RU2348633C2 - PYRASOLE[3,4-b]PYRIDINE COMPOUNDS AND THEIR APPLICATION AS PHOSPHODIESTERASE INHIBITORS - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention concerns compound of formula (I)

where R^y is

, or its pharmaceutically acceptable salts. These compounds have phosphodiesterase (PDE) inhibition effect, particularly for PDE-4. Additionally invention claims application of compound of the formula (I) or its pharmaceutically acceptable salt in manufacturing of medicine for treatment and/or prevention of cognitive ability depression or disorder of humans, e.g. of chronic neurological disorder, such as Alzheimer's disease.

EFFECT: enhanced efficiency of composition and treatment method.

17 cl, 21 tbl, 191 ex

Description

The present invention relates to pyrazolopyridine compounds, methods for their preparation, intermediate compounds used in these methods, and pharmaceutical compositions containing these compounds. This invention also relates to the use of pyrazolopyridine compounds in therapy, for example, as phosphodiesterase inhibitors (PDEs) and / or for the treatment and / or prevention of inflammatory and / or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.

US 3979399, US 3840546 and US 3966746 (ERSquibb & Sons) disclose 4-amino derivatives of pyrazolo [3,4-b] pyridine-5-carboxamides, where the 4-amino group NR ₃ R ₄ may be an acyclic amino group, where R ₃ and R ₄ may each be hydrogen, lower alkyl (e.g. butyl), phenyl, and so on; alternatively, NR ₃ R ₄ may be a 3-6 membered heterocyclic group such as pyrrolidino, piperidino and piperazino. These compounds are disclosed as central nervous system depressants, useful as sedative, analgesic, and antihypertensive agents.

US 3925388, US 3856799, US 3833594 and US 3755340 (ERSquibb & Sons) disclose 4-amino derivatives of pyrazolo [3,4-b] pyridine-5-carboxylic acids and esters. The 4-amino group NR ₃ R ₄ may be an acyclic amino group, where R ₃ and R ₄ may each be hydrogen, lower alkyl (eg, butyl), phenyl, and so on; alternatively, NR ₃ R ₄ may be a 5-6 membered heterocyclic group in which an additional nitrogen atom is present, such as pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl. These compounds are mentioned as being central nervous system depressants, useful as sedatives or tranquilizers, as having anti-inflammatory and analgesic properties. These compounds are mentioned as increasing the intracellular concentration of adenosine-3 ', 5'-cyclic monophosphate and to alleviate the symptoms of asthma.

In H. Hoehn et al., J. Heterocycl. Chem., 1972, 9 (2), 235-253, a series of derivatives of 1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid with substituents 4-hydroxy, 4-chloro, 4-alkoxy, 4-hydrazino and 4-amino.

CA 1003419, CH 553799 and T. Denzel, Archiv der Pharmazie, 1974, 307 (3), 177-186 disclose 4,5-disubstituted 1H-pyrazolo [3,4-b] pyridines unsubstituted at position 1.

US 3833598 and GB 1417489 (ERSquibb & Sons) disclose 4-amino derivatives of pyrazolo [3,4-b] pyridine-6-carboxylic acids and esters. The 4-amino group NR ₃ R ₄ may be an acyclic amino group, where R ₃ and R ₄ may each be hydrogen, lower alkyl, R ₆ , R _{7 is} phenyl, and so on; or NR ₃ R ₄ may be a 5-6 membered heterocyclic group in which an additional nitrogen atom is present, i.e. optionally substituted pyrrolidino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl. At the 5th position of pyrazolo [3,4-b] pyridine is an R ₅ group which is hydrogen, lower alkyl, phenyl, phenyl lower alkyl) or halogen; R ₅ preferably represents hydrogen, methyl or chlorine. These compounds are mentioned as being central nervous system depressants, useful as tranquilizers or sedatives to alleviate anxiety and tension states. These compounds are also mentioned as increasing the intracellular concentration of adenosine-3 ', 5'-cyclic monophosphate and to relieve symptoms of asthma. These compounds are also mentioned as having anti-inflammatory properties and as being useful as anti-inflammatory agents, for example, to reduce local inflammatory conditions, such as those that are edematous or result from proliferation of connective tissue in various species of mammals, such as rats and dogs.

US 4,115,394 and GB 1,511,006 (ERSquibb & Sons) disclose 4-amino derivatives of 6-phenyl-pyrazolo [3,4-b] pyridines. The 4-amino group ,, NR ₃ R ₄ represents an acyclic amino group, where R ₃ and R ₄ may each be hydrogen, lower alkyl, phenyl, phenyl lower alkyl) or substituted phenyl. In the 5th position of pyrazolo [3,4-b] pyridine there is a group R ₅ which represents hydrogen, lower alkyl, phenyl or phenyl lower alkyl); R _{3 is} preferably hydrogen. These compounds are mentioned as having anti-inflammatory properties and as being useful as anti-inflammatory agents, for example, to reduce local inflammatory conditions, such as those that are edematous in nature or resulting from proliferation of connective tissue in various species of mammals, such as rats and dogs. These compounds are also mentioned (a) as having diuretic activity and (b) as increasing the intracellular concentration of adenosine-3 ', 5'-cyclic monophosphate and to relieve symptoms of asthma.

Japanese Patent Laid-Open JP-2002-20386-A (Ono Yakuhin Koduo KK), published January 23, 2002, discloses pyrazolopyridine compounds of the following formula:

where R ¹ means 1) a group —OR ⁶ , 2) a group —SR ⁷ , 3) a group C _2-8 alkynyl, 4) a group nitro, 5) a group cyano, 6) a group C _1-8 alkyl substituted with a hydroxy group, or a group C _1-8 alkoxy, 7) a phenyl group, 8) a group -C (O) R ⁸ , 9) a group -SO ₂ NR ⁹ R ¹⁰ , 10) a group -NR ¹¹ SO ₂ R ¹² , 11) a group - NR ¹³ C (O) R ¹⁴ or 12) the group -CH = NR ¹⁵ . R ⁶ and R ⁷ mean 1) a hydrogen atom, 2) a group C _1-8 alkyl, 3) a group C _1-8 alkyl, substituted by a group C _1-8 alkoxy, 4) a trihalogenomethyl group, 5) a group C _3-7 cycloalkyl 6) a C _1-8 alkyl group substituted with a phenyl group, or 7) a 3-15-membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-3 atoms sulfur. R ² means 1) a hydrogen atom or 2) a group C _1-8 alkoxy. R ³ means 1) a hydrogen atom or 2) a group C _1-8 alkyl. R ⁴ means 1) a hydrogen atom, 2) a group C _1-8 alkyl, 3) a group C _3-7 cycloalkyl, 4) a group C _1-8 alkyl substituted by a group C _3-7 cycloalkyl, 5) a phenyl group, which can be substituted by 1-3 halogen atoms, or 6) a 3-15-membered mono-, di- or three cyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-3 sulfur atoms. R ⁵ means 1) a hydrogen atom, 2) a group C _1-8 alkyl, 3) a group C _3-7 cycloalkyl, 4) a group C _1-8 alkyl substituted by a group C _3-7 cycloalkyl, or 5) a phenyl group which may be substituted by 1-3 substituents. In the R ³ group, a hydrogen atom is preferred. In the R ⁴ group, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl are preferred. The compounds of JP-2002-20386-A are mentioned as having PDE-4 inhibitory activity and as being useful in the prevention and / or treatment of inflammatory diseases and many other diseases.

EP 0076035 A1 (ICI Americas) discloses pyrazolo [3,4-b] pyridine derivatives as central nervous system depressants, useful as tranquilizers or sedatives to alleviate anxiety and tension states.

The compound of cartazolate, ethyl-1-ethyl-4-n-butylamino-1H-pyrazolo [3,4-b] pyridine-5-carboxylate is known. In JW Daly et al., Med. Chem. Res., 1994, 4, 293-306 and D. Shi et al., Drug Development Research, 1997, 42, 41-56 a series of 4- (amino) substituted derivatives of 1H-pyrazolo [3,4-b] pyridine- 5-carboxylic acids, including ethyl 4-cyclopentylamino-1-methyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylate, and their affinities and antagonistic activities with respect to the A ₁ - and A _2A adenosine receptors, and the last article disclosed their affinities for various GABA _A receptor channel binding sites. In S. Schenone et al., Bioorg. Med. Chem. Lett., 2001, 11, 2529-2531, and F. Bondavalli et al., J. Med. Chem., 2002, vol. 45 (Issue 22, 24 October 2002, which are claimed to be published on the Internet on 09/24/2002), pp. 4875-4887, a number of 4-amino-1- (2-chloro-2-phenylethyl) ethyl esters are disclosed - 1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid as ligands of the A1-adenosine receptor.

WO 02/060900 A2 discloses, as antagonists of MCP-1 (monocytic chemotactic protein-1) for the treatment of allergic, inflammatory or autoimmune disorders or diseases, a number of bicyclic heterocyclic compounds with the substituent —C (O) —NR ⁴ —C (O) - N ^R 5R ⁶ , including isoxazolo [5,4-b] pyridines and 1H-pyrazolo [3,4-b] pyridines (referred to as pyrazolo [5,4-b] pyridines) with the group —C (O) —NR ⁴ -C (O) -NR ⁵ R ⁶ as a 5-substituent and optionally substituted at the 1st, 3rd, 4th and / or 6th positions. Bicyclic heterocyclic compounds with the substituent —C (O) NH ₂ instead of the substituent —C (O) —NR ⁴ —C (O) —NR ⁵ R ⁶ are said to be disclosed in WO 02/060900 as intermediates in the synthesis of —C (O) -NR ⁴ -C (O) -NR ⁵ R ⁶ -substituted compounds.

SSChakravorti et al., Indian J. Chem., 1978, 16B (2), 161-3 disclose 4-hydroxy-1,3-diphenyl-5- (3 ', 4'-dihydroisoquinol-1'-yl compounds ) -pyrazolo [3,4-b] pyridine and 1,3-diphenyl-4-hydroxy-5- (3'-methyl-3 ', 4'-dihydroisoquinol-1'-yl) -pyrazolo [3,4- b] pyridine. These two compounds were tested for antifilarial activity, but it was found that they do not have significant microfilaricidal activity.

G. Sabitha et al., Synthetic Commun., 1999, 29 (4), 655-665 disclosed a synthesis pathway for 5-substituted-6-amino-1-phenyl-3- (methyl or phenyl) pyrazolo [3, 4-b] pyridines, wherein the 5-substituent pyrazolo [3,4-b] pyridine is benzimidazol-2-yl, 5-chloro-benzoxazol-2-yl or benzothiazol-2-yl. Although it has been declared that these molecules are “biologically interesting”, it has never been disclosed that these compounds have been tested in any pharmacological tests and no general or specific biological activity of these compounds has been disclosed.

