (a) and (b), Rng2 is a carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, preferably a carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members.

In a preferred embodiment of the above described formulae (a) and (b), Rng2 is selected from phenyl, pyridinyl, pyrazolyl, and thiophenyl.

In a preferred embodiment of the above described formula (a), S1 is selected from halogen, CN, C1-C6 haloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, O-Ci-Ce alkyl, COOH, and CONH2.

In a preferred embodiment of the above described formula (b), S2 is selected from halogen, NO2, COOH, Ci-Ce alkyl-COOH, SO2NH2, S0₂NHCi-C_e alkyl, and NHS0₂Ci-C₆ alkyl, with the proviso that when S2 is halogen, Rng1 comprises a second S2 substituent, preferably selected from the group consisting of COOH and S0₂N(R^MR^IM).

In an embodiment of the present invention, R⁴ is selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkyl-C3-C6 cycloalkyl, and phenyl-C-i-Ce alkyl.

The compounds of formula (I) according to the present invention may form stable pharmaceutically acceptable acid or base salts with a pharmaceutically acceptable organic or inorganic acid or base, and in such cases administration of a compound as a salt may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p- toluenesulfonate), trifluoroacetate, and undecanoate.

Examples of base addition salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N- methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others. Non toxic physiologically-acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting the free form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble, such as for example water or ethanol, which is removed under vacuum or by freeze drying.

The present invention also includes the prodrugs, stereoisomers, and enantiomers of the compounds of formula (I) described above.

As used herein the term "prodrug" refers to an agent, which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention wherein it is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolysed once inside the cell where water solubility is beneficial.

Prodrugs have many useful properties. For example, a prodrug may be more water- soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A prodrug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue. In the present invention, prodrugs are particularly useful to make active beta-lactamase inhibitor compounds orally bioavailable following absorption from the gastrointestinal tract.

Ester prodrugs of the compounds disclosed herein are specifically contemplated. An ester may be formed from a hydroxyl functional group linked to a compound of formula (I) above by reaction with a carboxylic acid or an aminoacid. While not intending to be limiting, an ester may be an alkyl ester, an aryl ester, or a heteroaryl ester. The term alkyl has the meaning generally understood by those skilled in the art and refers to linear, branched, or cyclic alkyl moieties. Ci-e alkyl esters are particularly useful, where alkyl part of the ester has from 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and combinations thereof having from 1 to 6 carbon atoms.

Certain compounds of this invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of those compounds unless otherwise specified.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e. , the R and S configurations for each asymmetric centre. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Thus, this invention encompasses each diastereomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free from other stereoisomers on a molar basis) as well as a mixture of such isomers.

Particular optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another method involves synthesis of covalent diastereomers by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolysed to deliver the enantiomerically pure compound. Optically active compounds of the invention can be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

The compounds of this invention can exist in radiolabeled form, i.e. , said compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number ordinarily found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine and chlorine include ³H, ¹⁴C, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. Compounds of this invention which contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. , ³H, and carbon-14, i.e., ¹⁴C, radioisotopes are particularly preferred for their ease of preparation and detectability.

Radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed herein except substituting a readily available radiolabeled reagent for a non-radiolabelled reagent.

Typically, the b-lactamase inhibitors according to formula (I) useful in this invention are administered in the form of a pharmaceutical composition.

Accordingly, a further aspect of the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) as described above and at least one inert pharmaceutically acceptable excipient.

Preferably, the pharmaceutical composition of the present invention is prepared in suitable dosage forms comprising an effective amount of at least one compound of formula (I) as described above, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and at least one inert pharmaceutically acceptable excipient.

Examples of suitable dosage forms are tablets, capsules, coated tablets, granules, solutions and syrups for oral administration; solutions, pomade and ointment for topical administration; medicated patches for transdermal administration; suppositories for rectal administration and injectable sterile solutions.

Other suitable dosage forms are those with sustained release and those based on liposomes for oral, injectable or transdermal administration.

In the present description and in the following claims, the wording "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically- acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.

As described herein, the pharmaceutical composition of the present invention comprises a compound of the invention together with a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.

Some examples of materials which can serve as pharmaceutically acceptable excipient include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

The terms "pharmaceutically acceptable" and "physiologically acceptable" are intended to define, without any particular limitation, any material suitable for preparing a pharmaceutical composition to be administered to a living being.

The dosage forms can also contain other traditional ingredients such as: preservatives, stabilizers, surfactants, buffers, salts for regulating osmotic pressure, emulsifiers, sweeteners, colorants, flavourings and the like.

The amount of the b-lactamase inhibitors according to formula (I) or of the pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention can vary over a wide range depending on known factors, for example, the type of pathology, the severity of the disease, the patient's body weight, the dosage form, the chosen route of administration, the number of administrations per day and the efficacy of the selected b-lactamase inhibitors according to formula (I). However, a person skilled in the art can determine the optimum amount in easily and routinely manner.

Typically, the amount of compound of formula (I) or of the pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention will be such as to ensure a level of administration from 0.0001 to 100 mg/kg/day. Preferably, the level of administration is from 0.001 to 50 mg/kg/day, and even more preferably from 0.01 to 10 mg/kg/day.

As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, and the patient's disposition to the disease and the judgment of the treating physician. The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation or delivered by implantation (e.g., surgically), such as with an implantable or indwelling device like a stent.

The dosage forms of the pharmaceutical composition of the present invention can be prepared by techniques that are familiar to a pharmaceutical chemist, and comprise mixing, granulation, compression, dissolution, sterilization and the like.

In a further preferred embodiment, the pharmaceutical composition further comprises a beta-lactam antibiotic, wherein the beta-lactam antibiotic is a penicillin, cephalosporin, penem, carbapenem, clavam, monobactam, bridged monobactam, or any other compound susceptible to serine beta-lactamases, or a combination thereof.

In one aspect of this embodiment, the beta-lactam antibiotic is a penicillin selected from benzylpenicillin, benzathine benzylpenicillin, procaine benzylpenicillin, phenoxymethylpenicillin (V), propicillin, pheneticillin, azidocillin, clometocillin, penamecillin, cloxacillin, dicloxacillin, flucloxacillin, oxacillin, nafcillin, methicillin, amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, epicillin, ticarcillin, carbenicillin, carindacillin, temocillin, piperacillin, azlocillin, mezlocillin, mecillinam, pivmecillinam, and sulbenicillin, or a prodrug thereof.

In one aspect of this embodiment, the beta-lactam antibiotic is a cephalosporin selected from cefazolin, cefalexin, cefadroxil, cefapirin, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaloglycin, cefacetrile, cefalonium, cefaloridine, cefalotin, cefatrizine, cefaclor, cefotetan, cephamycins (cefoxitin, cefprozil, cefuroxime, cefuroxime axetil, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefbuperazone, cefuzonam, cefmetazole,) carbacephems (loracarbef), cefixime, ceftriaxone, antipseudomonals (ceftazidime, cefoperazone,) cefdinir cefcapene cefdaloxime ceftizoxime cefmenoxime cefotaxime, cefpiramide cefpodoxime ceftibuten cefditoren cefetamet, cefodizime, cefpimizole, cefsulodin, cefteram, ceftiolene, oxacephems (flomoxef, latamoxef), cefepime, cefozopran, cefpirome, cefquinome, ceftaroline fosamil, ceftolozane, and ceftobiprole, or a prodrug thereof.

In one aspect of this embodiment, the beta-lactam antibiotic is a penem selected from faropenem, and ritipenem, or a prodrug thereof. In one aspect of this embodiment, the beta-lactam antibiotic is a carbapenem selected from ertapenem, antipseudomonals (doripenem, imipenem, meropenem), biapenem, and panipenem, or a prodrug thereof.

In one aspect of this embodiment, the beta-lactam antibiotic is a monobactam selected from aztreonam, tigemonam, carumonam, and nocardicin A, or a prodrug thereof.

In another aspect of the invention, the b-lactamase inhibitor of formula (I) is administered in combination with a beta-lactam antibiotic and an additional antibiotic and/or an additional beta-lactamase inhibitor.

In one aspect of the invention, the additional antibiotic agent is selected from one of the classes of aminoglycosides, spectinomycins, macrolides, ketolides, streptogramins, oxazolidinones, tetracyclines, fluoroquinolones, quinolones, coumarin antibiotics, glycopeptides, lipoglycopeptides, nitroimidazoles, ansamycins, phenicols, mupirocyn, fosfomycin, tobramycin, linezolid, daptomycin, and vancomycin.

In one aspect of the invention, the b-lactamase inhibitor of formula (I) is administered in combination with a b-lactam antibiotic and a second agent which is designed to address b-lactam resistance, such as, for example, a metallo^-lactamase (MBL) inhibitor, also known as a Class B inhibitor.

As used herein, the terms "infection" and "bacterial infection" may refer to any one of the following infections: gynecological infection, a respiratory tract infection (RTI), a lower respiratory tract infection, an upper respiratory tract infection, a sexually transmitted disease, an uncomplicated urinary tract infection (UTI), a complicated urinary tract infection (CUTI), an acute exacerbation of chronic bronchitis (ACEB), an acute otitis media, an acute sinusitis, an infection caused by drug resistant bacteria, a catheter- related sepsis, a chancroid, chlamydia, an acute bacterial prostatitis, a community- acquired pneumonia (CAP), a complicated skin and skin structure infection, an uncomplicated skin and skin structure infection (SSSI), an acute bacterial skin and soft tissue infection, endocarditis, a febrile neutropenia, a gonococcal cervicitis, a gonococcal urethritis, a hospital-acquired pneumonia (HAP), osteomyelitis, sepsis, syphilis, an intra abdominal infection (IAI), kidney infection, and a diabetic foot infection.

All the above mentioned infections can be caused by a variety of bacteria that potentially could be treatable with a b-lactamase inhibitor of formula (I) in combination with a beta-lactam antibiotic. In one embodiment of the invention, the terms "infection" and "bacterial infection" refer to an infection caused by Gram-negative bacteria, also referred to as a "Gram-negative infection". In one aspect of this embodiment, the Gram-negative infection is an infection resistant to one or more antibiotics. In one aspect of this embodiment, the Gram-negative infection is a multi-drug resistant infection. In one aspect of this embodiment, the Gram negative infection is caused by one or more Enterobacteriaceae spp. pathogens. In one aspect of this embodiment, the one or more Enterobacteriaceae spp. pathogens includes one or more E. coli, K. pneumoniae, K. oxytoca, C. freundii, C. koseri, E. cloacae, P. mirabilis, M. morganii and/or S. marcescens. In one aspect of this embodiment, the one or more Enterobacteriaceae spp. pathogens includes one or more E. coli or K. pneumoniae pathogen. In another aspect of this embodiment, the Gram-negative infection is caused by one or more biothreat pathogens. In one aspect of this embodiment, the one or more biothreat pathogens is Burkholderia spp., Y. pestis, and/or F. tularensis. In any of these aspects of the embodiment, the one or more Gram-negative pathogens may express one or more serine beta-lactamase enzymes. In one aspect of this embodiment, the one or more serine beta-lactamase enzymes includes one or more Class A, Class C and/or Class D beta-lactamase.

General synthetic preparation of compounds of formula (I)

The man skilled in the art has a well-established literature of heterocyclic and other relevant chemical transformations, recovery and purification technologies to draw upon, in combination with the information contained in the examples which follow, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis, recovery and characterization of the compounds of this invention, including compounds containing the various choices for R¹-R⁴ and X¹-X³.

Various synthetic approaches may be used to produce the compounds described herein, including those approaches depicted schematically below. The man skilled in the art will appreciate that protecting groups may be used in these approaches. "Protecting groups", are moieties that are used to temporarily block chemical reaction at a potentially reactive site (e.g., an amine, hydroxyl, thiol, aldehyde, etc.) so that a reaction can be carried out selectively at another site in a multifunctional compound. In preferred embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is suitable for the planned reactions; the protecting group should be selectively removable in good yield by readily available, preferably nontoxic reagents that do not unduly attack the other functional groups present; the protecting group preferably forms an readily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group preferably has a minimum of additional functionality to avoid the complication of further sites of reaction. A wide variety of protecting groups and strategies, reagents and conditions for deploying and removing them are known in the art. Also, one may choose reagents enriched for a desired isotope, e.g. tritium in place of hydrogen, to create compounds of this invention containing such isotope(s). Compounds containing tritium in place of hydrogen in one or more locations, or containing various isotopes of C, N, P and O, are encompassed by this invention and may be used, for instance, for studying metabolism and/or tissue distribution of the compounds or to alter the rate or path of metabolism or other aspects of biological functioning. The compounds of this invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by a variation thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent the transformations proposed. This will sometimes require some judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

The following general preparations and schemes can be used to prepare the compounds of formula (I) according to the present invention.

Preparation I

Synthesis of compounds with general formula l^{(I V)} (Examples 1 -87, 108)

i) Synthesis of intermediate pyrazoleamines V

a)

b)

Scheme 1 . a) step 1 : (A) AcN, nBuLi, THF, or (B) AcN, NaH, toluene; step 2: R⁴NH- NH₂ (IV), EtOH; b) step 1 : EtOH, HCI; step 2: 1 M HCI.

ii) Synthesis of intermediate aldehydes XI, XVI (R³CHO), and XIX (R³CHO or

b)

c)

Scheme 2. a) step 1 : NH(R^NRⁱⁿ) (X), pyridine, DCM; b) step 1 : (A) i) Benzyl mercaptan, NaH, ii) SO₂CI₂, DCM, or (B) i) SOCI₂, cud, ii) NaN0₂; step 2: NH(R^NRⁱⁿ) (X), pyridine, DCM; step 3: CS₂CO3, KBFs(vinyl), Pd(dppf)Cl₂- DCM, DME/H₂O; step 4: OsC , Nal0₄, THF/ H₂O; c) step 1 : DMF, oxalyl chloride; step 2: i) CI₃CC(0)CI, Aids, ii) NaOMe, MeOH, iii) aq. HCI

iii) Synthesis of compounds with general formula l^(NV)

Scheme 3. Step 1 : (A) pyruvic acid, AcOFI, or (B) ethyl pyruvate, EtOH, HCI, or (c) methyl pyruvate, MeOH, HCI, or (D) pyruvic acid, EtOH, HCI; step 2: R²B(OH)2 or R²Bpin (XXI), Pd(dppf)CI₂ DCM, K2CO3, dioxane/ H₂0; step 3: 3,4-dihydro-2H-pyran, p-TSA, CHC ; step 4: R^IV-S0₂NH₂ (XXIII), /V,/V’-dimethylethane-1 ,2-diamine, Cul, K2CO3; step 5: HCI(4 M in dioxane); step 6: (A) R⁴B(OH)₂ (XXIV), Cu(OAc)₂, pyridine, DCM/DMF, or (B) R⁴B(0H)₂ (XXIV), CU(OAC)₂, pyridine, 0₂, DMF, or (c) R⁴B(OH)₂ (XXIV), K₂C0₃, AcN, or (D) R⁴Hal (XXV), Cu(OAc)₂, pyridine.

iv) Synthesis of compounds with general formula l^(V)

Scheme 4. Step 1 : (A) LiOH, THF/MeOH/H₂0, or (B) NaOH, MeOH/dioxane, or (c) 30% aq. NHs, or (D) 50% aq. N H₂OH, KCN, MeOH/THF, or (E) HCIconc, THF/ H₂0, or (F) when R⁴ = fe/f-butyl: i) TfOH, DCM; ii) LiOH, THF/MeOH/H₂0.

Preparation II

Synthesis of compounds with general formula l^(VNX) (Examples 88-92)

i) Synthesis of compounds with general formula |<^V|-^VIII>

Scheme 5. step 1 : R²CHO (XXVII), LDA, THF; step 2: TBDMScl, imidazole, DMAP; step 3: Dess-Martin periodinane, DCM; step 4: R⁴NH-NH₂ (IV), DIPEA, EtOH/THF; step 5: R³B(OH)₂ (XXXIV), Pd(dppf)CI₂ DCM, K₂C0₃, dioxane/ H₂0; step 6: TBAF, THF; step 7: Mn0₂, DCM; step 8: Y -PPh₃Br (XXXVII), KOtBu; step 9: H₂, Pd/C, EtOH, AcOH. ii) Synthesis of compounds with general formula l^(IX)

I ⁽vⁱ -vⁱⁱⁱ⁾ _r ³ ₌ cOOMe-/COOEt-/COOtBu-Aryl l"^x|: R³ = COOH-Aryl

Scheme 6. step 1 : (A) TFA/DCM (1 : 1 ), or (B) HCI, dioxane.

Preparation III

Synthesis of compounds with general formula l^{(X XM)} (Examples 92, 93, 107) i) Synthesis of intermediate boronic acid pinacol esters XXXIX (R³Bpin)

Scheme 7. step 1 : B₂pin₂, KOAc, Pd(dppf)CI₂ DCM, dioxane.

i) Synthesis of compounds with general formula l^(XII)

Scheme 8. step 1 : R⁴NH-NH₂ (IV), DIPEA, EtOH/THF; step 2: MeONa (30%), MeOH; step 3: R³Bpin (XXXIX), Pd(dppf)CI₂ DCM, K2CO3, THF/H₂0; step 4: BBr₃ (1 M DCM), THF; step 5: POCI₃, Neat; step 6: Pd(dppf)CI₂ DCM, CO, Et₃N, MeOH; step 7: LiOH, THF/MeOH/ H₂0.

Preparation IV

Synthesis of compounds with general formula |<^XII|-^XV> (Examples 94-97)

i) Synthesis of intermediate amines XLIV (R³NH)

Scheme 9. step 1 : NH(R^NRⁱⁿ) (X), pyridine; step 2: HCI(4M in dioxane).

ii) Synthesis of intermediate halides XLVI (R³Hal)

XII XLVI

Scheme 10. step 1: R^lvS0₂CI(XI_V), pyridine

iii) Synthesis of intermediate boronates XLVIII and Lll (R³B(OH)2)

^ XLIX L Lll

Scheme 11. a) step 1: R^lvS0₂CI(XLV), NMM, DCM; b) step 1: pinacol, MgS0_4, Et₂0; step 2: BrR^v (LI), K₂CO3, DMF.

iv) Synthesis of compounds with general formula |<^XII|-^XV>

Scheme 12. step 1: AcOH/hhO; step 2: neat POC ; step 3: NIS, HBF4, AcN; step 4: 3,4-dihydro-2H-pyran, p-TSA, CHC ; step 5: R²B(OH)₂ (XXI), Pd(dppf)CI₂ DCM, Na₂C0₃, dioxane; step 6: (A) R³NH (XLIV), DIPEA, DMSO, or (B) R³B(OH)₂ (XLVIII), Pd(dppf)CI₂, Na₂C0₃, dioxane, or (c) R³B(OH)₂ (Lll), Pd(dppf)CI₂, CsF, dioxane; step 7: mcPBA, DCM; step 8: HCI(4M in dioxane); step 9: LiOH, THF/MeOH/H₂0; step 10: R⁴B(OH)₂ (XXIV), CU(OAC)₂, pyr., 0₂, DMF; step 1 1 : Pd(dppf)CI₂ DCM_, B₂pin₂, KOAc, DME; step 12: R³Hal (XLVI), Pd(dppf)CI₂ DCM, Cs₂C0₃, dioxane/ H₂0.

Preparation VI

Synthesis of compounds with general formula |<^XVII|-^XX> (Examples 99-105, 109, 110)

i) Synthesis of intermediate pyrazoleamines V^(ll)

Scheme 14. step 1 : R⁴NH-NH₂ HCI(IV), NaOAc, EtOH.

ii) Synthesis of intermediate amines LXXV

Scheme 15. a) step 1 : MeOTf, AcN; step 2: N-Soc piperazine, AcN; step 3: MeOTf, AcN

LXXVIII

Scheme 16. step 1 : NH(R" R^m) (X), pyridine; step 2: Me₃Sn-Me₃Sn, Pd(PPh₃)4, dioxane.

iv) Synthesis of compounds with general formula |<^XVII|-^XX>

Scheme 17. step 1 : i) toluene, ii) AcOH; step 2: Tf₂0, pyridine; step 3: (A) R³ZnBr (LXXXV), Pd(dppf)CI₂ DCM, dioxane, or (B) R³Bpin (XXXIX), K2CO3, THF/H₂0, or (c) R³NH (LXXIII), DIPEA, MeCN, or (D) R³SnMe₃ (LXXVIII), Pd(PPh₃) , dioxane; step 4: TfOH, DCM; Step 5: LiOH, THF/MeOH/H₂0.

Preparation VII

Synthesis of compounds with general formula |^(cci- ^ccii> (Example 106)

i) Synthesis of compounds with general formula l^(XXI)

I'™’: R¹ = COOEt l^|xx">: R¹ = COOH

R³ can be COOMe-/COOEt-Aryl R³ can be COOH-Aryl Scheme 18. step 1 : R⁴Hal (XXV), CuBr, Cs₂C0₃, DMF; step 2: R³CHO (XX), Ethyl pyruvate, EtOH, HCI; step 3: LiOH, THF/MeOH/H₂0.

Example of compounds of formula (I)

Non-limiting examples of compounds of formula (I) are those of the following Table A. The R⁴ groups of the following Table 4 are always linked to the 1 -position of the nitrogen containing bicycle ring, but the R⁴ group of compound 106, which is linked to the 2-position of the nitrogen containing bicycle ring.

Table A

Further, non-limiting examples of compounds of formula (I) according to the present invention are those of the following Table B.

TABLE B

The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

EXPERIMENTAL PART

1H-NMR spectroscopy: internal standard = Tetramethylsilane; DMSO-d₆ = deuterated dimethyl sulfoxide; (s) = singlet; (d) = doublet; (t) = triplet; (br) = broad; (dd) = double doublet; (dt) = double triplet; (ddd) = double double doublet ;(dtd) = double triple doublet; (m) = multiplet; J = coupling constant; d = chemical shift (in ppm).

Detailed preparation of compounds of formula (I)

The procedures of the above described general preparations I to VII have been used to prepare compounds of the above Table A and B. Each preparation comprises several sub-procedures useful to prepare intermediates or compounds of the present invention.

The following Table C summarizes for each preparation the related sub-procedures and the prepared intermediates and end products.

Unless otherwise specified, R¹-R⁴ and X1-X2 have the meaning of the above described formula (I). The terms "aryl" and“alkyl”, as used in synthetic schemes below, mean the properly substituted “carbocyclic or heterocyclic aromatic rings having from 3 to 12 members” and“carbocyclic or heterocyclic aliphatic rings having from 3 to 12 members”, respectively.

Preparation I : Synthesis of compounds 1 -87, 108

Compounds 1 -87, 108 can be obtained by application of the chemical transformations reported in general procedures Ai - Ki herein described.

General procedures A1-F1 and H1-J1 relate to the preparation of intermediates and compounds of the Table B. The preparation of compounds 1 -20 of Table A and compounds of Table B is described in general procedure Gi. The preparation of compounds 21 -87 and 108 of Table A is described in general procedure Ki.

General procedure A-i: Synthesis of intermediate pyrazoleamines V

Step 1

Method (A): n-BuLi (2,5 M in i-Hexs, 2 eq.) was added to THF (2 M) at -70 °C and the mixture was stirred for 5 min. A solution of AcN (2 - 2.4 eq.) in THF (15 M) was then added dropwise and the mixture was stirred at -60 °C for 30 - 60 min. Finally, a solution of compound II (1 eq.) in THF (6 M) was added dropwise and the mixture was stirred at -70 °C for further 2 h, and then allowed to warm up to r.t. Subsequently, the reaction mixture was properly quenched, worked up and purified to give the proper intermediate compound having general formula III.

Method (B): To a suspension of NaH (1 - 1 .5 eq.) in toluene or DMSO (12.5 M), AcN (1 - 1 .5 eq.) was added. After stirring at r.t. for 15 min compound II (1 eq.) was added and the mixture was stirred at r.t. for further 10 min, then heated at 65 °C for 16 h. Subsequently, the reaction mixture was properly quenched, worked up and purified to give the proper intermediate compound having general formula III.

3-(4-Ethylphenyl)-3-oxopropanenitrile (Ilia). The title compound was obtained according to general procedure A-i, step 1 , method (A) using n-BuLi (25 ml_, 63 mmol), AcN (3.80 ml_, 72.8 mmol) and methyl-4-ethylbenzoate (lla, 4.98 g, 30.3 mmol). The mixture was quenched by careful addition of water (5 ml_) then allowed to warm to r.t. and partitioned between water (100 ml_) and TBME (50 ml_). The aqueous phase was separated and extracted with TBME (50 ml_). The aqueous phase was acidified to pH 2 by addition of aqueous 1 M HCI solution and extracted with TBME (2 ^c 50 ml_). The combined organic extracts were washed with water (50 ml_), brine (50 ml_), dried over MgS0₄, filtered and concentrated under reduced pressure to give 4.10 g (75% yield) of the title product. HPLC-MS (ESI) m/z: 172.0 [M-H]\

3-cyclohexyl-3-oxopropanenitrile (Nib). The title compound was obtained according to general procedure A-i, step 1 , method (A) using n-BuLi (8.0 ml_, 20 mmol), AcN (1 .05 ml_, 20.0 mmol) and methyl-cyclohexanecarboxylate (lib, 1 .43 ml_, 10.0 mmol). The mixture was quenched by addition of water (50 ml_), the phases were separated and the aqueous washed with Et₂0 (20 ml_). The aqueous phase was acidified to pH 2 by addition of aqueous 1 M HCI solution and extracted with Et₂0 (2 ^c 25 ml_). The combined organics were washed with water (25 ml_), brine (25 ml_), dried over MgSC and concentrated under reduced pressure to give 1 .34 g (84% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.

3-Oxo-3-(pyridin-4-yl)propanenitrile (lllc). The title compound was obtained according to general procedure A-i, step 1 , method (B) using AcN (8.0 mL, 17 mmol), NaH (1 .00 g, 25.0 mmol) and methyl-isonicotinate (lie, 1 .97 mL, 16.7 mmol) in DMSO. After coling to r.t., water (20 mL) was added and the basic aqueous solution was washed with Et₂0 (20 mL) and then acidified to pH 1 by addition of cone. HCI, resulting in the formation of a white precipitate. The solid was dissolved in water (30 mL) and extracted in Et₂0 (2 ^c 50 mL). The combined organic extracts were washed with brine (2 ^c 30 mL), dried over MgS0₄, filtered, and evaporated under reduced pressure to give 1.96 g (76% yield) of the title product. HPLC-MS (ESI) m/z: 147.1 [M-H]⁺.

3-Oxo-3-(pyridin-2-yl)propanenitrile (llld). The title compound was obtained according to general procedure Ai, step 1 , method (B) using AcN (1.14 mL, 21 .9 mmol), NaH (0.875 g, 21 .9 mmol) and methyl-picolinate (lid, 3.00 g, 21 .9 mmol) in toluene. After cooling to r.t., water (20 ml_) was slowly added and the mixture was stirred for 15 min. The phases were separated and the aqueous phase was extracted with Et₂0 (20 ml_). The aqueous phase was acidified to pH 5-6 by addition of aqueousl M HCI solution and the resulting precipiate was collected by filtration and washed with water (2 x 10 ml_) to give 1 .36 g (42% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.

3-Oxo-4-phenylbutanenitrile (llle). The title compound was obtained according to general procedure A-i, step 1 , method (A) using n-BuLi (8.00 ml_, 20 mmol), AcN (1 .25 ml_, 24.0 mmol) and methyl-2-phenylacetate (lie, 1 .00 ml_, 10.0 mmol). The mixture was quenched by addition of AcOH (2 ml_). The mixture was partitioned between water (100 ml_) and EtOAc (50 ml_), the phases were separated and the aqueous extracted with EtOAc (50 ml_). The combined organics were washed with water (50 ml_), brine (50 ml_), dried over MgSC , filtered and concentrated under reduced pressure to afford a brown oil. The crude was purified by flash chromatography (0-50% EtOAc//-Hex, product eluted at 30% EtOAc) to give 0.73 g (45% yield) of the title product. HPLC-MS (ESI) m/z: 160 [M-H]⁺.

3-cyclopropyl-3-oxopropanenitrile (lllf). The title compound was obtained according to general procedure A-i, step 1 , method (A) using n-BuLi (19.5 mL, 40 mmol), AcN (2.5 mL, 48 mmol) and methyl-cyclopropanecarboxylate (Ilf, 2.1 mL, 20 mmol). The mixture was quenched by addition of water (5 mL). The mixture was partitioned between TBME (100 mL) and water (100 mL), the phases were separated and the aqueous acidified to pH 1 with 1 M aqueous HCI solution. The aqueous phase was extracted with TBME (3 x 50 mL), dried over MgSC , filtered and concentrated under reduced pressure to give 1 .21 g (49% yield) of the title product. ¹H-NMR (500 MHz, DMSO -de) d: 3.61 (s, 2H), 2.10 (tt, J = 7.6, 4.5 Hz, 1 H), 1 .22 - 1 .16 (m, 2H), 1.1 1 - 1 .05 (m, 2H).

Step 2

To a solution of the proper compound III (1 eq.) in EtOH (0.2 - 1 M), the proper commercially available hydrazine IV (1 .2 eq.) was added and the mixture was heated at reflux for 18 h. After cooling to r.t., the mixture was concentrated under reduced pressure and purified to give the proper intermediate compound having general formula V.

3-(4-Ethylphenyl)-1H-pyrazol-5-amine (Va). The title compound was obtained according to general procedure A-i, step 2 using 3-(4-ethylphenyl)-3-oxopropanenitrile (Ilia, 4.10 g, 23.7 mmol) and hydrazine hydrate (IVa, 50 wt% in water: 1.7 mL, 27 mmol). The crude was purified by flash chromatography (0-100% [2%{0.7 M NH3 in MeOH} in EtOAc]//-Hex) to give 3.76 g (76 % yield) of the title product. HPLC-MS (ESI) m/z: 188.2 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 1 1 .80 (br s, 1 H), 7.64 - 7.48 (m, 2H), 7.21 (d, J = 8.1 Hz, 2H), 5.72 (s, 1 H), 4.75 (br s, 2H), 2.60 (q, J = 7.5 Hz, 2H), 1 .18 (t, J = 7.6 Hz, 3H). 3-cyclohexyl-1 H-pyrazol-5-amine (Vb). The title compound was obtained according to general procedure A-i, step 2 using 3-cyclohexyl-3-oxopropanenitrile (lllb, 1.35 g, 9.24 mmol) and hydrazine hydrate (IVa, 0.99 ml_, 10 mmol). The crude was azeotroped with toluene (2 ^c 20 ml_) to give 1.34 g (85% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.

3-(Pyridin-4-yl)-1H-pyrazol-5-amine (Vc). The title compound was obtained according to general procedure A-i, step 2 using 3-oxo-3-(pyridin-4-yl)propanenitrile (lllc, 1.95 g, 13.3 mmol) and hydrazine (IVa, 1 M in THF, 13.3 ml_, 13.3 mmol). The crude was purified by flash chromatography (0-10% (0.7 M NH₃/MeOH)/DCM) to give 1.29 g (48% yield) of the title product. HPLC-MS (ESI) m/z: 161 [M-H]⁺.

3-(Pyridin-2-yl)-1H-pyrazol-5-amine (Vd). The title compound was obtained according to general procedure A-i, step 2 using 3-oxo-3-(pyridin-2-yl)propanenitrile (Hid, 1.35 g, 9.24 mmol) and hydrazine hydrate (IVa, 0.99 mL, 10 mmol). The crude was triturated from Et₂0 (25 mL), filtered and dried under reduced pressure to give 1.31 g (88% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.

3-Benzyl-1 H-pyrazol-5-amine (Ve). The title compound was obtained according to general procedure A-i, step 2 using 3-oxo-4-phenylbutanenitrile (llle, 0.73 g, 4.6 mmol) and hydrazine hydrate (IVa, 0.54 mL, 5.5 mmol). The crude was azeotroped with toluene (2 x 20 mL) to give 0.81 g (85% yield) of the title product. HPLC-MS (ESI) m/z: 174 [M- H]⁺.

1-(Tert-butyl)-3-(4-ethylphenyl)-1H-pyrazol-5-amine (Vf). The title compound was obtained according to general procedure A-i, step 2 using 3-(4-ethylphenyl)-3- oxopropanenitrile (Ilia, 3.00 g, 16.3 mmol) and tert- butylhydrazine, HCI(IVb, 2.60 g, 20.9 mmol). The crude was purified by flash chromatography (0-10% EtOAc/toluene) to give impure compound as an orange oil. The crude oil was dissolved in TBME (50 mL) and washed with aqueous 2 M NaOH solution (2 ^c 50 mL) and brine (50 mL), dried over MgS0₄, filtered, and concentrated under reduced pressure to give 2.22 g (53% yield) of the title product. HPLC-MS (ESI) m/z: 244.2 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 7.69 - 7.64 (m, 2H), 7.20 - 7.15 (m, 2H), 5.88 (s, 1 H), 3.75 (s, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.70 (s, 9H), 1.23 (t, J = 7.6 Hz, 3H).

1 -(Tert-butyl)-3-cyclopropyl-1 H-pyrazol-5-amine (Vg). The title compound was obtained according to general procedure A-i, step 2 using 3-cyclopropyl-3- oxopropanenitrile (lllf, 1.15 g, 10.5 mmol) and tert- butylhydrazine, HCI(IVb, 1.6 g, 12.8 mmol). The crude oil was dissolved in TBME (20 mL) and washed with aqueous 2 M NaOH solution (2 x 20 mL) and brine (20 mL), dried over MgS0₄, filtered and concentrated under reduced pressure to give 1.56 g (76% yield) of the title product. HPLC-MS (ESI) m/z: 180.1 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 4.98 (s, 1 H), 4.68 (s, 2H), 1.62 (tt, J = 8.4, 5.0 Hz, 1 H), 1.47 (s, 9H), 0.77 - 0.65 (m, 2H), 0.49 - 0.39 (m, 2H). General procedure B-i: Synthesis of intermediate pyrazoleamines V^(l)

Step 1

A solution of the proper nitrile VI (1 eq.) and hydrazine IV (1 .05 eq.) in EtOH (0.35 M) was heated at 80 °C for 16 h. EtOH was then removed under reduced pressure and the solid was taken up with EtOH/aqueous 2 M NaOH solution (1 : 1 ) (0.4 M) and heated at 50 °C for 16 h. After concentrating in vacuo, the reaction mixture was diluted with water and TBME (1 : 1 ). The aqueous phase was separated and acidified with aqueous 1 M HCI solution. The resulting precipitate was collected by filtration and washed with water/TBME (1.5: 1 ) to give the proper intermediate compound having general formula VII.

5-Amino-1 -(4-ethyl phenyl)-1H-pyrazole-4-carboxylic acid-HCI (Vila). The title compound was obtained according to general procedure Bi, step 1 using (E)-ethyl-2- cyano-3-ethoxyacrylate (Via, 1 .20 g, 7.09 mmol) and (4-ethylphenyl)hydrazine (IVc, 1 .01 g, 7.42 mmol). The crude (1.29 g, 64% yield) was used in the next step without further purification. HPLC-MS (ESI) m/z: no ionisation. ¹H-NMR (400 MHz, DMSO -de) d: 12.06 (s, 1 H), 7.66 (s, 1 H), 7.48 - 7.42 (m, 2H), 7.40 - 7.34 (m, 2H), 6.23 (s, 2H), 2.68 (q, J = 7.6 Hz, 2H), 1 .22 (t, J = 7.6 Hz, 3H).

Step 2

Intermediate with general formula VII (1 eq.) was suspended in aqueous 1 M HCI solution (0.15 M) and heated at reflux for 1 .5 h. The reaction mixture was filtered to remove some insoluble material and aqueous 2 M NaOH solution was added to the filtrate. The aqueous mixture was extracted with DCM, the combined organic extracts were dried over MgS0₄, filtered, and concentrated under reduced pressure. The crude product was then purified by flash chromatography to give the intermediate with general formula V^(l) as free base.

1-(4-Ethylphenyl)-1H-pyrazol-5-amine (V^(l)a). The title compound was obtained according to general procedure Bi, step 2 using 5-amino-1 -(4-ethylphenyl)-1 /-/-pyrazole- 4-carboxylic acid, HCI (Vila, 1 .27 g, 4.74 mmol) and aqueous 1 M HCI solution (30 ml_). The crude was purified by flash chromatography (0-50% EtOAc//-Hex) to give 854 mg (93% yield) of the title product. HPLC-MS (ESI) m/z: 182.2 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 7.50 - 7.45 (m, 2H), 7.34 - 7.28 (m, 2H), 7.26 (d, J = 1 .8 Hz, 1 H), 5.46 (d, J = 1 .8 Hz, 1 H), 5.25 (s, 2H), 2.65 (q, J = 7.6 Hz, 2H), 1 .22 (t, J = 7.6 Hz, 3H).

General procedure C-i: Synthesis of intermediate aldehydes XI (R³CHO)

Step 1

To a solution of the proper amine (X, 1 - 1.1 eq.) and pyridine (1.1 eq.) in DCM (0.2 M), the proper sulfonyl chloride derivative (IX, 1 eq.) was added. The mixture was stirred at r.t. for 18 h and then either concentrated under reduced pressure or the resulting precipitate collected by filtration. When required, the crude product was purified by flash chromatography to give the intermediate compound having general formula XI.

4-((4-Formylphenyl)sulfonamido)benzamide (Xla). The title compound was obtained according to general procedure Ci, step 1 using 4-aminobenzamide (Xa, 0.732 ml_, 5.38 mmol), pyridine (0.43 ml_, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1.00 g, 4.89 mmol). The crude (1.384 g, 90% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 305 [M-H]⁺.

N-(2-fluorophenyl)-4-formylbenzenesulfonamide (Xlb). The title compound was obtained according to general procedure Ci, step 1 using 2-fluoroaniline (Xb, 0.597 g, 5.38 mmol), pyridine (0.43 ml_, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1.00 g, 4.89 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.906 g (66% yield) of the title product. HPLC-MS (ESI) m/z: 279.9 [M-H]⁺.

4-Formyl-N-(3-(trifluoromethyl)phenyl)benzenesulfonamide (Xlc). The title compound was obtained according to general procedure Ci, step 1 using 3-(trifluoromethyl)aniline (Xc, 0.67 mL, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1.00 g, 4.89 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.456 g (27% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.

N-(2,4-difluorophenyl)-4-formylbenzenesulfonamide (Xld). The title compound was obtained according to general procedure Ci, step 1 using 2,4-difluoroaniline (Xd, 0.547 mL, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1.00 g, 4.89 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.646 g (44% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.

N-(3-cyanophenyl)-4-formylbenzenesulfonamide (Xle). The title compound was obtained according to general procedure Ci, step 1 using 3-aminobenzonitrile (Xe, 0.635 g, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1.00 g, 4.89 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 1.22 g (87% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation. N-(4-cyano-2-fluorophenyl)-4-formylbenzenesulfonamide (Xlf). The title compound was obtained according to general procedure C-i, step 1 using 4-amino-3- fluorobenzonitrile (Xf, 0.732 g, 5.38 mmol), pyridine (0.43 ml_, 5.38 mmol) and 4- formylbenzene-1 -sulfonyl chloride (IXa, 1 .00 g, 4.89 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.814 g (54% yield) of the title product. HPLC-MS (ESI) m/z: no ionization.

4-Formyl-N-(4-(trifluoromethyl)phenyl)benzenesulfonamide (Xlg). The title compound was obtained according to general procedure C-i, step 1 using 4-(trifluoromethyl)aniline (Xg, 0.67 ml_, 5.38 mmol), pyridine (0.43 ml_, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1 .00 g, 4.89 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.960 g (55% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.

N-(5-fluoropyridin-3-yl)-4-formylbenzenesulfonamide (Xlh). The title compound was obtained according to general procedure Ci, step 1 using 5-fluoropyridin-3-amine (Xh, 0.603 g, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1 .00 g, 4.89 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 1 g (69% yield) of the title product. HPLC-MS (ESI) m/z: 280.8 [M- H]⁺.