On April 8, 2003, Chemical Abstracts (CAS) registered in their database a compound with registration number CAS 502143-17-1, having the chemical name "N-butyl-5- (4,5-dihydro-1H-imidazole-2- il) -1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine "and having the laboratory code NSC 235755. On November 5, 2003, registration in the CAS for this compound was not associated with any literature references , and thus, it turns out that on November 5, 2003, the chemical synthesis and uses of this compound were not disclosed. The structure of this connection from the CAS database is as follows:

It is desirable to find new compounds that bind to phosphodiesterase type IV (PDE-4) and preferably inhibit it.

The present invention provides a compound of formula (I) or a salt thereof (in particular a pharmaceutically acceptable salt thereof):

Where:

R ¹ represents C _1-4 alkyl, C _1-3 fluoroalkyl or - (CH ₂ ) ₂ OH;

R ² represents a hydrogen atom (H), methyl or C ₁ fluoroalkyl;

R ³ represents a possibly substituted branched C _3-6 alkyl, possibly substituted C _3-8 cycloalkyl, possibly substituted monounsaturated C _5-7 cycloalkenyl, possibly substituted phenyl or a possibly substituted heterocyclic group of sub-formula (aa), (bb) or ( cc):

where n ¹ and n ² independently represent 1 or 2; and Y represents O, S, SO ₂ or NR ⁴ ; where R ⁴ represents a hydrogen atom (H), C _1-2 alkyl, C _1-2 fluoroalkyl, CH ₂ C (O) NH ₂ , C (O) NH ₂ , C (O) -C _1-2 alkyl or C (O) -C ₁ fluoroalkyl;

where in R ^{3 a} possibly substituted branched C _3-6 alkyl is optionally substituted with one or two substituents representing oxo (= O), OH, C _1-2 alkoxy or C _1-2 fluoroalkoxy, and where any such substituent is not a substituent at carbon atom R ³ connected (linked) to the group —NH— of formula (I);

where in R ³ phenyl is optionally substituted with one substituent, which is fluoro, chloro, C _1-2 alkyl, C _1-2 fluoroalkyl C _1-2 alkoxy, C _1-2 fluoroalkoxy or cyano, or two or three fluoro substituents;

where in R ³ C _{3-8 a} cycloalkyl or heterocyclic group of a sub-formula (aa), (bb) or (cc) is optionally substituted with one or two substituents independently representing (for example, representing) oxo (= O); IT; C _1-2 alkoxy; C _1-2 fluoroalkoxy; NHR ²¹ , where R ²¹ represents a hydrogen atom (H) or C _1-4 straight chain alkyl; C _1-2 alkyl; C _1-2 fluoroalkyl (e.g., C ₁ fluoroalkyl such as —CH ₂ F or —CHF ₂ ); -CH ₂ OH; -CH ₂ CH ₂ OH; —CH ₂ NHR ²² , wherein R ²² is H or C _1-2 alkyl; —C (O) OR ²³ where R ²³ represents H or C _1-2 alkyl; —C (O) NHR ²⁴ , wherein R ²⁴ is H or C _1-2 alkyl; —C (O) R ²⁵ , wherein R ²⁵ is C _1-2 alkyl; fluoro; hydroxyimino (= N-OH); or (C _1-4 alkoxy) imino (= N-OR ²⁶ where R ²⁶ represents C _1-4 alkyl); and where any substituent OH, alkoxy, fluoroalkoxy or NHR ^{21 is} not substituted at the R ³ ring carbon atom (linked) to the —NH— group of formula (I), and is not substituted at any R ³ ring carbon atom associated with group Y of a heterocyclic group (aa), (bb) or (cc);

and where if R ³ is optionally substituted with monounsaturated C _5-7 cycloalkenyl, then this cycloalkenyl is optionally substituted with one or two substituents independently representing fluoro or C _1-2 alkyl, provided that if there are two substituents, they both do not represent C ₂ alkyl, and the ring carbon atom R ³ bonded to the —NH-group of formula (I) is not involved in the cycloalkenyl double bond;

and R ^3a represents a hydrogen atom (H) or C _1-3 straight chain alkyl;

with the proviso that if R ^3a is C _1-3 alkyl, then R ³ is tetrahydro-2H-pyran-4-yl, cyclohexyl (i.e., unsubstituted), 3-hydroxy-cyclohexyl, 4-oxo-cyclohexyl or 4 - (hydroxyimino) cyclohexyl;

and where Het corresponds to the sub-formula (i), (ii), (iii), (iv) or (v):

Where:

W ¹ , W ² , W ⁴ and W ⁵ are N; and W ³ represents NR ^W ;

X ¹ , X ³ and X ⁴ are N or CR ^X ; X ² represents O, S or NR ^X ; and X ⁵ represents CR ^X1 R ^X2 or CR ^X3 R ^X4 ;

Y ¹ , Y ^2, and Y ³ are CR ^Y or N; Y ⁴ represents O, S or NR ^Y ; and Y ⁵ represents CR ^Y1 R ^Y2 ;

Z ¹ and Z ⁵ represent O, S or NR ² ; and Z ² , Z ³ and Z ⁴ are N or CR ^Z ,

Where:

R ^W represents a hydrogen atom (H) or C _1-2 alkyl;

R ^X , R ^X2 , R ^Y and R ^Y2 independently represent:

hydrogen atom (H);

C _1-8 alkyl;

C _3-6 cycloalkyl optionally substituted with one or two C _1-2 alkyl groups and / or one oxo group (= O);

- (CH ₂ ) _n ^2a —C _3-6 cycloalkyl optionally substituted by —— (CH ₂ ) _n ^2a - either a C _3-6 cycloalkyl moiety of a C _1-2 alkyl group or optionally substituted by a C _3-6 cycloalkyl moiety a group —CH ₂ C (O) NHC _1-2 alkyl, wherein n ^2a is 1, 2 or 3;

- (CH ₂ ) n ³ -S (O) ₂ -R ⁵ , -CH (C _1-2 alkyl) -S (O) ₂ -R ⁵ , -CMe ₂ -S (O) ₂ -R ⁵ or C _3-5 cycloalkyl substituted on the connecting carbon atom with a group —S (O) ₂ —R ⁵ , wherein n ³ is 1 or 2;

and R ⁵ is C _1-4 alkyl (for example C _1-3 alkyl), —NR ¹⁵ R ¹⁶ , phenyl, pyridinyl bonded to a carbon atom, or benzyl (where phenyl and benzyl are independently optionally substituted on the aromatic ring with one or two substituents independently representing fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy, C ₁ fluoroalkoxy or OH, and where pyridinyl is optionally substituted with one methyl, methoxy or OH group (including any tautomer thereof);

where R ¹⁵ represents H, C _1-4 alkyl (for example C _1-2 alkyl), phenyl, benzyl (where phenyl and benzyl are independently optionally substituted on the aromatic ring with one or two substituents independently representing fluoro, chloro, C _{1- 2} alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy), CH (Me) Ph or pyridinyl bound to a carbon atom, optionally substituted with one methyl, methoxy or OH group (including any tautomer thereof);

and R ¹⁶ represents H or C _1-2 alkyl;

or where R ¹⁵ and R ¹⁶ together represent - (CH ₂ ) _n ^3a —X ^3a —C (CH ₂ ) _n ^3b -, where n ^3b and n ³ ′ ⁰ independently represent 2 or 3, and X ³³ represents a bond, —CH ₂ -, O or NR ^8a , where R ^8a is H or C _1-2 alkyl, acetyl, —S (O) ₂ Me or phenyl, and where the ring formed by NR ¹⁵ R ¹⁶ is optionally substituted a ring carbon atom with one or two substituents independently representing methyl or oxo (= O);

- (CH ₂ ) _n ⁴ -NR ⁶ R ⁷ , -CH (C _1-2 alkyl) -NR ⁶ R ⁷ , -CMe ₂ -NR ⁶ R ⁷ or C _3-5 cycloalkyl substituted at the carbon atom by the group - NR ⁶ R ⁷ where n ⁴ represents 0, 1, 2 or 3;

and R ⁶ and R ⁷ independently represent H, C _1-6 alkyl (e.g., C _1-4 alkyl), C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, —C (O) R ¹⁷ , -S (O) ₂ R ¹⁸ , phenyl, benzyl (where phenyl and benzyl are independently optionally substituted on the aromatic ring with one or two substituents independently representing fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy) or pyridinyl bonded to a carbon atom, optionally substituted with one methyl, methoxy or OH group (including any tautomer thereof);

and where R ¹⁷ and R ¹⁸ independently are C _1-6 alkyl (e.g., C _1-4 alkyl, or C _1-2 alkyl, or isopropyl, or n-propyl), C _3-6 cycloalkyl, optionally substituted 5- membered heteroaryl, which is furyl (furanyl, for example 2-furyl), or 1,3-oxazolyl, or isoxazolyl, or oxadiazolyl, or thienyl (for example 2- or 3-thienyl), or 1,3-thiazolyl, or isothiazolyl or pyrrolyl or imidazolyl or pyrazolyl (all independently possibly substituted by one oxo group and / or one or two methyl groups), or phenyl or benzyl (where phenyl and benzyl are independently possible substituted on the aromatic ring by one or two substituents independently is fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy, C ₁ fluoroalkoxy or OH), or pyridinyl bonded to a carbon atom optionally substituted by one a methyl, methoxy or OH group (including any tautomer thereof);

or R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) _n ⁶ -, where n ⁵ and n ⁶ independently represent 2 or 3, and X ⁵ represents a bond, —CH ₂ -, O or NR ⁸ , where R ⁸ represents H, C _1-2 alkyl, acetyl, -S (O) ₂ Me or phenyl, and where the ring formed by NR ⁶ R ⁷ is optionally substituted at the ring carbon atom with one or two substituents independently representing methyl or oxo (= O);

- (CH ₂ ) _n ⁷ -OR ⁹ ; where n ⁷ represents 0, 1, 2 or 3, and R ⁹ represents H, C _1-6 alkyl, C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, —C (O) R ¹⁷ , phenyl or benzyl (where phenyl and benzyl are independently possibly substituted on the aromatic ring with one or two groups of fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy); where n ⁷ represents O, only when - (CH ₂ ) _n ⁷ -OR ⁹ is bonded to a carbon atom in the Het ring; and where n ^{7 is} not 0 when Het corresponds to the sub-formula (v) (that is, n ^{7 is} not 0 for R ^X2 and for R ^Y2 );