4-Formyl-N-methyl-N-(pyridin-3-yl)benzenesulfonamide (Xli). The title compound was obtained according to general procedure Ci, step 1 using 3-(methylamino)pyridine (Xi, 1 .16 g, 10.75 mmol), pyridine (0.87 mL, 10.75 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 2.00 g, 9.77 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 2.02 g (70% yield) of the title compound. HPLC-MS (ESI) m/z: 276.9 [M-H]⁺.

4-Fluoro-3-((4-formylphenyl)sulfonamido)benzamide (Xlj). The title compound was obtained according to general procedure Ci, step 1 using 3-amino-4-fluorobenzamide (Xj, 2.39 g, 6.45 mmol), pyridine (0.52 mL, 6.45 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1 .2 g, 5.86 mmol). The crude was slurried in water, filtered, washed with Et₂0 and DCM and dried under vacuum to give 0.493 g (26% yield) of the title compound. HPLC-MS (ESI) m/z: 323 [M-H]⁺.

3-((4-Formylphenyl)sulfonamido)benzamide (Xlk). The title compound was obtained according to general procedure Ci, step 1 using 3-aminobenzamide (Xk, 0.732 g, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1 .0 g, 4.89 mmol). The crude was slurried in water, filtered, washed with Et₂0 and DCM and dried under vacuum to give 0.874 g (59% yield) of the title compound. HPLC-MS (ESI) m/z: 305 [M-H]⁺.

3-((4-Formylphenyl)sulfonamido)thiophene-2-carboxamide (XII). The title compound was obtained according to general procedure Ci, step 1 using 3-aminothiophene-2- carboxamide (XI, 0.500 g, 3.52 mmol), pyridine (0.31 mL, 3.87 mmol) and 4- formylbenzene-1 -sulfonyl chloride (IXa, 0.72 g, 3.52 mmol). The crude (0.256 g, 23% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 31 1 [M- H]⁺.

5-(Tert-butyl)-3-((4-formylphenyl)sulfonamido)thiophene-2-carboxamide (Xlm). The title compound was obtained according to general procedure C-i, step 1 using 3-amino-5- (fe/f-butyl)thiophene-2-carboxamide (Xm, 1 .066 g, 5.38 mmol), 4-formylbenzene-1 - sulfonyl chloride (IXa, 1 .0 g, 4.89 mmol) and pyridine (0.43 ml_, 5.38 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.339 g (19% yield) of the title product. HPLC-MS (ESI) m/z: 346.7 [M-H]\

4-Formyl-N-(pyridin-3-yl)benzenesulfonamide (Xln). The title compound was obtained according to general procedure Ci, step 1 using pyridin-3-amine (Xn, 207 mg, 2.20 mmol), pyridine (0.18 mL, 2.2 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 409 mg, 2.00 mmol). The crude was purified by flash chromatography (0-5% MeOH/DCM) to give 281 mg (51 % yield) of the title product. HPLC-MS (ESI) m/z: 261 [M-H]\

N-(5-cyano-2-fluorophenyl)-4-formylbenzenesulfonamide (Xlo). The title compound was obtained according to general procedure Ci, step 1 using 3-amino-4- fluorobenzonitrile (Xo, 0.732 g, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4- formylbenzene-1 -sulfonyl chloride (IXa, 1 .00 g, 4.89 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.462 g (31 % yield) of the title product. HPLC-MS (ESI) m/z: 303.0/305.0 [M-H]⁺.

N-(3-fluorophenyl)-4-formylbenzenesulfonamide (Xlp). The title compound was obtained according to general procedure Ci, step 1 using 3-fluoroaniline (Xp, 0.21 mL, 2.2 mmol), pyridine (0.18 mL, 2.2 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 409 mg, 2.00 mmol). The crude was purified by flash chromatography (0-5% MeOH/DCM) to give 431 mg (69% yield) of the title product. HPLC-MS (ESI) m/z: 278 [M-H]\

4-Formyl-N-(4-methoxyphenyl)benzenesulfonamide (Xlq). The title compound was obtained according to general procedure Ci, step 1 using 4-methoxyaniline (Xq, 271 mg, 2.20 mmol), pyridine (0.178 mL, 2.20 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 409 mg, 2.00 mmol). The crude was purified by flash chromatography (100% DCM) to give 590 mg (99% yield) of the title product. HPLC-MS (ESI) m/z: 292 [M-H]⁺.

N-(4-fluorophenyl)-4-formylbenzenesulfonamide (Xlr). The title compound was obtained according to general procedure Ci, step 1 using 4-fluoroaniline (Xr, 0.21 mL, 2.2 mmol), pyridine (0.18 mL, 2.2 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 409 mg, 2.00 mmol). The crude was purified by flash chromatography (0-5% MeOH/DCM) to give 431 mg (69% yield) of the title product. HPLC-MS (ESI) m/z: 280 [M-H]⁺.

4-Formyl-N-(pyridin-2-yl)benzenesulfonamide (Xls). The title compound was obtained according to general procedure Ci, step 1 using pyridin-2 -amine (Xs, 565 mg, 6.00 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 409 mg, 2.00 mmol). The crude was purified by flash chromatography (0-2% MeOH/ DCM) to give 80 mg (12% yield) of the title product. HPLC-MS (ESI) m/z: 263 [M-H]⁺.

4-Formyl-N-phenylbenzenesulfonamide (Xlt). The title compound was obtained according to general procedure C-i, step 1 using aniline (Xt, 0.201 ml_, 2.20 mmol), pyridine (0.178 ml_, 2.20 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 409 mg, 2.00 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 470 mg (89% yield) of the title product. HPLC-MS (ESI) m/z: 262 [M-H]⁺.

N-(4-cyano-1 -cyclopentyl-1 H-pyrazol-3-yl)-4-formylbenzenesulfonamide (Xlu). The title compound was obtained according to general procedure Ci, step 1 using 3-amino-1 - cyclopentyl-1 /-/-pyrazole-4-carbonitrile (Xu, 0.995 g, 5.64 mmol), pyridine (0.46 mL, 5.64 mmol), and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1 .05 g, 5.13 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 1 .04 g (59% yield) of the title product. HPLC-MS (ESI) m/z: 345.1 [M-H]⁺.

General procedure D-i: Synthesis of intermediate halides XIV (R³Hal)

Step 1

Method (A): Benzyl mercaptan (1 eq.) was dissolved in THF (0.35 M) and the solution was cooled down to 0° c. NaH (1.2 eq. 60% in mineral oil) was added portionwise and the reaction mixture was stirred for 30 min at 0° c. Then, the proper iodide XII (1 eq.) was added to the reaction and the mixture was stirred at r.t. for 3 h. Ice was added to the reaction mixture followed by the addition of EtOAc. The organic layer was separated, dried over MgSC , filtered and concentrated under vacuum. After dissolving the resulting residue in DCM, water and sulfuryl chloride (7 eq.) were added at 0° c under N2. The reaction mixture was slowly warmed up to r.t. and stirred for 30 min. The reaction was then cooled with an ice bath and diluted with water. The organic layer was separated, dried over MgSC , filtered and concentrated under vacuum to give the intermediate compound having general formula XIII, which was used for the next step without further purification.

Method (B): Thionyl chloride (4 eq.) was added dropwise to ice cooled water (2.3 M), maintaining the temperature of the mixture between 0 to 7 °c. The solution was allowed to warm up and stirred at r.t. overnight. After adding CuCI (0.01 eq.), the resulting mixture was cooled down to -3 °c (mixture 1 ). In the meantime, a solution of the proper amine XII (1 eq.) in 36% aqueous HCI (12 eq.) was prepared, maintaining the temperature of the mixture below 30 °c. Then, a solution of NaNCte (1 .1 eq.) in water (4 M) was slowly added maintaining the temperature between -5 to 0 °c. The resulting slurry was cooled to -2 °c and stirred for 10 min (mixture 2). Mixture 2 was slowly added to mixture 1 , keeping the internal temperature between -3 to 0 °c. The reaction mixture was then stirred for 1 h at 0 °c and the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give the intermediate compound having general formula XIII.

5-Bromopyridine-2-sulfonyl chloride (Xllla). The title compound was obtained according to general procedure Di, step 1 , method (A) using i) benzyl mercaptan (2.19 g, 17.61 mmol), NaH (0.845 g, 21 .13 mmol) and 5-bromo-2-iodopyridine (Xlla, 5.00 g, 17.61 mmol); ii) crude (5.5 g), DCM (65 ml_), water (12 ml_) and sulfuryl chloride (10 ml_, 123 mmol). The crude (7.0 g; quant yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: no ionization.

6-chloropyridine-3-sul†onyl chloride (Xlllb). The title compound was obtained according to general procedure Di, step 1 , method (B) using thionyl chloride (4.2 ml_, 57.6 mmol), CuCI (0.015 g, 0.148 mmol), HCI (13.5 ml_, 160 mmol), 6-chloropyridin-3- amine (Xllb, 1 .73 g, 13.46 mmol) and NaNCte (1 .021 g, 14.80 mmol). The crude (1 .75 g, 61 % yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 193.0 [M-H]⁺.

Step 2

General procedure Di, step 2 follows the same conditions described for general procedure Ci, step 1 .

5-Bromo-N-(2-fluorophenyl)pyridine-2-sulfonamide (XI Va). The title compound was obtained according to general procedure Di, step 2 using 5-bromopyridine-2-sulfonyl chloride (Xllla, 3 g, 1 1 .70 mmol), pyridine (0.94 mL, 1 1.70 mmol) and 2-fluoroaniline (Xb, 1 .30 g, 1 1 .70 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.850 g (22% yield) of the title product. HPLC-MS (ESI) m/z: 331 .0/333.0 [M-H]⁺.

6-chloro-N-(2-fluorophenyl)pyridine-3-sulfonamide (XlVb). The title compound was obtained according to general procedure Di, step 2 using 6-chloropyridine-3-sulfonyl chloride (Xlllb, 1 .40 g, 6.60 mmol), 2-fluoroaniline (Xb, 0.807 g, 7.26 mmol) and pyridine (0.59 mL, 7.26 mmol). The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 1 .50 g (79% yield) of the title product. HPLC-MS (ESI) m/z: 287 [M-H]⁺.

5-Bromo-N-(pyridin-3-yl)pyridine-2-sulfonamide (XIVc). The title compound was obtained according to general procedure Di, step 2 using 5-bromopyridine-2-sulfonyl chloride (Xllla, 4 g, 15.59 mmol), pyridine (1.21 mL, 15.59 mmol) and pyridin-3-amine (Xn, 1 .47 g, 15.59 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 1 .305 g (26% yield) of the title product. HPLC-MS (ESI) m/z: 313.9 [M-H]⁺.

6-chloro-N-(pyridin-3-yl)pyridine-3-sulfonamide (XlVd). The title compound was obtained according to general procedure Di, step 2 using 6-chloropyridine-3-sulfonyl chloride (Xlllb, 1 .75 g, 8.25 mmol), pyridin-3-amine (Xn, 0.855 g, 9.09 mmol) and pyridine (0.75 mL, 9.09 mmol). The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 1 .75 g (61 % yield) of the title product. HPLC-MS (ESI) m/z: 193.9 [M-H]⁺.

4-(4-Bromophenylsulfonamido)-3-fluorobenzamide (XlVe). The title compound was obtained according to general procedure Di, step 2 using 4-bromobenzene-1 -sulfonyl chloride (Xlllc, 5.1 g, 20.1 mmol), 4-amino-3-fluorobenzamide (Xv, 3.8 g, 22.1 mmol) and pyridine (25 mL). The resulting precipitate was partitioned with EtOAc (15 mL) and water (15 mL). The organic layer was washed with brine, dried over MgSC and concentrated in vacuo. The crude was suspended in water (25 mL), filtered and washed with water (2 x 25 mL) and EtOAc (2 x 10 mL) to afford 5.5 g (66% yield) of the title product. HPLC-MS (ESI) m/z: 373.0 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 10.59 (s, 1 H), 7.97 (s, 1 H), 7.84 - 7.78 (m, 2H), 7.72 - 7.67 (m, 2H), 7.67 - 7.61 (m, 2H), 7.47 (s, 1 H), 7.35 (t, J = 8.3 Hz, 1 H).

General procedure E-i: Synthesis of intermediate aldehydes XVI (R³CHO)

Step 1

The proper intermediate XIV (1 eq.), potassium trifluoro(vinyl)borate (1 .5 eq.), CS2CO3 (4 eq.) and PdCl2(dppf)-DCM adduct (0.1 eq.) were dissolved in DME/water (1 : 1 ) (0.07 M). The reaction mixture was heated at 130° c for 10 min in a MW reactor, then filtered through a celite plug and dried under vacuum. The resulting residue was purified by flash chromatography to obtain intermediate compound having general formula XV.

N-(2-fluorophenyl)-5-vinylpyridine-2-sulfonamide (XVa). The title compound was obtained according to general procedure Ei, step 1 using 5-bromo-/V-(2- fluorophenyl)pyridine-2-sulfonamide (XlVa, 0.804 g, 2.428 mmol), potassium trifluoro(vinyl)borate (0.488 g, 3.64 mmol), CS2CO3 (3.16 g, 9.71 mmol) and PdCl2(dppf)- DCM adduct (0.198 g, 0.243 mmol). The crude was purified by flash chromatography (S1O2, Hex/EtOAc and DCM/MeOH) to give 0.392 g (58% yield) of the title product. HPLC- MS (ESI) m/z: 279 [M-H]⁺.

N-(2-fluorophenyl)-6-vinylpyridine-3-sulfonamide (XVb). The title compound was obtained according to general procedure Ei, step 1 using 6-chloro-N-(2- fluorophenyl)pyridine-3-sulfonamide (XlVb, 1 .498 g, 5.22 mmol), potassium trifluoro(vinyl)borate (1 .050 g, 7.84 mmol), CS2CO3 (6.81 g, 20.90 mmol) and PdCl2(dppf)- CH2CI2 adduct (0.427 g, 0.522 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.817 g (56% yield) of the title product. HPLC-MS (ESI) m/z: 279 [M-H]⁺.

N-(pyridin-3-yl)-5-vinylpyridine-2-sulfonamide (XVc). The title compound was obtained according to general procedure Ei, step 1 using 5-bromo-/V-(pyridin-3-yl)pyridine-2- sulfonamide (XIVc, 0.45 g, 432 mmol), potassium trifluoro(vinyl)borate (0.288 g, 2.149 mmol), CS2CO3 (1 .86 g, 5.73 mmol) and PdCl2(dppf)-DCM adduct (0.1 17 g, 0.143 mmol). The crude was purified by flash chromatography (S1O2, Hex/EtOAc and DCM/MeOH) to give 0.361 g (54% yield) of the title product. HPLC-MS (ESI) m/z: 262 [M-H]⁺.

N-(pyridin-3-yl)-6-vinylpyridine-3-sulfonamide (XVd). The title compound was obtained according to general procedure Ei, step 1 using 6-chloro-/V-(pyridin-3-yl)pyridine-3- sulfonamide (XlVd, 1 .246 g, 4.62 mmol), potassium trifluoro(vinyl)borate (0.928 g, 6.93 mmol), CS₂CO3 (6.02 g, 18.48 mmol) and PdCl2(dppf)-cH2Cl2 adduct (0.377 g, 0.462 mmol). The crude was purified by flash chromatography (S1O₂, DCM/MeOH) to give 0.737 g (61 % yield) of the title product. HPLC-MS (ESI) m/z: 262 [M-H]⁺.

Step 2

To a solution of intermediate XV (1 eq.) in THF (0.2 M) and water (0.5 M), a solution of OSO4 (4% in water, 0.1 eq.) was added and the reaction was stirred at r.t. for 30 min. Then, Nal0₄ (1 .5 eq.) was added and the reaction was stirred at r.t. for 16 h. The mixture was diluted with water and finally extracted with EtOAc. The organic layer was dried over MgS0₄, filtered and evaporated under vacuum. When required, the crude was purified by flash chromatography to give intermediate compound having general formula XVI.

N-(2-fluorophenyl)-5-formylpyridine-2-sulfonamide (XVIa). The title compound was obtained according to general procedure Ei, step 2 using A/-(2-fluorophenyl)-5- vinylpyridine-2-sulfonamide (XVa, 0.392 g, 1 .409 mmol), OsC (0.86 mL, 0.141 mmol) and NalC (0.452 g, 2.1 13 mmol). The crude was purified by flash chromatography (S1O2, Hex/EtOAc and DCM/MeOH) to give 0.345 g (87% yield) of the title product. HPLC-MS (ESI) m/z: 281 [M-H]⁺.

N-(2-fluorophenyl)-6-formylpyridine-3-sulfonamide (XVIb). The title compound was obtained according to general procedure Ei, step 2 using N-(2-fluorophenyl)-6- vinylpyridine-3-sulfonamide (XVb, 1 .046 g, 3.76 mmol), OSO4 (0.46 mL, 0.075 mmol) and Nal0₄ (3.22 g, 15.03 mmol). The crude (1 .131 g, quant yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 281.0 [M-H]⁺.

5-Formyl-N-(pyridin-3-yl)pyridine-2-sulfonamide (XVIc). The title compound was obtained according to general procedure Ei, step 2 using A/-(pyridin-3-yl)-5-vinylpyridine-

2-sulfonamide (XVc, 0.361 g, 1 .381 mmol), OsC (0.84 mL, 0.138 mmol) and NalC (0.443 g, 2.072 mmol). The crude (0.154 g, 42% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 264.0 [M-H]⁺.

6-Formyl-N-(pyridin-3-yl)pyridine-3-sulfonamide (XVId). The title compound was obtained according to general procedure Ei, step 2 using A/-(pyridin-3-yl)-6-vinylpyridine-

3-sulfonamide (XVd, 0.737 g, 2.82 mmol), Os0₄ (1 .72 mL, 0.282 mmol) and Nal0₄ (0.905 g, 4.23 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.1 1 1 g (15% yield) of the title product. HPLC-MS (ESI) m/z: 264.0 [M-H]⁺. General procedure F-i: Synthesis of intermediate aldehyde XIX (R³CHO or

Step 1

To a solution of oxalyl chloride (6.46 ml_, 73.8 mmol) in DCM (6 ml_) cooled to 0°C, a solution of DMF (6 ml_) in DCM (6 ml_) was added dropwise. After stirring for 30 min, a solution of 1 H-pyrrole (XVII, 4.56 ml_, 67.1 mmol) in DCM (6 ml_) was added dropwise and the yellow solution obtained was stirred for 15 min at 0°C, then warmed to r.t. and stirred for a further 15 min. The mixture was concentrated (~ 20 ml_), i-hex (100 ml_) was added and the resulting solid was collected by filtration and washed with i-hex (2 x 10 ml_) to give 2.05 g (18% yield) of N-((1H-pyrrol-2-yl)methylene)-N-methylmethanaminium· HCI (XVIII). ¹H-NMR (400 MHz, DMSO-de) d: 13.20 (s, 1 H), 8.64 (s, 1 H), 7.79 (t, J = 2.2

Hz, 1 H), 7.46 (ddd, J = 3.9, 2.5, 1 .3 Hz, 1 H), 6.68 (dt, J = 4.3, 2.1 Hz, 1 H), 3.64 (s, 3H), 3.54 (s, 3H).

Step 2

To a suspension of N-((1 H-pyrrol-2-yl)methylene)-N-methylmethanaminium HCI (XVIII, 2.00 g, 12.6 mmol) in DcE (15 ml_), aluminium trichloride (3.70 g, 27.7 mmol) was added and the mixture was stirred at r.t. for 10 min. To the resulting red solution 2,2,2- trichloroacetyl chloride (1 .48 ml_, 13.2 mmol) was added and the mixture was heated at reflux for 3 h. After cooling to r.t., MeOH (10 ml_) was added carefully. After cooling to 0°C a solution of NaOMe (6.81 g, 126 mmol) in MeOH (50 ml_) was added over 5 min and the mixture was warmed to r.t., stirred for 1 h, allowed to stand over the weekend and finally concentrated under reduced pressure. Water (50 ml_) was added to the resulting solid and the pH was adjusted to 4-5 by addiction of aqueous 1 M HCI solution. The mixture was extracted with EtOAc (4 x 30 ml_), and the combined organics were washed with water (50 ml_), brine (50 ml_) dried over MgS0₄, filtered and concentrated under reduced pressure. The crude was crystallised from petroleum ether/EtOAc to give 744 mg (38% yield) of methyl-5-formyl-1H-pyrrole-3-carboxylate (XIX). ¹ H-NMR (400 MHz, DMSO-de) d: 12.73 (s, 1 H), 9.56 (d, J = 1 .0 Hz, 1 H), 7.76 (dd, J = 1 .5, 1 .0 Hz, 1 H), 7.38 (d, J = 1 .5 Hz, 1 H), 3.75 (s, 3H).

General procedure Gi: Synthesis of compounds with general formula l^(l), including Examples 1 -20

Step 1 Step 1

Method (A): Pyruvic acid (1 eq.), the opportunely substituted pyrazolamine V (1 eq.) and the proper aldehyde (XI, XVI, XIX or commercially available aldehydes of general formula XX: 1 eq.) were dissolved in AcOH (1 M) and the mixture was refluxed for 1 h. The solvent was evaporated under vacuum and the residue was purified by the appropriate technique to give the desired final compound having general formula l^(l).

Method (B): To a solution of the pyrazolamine intermediate V (1 eq.) in EtOH, ethyl- pyruvate (1 eq.), the proper aldehyde (XI, XVI, XIX or commercially available aldehydes of general formula XX: 1 eq.) and cone. HCI (one drop) were added. The mixture was heated in the MW at 150 °C for 10-30 min and then concentrated under reduced pressure. Finally, the crude product was purified by the appropriate technique to give the desired compound having general formula l^(l).

Method (c): To a solution of the pyrazolamine intermediate V (1 eq.) in MeOH, methyl- pyruvate (1 eq.), the proper aldehyde (XI, XVI, XIX or commercially available aldehydes of general formula XX: 1 eq.) and cone. HCI (one drop) were added. The mixture was heated in the MW at 150 °C for 10-30 min and then concentrated under reduced pressure. Finally, the crude product was purified by the appropriate technique to give the desired compound having general formula l^(l).

Method (D): To a solution of the pyrazolamine intermediate V (1 eq.) in EtOH, pyruvic acid (1 eq.), the proper aldehyde (XI, XVI, XIX or commercially available aldehydes of general formula XX: 1 eq.) and cone. HCI (one drop) were added. The mixture was heated in the MW at 150 °C for 15 min and then concentrated under reduced pressure. Finally, the crude product was purified by the appropriate technique to give the desired compound having general formula l^(l).

6-( 4-( N-(4-carbamoylphenyl)sulfamoyl)phenyl)-3-( 4-ethyl phenyl)- 1 Hpyrazolo[3, 4- b]pyridine-4-carboxylic acid (Example 1 ). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.615 g, 3.29 mmol), 4-((4-formylphenyl)sulfonamido)benzamide (Xla, 1 .0 g, 3.29 mmol) and pyruvic acid (0.289 g, 3.29 mmol). The crude was purified by reverse phase chromatography (Cis, 0.1 % NH4HCO3 in water/AcN) to give 19.3 mg (2% yield) of the title product. HPLC-MS (ESI) m/z: 541.8 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.45 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.91 (br s, 1 H), 7.85 (d, J = 8.7 Hz, 2H), 7.78 (br s, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.32 (br s, 1 H), 7.29 (d, J = 8.7 Hz, 2H), 2.76 (q, J = 7.8 Hz, 2H), 1 .34 (t, J = 7.6 Hz, 3H).

Ethyl-6-( 4-(N-( 4-carbamoylphenyl)sulfamoyl)phenyl)-3-( 4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (Example 2). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H- pyrazol-5-amine (Va, 0.209 g, 1 .1 17 mmol), 4-((4-formylphenyl)sulfonamido)benzamide (Xla, 0.340 g, 1 .1 17 mmol) and ethyl-pyruvate (0.124 ml_, 1 .1 17 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.159 g (25% yield) of the title product. HPLC-MS (ESI) m/z: 568.1 [M-H]\ ¹H-NMR (400 MHz, DMSO -c/e) d: 8.39 (d, J = 8.5 Hz, 2H), 8.05 (s, 1 H), 7.97 (d, J = 8.4 Hz, 2H), 7.80 (br s, 1 H), 7.75 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.22 (br s, 1 H), 7.18 (d, J = 8.6 Hz, 2H), 3.93 (q, J = 7.1 Hz, 2H), 2.68 (q, J = 7.4 Hz, 2H), 1 .22 (t, J = 7.6 Hz, 3H), 0.74 (t, J = 7.1 Hz, 3H).

Methyl-6-(4-(N-(4-carbamoylphenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (Example 3). The title compound was obtained according to general procedure Gi, step 1 , method (c) using 3-(4-ethylphenyl)-1 H- pyrazol-5-amine (Va, 0.209 g, 1 .1 17 mmol), 4-((4-formylphenyl)sulfonamido)benzamide (Xla, 0.340 g, 1 .1 17 mmol) and methyl-pyruvate (1 14 mg, 1 .1 17 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.125 g (27% yield) of the title product. ¹H-NMR (400 MHz, DMSO -c/e) d: 8.34 (d, J = 8.3 Hz, 2H), 8.06 (s, 1 H), 7.94 (d, J = 8.4 Hz, 2H), 7.72 (br s, 1 H), 7.68 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.14 - 7.06 (m, 3H), 2.68 (q, J = 7.5 Hz, 2H), 1 .23 (t, J = 7.5 Hz, 3H). HPLC-MS (ESI) m/z: no ionisation.

3-( 4-Ethylphenyl)-6-( 4-(N-( 2-fluorophenyl)sulfamoyl)phenyl)-1H-pyrazolo[3, 4- b]pyridine-4-carboxylic acid (Example 4). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.335 g, 1 .79 mmol), A/-(2-fluorophenyl)-4-formylbenzenesulfonamide (Xlb, 0.5 g, 1 .79 mmol) and pyruvic acid (0.158 g, 1 .79 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.215 g (23% yield) of the title product. HPLC-MS (ESI) m/z: 516.7 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 10.28 (br s, 1 H), 8.39 (d, J = 8.5 Hz, 2H), 8.03 (br s, 1 H), 7.88 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.28 - 7.12 (m, 4H), 2.68 (q, J = 7.5 Hz, 2H), 1 .24 (t, J = 7.5 Hz, 3H).

3-(4-Ethylphenyl)-6-(4-(N-(3-(trifluoromethyl)phenyl)sulfamoyl)phenyl)- 1Hpyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 5). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)- 1 H-pyrazol-5-amine (Va, 0.259 g, 1 .38 mmol), 4-formyl-/V-(3- (trifluoromethyl)phenyl)benzenesulfonamide (Xlc, 0.456 g, 1 .38 mmol) and pyruvic acid (0.122 g, 1 .38 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.180 g (23% yield) of the title product. HPLC-MS (ESI) m/z: 566.7 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.36 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.62 (br s, 2H), 7.54 - 7.46 (m, 1 H), 7.45 - 7.37 (m, 4H), 7.26 (d, J = 7.9 Hz, 2H), 2.66 (q, J = 7.4 Hz, 2H), 1 .23 (t, J = 7.5 Hz, 3H).

6-(4-(N-(2,4-difluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 6). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.407 g, 2.173 mmo), A/-(2,4-difluorophenyl)-4-formylbenzenesulfonamide (Xld, 0.646 g, 2.173 mmol) and pyruvic acid (0.153 ml_, 2.173 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.677 g (58% yield) of the title product. HPLC-MS (ESI) m/z: 533 [M-H]\ ¹H-NMR (400 MHz, DMSO -c/e) d: 10.22 (br s, 1 H), 8.39 (d, J = 8.4 Hz, 2H), 7.99 (br s, 1 H), 7.84 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H), 7.33 - 7.22 (m, 4H), 7.09 - 7.02 (m, 1 H), 2.68 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H).

6-(4-(N-(3-cyanophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 7). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.327 g, 1 .75 mmol), A/-(3-cyanophenyl)-4-formylbenzenesulfonamide (Xle, 0.5 g, 1 .75 mmol) and pyruvic acid (0.154 g, 1 .75 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.280 g (22% yield) of the title product. HPLC-MS (ESI) m/z: 523.8 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.31 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.75 (s, 1 H), 7.68 (d, J = 8.0 Hz, 2H), 7.50 - 7.48 (m, 1 H), 7.44 - 7.39 (m, 3H), 7.28 (d, J = 8.0 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1 .27 (t, J = 7.6 Hz, 3H).

6-(4-(N-(4-cyano-2-fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 8). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.091 g, 0.486 mmol), A/-(4-cyano-2-fluorophenyl)-4-formylbenzenesulfonamide (Xlf, 0.148 g, 0.486 mmol), and pyruvic acid (27 pL, 0.378 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.1 14 g (43% yield) of the title product. HPLC-MS (ESI) m/z: 540 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 8.39 (d, J = 8.2 Hz, 2H), 8.02 (s, 1 H), 7.96 (d, J = 8.4 Hz, 2H), 7.74 (br s, 1 H), 7.60 - 7.43 (m, 4H), 7.30 (d, J = 8.0 Hz, 2H), 2.68 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(4-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)phenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 9). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H- pyrazol-5-amine (Va, 0.284 g, 1 .52 mmol), 4-formyl-/V-(4- (trifluoromethyl)phenyl)benzenesulfonamide (Xlg, 0.5 g, 1 .52 mmol) and pyruvic acid (0.134 g, 1 .52 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.342 g (40% yield) of the title product. HPLC-MS (ESI) m/z: 566.7 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.36 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H), 7.80 (br s, 1 H), 7.62 (d, J = 8.5 Hz, 4H), 7.32 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 2.66 (q, J = 7.3 Hz, 2H), 1 .23 (t, J = 7.5 Hz, 3H).

3-(4-Ethylphenyl)-6-(4-(N-(5-fluoropyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 10). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.334 g, 1 .78 mmol), A/-(5-fluoropyridin-3-yl)-4-formylbenzenesulfonamide (Xlh, 0.5 g, 1 .78 mmol) and pyruvic acid (0.158 g, 1.78 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 98 mg (1 1 % yield) of the title product. HPLC- MS (ESI) m/z: 517.8 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.33 (d, J = 8.4 HZ, 2H), 8.1 1 (br s, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.83 (br s, 1 H), 7.61 (br d, J = 5.6 Hz, 2H), 7.33 (d, J = 10.8 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 2H), 2.66 (q, J = 7.3 Hz, 2H), 1 .23 (t, J = 7.5 Hz, 3H).

3-(4-Ethylphenyl)-6-(4-(N-methyl-N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 11 ). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 1 .285 g, 6.87 mmol), 4-formyl-/V-methyl-/\/-(pyridin-3-yl)benzenesulfonamide (Xli, 2.018 g, 6.87 mmol) and pyruvic acid (0.605 g, 6.87 mmol). The crude was purified by reverse phase chromatography (C18, NH4HCO3/ACN) to give 16 mg (1 % yield) of the title product. HPLC-MS (ESI) m/z: 513.8 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 8.48 - 8.43 (m, 2H), 8.36 (d, J = 8.6 Hz, 2H), 7.82 (s, 1 H), 7.71 - 7.65 (m, 4H), 7.63 - 7.59 (m, 1 H), 7.41 (dd, J = 8.3, 7.4 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 2H), 3.29 (s, 3H), 2.71 (q, J = 7.6 Hz, 2H), 1 .28 (t, J = 7.6 Hz, 3H).

6-(4-(N-(5-carbamoyl-2-fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 12). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)- 1 H-pyrazol-5-amine (Va, 0.286 g, 1 .53 mmol), 4-fluoro-3-((4- formylphenyl)sulfonamido)benzamide (Xlj, 0.493 g, 1 .53 mmol) and pyruvic acid (84 pL, 1 .188 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 61 mg (7% yield) of the title product. HPLC-MS (ESI) m/z: 560/558 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 10.42 (s, 1 H), 8.40 (d, J = 8.4 Hz, 2H), 8.05 - 7.98 (m, 2H), 7.91 - 7.84 (m, 3H), 7.77 - 7.70 (m, 1 H), 7.50 (d, J = 7.9 Hz, 2H), 7.41 (s, 1 H), 7.34 - 7.21 (m, 3H), 2.67 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).

6-( 4-( N-(3-carbamoylphenyl)sulfamoyl)phenyl)-3-( 4-ethyl phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylic acid (Example 13). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.538 g, 2.87 mmol), 3-((4-formylphenyl)sulfonamido)benzamide (Xlk, 0.874 g, 2.87 mmol), and pyruvic acid (0.2 mL, 2.87 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 24 mg (4% yield) of the title product. HPLC- MS (ESI) m/z: 540.1 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 10.53 (s, 1 H), 8.38 (d, J = 8.5 Hz, 2H), 8.00 (s, 1 H), 7.92 (d, J = 8.4 Hz, 3H), 7.68 - 7.64 (m, 1 H), 7.56 - 7.46 (m, 3H), 7.38 - 7.24 (m, 5H), 2.67 (q, J = 7.4 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).

6-(4-(N-(2-carbamoylthiophen-3-yl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 14). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)- 1 H-pyrazol-5-amine (Va, 0.154 g, 0.825 mmol), 3-((4- formylphenyl)sulfonamido)thiophene-2-carboxamide (XII, 0.256 g, 0.825 mmol) and pyruvic acid (0.073 g, 0.825 mmol). The crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 0.038 g (8% yield) of the title product. HPLC-MS (ESI) m/z: 546 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 13.69 (br s, 1 H), 1 1 .29 (br s, 1 H), 8.38 (d, J = 8.1 Hz, 2H), 8.00 (s, 1 H), 7.94 (d, J = 8.3 Hz, 2H), 7.70 (br s, 3H), 7.47 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 5.1 Hz, 1 H), 2.66 (q, J = 7.6 Hz, 2H), 1 .22 (t, J = 7.6 Hz, 3H).

6-(4-(N-(5-(Tert-butyl)-2-carbamoylthiophen-3-yl)sulfamoyl)phenyl)-3-(4-ethylphenyl)- 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 15). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)- 1 H-pyrazol-5-amine (Va, 0.153 g, 0.819 mmol), 5-(fe/f-butyl)-3-((4- formylphenyl)sulfonamido)thiophene-2-carboxamide (Xlm, 0.300 g, 0.819 mmol) and pyruvic acid (0.072 g, 0.819 mmol). The crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 26 mg (5% yield) of the title product. HPLC-MS (ESI) m/z: 602 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 1 1 .30 (br s, 1 H), 8.41 (d, J = 8.0 Hz, 2H), 8.03 (s, 1 H), 7.96 (d, J = 8.4 Hz, 2H), 7.63 (br s, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.04 (s, 1 H), 2.67 (q, J = 7.5 Hz, 2H), 1 .30 (s, 9H), 1.24 (t, J = 7.5 Hz, 3H).

3-(4-Ethylphenyl)-6-(6-(N-(2-fluorophenyl)sulfamoyl)pyridin-3-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 16). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.230 g, 1 .231 mmol), A/-(2-fluorophenyl)-5-formylpyridine-2-sulfonamide (XVIa, 0.345 g, 1.231 mmol) and pyruvic acid (0.67 mL g, 1 .231 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 37 mg (17% yield) of the title product. HPLC-MS (ESI) m/z: 516 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 10.47 (br s, 1 H), 9.50 (d, J = 1 .8 Hz, 1 H), 8.80 (dd, J = 8.3 Hz, 2.2 Hz, 1 H), 8.10 (s, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2H), 7.33 - 7.27 (m, 3H), 7.24 - 7.09 (m, 3H), 2.67 (q, J = 7.4 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H).

Methyl-3-(4-ethylphenyl)-6-(5-(N-(2-fluorophenyl)sulfamoyl)pyridin-2-yl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (Example 17). The title compound was obtained according to general procedure Gi, step 1 , method (c) using 3-(4-ethylphenyl)-1 H- pyrazol-5-amine (Va, 0.548 g, 2.93 mmol), N-(2-fluorophenyl)-6-formylpyridine-3- sulfonamide (XVIb, 0.821 g, 2.93 mmol) and methyl-pyruvate (265 pL, 2.93 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) and then slurryed in MeOH to give 1 17 mg (7% yield) of the title product. HPLC-MS (ESI) m/z: 532.1 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 10.54 (s, 1 H), 8.98 (d, J = 2.3 Hz, 1 H), 8.64 (d, J = 8.5 Hz, 1 H), 8.54 (s, 1 H), 8.31 (dd, J = 8.4 Hz, 2.3 Hz, 1 H), 7.44 - 7.39 (m, 2H), 7.37 - 7.15 (m, 7H), 3.47 (s, 3H), 2.69 (q, J = 7.5 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H). 3-(4-Ethylphenyl)-6-(6-(N-(pyridin-3-yl)sulfamoyl)pyridin-3-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 18). The title compound was obtained according to general procedure G-i, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.1 10 g, 0.585 mmol), 5-formyl-/V-(pyridin-3-yl)pyridine-2-sulfonamide (XVIc, 0.154 g, 0.585 mmol) and pyruvic acid (0.052 g, 0.585 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 18 mg (32% yield) of the title product. HPLC- MS (ESI) m/z: 499.1 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 10.94 (br s, 1 H), 9.47 (d, J = 1 .8 Hz, 1 H), 8.80 (dd, J = 8.2 Hz, 2.1 Hz, 1 H), 8.40 (br s, 1 H), 8.26 (br s, 1 H), 8.13 (d, J = 8.1 Hz, 1 H), 8.03 - 7.94 (m, 1 H), 7.65 - 7.55 (m, 3H), 7.34 - 7.24 (m, 3H), 2.66 (q, J = 7.4 Hz, 2H), 1 .22 (t, J = 7.5 Hz, 3H).

6-(5-carboxyfuran-2-yl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 19). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 250 mg, 1 .34 mmol), 5- formylfuran-2-carboxylic acid (XXa, 187 mg, 1 .34 mmol) and pyruvic acid (1 18 mg, 1 .34 mmol). The crude was recrystallised from EtOH, filtered and dried under reduced pressure to give 21 mg (4% yield) of the title product. HPLC-MS (ESI) m/z: 378 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.13 (s, 1 H), 13.70 (s, 1 H), 13.34 (s, 1 H), 7.83 (s, 1 H), 7.46 - 7.39 (m, 3H), 7.35 (d, J = 3.6 Hz, 1 H), 7.23 (d, J = 8.1 Hz, 2H), 2.61 (q, J = 7.5 Hz, 2H), 1 .18 (t, J = 7.6 Hz, 3H).

6-(4-(N-(2-fluorophenyl)sulfamoyl)phenyl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 20). The title compound was obtained according to general procedure Gi, step 1 , method (A) using commercially available 3-isopropyl-1 /-/-pyrazol-5- amine (Vh, 0.235 g, 1 .876 mmol), A/-(2-fluorophenyl)-4-formylbenzenesulfonamide (Xlb, 0.641 g, 2.29 mmol) and pyruvic acid (0.13 ml_ g, 1 .876 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.237 g (28% yield) of the title product. HPLC-MS (ESI) m/z: 454.1 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 10.27 (br s, 1 H), 8.33 (d, J = 8.5 Hz, 2H), 8.02 (s, 1 H), 7.86 (d, J = 8.5 Hz, 2H), 7.32 - 7.07 (m, 4H), 3.73 (sep, J = 6.8 Hz, 1 H), 1 .30 (d, J = 6.8 Hz, 6H).

Ethyl-3-bromo-6-(4-(methoxycarbonyl)phenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylate (l^(l)a-i). The title compound was obtained according to general procedure Gi, step 1 , method (B) using the commercially available 5-bromo-1 H-pyrazol-3-amine (Vi, 868 mg, 5.36 mmol), methyl-4-formylbenzoate (XXb, 880 mg, 5.36 mmol)) and ethyl- pyruvate (0.595 mL, 5.36 mmol). The crude was purified by flash chromatography (0-60% EtOAc//-Hex) to give 532 mg (22% yield) of the title product. HPLC-MS (ESI) m/z: 404/406 [M-H]⁺.¹H-NMR (400 MHz, DMSO -de) d: 14.20 (s, 1 H), 10.60 (s, 1 H), 8.37 - 8.30 (m, 2H), 8.29 - 8.17 (m, 2H), 8.00 (s, 1 H), 7.90 - 7.83 (m, 2H), 7.48 (ddd, J = 8.3, 2.7, 1.5 Hz, 1 H), 7.39 - 7.32 (m, 2H), 7.36 - 7.20 (m, 3H), 3.87 (q, J = 7.1 Hz, 2H), 2.62 (q, J = 7.5 Hz, 2H), 1 .16 (t, J = 7.6 Hz, 3H), 0.68 (t, J = 7.1 Hz, 3H). Ethyl-6-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

(l^(l)bi_A) and ethyl-4-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-6- carboxylate (I^(l)b-|_B). The title compounds were obtained according to general procedure Gi, step 1 , method (B) using the commercially available 1 /-/-pyrazo I -3-amine (Vj, 158 mg, 1 .90 mmol), methyl-4-formylbenzoate (XXb, 312 mg, 1 .90 mmol) and ethyl-pyruvate (21 1 pL, 1 .90 mmol). The crude product was filtered and washed with EtOH (2 x 2 ml_) to give 200 mg (32.3% yield) of 1 : 1 mixture of isomers. HPLC-MS (ESI) m/z: 326.2 [M-H]⁺.

Ethyl-6-(5-bromopyridin-2-yl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)ci). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 /-/-pyrazol-5-amine (Va, 5.03 g, 26.9 mmol), 5-bromopicolinaldehyde (XXc, 5.00 g, 26.9 mmol) and ethyl-pyruvate (3.12 g, 26.9 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 3.70 g (30% yield) of the title product. HPLC-MS (ESI) m/z: 450.8/452.8 [M-H]⁺.

Ethyl-3-( 4-ethylphenyl)-6-(4-(methoxycarbonyl)phenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylate (l^(l)di). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 250 mg, 1.34 mmol), methyl-4-formylbenzoate (XXb, 219 mg, 1 .34 mmol) and ethyl-pyruvate (0.148 mL, 1 .34 mmol). The crude (160 mg, 26% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 430 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)e-i). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 201 mg, 1 .07 mmol), 4-formyl-/V-(pyridin-3-yl)benzenesulfonamide (Xln, 281 mg, 1.07 mmol) and ethyl-pyruvate (0.1 19 mL, 1 .07 mmol). The crude was recystallised from water/EtOH to give 66 mg (12% yield) of the title product. HPLC-MS (ESI) m/z: 528 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 14.20 (s, 1 H), 10.60 (s, 1 H), 8.37 - 8.30 (m, 2H), 8.29 - 8.17 (m, 2H), 8.00 (s, 1 H), 7.90 - 7.83 (m, 2H), 7.48 (ddd, J = 8.3, 2.7, 1.5 Hz, 1 H), 7.39 - 7.32 (m, 2H), 7.36 - 7.20 (m, 3H), 3.87 (q, J = 7.1 Hz, 2H), 2.62 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H), 0.68 (t, J = 7.1 Hz, 3H).

Ethyl-3-cyclohexyl-6-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)f-i). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-cyclohexyl-1 H-pyrazol-5-amine (Vb, 0.435 g, 2.63 mmol), methyl-4-formylbenzoate (XXb, 0.432 g, 2.63 mmol) and ethyl-pyruvate (0.293 mL, 2.63 mmol). The crude was collected by filtration and washed with ice cold EtOH (3 x 2 mL) to give 233 mg (21 % yield) of the title product. HPLC-MS (ESI) m/z: 408 [M-H]⁺. ¹H-NMR (400 MHz, DMSO-d6) d: 13.77 (s, 1 H), 8.38 - 8.29 (m, 2H), 8.17 - 8.00 (m, 3H), 4.49 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.27 (tt, J = 1 1 .5, 3.2 Hz, 1 H), 1 .96 (d, J = 12.1 Hz, 2H), 1 .83 (d, J = 12.7 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1 H), 1 .56 (qd, J = 12.4, 3.0 Hz, 2H), 1.46 - 1 .20 (m, 6H). Ethyl-3-(4-ethylphenyl)-6-(5-(methoxycarbonyl)pyridin-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (I^(I)9IA) and ethyl-3-(4-ethylphenyl)-4-(5-

(methoxycarbonyl)pyridin-2-yl)-1H-pyrazolo[3, 4-b]pyridine-6-carboxylate (l^(l)gi _B)The title compounds were obtained according to general procedure G-i, step 1 , method (B) using 3-(4-ethylphenyl)-1 /-/-pyrazol-5-amine (Va, 374 mg, 2.00 mmol), methyl-6- formylnicotinate (XXd, 330 mg, 2.00 mmol) and ethyl-pyruvate (0.22 ml_, 2.00 mmol). The crude was purified by reverse phase chromatography (Cis, 25-100% AcN/0.1 % formic acid in water) to give 58 mg (7% yield) of l^(l)gi_A and 142 mg (16% yield) of l^(l)gi_B.

l^(l)g_1A: HPLC-MS (ESI) m/z: 431.5 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.38 (s, 1 H), 9.24 (dd, J = 2.2, 0.9 Hz, 1 H), 8.63 (dd, J = 8.3, 0.9 Hz, 1 H), 8.56 (s, 1 H), 8.53 (dd, J = 8.3, 2.2 Hz, 1 H), 7.47 - 7.41 (m, 2H), 7.39 - 7.33 (m, 2H), 4.01 - 3.93 (m, 5H), 2.70 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 0.77 (t, J = 7.1 Hz, 3H).

l^(l)g_1B: HPLC-MS (ESI) m/z: 431 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.44 (s, 1 H), 8.86 (d, J = 1.9 Hz, 1 H), 8.05 (s, 1 H), 8.04 (dd, J = 8.2, 2.1 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 6.95 (d, J = 1.4 Hz, 4H), 4.44 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 2.55 (m, 2H), 1.79 - 1.35 (m, 3H), 1.12 (t, J = 7.6 Hz, 3H).

Ethyl-6-(4-(N-(4-cyano-2-fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)hi). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 /-/-pyrazol-5-amine (Va, 0.439 g, 2.346 mmol), A/-(4-cyano-2-fluorophenyl)-4-formylbenzenesulfonamide (Xlf, 0.714 g, 2.346 mmol) and ethyl-pyruvate (0.272 g, 2.346 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.613 g (46% yield) of the title product. HPLC-MS (ESI) m/z: 570.2 [M-H]⁺.

Ethyl-6-(4-(N-(5-cyano-2-fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)ii). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.439 g, 2.346 mmol), A/-(5-cyano-2-fluorophenyl)-4-formylbenzenesulfonamide (Xlo, 0.714 g, 2.346 mmol) and ethyl-pyruvate (0.272 g, 2.346 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.387 g (44% yield) of the title product. HPLC-MS (ESI) m/z: 570.2 [M-H]⁺.

Ethyl-3-( 4-ethylphenyl)-6-(4-(N-( 3-fluorophenyl)sulfamoyl)phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(l)ji). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 230 mg, 1.23 mmol), A/-(3-fluorophenyl)-4-formylbenzenesulfonamide (Xlp, 343 mg, 1.23 mmol) and ethyl-pyruvate (0.14 mL, 1.23 mmol.) The crude was recystallised from /- Hexs/EtOAc to give 66 mg (10% yield) of the title product. HPLC-MS (ESI) m/z: 545 [M- H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(4-(N-(4-methoxyphenyl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)ki). The title compound was obtained according to general procedure G-i, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 186 mg, 0.992 mmol), 4-formyl-/V-(4-methoxyphenyl)benzenesulfonamide (Xlq, 295 mg, 0.992 mmol) and ethyl-pyruvate (0.1 10 ml, 0.992 mmol). The crude was purified by flash chromatography (DCM/EtOAc 0-100%) to give 56.4 mg (10% yield) of the crude product. HPLC-MS (ESI) m/z: 557 [M-H]⁺.¹ H-NMR (400 MHz, DMSO -de) d: 14.26 (s, 1 H), 10.02 (s, 1 H), 8.44 - 8.30 (m, 2H), 8.07 (s, 1 H), 7.92 - 7.79 (m, 2H), 7.45 - 7.38 (m, 2H), 7.38 - 7.31 (m, 2H), 7.07 - 6.96 (m, 2H), 6.88 - 6.76 (m, 2H), 3.95 (q, J = 7.1 Hz, 2H), 3.67 (s, 3H), 2.69 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H).

Ethyl-3-( 4-ethylphenyl)-6-(4-(N-( 4-fluorophenyl)sulfamoyl)phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(l)li). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 168 mg, 0.895 mmol), N-(4-fluorophenyl)-4-formylbenzenesulfonamide (Xlr, 250 mg, 0.895 mmol) and ethyl-pyruvate (0.099 ml, 0.90 mmol). The crude was purified by flash chromatography (DCM/EtOAc 0-50%) to give 1 16 mg (23% yield) of the title product. HPLC-MS (ESI) m/z: 545 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.27 (s, 1 H), 10.34 (s, 1 H), 8.44 - 8.33 (m, 2H), 8.07 (s, 1 H), 7.93 - 7.79 (m, 2H), 7.46 - 7.28 (m, 4H), 7.20 - 7.05 (m, 4H), 3.94 (q, J = 7.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H).

Ethyl-3-(4-ethylphenyl)-6-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)mi). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 57.1 mg, 0.305 mmol), 4-formyl-/V-(pyridin-2-yl)benzenesulfonamide (Xls, 80 mg, 0.31 mmol) and ethyl-pyruvate (0.034 ml, 0.31 mmol). The crude was purified by recrystallisation (EtOH/water) to give 21 mg (13% yield) of the title product. HPLC-MS (ESI) m/z: 528 [M- H]⁺.

Ethyl-3-( 4-ethylphenyl)-6-(4-(N-phenylsulfamoyl)phenyl)- 1 H-pyrazolo[3, 4-b ]pyridine- 4-carboxylate (l^(l)n₁). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 215 mg, 1 .15 mmol), 4-formyl-/V-phenylbenzenesulfonamide (Xlt, 300 mg, 1 .15 mmol) and ethyl- pyruvate (0.128 mL, 1 .15 mmol). The crude was recrystallised from EtOAc//-Hex to give 91 mg (15% yield) of the title product. HPLC-MS (ESI) m/z: 527 [M-H]⁺.

6-(4-(N-(4-cyano-1 -cyclopentyl-1 H-pyrazol-3-yl)sulfamoyl)phenyl)-3-(4-ethylphenyl)~ 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (l^(l)Oi). The title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H- pyrazol-5-amine (Va, 0.460 g, 2.46 mmol), A/-(4-cyano-1 -cyclopentyl-1 /-/-pyrazol-3-yl)-4- formylbenzenesulfonamide (Xlu, 0.846 g, 2.46 mmol), and pyruvic acid (173 pL, 2.457 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.201 g (14% yield) of the title product. HPLC-MS (ESI) m/z: 582.2 [M-H]⁺. Ethyl-3-(4-ethylphenyl)-6-(5-(N-(pyridin-3-yl)sulfamoyl)pyridin-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)pi). The title compound was obtained according to general procedure G-i, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.079 g, 0.422 mmol), 6-formyl-/V-(pyridin-3-yl)pyridine-3-sulfonamide (XVId, 0.1 1 1 g, 0.422 mmol) and ethyl-pyruvate (47 pL, 0.422 mmol). The crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 0.027 g (12% yield) of the title product. HPLC-MS (ESI) m/z: 527.1 [M-H]\

Ethyl-3-(4-ethylphenyl)-6-(4-(methoxycarbonyl)-1H-pyrrol-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)qi). The title compound was obtained according to general procedure G-i, step 1 , method (B) using 3-(4-ethylphenyl)-1 /-/-pyrazol-5-amine (Va, 193 mg, 1 .03 mmol), methyl-5-formyl-1 H-pyrrole-3-carboxylate (XIX, 157 mg, 1 .03 mmol) and ethyl-pyruvate (1 10 pl_, 1 .00 mmol). The crude was collected by filtration and washed with EtOH (2 x 1 ml_) to give 1 10 mg (26% yield) of the title product. HPLC-MS (ESI) m/z: 419 [M-H]⁺.

Ethyl-3-( 4-ethylphenyl)-6-(3-fluoro-4-(methoxycarbonyl)phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylate (I^(|)h). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 200 mg, 1 .07 mmol), methyl-2-fluoro-4-formylbenzoate (XXe, 195 mg, 1 .07 mmol) and ethyl- pyruvate (0.12 mL, 1 .1 mmol). The crude was recrystallised from water/EtOH to give 67 mg (14% yield) of the title product. HPLC-MS (ESI) m/z: 448 [M-H]⁺.¹H-NMR (400 MHz, DMSO -de) d: 14.31 (s, 1 H), 8.26 - 8.14 (m, 3H), 8.08 (t, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 4.01 - 3.88 (m, 5H), 2.70 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H), 0.77 (t, J = 7.1 Hz, 3H).

Ethyl-3-( 4-ethylphenyl)-6-(2-fluoro-4-(methoxycarbonyl)phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(l)si). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 200 mg, 1 .07 mmol), methyl-3-fluoro-4-formylbenzoate (XXf, 195 mg, 1 .07 mmol) and ethyl- pyruvate (120 mI, 1 .08 mmol). The crude was purified by flash chromatography (0-50% EtOAc//-Hex) to give 76 mg (16% yield) of the title product. HPLC-MS (ESI) m/z: 448 [M- H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.36 (s, 1 H), 8.19 (t, J = 7.9 Hz, 1 H), 7.99 (dd, J = 8.1 , 1 .6 Hz, 1 H), 7.93 - 7.86 (m, 2H), 7.47 - 7.41 (m, 2H), 7.38 - 7.33 (m, 2H), 3.99 - 3.90 (m, 5H), 2.70 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 0.74 (t, J = 7.1 Hz, 3H).

Ethyl-5-( 4-(ethoxycarbonyl)-3-(4-ethylphenyl)~ 1 H-pyrazolo[3, 4-b ]pyridin-6- yl)isoxazole-3-carboxylate (l^(l)ti). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.21 g, 1 .1 mmol), ethyl-5-formylisoxazole-3-carboxylate (XXg, 0.186 g, 1 .10 mmol) and ethyl- pyruvate (0.122 mL, 1 .10 mmol). The crude was purified by preparative HPLC (50-20%, 0.1 % formic acid in water/AcN) to give 34 mg (6% yield) of the title product. HPLC-MS (ESI) m/z: 435 [M-H]⁺. Ethyl-3-(4-ethylphenyl)-6-(4-(2-methoxy-2-oxoethyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)ui). The title compound was obtained according to general procedure G-i, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 200 mg, 1.07 mmol), methyl-2-(4-formylphenyl)acetate (XXh, 190 mg, 1 .07 mmol) and ethyl- pyruvate (0.1 19 ml_, 1 .07 mmol). The crude was recrystallised from EtOAc//-Hex to give 94 mg (20% yield) of the title product. HPLC-MS (ESI) m/z: 444 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(5-(methoxycarbonyl)thiophen-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)vi). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 1 17 mg, 0.625 mmol), methyl-5-formylthiophene-2-carboxylate (XXi, 106 mg, 0.625 mmol) and ethyl-pyruvate (0.069 ml_, 0.63 mmol). The crude was purified by chromatography (0-50% EtOAc//-Hex) and then recrystallised from EtOH/water to give 22 mg (8% yield) of the title product. HPLC-MS (ESI) m/z: 436 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(4-hydroxy-3-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)wi). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 300 mg, 1.60 mmol), 4-hydroxy-3-nitrobenzaldehyde (XXj, 268 mg, 1 .60 mmol) and ethyl-pyruvate (0.178 mL, 1 .60 mmol). The crude was purified by flash chromatography (0-100% EtOAc//-Hex) to give 229 mg (32% yield) of the title prosuct. HPLC-MS (ESI) m/z: 433 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.17 (s, 1 H), 1 1 .53 (s, 1 H), 8.78 (d, J = 2.3 Hz, 1 H), 8.43 (dd, J = 8.8, 2.3 Hz, 1 H), 8.05 (s, 1 H), 7.45 - 7.39 (m, 2H), 7.38 - 7.32 (m, 2H), 7.29 (d, J = 8.8 Hz, 1 H), 3.94 (q, J = 7.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H).

Ethyl-6-( 3-chloro-4-hydroxy-5-methoxyphenyl)-3-( 4-ethyl phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(l)xi). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 200 mg, 1.07 mmol), 3-chloro-4-hydroxy-5-methoxybenzaldehyde (XXk, 199 mg, 1 .07 mmol) and ethyl-pyruvate (120 pL, 1.08 mmol). The crude was purified by flash chromatography (0-50% EtOAc//-Hex) and by a further recrystallisation from DCM with /-Hex to give 55.5 mg (1 1 % yield) of the title product. HPLC-MS (ESI) m/z: 452/454 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -<*) d: 14.08 (s, 1 H), 9.96 (s, 1 H), 8.05 (s, 1 H), 7.89 (d, J = 2.1 Hz, 1 H), 7.78 (d, J = 2.1 Hz, 1 H), 7.44 - 7.40 (m, 2H), 7.37 - 7.32 (m, 2H), 3.98 (s, 3H), 3.94 (q, J = 7.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H).

Ethyl-6-(2,5-difluoro-4-hydroxyphenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine- 4-carboxylate (l^(l)yi)· The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 200 mg, 1 .07 mmol), 2,5-difluoro-4- hydroxybenzaldehyde (XXI, 169 mg, 1 .07 mmol) and ethyl- pyruvate (120 pL, 1 .08 mmol). The crude was purified by flash chromatography (0-50% EtOAc/i-Hex) to give 36 mg (8% yield) of the title product. HPLC-MS (ESI) m/z: 424 [M- H]⁺. ¹H-NMR (400 MHz, DMSO-de) d: 14.21 (s, 1 H), 1 1 .01 (s, 1 H), 7.85 (dd , J = 12.0, 7.4 Hz, 1 H), 7.81 (d, J = 1 .4 Hz, 1 H), 7.44 - 7.39 (m, 2H), 7.37 - 7.32 (m, 2H), 6.95 (dd, J = 12.5, 7.3 Hz, 1 H), 3.92 (q, J = 7.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H), 0.71 (t, J = 7.1 Hz, 3H).

Ethyl-3-( 4-ethylphenyl)-6-(3-(methoxycarbonyl)phenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylate (l^(l)zi). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 200 mg, 0.961 mmol), methyl-3-formylbenzoate (XXm, 175 mg, 1 .07 mmol) and ethyl-pyruvate (120 pi, 1 .08 mmol). The crude was purified by flash chromatography (0-50% EtOAc/i-Hex) to give 125 mg (29% yield) of the title product. HPLC-MS (ESI) m/z: 430 [M-H]⁺.¹H-NMR (400 MHz, DMSO -de) d: 14.26 (s, 1 H), 8.85 (app. t, J = 1 .8 Hz, 1 H), 8.52 (ddd, J = 7.9, 1 .9, 1 .1 Hz, 1 H), 8.1 1 (ddd, J = 7.7, 1 .7, 1 .1 Hz, 1 H), 8.10 (s, 1 H), 7.73 (app. t, J = 7.9 Hz, 1 H), 7.46 - 7.40 (m, 2H), 7.39 - 7.32 (m, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 2.70 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H).

Ethyl-3-(4-ethylphenyl)-6-(4-(methoxycarbonyl)thiophen-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)a₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 86 mg, 0.46 mmol), methyl-5-formylthiophene-3-carboxylate (XXn, 78 mg, 0.46 mmol) and ethyl-pyruvate (51 .0 mI, 0.459 mmol). The crude was purified by flash chromatography (0- 40% EtOAc//-Hex) to give 40 mg (19% yield) of the title product. HPLC-MS (ESI) m/z: 436.2 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.19 (s, 1 H), 8.52 (d, J = 1 .3 Hz, 1 H), 8.40 (d, J = 1 .3 Hz, 1 H), 8.17 (s, 1 H), 7.44 - 7.39 (m, 2H), 7.37 - 7.32 (m, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.69 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H), 0.80 (t, J = 7.1 Hz, 3H).

6-( 5-( Ethoxycarbonyl)- 1 H-pyrrol-2-yl)-3-( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylate (l^(l)b₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 495 mg, 2.64 mmol), ethyl-5-formyl-1 /-/-pyrrole-2-carboxylate (XXo, 500 mg, 2.99 mmol) and ethyl-pyruvate (268 mg, 3.04 mmol). The crude was purified by flash chromatography (0-100 % EtOAc //- hex) to give 155 mg (15% yield) of the title product. HPLC-MS (ESI) m/z: 405 [M-H]⁺.

Ethyl-6-(3,5-difluoro-4-hydroxyphenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine- 4-carboxylate (l^(l)c₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 300 mg, 1 .60 mmol), 3,5-difluoro-4-hydroxybenzaldehyde (XXp, 253 mg, 1 .60 mmol) and ethyl- pyruvate (180 pL, 1.62 mmol). The crude was purified by reverse phase chromatography (C-18, 15-80%, 1 % formic acid in water/1 % formic acid in AcN) to give 202 mg (29% yield) of the title product. HPLC-MS (ESI) m/z: 424 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.13 (s, 1 H), 10.84 (s, 1 H), 8.03 (s, 1 H), 8.01 - 7.91 (m, 2H), 7.45 - 7.38 (m, 2H), 7.37 - 7.32 (m, 2H), 3.94 (q, J = 7.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H).

Ethyl-2-(4-(ethoxycarbonyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)thiazole- 4-carboxylate (l^(l)d₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 200 mg, 1 .07 mmol), ethyl-2-formylthiazole-4-carboxylate (XXq, 198 mg, 1 .07 mmol) and ethyl- pyruvate (120 pi, 1 .08 mmol). The crude was washed with EtOH and /-Hex to give 68 mg (14% yield) of the title product. HPLC-MS (ESI) m/z: 451 [M-H]⁺. ¹H-NMR (400 MHz, DMSO-de) d: 14.56 (s, 1 H), 8.65 (s, 1 H), 8.09 (s, 1 H), 7.12 - 7.08 (m, 2H), 7.08 - 7.05 (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 2.58 (q, J = 7.6 Hz, 2H), 1 .41 (t, J = 7.1 Hz, 3H), 1 .27 (t, J = 7.1 Hz, 3H), 1 .16 (t, J = 7.6 Hz, 3H).

Ethyl-6-(2,3-difluoro-4-hydroxyphenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine- 4-carboxylate (l^(l)e₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 200 mg, 1 .07 mmol), 2,3-difluoro-4-hydroxybenzaldehyde (XXr, 169 mg, 1 .07 mmol) and ethyl- pyruvate (120 mI_, 1 .08 mmol). The crude was purified by flash chromatography (0-50% EtOAc/i-Hex) to give 88 mg (18% yield) of the title product. HPLC-MS (ESI) m/z: 424 [M- H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.22 (s, 1 H), 10.97 (s, 1 H), 7.78 (d, J = 1 .7 Hz, 1 H), 7.70 (td, J = 8.7, 2.2 Hz, 1 H), 7.45 - 7.40 (m, 2H), 7.37 - 7.32 (m, 2H), 7.02 - 6.95 (m, 1 H), 3.93 (q, J = 7.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H), 0.72 (t, J = 7.1 Hz, 3H).

Ethyl-6-( 3-chloro-5-fluoro-4-hydroxyphenyl)-3-( 4-ethyl phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(l)f₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 200 mg, 1 .07 mmol), 3-chloro-5-fluoro-4-hydroxybenzaldehyde (XXs, 186 mg, 1 .07 mmol) and ethyl-pyruvate (0.1 19 ml, 1 .07 mmol). The crude was purified by flash chromatography (0-50% EtOAc//-Hex) and then recrystallised from EtOH/water to give 104 mg (22% yield) of the title product. HPLC-MS (ESI) m/z: 440/442 [M-H]⁺.

Ethyl-3-( 4-ethylphenyl)-6-(4-(N-methylsulfamoyl)phenyl)- 1 H-pyrazolo[3, 4-b ]pyridine- 4-carboxylate (l^(l)g₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 235 mg, 1 .26 mmol), 4-formyl-/V-methylbenzenesulfonamide (XXt, 250 mg, 1 .26 mmol) and ethyl- pyruvate (0.139 mL, 1 .26 mmol). The crude was recrystallised from EtOH/water (10 mL) to give 141 mg (24% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.

Ethyl-3-(4-ethylphenyl)-6-(4-sulfamoylphenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)h₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 255 mg, 1 .36 mmol), 4-formylbenzenesulfonamide (XXu, 250 mg, 1 .35 mmol) and ethyl-pyruvate (158 mg, 1 .36 mmol). The crude was purified by flash chromatography (0-50% EtOAc//-hex) to give 17 mg (3% yield) of the title product. HPLC-MS (ESI) m/z: 451 [M-H]⁺.

Ethyl-6-(3-(ethoxycarbonyl)-1H-pyrazol-5-yl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)i ). The title compound was obtained according to general procedure G-i, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 255 mg, 1 .36 mmol), ethyl-5-formyl-1 /-/-pyrazole-2-carboxylate (XXv, 250 mg, 1 .49 mmol) and ethyl-pyruvate (158 mg, 1.36 mmol). The crude was purified by flash chromatography (0- 50% EtOAc//-hex) to give 47 mg (8% yield) of the title product. HPLC-MS (ESI) m/z: 434 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(6-oxo-1 ,6-dihydropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine- 4-carboxylate (l^(l)j₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 300 mg, 1.60 mmol), 6-OXO-1 ,6-dihydropyridine-3-carbaldehyde (XXw, 197 mg, 1.60 mmol) and ethyl-pyruvate (0.18 mL, 1 .6 mmol). The crude was washed with EtOH (10 mL) to give 143 mg (23% yield) of the title product. HPLC-MS (ESI) m/z: 389 [M-H]⁺. ¹H-NMR (400 MHz, DMSO- de) d: 14.02 (s, 1 H), 12.10 (s, 1 H), 8.39 - 8.29 (m, 2H), 7.91 (s, 1 H), 7.44 - 7.37 (m, 2H),

7.37 - 7.29 (m, 2H), 6.51 (dd, J = 9.5, 0.8 Hz, 1 H), 3.92 (q, J = 7.1 Hz, 2H), 2.68 (q, J = 7.6 Hz, 2H), 1 .23 (t, J = 7.6 Hz, 3H), 0.75 (t, J = 7.1 Hz, 3H).

Ethyl-6-(5-chloropyridin-2-yl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)k₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 /-/-pyrazol-5-amine (Va, 300 mg, 1 .602 mmol), 5-chloropicolinaldehyde (XXx, 227 mg, 1 .602 mmol) and ethyl-pyruvate (0.178 mL, 1 .602 mmol). The crude was purified by flash chromatography on silica gel (0-50% EtOAc/DCM) and then recrystallised from a mixture of water/EtOH to give 180 mg (26% yield) of the title product. HPLC-MS (ESI) m/z: 407.2 [M-H]⁺. ¹H-NMR (500 MHz, DMSO- de) d: 14.30 (s, 1 H), 8.81 (d, J = 2.5 Hz, 1 H), 8.52 - 8.44 (m, 2H), 8.17 (dd, J = 8.6, 2.6 Hz, 1 H), 7.47 - 7.39 (m, 2H), 7.37 - 7.30 (m, 2H), 3.96 (q, J = 7.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1 .23 (t, J = 7.6 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H.

Ethyl-3-( 4-ethylphenyl)-6-(5-fluoropyridin-2-yl)~ 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylate (l^(l)l₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 285 mg, 1 .522 mmol), 5-fluoropicolinaldehyde (XXy, 190 mg, 1 .522 mmol) and ethyl-pyruvate (170 pi, 1 .522 mmol). The crude was purified by reverse phase chromatography (Cis, 15-75% AcN/0.1 % formic acid in water) to give 42 mg (7% yield) of the title product. HPLC-MS (ESI) m/z: 391 .4 [M-H]⁺. ¹H-NMR (500 MHz, cDcls) d: 8.62 (d, J = 3.0 Hz, 1 H), 8.59 (s, 1 H), 8.53 - 8.49 (m, 1 H), 7.58 (ddd, J = 8.7, 8.0, 2.9 Hz, 1 H), 7.53 - 7.50 (m, 2H), 7.33 - 7.30 (m, 2H), 3.99 (q, J = 7.2 Hz, 2H), 2.73 (q, J = 7.6 Hz, 2H), 1 .29 (t, J = 7.6 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H). Ethyl-3-(4-ethylphenyl)-6-(5-fluoropyrimidin-2-yl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)m₂). The title compound was obtained according to general procedure G-i, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 386 mg, 2.1 mmol), 5-fluoropyrimidine-2-carbaldehyde (XXz, 433 mg, 2.1 mmol), and pyruvic acid (0.2 ml_, 2.1 mmol). The product was recrystallised in a mixture of water/EtOH (1 :60) and then filtered hot to afford a white solid. The filtrate was then allowed to cool to rt and cooled to 0 °C for 15 min. The white solid was finally filtered, washed with EtOH and dried, to give 95 mg (1 1 % yield) of the title product. HPLC-MS (ESI) m/z: 392.1 [M-H]⁺. ¹H-NMR (500 MHz, cDcls) d: 14.40 (s, 1 H), 9.13 (s, 2H), 8.48 (s, 1 H), 7.45 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 3.97 (q, J = 7.1 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H), 0.77 (t, J = 7.1 Hz, 3H).

Ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)n₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(pyridin-4-yl)-1 H-pyrazol-5-amine (Vc, 1 .29 g, 8.05 mmol), methyl-4-formylbenzoate (XXb, 1 .32 g, 8.05 mmol) and ethyl-pyruvate (0.895 ml_, 8.05 mmol). The residue was slurried in EtOH (30 ml_), filtered and dried under reduced pressure to give 843 mg (23% yield). HPLC-MS (ESI) m/z: 403 [M-H]⁺.

Ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)o₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(pyridin-2-yl)-1 H-pyrazol-5-amine (Vd, 481 mg, 3.00 mmol), methyl-4-formylbenzoate (XXb, 492 mg, 3.00 mmol) and ethyl-pyruvate (0.333 mL, 3.00 mmol). The crude was purified by recrystallisation from EtOH/water to give 189 mg (15% yield) of the title product. HPLC-MS (ESI) m/z: 403 [M-H]⁺. ¹H-NMR (400 MHz, DMSO- de) d: 14.42 (s, 1 H), 8.65 (ddd, J = 4.9, 1 .8, 1 .0 Hz, 1 H), 8.49 - 8.36 (m, 2H), 8.20 - 8.12 (m, 2H), 8.12 - 8.02 (m, 2H), 7.97 (td, J = 7.7, 1.8 Hz, 1 H), 7.44 (ddd, J = 7.5, 4.9, 1.2 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H).

Ethyl-3-benzyl-6-( 4-(methoxycarbonyl) phenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylate (l^(l)p₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-benzyl-1 H-pyrazol-5-amine (Ve, 260 mg, 1 .50 mmol), methyl- 4-formylbenzoate (XXb, 246 mg, 1 .50 mmol) and ethyl-pyruvate (0.167 mL, 1 .50 mmol). The crude was recrystallised from EtOH/water to give 95 mg (15% yield) of the title product. HPLC-MS (ESI) m/z: 416 [M-H]⁺. ¹H-NMR (400 MHz, DMSO-d6) d: 13.98 (s, 1 H), 8.38 - 8.28 (m, 2H), 8.17 - 8.10 (m, 2H), 8.08 (s, 1 H), 7.29 - 7.21 (m, 2H), 7.20 - 7.13 (m, 1 H), 7.13 - 7.07 (m, 2H), 4.47 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1 .24 (t, J = 7.1 Hz, 3H).

Ethyl-6-(4-(methoxycarbonyl)phenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)q₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using the commercially available 5-phenyl-1 H-pyrazol-3-amine (Vk, 510 mg, 3.20 mmol), methyl-4-formylbenzoate (XXb, 526 mg, 3.20 mmol) and ethyl- pyruvate (356 mI, 3.20 mmol). The crude was slurried in refluxing EtOH (15 ml_) for 10 min and then filtered and washed with EtOH (10 ml_) to give 0.34 g (26% yield) of the title product. HPLC-MS (ESI) m/z: 402 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 14.33 (s, 1 H), 8.43 - 8.37 (m, 2H), 8.19 - 8.1 1 (m, 3H), 7.56 - 7.45 (m, 5H), 3.95 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 0.78 (t, J = 7.1 Hz, 3H).

3-lsopropyl-6-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)r₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using the commercially available 5-isopropyl-1 H-pyrazol-3-amine (VI, 325 mg, 2.60 mmol), methyl-4-formylbenzoate (XXb, 427 mg, 2.60 mmol) and ethyl-pyruvate (0.291 ml_, 2.60 mmol). The crude was recrystallised from water/I PA to give 109 mg (12% yield) of the title product. HPLC-MS (ESI) m/z: 340 [M-H]⁺. ¹H-NMR (400 MHz, DMSO- d6) d: 14 (s, 1 H), 13.72 (s, 1 H), 8.38 - 8.30 (m, 2H), 8.16 - 8.04 (m, 3H), 3.90 (s, 3H), 3.74 (h, J = 6.8 Hz, 1 H), 1 .24 (t, J = 7.6 Hz, 3H), 1 .32 (d, J = 6.8 Hz, 6H).

6-( 4-( Methoxycarbonyl)phenyl)-3-methyl- 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid (l^(l)s₂). The title compound was obtained according to general procedure Gi, step 1 , method (B) using the commercially available 5-methyl-1 H-pyrazol-3-amine (Vm, 253 mg, 2.60 mmol), methyl-4-formylbenzoate (XXb, 427 mg, 2.60 mmol) and ethyl-pyruvate (0.291 mL, 2.60 mmol). The crude was recrystallised from EtOH/water to give 58 mg (7% yield) of the title product. HPLC-MS (ESI) m/z: 312 [M-H]⁺.

Ethyl- 1-( 4-ethyl phenyl)-6-(4-(methoxycarbonyl) phenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylate (l^(l)t_2A) and ethyl-1 -(4-ethylphenyl)-4-(4-(methoxycarbonyl)phenyl)-1H- pyrazolo[3,4-b]pyridine-6-carboxylate (l^(l)t_2B). The title compounds were obtained according to general procedure Gi, step 1 , method (B) using 1 -(4-ethylphenyl)-1 /-/- pyrazol-5-amine (V^(l)a, 306 mg, 1 .63 mmol), methyl-4-formylbenzoate (XXb, 268 mg, 1 .63 mmol) and ethyl-pyruvate (180 pL, 1 .62 mmol). The crude was purified by reverse phase chromatography (Cis, 25-100%, 0.1 % formic acid in AcN /0.1 % formic acid in water) to give 57 mg (8% yield) of l^(l)t_2A and 61 mg (8% yield) of l^(l)t_2B.

l^(l)t_2A: HPLC-MS (ESI) m/z: 430.3 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 8.74 (s, 1 H), 8.22 - 8.18 (m, 2H), 8.18 - 8.14 (m, 2H), 8.13 (s, 1 H), 8.12 - 8.08 (m, 2H), 7.48 - 7.44 (m, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 2.71 (q, J = 7.6 Hz, 2H), 1 .40 (t, J = 7.1 Hz, 3H), 1 .26 (t, J = 7.6 Hz, 3H).

l^(l)t_2B: HPLC-MS (ESI) m/z: 430.3 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 8.57 (s, 1 H), 8.31 - 8.27 (m, 1 H), 8.27 (s, 1 H), 8.12 - 8.07 (m, 1 H), 8.07 - 8.03 (m, 1 H), 7.42 - 7.35 (m, 1 H), 4.45 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 1 .40 (t, J = 7.1 Hz, 3H), 1 .19 (t, J = 7.6 Hz, 3H).

Ethyl-1 -(tert-butyl)-3-cyclopropyl-6-(5-(methoxycarbonyl)pyridin-2-yl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)u₂). The title compound was obtained according to general procedure Gi , step 1 , method (B) using 1 -(tert-butyl)-3-cyclopropyl-1 H-pyrazol- 5-amine (Vg, 588 mg, 3.3 mmol), methyl-6-formylnicotinate (XXd, 596 mg, 3.6 mmol) and ethyl-pyruvate (0.4 mL, 3.3 mmol). The crude was purified by flash chromatography (0- 50% EtOAc/DCM, DCM loading) to give 184 mg (13% yield) of the title product. HPLC- MS (ESI) m/z: 423.5 [M-H]⁺.

General procedure H-i: Synthesis of compounds with general formula l^(ll)

Step 1

A solution of compound l^(l) (1 eq.), the proper commercially available boronic acid or pinacolic ester (XXI, 1 - 1 .5 eq.) and K2CO3 (1.5 -2.5 eq.) in dioxane/water (4: 1 ) (0.1 M) was evacuated and purged three times with N2. Pd(dppf)Cl2- DCM (0.1 eq.) was added and the tube was evacuated and purged three times with N2. The mixture was heated at 120-140°C for 1 -3 h under MW irradiation then cooled to r.t. , diluted with EtOAc and water (1 : 1 ) and filtered through celite. The phases were separated and the aqueous extracted with EtOAc. The combined organics were washed with water and brine, dried over MgS0₄, filtered and concentrated under reduced pressure. The crude was then purified by flash chromatography to give the intermediate compound with general formula l^(ll).

Ethyl-3-(4-isopropylphenyl)-6-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(ll)a). The title compound was obtained according to general procedure Hi, step 1 , using ethyl-3-bromo-6-(4-(methoxycarbonyl)phenyl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (I¾i, 205 mg, 0.507 mmol), (4- isopropylphenyl)boronic acid (XXIa, 87 mg, 0.53 mmol), K2CO3 (105 mg, 0.761 mmol) and Pd(dppf)Cl2- DCM (41 mg, 0.051 mmol). The crude was purified by flash chromatography (0-100% EtOAc//-Hex) to give 46 mg (20% yield) of the title product. HPLC-MS (ESI) m/z: 444 [M-H]⁺.

Ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(ll)b). The title compound was obtained according to general procedure Hi, step 1 , using ethyl-3-bromo-6-(4-(methoxycarbonyl)phenyl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (I¾i, 250 mg, 0.618 mmol), (4- methoxyphenyl)boronic acid (XXIb, 99 mg, 0.65 mmol), K2CO3 (171 mg, 1.24 mmol) and Pd(dppf)Cl2- DCM (51 mg, 0.062 mmol). The crude was purified by flash chromatography (0-100% EtOAc/i-Hex) to give 34 mg (12% yield) of the title product. HPLC-MS (ESI) m/z: 432 [M-H]⁺.

Ethyl-3-(furan-3-yl)-6-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(ll)c). The title compound was obtained according to general procedure Hi, step 1 , using ethyl-3-bromo-6-(4-(methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine- 4-carboxylate (I¾i, 236 mg, 0.584 mmol), furan-3-ylboronic acid (XXIc, 98 mg, 0.88 mmol), K₂CO₃ (202 mg, 1.46 mmol) and Pd(dppf)Cl₂ DCM (48 mg, 0.058 mmol). The crude was purified by flash chromatography (0-100% /- Hex-EtOAc, 1 % AcOH) to give 94 mg (37% yield) of the title product. HPLC-MS (ESI) m/z: 392 [M-H]⁺.

Ethyl-3-(cyclohex-1-en- 1-yl)-6-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(ll)d). The title compound was obtained according to general procedure Hi, step 1 , using ethyl-3-bromo-6-(4-(methoxycarbonyl)phenyl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (I¾i, 500 mg, 1.24 mmol), 2-(cyclohex-1 -en-1 -yl)- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (XXId, 257 mg, 1.24 mmol), K2CO3 (342 mg, 2.47 mmol) and Pd(dppf)Cl2-DCM (101 mg, 0.124 mmol). The crude was purified by flash chromatography (0-100% /- Hex-EtOAc) to give 32 mg (6% yield) of the title product. HPLC-MS (ESI) m/z: 406 [M-H]⁺.

Ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(ll)e). The title compound was obtained according to general procedure Hi, step 1 , using ethyl-3-bromo-6-(4-(methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine- 4-carboxylate (I¾i, 200 mg, 0.495 mmol), pyridin-3-ylboronic acid (XXIe, 91 mg, 0.74 mmol), K2CO3 (171 mg, 1.24 mmol) and Pd(dppf)Cl2 DCM (40 mg, 0.049 mmol). The crude product was purified by flash chromatography (25-100% EtOAc//-Hex) to give 28 mg (14% yield) of the title product. HPLC-MS (ESI) m/z: 403 [M-H]⁺.