- (CH ₂ ) _n -C (O) -NR ¹⁰ R ¹¹ , -CH (C _1-2 alkyl) -C (O) -NR ¹⁰ R ¹¹ , -CMe ₂ -C (O) -NR ¹⁰ R ¹¹ or C _3-5 cycloalkyl substituted at the carbon atom by the group —C (O) —NR ¹⁰ R ¹¹ , wherein n ¹¹ is 0, 1 or 2;

and where R ¹⁰ and R ¹¹ independently represent: H; C _1-6 alkyl; C _1-4 fluoroalkyl; C _2-4 alkyl substituted with one OH group or —O— _1-2 alkyl at a position other than the point of attachment; C _3-6 cycloalkyl optionally substituted with one or two methyl groups; —CH ₂ —C _3-6 cycloalkyl optionally substituted with one methyl group, NH ₂ or NHMe; - (CH ₂ ) _n ¹⁷ -Het ² ; pyridinyl bonded to a carbon atom, optionally substituted with one methyl, methoxy or OH group (including any tautomer thereof); phenyl; benzyl; or —CH (C _1-2 alkyl) Ph [where phenyl, benzyl and —CH (C _1-2 alkyl) Ph are independently optionally substituted on the aromatic ring with one or two substituents independently representing fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy, C ₁ fluoroalkoxy, OH, -NR ^10a R ^10b (where R ^10a represents H or C _1-2 alkyl, and R ^10b represents H, C _1-2 alkyl, —C (O) —C _1-2 alkyl or —S (O) ₂ —C _1-2 alkyl), —C (O) —NR ^10c R ^11d (where R ^10c and R ^{10d are} independently H or C _{1 -2} alkyl) or —S (O) ₂ —R ^10e (where R ^10e represents C _1-2 alkyl, NH ₂ , NHMe or NMe ₂ )],

where n ¹⁷ represents 0, 1 or 2, and where Het ² represents a 4-, 5- or 6-membered saturated heterocyclic ring containing one O or S ring atom or one NR ²⁷ ring group, where R ²⁷ represents H , C _1-2 alkyl, —C (O) Me or —S (O) ₂ Me, where the Het ² ring is optionally substituted on the ring carbon atom with one or two substituents independently representing methyl or oxo (= O);

and where, if n ¹⁷ is 2, then the Het ² ring may possibly contain one additional ring atom N at the position of the Het ² ring associated with the group - (CH ₂ ) _n ¹⁷ -; provided that if Het ² contains one (one) ring (s) atom / group O or S or NR ²⁷ and one additional ring atom N, then this (this) ring (s) atom / group O / S / NR ²⁷ and this one additional ring atom N is not directly connected to each other and separated by more than one carbon atom;

or R ¹⁰ and R ¹¹ together represent - (CH ₂ ) _n ⁸ —X ⁶ - (CH ₂ ) _n ⁹ -, where n ⁸ and n ⁹ independently represent 2 or 3, and X ⁶ represents a bond, —CH ₂ -, O or NR ¹² , where R ¹² represents H, C _1-2 alkyl, acetyl, -S (O) ₂ Me or phenyl, and where the ring formed by NR ¹⁰ R ¹¹ is optionally substituted on the ring carbon atom by one or two substituents independently representing methyl or oxo (= O);

- (CH ₂ ) _n ¹² -C (O) -OR ¹³ where n ¹² represents 0, 1 or 2; and where R ¹³ represents H, C _1-6 alkyl, C _3-6 cycloalkyl, -CH ₂ -C _3-6 cycloalkyl, phenyl or benzyl (where phenyl and benzyl are independently optionally substituted on the aromatic ring by one or two groups (independently ) fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy);

- (CH ₂ ) _n ¹³ -C (O) -R ^13a , where n ¹³ represents 0, 1 or 2; and where R ^13a represents a hydrogen atom (H), C _1-6 alkyl, C _1-2 fluoroalkyl, C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, benzyl or phenyl; where phenyl and benzyl are independently possibly substituted on the aromatic ring with one or two groups (independently) of fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy;

- (CH ₂ ) _n ¹⁴ -Het ¹ , -CH (C _1-2 alkyl) -Het ¹ , -CMe2-Het ¹ or C _3-5 cycloalkyl substituted at the carbon atom by the Het ¹ group, where n ¹⁴ represents 0, 1 or 2, and where Het ¹ represents a 4-, 5-, 6- or 7-membered saturated heterocyclic ring;

where the specified heterocyclic ring Het ¹ contains one ring atom of O or S and / or one ring group NR ¹⁴ , where R ¹⁴ represents H, C _1-4 alkyl, C _3-6 cycloalkyl, benzyl, phenyl, -C (O) R ¹⁹ or -S (O) ₂ R ¹⁹ ;

where R ¹⁹ , independently of any other R ¹⁹ , is C _1-6 alkyl (e.g. C _1-4 alkyl or C _1-3 alkyl), C _3-6 cycloalkyl, thienyl (e.g. 2-thienyl), furyl (furanyl for example furan-2-yl) or phenyl or benzyl; wherein phenyl and benzyl are independently optionally substituted with one or two groups (independently) of fluoro, methyl or methoxy;

and wherein said heterocyclic ring Het ^{1 is} optionally substituted (at a position or positions different from any position of NR ¹⁴ ) with one or two oxo substituents (= O) and / or one C _1-4 alkyl substituent;

provided that if the heterocyclic ring Het ¹ contains one O or S ring atom and one NR ¹⁴ ring group, then: (a) this O / S ring atom and this NR ¹⁴ ring group are not directly connected to each other, and (b ) this O / S ring atom and this NR ¹⁴ ring group are separated by more than one carbon atom, unless Het ¹ contains the group —NR ¹⁴ —C (O) —O— or —NR ¹⁴ - (O) —S— as part of the ring; or

- (CH ₂ ) _n ¹⁰ —Ar, —CH (C _1-2 alkyl) —Ar, —CMe ₂ —Ar or C _3-5 cycloalkyl substituted at the carbon connecting atom with Ar group, where n ¹⁰ represents 0, 1 or 2, and

(1) Ar is phenyl optionally substituted with one or two substituents independently representing fluoro, chloro, bromo, C _1-2 alkyl, C _1-2 fluoroalkyl, C _1-2 alkoxy, C ₁ fluoroalkoxy, OH, -NR ^11a R ^11b (where R ^11a represents H or C _1-2 alkyl, and R ^11b represents H, C _1-2 alkyl, —C (O) —C _1-2 alkyl or —S (O) ₂ —C _1-2 alkyl), cyano, —C (O) —NR ^11c R ^11d (where R ^11c and R ^11d independently represent H or C _1-2 alkyl), —C (O) —OR ^11e , where R ^11e represents H or C _1-2 alkyl, or —S (O) ₂ —R ^11f (wherein R ^11f is C _1-2 alkyl, NHz, NHMe or NMe2); or phenyl Ar is optionally substituted at two adjacent ring Ar atoms with two ends of the chain, which is: - (CH ₂ ) ₄ -, - (CH ₂ ) ₃ - or —CH = CH — CH = CH—; or

(2) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms (e.g., 1, 2, or 3 heteroatoms) selected from O, N, or S; and where if the heterocyclic aromatic ring Ar contains 2, 3 or 4 heteroatoms (for example, 2 or 3 heteroatoms), then one is selected from O, N and S and the remaining heteroatom (s) is (are) N; and where the heterocyclic aromatic ring Ar is optionally substituted with one or two groups independently representing C _1-4 alkyl (e.g., C _1-2 alkyl) or OH (including any keto-tautomer of the OH-substituted aromatic ring), or the heterocyclic aromatic ring Ar possibly substituted on two adjacent ring Ar atoms by two ends of the chain, which is: - (CH ₂ ) 4-, - (CH ₂ ) ₃ - or —CH = CH — CH═CH—;

R ^X1 and R ^Y1 independently represent a hydrogen atom (H), C _1-2 alkyl or C ₁ fluoroalkyl;

R ^X3 and R ^X4 together represent - (CH ₂ ) _n ¹⁵ -X ⁷ - (CH ₂ ) _n ¹⁶ -, where n ¹⁵ and n ¹⁶ independently represent 1 or 2, and X ⁷ represents a bond, -CH ₂ -, O or NR ^X5 , where R ^X5 is H, C _1-2 alkyl, acetyl or —S (O) ₂ Me; and

R ^Z represents a hydrogen atom (H) or C _1-2 alkyl,

provided that:

if R ³ represents a heterocyclic group of sub-formula (bb), n ¹ represents 1, and Y represents NR ⁴ , then R ⁴ does not represent C _1-2 alkyl, C _1-2 fluoroalkyl or CH ₂ C (O ) NH ₂ .

Preferably R ^3a represents a hydrogen atom (H) or methyl.

Particularly preferably, when R ^3a represents a hydrogen atom (H).

In one possible embodiment of the present invention, R ³ is an optionally substituted branched C _3-6 alkyl, an optionally substituted C _3-8 cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc):

where n ¹ and n ² represent 1 or 2; and Y represents O, S, SO ₂ or NR ⁴ ; where R ⁴ represents a hydrogen atom, C _1-2 alkyl, C _1-2 fluoroalkyl, C (O) NH ₂ , C (O) -C _1-2 alkyl or C (O) -C ₁ fluoroalkyl; provided that Y is not NR ⁴ when the heterocyclic group corresponds to the sub-formula (aa).

Alternatively or additionally, in one possible embodiment of the present invention, in R ³ branched C _3-6 alkyl is optionally substituted with one or two substituents representing oxo (= O), OH, C _1-2 alkoxy, or C _1-2 fluoroalkoxy; and where any such substituent is not a substituent at the R ³ carbon atom attached to the —NH— group of formula (I).

Alternatively or additionally, in one possible embodiment of the present invention in R ^3, phenyl is optionally substituted with one substituent, which is fluoro, chloro, C _1-2 alkyl, C _1-2 fluoroalkyl, C _1-2 alkoxy, C _1-2 fluoroalkoxy or cyano .

Alternatively or additionally, in one possible embodiment of the invention, in R ³ C _{3-8 a} cycloalkyl or heterocyclic group of a sub-formula (aa), (bb) or (cc) is optionally substituted (a) with one or two substituents representing (= O ), OH, C _1-2 alkoxy C _1-2 fluoroalkoxy or C _1-2 alkyl; and where any OH, alkoxy or fluoroalkoxy substituent is not substituted at the carbon atom of the R ³ ring attached to the —NH— group of formula (I) and is not substituted at any carbon R ³ ring attached to the Y group of the heterocyclic group (aa), ( bb) or (cc).

Alternatively or additionally, in one possible embodiment of the present invention, Het corresponds to the sub-formula (i), (ii), (iii) or (iv):

Where:

W ¹ , W ² and W ⁴ are N; and W ² represents NR ^W ;

X ¹ , X ³ and X ⁴ are N or CR ^X ; and X ² represents O, S or NR ^X ;

Y ¹ , Y ^2, and Y ³ are CR ^Y or N; and Y ⁴ represents O, S or NR ^Y ;

Z ¹ represents O, S or NR ^Z ; and Z ² , Z ³ and Z ⁴ are N or CR ^Z ;

and where:

R ^W represents a hydrogen atom (H) or C _1-2 alkyl; and

R ^Z represents a hydrogen atom (H) or C _1-2 alkyl.