General procedure : Synthesis of compounds with general formula l^(lll)

I""¹: R¹ = COOH, COOMe, COOEt

R³ = R^lv-S0₂NH-Aryl

Step 1

Intermediate l^(l) (1 eq.), 3,4-dihydro- 2/-/-pyran (1.5 eq.) and p-toluenesulfonic acid monohydrate (0.1 eq.) were dissolved in CHC (0.3 M) and the mixture was stirred at r.t. overnight. The solvent was removed under vacuum and the resulting crude was purified by flash chromatography to give the proper intermediate compound having general formula XXII^(I).

Ethyl-6-(5-bromopyridin-2-yl)-3-(4-ethylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(l)a). The title compound was obtained according to general procedure h, step 1 using ethyl-6-(5-bromopyridin-2-yl)-3-(4- ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)ci, 3.70 g, 8.20 mmol), 3,4- dihydro-2/-/-pyran (1.g, 12.30 mmol) and p-toluenesulfonic acid monohydrate (0.156 g, 0.820 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 1 .67 g (38 % yield) of the title product. HPLC-MS (ESI) m/z: 535.1/537.1 [M-H]⁺.

Step 2

To a solution of the proper intermediate XXII^(I) (1 eq.) in dioxane (0.04 M), K2CO3 (2 eq.), A/,/V’-dimethylethane-1 ,2-diamine (0.2 - 1 eq.), Cul (0.1 - 1 eq.) and the proper commercially available sulfonamide XXIII (2 eq.) were added. The mixture was stirred at 1 10 °c for 16 h. Water was added to the reaction and the layers were separated. The aqueous layer was extracted with EtOAc and the organic fractions were dried over Na₂S0₄, filtered and evaporated under vacuum. The resulting crude was purified by flash chromatography to give the intermediate compound having general formula XXII^(II).

Ethyl-3-(4-ethylphenyl)-6-(5-(methylsulfonamido)pyridin-2-yl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(ll)a). The title compound was obtained according to general procedure h, step 2 using ethyl-6-(5-bromopyridin-2-yl)-3- (4-ethylphenyl)-1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(l)a, 0.850 g, 1 .588 mmol), K₂CO₃ (0.439 g, 3.18 mmol), /V,/V’-dimethylethane-1 ,2- diamine (0.140 g, 1 .588 mmol), Cul (0.302 g, 1 .588 mmol) and methanesulfonamide (XXIIIa, 0.302 g, 3.18 mmol). The crude was purified by flash chromatography (S1O₂, DCM/MeOH) to give 0.687 g (79% yield) of the title product. HPLC-MS (ESI) m/z: 550.2 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(5-(pyridine-3-sulfonamido)pyridin-2-yl)-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(ll)b). The title compound was obtained according to general procedure h, step 2 using ethyl-6-(5-bromopyridin-2-yl)-3- (4-ethylphenyl)-1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(l)a, 0.600 g, 1 .12 mmol), K₂CO₃ (0.310 g, 2.24 mmol), /V,/V’-dimethylethane-1 ,2- diamine (0.098 g, 1 .12 mmol), Cul (0.214 g, 0.1 12 mmol) and pyridine-3-sulfonamide (XXIIIb, 0.354 g, 2.24 mmol). The crude was purified by flash chromatography (S1O₂, DCM/MeOH) to give 0.568 g (83% yield) of the title product. HPLC-MS (ESI) m/z: 613.2 [M-H]⁺.

Step 3

To a solution of the proper intermediate XXII^(II) (1 eq.) in 1 ,4-dioxane (0.06 M), HCI solution (4 M in 1 ,4-dioxane, 30 eq.) was added. The mixture was stirred at r.t. for 2-16 h and then the solvent was removed under vacuum. The crude was either used in the next step without further purification or purified by the opportune technique to obtain the intermediate compound having general formula l^(lll).

Ethyl-3-(4-ethylphenyl)-6-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate HCI (l^(lll)a). The title compound was obtained according to general procedure h, step 3 using ethyl-3-(4-ethylphenyl)-6-(5- (methylsulfonamido)pyridin-2-yl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4- b]pyridine-4-carboxylate (XXII^(ll)a, 0.687 g, 1 .25 mmol) and HCI solution (3.12 ml_, 12.5 mmol). The crude was slurried in Et₂0 to give 0.319 g (55% yield) of the title product. HPLC-MS (ESI) m/z: 466.1 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(5-(pyridine-3-sulfonamido)pyridin-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate HCI (l^(lll)b). The title compound was obtained according to general procedure h, step 3 using ethyl-3-(4-ethylphenyl)-6-(5-(pyridine-3- sulfonamido)pyridin-2-yl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (XXII^(ll)b, 0.428 g, 0.699 mmol) and HCI solution (5.24 ml_, 20.96 mmol). The crude (0.369 g, quant yield) was used in the next step without further purification. HPLC- MS (ESI) m/z: 529.1 [M-H]⁺.

General procedure J : Synthesis of compounds with general formula l^(IV)

Step 1

Method (A): To a solution of the proper intermediate compound l^(l· ^Ml) (1 eq.) in DCM/DMF (0.05 M), the proper commercially available boronic acid (XXIV, 3 - 4 eq.), pyridine (12 - 15 eq.) and Cu(OAc)2 (3.5 eq.) were added and the mixture was stirred at 50 °C for 22 h. The mixture was then diluted with EtOAc, washed with water, aqueous sat. NaHCC solution and brine. The organic phase was concentrated under reduced pressure to afford the crude product, which was then purified by the opportune technique to give the intermediate compound having general formula l^(IV).

Method (B): To a solution of the proper intermediate compound l^(l· ^Ml) (1 eq.) in DMF (0.07 M), the proper commercially available boronic acid (XXIV, 1 .5 eq.), pyridine (3 eq.) and CU(OAC)2 (0.3 eq.) were added and the mixture was purged with oxygen and it was heated up to 90 °c for 16 h. Reaction was concentrated under vacuum and water and EtOAc were added. The layers were separated and the organic phase was dried over MgS0₄, filtered and concentrated under vacuum. The crude product was either used in next step without further purification or purified by the opportune technique to give the intermediate compound having general formula l^(IV).

Method (c): To a solution of the proper intermediate compound l^{(l, lll)} (1 eq.) and the proper commercially available boronic acid (XXIV, 4 eq.) in pyridine (0.1 M), Cu(OAc)2 (3.5 eq.) was added and the reaction was stirred at r.t. overnight. The resulting mixture was diluted with DCM, filtered over celite and washed with a saturated solution of NaHCC and brine. The organic phase was then separated, dried over MgSC , filtered and concentrated under vacuum. The crude product was purified by the opportune technique to give the intermediate compound having general formula l^(IV).

Method (D): To a solution of the proper intermediate compound l^(UII) (1 eq.) in AcN (0.12-0.17 M), the proper commercially available halide (XXV, 1 - 2 eq.) and K2CO3 (1.2 eq.) were added and the reaction was stirred at r.t. overnight. The resulting mixture was concentrated under vacuum to afford the crude product, then purified by the opportune technique to give the intermediate compound having general formula l^(IV).

Ethyl-3-bromo- 1 -(4-ethyl phenyl)-6-( 4-(methoxycarbonyl) phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(IV)a). The title compound was obtained according to general procedure Ji, step 1 , method (A) using ethyl-3-bromo-6-(4-(methoxycarbonyl)phenyl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (I¾i, 50 mg, 0.12 mmol), (4-ethylphenyl)boronic acid (XXIVa, 55.7 mg, 0.371 mmol), pyridine (0.150 ml, 1 .86 mmol) and Cu(OAc)2 (79 mg, 0.43 mmol) in DCM. The crude product was purified by flash chromatography (DCM/EtOAc 100:0 to 50:50) to give 43 mg (66% yield) of the title product. HPLC-MS (ESI) m/z: 509.2 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.44 - 8.35 (m, 2H), 8.17 - 8.04 (m, 4H), 7.52 - 7.44 (m, 2H), 4.53 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 2.72 (q, J = 7.6 Hz, 2H), 1 .45 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H).

Ethyl- 1, 3-bis( 4-ethyl phenyl)-6-( 4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(IV)b). The title compound was obtained according to general procedure Ji, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4- (methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)d-i, 50 mg, 0.12 mmol), (4-ethylphenyl)boronic acid (XXIVa, 69.8 mg, 0.466 mmol), pyridine (1 13 pL, 1 .40 mmol) and Cu(OAc)2 (74.0 mg, 0.407 mmol) in DMF. The crude was purified by flash chromatography (DCM/EtOAc 100:0 to 50:50) to give 48 mg (76% yield) of the title product. HPLC-MS (ESI) m/z: 534 [M-H]⁺.

Ethyl-1 ,3-bis(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(IV)c). The title compound was obtained according to general procedure Ji, step 1 , method (B) using ethyl-3-(4-ethylphenyl)-6-(4-(/V-(pyridin-3- yl)sulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)e-i, 0.1 17 g, 0.222 mmol), (4-ethylphenyl)boronic acid (XXIVa, 0.050 g, 0.333 mmol), pyridine (54 pL, 0.665 mmol) and Cu(OAc)2 (0.012 g, 0.067 mmol). The crude (0.145 g, quant yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 631.8 [M-H]⁺.

Ethyl-1 -(cyclopropylmethyl)-3-(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)- 1H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)d). The title compound was obtained according to general procedure Ji, step 1 , method (D) using ethyl-3-(4-ethylphenyl)-6-(4- (A/-(pyridin-3-yl)sulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)e-i, 0.440 g, 0.834 mmol), (bromomethyl)cyclopropane (XXVa, 0.225 g, 1 .668 mmol) and K2CO3 (0.138 g, 1 .00 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.134 g (27% yield) of the title product. HPLC-MS (ESI) m/z: 581 .8 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-1-isopropyl-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)e). The title compound was obtained according to general procedure J-i, step 1 , method (D) using ethyl-3-(4-ethylphenyl)-6-(4-(N-(pyridin- 3-yl)sulfamoyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)e-i, 0.310 g, 0.588 mmol), 2-iodopropane (XXVb, 0.100 g, 0.588 mmol) and K2CO3 (0.097 g, 0.705 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 65 mg (19% yield) of the title product. HPLC-MS (ESI) m/z: 569.8 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-1-methyl-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)f). The title compound was obtained according to general procedure J-i, step 1 , method (D) using ethyl-3-(4-ethylphenyl)-6-(4-(N-(pyridin- 3-yl)sulfamoyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)e-i, 0.310 g, 0.588 mmol), Mel (XXVc, 70 pL, 1.175 mmol) and K2CO3 (0.097 g, 0.705 mmol). The crude was filtered, washed with DCM, discarded and evaporated under vacuum to give 0.171 g (54% yield) of the title product. HPLC-MS (ESI) m/z: 541.8 [M-H]⁺.

Ethyl-3-cyclohexyl- 1 -(4-ethyl phenyl)-6-( 4-( methoxycarbonyl)phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(IV)g). The title compound was obtained according to general procedure Ji, step 1 , method (A) using ethyl-3-cyclohexyl-6-(4- (methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)fi, 80 mg, 0.19 mmol), (4-ethylphenyl)boronic acid (XXIVa, 87 mg, 0.58 mmol), pyridine (0.233 mL, 2.89 mmol) and Cu(OAc)2 (122 mg, 0.673 mmol) in DMF. The crude was purified by flash chromatography (DCM/EtOAc 100:0 to 50:50) to give 97.2 mg (94% yield) of the title product. HPLC-MS (ESI) m/z: 512 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.42 - 8.32 (m, 2H), 8.24 - 8.05 (m, 5H), 7.44 (d, J = 8.4 Hz, 2H), 4.52 (q, J = 7.0 Hz, 2H), 3.91 (s, 3H), 2.71 (q, J = 7.8 Hz, 2H), 2.02 (t, J = 1 1.0 Hz, 2H), 1 .91 - 1 .80 (m, 2H), 1 .80 - 1.57 (m, 3H), 1.49 - 1 .22 (m, 9H), 1 .18 (t, J = 7.5 Hz, 1 H).

Ethyl-1, 3-bis(4-ethylphenyl)-6-(5-(methoxycarbonyl)pyridin-2-yl)-1H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(IV)h). The title compound was obtained according to general procedure Ji, step 1 , method (c) using ethyl-3-(4-ethylphenyl)-6-(5-

(methoxycarbonyl)pyridin-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)g-i_A, 243 mg, 0.565 mmol), (4-ethylphenyl)boronic acid (XXIVa, 339 mg, 2.258 mmol) and Cu(OAc)2 (359 mg, 1 .976 mmol). The crude was purified by flash chromatography on silica gel (0- 50% EtOAc/DCM) to give 107 mg (33% yield) of the title product. HPLC-MS (ESI) m/z: 535.3 [M-H]⁺.

Ethyl-1, 3-bis(4-ethylphenyl)-6-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazolo[3, 4- b]pyridine-4-carboxylate (l^(IV)i). The title compound was obtained according to general procedure Ji, step 1 , method (B) using ethyl-3-(4-ethylphenyl)-6-(5-

(methylsulfonamido)pyridin-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate hydrochloride (l^(lll)a, 0.319 g, 0.685 mmol), (4-ethylphenyl)boronic acid (XXIVa, 0.154 g, 1 .028 mmol), CU(OAC)2 (0.037 g, 0.206 mmol) and pyridine (0.222 ml_, 2.74 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.258 g (66% yield) of the title product. HPLC-MS (ESI) m/z: 570.2 [M-H]⁺.

General procedure K-i: Synthesis of compounds with general formula l^(V) (Examples 21-87, 108)

Step 1

Method (A): To a solution of the intermediate compound l^(NV) (1 eq.) in THF/water/MeOH (1 :1 : 1 , 0.01 - 0.05 M), LiOH (1 -30 eq.) was added and the resulting mixture was stirred at 40-45°C for 20 to 72 h. The reaction mixture was then diluted with water, and acidified to pH~2 by addition of aqueous 1 M HCI solution. The aqueous phase was either directly evaporated under reduced pressure, or first extracted with EtOAc and then dried under vacuum. Alternatively, when precipitation was observed upon acidification, the resulting solid was filtered and washed with water. Both methodologies were applied to afford a residue further purified by the opportune technique to give the final compound having general formula l^(V).

Method (B): To a solution of the intermediate compound l^(NV)(1 eq.) in dioxane/MeOH (9.5:0.5, 0.0 5M), a 4 M solution of NaOH in MeOH (5 eq.) was added and the reaction was heated up to 100° c for 1 .5-16 h. Solvents were removed under vacuum and the residue was purified by the opportune technique to give the final compound having general formula l^(V).

Method (c): In a pressure flask, a mixture of intermediate compound l^(NV) (1 eq.) and aqueous 30% NH3 solution (144 eq.) was heated up to 80 °c for 16 h. Solvents were removed under vacuum and the residue was purified by the opportune technique to give the final compound having general formula l^(V).

Method (D): To a solution of the intermediate compound l^(NV) (1 eq.) in MeOH/THF (1 : 1 , 0.05 M), aqueous 50% NH2OH solution (96 eq.) was added, followed by KCN (1 eq.). The reaction was heated up to 50° c for 16h. Solvents were removed under vacuum and the residue was purified by the opportune technique to give the final compound having general formula l^(V).

Method (E): To a solution of the intermediate compound l^(NV) (1 eq.) in THF / water (3: 1 , 0.1 M), concentrated HCI (0.3 M) was added. The reaction was heated at 120° c for 1 h in the microwave. Water was then added, and the resultant precipitate was collected by filtration, rinsed with water and isohexanes and purified by the opportune technique to give the final compound having general formula l^(V).

Method (F): To a solution of the intermediate compound l^(NV) (1 eq.) in DCM (0.1 M) triflic acid (10.8 eq.) was added and the resultant solution was stirred at rt for 1 h. A saturated aqueous solution of NaHCC was then added until basic pH and the product was extracted with DCM. After removing the solvent, the crude (1 eq.) was redissolved in THF/H₂0/MeOH (0.04 M, 3/1/1 ) and LiOH (10 eq.) was added in one portion. The obtained mixture was stirred at 50 °C for 3 h. 1 M aqueous solution of HCI was added and the resulting solid was filtered and rinsed with water. The product was purified by the opportune technique to give the final compound having general formula l^(V).

3-Bromo-6-( 4-(carboxyphenyl)~ 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid

(Example 21). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-bromo-6-(4-(methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4- b]pyridine-4-carboxylate (I¾i, 35 mg, 0.087 mmol) and LiOH (29.8 mg, 1 .24 mmol). The reaction mixture was evaporated under reduced pressure, the resulting residue was triturated with water, filtered, and dried to give 22 mg (68% yield) of the title product. HPLC-MS (ESI) m/z: 362/364 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.52 (s, 1 H), 14.17 (s, 1 H), 13.23 (s, 1 H), 8.41 - 8.38 (m, 2H), 8.18 - 8.15 (m, 3H).

3-(4-Ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridine- 4-carboxylic acid (Example 22). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(/V-(pyridin-3- yl)sulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)e-i, 66 mg, 0.13 mmol) and LiOH (30.0 mg, 1 .25 mmol). The precipiate was filtered and washed with water and dried under vacuum to give 48 mg (75% yield) of the title product. HPLC-MS (ESI) m/z: 500 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.12 (s, 1 H), 13.66 (s, 1 H), 10.60 (s, 1 H), 8.37 - 8.29 (m, 2H), 8.30 - 8.18 (m, 2H), 7.95 (s, 1 H), 7.90 - 7.82 (m, 2H), 7.50 - 7.39 (m, 3H), 7.29 - 7.20 (m, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H).

6-( 4-carboxyphenyl)-3-cyclohexyl- 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid

(Example 23). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-cyclohexyl-6-(4-(methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)fi, 200 mg, 0.491 mmol) and LiOH (58.8 mg, 2.45 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 152 mg (82% yield) of the title product. HPLC-MS (ESI) m/z: 366 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.99 (s, 1 H), 13.67 (s, 1 H), 13.17 (s, 1 H), 8.34 - 8.27 (m, 2H), 8.13 - 8.07 (m, 2H), 8.04 (s, 1 H), 3.40 (tt, J = 1 1 .3, 3.2 Hz, 1 H), 2.00 (d, J = 12.5 Hz, 2H), 1 .88 - 1 .67 (m, 3H), 1 .55 (qd, J = 12.5, 3.0 Hz, 2H), 1 .46 - 1 .33 (m, 2H), 1 .27 (dd, J = 14.1 , 10.6 Hz, 1 H). 6-(5-carboxypyridin-2-yl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 24). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(5-(methoxycarbonyl)pyridin-2-yl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)g-i_A, 142 mg, 0.33 mmol) and LiOH (39.5 mg, 1 .65 mmol). The resulting solid was collected by filtration and washed with EtOH to give 1 12 mg (87% yield) of the title product. HPLC-MS (ESI) m/z: 389 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.30 (s, 1 H), 13.67 (s, 2H), 9.23 (dd, J = 2.2, 0.9 Hz, 1 H), 8.61 (dd, J = 8.3, 0.9 Hz, 1 H), 8.58-8.47 (m, 2H), 7.58-7.44 (m, 2H), 3.98 (q, J = 7.1 Hz, 2H), 7.37- 7.27 (m, 2H), 2.69 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 25). The title compound was obtained according to general procedure Ki, step 1 , method (B) using ethyl-6-(4-(/V-(4- cyano-2-fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)hi_, 0.240 g, 0.421 mmol) and a 4 M solution of NaOH in MeOH (0.527 ml_, 2.107 mmol). The crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 50 mg (21 % yield) of the title product. HPLC-MS (ESI) m/z: 558.1 [M- H]-. ¹H-NMR (400 MHz, DMSO -de) d: 10.54 (br s, 1 H), 8.33 (d, J = 8.5 Hz, 2H), 7.95 (s, 1 H), 7.90 - 7.84 (m, 3H), 7.60 - 7.53 (m, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.39 - 7.30 (m, 2H), 7.23 (d, J = 8.1 Hz, 2H), 2.61 (q, J = 7.7 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H).

6-(4-(N-(5-cyano-2-fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 26). The title compound was obtained according to general procedure Ki, step 1 , method (B) using ethyl-6-(4-(/V-(5-cyano-2- fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)i₁, 0.190 g, 0.334 mmol) and a 4 M solution of NaOH in MeOH (0.42 mL, 1 .668 mmol). The crude was purified by preparative HPLC (0.1 % (NH^COs in water/AcN) to give 27 mg (15% yield) of the title product. HPLC-MS (ESI) m/z: 540.0 [M- H]-. ¹H-NMR (400 MHz, DMSO -de) d: 8.35 (d, J = 8.3 Hz, 2H), 7.98 (br s, 1 H), 7.89 (d, J = 8.5 Hz, 2H), 7.68 (br d, J = 7.3 Hz, 1 H), 7.56 - 7.44 (m, 3H), 7.37 - 7.25 (m, 3H), 2.67 (q, J = 7.4 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).

3-( 4-Ethylphenyl)-6-( 4-(N-( 3-fluorophenyl)sulfamoyl)phenyl)-1H-pyrazolo[3, 4- b]pyridine-4-carboxylic acid (Example 27). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(/V-(3- fluorophenyl)sulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)ji, 65 mg, 0.12 mmol) and LiOH (28.6 mg, 1 .19 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 36 mg (58% yield) of the title product. HPLC-MS (ESI) m/z: 517 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.09 (s, 1 H), 13.69 (s, 1 H), 10.64 (s, 1 H), 8.37 - 8.29 (m, 2H), 7.95 - 7.85 (m, 3H), 7.45 (d, J = 8.2 Hz, 2H), 7.26 - 7.19 (m, 3H), 6.94 - 6.76 (m, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1 .17 (t, J = 7.6 Hz, 3H). 3-( 4-Ethylphenyl)-6-( 4-( N-( 4-methoxyphenyl)sulfamoyl)phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxylic acid (Example 28). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(/V-(4- methoxyphenyl)sulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)ki, 54 mg, 0.097 mmol) and LiOH (1 1 .6 mg, 0.485 mmol). The resulting solid was collected by filtration and dried under vacuum to give 9.1 mg (18% yield) of the title product. HPLC- MS (ESI) m/z: 529 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.23 (s, 1 H), 13.81 (s, 1 H), 10.08 (s, 1 H), 8.44 - 8.37 (m, 2H), 8.06 (s, 1 H), 7.91 - 7.81 (m, 2H), 7.57 - 7.50 (m, 2H), 7.38 - 7.31 (m, 2H), 7.09 - 7.03 (m, 2H), 6.90 - 6.82 (m, 2H), 3.70 (s, 3H), 2.72 (q, J = 7.6 Hz, 2H), 1 .27 (t, J = 7.6 Hz, 3H).

3-( 4-Ethylphenyl)-6-( 4-(N-( 4-fluorophenyl)sulfamoyl)phenyl)-1H-pyrazolo[3, 4- b]pyridine-4-carboxylic acid (Example 29). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(/V-(4- fluorophenyl)sulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)l₁, 1 10 mg, 0.202 mmol) and LiOH (24.2 mg, 1 .01 mmol). The resulting solid was collected by filtration, washed with water dried under vacuum to give 98.5 mg (93% yield) of the title product. HPLC-MS (ESI) m/z: 517 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 14.27 (s, 1 H), 13.83 (s, 1 H), 10.42 (s, 1 H), 8.52 - 8.36 (m, 2H), 8.09 (s, 1 H), 7.96 - 7.88 (m, 2H), 7.59 - 7.51 (m, 2H), 7.39 - 7.33 (m, 2H), 7.23 - 7.12 (m, 4H), 2.74 (q, J = 7.6 Hz, 2H), 1 .30 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridine- 4-carboxylic acid (Example 30). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(/V-(pyridin-2- yl)sulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)mi, 21 mg, 0.040 mmol) and LiOH (9.53 mg, 0.398 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 17 mg (83% yield) of the title product. HPLC-MS (ESI) m/z: 500 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.20 (s, 1 H), 13.59 (br s, 2H), 8.41 - 8.34 (m, 2H), 8.06 -7.92 (m, 4H), 7.77 (m, 1 H), 7.54 - 7.46 (m, 2H), 7.34 - 7.27 (m, 2H), 7.24 (d, J = 8.6 Hz, 1 H), 6.88 (s, 1 H), 2.68 (q, J = 7.6 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(4-(N-phenylsulfamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 31 ). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(/V- phenylsulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)n₁, 91 mg, 0.17 mmol) and LiOH (12.4 mg, 0.518 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 55 mg (63% yield) of the title product. HPLC-MS (ESI) m/z: 499 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.03 (s, 1 H), 13.76 (s, 1 H), 10.31 (s, 1 H), 8.33 - 8.25 (m, 2H), 7.88 - 7.81 (m, 3H), 7.51 - 7.44 (m, 2H), 7.25 - 7.1 1 (m, 4H), 7.1 1 - 7.03 (m, 2H), 7.02 - 6.93 (m, 1 H), 2.60 (q, J = 7.6 Hz, 2H), 1 .17 (t, J = 7.6 Hz, 3H).

6-( 4-( N-(4-carbamoyl- 1 -cyclopentyl- 1 H-pyrazol-3-yl)sulfamoyl)phenyl)-3-( 4- ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 32) The title compound was obtained according to general procedure Ki, step 1 , method (B) using 6- (4-(/V-(4-cyano-1 -cyclopentyl-1 /-/-pyrazol-3-yl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (l^(l)oi, 0.149 g, 0.256 mmol) and 4 M solution of NaOH in MeOH (0.32 ml_, 1 .281 mmol). The crude was purified by preparative HPLC (0.1 % (NH₄)₂C03 in water/AcN) to give 39 mg (25% yield) of the title product. HPLC-MS (ESI) m/z: 598.1 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 9.97 (br s, 1 H), 8.34 (d, J = 8.5 Hz, 2H), 8.06 (br s, 1 H), 8.02 (d, J = 8.6 Hz, 2H), 7.92 (br s, 1 H), 7.54 (br d, J = 7.6 Hz, 3H), 7.27 (d, J = 8.1 Hz, 2H), 7.22 (br s, 1 H), 4.56 - 4.47 (m, 1 H), 2.65 (q, J = 7.5 Hz, 2H), 2.01 - 1 .90 (m, 2H), 1.79 - 1 .50 (m, 6H), 1 .22 (t, J = 7.5 Hz, 3H).

3-(4-Ethylphenyl)-6-(5-(N-(pyridin-3-yl)sulfamoyl)pyridin-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 33). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(5-(/V- (pyridin-3-yl)sulfamoyl)pyridin-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)Pi, 0.027 g, 0.133 mmol) and LiOH (1 M solution in water, 0.5 ml_, 0.5 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 18 mg (70% yield) of the title product. HPLC-MS (ESI) m/z: 501 .1 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 9.02 (d, J = 1 .9 Hz, 1 H), 8.59 (d, J = 8.4 Hz, 1 H), 8.35 - 8.28 (m, 3H), 8.27

- 8.22 (m, 1 H), 7.66 - 7.51 (m, 3H), 7.33 - 7.22 (m, 3H), 2.66 (q, J = 7.4 Hz, 2H), 1 .23 (t, J = 7.4 Hz, 3H).

6-( 4-carboxy- 1 H-pyrrol-2-yl)-3-( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 34). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(methoxycarbonyl)- 1 H-pyrrol-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)q-i, 150 mg, 0.358 mmol) and LiOH (43 mg, 1 .8 mmol). The resulting solid was collected by filtration and washed with EtOH to give 75 mg (55% yield) of the title product. HPLC-MS (ESI) m/z: 377 [M-H]⁺. ¹H- NMR (400 MHz, DMSO -de) d: 14.20 - 13.60 (br m, 2H), 12.22 (s, 1 H), 7.83 (s, 1 H), 7.59

- 7.38 (m, 3H), 7.37 - 7.20 (m, 3H), 2.68 (q, J = 7.6 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H).

6-( 4-carboxy-3-fluorophenyl)-3-( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 35). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(3-fluoro-4- (methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (I^(|)h, 67 mg, 0.15 mmol) and LiOH (17.93 mg, 0.749 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 49 mg (77% yield) of the title product. HPLC-MS (ESI) m/z: 406 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.20 (s, 1 H), 13.58 (s, 2H), 8.22 - 8.1 1 (m, 2H), 8.1 1 - 8.00 (m, 2H), 7.56 - 7.49 (m, 2H), 7.31 (d, J = 8.2 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

6-( 4-carboxy-2-fluorophenyl)-3-( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 36). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(2-fluoro-4- (methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)si, 72 mg, 0.16 mmol) and LiOH (40 mg, 1 .7 mmol). The resulting solid was collected by filtration, washed with water/TBME/i-Hex (2.5: 1 :2.5) and dried under vacuum to give 62 mg (94% yield) of the title product. HPLC-MS (ESI) m/z: 406 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.33 (s, 1 H), 13.62 (s, 2H), 8.22 (t, J = 7.9 Hz, 1 H), 8.02 (dd, J = 8.1 , 1 .6 Hz, 1 H), 7.94 - 7.88 (m, 2H), 7.60 - 7.54 (m, 2H), 7.40 - 7.34 (m, 2H), 2.74 (q, J = 7.6 Hz, 2H), 1 .31 (t, J = 7.6 Hz, 3H).

5-(4-carboxy-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)isoxazole-3-carboxylic acid. (Example 37). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-5-(4-(ethoxycarbonyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4- b]pyridin-6-yl)isoxazole-3-carboxylate (l^(l)t_|, 35 mg, 0.081 mmol) and LiOH (5.79 mg, 0.242 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 15 mg (44% yield) of the title product. HPLC-MS (ESI) m/z: 379 [M- H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.40 (s, 1 H), 14.22 (s, 1 H), 13.92 (s, 1 H), 8.09 (s, 1 H), 7.69 (s, 1 H), 7.55 - 7.45 (m, 2H), 7.36 - 7.28 (m, 2H), 2.69 (q, J = 7.5 Hz, 2H), 1 .25 (t, J = 7.5, 3H).

6-(4-(carboxymethyl)phenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 38). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(2-methoxy-2- oxoethyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (I^(I)IH , 94 mg, 0.21 mmol) and LiOH (30.5 mg, 1 .27 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 74.8 mg (87% yield) of the title product. HPLC-MS (ESI) m/z: 402 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.99 (s, 1 H), 13.58 (s, 1 H), 12.36 (s, 1 H), 8.14 - 8.07 (m, 2H), 7.87 (s, 1 H), 7.48 - 7.34 (m, 4H), 7.26 - 7.19 (m, 2H), 3.61 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H).

6-(5-carboxythiophen-2-yl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 39). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(5-(methoxycarbonyl)thiophen-2-yl)- 1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)v₁, 35 mg, 0.080 mmol) and LiOH (9.62 mg, 0.402 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 13 mg (40% yield) of the title product. Yield = 40%. HPLC-MS (ESI) m/z: 394 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.10 (s, 1 H), 13.70 (s, 1 H), 13.25 (s, 1 H), 8.03 (d, J = 4.0 Hz, 1 H), 7.82 (s, 1 H), 7.71 (d, J = 4.0 Hz, 1 H), 7.42 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1 .17 (t, J = 7.6 Hz, 3H). 3-( 4-Ethylphenyl)-6-( 4-hydroxy-3-nitrophenyl)-1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid (Example 40). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-hydroxy-3-nitrophenyl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)wi, 226 mg, 0.523 mmol) and LiOH (125 mg, 5.23 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 146 mg (68% yield) of the title product. HPLC-MS (ESI) m/z: 405 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.10 (s, 1 H), 13.72 (s, 1 H), 1 1 .53 (s, 1 H), 8.78 (d, J = 2.4 Hz, 1 H), 8.43 (dd, J = 8.8, 2.4 Hz, 1 H), 8.00 (s, 1 H), 7.54 - 7.48 (m, 2H), 7.34 - 7.27 (m, 3H), 2.69 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

6-(3-chloro-4-hydroxy-5-methoxyphenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 41 ). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(3-chloro-4-hydroxy-5- methoxyphenyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)xi, 53 mg, 0.12 mmol) and LiOH (28 mg, 1 .169 mmol). The resulting solid was collected by filtration, washed with water/Hex (1 :2) and dried under vacuum to give 41 mg (82% yield) of the title product. HPLC-MS (ESI) m/z: 424.0/425.9 [M-H]⁺. ¹H-NMR (400 MHz, DMSO- de) d: 14.02 (s, 1 H), 13.69 (s, 1 H), 9.96 (s, 1 H), 8.00 (s, 1 H), 7.88 (d, J = 2.1 Hz, 1 H), 7.78 (d, J = 2.1 Hz, 1 H), 7.53 - 7.47 (m, 2H), 7.33 - 7.27 (m, 2H), 3.98 (s, 3H), 2.68 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H).

6-( 2, 5-Difluoro-4-hydroxyphenyl)-3-( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 42). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(2,5-difluoro-4-hydroxyphenyl)-3-(4- ethylphenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)yi, 35 mg, 0.083 mmol) and LiOH (19.8 mg, 0.827 mmol). The resulting solid was collected by filtration, washed with water/Hex (1 :2) and dried under vacuum to give 25 mg (75% yield) of the title product. HPLC-MS (ESI) m/z: 396 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.13 (s, 1 H), 13.70 (s, 1 H), 10.98 (s, 1 H), 7.84 (dd, J = 12.0, 7.4 Hz, 1 H), 7.76 (d, J = 1 .5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 6.94 (dd, J = 12.4, 7.3 Hz, 1 H), 2.67 (q, J = 7.7 Hz, 2H), 1 .24 (t, J = 7.7 Hz, 3H).

6-(3-carboxyphenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxyHc acid (Example 43). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(3-(methoxycarbonyl)phenyl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)zi, 122 mg, 0.273 mmol) and LiOH (6.5 mg, 0.27 mmol). The resulting solid was collected by filtration, washed with water/TBME (2: 1 ) and dried under vacuum to give 90.5 mg (85% yield) of the title product. HPLC-MS (ESI) m/z: 388 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.21 (s, 1 H), 13.73 (s, 1 H), 13.29 (s, 1 H), 8.89 (t, J = 1 .8 Hz, 1 H), 8.53 (ddd, J = 7.9, 2.0, 1 .1 Hz, 1 H), 8.15 - 8.12 (m, 1 H), 8.09 (s, 1 H), 7.75 (t, J = 7.8 Hz, 1 H), 7.59 - 7.54 (m, 2H), 7.40 - 7.33 (m, 2H), 2.75 (q, J = 7.6 Hz, 2H), 1 .31 (t, J = 7.6 Hz, 3H). 6-(4-carboxythiophen-2-yl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 44). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(methoxycarbonyl)thiophen-2-yl)- 1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)a₂, 39 mg, 0.088 mmol) and LiOH (21 .2 mg, 0.884 mmol). The resulting solid was collected by filtration, washed with water and Et₂0 and dried under vacuum to give 22 mg (60% yield) of the title product. HPLC-MS (ESI) m/z: 394 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.1 1 (s, 1 H), 13.70 (s, 1 H), 12.91 (s, 1 H), 8.43 (d, J = 1 .3 Hz, 1 H), 8.32 (d, J = 1 .3 Hz, 1 H), 8.06 (s, 1 H), 7.54 - 7.45 (m, 2H), 7.34 - 7.27 (m, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

6-( 5-carboxy- 1 H-pyrrol-2-yl)-3-( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 45). The title compound was obtained according to general procedure Ki, step 1 , method (A) using 6-(5-(ethoxycarbonyl)-1 /-/-pyrrol-2-yl)-3-(4- ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)b₂, 155 mg, 0.383 mmol) and LiOH (92 mg, 3.8 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 128 mg (86% yield) of the title product. HPLC-MS (ESI) m/z: 377 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.93 (s, 1 H), 13.60 (s, 1 H), 12.64 (s, 1 H), 12.17 (s, 1 H), 8.18 (s, 1 H), 7.52 - 7.47 (m, 2H), 7.32 - 7.27 (m, 2H), 7.06 - 7.03 (m, 2H), 6.90 - 6.87 (m, 2H), 2.68 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

6-( 3, 5-Difluoro-4-hydroxyphenyl)-3-( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 46). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(3,5-difluoro-4-hydroxyphenyl)-3-(4- ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)c₂, 191 mg, 0.451 mmol) and LiOH (108 mg, 4.51 mmol). The crude was recrystallised from EtOH to give 51 mg (27% yield) of the title product. HPLC-MS (ESI) m/z: 396 [M-H]⁺. ¹H-NMR (400 MHz, DMSO- de) d: 13.98 (s, 1 H), 13.62 (s, 1 H), 10.68 (s, 1 H), 7.94 - 7.84 (m, 3H), 7.46 - 7.40 (m, 2H), 7.26 - 7.20 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H).

2-(4-carboxy-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)thiazole-4-carboxylic acid (Example 47). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-2-(4-(ethoxycarbonyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4- b]pyridin-6-yl)thiazole-4-carboxylate (l^(l)d₂, 65 mg, 0.14 mmol) and LiOH (35 mg, 1 .5 mmol). The resulting solid was collected by filtration, washed with water/TBME/i-Hex (2.5: 1 :2.5) and dried under vacuum to give 50 mg (85% yield) of the title product. HPLC- MS (ESI) m/z: 395 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.53 (s, 1 H), 13.35 (s, 2H), 8.60 (s, 1 H), 8.15 (s, 1 H), 7.20 - 7.16 (m, 2H), 7.15 - 7.12 (m, 2H), 2.65 (q, J = 7.6 Hz, 2H), 1 .23 (t, J = 7.6 Hz, 3H).

6-( 2, 3-Difluoro-4-hydroxyphenyl)-3-( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 48). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(2,3-difluoro-4-hydroxyphenyl)-3-(4- ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)e₂, 85 mg, 0.20 mmol) and LiOH (48.1 mg, 2.01 mmol). The resulting solid was collected by filtration, washed with water/ i-Hex (1 :2) and dried under vacuum to give 62.5 mg (78% yield) of the title product. HPLC-MS (ESI) m/z: 396 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -c/e) d: 14.14 (s, 1 H), 13.70 (s, 1 H), 10.94 (s, 1 H), 7.73 (d, J = 1 .8 Hz, 1 H), 7.69 (td, J = 8.7, 2.2 Hz, 1 H), 7.51 - 7.46 (m, 2H), 7.33 - 7.27 (m, 2H), 7.01 - 6.94 (m, 1 H), 2.67 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H).

6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 49). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-(4- ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)f₂, 104 mg, 0.236 mmol) and LiOH (57.6 mg, 2.36 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 86 mg (87% yield) of the title product. HPLC-MS (ESI) m/z: 412 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.07 (s, 1 H), 13.71 (s, 1 H), 10.97 (d, J = 1.3 Hz, 1 H), 8.15 (t, J = 1.8 Hz, 1 H), 8.09 (dd, J = 1 1.9, 2.2 Hz, 1 H), 8.00 (s, 1 H), 7.53 - 7.46 (m, 2H), 7.34 - 7.27 (m, 2H), 2.68 (q, J = 7.6 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(4-(N-methylsulfamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 50). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-(/V- methylsulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)g₂, 130 mg, 0.280 mmol) and LiOH (33.5 mg, 1 .34 mmol). The resulting solid was collected by filtration, washed with water/TBME (1 : 1 ) and dried under vacuum to give 58.6 mg (48% yield) of the title product. HPLC-MS (ESI) m/z: 437 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.12 (s, 1 H), 13.70 (s, 1 H), 8.42 - 8.32 (m, 2H), 7.99 (s, 1 H), 7.93 - 7.83 (m, 2H), 7.51 (q, J = 5.0 Hz, 1 H), 7.49 - 7.41 (m, 2H), 7.29 - 7.20 (m, 2H), 2.62 (q, J = 7.5 Hz, 2H), 2.41 (d, J = 5.0 Hz, 3H), 1 .18 (t, J = 7.5 Hz, 3H).

3-( 4-Ethylphenyl)-6-( 4-sulfamoylphenyl)-1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid (Example 51). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(4-sulfamoylphenyl)-1 /-/-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)h₂, 16 mg, 0.036 mmol) and LiOH (29.8 mg, 1.24 mmol). The crude was recrystallised from EtOH to give 12 mg (79% yield) of the title product. HPLC- MS (ESI) m/z: 423 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.21 (s, 1 H), 13.81 (s, 1 H), 8.47 - 8.39 (m, 2H), 8.06 (s, 1 H), 8.04 - 7.96 (m, 2H), 7.52 (d, J = 7.1 Hz, 4H), 7.31 (d, J = 8.0 Hz, 2H), 2.69 (q, J = 7.5 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H).

6-( 3-carboxy- 1 H-pyrazol-5-yl)-3-(4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 52). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(3-(ethoxycarbonyl)-1 /-/-pyrazol-5-yl)-3-(4- ethylphenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)i₂, 45 mg, 0.10 mmol) and LiOH (29.8 mg, 1 .24 mmol). The reaction mixture was evaporated under reduced pressure, the resulting residue was triturated with water, filtered, and dried to give 36 mg (92% yield) of the title product. HPLC-MS (ESI) m/z: 378 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -c/e) d: 14.34 (s, 1 H), 14.16 (s, 1 H), 13.75 (s, 2H), 8.09 (s, 1 H), 7.55 (d, J = 7.8 Hz, 2H), 7.43 (s, 1 H), 7.36 (d, J = 7.9 Hz, 2H), 2.74 (q, J = 7.6 Hz, 2H), 1 .30 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(6-oxo-1 ,6-dihydropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 53). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(6-oxo-1 ,6- dihydropyridin-3-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)j₂, 141 mg, 0.363 mmol) and LiOH (87 mg, 3.6 mmol). The resulting solid was collected by filtration, washed with Et₂0 and dried under vacuum to give 106 mg (79% yield) of the title product. HPLC-MS (ESI) m/z: 361 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.94 (s, 1 H), 13.64 (s, 1 H), 12.08 (s, 1 H), 8.37 - 8.29 (m, 2H), 7.85 (s, 1 H), 7.52 - 7.45 (m, 2H), 7.33 - 7.26 (m, 2H), 6.54 - 6.47 (m, 1 H), 2.68 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).

6-( 5-chloropyridin-2-yl)-3-(4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid (Example 54). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(5-chloropyridin-2-yl)-3-(4-ethylphenyl)-1 H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)k₂, 102 mg, 0.251 mmol) and LiOH (30 mg, 1 .253 mmol). The resulting solid was collected by filtration, washed with water/i-Hex (1 :1 ) and dried under vacuum to give 79 mg (79% yield) of the title product. HPLC-MS (ESI) m/z: 379.2 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 14.23 (s, 1 H), 13.72 (s, 1 H), 8.82 (d, J = 2.6 Hz, 1 H), 8.50 (d, J = 8.6 Hz, 1 H), 8.43 (s, 1 H), 8.20 - 8.14 (m, 1 H), 7.51 (d, J = 7.7 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 55). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(5-fluoropyridin-2-yl)-1 H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)l₂, 42 mg, 0.098 mmol) and LiOH (23 mg, 0.979 mmol). The resulting mixture was extracted with EtOAc and the organic phases were collected, passed through a hydrophobic frit and evaporated under reduced pressure to give 25 mg (68.5% yield) of the title product. HPLC-MS (ESI) m/z: 363.1 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 13.70 (br s, 1 H), 8.71 (d, J = 2.9 Hz, 1 H), 8.49 (dd, J = 8.9, 4.6 Hz, 1 H), 8.02 (s, 1 H), 7.90 (td, J = 8.7, 2.9 Hz, 1 H), 7.78 (d, J = 7.7 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 2.65 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H).

3-( 4-Ethylphenyl)-6-( 5-methoxypyrimidin-2-yl)-1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 56). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(5-fluoropyrimidin-2-yl)- 1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)m₂ 93 mg, 0.24 mmol) LiOH (57 mg, 2.34 mmol). The resulting precipitate was filtered, rinsed with diethyl ether (5 mL), and dried in vacuo to give 66 mg (70% yield) of the title product. HPLC-MS (ESI) m/z: 376.2 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 14.23 (s, 1 H), 13.67 (s, 1 H), 8.77 (s, 2H), 8.42 (s, 1 H), 7.51 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.03 (s, 3H), 2.69 (q, J = 7.6 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(5-fluoropyrimidin-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 57). The title compound was obtained according to general procedure Ki, step 1 , method (E) using ethyl-3-(4-ethylphenyl)-6-(5-fluoropyrimidin-2-yl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)m₂, 215 mg, 0.549 mmol) and HCI cone (2 ml_). The resulting precipitate was filtered, rinsed with water (20 ml_) and isohexanes (5 ml_) and purified by SAX column. The column of SAX (10 g) was previously treated with MeOH (100 ml_), water (100 ml_), acetate buffer (100 ml_), water (100 ml_) and MeOH (100 ml_). The crude product was loaded onto the SAX column in MeOH. The column was washed with MeOH and then the product was eluted with 5% AcOH in MeOH. The resultant mixture was concentrated in vacuo to afford 25 mg (12% yield) of the title product. HPLC- MS (ESI) m/z: 364.2 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 14.15 (s, 1 H), 13.81 (s, 1 H), 9.1 1 (s, 2H), 8.30 (s, 1 H), 7.60 (s, 2H), 7.29 (d, J = 7.8 Hz, 2H), 2.68 (q, J = 7.6 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H). ¹⁹F NMR (471 MHz, DMSO-d6) d -137.47.

6-(4-carboxyphenyl)-3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

(Example 58). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(pyridin-4-yl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)n₂, 259 mg, 0.644 mmol) and LiOH (29.8 mg, 1 .24 mmol). The reaction mixture was evaporated under reduced pressure, the resulting residue was triturated with water, filtered, and dried to give 206 mg (86% yield) of the title product. HPLC-MS (ESI) m/z: 361 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 14.54 (s, 1 H), 13.90 (br s, 1 H), 13.16 (br s, 1 H), 8.76 - 8.55 (m, 2H), 8.48 - 8.28 (m, 2H), 8.23 - 7.98 (m, 3H), 7.62 - 7.39 (m, 2H).

6-(4-carboxyphenyl)-3-(pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

(Example 59). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(pyridin-2-yl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)o₂, 185 mg, 0.460 mmol) and LiOH (55.0 mg, 2.30 mmol). The resulting solid was collected by filtration, washed with water/EtOH (1 : 1 ) and dried under vacuum. The crude was slurried in EtOH/water (1 : 1 , 5 mL) for 2 h, filtered and washed with EtOH (1 mL) to give 120 mg (70% yield) of the title product. HPLC-MS (ESI) m/z: 361 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 14.32 (s, 1 H), 13.29 (s, 2H), 8.63 (dt, J = 4.8, 1 .3 Hz, 1 H), 8.43 - 8.33 (m, 2H), 8.16 - 8.09 (m, 2H), 8.06 - 7.98 (m, 2H), 7.93 (td, J = 7.7, 1 .8 Hz, 1 H), 7.42 (ddd, J = 7.5, 4.8, 1 .3 Hz, 1 H).

3-Benzyl-6-(4-carboxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 60). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-benzyl-6-(4-(methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)p₂, 90 mg, 0.22 mmol) and LiOH (25.9 mg, 1.08 mmol). The resulting solid was collected by filtration, washed with water/EtOH (1 : 1 ) and dried under vacuum to give 79 mg (96% yield) of the title product. HPLC-MS (ESI) m/z: 374 [M-H]⁺. ¹H-NMR (400 MHz, DMSO-de) d: 13.91 (s, 1 H), 13.81 (s, 1 H), 13.06 (s, 1 H), 8.23 (d, J = 8.6 Hz, 2H), 8.07 - 7.98 (m, 2H), 7.21 - 7.12 (m, 2H), 7.17 - 7.03 (m, 4H), 4.44 (s, 2H).

6-(4-carboxyphenyl)-3-phenyl-1H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid (Example 61 ). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(4-(methoxycarbonyl)phenyl)-3-phenyl-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(l)q , 100 mg, 0.249 mmol) and LiOH (60 mg, 2.5 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 76.5 mg (85% yield) of the title product. HPLC-MS (ESI) m/z: 360 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.25 (s, 1 H), 14.01 - 12.86 (m, 2H), 8.41 - 8.33 (m, 2H), 8.15 - 8.09 (m, 2H), 8.08 (s, 1 H), 7.63 - 7.57 (m, 2H), 7.52 - 7.41 (m, 3H).

6-( 4-carboxyphenyl)-3-isopropyl- 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid

(Example 62). The title compound was obtained according to general procedure Ki, step 1 , method (A) using 3-isopropyl-6-(4-(methoxycarbonyl)phenyl)-1 H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(l)r₂, 100 mg, 0.295 mmol) and LiOH (28 mg, 1 .2 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 84 mg (83% yield) of the title product. HPLC-MS (ESI) m/z: 326 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.68 (br s, 3H), 8.40 - 8.23 (m, 2H), 8.17 - 8.00 (m, 3H), 3.83 - 3.68 (m, 1 H), 1 .31 (d, J = 6.9 Hz, 6 H).

6-(4-carboxyphenyl)-3-methyl-1H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid (Example 63). The title compound was obtained according to general procedure Ki, step 1 , method (A) using 6-(4-(methoxycarbonyl)phenyl)-3-methyl-1 H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (l^(l)s₂, 58 mg, 0.19 mmol) and LiOH (17.9 mg, 0.745 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 46 mg (79% yield) of the title product. HPLC-MS (ESI) m/z: 298 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.66 (br s, 3H), 8.43 - 8.20 (m, 2H), 8.20 - 7.99 (m, 3H), 2.63 (s, 3H).

6-( 4-carboxyphenyl)- 1 -( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid (Example 64). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-1 -(4-ethylphenyl)-6-(4-(methoxycarbonyl)phenyl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)t_2A, 52 mg, 0.12 mmol) and LiOH (29.0 mg, 1.21 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 42 mg (89% yield) of the title product. HPLC-MS (ESI) m/z: 388 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.16 (s, 1 H), 13.18 (s, 1 H), 8.66 (s, 1 H), 8.41 - 8.33 (m, 3H), 8.24 - 8.16 (m, 2H), 8.16 - 8.08 (m, 2H), 7.52 - 7.43 (m, 2H), 2.72 (q, J = 7.6 Hz, 2H), 1 .27 (t, J = 7.6 Hz, 3H).

6-( 4-carboxyphenyl)-3-( 4-isopropylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid (Example 65). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-isopropylphenyl)-6-(4-(methoxycarbonyl)phenyl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(ll)a, 46 mg, 0.10 mmol) and LiOH (12.4 mg, 0.519 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 30 mg (68% yield) of the title product. HPLC-MS (ESI) m/z: 402 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -c/e) d: 14.10 (s, 1 H), 13.69 (s, 1 H), 13.05 (s, 1 H), 8.33 - 8.23 (m, 2H), 8.08 - 8.01 (m, 2H), 7.97 (s, 1 H), 7.50 - 7.42 (m, 2H), 7.31 - 7.23 (m, 2H), 2.90 (hept, J = 6.9 Hz, 1 H), 1 .20 (d, J = 6.9 Hz, 6H).

6-( 4-carboxyphenyl)-3-( 4-methoxyphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid (Example 66). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(4-methoxyphenyl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(ll)b, 34 mg, 0.079 mmol) and LiOH (9.4 mg, 0.39 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 25 mg (81 % yield) of the title product. HPLC-MS (ESI) m/z: 390 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.13 (s, 1 H), 13.65 (s, 1 H), 13.18 (s, 1 H), 8.45 - 8.28 (m, 2H), 8.17 - 8.07 (m, 2H), 8.04 (s, 1 H), 7.59 - 7.44 (m, 2H), 7.10 - 6.97 (m, 2H), 3.83 (s, 3H).

6-( 4-carboxyphenyl)-3-( furan-3-yl)- 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid

(Example 67). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(furan-3-yl)-6-(4-(methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(ll)c, 89 mg, 0.23 mmol) and LiOH (54.4 mg, 2.27 mmol). The resulting solid was collected by filtration and dried under vacuum to give 58 mg (72% yield) of the title product. HPLC-MS (ESI) m/z: 350 [M-H]⁺. ¹H-NMR (400 MHz, DMSO- de) d: 14.13 (s, 1 H), 14.12 (br s, 1 H), 13.15 (br s, 1 H), 8.39 - 8.31 (m, 2H), 8.16 - 8.07 (m, 2H), 8.04 - 7.95 (m, 2H), 7.79 (t, J = 1 .8 Hz, 1 H), 6.85 (dd, J = 1 .8, 0.8 Hz, 1 H).

6-( 4-carboxyphenyl)-3-( cyclohex- 1 -en- 1 -yl)- 1H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid (Example 68). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(cyclohex-1 -en-1 -yl)-6-(4-(methoxycarbonyl)phenyl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(ll)d, 32 mg, 0.079 mmol) and LiOH (29.8 mg, 1 .24 mmol). The reaction mixture was evaporated under reduced pressure, the resulting residue was triturated with water, filtered, and dried to give 25.7 mg (88% yield) of the title product. HPLC-MS (ESI) m/z: 364 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.85 (s, 2H), 13.1 1 (s, 1 H), 8.34 - 8.31 (m, 2H), 8.1 1 - 8.08 (m, 2H), 7.96 (s, 1 H), 5.91 - 5.87 (m, 1 H), 2.46 - 2.39 (m, 2H), 2.23 - 2.15 (m, 2H), 1.78 - 1 .72 (m, 2H), 1.71 - 1 .64 (m, 2H).

6-(4-carboxyphenyl)-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 69). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(pyridin-3-yl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(ll)e, 28 mg, 0.070 mmol) and LiOH (8.33 mg, 0.348 mmol). The resulting solid was collected by filtration washed with water/EtOH (1 : 1 ) and dried under vacuum. The crude was slurried in EtOH/water (1 : 1 , 2 mL) for 30 min and collected by filtration to give 19 mg (72% yield) of the title product. HPLC-MS (ESI) m/z: 361 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.46 (s, 1 H), 13.82 (s, 1 H), 13.15 (s, 1 H), 8.79 (dd, J = 2.2, 0.8 Hz, 1 H), 8.65 (dd, J = 4.8, 1 .7 Hz, 1 H), 8.42 - 8.32 (m, 2H), 8.18 (s, 1 H), 8.16 - 8.09 (m, 2H), 8.02 (dt, J = 7.8, 1 .9 Hz, 1 H), 7.54 (ddd, J = 7.9, 4.9, 0.9 Hz, 1 H).

3-(4-Ethylphenyl)-6-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 70). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(5- (methylsulfonamido)pyridin-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate HCI (l^(lll)a, 0.067 g, 0.133 mmol), and LiOH (2.9 ml_, 2.88 mmol). The reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 22 mg (35% yield) of the title product. HPLC-MS (ESI) m/z: 438.1 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 10.35 (br s, 1 H), 8.57 (d, J = 2.6 Hz, 1 H), 8.45 (d, J = 8.7 Hz, 1 H), 8.37 (s, 1 H), 7.84 (dd, J = 8.6 Hz, 2.6 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 3.16 (s, 3H), 2.67 (q, J = 7.4 Hz, 2H), 1 .24 (t, J = 7.5 Hz, 3H).

3-(4-Ethylphenyl)-6-(5-(pyridine-3-sulfonamido)pyridin-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 71 ). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-6-(5-(pyridine- 3-sulfonamido)pyridin-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate HCI (l^(lll)b, 0.360 g, 0.681 mmol) and LiOH (2.88 mL, 2.88 mmol). The reaction mixture was evaporated under reduced pressure, and the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 22 mg (12% yield) of the title product. HPLC-MS (ESI) m/z: 499.0 [M- H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.97 (br s, 1 H), 8.77 (br s, 1 H), 8.40 (br s, 1 H), 8.36

- 8.27 (m, 2H), 8.19 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.64 - 7.57 (m, 1 H), 7.54

- 7.43 (m, 2H), 7.33 - 7.22 (m, 2H), 6.53 (s, 1 H), 2.66 (q, J = 7.6 Hz, 2H), 1 .23 (t, J = 7.6 HZ, 3H).

3-Bromo-6-( 4-carboxyphenyl)-1-(4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 72). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-bromo-1 -(4-ethylphenyl)-6-(4- (methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)a, 41 mg, 0.084 mmol) and LiOH (10.0 mg, 0.419 mmol). The resulting solid was collected by filtration washed with water and dried under vacuum to give 14 mg (36% yield) of the title product. HPLC-MS (ESI) m/z: 467 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.42 - 8.35 (m, 2H), 8.26 (s, 1 H), 8.16 - 8.03 (m, 4H), 7.52 - 7.42 (m, 2H), 2.72 (q, J = 7.6 Hz, 2H), 1 .26 (t, J = 7.6 Hz, 3H).

6-(4-carboxyphenyl)-1,3-bis(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 73). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-1 ,3-bis(4-ethylphenyl)-6-(4-(methoxycarbonyl)phenyl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)b, 48 mg, 0.088 mmol) and LiOH (10.6 mg, 0.442 mmol). The resulting solid was collected by filtration washed with water and dried under vacuum to give 42.3 mg (97% yield) of the title product. HPLC-MS (ESI) m/z: 529 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -c/e) d: 13.74 (s, 1 H), 13.03 (s, 1 H), 8.33 (d, J = 8.2 Hz, 2H), 8.19 - 8.13 (m, 2H), 8.10 (d, J = 2.1 Hz, 1 H), 8.08 - 8.02 (m, 2H), 7.57 - 7.50 (m, 2H), 7.46 - 7.37 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 2.65 (m, 4H), 1 .25 - 1 .16 (m, 6H).

1,3-Bis(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid. (Example 74). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-1 , 3-bis(4-ethylphenyl)-6-(4-(/V- (pyridin-3-yl)sulfamoyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)c, 0.140 g, 0.222 mmol) and LiOH (4.4 ml_, 4.43 mmol). The reaction mixture was evaporated under reduced pressure, and the crude was purified by flash chromatography (Cie, aqueous 0.1 %NH₄HCO₃ Solution/AcN) followed by crystallization in EtOH to give 10 mg (7% yield) of the title product. HPLC-MS (ESI) m/z: 603.8 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -cie) d: 8.44 (d, J = 8.4 Hz, 2H), 8.34 (br s, 1 H), 8.26 (br d, J = 4.3 Hz, 1 H), 8.20 (d, J = 8.4 Hz, 2H), 8.04 (br s, 1 H), 7.94 (d, J = 8.5 Hz, 2H), 7.66 (br d, J = 6.2 Hz, 2H), 7.58 - 7.52 (m, 1 H), 7.46 (d, J = 8.4 Hz, 2H), 7.36 - 7.27 (m, 3H), 2.75 (m, 4H), 1 .30 - 1 .20 (m, 6H).

1-(cyclopropylmethyl)-3-(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 75). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-1 - (cyclopropylmethyl)-3-(4-ethylphenyl)-6-(4-(/V-(pyridin-3-yl)sulfamoyl)phenyl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)d, 0.134 g, 0.230 mmol) and LiOH (4 mL, 4.0 mmol). The reaction mixture was evaporated under reduced pressure, and the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 18 mg (14% yield) of the title product. HPLC-MS (ESI) m/z: 554.2 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.28 - 8.24 (m, 3H), 8.05 (d, J = 5.8 Hz, 1 H), 7.95 - 7.90 (m, 3H), 7.80 (ddd, J = 8.7 Hz, 2.4 Hz, 0.8 Hz, 1 H), 7.58 (dd, J = 8.7 Hz, 5.7 Hz, 1 H), 7.51 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 4.24 (d, J = 7.4 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 1 .39 - 1 .27 (m, 1 H), 1 .24 (t, J = 7.5 Hz, 3H), 0.60 - 0.53 (m, 2H), 0.50 - 0.44 (m, 2H).

3-(4-Ethylphenyl)-1-isopropyl-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 76). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-1 -isopropyl-6- (4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)e, 0.065 g, 0.1 14 mmol) and LiOH (2.3 mL, 2.30 mmol). The reaction mixture was evaporated under reduced pressure, and the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 21 mg (34% yield) of the title product. HPLC-MS (ESI) m/z: 542.2 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.28 - 8.23 (m, 3H), 8.09 (d, J = 6.1 Hz, 1 H), 7.94 (br s, 1 H), 7.92 (d, J = 8.5 Hz, 2H), 7.79 (ddd, J = 8.7 Hz, 2.3 Hz, 0.7 Hz, 1 H), 7.55 (dd, J = 8.7 Hz, 5.8 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 4.73 (sept, J = 6.7 Hz, 1 H), 2.66 (q, J = 7.4 Hz, 2H), 1 .49 (d, J = 6.7 Hz, 6H), 1 .22 (t, J = 7.5 Hz, 3H). 3-(4-Ethylphenyl)-1-methyl-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1Hpyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 77). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-1 -methyl-6-(4- (N-(pyridin-3-yl)sulfamoyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)f, 0.097 g, 0.705 mmol) and LiOH (5 ml_, 5 mmol). The reaction mixture was evaporated under reduced pressure, and the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 1 1 mg (7% yield) of the title product. HPLC-MS (ESI) m/z: 514.2 [M- H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.61 (br s, 1 H), 8.54 (d, J = 8.5 Hz, 2H), 8.55 (br s, 1 H), 8.18 (t, J = 4.3 Hz, 4H), 8.00 - 7.92 (m, 1 H), 7.66 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 4.41 (s, 3H), 2.85 (q, J = 7.5 Hz, 2H), 1.41 (t, J = 7.5 Hz, 3H)

6-( 4-carboxyphenyl)-3-cyclohexyl- 1-( 4-ethyl phenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 78). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-cyclohexyl-1 -(4-ethylphenyl)-6-(4- (methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)g, 95 mg, 0.19 mmol) and LiOH (22.2 mg, 0.928 mmol). The resulting solid was collected by filtration washed with water and dried under vacuum to give 75.9 mg (87% yield) of the title product. HPLC-MS (ESI) m/z: 529 [M-H]⁺. ¹H-NMR (400 MHz, DMSO-d6) d: 14.24 (s, 1 H), 13.18 (s, 1 H), 8.37 - 8.30 (m, 2H), 8.20 - 8.13 (m, 3H), 8.13 - 8.06 (m, 2H), 7.46 - 7.39 (m, 2H), 3.46 (tt, J = 1 1 .4, 3.2 Hz, 1 H), 2.69 (q, J = 7.6 Hz, 2H), 2.1 1 - 2.01 (m, 2H), 1 .90 - 1 .78 (m, 2H), 1 .78 - 1 .69 (m, 1 H), 1 .61 (qd, J = 12.5, 3.1 Hz, 2H), 1 .48 - 1 .20 (m, 6H).

6-(5-carboxypyridin-2-yl)-1,3-bis(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 79). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-1 , 3-bis(4-ethylphenyl)-6-(5-

(methoxycarbonyl)pyridin-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)h, 107 mg, 0.186 mmol) and LiOH (22.29 mg, 0.931 mmol). The resulting solid was collected by filtration washed with water and dried under vacuum to give 73 mg (79% yield) of the title product. HPLC-MS (ESI) m/z: 493.3 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 13.92 (s, 1 H), 13.61 (s, 1 H), 9.25 (dd, J = 2.2, 0.9 Hz, 1 H), 8.68 - 8.62 (m, 2H), 8.52 (dd, J = 8.2, 2.2 Hz, 1 H), 8.26 - 8.20 (m, 2H), 7.63 - 7.57 (m, 2H), 7.54 - 7.48 (m, 2H), 7.39 - 7.33 (m, 2H), 2.73 (m, 4H), 1 .28 (m, 6H).

1,3-Bis(4-ethylphenyl)-6-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 80). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-1 , 3-bis(4-ethylphenyl)-6-(5- (methylsulfonamido)pyridin-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(IV)i, 0.258 g, 0.453 mmol) and LiOH (9 mL, 9.06 mmol). The reaction mixture was evaporated under reduced pressure, and the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 20 mg (16% yield) of the title product. HPLC-MS (ESI) m/z: 540.2 [M- H]\ ¹H-NMR (400 MHz, DMSO -de) d: 8.58 (d, J = 3.0 Hz, 1 H), 8.52 (d, J = 9.1 Hz, 1 H), 8.42 (br s, 1 H), 8.25 (d, J = 8.5 Hz, 2H), 7.87 (dd, J = 8.6 Hz, 2.6 Hz, 1 H), 7.64 (br d, J = 7.4 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 3.17 (s, 3H), 2.76 - 2.65 (m, 4H), 1.31 - 1 .21 (m, 6H).

6-(4-carboxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 81 ). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(4-(methoxycarbonyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)bi_A, 20 mg, 0.05 mmol) and LiOH (15 mg, 0.63 mmol). The resulting solid was collected by filtration washed with water and dried under vacuum to give 9.3 mg (62% yield) of the title product. HPLC-MS (ESI) m/z: 284 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.12 (m, 2H), 13.18 (s, 1 H), 8.42 (s, 1 H), 8.37 - 8.29 (m, 2H), 8.26 (s, 1 H), 8.15 - 8.09 (m, 2H).

4-(4-carboxyphenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (Example 82). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-4-(4-(methoxycarbonyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-6-carboxylate (I^(l)b- _B, 52 mg, 0.16 mmol) and LiOH (38 mg, 1 .6 mmol). The resulting solid was collected by filtration washed with water and dried under vacuum to give 25 mg (54% yield) of the title product. HPLC-MS (ESI) m/z: 284 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.21 (s, 1 H), 13.38 (br m, 2H), 8.51 (s, 1 H), 8.21 - 8.13 (m, 2H), 8.10 - 8.03 (m, 3H).

4-(5-carboxypyridin-2-yl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (Example 83). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-4-(5-(methoxycarbonyl)pyridin-2-yl)-1 H- pyrazolo[3,4-b]pyridine-6-carboxylate (l^(l)gi_B, 58 mg, 0.14 mmol) and LiOH (16.1 mg, 0.674 mmol). The resulting solid was collected by filtration washed with EtOH and dried under vacuum to give 45 mg (85% yield) of the title product. HPLC-MS (ESI) m/z: 389 [M- H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.35 (s, 1 H), 13.55 (br s, 2H), 8.86 (dd, J = 2.1 , 0.9 Hz, 1 H), 8.08-7.96 (m, 2H), 7.43 (dd, J = 8.0, 0.9 Hz, 1 H), 6.97 (s, 4H), 2.55 (q, J = 7.6 Hz, 2H), 1 .13 (t, J = 7.6 Hz, 3H).

4-( 4-carboxyphenyl)- 1 -( 4-ethylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-6-carboxylic acid (Example 84). The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-1 -(4-ethylphenyl)-4-(4-(methoxycarbonyl)phenyl)-1 /-/- pyrazolo[3,4-b]pyridine-6-carboxylate (l^(l)t_2B, 56.5 mg, 0.132 mmol) and LiOH (31 .5 mg, 1 .32 mmol). The resulting solid was collected by filtration washed with EtOH and dried under vacuum to give 45 mg (84% yield) of the title product. HPLC-MS (ESI) m/z: 388 [M- H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.69 (s, 1 H), 13.32 (s, 1 H), 8.81 (s, 1 H), 8.28 - 8.23 (m, 4H), 8.21 (s, 1 H), 8.19 - 8.13 (m, 2H), 7.58 - 7.50 (m, 2H), 2.77 (q, J = 7.6 Hz, 2H), 1 .32 (t, J = 7.6 Hz, 3H).

6-( 4-( N-(4-carbamoylphenyl)sulfamoyl)phenyl)-3-( 4-ethyl phenyl)-N-hydroxy- 1 H- pyrazolo[3,4-b]pyridine-4-carboxamide (Example 85). The title compound was obtained according to general procedure Ki, step 1 , method (D) using ethyl-6-(4-(/V-(4- carbamoylphenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (example 2, 0.7g, 1 .23 mmol), aqueous 50% NH2OH solution (7.3 ml_, 1 18 mmol) and KCN (0.08 g, 1 .23 mmol). The crude was purified by flash chromatography (C18, 0.1 % NhUHCC in water/AcN)) to give 21 mg (7% yield) of the title product. HPLC- MS (ESI) m/z: 555.1 [M-H]\ ¹ H-NMR (400 MHz, DMSO-de) d: 1 1 .19 (br s, 1 H), 10.72 (br s, 1 H), 9.24 (s, 1 H), 8.35 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.77 (br s, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.20 (br s, 1 H), 7.16 (d, J = 8.6 Hz, 2H), 2.65 (q, J = 7.2 Hz, 2H), 1 .22 (t, J = 7.4 Hz, 3H).

6-( 4-( N-(4-carbamoylphenyl)sulfamoyl)phenyl)-3-( 4-ethyl phenyl)- 1 H-pyrazolo[3, 4- b]pyridine-4-carboxamide (Example 86). The title compound was obtained according to general procedure Ki, step 1 , method (c) using ethyl-6-(4-(/V-(4- carbamoylphenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (example 2, 0.250 g, 0.439 mmol) and 30% NH3 solution in water (4 ml_, 63.4 mmol). The crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 8 mg (3% yield) of the title product. HPLC-MS (ESI) m/z: 539.1 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 10.74 (br s, 1 H), 8.37 (d, J = 8.5 Hz, 2H), 8.06 (br s, 1 H), 7.95 (d, J = 8.5 Hz, 2H), 7.82 (s, 1 H), 7.77 (br s, 2H), 7.73 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.19 (br s, 1 H), 7.16 (d, J = 8.5 Hz, 2H), 2.66 (q, J = 7.4 Hz, 2H), 1 .23 (t, J = 7.5 Hz, 3H).

3-(4-Ethylphenyl)-6-(5-(N-(2-fluorophenyl)sulfamoyl)pyridin-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 87). The title compound was obtained according to general procedure Ki, step 1 , method (A) using methyl-3-(4-ethylphenyl)-6-(5-(N-(2- fluorophenyl)sulfamoyl)pyridin-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (example 17, 0.067 g, 0.126 mmol) and LiOH (1 M solution in water, 1 .3 ml_, 1 .3 mmol). The resulting solid was collected by filtration washed with water and dried under vacuum to give 42 mg (64% yield) of the title product. HPLC-MS (ESI) m/z: 516 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 8.97 (d, J = 2.2 Hz, 1 H), 8.60 (d, J = 8.4 Hz, 1 H), 8.35 (s, 1 H), 8.28 (dd, J = 8.4 Hz, 2.3 Hz, 1 H), 7.59 (d, J = 7.9 Hz, 2H), 7.33 - 7.12 (m, 7H), 2.66 (q, J = 7.6 Hz, 2H), 1 .23 (t, J = 7.6 Hz, 3H).

6-(5-carboxypyridin-2-yl)-3-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 108). The title compound was obtained according to general procedure Ki, step 1 , method (F) using: i) ethyl-1 -(fe/f-butyl)-3-cyclopropyl-6-(5-

(methoxycarbonyl)pyridin-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(l)u₂, 182 mg, 0.4 mmol) and triflic acid (0.4 mL, 4.3 mmol); ii) ethyl 3-cyclopropyl-6-(5- (methoxycarbonyl)pyridin-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (158 mg, 0.431 mmol) and LiOH (103 mg, 4.31 mmol). The resulting solid was suspended in MeOH and concentrated in vacuo to give 42 mg (29% yield) of the title product. HPLC-MS (ESI) m/z: 325.2 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.19 - 13.37 (m, 3H), 9.22 (d, J = 2.1 Hz, 1 H), 8.65 (s, 1 H), 8.56 (d, J = 8.3 Hz, 1 H), 8.48 (dd, J = 8.3, 2.2 Hz, 1 H), 2.74 (p, J = 6.8 Hz, 1 H), 1.02 - 0.85 (m, 4H). Preparation II: Synthesis of compounds 88-91

Compounds 88-91 can be obtained by application of the chemical transformations reported in general procedures Li - Si herein described. General procedures L1-R1 relate to the preparation of intermediates and compounds of Table B. The preparation of compounds 88-91 of Table A is described in general procedure Si.

General procedure Lp Synthesis of intermediate pyridinyl-alcohols XXVIII

XXVI S p ₁ XXVIII

Step 1

To a stirred solution of the proper 2,6-dichloropyridin-4-yl derivative (XXVI, 1 eq.) in THF (0.2 M) at -78 °C, LDA (2 M solution in THF/n-heptane/ethylbenzene, 3 eq.) was added dropwise. The resulting mixture was stirred at -78 °C for 30 min. Then, the proper commercially available aldheide (XXVII, 2.5 eq.) was added dropwise and the resulting mixture was stirred at -78 °C for further 15 min. The reaction mixture was quenched with a aqueous saturated NFUCI solution. Water was added and the aqueous phase was extracted with EtOAc. The combined organics were dried over MgSC , filtered and evaporated under reduced pressure. The crude was then purified by flash chromatography to give the proper compound having general formula XXVIII.

(2, 6-Dichloro-4-(hydroxymethyl)pyridin-3-yl)(4-ethylphenyl)methanol (XXVIlla). The title compound was obtained according to general procedure L-i, step 1 using (2,6- dichloropyridin-4-yl)methanol (XXVIa, 956 mg, 5.37 mmol), LDA (8.06 mL, 16.1 mmol) and 4-ethylbenzaldehyde (XXVIla, 1 .84 mL, 13.4 mmol). The crude was purified by flash chromatography (0-40% /-Hex-EtOAc) to give 41 1 mg (23% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.

(2,6-Dichloropyridin-3-yl)(4-ethylphenyl)methanol (XXVIIIb). The title compound was obtained according to general procedure Li, step 1 using 2,6-dichloropyridine (XXVIb, 1 .02 g, 6.91 mmol), LDA (3.80 mL, 7.60 mmol) and 4-ethylbenzaldehyde (XXVIla, 1 .04 mL, 7.60 mmol). The crude was purified by flash chromatography (0-20% /-Hex-EtOAc) to give 1 .68 g (82% yield) of the title product. HPLC-MS (ESI) m/z: 282/284 [M-H]⁺.

(2, 6-Dichloro-4-(trifluoromethyl)pyridin-3-yl)(4-ethylphenyl)methanol (XXVIIIc). The title compound was obtained according to general procedure Li, step 1 using 2,6-dichloro- 4-(trifluoromethyl)pyridine (XXVIc, 500 mg, 2.32 mmol), LDA (1 .45 mL, 2.89 mmol) and 4-ethylbenzaldehyde (XXVIla, 412 pL, 3.01 mmol). The crude was purified by flash chromatography (0-20% /-Hex-EtOAc) to give 772 mg (95% yield) of the title product. HPLC-MS (ESI) m/z: 350/352 [M-H]⁺.

(4-Ethylphenyl)(2,4,6-trichloropyridin-3-yl)methanol (XXVIIId). The title compound was obtained according to general procedure Li, step 1 using 2,4,6-trichloropyridine (XXVId, 5 g, 27.4 mmol), LDA (15.0 ml_, 30.1 mmol) and 4-ethylbenzaldehyde (XXVIla, 4.5 ml_, 32.9 mmol). The crude was purified by flash chromatography (0-30% EtOAc/isohexane) to give 7.1 g (79% yield) of the title product. HPLC-MS (ESI) m/z: 316.5 / 318.5 / 320.5 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 7.87 (s, 1 H), 7.22 - 7.18 (br d, J = 8.2 Hz, 2H), 7.15 (br d, J = 8.2 Hz, 2H), 6.39 (d, J = 4.8 Hz, 1 H), 6.35 (d, J = 4.8 Hz, 1 H), 2.57 (q, J = 7.6 Hz, 2H), 1 .15 (t, J = 7.6 Hz, 3H).

General procedure M : Synthesis of TBDMS-protected intermediates XXIX

Step 1

To a stirred solution of the proper intermediate XXVIII (1 eq.), imidazole (1 .1 eq.) and 4-dimethylaminopyridine (0.1 eq.) in DCM (0.06 M), TBDMS-CI (1 .1 eq.) was added and the resulting solution was stirred at r.t. for 16 h. The solution was diluted with DCM and washed with water and brine. The organic phase was separated, dried over MgSC , filtered and evaporated under reduced pressure. The crude was then purified by flash chromatography to afford the intermediate compound having general formula XXIX.

( 4-( ( (Tert-butyldimethylsilyl)oxy)methyl)-2, 6-dichloropyridin-3-yl) ( 4- ethylphenyl)methanol (XXIXa). The title compound was obtained according to general procedure Mi, step 1 using (2,6-dichloro-4-(hydroxymethyl)pyridin-3-yl)(4- ethylphenyl)methanol (XXVIlla, 394 mg, 1 .26 mmol), imidazole (103 mg, 1 .51 mmol), 4- dimethylaminopyridine (15.4 mg, 0.126 mmol) and TBDMS-CI (228 mg, 1.51 mmol). The crude was purified by flash chromatography (0-20% /-Hex-diethyl-ether) to give 489 mg (91 % yield) of the title product. LcMS (ESI) m/z: 426/428 [M-H]⁺.

General procedure N-i: Synthesis of intermediate chloropyridin-methanones XXX and XXXI

Step 1

To a stirred solution of the proper intermediate XXVIII or XXIX (1 eq.) in DCM (0.2 M), Dess-Martin periodinane (1.2 eq.) was added at 0 °C. The resulting mixture was stirred at r.t. for 15 min. The solids were removed by filtration, then the filtrate was washed with aqueous 1 M NaOH solution, saturated brine, dried over MgSC , filtered and evaporated under reduced pressure. The crude was then purified by flash chromatography to give the proper compound having general formula XXX or XXXI. (2,6-Dichloropyridin-3-yl)(4-ethylphenyl)methanone (XXXa). The title compound was obtained according to general procedure Ni, step 1 using (2,6-dichloropyridin-3-yl)(4- ethylphenyl)methanol (XXVIIIb, 1 .58 g, 5.61 mmol) and Dess-Martin periodinane (2.86 g, 6.74 mmol). The crude was purified by flash chromatography (0-20% /- Flex-EtOAc) to give 1 .29 g (80% yield) of the title product. HPLC-MS (ESI) m/z: 280/282 [M-H]⁺.

(2, 6-Dichloro-4-(trifluoromethyl)pyridin-3-yl)(4-ethylphenyl)methanone (XXXb). The title compound was obtained according to general procedure Ni, step 1 using (2,6- dichloro-4-(trifluoromethyl)pyridin-3-yl)(4-ethylphenyl)methanol (XXVIIIc, 772 mg, 2.21 mmol) and Dess-Martin periodinane (1 .12 g, 2.65 mmol). The crude was purified by flash chromatography (0-20% /- Flex-EtOAc) to give 748 mg (99% yield) of the title product. HPLC-MS (ESI) m/z: 348/350 [M-H]⁺.

(4-Ethylphenyl)(2,4,6-trichloropyridin-3-yl)methanone (XXXc). The title compound was obtained according to general procedure Ni, step 1 using (4-ethylphenyl)(2,4,6- trichloropyridin-3-yl)methanol (XXVIIId, 7.1 g, 21.8 mmol) and Dess-Martin periodinane (1 1 .0 g, 26.1 mmol). The crude was purified by flash chromatography (0-30% EtOAc/isohexane) to give 6.9 g, (99% yield) of the title product. ¹H-NMR (500 MHz, DMSO -de) d: 8.14 (s, 1 H), 7.88 - 7.79 (m, 2H), 7.48 - 7.39 (m, 2H), 2.72 (q, J = 7.6 Hz, 2H), 1 .21 (t, J = 7.6 Hz, 3H).

( 4-( ( (Tert-butyldimethylsilyl)oxy)methyl)-2, 6-dichloropyridin-3-yl) ( 4- ethylphenyl)methanone (XXXIa). The title compound was obtained according to general procedure Ni, step 1 using (4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyridin-3- yl)(4-ethylphenyl)methanol (XXIXa, 488 mg, 1 .14 mmol) and Dess-Martin periodinane (582 mg, 1 .37 mmol). The crude was purified by flash chromatography (0-20% /-Hex- diethyl-ether) to give 470 mg (96% yield) of the title product. HPLC-MS (ESI) m/z: 424/426 [M-H]⁺.