Alternatively or additionally, in one possible embodiment of the present invention, R ^X and R ^Y independently represent:

hydrogen atom (H);

C _1-8 alkyl;

C _3-6 cycloalkyl;

- (CH ₂ ) _n ³ —SO ₂ —R ⁵ where n ³ is 1 or 2 and R ⁵ is C _1-3 alkyl or —NH — C _1-2 alkyl;

- (CH ₂ ) _n ⁴ —NR ⁶ R ⁷ , where n ⁴ represents 0, 1 or 2, and R ⁶ and R ⁷ independently represent H, C _1-6 alkyl, for example C _1-4 , —C ( O) —C _1-2 alkyl or —SO ₂ —C _1-2 alkyl; or R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) _n ⁶ -, where n ⁵ and n ⁶ independently represent 2 or 3, and X ⁵ represents a bond, —CH ₂ -, O or NR ⁸ , where R ⁸ represents H or C _1-2 alkyl;

- (CH ₂ ) _n ⁷ —O — R ⁹ , where n ⁷ is 1 or 2, and R ⁹ is H or C _1-6 alkyl;

—C (O) —NR ¹⁰ R ¹¹ where R ¹⁰ and R ¹¹ independently are H or C _1-6 alkyl; or R ¹⁰ and R ¹¹ together represent - (CH ₂ ) _n ⁸ —X ⁶ - (CH ₂ ) _n ⁹ -, where n ⁸ and n ⁹ independently represent 2 or 3, and X ⁶ represents a bond, —CH ₂ -, O or NR ¹² , where R ¹² represents H or C _1-2 alkyl;

—C (O) —OR ¹³ wherein R ¹³ is H or C _1-6 alkyl;

A 4-, 5-, 6- or 7-membered saturated heterocyclic ring containing one O ring atom or one NR ¹⁴ ring group, where R ¹⁴ is H or C _1-4 alkyl, wherein said heterocyclic ring is optionally substituted (by a position or positions different from any position NR ¹⁴ ) by one oxo substituent (= O) and / or one C _1-4 alkyl substituent; or

- (CH ₂ ) _n ¹⁰ -Ar, where n ¹⁰ represents 0, 1 or 2, and

(1) Ar is phenyl, optionally substituted with one or two substituents representing fluoro, chloro, C _1-2 alkyl, C _1-2 fluoroalkyl, C _1-2 alkoxy, C _1-2 fluoroalkoxy or cyano;

or

(2) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N or S; and where if the heterocyclic aromatic ring Ar contains 2 or 3 heteroatoms, then one is selected from O, N and S, and the remaining heteroatom (s) is (are) N; and wherein the heterocyclic aromatic ring Ar is optionally substituted with one or two C _1-4 alkyl groups.

Alternatively or additionally, in one possible embodiment of the present invention, Het corresponds to the sub-formula (i), (ii), (iii), (iv) or (v):

Where:

W ¹ , W ² , W ⁴ and W ⁵ are N; and W ³ represents NR ^W ;

X ¹ , X ³ and X ⁴ are N or CR ^X ; X ² represents O, S or NR ^X ; and X ⁵ are CR ^X1 R ^X2 ;

Y ¹ , Y ^2, and Y ³ are CR ^Y or N; Y ⁴ represents O, S or NR ^Y ; and Y ⁵ represents CR ^Y1 R ^Y2 ;

Z ¹ and Z ⁵ represent O, S or NR ² ; and Z ² , Z ³ and Z ⁴ are N or CR ² ;

and where:

R ^W represents a hydrogen atom (H) or C _1-2 alkyl; and

R ^Z represents a hydrogen atom (H) or C _1-2 alkyl.

In one possible embodiment of the present invention, R ^X , R ^X2 , R ^Y and R ^Y2 independently represent, or R ^x and R ^Y independently represent:

hydrogen atom (H);

C _1-8 alkyl;

C _3-6 cycloalkyl optionally substituted with a C _1-2 alkyl group;

- (CH ₂ ) _n ^2a -C _3-6 cycloalkyl optionally substituted by the group - (CH ₂ ) _n ^2a - or by a C _3-6 cycloalkyl group by a C _1-2 alkyl group, where n ^2a represents 1, 2 or 3;

- (CH ₂ ) _n ³ —SO ₂ —R ⁵ where n ³ is 1 or 2 and R ⁵ is C _1-3 alkyl or —NH — C _1-2 alkyl or phenyl;

- (CH ₂ ) _n ⁴ —NR ⁶ R ⁷ , where n ⁴ represents 0, 1, 2 or 3, and R ⁶ and R ⁷ independently represent H, C _1-6 alkyl, for example C _1-4 alkyl, C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, —C (O) —C _1-2 alkyl, —SO ₂ —C _1-2 alkyl, phenyl or benzyl (where phenyl or benzyl are independently optionally substituted by an aromatic ring with one group of fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy); or

R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) _n ⁶ -, where n ⁵ and n ⁶ independently represent 2 or 3, and X ⁵ represents a bond, —CH ₂ -, O or NR ⁸ , where R ⁸ represents H or C _1-2 alkyl;

- (CH ₂ ) _n ⁷ -OR ⁹ where n ⁷ represents 0, 1, 2 or 3, and R ⁹ represents H or C _1-6 alkyl; where n ⁷ represents 0 only when - (CH ₂ ) _n ⁷ -OR ⁹ is bonded to a carbon atom in the Het ring;

and where n ^{7 is} not 0 when Het corresponds to the sub-formula (v) (that is, n ^{7 is} not 0 for R ^X2 and for R ^Y2 );

—C (O) —NR ¹⁰ R ¹¹ , where R ¹⁰ and R ¹¹ independently represent H, C _1-6 alkyl, C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, phenyl or benzyl (where phenyl or benzyl is independently possibly substituted on the aromatic ring with one group of fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy); or R ¹⁰ and R ¹¹ together represent - (CH ₂ ) _n ⁸ —X ⁶ - (CH ₂ ) _n ⁹ -, where n ⁸ and n ⁹ independently represent 2 or 3, and X ⁶ represents a bond, —CH ₂ -, O or NR ¹² , where R ¹² represents H or C _1-2 alkyl; -

—C (O) —OR ¹³ where R ¹³ is H, C _1-6 alkyl, C _3-6 cycloalkyl, —CH ₂ —C _1-3 cycloalkyl, phenyl or benzyl (where phenyl or benzyl are independently optionally substituted at an aromatic ring with one group fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy);

—C (O) —R ^13a , where R ^13a represents a hydrogen atom (H), C _1-6 alkyl, C _1-2 fluoroalkyl, C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, benzyl or phenyl; where phenyl or benzyl are independently possibly substituted on the aromatic ring with one group of fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy;

A 4-, 5-, 6- or 7-membered saturated heterocyclic ring containing one O ring atom or one NR ¹⁴ ring group, where R ¹⁴ is H or C _1-4 alkyl, wherein said heterocyclic ring is optionally substituted (in position or to positions other than any position NR ¹⁴ ) with one oxo substituent (= O) and / or one C _1-4 alkyl substituent; or

- (CH ₂ ) _n ¹⁰ -Ar, where n ¹⁰ represents 0, 1 or 2, and

(1) Ar is phenyl, optionally substituted with one or two substituents representing fluoro, chloro, C _1-2 alkyl, C _1-2 fluoroalkyl, C _1-2 alkoxy, C _1-2 fluoroalkoxy or cyano;

or

(2) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N or S; and where, when the heterocyclic aromatic ring Ar contains 2 or 3 heteroatoms, one is selected from O, N and S, and the remaining heteroatom (s) is (are) N; and where the heterocyclic aromatic ring Ar is optionally substituted with one or two C _1-4 alkyl groups; and

R ^X1 and R ^X2 independently represent a hydrogen atom (H), C _1-2 alkyl or C ₁ fluoroalkyl.

In the compounds, for example in the compounds of formula (I), the “alkyl” group or group may be straight or branched chain. Alkyl groups, for example C _1-8 alkyl, or C _1-6 alkyl, or C _1-4 alkyl, or C _1-3 alkyl, or C _1-2 alkyl that may be used include C _1-6 alkyl, or C _1-4 , or C _1-3 alkyl, or C _1-2 alkyl, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl, or any branched isomers thereof, such as isopropyl, tert-butyl, sec-butyl, isobutyl, 3-methylbutan-2-yl, 2-ethylbutan-1-yl or the like.

The corresponding meaning is intended for "alkoxy", "alkylene" and similar terms derived from alkyl. For example, “alkoxy,” such as C _1-6 alkoxy, or C _1-4 alkoxy, or C _1-2 alkoxy, includes methoxy, ethoxy, propyloxy and hydroxy derivatives of the alkyls listed above. “Alkylsulfonyl,” such as C _1-4 alkylsulfonyl, includes methylsulfonyl (methanesulfonyl), ethylsulfonyl and the other alkyl derivatives listed above. “Alkylsulfonyloxy,” such as C _1-4 sulfonyloxy, includes methanesulfonyloxy (methylsulfonyloxy), ethanesulfonyloxy, and others.

"Cycloalkyl", for example C _3-8 cycloalkyl, includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, the C _3-8 cycloalkyl group is C _3-6 cycloalkyl or C _5-6 cycloalkyl, i.e. the cycloalkyl group contains a 3-6 membered or 5-6 membered carbocyclic ring, respectively.

"Fluoroalkyl" includes alkyl groups with one, two, three, four, five or more fluoro substituents, for example C _1-4 fluoroalkyl, or C _1-3 fluoroalkyl, or C _1-2 fluoroalkyl, such as monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl (CF ₃ CH ₂ -), 2,2-difluoroethyl (CHF ₂ -CH ₂ -) or 2-fluoroethyl (CH ₂ F-CH ₂ -) and so on. “Fluoroalkoxy” includes C _1-4 fluoroalkoxy or C _1-2 fluoroalkoxy, such as trifluoromethoxy, pentafluoroethoxy, monofluoromethoxy, difluoromethoxy and so on. “Fluoroalkylsulfonyl,” such as C _1-4 fluoroalkylsulfonyl, includes trifluoromethanesulfonyl, pentafluoroethylsulfonyl, and so on.

The halogen atom (“halogen”) present in the compounds, for example in the compounds of formula (I), may be a fluorine, chlorine, bromine or iodine atom (“fluoro”, “chloro”, “bromo” or “iodo”).

When it is determined in this description that an atom or group A is “linked (a)” or “connected (a)” to an atom or group B, this means that this (this) atom / group A is directly connected (a) to the atom / by group B, usually through one or more than one covalent bond, and excludes that A is indirectly linked to B through one (one) or more than one (one) intermediate atom (s) / group (e.g. excludes A -C-B); unless it is clear from the context that another meaning is meant.

By "pyridinyl bound to a carbon atom" is meant pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

Preferably, R ¹ is C _1-3 alkyl, C _1-3 fluoroalkyl or - (CH ₂ ) ₂ OH; more preferably C _1-3 alkyl, C-1-2 fluoroalkyl or - (CH ₂ ) ₂ OH; even more preferably C _2-3 alkyl, C ₂ fluoroalkyl or - (CH ₂ ) ₂ OH; and even more preferably C ₂ alkyl or C ₂ fluoroalkyl. If R ₁ is C _1-4 alkyl or C _1-3 fluoroalkyl, then it may be straight or branched chain. R ¹ may, for example, be methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C ₂ fluoroalkyl or - (CH ₂ ) ₂ OH; and more preferably, R ¹ is ethyl, n-propyl, C ₂ fluoroalkyl (e.g. C ₁ fluoroalkyl-CH ₂ - such as CF ₃ —CH ₂ -) or - (CH ₂ ) ₂ OH. Most preferably, R ¹ is ethyl.

Preferably R ² represents a hydrogen atom (H) or methyl, more preferably a hydrogen atom (H).

If R ³ is optionally substituted phenyl, preferably said phenyl is optionally substituted with one substituent, which is fluoro, chloro, C _1-2 alkyl, C _1-2 fluoroalkyl, C _1-2 alkoxy, C _1-2 fluoroalkoxy or cyano. If R ³ is a possibly substituted phenyl, then a possible substituent may be at the 2nd, 3rd or 4th position of the phenyl ring, for example at the 4th position. For example, R ³ may be phenyl or fluorophenyl, especially 4-fluorophenyl.

R ^{3 is} preferably an optionally substituted branched C _3-6 alkyl, an optionally substituted C _3-8 cycloalkyl or an optionally substituted heterocyclic group of a sub-formula (aa), (bb) or (cc). More preferably, R ³ is an optionally substituted C _3-8 cycloalkyl or an optionally substituted heterocyclic group of a sub-formula. (Aa), (bb) or (cc).

Preferably in R ³ there is one substituent or not.

If R ³ is a possibly substituted branched C _3-6 alkyl, then preferably R ³ is a possibly substituted branched C _4-5 alkyl and / or unsubstituted C _3-6 alkyl, such as isopropyl, isobutyl, sec-butyl, tert- butyl, 3-methylbutan-2-yl or 2-ethylbutan-1-yl. If R ³ is a possibly substituted branched C _3-6 alkyl, then it is most preferably isobutyl, sec-butyl, tert-butyl or 3-methylbutan-2-yl (e.g. (R) -3-methylbutan-2-yl or (S) -3-methylbutan-2-yl).

In one possible embodiment, if R ³ is a possibly substituted C _3-8 cycloalkyl, then it is not a possibly substituted C ₅ cycloalkyl, that is, it is not a possibly substituted cyclopentyl. In this case, more preferably, R ³ is optionally substituted C _6-8 cycloalkyl or optionally substituted C _6-7 cycloalkyl.

If R ³ is a possibly substituted C _3-8 cycloalkyl, then it is more preferably a possibly substituted C ₆ cycloalkyl (i.e., possibly substituted cyclohexyl); for example With ₆ cycloalkyl, possibly substituted by one or two substituents, independently representing (for example, representing) oxo (= O), OH, C _1-2 alkoxy, C _1-2 fluoroalkoxy (e.g. trifluoromethoxy) or C _1-2 alkyl, and wherein any OH, alkoxy, or fluoroalkoxy substituent is not substituted at the R ³ carbon ring atom (connected) to the —NH— group of formula (I).

If R ³ is a possibly substituted C _3-8 cycloalkyl, then one or two possible substituents preferably contain (for example, represent or independently represent (for example, represent or represent)) oxo (= O); IT; C ₁ alkoxy; C ₁ fluoroalkoxy (e.g. trifluoromethoxy); NHR ₂₁ , where R ²¹ represents a hydrogen atom (H) or C _1-2 alkyl with a straight chain; C _1-2 alkyl, such as methyl; C ₁ fluoroalkyl such as —CH ₂ F or —CHF ₂ ; -CH ₂ OH; —CH ₂ NHR ²² , wherein R ²² is H; —C (O) OR ²³ where R ²³ is H or methyl; —C (O) NHR ²⁴ , wherein R ²⁴ is H or methyl; —C (O) R ²⁵ , where R ²⁵ is methyl; fluoro; hydroxyimino (= N-OH); or (C _1-2 alkoxy) imino (= N-OR ²⁶ , where R ²⁶ represents C _1-2 alkyl); and where any substituent OH, alkoxy, fluoroalkoxy or NHR ^{21 is} not substituted at the R ³ carbon ring atom (linked) to the —NH-group of formula (I) and is not substituted at any R ³ carbon ring linked to the heterocyclic group Y groups (aa), (bb) or (cc).

More preferably, if R ³ is a possibly substituted C _3-8 cycloalkyl, then one or two possible substituents contain (for example, represent or independently represent (for example, represent or represent)) oxo (= O); IT; NHR ²¹ , where R ²¹ represents a hydrogen atom (H); C _1-2 alkyl, such as methyl; C ₁ fluoroalkyl, such as —CH ₂ F or —CHF ₂ ; —C (O) OR ²³ where R ²³ is H or methyl; —C (O) NHR ²⁴ , wherein R ²⁴ is H or methyl; fluoro; hydroxyimino (= N-OH); or (C _1-2 alkoxy) imino (= N-OR ²⁶ , where R ²⁶ represents C _1-2 alkyl).

Even more preferably, if R ³ is a possibly substituted C _3-8 cycloalkyl, then one or two possible substituents contain (for example, represent or independently represent (for example, represent or represent)) oxo (= O); IT; NHR ²¹ , where R ²¹ represents a hydrogen atom (H); methyl; -CH ₂ F; -CHF ₂ ; -C (O) OR ²³ where R ²³ represents H; fluoro; hydroxyimino (= N-OH); or (C _1-2 alkoxy) imino (= N-OR ²⁶ , where R ²⁶ represents C _1-2 alkyl). And even more preferably, if R ³ is a possibly substituted C _3-8 cycloalkyl, then one or two possible substituents contain (for example, represent or independently represent (for example, represent or represent)) oxo (= O); IT; methyl; fluoro; hydroxyimino (= N-OH); or (C _1-2 alkoxy) imino (= N-OR ²⁶ , where R ²⁶ represents C _1-2 alkyl).

Most preferably, if R ³ is a possibly substituted C _3-8 cycloalkyl, then one or two possible substituents contain (for example, represent or independently represent (for example, represent or represent)) OH, oxo (= O) or hydroxyimino (= N-OH). For example, if R ³ is a possibly substituted C _3-8 cycloalkyl, then one or two possible substituents preferably contain (for example, represent or represent) OH and / or oxo (= O).

Perhaps in R ³ C _3-8 cycloalkyl is unsubstituted.

If R ³ is a possibly substituted C _3-8 cycloalkyl, for example a possibly substituted C _5-8 cycloalkyl, such as a possibly substituted C ₆ cycloalkyl (possibly substituted cyclohexyl), then one or two possible substituents, if any, preferably comprises (al) substituent (for example is or are substituent (s)) on the 3rd, 4th or 5th position (s) of the R ³ cycloalkyl ring. (In this regard, it is believed that the 1st position of the cycloalkyl ring R ³ represents the point of attachment to —NH— in formula (I)).

If R ³ is a possibly substituted C _3-8 cycloalkyl, then any substituent OH, alkoxy, fluoroalkoxy, —CH ₂ OH, —CH ₂ CH ₂ OH, —CH ₂ NHR ²² , —C (O) OR ²³ , —C (O) NHR ²⁴ , —C (O) R ²⁵ or fluoro (especially any OH substituent) is more preferably at the 3rd, 4th or 5th position, for example at the 3rd or 5th position, cycloalkyl (e.g., C _6-8 cycloalkyl) ring R ³ . For example, any substituent OH, alkoxy, fluoroalkoxy, —CH ₂ OH, —CH ₂ CH ₂ OH, —CH ₂ NHR ²² , —C (O) OR ²³ , —C (O) NHR ²⁴ , —C (O) R ²⁵ or fluoro (especially any OH substituent) can be located at the 3rd position of the C ₆ cycloalkyl (cyclopentyl) ring R ³ or at the 3rd, 4th or 5th position, for example the 3rd or 5th position, C ₆ cycloalkyl (cyclohexyl) ring R ³ . (In this regard, as well as below, it is believed that the 1st position of the cycloalkyl ring R ³ represents the point of attachment to —NH— in formula (I)).

If R ³ is a possibly substituted C _3-8 cycloalkyl, then any substituent of NHR ^{21 is} preferably at the 2nd, 3rd, 4th or 5th position, preferably at the 2nd or 3rd position or more preferably at the 3rd position of the cycloalkyl (eg, C _6-8 cycloalkyl, eg cyclohexyl) ring R ³ .

If R ³ is a possibly substituted C _3-8 cycloalkyl, then any alkyl or fluoroalkyl substituent is preferably located at the 1st, 2nd, 3rd, 4th or 5th position, more preferably at the 1st, The 2nd, 3rd or 5th position, even more preferably at the 1st or 3rd position of the cycloalkyl (e.g., C _6-8 cycloalkyl, e.g. cyclohexyl) ring R ³ .

If R ³ is a possibly substituted C _3-8 cycloalkyl, any substituent oxo (= O), hydroxyimino (= N-OH) or (C _1-4 alkoxy) imino (= N-OR ²⁶ ) is preferably in the 3rd or 4-position, preferably 4-position, of a cycloalkyl (eg, C _6-8 cycloalkyl, eg cyclohexyl) ring R ³ .

If R ³ is a possibly substituted C _3-8 cycloalkyl, R ^{3 is} preferably cyclohexyl (i.e., unsubstituted), or cyclohexyl substituted with one oxo substituent (= O), OH, NHR ²¹ , C _1-2 alkyl, C _{1 -2} fluoroalkyl, -CH ₂ OH, -C (O) OR ²³ , -C (O) NHR ²⁴ , -C (O) R ²⁵ , fluoro, hydroxyimino (= N-OH) or (C _1-4 alkoxy) imino (= N-OR ²⁶ ), or cyclohexyl substituted with two fluoro substituents. More preferably, R ³ is cyclohexyl (i.e. unsubstituted) or cyclohexyl substituted with one substituent oxo (= O), OH, NHR ²¹ , C _1-2 alkyl, C _1-2 fluoroalkyl, —C (O) OR ²³ , fluoro hydroxyimino (= N-OH) or (C _1-4 alkoxy) imino (= N-OR ²⁶ ), or cyclohexyl substituted with two fluoro substituents. Even more preferably, R ³ is cyclohexyl (i.e. unsubstituted) or cyclohexyl substituted with one substituent oxo (= O), hydroxyimino (= N-OH), C _1-2 alkyl or OH, for example, R ³ may be cyclohexyl ( that is, unsubstituted) or cyclohexyl substituted with one substituent oxo (= O) or OH. A possible substituent may be at the 3rd or 4th position, for example at the 3rd position, of a cyclohexyl ring R ³ ; more preferably, any OH substituent is preferably located at the 3-position of the cyclohexyl ring R ³ and / or any substituent is oxo (= O), hydroxyimino (= N-OH) or (C _1-4 alkoxy) imino (= N-OR ²⁶ ) is preferably located at the 4th position of the cyclohexyl ring R ³ .