General procedure Oi: Synthesis of intermediate pyrazolopyridines XXXII and

XXXIII

Step 1

To a stirred solution of the proper intermediate XXX or XXXI (1 eq.) in EtOH/THF (4: 1 ) (0.5 M), DIPEA (1 .05 eq.) was added. The mixture was then cooled to 0 °C and the proper commercially available hydrazine (IV, 1 M solution in THF, 1.2 eq.) was added dropwise. The resulting solution was stirred at 0 °C for 5 min, then heated at 80 °C for 16 h. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography to give the intermediate compound having general formula XXXII or XXXIII

6-chloro-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine (XXXIIa). The title compound was obtained according to general procedure Oi, step 1 , using (2,6-dichloropyridin-3- yl)(4-ethylphenyl)methanone (XXXa, 1 .28 g, 4.58 mmol), DIPEA (0.84 ml_, 4.8 mmol) and hydrazine (IVa, 5.5 ml_, 5.5 mmol). The crude was purified by flash chromatography (0-60% /- Hex-EtOAc) to give 995 mg (83% yield) of the title product. HPLC-MS (ESI) m/z: 258/260 [M-H]⁺.

6-chloro-3-( 4-ethyl phenyl)-4-(trifluoromethyl)- 1 H-pyrazoio[3, 4-b ] pyridine (XXXI I b) . The title compound was obtained according to general procedure O-i, step 1 , using (2,6- dichloro-4-(trifluoromethyl)pyridin-3-yl)(4-ethylphenyl)methanone (XXXb, 603 mg, 1 .73 mmol), DIPEA (318 pi, 1 .82 mmol) and hydrazine (IVa, 2.08 ml_, 2.08 mmol). The crude was purified by flash chromatography (0-60% /- Hex-EtOAc) to give 250 mg (43% yield) of the title product. HPLC-MS (ESI) m/z: 326/328 [M-H]⁺.

4-(((Tert-butyldimethylsilyl)oxy)methyl)-6-chloro-3-(4-ethylphenyl)-1H-pyrazolo[3,4- bjpyridine (XXXIIIa). The title compound was obtained according to general procedure Oi, step 1 , using (4-(((fe/f-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyridin-3-yl)(4- ethylphenyl)methanone (XXXIa, 2.45 g, 5.77 mmol), DIPEA (1 .06 mL, 6.06 mmol) and hydrazine (IVa, 6.93 ml, 6.93 mmol). The crude was purified by flash chromatography (0- 60% /-Hex-EtOAc) to give 1 .03 g (43% yield) of the title product. HPLC-MS (ESI) m/z: 402/404 [M-H]⁺.

General procedure P : Synthesis of compounds with general formula l^(VI) and XXXV

Step 1

A solution of compound XXXII or XXXIII (1 eq.), the proper commercially available boronic acid (XXXIV, 1 - 1 .5 eq.) and K2CO3 (1 .5 - 2.5 eq.) in dioxane/water (4: 1 ) (0.15 M) was evacuated and purged three times with N2. Pd(dppf)Cl2- DCM (0.1 eq.) was added and the tube was evacuated and purged three times with N2. The mixture was heated at 120-140°C for 1 -3 h under MW irradiation then cooled to r.t. , diluted with EtOAc and water (1 : 1 ) and filtered through celite. The phases were separated and the aqueous extracted with EtOAc. The combined organics were washed with water and brine, dried over MgS0₄, filtered and concentrated under reduced pressure to afford the crude product. The crude was then purified by flash chromatography to give the intermediate compound with general formula l^(VI) or XXXV. Tert-butyl 4-(3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzoate (l^(VI)a). The title compound was obtained according to general procedure P-i, step 1 , using 6-chloro- 3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine (XXXIIa, 313 mg, 1 .22 mmol), (4 -(tert- butoxycarbonyl)phenyl)boronic acid (XXXIVa, 324 mg, 1 .46 mmol), K2CO3 (420 mg, 3.04 mmol) and Pd(dppf)Cl2- DCM (99 mg, 0.12 mmol). The crude was purified by flash chromatography (0-30% /- Hex-EtOAc) to give 254 mg (50% yield) of the title product. HPLC-MS (ESI) m/z: 400 [M-H]⁺.

Tert-butyl-4-(3-(4-ethylphenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6- yl)benzoate (l^(VI)b). The title compound was obtained according to general procedure Pi, step 1 , using 6-chloro-3-(4-ethylphenyl)-4-(trifluoromethyl)-1 H-pyrazolo[3,4-b]pyridine (XXXIIb, 250 mg, 0.768 mmol), (4-(tert-butoxycarbonyl)phenyl)boronic acid (XXXIVa, 205 mg, 0.921 mmol), K2CO3 (265 mg, 1 .92 mmol) and Pd(dppf)Cl2 DCM (62.7 mg, 0.077 mmol). The crude was purified by flash chromatography (0-30% /- Hex-EtOAc) to give 191 mg (49% yield) of the title product. HPLC-MS (ESI) m/z: 468 [M-H]⁺.

Tert-butyl-4-( 4-( ((tert-butyldimethylsilyl)oxy)methyl)-3-( 4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridin-6-yl)benzoate (XXXVa). The title compound was obtained according to general procedure Pi, step 1 , using 4-(((fe/f-butyldimethylsilyl)oxy)methyl)- 6-chloro-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine (XXXIIIa, 388 mg, 0.965 mmol), (4- (fe/f-butoxycarbonyl)phenyl)boronic acid (XXXIVa, 257 mg, 1 .16 mmol), K2CO3 (333 mg, 2.41 mmol) and Pd(dppf)Cl2- DCM (79 mg, 0.097 mmol). The crude was purified by flash chromatography (0-30% /-Hex-EtOAc) to give 335 mg (54% yield) of the title product. HPLC-MS (ESI) m/z: 544 [M-H]⁺.

General procedure Q : Synthesis of compounds with general formula l^(VII)

Step 1

To a stirred solution of intermediate XXXV (1 eq.) in THF (0.2M), TBAF (1 M solution in THF, 2 eq.) was added and the resulting solution was stirred at r.t. for 16 h. The reaction was diluted with DCM and washed with brine. The organic layer was dried over MSSO4, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography to give the intermediate compound having general formula l^(VII).

Tert-butyl-4-(3-(4-ethylphenyl)-4-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyridin-6- yl)benzoate (l^(VII)a). The title compound was obtained according to general procedure Qi, step 1 , using fe/f-butyl-4-(4-(((fe/f-butyldimethylsilyl)oxy)methyl)-3-(4-ethylphenyl)-1 /-/- pyrazolo[3,4-b]pyridin-6-yl) benzoate (XXXVa, 924 mg, 1 .70 mmol) and TBAF (3.4 mL, 3.4 mmol). The crude was purified by flash chromatography (0-60% /-Hex-EtOAc, then flushed with EtOH) to give 380 mg (52% yield) of the title product. HPLC-MS (ESI) m/z: 430 [M-H]⁺.

General procedure Ri: Synthesis of compounds with general formula l^(VIII)

Step 1

To a stirred solution of intermediate l^(VII) (1 eq.) in DCM (0.5M), MnC^ (15 eq.) was added and the resulting mixture was stirred at 95 °C for 16 h. The reaction mixture was filtered through celite and the filtrate was purified by flash chromatography to give the intermediate compound having general formula XXXVI.

Tert-butyl-4-(3-(4-ethylphenyl)-4-formyl-1H-pyrazolo[3,4-b]pyridin-6-yl)benzoate

(XXXVIa). The title compound was obtained according to general procedure R-i, step 1 , using fe/f-butyl-4-(3-(4-ethylphenyl)-4-(hydroxymethyl)-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)benzoate (l^(VII)a, 1.01 g, 2.35 mmol) and MnC^ (3.07 g, 35.3 mmol). The crude was purified by flash chromatography (0-50% /- Hex-EtOAc) to give 817 mg (74% yield) of the title product. HPLC-MS (ESI) m/z: 428 [M-H]⁺.

Step 2

To a stirred mixture of the proper commercially available triphenylphosphonium bromide (XXXVII, 2.8 eq.) in Et₂0 (0.2 M), KOtBu was added at 0 °C and the mixture was stirred at r.t. for 3 h. The proper intermediate XXXVI (1 eq.) was then added and the resulting mixture was stirred at r.t. for further 16 h. The solvent was evaporated under vacuum and the crude was purified by flash chromatography to give the intermediate compound having general formula XXXVIII.

Tert-butyl-4-(3-(4-ethylphenyl)-4-vinyl-1H-pyrazolo[3,4-b]pyridin-6-yl)benzoate

(XXXVIlla). The title compound was obtained according to general procedure R-i, step 2, using methyltriphenylphosphonium bromide (XXXVIla, 685 mg, 1.92 mmol), KOtBu (217 mg, 1.93 mmol) and fe/f-butyl-4-(3-(4-ethylphenyl)-4-formyl-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)benzoate (XXXVIa, 300 mg, 0.702 mmol). The crude was purified by flash chromatography (0-40% /- Hex-EtOAc) to give 232 mg (78% yield) of the title product. HPLC-MS (ESI) m/z: 426 [M-H]⁺.

Step 3

A mixture of the proper intermediate XXXVIII (1 eq.) and Pd/c (5%, 0.5 eq.) in EtOH (0.1 M) and AcOH (one drop) was hydrogenated at 5 bar at r.t. for 5 h. The reaction mixture was then purified by flash chromatography to give the proper intermediate compound having general formula l^(VIII). Tert-butyl-4-(4-ethyl-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzoate

(l^(VIII)a). The title compound was obtained according to general procedure R-i, step 3, using fe f-butyl-4-(3-(4-ethylphenyl)-4-vinyl-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)benzoate (XXXVIlla, 86 mg, 0.20 mmol) and Pd/c (27 mg, 0.10 mmol). The crude was purified by flash chromatography (0-40% /- Hex-EtOAc) to give 86 mg (91 % yield) of the title product. HPLC-MS (ESI) m/z: 428 [M-H]⁺.

General proce

Step 1

Method (A): intermediate compound |<^V|-^VIII> (1 eq.) was dissolved in TFA/DCM (1 : 1 , 0.15 M) at r.t. and the resulting solution was stirred at r.t. for 16 h. Solvents were removed under vacuum and the residue was purified by the opportune technique to give the final compound having general formula l^(IX).

Method (B): 4 M HCI in 1 ,4-dioxane (10 eq.) was added to intermediate compound l^(VI ^Vlll) (1 eq.), and the resulting solution was stirred at r.t. for 40 h. Solvents were removed under vacuum and the residue was purified by the opportune technique to give the final compound having general formula l^(IX).

4-(3-(4-Ethylphenyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzoic acid (Example 88). The title compound was obtained according to general procedure Si, step 1 , method (A) using tert- butyl 4-(3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)benzoate (l^(VI)a, 252 mg, 0.631 mmol), TFA/DCM (1 : 1 , 4 ml_). The crude was purified by flash chromatography (0- 100% /- Hex-EtOAc, 1 % AcOH, product eluted at 60% EtOAc) to give 95 mg (43% yield) of the title product. HPLC-MS (ESI) m/z: 344 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.88 (s, 1 H), 13.10 (s, 1 H), 8.68 (d, J = 8.5 Hz, 1 H), 8.37 - 8.29 (m, 2H), 8.17 - 8.07 (m, 2H), 8.02 - 7.91 (m, 3H), 7.43 - 7.36 (m, 2H), 2.70 (q, J = 7.5 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H).

4-(3-(4-Ethylphenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzoic acid (Example 89). The title compound was obtained according to general procedure Si, step 1 , method (A) using fe/f-butyl-4-(3-(4-ethylphenyl)-4-(trifluoromethyl)-1 /-/-pyrazolo[3,4- b]pyridin-6-yl)benzoate (l^(VI)b, 190 mg, 0.406 mmol), TFA/DCM (1 : 1 , 4 mL). The crude was purified by flash chromatography (0-100% /-Hex-EtOAc, 1 % AcOH) to give 58 mg (34% yield) of the title product. HPLC-MS (ESI) m/z: 412 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 14.51 (s, 1 H), 13.21 (s, 1 H), 8.41 (d, J = 8.6 Hz, 2H), 8.20 (s, 1 H), 8.17 - 8.10 (m, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1 .26 (t, J = 7.6 Hz, 3H). 4-(3-(4-ethylphenyl)-4-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzoic acid (Example 90). The title compound was obtained according to general procedure Si, step 1 , method (B) using fe/f-butyl-4-(3-(4-ethylphenyl)-4-(hydroxymethyl)-1 /-/-pyrazolo[3,4- b]pyridin-6-yl)benzoate (l^(VII)a, 70 mg, 0.16 mmol) and 4 M HCI in 1 ,4-dioxane (407 pi, 1.63 mmo). The crude was purified by flash chromatography (0-80% /- Hex-EtOAc, 1 % AcOH) to give 41 mg (65% yield) of the title product. HPLC-MS (ESI) m/z: 374 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.86 (s, 1 H), 13.12 (s, 1 H), 8.31 - 8.24 (m, 2H), 8.16 - 8.09 (m, 2H), 7.95 (d, J = 1.1 Hz, 1 H), 7.63 - 7.55 (m, 2H), 7.36 (d, J = 8.2 Hz, 2H), 5.54 (s, 1 H), 4.74 (d, J = 4.0 Hz, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).

4-(4-Ethyl-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzoic acid (Example 91). The title compound was obtained according to general procedure Si, step 1 , method (B) using fe/f-butyl-4-(4-ethyl-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)benzoate (l^(VIII>a, 85 mg, 0.20 mmol) and 4 M HCI in 1 ,4-dioxane (0.5 ml_, 2.0 mmol). The crude was purified by flash chromatography (0-100% /- Hex-EtOAc, 1 % AcOH) to give 23 mg (31 % yield) of the title product. HPLC-MS (ESI) m/z: 372 [M-H]⁺. ¹H-NMR (400 MHz, DMSO- de) d: 13.80 (s, 1 H), 13.11 (s, 1 H), 8.36 - 8.28 (m, 2H), 8.14 - 8.05 (m, 2H), 7.73 (s, 1 H), 7.60 - 7.51 (m, 2H), 7.40 - 7.31 (m, 2H), 2.88 (q, J = 7.5 Hz, 2H), 2.72 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H).

Preparation III: Synthesis of compounds 92, 93, 107

Compounds 92, 93 and 107 can be obtained by application of the chemical transformations reported in general procedures Ti - Yi herein described.

General procedures T1-V1 relate to the preparation of intermediates. The preparation of compound 92, 93 and 107 of Table A is described in general procedure Wi, Yi, and Xi, respectively. Compounds of Table B were also prepared according to general procedure Yi and X

General procedure T-i: Synthesis of intermediate boronic acid pinacol esters

XXXIX (R³Bpin)

Step 1

A vial containing PdCl2(dppf) DCM adduct (0.03 eq.), KOAc (1.3 eq.), the proper intermediate XIV (1 eq.) and bis(pinacolato)diboron (1.1 eq.) was evacuated and backfilled with N2 (x3). Dioxane (2.5 ml_) was added and the resultant orange solution was heated at 95 °C for 3.5 h. The reaction mixture (XXXIX) was then cooled to rt and used as such for the next step.

N-(pyridin-3-yl)-4-( 4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)benzene-1 - sulfonamide (XXXIXa). The title compound was obtained according to general procedure Y2, step 1 using 4-bromo-N-(pyridin-3-yl)benzenesulfonamide (XlVf, 1079 mg, 3.4 mmol), PdCl2(dppf) DCM adduct (94 mg, 0.12 mmol), KOAc (451 mg, 4.6 mmol), and bis(pinacolato)diboron (904 mg, 3.6 mmol). The product has not been isolated and the total mixture has been used us such for the next step.

3-fluoro-4-{[4-( 4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)benzene-1- sulfonyl]amino}benzamide (XXXIXb). The title compound was obtained according to general procedure Y2, step 1 using 4-(4-bromophenylsulfonamido)-3-fluorobenzamide (XlVe, 0.91 g, 2.4 mmol), PdCI₂(dppf) DCM adduct (66 mg, 0.08 mmol), KOAc (319 mg, 3.3 mmol), and bis(pinacolato)diboron (0.640 g, 2.5 mmol). The product has not been isolated and the total mixture has been used us such for the next step.

General procedure Ui: Synthesis of intermediate pyrazolopyridines XL

Step 1

To a solution of intermediate XXX (1 eq.) in EtOH (0.3 M) hydrazine in water (10 eq.) was added. The resultant colourless solution was stirred at rt for 15 h. The reaction mixture was quenched by adding a saturated aqueous solution of NaHCC and extracted with EtOAc. The organic layers were combined, washed with brine and concentrated under reduced pressure. The resulting crude was purified by flash chromatography to give the intermediate compound having general formula XL, separated from its undisered regioisomer.

4,6-Dichloro-3-(4-ethylphenyl)-1H-pyrazolo[4,3-c]pyridine (XLa). The title compound was obtained according to general procedure Ui, step 1 , using (4-ethylphenyl)(2,4,6- trichloropyridin-3-yl)methanone (XXXc, 6.9 g, 21 .5 mmol) and hydrazine in water (IVa, 19.3 mL, 215 mmol). The crude was purified twice by flash chromatography (0-50% EtOAc/isohexane) to give 3.4 g (52% yield) of the title product. HPLC-MS (ESI) m/z: 292.6 / 294.6 / 296.6 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 14.07 (s, 1 H), 7.77 (s, 1 H), 7.63 - 7.58 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H). The regioselectivity of the title product has been confirmed by NMR: 1 D nOe showed a signal between protons at 14.05 and 7.75 ppm.

General procedure V-i: Synthesis of intermediate pyrazolopyridines XLI

Step 1 In a vial, the proper intermediate XL (1 eq.) and MeONa (30% in MeOH) (15 eq.) were added sequentially and the resultant solution was heated in the microwave at 1 10 °C for 5 h. The reaction was quenched with a saturated aqueous solution of NaHCC and extracted with EtOAc. The organic layers were combined, washed with brine and concentrated under reduced pressure. The resulting crude was purified by flash chromatography to give the intermediate compound having general formula XLI.

6-chloro-3-(4-ethylphenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridine (XLIa). The title compound was obtained according to general procedure Vi, step 1 , using 4,6-dichloro-3- (4-ethylphenyl)-1 H-pyrazolo[4,3-c]pyridine (XLa, 1 g, 3.4 mmol) and sodium methoxide (30% in MeOH) (9.5 mL, 51 .3 mmol). The crude was purified by flash chromatography (0-35% EtOAc/isohexane) to give 825 mg (83% yield) of the title product. HPLC-MS (ESI) m/z: 288.5 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 13.61 (s, 1 H), 7.83 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.24 (s, 1 H), 3.99 (s, 3H), 2.67 (q, J = 7.6 Hz, 2H), 1 .24 (t, J = 7.6 Hz, 3H). The regioselectivity has been confirmed with nOe correlation between signal at 3.99 (OMe) and 7.83 ppm (CH of Ethylphenyl).

General procedure W-i: Synthesis of compounds with general formula l^(X) (Example 92)

Step 1

A solution of intermediate XLI (1 eq.) in THF (0.5 M), a solution of K2CO3 (4.3 eq.) in water (1 M) and a microspatula of PdCl2(dppf)-cH2Cl2 adduct were added sequentially to the not purified reaction mixture containing the proper boronate XXXIX. The total mixture was heated in the microwave at 1 10 °C for 90 min, then at 100 °C for further 2 days. The reaction mixture was allowed to cool to r.t., quenched with a saturated aqueous solution of NaHCC and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgS0₄, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give the intermediate compound with general formula |^(X)

4-(3-(4-Ethylphenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-N-(pyridin-3- yljbenzenesulfonamide (Example 92). The title compound was obtained according to general procedure Wi, step 1 using 6-chloro-3-(4-ethylphenyl)-4-methoxy-1 H- pyrazolo[4,3-c]pyridine (XLIa, 268 mg, 0.9 mmol), the total mixture containing the boronate N-(pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 - sulfonamide XXXIXa, and K₂CO₃ (534 mg, 3.9 mmol). The crude was purified by flash chromatography (0-100% EtOAc/isohexane) to give 90 mg (20% yield) of the title product. HPLC-MS (ESI) m/z: 486.4 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 13.70 (s, 1 H), 10.64 (s, 1 H), 8.39 - 8.35 (m, 2H), 8.35 - 8.31 (m, 1 H), 8.26 (dd, J = 4.7, 1 .5 Hz, 1 H), 7.91 - 7.84 (m, 4H), 7.76 (s, 1 H), 7.55 (ddd, J = 8.3, 2.7, 1 .5 Hz, 1 H), 7.35 - 7.28 (m, 3H), 4.10 (s, 3H), 2.67 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).

General procedure Xi: Synthesis of compounds with general formula l^(XXIII) (Example

Step 1

To a solution of intermediate l^(X) (1 eq.) in THF (0.1 M), BBr3 (1 M in DCM; 10 eq.) was added. The resultant suspension was heated at 50 °C for 6 h. The solvent was removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of NaHCC and EtOAc. The solid was filtered and dried under vacuum to give the intermediate compound with general formula l^(XI).

4-(3-(4-Ethylphenyl)-4-hydroxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-N-(pyridin-3- yljbenzenesulfonamide (l^(XI)a). The title compound was obtained according to general procedure Xi, step 1 using 4-(3-(4-ethylphenyl)-4-methoxy-1 H-pyrazolo[4,3-c]pyridin-6- yl)-N-(pyridin-3-yl)benzenesulfonamide (Example 92, 602 mg, 1 .2 mmol) and BBr3 (1 M in DCM; 12.4 ml_, 12 mmol). The solid was filtered, rinsed with water (2 ml_) and Et₂0 (5 ml_) and dried at 40 °C under vacuum for 2 h to give 376 mg (60% yield) of the title product. HPLC-MS (ESI) m/z: 472.4 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 13.51 (s, 1 H), 1 1 .22 (s, 1 H), 10.74 (s, 1 H), 8.34 (d, J = 2.6 Hz, 1 H), 8.29 (dd, J = 4.7, 1 .5 Hz, 1 H), 8.25 (d, J = 7.9 Hz, 2H), 7.98 - 7.94 (m, 2H), 7.89 - 7.85 (m, 2H), 7.58 (ddd, J = 8.4, 2.7, 1 .4 Hz, 1 H), 7.34 (dd, J = 8.3, 4.7 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 2H), 6.78 (s, 1 H), 2.66 (q, J = 7.5 Hz, 2H), 1 .23 (t, J = 7.6 Hz, 3H).

Step 2

The intermediate l^(XI) (1 eq.) and POCI3 (132 eq.) were charged sequentially in a vial. The resultant solution was heated at 90 °C for 3 h. The excess of POCI3 was removed under reduced pressure and the residue was partitioned between a saturated solution of NaHCC and EtOAc. The organic layer was washed with brine, passed through a phase separator and evaporated under reduced pressure. The crude product was then purified by the opportune technique to give the final compound having general formula |<^XXIII>.

4-(4-chloro-3-(4-ethylphenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-N-(pyridin-3- yljbenzenesulfonamide (Example 107). The title compound was obtained according to general procedure Xi, step 2 using 4-(3-(4-ethylphenyl)-4-hydroxy-1 H-pyrazolo[4,3- c]pyridin-6-yl)-N-(pyridin-3-yl)benzenesulfonamide (l^(XI)a, 195 mg, 0.41 mmol) and POCI3 (5 ml_, 54 mmol). The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give 1 15 mg (56% yield) of the title product. HPLC-MS (ESI) m/z: 490.3 / 492.3 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 14.15 (s, 1 H), 10.65 (s, 1 H), 8.36 - 8.31 (m, 3H), 8.27 (dd, J = 4.7, 1 .5 Hz, 1 H), 8.20 (s, 1 H), 7.91 - 7.88 (m, 2H), 7.66 - 7.63 (m, 2H), 7.55 (ddd, J = 8.3, 2.7, 1 .5 Hz, 1 H), 7.38 - 7.35 (m, 2H), 7.31 (ddd, J = 8.3, 4.7, 0.7 Hz, 1 H), 2.71 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).

General procedure Yi: Synthesis of compounds with general formula l^(XII) (Example 93)

Step 1

A sealed microwave vial containing PdCl2(dppf)-cH2d2 adduct (0.1 eq.) and intermediate l^(XXIII) (1 eq.) was evacuated and backfilled with N2 (x3). MeOH (0.1 M) and triethylamine (3 eq.) were added and carbon monoxide was bubbled through the reaction for around 5 minutes using a balloon. The balloon was removed and the reaction stirred at 80 °C overnight. At rt, the vial was purged with N2 and the solvent removed. The residue was dissolved in EtOAc and washed with a saturated solution of NaHCOs and brine. The solvent was evaporated and the crude product was purified by the opportune technique to give a mixture of compounds having general formula l^(XXIV) which was used in the next step without further purification.

Methyl 3-(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[4,3- c]pyridine-4-carboxylate (l^(XXIV)a). The title compound was obtained according to general procedure Yi, step 1 using 4-(4-chloro-3-(4-ethylphenyl)-1 H-pyrazolo[4,3-c]pyridin-6-yl)- N-(pyridin-3-yl)benzenesulfona-mide (example 107, 200 mg, 0.39 mmol) PdCl2(dppf)- CH2CI2 adduct (32 mg, 0.039 mmol) and triethylamine (162 pi, 1 .2 mmol). The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give 1 10 mg (42% yield) of the title product as a 76(COOY)/15(OCH₃)/8(H) mixture of compounds. The product was used in the next step without further purification. ¹H-NMR (500 MHz, DMSO -c/e) S: 14.10 (br s, 1 H), 10.65 (s, 1 H), 8.37 - 8.35 (m, 2H), 8.34 - 8.31 (m, 2H), 8.27 (dd, J = 4.7, 1 .5 Hz, 1 H), 7.93 - 7.89 (m, 2H), 7.55 (ddd, J = 8.2, 2.7, 1 .5 Hz, 1 H), 7.46 - 7.42 (m, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.31 (dd, J = 8.4, 4.8 Hz, 1 H), 3.48 (s, 3H), 2.70 (q, J = 7.7 Hz, 2H), 1 .28 - 1 .22 (m, 3H).

Step 2

General procedure Yi step 2 follows the same conditions described for general procedure Ki, step 1 , method (A).

3-(4-Ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[4,3-c]pyridine- 4-carboxylic acid (Example 93). The title compound was obtained according to general procedure Xi, step 2 using methyl 3-(4-ethylphenyl)-6-(4-(N-(pyridin-3- yl)sulfamoyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine-4-carboxylate (l^(XXIV)a, 1 10 mg, 0.163 mmol) and LiOH (20 mg, 0.814 mmol). The crude product was first purified by chromatography on silica gel (0-10% MeOH/DCM with 1 % of AcOH) and then dissolved in methanol, concentrated down (x3) and dried in desiccator (50 °C, 4 days) to give 40 mg (47% yield) of the title product. HPLC-MS (ESI) m/z: 500.3 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 14.00 (br s, 1 H), 13.69 (br s, 1 H), 10.64 (s, 1 H), 8.37 (d, J = 8.3 Hz, 2H), 8.33 (d, J = 2.6 Hz, 1 H), 8.27 (d, J = 4.7 Hz, 1 H), 8.23 (s, 1 H), 7.90 (d, J = 8.3 Hz, 2H), 7.60 - 7.53 (m, 3H), 7.34 - 7.29 (m, 3H), 2.69 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

Preparation IV: Synthesis of compounds 94-97

Compounds 94-97 can be obtained by application of the chemical transformations reported in general procedures Zi - N2 herein described.

General procedures Z1-J2 and L2-M2 relate to the preparation of intermediates and compounds of Table B. The preparation of compounds 94-96 of Table A is described in general procedure K2. The preparation of compound 97 of Table A is described in general procedure N2.

General procedure Zy. Synthesis of intermediate amines XLIV (R³NH)

Step 1

The proper amine (X, 1 eq.) was dissolved in pyridine (2M) and the solution was cooled down to 0 °c. To this solution tert- butyl 4-(chlorosulfonyl)piperidine-1 -carboxylate (XLII, 1 .05 eq.) was added and the reaction was allowed to warm up to r.t. and stirred overnight. Solvent was removed under vacuum and the residue was purified by flash chromatography to give intermediate compound having general formula XLIII.

Tert-butyl 4-(N-(pyridin-3-yl)sulfamoyl)piperidine-1-carboxylate (XLIIIa). The title compound was obtained according to general procedure Z^, step 1 using tert- butyl 4- (chlorosulfonyl)piperidine-l -carboxylate (XLII, 1 .732 g, 6.10 mmol) and pyridin-3-amine (Xn, 0.547 g, 5.81 mmol). The crude was purified by flash chromatography (C₁₈, 0.1 % NH₄HCO3 in water/AcN) to give 0.613 g (30% yield) of the title product. HPLC-MS (ESI) m/z: 286 [M-H]⁺.

Step 2

The N -boc intermediate XLIII (1 eq.) was dissolved in HCI solution (4 M in dioxane, 32 eq.) and the reaction was stirred at r.t. for 1 h. The solvent was evaporated under vacuum to afford the proper intermediate compound having general formula XLIV, which was used for the next step without further purification.

N-(pyridin-3-yl)piperidine-4-sulfonamide hydrochloride (XLIVa). The title compound was obtained according to general procedure Z^, step 2 using fe/f-butyl 4-(/V-(pyridin-3- yl)sulfamoyl)piperidine-1 -carboxylate (XLIIIa, 0.613 g, 1 .795 mmol) and HCI solution (14 mL, 57.5 mmol). The crude (0.431 g, 86% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 242.1 [M-H]⁺.

General procedure A₂: Synthesis of intermediate halides XLVI (R³Hal)

Step 1

The proper intermediate XII (1 eq.) was dissolved in pyridine (0.2 M) and the appropriate commercially available sulfonyl chloride (XLV, 1 .1 eq.) was added dropwise at r.t. The reaction was stirred at r.t. overnight. Pyridine was evaporated under vacuum and the residue was purified by flash chromatography to give the intermediate compound having general formula XLVI.

N-(6-bromopyridin-3-yl)methanesulfonamide (XLVIa). The title compound was obtained according to general procedure A₂, step 1 , using 6-bromopyridin-3-amine (Xllc, 0.200 g, 1 .156 mmol) and methanesulfonyl chloride (XLVa, 0.100 ml_, 1.272 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 91 mg (31 % yield) of the title product. HPLC-MS (ESI) m/z: 250.0/251.0 [M-H]⁺.

General procedure B₂: Synthesis of intermediate boronates XLVIII (R³B(OH)₂)

The proper intermediate XLVII (1 eq.) and NMM (7 eq.) were dissolved in DCM (0.2 M) and the solution was cooled down to 0 °c. The appropriate sulfonyl chloride derivative (XLV, 1 .2 eq.) was then added to the solution and the reaction was stirred at r.t. for 2 h. EtOAc and brine were added, the layers were separated and the organic phase was dried over MgSC , filtered and evaporated under reduce pressure to give the intermediate compound having general formula XLVIII.

(6-(Methylsulfonamido)pyridin-3-yl)boronic acid (XLVIlla). The title compound was obtained according to general procedure B₂, step 1 , using 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-amine (XLVIla, 0.24 g, 1 .091 mmol), NMM (0.84 ml_, 7.63 mmol) and methanesulfonyl chloride (XLVa, 0.1 ml_, 1.330 mmol). The crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.325 g (99% yield) of the title product. HPLC-MS (ESI) m/z: 216.9 [M-H]⁺.

General procedure C₂: Synthesis of intermediate boronates Lll (R³B(OH)₂):

Step 1 4-Mercaptophenylboronic acid (XLIX, 1 .0 g, 6.49 mmol), pinacol (0.767 g, 6.49 mmol) and MgSC (4.69 g, 39.0 mmol) were mixed in Et₂0 (0.26 M) and the mixture was stirred at r.t. overnight. The reaction was filtered, the solid was washed with Et₂0 and discarded. The filtrate was concentrated under vacuum to give 1 .53 g (99% yield) of 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenethiol (L) which was used for the next step without further purification. HPLC-MS (ESI) m/z: no ionisation.

Step 2

Intermediate L (1 eq.) was dissolved in DMF (0.6 M). K2CO3 (4 eq.) and the proper bromo derivative (LI, 1 .5 eq.) were added to the solution and the reaction was stirred at r.t. for 1 .5 h. EtOAc was added and the mixture was washed with water and brine. The organic phase was dried over MgSC , filtered and evaporated under reduce pressure to give the intermediate compound having general formula Lll.

(4-((Pyridin-3-ylmethyl)thio)phenyl)boronic acid (Lila). The title compound was obtained according to general procedure C2, step 2 using 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzenethiol (L, 1 .53 g, 6.49 mmol), K₂C0₃ (3.59 g, 26.0 mmol) and 3- (bromomethyl)pyridine (Lla, 1.675 g, 9.74 mmol). The crude (1 .59 g, 99% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 245.9 [M-H]⁺.

General procedure D₂: Synthesis of intermediate pyrazolopyridines LV

Step 1

A solution of the proper pyrazolamine (V, 1 eq.) in water and AcOH (0.5 M, 3: 1 ) was cooled down to 0 °c. Intermediate LIN (1 eq.) was slowly added in portions to the solution and the mixture was heated up to reflux for 1 .5 h (a precipitate is formed after 1 h of reaction). The reaction was allowed to cool down to r.t. and the solid was filtered, washed with water and dried overnight in a vacuum oven at 40 °c to give the intermediate compound having general formula LIV which was used for the next step without further purification.

Ethyl-6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (LIVa). The title compound was obtained according to general procedure D2, step 1 using 1 /-/-pyrazol-3-amine (Vj, 25 g, 301 mmol) and sodium-1 ,4-diethoxy-1 ,4-dioxobut-2-en-2-olate (Lilia, 63.2 g, 301 mmol). The crude (14.4 g, 23% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 207.9 [M-H]⁺.

Step 2

Intermediate LIV (1 eq.) was slowly added in portions to POCI3 (10 eq.) and the mixture was heated to reflux for 3 h. The reaction was cooled down to r.t. and slowly added to a mixture of ice/water. The resulting precipitate was filtered, rinsed with water (until neutral pH) and dried overnight in a vacuum oven at 40 °c to obtain the intermediate compound having general formula LV which was used for the next step without further purification.

Ethyl-6-chloro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVa). The title compound was obtained according to general procedure D2, step 2 using ethyl-6-hydroxy-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (LIVa, 14.4 g, 69.5 mmol) and POCI₃ (65 mL, 695 mmol). The crude (12.16 g, 78% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 225.8 [M-H]⁺.

General procedure E₂: Synthesis of intermediate pyrazolopyridines LVI

Step 1

Intermediate LV (1 eq.), aqueous 48% HBF4Solution (5 eq.) and NIS (1 eq.) were dissolved in AcN (0.3 M). The reaction was heated up to 80 °c for 1 h, then cooled down to r.t. , poured into an aqueous sat. NaHCC solution and vigorously stirred for 30 min. The resulting solid was filtered, washed with aqueous sat. Na₂S₂0₃ solution and water and finally dried under vacuum to give the intermediate compound having general formula LVI which was used for the next step without further purification.

Ethyl-6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVIa). The title compound was obtained according to general procedure E2, step 1 using ethyl-6-chloro- 1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVa, 12.16 g, 53.9 mmol), aqueous 48% HBF4Solution (42 ml_, 270 mmol) and NIS (12.13 g, 53.9 mmol). The crude (17.02 g, 90% yield) was used for the next step without further purification. FIPLC-MS (ESI) m/z: 351 .7 [M-H]⁺.

General procedure F₂: Synthesis of intermediate pyrazolopyridines LVII

Step 1

Intermediate LVI (1 eq.), 3,4-dihydro-2/-/-pyran (1.5 eq.) and p-toluenesulfonic acid (0.1 eq.) were dissolved in CHC (0.3 M) and the mixture was stirred at r.t. overnight. The solvent was removed under vacuum and the resulting crude was purified by flash chromatography to give the proper intermediate compound having general formula LVII.

Ethyl-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3, 4-b]pyridine-4- carboxylate (LVIla). The title compound was obtained according to general procedure F2, step 1 using ethyl-6-chloro-3-iodo-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (LVIa, 17.02 g, 48.4 mmol), 3,4-dihydro- 2/-/-pyran (6.63 mL, 72.6 mmol) and p-toluenesulfonic acid (0.921 g, 4.84 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 6.17 g (26% yield) of the title product. HPLC-MS (ESI) m/z: 351 .8 [M-H]⁺.

General procedure G2: Synthesis of intermediate pyrazolopyridines LVIII

Step 1

Intermediate LVII (1 eq.), the proper boronic acid (XXI, 2 eq.), aqueous 2 M Na₂C0₃ solution (2.6 eq.), PdCl2(dppf) DCM adduct (0.08 eq.) and 1 ,4-dioxane (0.1 M) were placed in a Schlenk flask, purged under argon and heated to 80 °c for 70 min. The mixture was filtered through a pad of celite, that was rinsed with MeOH and the filtrate was concentrated under reduced pressure. The resulting crude was purified by flash chromatography to give the intermediate compound with general formula LVIII.

Ethyl-6-chloro-3-(4-ethylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (LVIlla). The title compound was obtained according to general procedure G2, step 1 using ethyl-6-chloro-3-iodo-1 -(tetrahydro-2/-/-pyran-2-yl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (LVIla, 6.17 g, 14.16 mmol), (4-ethylphenyl)boronic acid (XXIf, 4.25 g, 28.3 mmol), aqueous 2 M Na₂C0₃ solution (18.4 ml_, 36.8 mmol), PdCl2(dppf) DCM adduct (1.15 g, 1 .14 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 5.40 g (92% yield) of the title product. HPLC- MS (ESI) m/z: 329.8 [M-H]⁺.

General procedure H₂: Synthesis of intermediate pyrazolopyridines XXII^(III)

Step 1

Method (A): In a MW vial, intermediate LVIII (1 eq.), the proper amine XLIV (1 .1 eq.) and DIPEA (3.3 eq.) were dissolved in DMSO (0.6 M). The reaction was heated up to 150 °c for 1 h in a MW reactor. The solvent was removed under vacuum and the residue was purified by flash chromatography to obtain the proper intermediate compound having formula XXII^(III).

Method (B): intermediate LVIII (1 eq.), the proper boronic acid XLVIII (1 .1 eq.), PdCl2(dppf) DCM adduct (0.1 eq.), Na₂C0₃ (3 eq.) and 1 ,4-dioxane (0.1 M) were placed in a MW vial. The mixture was purged three times with Ar and irradiated at 140 °c for 15 min. The reaction mixture was filtered through a pad of celite that was rinsed with MeOH and the filtrate was evaporated to dryness under vacuum. The reaction crude was purified by flash chromatography to obtain the proper intermediate compound having formula

XXIIC"⁾.

Method (c): In a MW vial, intermediate LVIII (1 eq.), the proper boronic acid Lll (1 .5 eq.), PdCl2(dppf) DCM adduct (0.1 eq.l) and CsF (3 eq.) were mixed in dioxane (5 ml_). The reaction was purged three times with Ar and heated at 120 °c for 30 min in a MW reactor. The reaction was filtered through a celite plug and the filtrate was concentrated under vacuum. The residue purified by flash chromatography to obtain the proper intermediate compound having formula XXII^(III).