If R ³ is a possibly substituted C ₆ cycloalkyl, then R ³ can be, for example, 4-hydroxy-cyclohexyl (i.e. 4-hydroxycyclohexan-1-yl) or 3-oxo-cyclohexyl, but more preferably R ³ is cyclohexyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-1-yl), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-1-yl), 4- (hydroxyimino) cyclohexyl (i.e. 4- (hydroxyimino) cyclohexan-1-yl), 4- (C _1-2 alkoxyimino) cyclohexyl, 1-methylcyclohexyl or 3-methylcyclohexyl. In one embodiment, R ³ may optionally be cyclohexyl (i.e., unsubstituted) or 3-hydroxy-cyclohexyl or 4-oxo-cyclohexyl. If R ³ is a possibly substituted C ₆ cycloalkyl, then R ³ most preferably is cyclohexyl (i.e., unsubstituted), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-1-yl) or 4- (hydroxyimino) cyclohexyl (i.e. there is 4- (hydroxyimino) cyclohexan-1-yl).

If R ³ is a possibly substituted C ₅ cycloalkyl (possibly substituted cyclopentyl), then R ³ can be, for example, cyclopentyl (i.e., unsubstituted) or 3-hydroxy-cyclopentyl.

If R ³ represents an optionally substituted mono-unsaturated C _5-7 cycloalkenyl, preferably it is optionally substituted mono-unsaturated C _5-6 cycloalkenyl, more preferably optionally substituted mono-unsaturated C ₆ cycloalkenyl (i.e. optionally substituted mono-unsaturated cyclohexenyl = optionally substituted cyclohexenyl). Even more preferably, cyclohexenyl R ³ is optionally substituted cyclohex-3-en-1-yl.

If R ³ is a possibly substituted mono-unsaturated C _5-7 cycloalkenyl, then preferably cycloalkenyl R ^{3 is} optionally substituted with one or two substituents independently representing fluoro or methyl; preferably, if there are two substituents, then both of them are not methyl. Preferably, cycloalkenyl R ^{3 is} optionally substituted with one substituent, which is fluoro or C _1-2 alkyl (e.g. methyl); more preferably cycloalkenyl R ^{3 is} substituted with one fluoro substituent or is unsubstituted. For cycloalkenyl R ^{3, the} possible substituent (s) may (gut) be located at the 1st, 2nd, 3rd, 4th or 5th position (s) of the cycloalkenyl ring.

If R ³ is a heterocyclic group of the sub-formula (aa), (bb) or (cc), then Y is preferably O, S, SO ₂ , NH or N — C (O) -Me (for example, O, S , SOs or NC (O) -Me), more preferably O, NH or NC (O) -Me, even more preferably O or N-C (O) -Me, most preferably O. (If Y is NH or NC (O) -Me, then R ⁴ represents H or -C (O) -Me.)

Preferably R ⁴ represents a hydrogen atom (H), C _1-2 alkyl, C (O) NH ₂ , C (O) -Me or C (O) -CF ₃ . Optionally, R ⁴ may be a hydrogen atom (H), C _1-2 alkyl, C (O) -Me or C (O) -CF ₃ , more preferably H, C (O) -Me or C (O) -CF ₃ , even more preferably H or C (O) -Me.

Preferably, Y is not N — C (O) —Me when the heterocyclic group corresponds to sub-formula (aa).

If R ³ is a heterocyclic group of a sub-formula (aa), (bb) or (cc), then preferably R ³ is a heterocyclic group of a sub-formula (aa) or (bb). More preferably, when in R ^{3 the} heterocyclic group corresponds to the sub-formula (bb).

In the sub-formula (bb), n ^{1 is} preferably 1. In the sub-formula (cc), n ^{2 is} preferably 1. That is, six-membered rings are preferred in the heterocyclic group R ³ .

Preferably, in R ^{3, the} heterocyclic group of the sub-formula (aa), (bb) or (cc) is unsubstituted. (In this regard, if Y represents NR ⁴ , then R ^{4 is} not classified as a substituent).

In the heterocyclic group R ^{3 of the} sub-formula (aa), (bb) or (cc), one or two possible substituents preferably contain (for example, represent or independently represent (for example, represent or represent)): OH; oxo (= O); C _1-2 alkyl (e.g. methyl) or C _1-2 fluoroalkyl (e.g. C ₁ fluoroalkyl such as -CH ₂ F or -CHF ₂ ). More preferably, in the heterocyclic group R ^{3 of the} sub-formula (aa), (bb) or (cc), one or two possible substituents contain (for example, represent or independently represent (for example, represent or represent)) OH and / or oxo; most preferably, one or two possible substituents contain (for example, represent or represent) oxo (= O). In the heterocyclic group R ^{3 of the} sub-formula (aa), (bb) or (cc), any oxo substituents (= O) are preferably on the carbon atom bound (adjacent) to X, and / or can be on the 2nd, 3 th, 4th or 5th position (s) of the heterocyclic ring R ³ . (In this regard, it is believed that the 1st position of the heterocyclic ring R ³ represents the point of attachment to —NH — in formula (I)). Preferably, only substitution with C _1-2 alkyl, C _1-2 fluoroalkyl, fluoro or oxo (= O) or the absence of substitution are permissible for each of the 2nd and 6th positions of the heterocyclic ring R ³ .

If R ³ is a heterocyclic group of sub-formula (aa) and Y is NR ⁴ , then preferably R ^{4 is} not C (O) -Me. More preferably, if R ³ is a heterocyclic group of sub-formula (aa) and Y is NR ⁴ , then R ^{4 is} preferably not C (O) R, that is, or, for example, R ^{4 is} preferably not C (O ) NH ₂ , C (O) -C _1-2 alkyl or C (O) -C ₁ fluoroalkyl. In one embodiment, Y represents O, S, SO ₂ or NH, if R ³ represents a heterocyclic group of sub-formula (aa).

If R ³ is a heterocyclic group of sub-formula (aa), preferably Y is not NR ⁴ .

Perhaps, in accordance with one embodiment of the present invention, NHR ³ or NR ³ R ^{3a is} not

.

.

More preferably, when R ³ is a heterocyclic group of sub-formula (bb) and Y is NR ⁴ , and possibly when n ¹ is 1, then preferably R ^{4 is} not methyl. More preferably, when R ³ is a heterocyclic group of sub-formula (bb) and Y is NR ⁴ , and possibly when n ¹ is 1, then R ^{4 is} preferably not alkyl or substituted alkyl, that is, or, for example, R ⁴ preferably is not C _1-2 alkyl, C _1-2 fluoroalkyl or CH ₂ C (O) NH ₂ . In one embodiment, if R ³ is a heterocyclic group of sub-formula (bb), Y is preferably O, S, SO ₂ or NR ⁴ , where R ⁴ is H, C (O) NH ₂ , C (O) —C _1-2 alkyl or C (O) —C ₁ fluoroalkyl, or more preferably Y is H or C (O) —Me. More preferably, for sub-formula (bb), Y is O or NR ⁴ .

Preferably, NHR ³ or NR ³ R ^3a corresponds to the sub-formula (a), (a1), (b), (c), (c1), (c2), (c3), (c4), (c5), (d ), (e), (f), (e), (d1), (d2), (d3), (d4), (h), (h1), (i), (j), (k), (k1), (L), (m), (m1), (m2), (m3), (m5), (n), (o), (o1), (o2), (o3), (o4 ), (o5), (p), (p2), (p3), (p5), (p6), (p7), (p8), (q), (r), (s), (t), (t1) or (t2):

In the above sub-formulas from (a) to (t2) and so on, the point of attachment of the —NH— group of NHR ³ or NR ³ R ^3a to the 4th position of the pyrazolopyridine of formula (I) is underlined. In general, in this description for a group or radical, when NH or N are underlined, this is an indication of the point of attachment.

Preferably, NHR ³ or NR ³ R ^3a corresponds to the sub-formula (c), (c1), (c2), (c3), (c4), (c5), (d), (e), (f), (d1 ), (q4), (h), (h1), (i), (j), (k), (k1), (L), (m), (m1), (m2), (m3), (m5), (n), (o), (o1), (o2), (o3), (o4), (o5), (p), (p2), (p3), (p5), (p6 ), (p7), (q), (r), (s), (t), (t1) or (t2). More preferably, NHR ³ or NR ³ R ^3a corresponds to the sub-formula (c), (c1), (c4), (c5), (h), (i), (j), (k), (m1), ( m2), (n), (o), (o2), (o3), (p2), (p5), (p6), (r), (s) or (t1). Even more preferably, NHR ³ or NR ³ R ^3a corresponds to the sub-formula (c), (h), (k), (n), (o), (o2) or (s); e.g. (c), (h), (o), (o2) or (s). Most preferably, R ³ is tetrahydro-2H-pyran-4-yl; that is, NHR ³ or NR ³ R ^3a most preferably corresponds to sub-formula (h) as described above.

In one embodiment of the invention, NHR ³ or NR ³ R ^3a corresponds to the sub-formula (a), (b), (c), (d), (e), (f), (d), (h), (i ), (j), (k), (L), (m), (n), (o), (p), (q), (r), (s) or (t). In this embodiment, NHR ³ or NR ³ R ^3a preferably corresponds to the sub-formula (c), (h), (k), (n), (o), (r), (s) or (t), even more preferably (c), (h), (k), (n), (o) or (s).

In another embodiment of this invention, NHR ³ or NR ³ R ^3a corresponds to the sub-formula (a), (b), (c), (d), (e), (f), (e), (d1), (d2 ), (d3), (h), (i), (j), (k), (L), (m), (m1), (n), (o), (o1), (p), (q), (d), (s), (t), (t1) or (t2). In this embodiment, preferably NHR ³ or NR ³ R ^3a corresponds to the sub-formula (c), (d), (e), (f), (h), (d1), (i), (j), (k) , (m), (m1), (n), (o), (o1), (p), (q), (d), (s), (t), (t1) or (t2). More preferably, NHR ³ or NR ³ R ^3a corresponds to the sub-formula (c), (h), (k), (n), (o), (g), (s), (t) or (t1), more preferably (c), (h), (k), (n), (o), (s) or (t1). Most preferably, R ³ is tetrahydro-2H-pyran-4-yl; that is, NHR ³ or NR ³ R ^3a most preferably corresponds to subformula (h) as described above.

If NHR ³ or NR ³ R ^3a corresponds to the sub-formula (n), then preferably it is a group of cis - ('3-hydroxycyclohex-1-yl) amino, for example, in any enantiomeric form or in a mixture of forms, but it can to be racemic.

Preferably, Het corresponds to the sub-formula (i), (ii), (iii) or (v); more preferably, Het corresponds to the sub-formula (i), (ii) or (v); even more preferably, Het corresponds to sub-formula (i).

X ¹ , X ³ and / or X ⁴ often independently represent (s) N (nitrogen atom).

Y ¹ , Y ² and / or Y ³ often independently represent (s) CR ^Y.

Suitably, Z ¹ and / or Z ⁵ independently represents O or S. Preferably Z ¹ and / or Z ⁵ represents O.