Ethyl-3-(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)piperidin-1-yl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(lll)a). The title compound was obtained according to general procedure hh, step 1 , method (A) using ethyl-6-chloro- 3-(4-ethylphenyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVIlla, 0.530 g, 1 .280 mmol), A/-(pyridin-3-yl)piperidine-4-sulfonamide hydrochloride (XLIVa, 0.391 g, 1 .408 mmol) and DIPEA (0.75 ml_, 4.22 mmol). The crude was purified by flash chromatography (Si02, DCM/MeOH) to give 0.214 g (27% yield) of the title product. HPLC-MS (ESI) m/z: 619.3 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(6-(methylsulfonamido)pyridin-3-yl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(lll)b). The title compound was obtained according to general procedure hh, step 1 , method (B) using ethyl-6-chloro-3- (4-ethylphenyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVIlla, 0.205 g, 0.495 mmol), (6-(methylsulfonamido)pyridin-3-yl)boronic acid (XLVIlla, 0.1 18 g, 0.545 mmol), PdCl2(dppf) DCM adduct (0.040 g, 0,050 mmol) and Na₂C0₃ (0.743 mL, 1 .486 mmol). The crude was purified by flash chromatography (Si02, DCM/MeOH) twice to give 0.140 g (40% yield) of the title product. HPLC-MS (ESI) m/z: 549.8 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(4-((pyridin-3-ylmethyl)thio)phenyl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(lll)c). The title compound was obtained according to general procedure H2, step 1 , method (c) using ethyl-6-chloro-3- (4-ethylphenyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVIlla, 0.52 g, 1 .256 mmol), (4-((pyridin-3-ylmethyl)thio)phenyl)boronic acid (Lila, 0.462 g, 1 .885 mmol), PdCl2(dppf) DCM adduct (0.103 g, 0.126 mmol) and CsF (0.573 g, 3,77 mmol). The crude was purified by flash chromatography (Si02, DCM/MeOH) to give 0.290 g (40% yield) of the title product. HPLC-MS (ESI) m/z: 578.8[M-H]⁺.

General procedure l₂: Synthesis of intermediate pyrazolopyridines XXII^(IV)

XXII^(III>: R² = Aryl, alkyl XXII^|IV): R² = Aryl, alkyl

R³ = SR^v-aryl R³ = S0₂R^v-aryl

Step 1

To an ice-cold solution of the thio-phenil derivative XXII^(III) (1 eq.) in DCM (0.05 M), a solution of mcPBA (2.3 eq.) in DCM (0.6 M) was added. The mixture was stirred at 0 °c for 30 min and then at r.t. for further 30 min. Aqueous 10% K2CO3 solution was added to the reaction mixture, layers were separated and the organic phase was washed with brine. The combined organic layers were dried over MgSC , filtered and concentrated under vacuum. The crude was purified by flash chromatography to give the intermediate compound with general formula XXII^(IV).

Ethyl-3-(4-ethylphenyl)-6-(4-((pyridin-3-ylmethyl)sulfonyl)phenyl)-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(IV)a). The title compound was obtained according to general procedure I2, step 1 using ethyl-3-(4-ethylphenyl)-6-(4- ((pyridin-3-ylmethyl)thio)phenyl)-1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4- b]pyridine-4-carboxylate (XXII^(lll)c, 0.290 g, 0.501 mmol) and mcPBA (0.259 g, 1 .157 mmol). The crude was purified by flash chromatography (S1O2, EtOAc/MeOH) to give 0.150 g (49% yield) of the title product. HPLC-MS (ESI) m/z: 594.8 [M-H]⁺.

General procedure J₂: Synthesis of compounds with general formula l^(XIII)

Step 3

To a solution of the proper intermediate XXII^{(IM, IV)} (1 eq.) in 1 ,4-dioxane (0.06 M), HCI solution (4 M in 1 ,4-dioxane, 30 eq.) was added. The mixture was stirred at r.t. for 2-16 h and then the solvent was removed under vacuum. The crude was either used in the next step without further purification or purified by flash chromatography to give intermediate compound having general formula l^(XIII).

Ethyl-3-(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)piperidin-1-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate HCI (l^(XIII)a). The title compound was obtained according to general procedure J2, step 1 using ethyl-3-(4-ethylphenyl)-6-(4-(/V-(pyridin-3- yl)sulfamoyl)piperidin-1 -yl)-1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (XXII^(lll)a, 0.214 g, 0.346 mmol) and HCI solution (3.2 ml_, 12.80 mmol). The crude (0.519 g, quant yield) was used for the next step without further purification. HPLC- MS (ESI) m/z: 535.2 [M-H]⁺. Ethyl-3-(4-ethylphenyl)-6-(6-(methylsulfonamido)pyridin-3-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(XIII)b). The title compound was obtained according to general procedure J2, step 1 using ethyl-3-(4-ethylphenyl)-6-(6-(methylsulfonamido)pyridin-3-yl)- 1 -(tetrahydro-2/-/-pyran-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (XXII^(lll)b, 0.108 g, 0.196 mmol) and HCI solution (1 .47 ml_, 5.89 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 44 mg (35% yield) of the title product. HPLC- MS (ESI) m/z: 465.8 [M-H]⁺.

Ethyl-3-(4-ethylphenyl)-6-(4-((pyridin-3-ylmethyl)sulfonyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate HCI (l^(XIII)c). The title compound was obtained according to general procedure J2, step 1 using ethyl-3-(4-ethylphenyl)-6-(4-((pyridin-3- ylmethyl)sulfonyl)phenyl)-1 -(tetrahydro-2/-/-pyran-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (XXII^(IV)a, 0.150 g, 0.246 mmol) and HCI solution (1.842 ml_, 7.37 mmol). The crude (0.139 g, quant yield) was used in the next step without further purification. HPLC- MS (ESI) m/z: 526.8[M-H]⁺.

General procedure K₂: Synthesis of compounds with general formula l^(XIII) (Examples 94-96)

Step 1

I'™¹: R = COOMe, COOEt l^,xlv|: R = COOH

R = Aryl, alkyl R = Aryl, alkyl

Step 1

General procedure K2 step 1 follows the same conditions described for general procedure Ki, step 1 , method (A).

3-(4-Ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)piperidin-1-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 94). The title compound was obtained according to general procedure K2, step 1 using ethyl-3-(4-ethylphenyl)-6-(4-(/V-(pyridin-3- yl)sulfamoyl)piperidin-1 -yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate HCI (l^(XIII)a, 0.210 g, 0.346 mmol) and LiOH solution (17 ml_, 17.4 mmol). The reaction mixture was evaporated under reduced pressure, and the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 27 mg (5% yield) of the title product. HPLC-MS (ESI) m/z: 507.1 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 3.12 (br s, 1 H), 10.15 (br s, 1 H), 8.45 (dd, J = 2.5 Hz, 0.5 Hz, 1 H), 8.30 (dd, J = 4.7 Hz, 1 .4 Hz, 1 H), 7.65 - 7.61 (m, 1 H), 7.45 (d, J = 7.4 Hz, 2H), 7.35 (ddd, J = 8.6 Hz, 4.7 Hz, 0.7 Hz, 1 H), 7.22 (d, J = 8.2 Hz, 2H), 6.90 (br s, 1 H), 4.51 (s, 1 H), 4.48 (s, 1 H), 3.60 - 3.50 (m, 1 H), 3.01 (t, J = 1 1.7 Hz, 2H), 2.64 (q, J = 7.6 Hz, 2H), 2.10 - 2.01 (m, 2H), 1.72 - 1 .57 (m, 2H), 1 .22 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(6-(methylsulfonamido)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 95). The title compound was obtained according to general procedure K2, step 1 , using ethyl-3-(4-ethylphenyl)-6-(6-(methylsulfonamido)pyridin-3-yl)- 1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIII)b, 0.044 g, 0.069 mmol) and LiOH (1 mL, 1 .00 mmol). The reaction mixture was evaporated under reduced pressure, and the crude was purified by reverse phase chromatography (C18, 0.1 % NH4HCO3 in water/AcN) to give 7.4 mg (18% yield) of the title product. HPLC-MS (ESI) m/z: 437.8 [M-H]⁺. ¹ H-NMR (400 MHz, DMSO -de) d: 8.95 (s, 1 H), 8.46 (dd, J = 8.7, 2.2 Hz, 1 H), 7.79 (br d, J = 6.4 Hz, 2H), 7.49 (s, 1 H), 7.22 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.7 Hz, 1 H), 3.24 (s, 3H), 2.65 (q, J = 7.7 Hz, 2H), 1 .22 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(4-((pyridin-3-ylmethyl)sulfonyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 96). The title compound was obtained according to general procedure K2, step 1 using ethyl-3-(4-ethylphenyl)-6-(4-((pyridin-3- ylmethyl)sulfonyl)phenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate- HCI (l^(XIII)c, 0.139 g, 0.246 mmol) and LiOH (4.92 mL, 4.92 mmol). The reaction mixture was evaporated under reduced pressure, and the crude was purified by flash chromatography (Cis, 0.1 % NH4HCO3 in water/AcN) to give 20 mg (16% yield) of the title product. HPLC-MS (ESI) m/z: 498.8 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.52 (dd, J = 4.7, 1 .5 Hz, 1 H), 8.37 (d, J = 1 .5 Hz, 1 H), 8.35 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1 H), 7.48 (s, 1 H), 7.36 (dd, J = 7.5, 4.8 Hz, 1 H), 7.21 (d, J = 8.2 Hz, 2H), 4.82 (s, 2H), 2.65 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).

General procedure L₂: Synthesis of intermediate pyrazolopyridines LIX

y , yl

Step 1

General procedure l_2 step 1 follows the same conditions described for general procedure J-i, step 1 , method (B).

Ethyl-6-chloro-1-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (LIXa). The title compound was obtained according to general procedure l_2, step 1 , using ethyl-6- chloro-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVa, 0.8 g, 3.55 mmol), (4- ethylphenyl)boronic acid (XXIVa, 0.798 g, 5.32 mmol), Cu(OAc)2 (0.193 g, 1 .064 mmol) and pyridine (0.86 ml_, 10.64 mmol). The crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.472 g (39% yield) of the title product. HPLC-MS (ESI) m/z: 329.8 [M-H]⁺.

General procedure M₂: Synthesis of intermediate pyrazolopyridines LX

Step 1

LIX: R⁴ = Aryl, alkyl LX: R⁴ = Aryl, alkyl Step 1

In a Schlenk tube were placed the proper intermediate LIX (1 eq.), bis(pinacolato)diboron (1.1 eq.) and KOAc (3 eq.) in DME (0.5 M). After purging with Ar, PdCl2(dppf) DCM adduct (0.2 eq.) was added and the mixture was purged again with Ar and heated at 80 °c overnight. The reaction mixture was filtered through a celite pad that was rinsed with MeOH. The solvent was evaporated under vacuum to give the intermediate compound having general formula LX which was used for the next step without further purification.

Ethyl-1 -( 4-ethyl phenyl)-6-( 4, 4, 5, 5-tetra methyl-1 , 3, 2-dioxaborolan-2-yl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (LXa). The title compound was obtained according to general procedure M2, step 1 using ethyl-6-chloro-1 -(4-ethylphenyl)-1 H-pyrazolo[3,4- b]pyridine-4-carboxylate (LIXa, 0.372 g, 1 .128 mmol), bis(pinacolato)diboron (0.315 g, 1 .241 mmol), KOAc (0.332 g, 3.38 mmol) and PdCI₂(dppf)-DCM adduct (0.184 g, 0.226 mmol). The crude (0.420 g, 72% yield) was used in the next step without further purification. HPLC-MS (ESI) m/z: 339.9 [M-H]⁺.

General procedure N₂: Synthesis of compounds with general formula l^(XIII) (Example 97)

Step 1

In a Schlenk tube compound LX (1 .1 eq.), the proper halide (XLVI, 1 eq.), and PdCl2(dppf) DCM adduct (0.1 eq.) were dissolved in 1 ,4-dioxane/water (3:1 ) (0.1 M). The mixture was purged with Ar and stirred at 100 °c overnight. The reaction mixture was then filtered through a pad of celite. The filter cake was rinsed with MeOH and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography to give the final compound having general formula l^(XV).

1-( 4-Ethylphenyl)-6-( 5-( methylsulfonamido)pyridin-2-yl)- 1 H-pyrazolo[3, 4-b ]pyridine-4- carboxylic acid (Example 97). The title compound was obtained according to general procedure N2, step 1 , using ethyl-1 -(4-ethylphenyl)-6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (LXa, 0.210 g, 0.399 mmol), A/-(6-bromopyridin-3-yl)methanesulfonamide (XLVIa, 0.091 g, 0.362 mmol), and PdCl2(dppf) DCM adduct (0.030 g, 0.036 mmol). The crude was purified by reverse phase chromatography (C18, 0.1 % NH4HCO3 in water/AcN) followed by normal phase flash chromatography (S1O2, cHex/EtOAc) to give 5.5 mg (3% yield) of the title product. HPLC- MS (ESI) m/z: 437.8 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 8.78 (s, 1 H), 8.65 (s, 1 H), 8.59 (d, J = 2.4 HZ, 1 H), 8.52 (d, J = 9.0 Hz, 1 H), 8.23 (d, J = 8.5, 2H), 7.86 (dd, J = 8.5, 2.6 Hz, 1 H), 7.48 (d, J = 8.6 Hz, 2H), 3.16 (s, 3H), 2.71 (q, J = 7.5 Hz, 2H), 1 .26 (t, J = 7.5 Hz, 3H).

Preparation VI: Synthesis of compounds 99-105, 109, 110

Compounds 99-105 and 109-1 10 can be obtained by application of the chemical transformations reported in general procedures V2 - C3 herein described. General procedures V2 - B3 relate to the preparation of intermediates and compounds of Table B. The preparation of compounds 99-105, 109-1 10 of Table A is described in general procedure C3.

General procedure V₂: Synthesis of intermediate pyrazoleamines V^(ll)

Step 1

To a solution of the proper intermediate IV (1 eq.) and sodium acetate (2 eq.) in EtOH (0.8 M) was added 2-chloroacrylonitrile (LXVIII, 1 .1 eq.) dropwise at rt. The resultant suspension was heated at 80 °C for 15 h. The reaction was quenched with a saturated aqueous solution of NaHCC and extracted with EtOAc. The organic layers were combined, washed with brine and evaporated under reduced pressure. The crude product was purified by flash chromatography to give the intermediate compound with general formula V^(ll).

1 -(tert-Butyl)-l H-pyrazol-5-amine (V^(ll)a). The title compound was obtained according to general procedure V2, step 1 using tert-butylhydrazine hydrochloride (IVb, 10 g, 80 mmol), sodium acetate (13.2 g, 160 mmol) and 2-chloroacrylonitrile (LXVIII, 7 ml, 88 mmol). The crude product was purified by flash chromatography (0-70% EtOAc/isohexane) to give 6.7 g (49% yield) of the title product. HPLC-MS (ESI) m/z: 84.3 (M-tBu+H)⁺, 140.5 (M+H)⁺. ¹H-NMR (400 MHz, DMSO -de) d: 6.95 (d, J = 1.7 Hz, 1 H), 5.36 (d, J = 1 .7 Hz, 1 H), 4.81 (br s, 2H), 1.51 (s, 9H).

General procedure W₂: Synthesis of intermediate sulfonyl-imidazoles LXXIII

Step 1

To a solution of 1 ,T-sulfonylbis(1 H-imidazole) (LXX, 10.8 g, 55 mmol) in DCM (100 mL) at 0 °C, methyl trifluoromethanesulfonate (6 mL, 55 mmol) was added. The reaction mixture was stirred at 0 °C for 3 h. The precipitate was collected by filtration, washed with DCM (3 x 10 mL) and dried under vacuum to afford 18.5 g (89% yield) of 1 -((1 H-imidazol- 1 -yl)sulfonyl)-3-methyl-1 H-imidazol-3-ium, triflic acid (LXXI). HPLC-MS (ESI) m/z: 213.2 [M-H]⁺. ¹H-NMR (500 MHz, cDcls) d: 10.14 (s, 1 H), 8.62 - 8.53 (m, 1 H), 8.49 (t, J = 2.1 Hz, 1 H), 8.00 (q, J = 1 .8 Hz, 2H), 7.42 - 7.29 (m, 1 H), 3.89 (s, 3H).

Step 2

To a suspension of fe/f-butyl piperazine-1 -carboxylate (1 1 .4 g, 61 mmol) in MeCN (100 mL), 1 -((1 H-imidazol-1 -yl)sulfonyl)-3-methyl-1 H-imidazol-3-ium (LXXI, 18.5 g, 51 mmol) was added and the resultant solution was stirred at rt for 18 h. A saturated aqueous solution of NaHCC was added (50 mL) and the product extracted with EtOAc (2 x 150 mL). The organic layers were combined, washed with brine (30 mL), dried over Na₂S0₄, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-100% EtOAc/isohexanes, solid loading) to afford 9.7 g (57% yield) of tert- butyl 4-((1 H-imidazol-1 -yl)sulfonyl)piperazine-1 -carboxylate (LXXI I) HPLC-MS (ESI) m/z: 317.2 [M-H]⁺. ¹H-NMR (500 MHz, cDcls) d: 8.17 (t, J = 1 .1 Hz, 1 H), 7.64 (t, J = 1 .5 Hz, 1 H), 7.19 (dd, J = 1 .5, 0.9 Hz, 1 H), 3.46 - 3.34 (m, 4H), 3.19 - 3.04 (m, 4H), 1 .47 - 1 .30 (m, 9H).

Step 3

To a solution of tert- butyl 4-((1 H-imidazol-1 -yl)sulfonyl)piperazine-1 -carboxylate (LXXI I, 5 g, 15 mmol) in DCM (45 mL) at 0 °C, methyl trifluoromethanesulfonate (1 .7 mL, 15 mmol) was added. The resultant solution was stirred at rt for 1 h. Isohexanes (10 mL) was added and the precipitate was collected by filtration, washed with isohexanes (2 x 10 mL) and dried under vacuum to afford 6.4 g (83% yield) of 1 -((4-(tert- butoxycarbonyl)piperazin-1 -yl)sulfonyl)-3-methyl-1 H-imidazol-3-ium, triflic acid (LXXIII). HPLC-MS (ESI) m/z: 331 .2 [M-H]⁺. ¹H-NMR (500 MHz, cDcls) d: 9.81 (s, 1 H), 8.17 (t, J = 2.0 Hz, 1 H), 7.98 (t, J = 1 .8 Hz, 1 H), 3.89 (s, 3H), 3.52 - 3.46 (m, 4H), 3.40 - 3.34 (m, 4H), 1 .39 (s, 9H).

General procedure X₂: Synthesis of intermediate sulfamoyl-piperazine LXXV

Step 1

To a suspension of intermediate LXXIII (1 eq.) in MeCN (0.2 M), the proper amine X (1 .2 eq.) was added and the resultant solution was stirred at 70 °C for 18 h. Isohexanes was then added and the precipitate was collected by filtration and washed with isohexanes to afford a pale solid. A saturated aqueous solution of NaHCC was added to the filtrate and the product was extracted with EtOAc, washed with brine, dried and purified by the opportune technique to give the intermediate compound with general formula LXXIV. tert-Butyl 4-(N-(pyridin-3-yl)sulfamoyl)piperazine-1-carboxylate (LXXIVa). The title compound was obtained according to general procedure X2, step 1 , using 1 -((4-(tert- butoxycarbonyl)piperazin-1 -yl)sulfonyl)-3-methyl-1 H-imidazol-3-ium, triflic acid (LXXIII, 3.9 g, 1 1 .2 mmol) and pyridin-3-amine (Xn, 1 .3 g, 13.4 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 2.5 g (62% yield) of the title product. HPLC-MS (ESI) m/z: 343.2 [M-H]⁺. ¹H-NMR (500 MHz, cDcls) d: 10.31 (s, 1 H), 8.44 - 8.40 (m, 1 H), 8.29 (dd, J = 4.7, 1 .5 Hz, 1 H), 7.60 (ddd, J = 8.3, 2.7, 1 .5 Hz, 1 H), 7.35 (dd, J = 8.3, 4.7 Hz, 1 H), 3.33 - 3.27 (m, 4H), 3.1 1 - 3.05 (m, 4H), 1.38 (s, 9H).

tert-Butyl 4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)piperazine-1-carboxylate (LXXIVb). The title compound was obtained according to general procedure X2, step 1 , using 1 -((4-(fe/f-butoxycarbonyl)piperazin-1 -yl)sulfonyl)-3-methyl-1 H-imidazol-3-ium, triflic acid salt (LXXIII, 5.6 g, 1 1 .0 mmol) and 4-amino-3-fluorobenzamide (Xv, 2.5 g, 16.2 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 380 mg (7% yield) of the title product. HPLC-MS (ESI) m/z: 347.1 (M-tBu+H)⁺; 425.2 (M+Na)⁺; 343.2 [M-H]⁺.

Step 2

To a solution of intermediate LXXIV (1 eq.) in DCM (0.2 M), TFA (1.3 M) was added. The resultant solution was stirred at rt for 3 h. The solvent was removed under reduced pressure azeotroping with toluene to afford a residue which was then basified with a saturated aqueous solution of NaHCOs and extracted with DCM. The aqueous layer was concentrated in vacuo and the obtained crude product was purified by the opportune technique to give the intermediate compound with general formula LXXV.

N-(Pyridin-3-yl)piperazine-1-sulfonamide, TFA salt (LXXVa). The title compound was obtained according to general procedure X2, step 2, using tert- butyl 4-(N-(pyridin-3- yl)sulfamoyl)piperazine-1 -carboxylate (LXXIVa, 2.5 g, 7.30 mmol) and TFA (5.6 mL). The crude was purified by flash chromatography (0-10% (0.7 M Ammonia/MeOH)/DCM, dry load) to give 2.5 g (91 % yield) of the title product. HPLC-MS (ESI) m/z: 243.2 [M-H]⁺. ¹H- NMR (500 MHz, cDcls) d: 8.45 (d, J = 2.6 Hz, 1 H), 8.32 (dd, J = 4.7, 1 .4 Hz, 1 H), 7.64 (ddd, J = 8.3, 2.7, 1.5 Hz, 1 H), 7.38 (dd, J = 8.3, 4.7 Hz, 1 H), 3.36 - 3.30 (m, 4H), 3.24 - 3.09 (m, 4H). 2 NH signals missing.

3-Fluoro-4-(piperazine-1-sulfonamido)benzamide, TFA salt (LXXVb). The title compound was obtained according to general procedure X2, step 2, using tert- butyl 4-(N- (4-carbamoyl-2-fluorophenyl)sulfamoyl)piperazine-1 -carboxylate (LXXIVb, 440 mg, 1 .1 mmol) and TFA (1 mL). The crude product was loaded onto a column of ScX (10 g) in MeOH. The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH to afford 220 mg (51 % yield) of the title product. HPLC-MS (ESI) m/z: 303.1 [M-H]⁺.

General procedure Y₂: Synthesis of intermediate stannanes LXXVIII (R³SnMe₃)

Step 1

To a solution of intermediate LXXVI (1 eq.) in pyridine (1.6 M) cooled to 0 °C, the proper amine X (1 eq.) was added slowly and the mixture was warmed to 25 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated to dryness and the resulting solid was suspended in water and filtered, washing with water. The solid was extracted with EtOAc and water, the combined organic layers were dried over MgSC , filtered and concentrated under reduced pressure. The crude product product was finally purified by the opportune technique to give the intermediate compound with general formula LXXVII.

4-(6-chloropyridine-3-sulfonamido)-3-fluorobenzamide (LXXVIla). The title compound was obtained according to general procedure Y2, step 1 , using 6-chloropyridine-3-sulfonyl chloride (LXXVIa, 3.9 g, 18.5 mmol) and 4-amino-3-fluorobenzamide (Xv, 3 g, 18.5 mmol). The crude was triturated in EtOAc (5 mL) and collected by filtration to give 2.5 g (40% yield) of the title product. HPLC-MS (ESI) m/z: 330.1 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -c/e) S: 10.81 (s, 1 H), 8.73 (d, J = 2.6 Hz, 1 H), 8.15 (dd, J = 8.4, 2.6 Hz, 1 H), 7.99 (s, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.72 - 7.57 (m, 2H), 7.49 (s, 1 H), 7.38 (t, J = 8.2 Hz, 1 H).

2-chloro-N-(pyridin-3-yl)pyrimidine-5-sulfonamide (LXXVIlb). The title compound was obtained according to general procedure Y2, step 1 , using 2-chloropyrimidine-5-sulfonyl chloride (LXXVIb, 2.1 g, 10 mmol) and pyridin-3-amine (Xn, 0.94 g, 10 mmol). The crude was triturated in EtOAc (5 mL) and collected by filtration to give 1.5 g (55% yield) of the title product. HPLC-MS (ESI) m/z: 271.4 [M-H]⁺.

4-[(2-chloropyrimidine-5-sulfonyl)amino]-3-fluorobenzamide (LXXVIlc). The title compound was obtained according to general procedure Y2, step 1 , using 2- chloropyrimidine-5-sulfonyl chloride (LXXVIb, 2.1 g, 10 mmol) and 4-amino-3- fluorobenzamide (Xv, 1.54 g, 10 mmol). The crude was triturated in EtOAc (5 mL) and collected by filtration to give 1.7 g (51 % yield) of the title product. HPLC-MS (ESI) m/z: 331.5 [M-H]⁺.

Step 2

1 ,1 ,1 ,2,2,2-hexamethyldistannane (1 eq.) and palladium tetrakis (0.05 eq.) were added to the proper halide LXXVII (1 eq.) in dioxane (0.4 M) was added. The reaction mixture (LXXVIII) was degassed with nitrogen, heated at 110 °C for 2 h, and used us such for the next step.

3-Fluoro-4-{[ 6-(trimethylstannyl)pyridine-3-sulfonyl]amino}benzamide ( LXXVI 11 a) . The title compound was obtained according to general procedure Y2, step 2, using 4-(6- chloropyridine-3-sulfonamido)-3-fluorobenzamide (LXXVIla, 250 mg, 0.8 mmol), 1 ,1 ,1 ,2,2,2-hexamethyldistannane (0.16 ml_, 0.8 mmol) and palladium tetrakis (44 mg, 0.04 mmol). The product has not been isolated and the total mixture has been used us such for the next step.

5-[(Pyridin-3-yl)methanesulfonyl]-2-(trimethylstannyl)pyrimidine (LXXVIIIb). The title compound was obtained according to general procedure Y2, step 2, using 2-chloro-N- (pyridin-3-yl)pyrimidine-5-sulfonamide (LXXVIlb, 274 mg, 1 mmol), 1 ,1 ,1 ,2,2,2- hexamethyldistannane (0.2 ml_, 1 mmol) and palladium tetrakis (55 mg, 0.05 mmol). The product has not been isolated and the total mixture has been used us such for the next step.

3-Fluoro-4-{[2-(trimethylstannyl)pyrimidine-5-sulfonyl]amino}benzamide (LXXVIIIc). The title compound was obtained according to general procedure Y2, step 2, using 4-[(2- chloropyrimidine-5-sulfonyl)amino]-3-fluorobenzamide (LXXVIlc, 330 mg, 1 mmol), 1 ,1 ,1 ,2,2,2-hexamethyldistannane (0.2 ml_, 1 mmol) and palladium tetrakis (55 mg, 0.05 mmol). The product has not been isolated and the total mixture has been used us such for the next step.

General procedure Z₂: Synthesis of intermediate pyrazolopyridines LXXXIV

Step 1

Intermediate LXXXII (1.1 eq.) was added to a solution of the proper pyrazolamine V or V^(ll) (1 eq.) in toluene (0.2 M) and the reaction mixture was heated at 70 - 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in AcOH (0.2 M) and heated at reflux for 22 h. The solvent was removed under reduced pressure and the residue was purified to give the intermediate compound with general formula LXXXIII.

Ethyl-1 -(tert-butyl)-3-(4-ethylphenyl)-6-oxo-6J-dihydro-1H-pyrazolo[3,4-b]pyridine-4- carboxylate (LXXXIIIa). The title compound was obtained according to general procedure Z2, step 1 , using diethyl-2-oxosuccinate (LXXXIIa, 1.79 g, 9.51 mmol) and 1 -(fe f-butyl)- 3-(4-ethylphenyl)-1 /-/-pyrazol-5-amine (Vf, 2.21 g, 8.63 mmol). The crude was triturated in /-Hex (~50 mL) at reflux to give 2.49 g (74% yield) of the title product. HPLC-MS (ESI) m/z: 368.3 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 11.56 (s, 1 H), 7.35 - 7.26 (m, 4H), 6.74 (s, 1 H), 3.84 (q, J = 7.1 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 1.78 (s, 9H), 1.21 (t, J = 7.6 Hz, 3H), 0.69 (t, J = 7.1 Hz, 3H).

Ethyl-1 -(tert-butyl)-3-cyclopropyl-6-oxo-6, 7 -dihydro-1 H-pyrazolo[3, 4-b]pyridine-4- carboxylate (LXXXIIIb). The title compound was obtained according to general procedure Z2, step 1 , using diethyl-2-oxosuccinate (LXXXIIa, 1.7 mL, 10.2 mmol) and 1 -(tert-butyl)- 3-cyclopropyl-1 H-pyrazol-5-amine (Vg, 1.56 g, 8.4 mmol). The crude was purified by flash chromatography (0-10% EtOAc/isohexane) to give 2.02 g (77% yield) of the title product. HPLC-MS (ESI) m/z: 304.3 [M-H]⁺. ¹H-NMR (400 MHz, cDcls) d: 6.72 (s, 1 H), 4.44 (q, J = 7.1 Hz, 2H), 2.26 (tt, J = 8.3, 5.1 Hz, 1 H), 1 .69 (s, 9H), 1 .42 (t, J = 7.1 Hz, 3H), 0.93 (dt, J = 5.5, 2.8 Hz, 2H), 0.88 - 0.83 (m, 2H).

Ethyl 1 -(tert-butyl)-6-oxo-6, 7-dihydro- 1H-pyrazolo[3, 4-b]pyridine-4-carboxylate

(LXXXIIIc) The title compound was obtained according to general procedure Z2, step 1 , using diethyl-2-oxosuccinate (LXXXIIa, 4 ml, 25.6 mmol) and 1 -(tert-butyl)-l H-pyrazol-5- amine (V^(ll)a, 2.2 g, 12.8 mmol). The crude was purified by flash chromatography (0-60% EtOAc/isohexanes) to give 3.1 g (64% yield) of the title product. HPLC-MS (ESI) m/z: 264.2 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 1 1 .53 (br s, 1 H), 8.10 (s, 1 H), 7.01 (s, 1 H), 4.41 (q, J = 7.1 Hz, 2H), 1.74 (s, 9H), 1 .39 (t, J = 7.1 Hz, 3H).

Step 2

Trifluoromethanesulfonic anhydride (1.5 eq.) was added dropwise over 2 min to a solution of intermediate LXXXIII (1 eq.) in pyridine (0.1 M) and the reaction mixture was stirred at r.t. for 17 h. The reaction mixture was diluted with EtOAc and washed with aqueosus sat. NaHCC solution and brine. The organic phase was dried over MgSC , filtered, and concentrated under reduced pressure. The crude product was purified by the opportune thecnique to give the intermediate compound with general formula LXXXIV.

Ethyl-1 -(tert-butyl)-3-(4-ethylphenyl)-6-(((trifluoromethyl)sulfonyl)oxy)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIVa). The title compound was obtained according to general procedure Z2, step 2, using trifluoromethanesulfonic anhydride (330 pL, 1 .97 mmol) and ethyl-1 -(fe/f-butyl)-3-(4-ethylphenyl)-6-oxo-6,7-dihydro-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIIIa, 500 mg, 1 .28 mmol). The crude was purified by flash chromatography (0-50% DCM//-Hex) to give 554 mg (86% yield) of the title product. HPLC-MS (ESI) m/z: no ionisation.¹H-NMR (400 MHz, cDcls) d: 7.46 - 7.41 (m, 2H), 7.31 - 7.27 (m, 2H), 3.93 (q, J = 7.2 Hz, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1 .85 (s, 9H), 1 .27 (t, J = 7.6 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H).

Ethyl-1 -(tert-butyl)-3-cyclopropyl-6-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (LXXXIVb). The title compound was obtained according to general procedure Z2, step 2, using trifluoromethanesulfonic anhydride (1.4 mL, 8.3 mmol) and ethyl-1 -(fe/f-butyl)-3-cyclopropyl-6-oxo-6, 7-dihydro- 1 H-pyrazolo[3,4- b]pyridine-4-carboxylate (LXXXIIIb, 1 .7 g, 5.6 mmol). The crude was purified by flash chromatography (0-50% DCM/isohexane) to give 2.0 g (82% yield) of the title product. HPLC-MS (ESI) m/z: 436.1 (M+H)⁺.¹H-NMR (500 MHz, cDcls) d: 7.63 (s, 1 H), 4.47 (q, J = 7.1 Hz, 2H), 2.43 - 2.33 (m, 1 H), 1 .68 (s, 9H), 1 .37 (t, J = 7.1 Hz, 3H), 0.94 (dt, J = 8.0, 2.5 Hz, 2H), 0.90 (dt, J = 4.9, 2.6 Hz, 2H).

(LXXXIVc). The title compound was obtained according to general procedure Z2, step 2, using trifluoromethanesulfonic anhydride (4.5 mL, 26.6 mmol) and ethyl 1 -(tert-butyl)-6- oxo-6, 7-dihydro-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIIIc, 4.7 g, 17.9 mmol). The crude (6.6 g, 84% yield) was used for the next step without further purification. HPLC- MS (ESI) m/z: 396.3 (M+H)⁺, 340.2 (M+H-tBu)⁺.

General procedure A₃: Synthesis of compounds with general formula l^(XVIII)

Step 1

Method (A): A flask containing the intermediate LXXXIV (1 eq.) and Pd(dppf)Cl2- DCM (0.05 eq.) was purged with N2 for 5 min. Degassed dioxane (0.04 M) was added and the reaction mixture was heated at 100 °C until the aryl triflate dissolved. Zinc bromide derivative (LXXXV, 0.5 M in THF, 1 .5 eq.) was added and heating at 100 °C was continued for 1 h. The reaction mixture was allowed to cool to r.t., quenched with EtOH, and left to stand for 16 h. Then it was diluted with EtOAc and washed with aqueous sat. NH4CI solution and brine. The organic phase was dried over MgSC , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the intermediate compound with general formula |<^XVIII>.

Method (B): A solution of intermediate LXXXIV (1 eq.) in THF (0.4 M) and a solution of K2CO3 (4.2 eq.) in water (1 .15 M) were added sequentially to the not purified reaction mixture containing the proper boronate XXXIX. A microspatula of PdCl2(dppf) cH2Cl2 adduct was added and the reaction mixture was degassed and then heated in the microwave at 1 10 °C for 90 min. The reaction mixture was allowed to cool to r.t. , quenched with a saturated aqueous solution of NaHCC and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgS0₄, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give the intermediate compound with general formula |<^XVIII>.

Method (c): To a solution of the proper amine, TFA LXXIII (1 .5 eq) and the intermediate LXXXIV (1 eq.) in MeCN (0.15 M), DIPEA (3 eq.) was added. The reaction mixture was heated in the microwave for 90 min, then quenched with a saturated aqueous solution of NaHCC and extracted with DCM. The organics were combined, passed through a phase separator and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography to give the intermediate compound with general formula |<^XVIII>.

Method (D): The intermediate LXXXIV (1 eq.) and palladium tetrakis (0.05 eq.) were added to the not purified reaction mixture containing the stannane LXXVIII and the total mixture was stirred at 1 10 °C for 3 h. The reaction mixture was then concentrated in vacuo and the crude product was purified by flash chromatography to give the intermediate compound with general formula |<^XVIII>.

Ethyl-1 -(tert-butyl)-6-(3-ethoxy-3-oxopropyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(XVIII)a). The title compound was obtained according to general procedure A₃, step 1 , method (A) using ethyl-1 -(fe/f-butyl)-3-(4-ethylphenyl)-6- (((trifluoromethyl)sulfonyl)oxy)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIVa, 500 mg, 1.00 mmol), Pd(dppf)Cl2 DCM (40.9 mg, 0.050 mmol) and (3-ethoxy-3- oxopropyl)zinc(ll) bromide (LXXXVa, 0.5 M in THF, 3 ml_, 1.50 mmol). The crude was purified by flash chromatography (0-100% DCM//-Hex) to give 397 mg (85% yield) of the title product. HPLC-MS (ESI) m/z: 452 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 7.40 (s, 1 H), 7.38 - 7.34 (m, 2H), 7.34 - 7.30 (m, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.87 (q, J = 7.1 Hz, 2H), 3.29 (dd, J = 7.6, 5.7 Hz, 2H), 2.90 (dd, J = 7.6, 5.7 Hz, 2H), 2.67 (q, J = 7.7 Hz, 2H), 1.80 (s, 9H), 1.22 (t, J = 7.7 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H), 0.69 (t, J = 7.1 Hz, 3H).

Ethyl 1-(tert-butyl)-3-(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)piperazin-1-yl)- 1H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)b). The title compound was obtained according to general procedure A₃, step 1 , method (c) using ethyl-1 -(fe/f-butyl)-3-(4- ethylphenyl)-6-(((trifluoromethyl)sulfonyl)oxy)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIVa, 1 g, 2.0 mmol), N-(pyridin-3-yl)piperazine-1 -sulfonamide, TFA (LXXVa, 1.070 g, 3.0 mmol) and DIPEA (1 mL, 6.01 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 595 mg (48% yield) of the title product. HPLC-MS (ESI) m/z: 592.3 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 10.26 (s, 1 H), 8.44 (d, J = 2.6 Hz, 1 H), 8.27 (dd, J = 4.7, 1.4 Hz, 1 H), 7.63 (ddd, J = 8.3, 2.7, 1.5 Hz, 1 H), 7.35 (dd, J = 8.4, 4.7 Hz, 1 H), 7.32 - 7.26 (m, 4H), 7.03 (s, 1 H), 3.83 (q, J = 7.1 Hz, 2H), 3.72 - 3.66 (m, 4H), 3.30 - 3.25 (m, 4H), 2.65 (q, J = 7.6 Hz, 2H), 1.75 (s, 9H), 1.21 (t, J = 7.6 Hz, 3H), 0.68 (t, J = 7.1 Hz, 3H).

Ethyl-1 -(tert-butyl)-6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)piperazin-1-yl)-3- (4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)c). The title compound was obtained according to general procedure A₃, step 1 , method (c) using ethyl-1 -{tert- butyl)-3-(4-ethylphenyl)-6-(((trifluoromethyl)sulfonyl)oxy)-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (LXXXIVa, 456 mg, 0.9 mmol), 3-fluoro-4-(piperazine-1 - sulfonamido)benzamide, TFA salt (LXXVb, 380 mg, 0.9 mmol). The crude was purified by flash chromatography (DCM loading, 0-10% MeOH/DCM) to give 177 mg (26% yield) of the title product. HPLC-MS (ESI) m/z: 652.2 [M-H]⁺.

Ethyl-1 -(tert-butyl)-3-cyclopropyl-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)d). The title compound was obtained according to general procedure A₃, step 1 , method (B) using ethyl-1 -(tert-butyl)-3- cyclopropyl-6-(((trifluoromethyl)sulfonyl)oxy)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIVb, 500 mg, 1.15 mmol), the total mixture containing the boronate N-(pyridin-3- yl)-4-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)benzene-1 -sulfonamide (XXXIXa), and K2CO3 (659 mg, 4.8 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 445 mg (67% yield) of the title product. HPLC-MS (ESI) m/z: 520.3 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -c/e) d: 10.72 (s, 1 H), 8.42 - 8.36 (m, 2H), 8.34 (d, J = 2.6 Hz, 1 H), 8.30 - 8.23 (m, 1 H), 8.08 (s, 1 H), 7.99 - 7.92 (m, 2H), 7.56 (ddd, J = 8.3, 2.7, 1 .5 Hz, 1 H), 7.31 (dd, J = 8.3, 4.7 Hz, 1 H), 4.47 (q, J = 7.1 Hz, 2H), 2.46 - 2.37 (m, 1 H), 1 .78 (s, 9H), 1 .39 (t, J = 7.1 Hz, 3H), 0.99 - 0.82 (m, 4H).

Ethyl-1 -(tert-butyl)-6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)phenyl)-3- cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)e). The title compound was obtained according to general procedure A₃, step 1 , method (B) using ethyl-1 -(tert-butyl)- 3-cyclopropyl-6-(((trifluoromethyl)sulfonyl)oxy)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIVb, 354 mg, 0.8 mmol), the total mixture containing the boronate 3-fluoro-4-{[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 -sulfonyl]amino}benzamide

(XXXIXb) and K2CO3 (466 mg, 3.4 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 0.38 g (77% yield) of the title product. HPLC-MS (ESI) m/z: 580.4 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 10.65 (s, 1 H), 8.42 - 8.36 (m, 2H), 8.09 (s, 1 H), 7.98 - 7.91 (m, 3H), 7.67 - 7.59 (m, 2H), 7.46 - 7.38 (m, 2H), 4.47 (q, J = 7.1 Hz, 2H), 3.92 (s, 1 H), 1 .78 (s, 9H), 1 .39 (t, J = 7.1 Hz, 3H), 0.95 - 0.87 (m, 4H).

Ethyl-1 -(tert-butyl)-6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)phenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)f). The title compound was obtained according to general procedure A3, step 1 , method (B) using ethyl 1 -(tert-butyl)-6- (((trifluoromethyl)sulfonyl)oxy)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIVc, 1 .5 g, 3.8 mmol), the boronate 3-fluoro-4-{[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzene-1 -sulfonyl]amino}benzamide (XXXIXb) and K2CO3 (1 .6 g, 1 1.4 mmol). The crude was purified by flash chromatography (0-100% EtOAc/isohexane) to give 1 g (46% yield) of the title product. HPLC-MS (ESI) m/z: 540.4 [M-H]⁺. ¹H-NMR (500 MHz, DMSO- de) d: 10.67 (s, 1 H), 8.46 - 8.37 (m, 3H), 8.28 (d, J = 1 .4 Hz, 1 H), 8.01 - 7.93 (m, 3H), 7.69 - 7.59 (m, 2H), 7.47 - 7.39 (m, 2H), 4.53 - 4.45 (m, 2H), 1.86 (d, J = 1.1 Hz, 9H), 1 .44 (td, J = 7.1 , 1 .0 Hz, 3H).

Ethyl-1 -(tert-butyl)-6-(5-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)pyridin-2-yl)-3- cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)g). The title compound was obtained according to general procedure A₃, step 1 , method (D) using ethyl-1 -(tert-butyl)- 3-cyclopropyl-6-(((trifluoromethyl)sulfonyl)oxy)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIVb, 330 mg, 0.758 mmol), the total mixture containing the stannane 3-fluoro-4-{[6- (trimethylstannyl)pyridine-3-sulfonyl]amino}benzamide (LXXVIlla) and palladium tetrakis (44 mg, 0.04 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 217 mg (30% yield) of the title product. HPLC-MS (ESI) m/z: 581 .1 [M-H]⁺. Ethyl-1 -tert-butyl-3-(4-ethylphenyl)-6-{5-[(pyridin-3-yl)sulfamoyl]pyrimidin-2-yl}-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)h). The title compound was obtained according to general procedure A₃, step 1 , method (D) using ethyl-1 -(tert-butyl)-3-(4- ethylphenyl)-6-(((trifluoromethyl)sulfonyl)oxy)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LXXXIVa, 500 mg, 1 .00 mmol), the total mixture containing the stannane 5-[(pyridin-3- yl)methanesulfonyl]-2-(trimethylstannyl)pyrimidine (LXXVIIIb) and palladium tetrakis (55 mg, 0.05 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 225 mg (38% yield) of the title product. HPLC-MS (ESI) m/z: 586.5 [M-H]⁺.

Ethyl-1 -tert-butyl-6-{5-[(4-carbamoyl-2-fluorophenyl)sulfamoyl]pyrimidin-2-yl}-3-(4- ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)i). The title compound was obtained according to general procedure A₃, step 1 , method (D) using ethyl-1 -(tert-butyl)- 3-(4-ethylphenyl)-6-(((trifluoromethyl)sulfonyl)oxy)-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (LXXXIVa, 500 mg, 1 .00 mmol), the total mixture containing the stannane 3- fluoro-4-{[2-(trimethylstannyl)pyrimidine-5-sulfonyl]amino}benzamide (LXXVIIIc) and palladium tetrakis (55 mg, 0.05 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 1 17 mg (18% yield) of the title product. HPLC-MS (ESI) m/z: 646.5 [M-H]⁺.

General procedure B₃: Synthesis of compounds with general formula l^(XIX)

l^,xv"": R¹ = COOMe, COOEt l^,xlx|: R¹ = COOMe, COOEt

R⁴ = fBu R⁴= H

Step 1

To a solution of intermediate l^(XVIII) (1 eq.) in DCM (0.1 M) at 0 °C, triflic acid (3 - 20 eq.) was added. The resultant yellow solution was stirred at 0 °C for 2 h and at rt for 1 h. A saturated aqueous solution of NaHCOs was added until basic pH and the product was extracted with DCM. The organic layers were combined, dried over MgSC , filtered and concentrated under reduced pressure. The resultant precipitate was then purified by the opportune technique to give the intermediate compound with general formula l^(XIX).

Ethyl-3-(4-ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)piperazin-1-yl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)a). The title compound was obtained according to general procedure B3, step 1 using ethyl 1 -(fe/f-butyl)-3-(4-ethylphenyl)-6- (4-(N-(pyridin-3-yl)sulfamoyl)piperazin-1 -yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII>b, 595 mg, 0.9 mmol) and triflic acid (1.6 mL, 18.0 mmol). The crude (600 mg, 100% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 536.2 [M-H]⁺.

Ethyl-6-( 4-(N-( 4-carbamoyl-2-fluorophenyl)sulfamoyl)piperazin- 1 -yl)-3-( 4- ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)b). The title compound was obtained according to general procedure B3, step 1 using ethyl-1 -(fe/f-butyl)-6-(4-(N-(4- carbamoyl-2-fluorophenyl)sulfamoyl)piperazin-1 -yl)-3-(4-ethylphenyl)-1 H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(XVIII)c, 170 mg, 0.3 mmol) and triflic acid (0.5 ml_, 5.1 mmol). The crude (177 mg, 100% yield) was used for the next step without further purification. HPLC-MS (ESI) m/z: 596.4 [M-H]⁺.

Ethyl-3-cyclopropyl-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(XIX)c). The title compound was obtained according to general procedure B3, step 1 using ethyl-1 -(fe/f-butyl)-3-cyclopropyl-6-(4-(N-(pyridin-3- yl)sulfamoyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)d, 253 mg, 0.5 mmol) and triflic acid (150 pL, 1 .7 mmol). The crude was purified by flash chromatography (0-100% EtOAc/DCM) to give 128 mg (47% yield) of the title product. HPLC-MS (ESI) m/z: 464.3 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 13.70 (s, 1 H), 10.67 (s, 1 H), 8.35 (d, J = 8.4 Hz, 2H), 8.33 (d, J = 2.7 Hz, 1 H), 8.28 (d, J = 4.3 Hz, 1 H), 8.08 (s, 1 H), 7.93 (d, J = 8.4 Hz, 2H), 7.58 - 7.51 (m, 1 H), 7.31 (dd, J = 8.3, 4.7 Hz, 1 H), 4.48 (q, J = 7.1 Hz, 2H), 1 .40 (t, J = 7.1 Hz, 3H), 0.98 - 0.88 (m, 4H). 1 H missing, hydrogen of cyclopropyl under the DMSO peak.

Ethyl-6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)phenyl)-3-cyclopropyl-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)d). The title compound was obtained according to general procedure B3, step 1 using ethyl-1 -(fe/f-butyl)-6-(4-(N-(4-carbamoyl- 2-fluorophenyl)sulfamoyl)phenyl)-3-cyclopropyl-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(XVIII)e, 356 mg, 0.6 mmol) and triflic acid (0.17 mL, 1 .9 mmol). The resultant precipitate was washed with water to give 126 mg (38% yield) of the title product. HPLC- MS (ESI) m/z: 524.3 [M-H]⁺. ¹H-NMR (500 MHz, Methanol-c/4) d: 8.31 (d, J = 8.3 Hz, 2H), 8.07 (s, 1 H), 7.96 (d, J = 8.4 Hz, 2H), 7.68 - 7.61 (m, 2H), 7.58 - 7.52 (m, 1 H), 4.53 (q, J = 7.1 Hz, 2H), 2.60 (p, J = 6.9 Hz, 1 H), 1 .46 (t, J = 7.1 Hz, 3H), 0.96 (d, J = 6.6 Hz, 4H).

Ethyl-6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)phenyl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(XIX)e). The title compound was obtained according to general procedure B3, step 1 using ethyl-1 -(tert-butyl)-6-(4-(N-(4-carbamoyl-2- fluorophenyl)sulfamoyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)f, 1 g, 1.9 mmol) and triflic acid (500 pL, 7.4 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 21 mg (2% yield) of the title product. HPLC-MS (ESI) m/z: 484.3 [M-H]⁺.

Ethyl-6-(5-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)pyridin-2-yl)-3-cyclopropyl-1H- pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)f). The title compound was obtained according to general procedure B3, step 1 using ethyl-1 -(fe/f-butyl)-6-(5-(N-(4-carbamoyl-2- fluorophenyl)sulfamoyl)pyridin-2-yl)-3-cyclopropyl-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(XVIII)g, 217 mg, 0.4 mmol) and triflic acid (100 pi, 1 .1 mmol). The product was extracted with DCM and concentrated in vacuo to give 45 mg (20% yield) of the title product. HPLC-MS (ESI) m/z: 525.2 [M-H]⁺. Ethyl-3-(4-ethylphenyl)-6-{5-[(pyridin-3-yl)sulfamoyl]pyrimidin-2-yl}-1H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(XIX)g). The title compound was obtained according to general procedure B3, step 1 using ethyl-1 -tert-butyl-3-(4-ethylphenyl)-6-{5-[(pyridin-3- yl)sulfamoyl]pyrimidin-2-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)h, 225 mg, 0.38 mmol) and triflic acid (100 pi, 1.1 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 51 mg (25% yield) of the title product. HPLC-MS (ESI) m/z: 530.2 [M-H]⁺.

Ethyl-6-{5-[(4-carbamoyl-2-fluorophenyl)sulfamoyl]pyrimidin-2-yl}-3-(4-ethylphenyl)- 1H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)h). The title compound was obtained according to general procedure B3, step 1 using ethyl-1 -tert-butyl-6-{5-[(4-carbamoyl-2- fluorophenyl)sulfamoyl]pyrimidin-2-yl}-3-(4-ethylphenyl)-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(XVIII)i, 117 mg, 0.18 mmol) and triflic acid (100 mI, 1.1 mmol). The crude was purified by flash chromatography (0-10% MeOH/DCM) to give 48 mg (25% yield) of the title product. HPLC-MS (ESI) m/z: 590.3 [M-H]⁺.

General procedure C₃: Synthesis of compounds with general formula l^(XX) (Examples 99

Step 1

General procedure C3 step 1 follows the same conditions described for general procedure Ki, step 1 , method (A).

1-(Tert-butyl)-6-(2-carboxyethyl)-3-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 99). The title compound was obtained according to general procedure C3, step 1 using ethyl-1 -(fe/f-butyl)-6-(3-ethoxy-3-oxopropyl)-3-(4- ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XVIII)a, 115 mg, 0.247 mmol) and LiOH (61 mg, 2.55 mmol). The resulting solid was collected by filtration washed with water/TBME//-Hex (2.5: 1 :2.5) and dried under vacuum to give 75 mg (76% yield) of the title product. HPLC-MS (ESI) m/z: 396 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 13.49 (s, 1 H), 12.14 (s, 1 H), 7.46 - 7.41 (m, 2H), 7.33 (s, 1 H), 7.30 - 7.25 (m, 2H), 3.23 (t, J = 6.8 Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 1.82 (s, 9H), 1.23 (t, J = 7.6 Hz, 3H).

3-(4-Ethylphenyl)-6-(4-(N-(pyridin-3-yl)sulfamoyl)piperazin-1-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 100). The title compound was obtained according to general procedure C3, step 1 using ethyl-3-(4-ethylphenyl)-6-(4-(N-(pyridin-3- yl)sulfamoyl)piperazin-1 -yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)a, 497 mg, 0.9 mmol) and LiOH (111 mg, 4.6 mmol). The mixture was extracted with a saturated aqueous solution of NhUCI (15 mL) and DCM (20 mL). The organic layer was dried over MgSC , filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-10% (1 % acetic acid in MeOH)/DCM) and then suspended in toluene/MeOH and co-evaporated twice (2 x 10 mL) and once with MeOH (10 mL) to afford 1 10 mg (22% yield) of the title product. HPLC-MS (ESI) m/z: 508.4 [M- H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 13.93 - 12.95 (m, 2H), 10.32 (s, 1 H), 8.45 (d, J =

2.6 Hz, 1 H), 8.28 (d, J = 4.7 Hz, 1 H), 7.75 - 7.54 (m, 1 H), 7.42 (d, J = 7.8 Hz, 2H), 7.36 (dd, J = 8.4, 4.7 Hz, 1 H), 7.24 (d, J = 7.9 Hz, 2H), 6.96 (s, 1 H), 3.67 (t, J = 5.0 Hz, 4H), 3.26 (t, J = 5.0 Hz, 4H), 2.65 (q, J = 7.6 Hz, 2H), 1 .22 (t, J = 7.6 Hz, 3H).

6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)piperazin-1-yl)-3-(4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 101). The title compound was obtained according to general procedure C3, step 1 using ethyl-6-(4-(N-(4-carbamoyl-2- fluorophenyl)sulfamoyl)piperazin-1 -yl)-3-(4-ethylphenyl)-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(XIX)b, 155 mg, 0.3 mmol) and LiOH (31 mg, 1 .3 mmol). A saturated aqueous solution of NH4CI (50 mL) and DCM (80 mL) were added to the reaction mixture. The organic layer was dried over MgSC , filtered and concentrated in vacuo. The crude product was first purified by chromatography on silica gel (0-10% (1 % acetic acid/MeOH)/DCM) and then suspended in toluene/MeOH and co-evaporated twice (2 x 10 mL) and twice with MeOH (2 x 10 mL) to afford 69 mg (44% yield) of the title product. HPLC-MS (ESI) m/z: 568.3 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 13.40 (s, 1 H), 13.25 (s, 1 H), 10.1 1 (s, 1 H), 7.98 (s, 1 H), 7.74 - 7.67 (m, 2H), 7.59 - 7.51 (m, 1 H), 7.47 - 7.39 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 6.98 (s, 1 H), 3.70 (t, J = 5.1 Hz, 4H), 3.25 (t, J = 5.1 Hz, 4H), 2.65 (q, J = 7.5 Hz, 2H), 1 .23 (t, J = 7.6 Hz, 3H). ¹⁹F NMR (471 MHz, DMSO-d6) d: -123.57.

3-cyclopropyl-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 102). The title compound was obtained according to general procedure C3, step 1 using ethyl-3-cyclopropyl-6-(4-(N-(pyridin-3-yl)sulfamoyl)phenyl)- 1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)c, 126 mg, 0.3 mmol) and LiOH (65 mg,

2.7 mmol). The solid was slurried in water (5 mL), collected by filtration and rinsed with water (5 mL), then was dissolved in MeOH and concentrated in vacuo (x2) to give 50 mg (40% yield) of the title compound. HPLC-MS (ESI) m/z: 436.4 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 13.90 (s, 1 H), 13.63 (s, 1 H), 10.66 (s, 1 H), 8.42 - 8.31 (m, 3H), 8.28 (dd, J = 4.7, 1 .5 Hz, 1 H), 8.06 (s, 1 H), 7.95 - 7.87 (m, 2H), 7.55 (ddd, J = 8.3, 2.7, 1 .5 Hz, 1 H), 7.31 (dd, J = 8.3, 4.7 Hz, 1 H), 2.73 - 2.60 (m, 1 H), 1.04 - 0.79 (m, 4H).

6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)phenyl)-3-cyclopropyl-1H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 103). The title compound was obtained according to general procedure C3, step 1 using ethyl-6-(4-(N-(4-carbamoyl-2- fluorophenyl)sulfamoyl)phenyl)-3-cyclopropyl-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)d, 126 mg, 0.2 mmol) and LiOH (58 mg, 2.4 mmol). The resultant solid was slurried in water, filtered and washed with water, then triturated in Et20, filtered, rinsed with further Et₂0, and dried in vacuo to give 72 mg (59% yield) of the title product. HPLC-MS (ESI) m/z: 496.3 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 14.00 (s, 1 H), 13.63 (s, 1 H), 10.61 (s, 1 H), 8.40 - 8.34 (m, 2H), 8.07 (s, 1 H), 7.97 - 7.90 (m, 3H), 7.68 - 7.60 (m, 2H), 7.45

(s, 1 H), 7.40 (t, J = 8.3 Hz, 1 H), 2.74 - 2.60 (m, 1 H), 0.96 - 0.90 (m, 4H).

3-(4-Ethylphenyl)-6-{5-[(pyridin-3-yl)sulfamoyl]pyrimidin-2-yl}-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 104). The title compound was obtained according to general procedure C3, step 1 using ethyl-3-(4-ethylphenyl)-6-{5-[(pyridin-3- yl)sulfamoyl]pyrimidin-2-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)g, 51 mg, 0.09 mmol) and LiOH (21 mg, 0.9 mmol). The resultant solid was triturated with ether (10 ml_) and collected by filtration to give 22 mg (49% yield) of the title product. HPLC-MS (ESI) m/z: 502.2 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -c/e) S: 14.1 1 (s, 1 H), 13.65 (s, 1 H), 10.80 (s, 1 H), 9.37 - 9.06 (m, 1 H), 8.19 (s, 1 H), 8.04 (s, 1 H), 7.96 (s, 1 H), 7.83 (s, 1 H), 7.58 -

7.51 (m, 1 H), 7.41 (s, 1 H), 7.36 - 7.29 (m, 1 H), 7.23 (s, 1 H), 2.60 - 2.47 (m, 1 H), 1 .35 -

1 .22 (m, 1 H).

6-{5-[(4-carbamoyl-2-fluorophenyl)sulfamoyl]pyrimidin-2-yl}-3-(4-ethylphenyl)-1H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 105). The title compound was obtained according to general procedure C3, step 1 using ethyl-6-{5-[(4-carbamoyl-2- fluorophenyl)sulfamoyl]pyrimidin-2-yl}-3-(4-ethylphenyl)-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(XIX)h, 48 mg, 0.08 mmol) and LiOH (23 mg, 1 mmol). The resultant solid suspended in MeOH and concentrated in vacuo to give 31 mg (69% yield) of the title product. HPLC-MS (ESI) m/z: 562.2 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 14.05 (s, 1 H), 10.62 (s, 1 H), 9.39 - 9.27 (m, 1 H), 8.10 (s, 1 H), 7.81 (s, 1 H), 7.62 - 7.57 (m, 1 H), 7.54 (s, 1 H), 7.41 (s, 1 H), 7.36 - 7.30 (m, 1 H), 7.27 - 7.21 (m, 1 H), 6.71 (s, 1 H), 2.64 -

2.51 (m, 1 H), 1 .35 - 1 .17 (m, 2H).

6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (Example 109). The title compound was obtained according to general procedure C3, step 1 using ethyl-6-(4-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl) phenyl)- 1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l^(XIX)e, 21 mg, 0.04 mmol) and LiOH (10 mg, 0.4 mmol). The resultant solid was triturated with ether (10 mL) and collected by filtration to give 9 mg (43% yield) of the title product. HPLC-MS (ESI) m/z: 456.3 [M-H]⁺. ¹ H-NMR (500 MHz, DMSO -de) d: 14.1 1 (s, 1 H), 10.62 (s, 1 H), 8.44 - 8.36 (m, 3H), 8.24 (s, 1 H), 7.97 - 7.91 (m, 3H), 7.68 - 7.60 (m, 2H), 7.46 - 7.36 (m, 2H). 1 H missing (CO2H).

6-(5-(N-(4-carbamoyl-2-fluorophenyl)sulfamoyl)pyridin-2-yl)-3-cyclopropyl-1H- pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 110). The title compound was obtained according to general procedure C3, step 1 using ethyl-6-(5-(N-(4-carbamoyl-2- fluorophenyl)sulfamoyl)pyridin-2-yl)-3-cyclopropyl-1 H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(XIX)f, 45 mg, 0.09 mmol) and LiOH (21 mg, 0.9 mmol). The product was suspended in EtOH and heated at 80 °C for 1 h and then filtered hot to afford a white solid. The filtrate was concentrated in vacuo, suspended in MeOH and concentrated in vacuo to give 20 mg (45% yield) of the title product. HPLC-MS (ESI) m/z: 497.3 [M-H]⁺. ¹H-NMR (500 MHz, DMSO -de) d: 14.05 (s, 1 H), 13.73 (s, 1 H), 10.85 (s, 1 H), 9.05 (d, J = 2.3 Hz, 1 H), 8.63 - 8.55 (m, 2H), 8.32 (dd, J = 8.4, 2.4 Hz, 1 H), 7.94 (s, 1 H), 7.68 - 7.60 (m, 2H), 7.47 - 7.37 (m, 2H), 2.73 (p, J = 6.8 Hz, 1 H), 0.97 - 0.91 (m, 4H).

Preparation VII: Synthesis of compound 106

Compound 106 can be obtained by application of the chemical transformations reported in general procedures D3 - F3 herein described. General procedures D3-E3 relate to the preparation of intermediates and compounds of Table B. The preparation of compound 106 of Table A is described in general procedure F3.

General procedure D₃: Synthesis of intermediate pyrazoleamines LXXXVI

Step 1

Copper(ll) bromide (0.1 eq.), CS2CO3 (1 eq.), DMF (0.4 M), the proper pyrazolamine (V, 1.4 eq.) and the proper commercially available halide (XXV, 1 eq.) were added sequentially to a MW tube and the reaction mixture was heated in a MW reactor at 180 °C for 30 min. The reaction mixture was loaded onto a pad of ScX resin (Si-TsOH), washed with MeOH and eluted with 0.7 M NH3 in MeOH. The crude was purified by flash chromatography to give the intermediate compound with general formula LXXXVI.

1 -(4-Ethylphenyl)-1 H-pyrazol-3-amine (LXXXVIa). The title compound was obtained according to general procedure D3, step 1 using copper(ll) bromide (106 mg, 0.473 mmol), CS2CO3 (1.40 mg, 4.30 mmol), 1 /-/-pyrazol-5-amine (Vn, 500 mg, 6.02 mmol) and 1 -ethyl-4-iodobenzene (XXVd, 0.62 ml_, 4.3 mmol). The crude was purified by flash chromatography (0-50% EtOAc//-Hex) to give 0.27 g (29% yield) of the title product. HPLC-MS (ESI) m/z: 188 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 8.07 (d, J = 2.5 Hz, 1 H), 7.61 - 7.51 (m, 2H), 7.25 - 7.16 (m, 2H), 5.70 (d, J = 2.5 Hz, 1 H), 5.01 (s, 2H), 2.59 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H).

General procedure E₃: Synthesis of compounds with general formula l^(XXI)

General procedure E₃ step 1 follows the same conditions described for general procedure Gi, step 1 , method (B). Ethyl-2-(4-ethylphenyl)-6-(4-(methoxycarbonyl)phenyl)-2H-pyrazolo[3,4-b]pyridine-4- carboxylate (l^(XXI)a). The title compound was obtained according to general procedure E3, step 1 using 1 -(4-ethylphenyl)-1 /-/-pyrazol-3-amine (LXXXVIa, 200 mg, 1 .07 mmol), methyl-4-formylbenzoate (XXb, 175 mg, 1 .07 mmol) and ethyl pyruvate (0.12 ml_, 1 .1 mmol). The mixture was filtered and washed with EtOH. The resulting crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 48 mg (10% yield) of the title product. HPLC-MS (ESI) m/z: 430 [M-H]⁺. ¹H-NMR (400 MHz, DMSO -de) d: 9.22 (s, 1 H), 8.46 - 8.34 (m, 2H), 8.29 (s, 1 H), 8.23 - 8.07 (m, 4H), 7.56 - 7.41 (m, 2H), 4.53 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 2.73 (q, J = 7.6 Hz, 2H), 1 .47 (t, J = 7.1 Hz, 3H), 1 .26 (t, J = 7.6 Hz, 3H).

General procedure F₃: Synthesis of compounds with general formula l^(XXII) 106

l^,xxl): R = COOEt Step 1 _|( ^cc")_{: R1} _ cooH

R can be COOMe-/COOEt-Aryl R can be COOH-Aryl

Step 1

General procedure F3 step 1 follows the same conditions described for general procedure Ki, step 1 , method (A).

6-(4-carboxyphenyl)-2-(4-ethylphenyl)-2/-/-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Example 106). The title compound was obtained according to general procedure F3, step 1 using ethyl-2-(4-ethylphenyl)-6-(4-(methoxycarbonyl)phenyl)-2H-pyrazolo[3,4- b]pyridine-4-carboxylate (l^(XXI)a, 48 mg, 0.1 1 mmol) and LiOH (13.4 mg, 0.559 mmol). The resulting solid was collected by filtration and washed with EtOH/water (1 :1 ) to give 38 mg (86% yield) of the title product. HPLC-MS (ESI) m/z: 388 [M-H]\ ¹H-NMR (400 MHz, DMSO -de) d: 13.99 (s, 1 H), 13.16 (s, 1 H), 9.23 (s, 1 H), 8.44 - 8.32 (m, 2H), 8.29 (s, 1 H), 8.19 - 8.08 (m, 4H), 7.52 - 7.39 (m, 2H), 2.72 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

Pharmacological properties

The pharmacological properties of the compounds of formula (I) were evaluated by the methods described in the following sections.

Fluorescence-quenching enzymatic assay for OXA-48 screening

The OXA-48 inhibiting activity of test compounds was evaluated with the fluorescence quenching assay with nitrocefin. The assay has been adapted to automated screening- compatible conditions.

This assay takes advantage of the fluorescent properties of white microtiter plates. Nitrocefin is a yellow chromogenic substrate of beta-lactamases (Amax = 395 nm). Upon hydrolysis by beta-lactamases, nitrocefin yields a red product with increased absorbance properties (Amax=495nm) that quenches the plate’s fluorescence by absorbing the plate's emission light.

Concentrations of OXA-48 and nitrocefin used in final assay conditions were 0.0014 ng/pL and 25 pM, respectively.

Compounds and reference inhibitor (tazobactam) were tested at eight final concentrations in quadruplicate.

The assay (20 pL/well) was assembled directly in a white Optiplate-384 (PerkinElmer) in quadruplicate, as follows:

• Dispensing of 10 pL 2X compound or 2% DMSO in 1X reaction buffer

• Addition of 5 pL 4X OXA-48

• Addition of 5 pL 4X Nitrocefin

The plate was incubated at room temperature (RT) for 35 minutes and fluorescent signal was measured at PHERAstar (BMG Labtech). The reading conditions were the followings:

• Optic module: FI 485/520

• Excitation: 485 nm

• Emission: 520 nm

• Focal height: adjustment before reading

• Numbers of flashes: 10

• Position delay: 0.1 s

• Gain: 400

Compound activity was quantified on fluorescence signal measured at 520 nm (endpoint measurement) as follows:

Activity %= -100 ((RV- <NC»)/«IC) - (NC))

• where the Response Value, RV = -Log (RFU sample/RFU background control); “RFU sample” was the fluorescence emission at 520 nm of samples containing enzyme and substrate;“RFU background control” was the fluorescence emission at 520 nm of only buffer (background control, plate intrinsic fluorescence);

• <NC> is the median of the calculated signal values (RV) for the median of Neutral Controls, corresponding to Max signal: OXA-48 enzymatic reaction;

• <IC> is the median of the calculated signal values (RV) for the median of Inhibitor Controls, corresponding to Min signal enzymatic reaction performed in the presence of Tazobactam IC100 (31 .6 pM).

The activity [%] results in a negative value for compounds displaying an inhibitory activity and a positive value for stimulators. Consistently, a compound causing a complete inhibition of the target signal displays a value of percent activity equivalent to -100.

AC50 values were calculated as concentration at which activity reaches 50% of maximum level. This term corresponds to IC50 in this assay.

The Ic50 of the test compounds has been reported in the following Table 1 . TABLE 1

Checkerboard assay

The aim of the assay is the evaluation of the capacity of test compounds to restore the known b-lactam antibiotics activity against resistant strains.

Test compounds were tested in combination with imipenem against three strains producing or not OXA-48 carbapenemase (E.coli 877648, E. coli ATCC BAA-2523 and K. pneumoniae ATCC BAA-2524) to evaluate the MIC values decrease of the known b- lactam antibiotics.

All test compounds were dissolved in 100% DMSO and they were tested at a fixed concentration of 32 pg/ml and 1 % of DMSO final concentration. Avibactam was used as reference b-lactamase inhibitor. All antimicrobials were prepared in line with cLSI susceptibility testing standards. Solutions at 4X the final concentrations of the test range were made in cation adjusted Mueller-Hinton broth (cA-MHB) by serial dilutions, and then diluted 2-fold with cA-MHB (for antimicrobials alone), or with the test compounds /avibactam (for combinations of new/reference inhibitors and antimicrobials).

MIC tests were performed by broth microdilution in line with cLSI susceptibility testing standards. Bacterial inocula were prepared at about 1x10⁶ cFU/ml in medium. Different combinations containing 50 pi of antibacterial solutions at 2X the final concentrations were diluted 1 :2 with 50 mI of inoculum to give a final inoculum of about 5x10⁵ cFU/ml and the desired test concentrations of antibacterial agents and test compounds. Test plates were incubated according to CLSI guidelines and read visually. MIC values corresponded to the first well with no visible growth.

The resulting MIC values are illustrated in the following Table 2.

TABLE 2

Claims

1. A b-lactamase inhibitor having the following general formula (I):

wherein

R² is selected from the group consisting of halogen, OH, C₂-C6 alkyl, C₁-C6 alkyl- phenyl, aliphatic carbocyclic ring having from 3 to 12 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, C₁-C₆ haloalkyl, C₁-C6 haloalkoxy, C₁-C6 alkyl-OH, and C₁-C6 alkyl, aromatic carbocyclic ring having from 3 to 12 members substituted by one or more substituents selected from the group consisting of halogen, OH, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, C₁-C6 alkyl-OH, and C₁-C₆ alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, other than pyridyl and thienyl, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, 0-Ci-Ce alkyl, Ci-Ob alkyl-OH, and Ci-Ce alkyl,

wherein R", R¹¹¹, R^IV, and R^v, are independently hydrogen, Ci-Ce alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, C₁-C6 alkyl, C3-C6 cycloalkyl, 0-Ci-Ce alkyl, Ci-Ce alkyl-OH, COOH, COO-Ci-C₆ alkyl, CONH₂, NHCOCH3, and

R⁴ is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, O-Ci-Ce alkyl, C1-C6 alkyl-OH, and O-i-Ob alkyl.

2. A b-lactamase inhibitor according to claim 1 , wherein said b-lactamase inhibitor has on

3. A b-lactamase inhibitor according to any one of claims 1 and 2, wherein R¹ is selected from the group consisting of halogen, O-C₁-C₄ alkyl, C₁-C₄ alkyl-OH, COOH, COO-C₁-C₄ alkyl, CONH₂, CONHOH, and C₁-C₄ alkyl,.

4. A b-lactamase inhibitor according to any one of claims 1 and 2, wherein R² is selected from the group consisting of halogen, OH, C₂-C₄ alkyl, C₁-C₄ alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 6 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, C₁-C₄ haloalkyl, Ci- C₄ haloalkoxy, C₁-C₄ alkyl-OH, and C₁-C₄ alkyl, aromatic carbocyclic ring having from 3 to 6 members substituted by one or more substituents selected from the group consisting of halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkyl-OH, and C₁-C₄ alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 6 members, other than pyridyl and thienyl, substituted by one or more substituents selected from the group consisting of hydrogen, halogen, O-C₁-C₄ alkyl, and C₁-C₄ alkyl.

5. A b-lactamase inhibitor according to any one of claims 1 and 2, wherein R³ is represented by any one of the following general formula (a) and (b):

-Rng1 -L-Rng2-S1 (a)

-Rng1 -S2 (b)

wherein Rng1 is selected from the group consisting of carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members,

51 is one or more substituents selected from the group consisting of halogen, OH, CN, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, Ci-Ce alkyl, C3-C6 cycloalkyl, O-Ci-Ce alkyl, C-i-Ce alkyl- OH, COOH, COO-Ci-C₆ alkyl, CONH₂, and NHCOCH3, and

52 is one or more substituents selected from the group consisting of halogen, NO2, COOH, C1-C6 alkyl-COOH, COO-Ci-C₆ alkyl, SO2NH2, S0₂NHCi-C₆ alkyl, NHS0₂Ci-C₆ alkyl, S-C1-C6 alkyl, and SO2-C1-C6 alkyl, with the proviso that when S2 is halogen, Rng1 comprises a second S2 substituent, preferably selected from the group consisting of COOH and S0₂N(R^llR^l11).

6. A b-lactamase inhibitor according to any one of claims 1 and 2, wherein R⁴ is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6 alkyl-C3-C6 cycloalkyl, and phenyl-Ci-C₆ alkyl.

7. A b-lactamase inhibitor according to any one of claims 1 to 6, wherein any of said carbocyclic or heterocyclic ring, aliphatic or aromatic, equal or different each other, is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cyclobutenyl, cyclopentenyl cyclohexenyl, decalinyl, phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, imidazolyl, morpholinyl, thiazolyl, thiazolidinyl, thiadiazolyl, thiadiazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, triazolyl, and pyrazolyl.

8. A b-lactamase inhibitor according to any one of claims 1 to 7, wherein any of said carbocyclic or heterocyclic ring, aliphatic or aromatic, equal or different each other, is selected from the group consisting of phenyl, cyclopropyl, cyclohexenyl, cyclohexyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, furanyl, thiophenyl, pyrrolyl, isoxazolyl, triazolyl, thiazolyl, and pyrazolyl.

9. A b-lactamase inhibitor according to any one of claims 1 to 4, wherein at least one of Ri and R3, preferably both Ri and R3, comprises at least one acidic hydrogen containing group or substituent.

10. A b-lactamase inhibitor according to claim 9, wherein said at least one acidic hydrogen containing group or substituent is selected from the group consisting of -COOH, -OH (linked to an aromatic or heteroaromatic ring), -SO2NH-, -NHSO2-, -CONH2, -CONH- , -NHCO-, -CONHOH, -SO2NH2, and -NHS0₂-Ci-C₆ alkyl.

1 1 . A pharmaceutical composition comprising at least one b-lactamase inhibitor of formula (I) as defined in any one of claims 1 to 10 and 20, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and at least one inert pharmaceutically acceptable excipient.

12. The pharmaceutical composition according to claim 1 1 , wherein said pharmaceutical composition further comprises a beta-lactam antibiotic.

13. The pharmaceutical composition according to claim 12, wherein said beta-lactam antibiotic is selected from the group consisting of penicillin, cephalosporin, penem, carbapenem, clavam, monobactam, bridged monobactam, any other compound susceptible to serine beta-lactamases, or a combination thereof.

14. The pharmaceutical composition according to any one of preceding claims 1 1 to 13, wherein said pharmaceutical composition further comprises an additional antibiotic other than said beta-lactam antibiotic.

15. The pharmaceutical composition according to claim 14, wherein said additional antibiotic is selected from the group consisting of aminoglycosides, spectinomycins, macrolides, ketolides, streptogramins, oxazolidinones, tetracyclines, fluoroquinolones, quinolones, coumarin antibiotics, glycopeptides, lipoglycopeptides, nitroimidazoles, ansamycins, phenicols, mupirocyn, fosfomycin, tobramycin, linezolid, daptomycin, and vancomycin.

16. The pharmaceutical composition according to any one of preceding claims 1 1 to 15, wherein said pharmaceutical composition further comprises an additional b- lactamase inhibitor other than said b-lactamase inhibitor of formula (I).

17. The pharmaceutical composition according to claim 16, wherein said additional b- lactamase inhibitor is selected from the group consisting of metallo^-lactamase (MBL) inhibitors, also known as Class B inhibitors.

18. A combination of (i) at least one b-lactamase inhibitor of formula (I) as defined in any one of claims 1 to 10 and 20, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and (ii) a beta-lactam antibiotic as defined in any one of claims 12 to 13, for use in the treatment of a bacterial infection.

19. A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a b-lactamase inhibitor of formula (I) as defined in any one of claims 1 to 10 and 20, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, in combination with a therapeutically effective amount of a beta-lactam antibiotic as defined in any one of claims 12 to 13.

20. A b-lactamase inhibitor having the following general formula (I):

wherein

Xi and X₂ are CH or N, at least one thereof being N and at least one thereof being CH,

R¹ is selected from the group consisting of hydrogen, halogen, C₁-C₆ haloalkyl, O-C₁- Ce alkyl, C1-C6 alkyl-OH, COOH, Ci-Ce alkyl-COOH, COO-Ci-Ce alkyl, Ci-Ce alkyl-COO- Ci-Ce alkyl, CONH₂, CONHOH, SO2NH2, NHS0₂-Ci-Ce alkyl, Ci-Ce alkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, OH, O-Ci-Ce alkyl, C₁-C6 alkyl-OH, COOH, and COO-C1-C6 alkyl,

R² is selected from the group consisting of hydrogen, halogen, OH, Ci-Ce alkyl, C₁-C6 alkyl-phenyl, C₁-C6 alkyl-OH, C-i-Ce haloalkyl, O-C-i-Ce alkyl, O-phenyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, C-i-Ce haloalkyl, C₁-C6 haloalkoxy, O-C-i-Ce alkyl, C₁-C6 alkyl-OH, and C₁-C6 alkyl,

R³ is represented by the following general formula (a):

-Rng1 -L-Rng2-S1 (a)

wherein

L is a divalent linking group selected from the group consisting of -SO₂NH-, -NHSO2-, -SO2CH2-, -CH2SO2-, -S-, and -SO2-,

S1 is one or more substituents selected from the group consisting of halogen, OH, CN, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, C₁-C6 alkyl, C3-C6 cycloalkyl, 0-Ci-Ce alkyl, Ci-Ce alkyl-OH, COOH, COO-Ci-Ce alkyl, CONH₂, and NHCOCH3, and

R⁴ is selected from the group consisting of hydrogen, C₁-C6 alkyl, C₁-C6 alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, OH, O-Ci-Ce alkyl, C₁-C₆ alkyl-OH, and C-i-Ce alkyl.

21. A b-lactamase inhibitor for use to inhibit b-lactamases in the treatment of a bacterial infection together with a beta-lactam antibiotic, said b-lactamase inhibitor having the following general formula (I):

wherein

R¹ is selected from the group consisting of hydrogen, halogen, C₁-C₆ haloalkyl, O-C₁- Ce alkyl, C1-C6 alkyl-OH, COOH, Ci-Ce alkyl-COOH, COO-Ci-Ce alkyl, Ci-Ce alkyl-COO- Ci-Ce alkyl, CONH₂, CONHOH, SO₂NH₂, NHSO₂- Ci-C₆alkyl, Ci-C₆alkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, OH, O-Ci-Ce alkyl, C₁-C6 alkyl-OH, COOH, and COO-C₁-C₆ alkyl,

R² is selected from the group consisting of hydrogen, halogen, OH, Ci-Ce alkyl, C₁-C6 alkyl-phenyl, C₁-C6 alkyl-OH, C₁-C6 haloalkyl, O-Ci-Ce alkyl, O-phenyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, O-Ci-Ce alkyl, C₁-C6 alkyl-OH, and C₁-C6 alkyl,

R³ is selected from the group consisting of COOH, C₁-C6 alkyl-COOH, COO-C₁-C6 alkyl, C₁-C6 alkyl-COO-alkyl, CONH₂, CONHOH, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of halogen, OH, 0- C₁-C6 alkyl, NO₂, COOH, Ci-Ce alkyl-COOH, COO-Ci-Ce alkyl, S0₂N(R^llR^l11), NHS0₂-R^IV, S-R^v, S0₂-R^v, wherein R", R¹¹¹, R^IV, and R^v, are independently hydrogen, Ci-Ce alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, C₁-C6 alkyl, C3-C6 cycloalkyl, 0-Ci-Ce alkyl, Ci-Ce alkyl-OH, COOH, COO-Ci-C₆ alkyl, CONH₂, NHCOCH3, and R⁴ is selected from the group consisting of hydrogen, C₁-C6 alkyl, C₁-C6 alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C₁-C6 haloalkyl, C₁-C6 haloalkoxy, OH, O-Ci-Ce alkyl, Ci-Ce alkyl-OH, and C₁-C₆ alkyl.