Preferably, Het corresponds to the sub-formula (ia), (ib), (ic), (id), (ie), (if) or (ig); more preferably, the sub-formula (ia), (ib), (ic), (id), (if) or (ig), or the sub-formula (ia), (ib), (ic), (id) or (i.e. ); even more preferably the sub-formula (ia), (ib), (ic) or (id) and even more preferably the sub-formula (ia), (ic) or (id):

Alternatively, when Het corresponds to sub-formula (v), Het may correspond, for example, to sub-formula (va) or (vb), more preferably sub-formula (va):

Alternatively, when Het corresponds to sub-formula (ii), Het may correspond, for example, to sub-formula (iia):

Preferably, Het corresponds to the sub-formula (ia), (ib), (ic), (id), (if), (ig), (va) or (iia). More preferably, Het corresponds to the sub-formula (ia), (ic), (id) or (va).

For the Het group, in general, R ^W and / or R ^Z independently represents (are) suitably a hydrogen atom (H).

For a Het group, it is generally preferred that one of R ^X and R ^Y (or R ^X2 and R ^Y2 ) is as defined herein and the other of R ^X and R ^Y (or R ^X2 and R ^Y2 ) is a hydrogen atom (H) or C _1-2 alkyl. More preferably, one of R ^X and R ^Y (or R ^X2 and R ^Y2 ) is as defined herein, and the other of R ^X and R ^Y (or R ^X2 and R ^Y2 ) is a hydrogen atom (H).

In general, for a Het group, it is generally preferred that one of R ^X and R ^Y , and for Het a sub-formula (v) one of R ^X2 and R ^Y2, is:

C _1-8 alkyl;

optionally substituted C _3-6 cycloalkyl;

- (CH ₂ ) _n ³ -S (O) ₂ -R ⁵ , -CH (C _1-2 alkyl) -S (O) ₂ -R ⁵ , -CMe ₂ -S (O) ₂ -R ⁵ or C _3-5 cycloalkyl substituted on the connecting carbon atom with a group -S (O) ₂ -R ⁵ ; preferably - (CH ₂ ) _n ³ —S (O) ₂ —R ⁵ ;

- (CH ₂ ) _n ⁴ -NR ⁶ R ⁷ , -CH (C ₁ -alkyl) -NR ⁶ R ⁷ , -Cme ₂ -NR ⁶ R ⁷ or C _3-5 cycloalkyl substituted at the carbon atom by the group -NR ⁶ R ⁷ ; preferably - (CH ₂ ) _n ⁴ —NR ⁶ R ⁷ or —CH (Me) —NR ⁶ R ⁷ ;

- (CH ₂ ) _n ¹¹ -C (O) -NR ¹⁰ R ¹¹ , -CH (C _1-2 alkyl) -C (O) -NR ¹⁰ R ¹¹ , -CMe ₂ -C (O) -NR ¹⁰ R ¹⁰ or C _3-5 cycloalkyl substituted on the carbon atom by the group —C (O) —NR ¹⁰ R ¹¹ ; preferably - (CH ₂ ) _n ¹¹ —C (O) —NR ¹⁰ R ¹¹ ;

- (CH ₂ ) _n ¹⁴ -Het ¹ , -CH (C _1-2 alkyl) -Het ¹ , -CMe ₂ -Het ¹ or C _3-5 cycloalkyl substituted at the carbon atom by the Het ¹ group; preferably - (CH ₂ ) _n -Het ¹ ;

- (CH ₂ ) _n ¹⁰ -Ag, -CH (C _1-2 alkyl) -Ar, -CMe ₂ -Ar or C _3-5 cycloalkyl substituted at the carbon connecting atom by Ar group; preferably - (CH) ₂ ¹⁰ -Ar;

(1) where Ar is a possibly substituted phenyl or more preferably, (2) where Ar is a possibly substituted 5- or 6-membered heterocyclic aromatic ring.

In general, for a Het group, it is generally more preferred that one of R ^X and R ^Y and, for Het a sub-formula (v) one of R ^X2 and R ^Y2 is:

- (CH ₂ ) _n ⁴ -NR ⁶ R ⁷ , -CH (C _1-2 alkyl) -NR ⁶ R ⁷ , -CMe ₂ -NR ⁶ R ⁷ or C _3-5 cycloalkyl substituted at the carbon atom by the group - NR ⁶ R ⁷ ; preferably - (CH ₂ ) _n ⁴ —NR ⁶ R ⁷ or —CH (Me) —NR ⁶ R ⁷ ;

- (CH ₂ ) n ¹¹ -C (O) -NR ¹⁰ R ¹¹ , -CH (C _1-2 alkyl) -C (O) -NR ¹⁰ R ¹¹ , -CMe ₂ -C (O) -NR ¹⁰ R ¹¹ or C _3-5 cycloalkyl substituted at the carbon atom by the group —C (O) —NR ¹⁰ R ¹¹ ; preferably - (CH ₂ ) _n ¹¹ —C (O) —NR ¹⁰ R ¹¹ ;

- (CH ₂ ) _n ¹⁴ -Het ¹ , -CH (C _1-2 alkyl) -Het ¹ , -CMe ₂ -Het ¹ or C _3-5 cycloalkyl substituted at the carbon atom by the Het ¹ group; preferably - (CH ₂ ) _n ¹⁰ Het ¹ ; or

- (CH ₂ ) _n ¹⁰ —Ar, —CH (C _1-2 alkyl) —Ar, —CMe ₂ —Ar or C _3-5 cycloalkyl substituted at the carbon-connecting atom Ar group; preferably - (CH ₂ ) _n ¹⁰ -Ar;

(1) where Ar is a possibly substituted phenyl or, more preferably (2) where Ar is a possibly substituted 5- or 6-membered heterocyclic aromatic ring.

Perhaps one of R ^X and R ^Y may be: C _1-2 alkyl; C _3-6 cycloalkyl; - (CH ₂ ) _n ³ -SO ₂ -R ⁵ ; - (CH ₂ ) _n -NR ⁶ R ⁷ ; - (CH ₂ ) _n ⁷ -OR ⁹ ; -C (O) -NR ¹⁰ R ¹¹ ; -C (O) -OR ¹³ or 4-, 5-, 6- or 7-membered optionally substituted saturated heterocyclic ring Het ¹ . More preferably, one of R ^X and R ^Y is: C _1-8 alkyl; - (CH ₂ ) _n ³ -SO ₂ -R ⁵ or 4-, 5-, 6- or 7-membered optionally substituted saturated heterocyclic ring Het ¹ . In these cases, as mentioned above, it is preferred that the other of R ^X and R ^Y represents a hydrogen atom (H) or C _1-2 alkyl.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is C _1-8 alkyl, then preferably he / they independently represents (are) C _1-6 alkyl, for example C _3-6 alkyl and / or C _{1 -4} alkyl, such as methyl, isopropyl, isobutyl or tert-butyl.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is optionally substituted C _3-6 cycloalkyl, then possibly he / they independently can / can be C _3-6 cycloalkyl, possibly substituted with a C _1-2 alkyl group.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is optionally substituted C _3-6 cycloalkyl, then preferably he / they independently represents C _3-6 cycloalkyl (i.e. unsubstituted), for example cyclopropyl or cyclobutyl .

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is optionally substituted - (CH ₂ ) _n ^2a -C _3-6 cycloalkyl, then preferably he / they independently represents (-) (- CH ₂ ) _n ^2a —C _3-6 cycloalkyl optionally substituted by the group - (CH ₂ ) _n ^2a - or by the group C _3-6 cycloalkyl with a C _1-2 alkyl group, where n ^2a represents 1, 2 or 3.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is optionally substituted - (CH ₂ ) _n ^2a —C _3-6 cycloalkyl, then n ^{2a is} preferably 1 or 2 or more preferably 1; and / or preferably R ^X , R ^X2 , R ^Y and / or R ^Y2 independently represents (are) optionally substituted - (CH ₂ ) _n -C _3-6 cycloalkyl or optionally substituted - (CH ₂ ) _n ^2a -C ₆ cycloalkyl. If R ^X , R ^X2 , R ^Y and / or R ^Y2 is optionally substituted - (CH ₂ ) _n ^2a —C _3-6 cycloalkyl, then preferably he / they independently represents (-) CH - (CH ₂ ) _n ^2a —C _3-6 cycloalkyl (i.e. unsubstituted). More preferably, R ^X , R ^X2 , R ^Y and / or R ^Y2 independently represents (are) (cyclohexyl) methyl-, i.e., -CH ₂ -cyclohexyl. If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ³ —S (O) ₂ —R ⁵ , —CH (C _1-2 alkyl) —S (O) ₂ —P ⁵ (for example, —CH (Me) —S (O) ₂ —R ⁵ ), —CMe ₂ —S (O) ₂ —R ^5, or C _3-6 cycloalkyl substituted at the carbon atom by the group —S (O) ₂ -R ⁵ , then preferably he / they independently represents (-) (- CH ₂ ) _n ³ -S (O) ₂ -R ⁵ .

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is C _3-5 cycloalkyl substituted on the carbon atom by the group -S (O) ₂ -R ⁵ , then preferably he / they independently represent C ₃ cycloalkyl (cyclopropyl), substituted on the connecting carbon atom with a group -S (O) ₂ -R ⁵ , for example

(например, смотри Пример 178).

(e.g. see Example 178).

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ³ —S (O) ₂ —R ⁵ , then preferably n ³ is 1.

Preferably, R ⁵ is C _1-4 alkyl (e.g., C _1-3 alkyl), —NR ¹⁵ R ^16, or optionally substituted phenyl. More preferably, R ⁵ is C _1-3 alkyl or —NH — C _1-2 alkyl or phenyl; even more preferably, R ⁵ is C _1-3 alkyl or C _1-2 alkyl, such as methyl. Most preferably, (CH ₂ ) _n ³ —S (O) ₂ —R ⁵ is —CH ₂ SO ₂ Me.

Preferably R ¹⁵ represents H, C _1-4 (for example, C _1-4 alkyl), optionally substituted phenyl or optionally substituted benzyl; and / or preferably R ¹⁶ represents H or methyl, for example N.

If R ¹⁵ and R ¹⁶ together represent - (CH ₂ ) _n ^3a —X ^3a - (CH ₂ ) _n ^3b -, then preferably n ^3a and / or n ^3b independently represent 2; and / or preferably X ^3a is a bond, —CH ₂ -, O or NR ^8a , where R ^8a is C _1-2 alkyl or acetyl; and / or preferably the ring formed by NR ¹⁵ R ¹⁶ is not substituted on the ring carbon atom or is substituted on the ring carbon atom with one methyl or oxo substituent (= O).

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ⁴ —NR ⁶ R ⁷ , —CH (C _1-2 alkyl) —NR ⁶ R ⁷ (e.g., —CH (Me ) -NR ⁶ R ⁷ ), -CMe ₂ -NR ⁶ R ⁷ or C _3-5 cycloalkyl (e.g. C ₃ cycloalkyl) substituted at the carbon atom connecting with the group -NR ⁶ R ⁷ , then preferably he / they independently represent ( yut) by themselves - (CH ₂ ) _n ⁴ —NR ⁶ R ⁷ , —CH (C _1-2 alkyl) —NR ⁶ R ⁷ (for example, —CH (Me) —NR ⁶ R ⁷ ) or —Cme ₂ —NR ⁶ R ⁷ ; more preferably he / they independently represents -CH (Me) -NR ⁶ R ⁷ or even more preferably (CH ₂ ) _n ⁴ -NR ⁶ R ⁷ .

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ⁴ -NR ⁶ R ⁷ , then preferably n ⁴ is 0 only when - (CH ₂ ) _n ⁴ -NR ⁶ R ⁷ is bonded to a carbon atom in a Het ring.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ⁴ —NR ⁶ R ⁷ , then preferably n ⁴ is 0, 1 or 2; more preferably n ⁴ is 0 or 1, even more preferably n ⁴ is 1.

In one possible embodiment of the present invention, R ⁶ and R ⁷ independently represent H, C _1-6 alkyl, for example C _1-4 alkyl, C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, —C (O) -C _1-2 alkyl, -SO ₂ -C _1-2 alkyl, phenyl or benzyl (where phenyl and benzyl are independently possibly substituted on the aromatic ring with one group of fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _{1- 2} alkoxy or C ₁ fluoroalkoxy); or R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) ⁿ⁶ -, where n ⁵ and n ⁶ independently represent 2 or 3, and X ⁵ represents a bond, —CH ₂ -, O or NR ⁸ , where R ⁸ represents H or C _1-2 alkyl and where the ring formed by NR ⁶ R ⁷ is not substituted at the ring carbon atom.

In one possible embodiment of the present invention, R ⁶ and R ⁷ independently represent H, C _1-6 alkyl, for example C _1-4 alkyl, —C (O) —C _1-2 alkyl or —SO ₂ —C _1-2 alkyl ; or R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) _n ⁶ -, where n ⁵ and n ⁶ independently represent 2 or 3, and X ⁵ represents a bond, —CH ₂ -, O or NR ⁸ , where R ⁸ represents H or C _1-2 alkyl and where the ring formed by NR ⁶ R ⁷ is not substituted at the ring carbon atom.

R ^{6 is} preferably H or C _1-6 alkyl. R ^{7 is} preferably C _1-6 alkyl, —C (O) R ¹⁷ or —S (O) ₂ R ¹⁸ , for example C _1-6 alkyl. If R ⁶ and / or R ⁷ is C _1-6 alkyl, then he / they independently represents (preferably) C _1-4 alkyl, for example methyl.

Preferably, R ¹⁷ and R ¹⁸ independently are C _1-6 alkyl (e.g., C _1-4 alkyl, or C _1-2 alkyl, or isopropyl, or n-propyl), C _3-9 cycloalkyl, optionally substituted 5-membered heteroaryl, which is furyl (furanyl, for example 2-furyl), or thienyl (for example 2- or 3-thienyl) (where furyl or thienyl are independently optionally substituted with one oxo group and / or one or two methyl groups), or phenyl or benzyl (where phenyl and benzyl are independently possibly substituted on the aromatic ring with one or two substituents independently representing toro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy).

In an alternative preferred embodiment, R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) _n ⁶ -, in which case it is preferred that n ⁵ represents 2 and / or n ⁶ represents 2 Preferably, if R ⁶ and R ⁷ together are - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) _n ⁶ - and if the ring formed by NR ⁶ R ⁷ is substituted on the ring carbon atom with one or two substituents representing is oxo (= O), then the indicated one or two oxo substituents are substituted on the ring carbon atom, which is adjacent (bonded) to the connecting nitrogen atom N in NR ⁶ R ⁷ . If R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) _n ⁶ -, then preferably the ring formed by NR ⁶ R ⁷ is optionally substituted on the ring carbon atom with one or two substituents, independently representing methyl or oxo (= O) only when X ⁵ is a bond or —CH ₂ -.

If R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) _n ⁶ -, preferably when the ring formed by NR ⁶ R ⁷ is not substituted on the ring carbon atom or is substituted on the ring carbon atom one substituent is methyl or oxo (= O).

(n⁴=1; R⁶ и R⁷ вместе представляют собой -(СН₂)₂-М(Ме)-(СН₂)₂-), или

, или

,(n⁴=1, R⁶ и R⁷ вместе представляют собой -(СН₂)₂-O-(СН₂)₂-), или

, или

, или

, или

.Preferably, R ⁸ is C _1-2 alkyl or phenyl. For example, - (CH ₂ ) _n ⁴ —NR ⁶ R ⁷ , —CH (C _1-2 alkyl) —NR ⁶ R ⁷ or —Cme ₂ —NR ⁶ R ⁷ may be: —CH ₂ —NHC (O) R ¹⁷ , —CH ₂ —NMeC (O) R ¹⁷ , —CH (Me) —NHC (O) R ¹⁷ , —CH ₂ —NHS (O) ₂ R ¹⁸ , —CH ₂ —NMeS (O) ₂ R ¹⁸ , -CH (Me) -NHS (O) ₂ R ¹⁸ , NMe ₂ (n ⁴ = 0; R ⁶ = R ⁷ = Me), or -CH ₂ NMe ₂ (n ⁴ = 1; R ⁶ = R ⁷ = Me), or

(n ⁴ = 1; R ⁶ and R ⁷ together represent - (CH ₂ ) ₂ —M (Me) - (CH ₂ ) ₂ -), or

, or

, (n ⁴ = 1, R ⁶ and R ⁷ together represent - (CH ₂ ) ₂ —O— (CH ₂ ) ₂ -), or

, or

, or

, or

.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ⁷ -OR ⁹ , then in one embodiment n ⁷ is 1, 2 or 3 and / or R ⁹ is H, C _1-6 alkyl or phenyl, or more preferably R ⁹ represents H or C _1-6 alkyl. n ^{7 is} preferably 1 or 2, more preferably 1. R ^{9 is} preferably C _1-4 alkyl, such as methyl or tert-butyl. For example, - (CH _{2) n} ⁷ -O-R ⁹ can be -CH ₂ -O- ^t Bu or -CH ₂ -O-Me.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹¹ —C (O) —NR ¹⁰ R ¹¹ , —CH (C _1-2 alkyl) —C (O) —NP ¹⁰ R ¹¹ (e.g., -CH (Me) -C (O) -NR ¹⁰ R ¹¹ ), -CMe ₂ -C (O) -NR ¹⁰ R ^11, or C _3-5 cycloalkyl (e.g. C ₃ cycloalkyl), substituted at the carbon atom by the group —C (O) —NR ¹⁰ R ¹¹ , it is preferred that he / they independently represents (- CH ₂ ) _n —C (O) —NR ¹⁰ R ¹¹ , —CH (C _{1 -2} alkyl) -C (O) -NR ¹⁰ R ¹¹ (e.g., -CH (Me) - (C (O) -NR ¹⁰ R ¹¹ ) or -CMe ₂ -C (O) -NR ¹⁰ R ¹¹ ; more preferably - (CH _{2) n} ¹¹ -C (O) - NR ¹⁰ R ^11; more preferably -CH ₂ -C (O) -NR ¹⁰ R ¹¹ or -C (O) -NR ¹⁰ R ^11.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹¹ —C (O) —NR ¹⁰ R ¹¹ , then n ^{11 is} preferably 0 or 1, more preferably 1.

Preferably, R ¹⁰ is H or C _1-6 alkyl (e.g., C _1-4 or C _1-2 alkyl or methyl) or R ¹⁰ and R ¹¹ together are - (CH ₂ ) _n ⁸ —X ⁶ (CH ₂ ) _n ⁹ -.

Preferably R ¹⁰ and R ¹¹ independently represent and more preferably R ¹¹ represents H; C _1-6 alkyl; C _1-2 fluoroalkyl; C _2-3 alkyl substituted with one OH group or —O— _1-2 alkyl at a position other than the point of attachment; C _3-6 cycloalkyl optionally substituted with one or two methyl groups; —CH ₂ —C _3-6 cycloalkyl optionally substituted with one NHMe group (preferably unsubstituted); - (CH ₂ ) _n ¹⁷ -Het ² ; optionally substituted pyridinyl bonded to a carbon atom, optionally substituted phenyl; possibly substituted benzyl or possibly substituted —CH (C _1-2 alkyl) Ph.

More preferably, R ¹⁰ and R ¹¹ independently represent and even more preferably R ¹¹ represents H; C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with one or two methyl groups; —CH ₂ —C _3-6 cycloalkyl (unsubstituted); - (CH ₂ ) _n ¹⁷ -Het ² ; optionally substituted pyridinyl bonded to a carbon atom; optionally substituted phenyl, optionally substituted benzyl, or optionally substituted —CH (C _1-2 alkyl) Ph (for example, optionally substituted —CH (Me) Ph).

Preferably in R ¹⁰ and / or R ¹¹ phenyl, benzyl and —CH (C _1-2 alkyl) Ph (for example, —CH (Me) Ph) are independently optionally substituted on the aromatic ring with one or two substituents independently representing: fluoro, chloro, C _1-2 alkyl (e.g. methyl), C ₁ fluoroalkyl (e.g. CF ₃ ), C _1-2 alkoxy (e.g. methoxy), C ₁ fluoroalkoxy (e.g. CF ₃ O- or CHF ₂ O-) , —NR ^10a R ^10b (where R ^10a represents H or methyl, and R ^10b represents H, C _1-2 alkyl (e.g. methyl), —C (O) Me or —S (O) ₂ Me), —C (O) —NR ^10c R ^10d (where R ^10c and R ^10d independently are H or C _1-2 alkyl, for example H or Me) or —S (O) ₂ —R ^10e (where R ^10e is C _1-2 alkyl (e.g. methyl), NH ₂ , NHMe, or NMe ₂ ). One substituent is preferred.

In R ¹⁰ and / or R ¹¹ and / or (independently) in R ⁵ and / or (independently) in R ¹⁵ and / or (independently) in R ⁶ and / or R ⁷ and / or (independently) in R ¹⁷ , and / or (independently) in R ^18, pyridinyl bonded to a carbon atom is preferably optionally substituted with one OH group (including any keto tautomer thereof) and more preferably is not substituted.

In R ¹⁰ and / or R ¹¹ for - (CH ₂ ) _n ¹⁷ -Het ^2, preferably n ¹⁷ is 0 or 1; and / or preferably Het ² is a 5- or 6-membered saturated optionally substituted heterocyclic ring containing one O or S (preferably O) ring atom or one NR ²⁷ ring group. Preferably, R ²⁷ is C _1-2 alkyl or —C (O) Me. Preferably, the ring Het ^{2 is} substituted on the ring carbon atom by one or two methyl substituents, or is not substituted on the ring carbon atom.

In one embodiment, if R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹¹ —C (O) —NR ¹⁰ R ¹¹ , —CH (C _1-2 alkyl) —C (O ) -NR ¹⁰ R ¹¹ or -CMe ₂ -C (O) -NR ¹⁰ R ¹¹ , it is possible: R ¹⁰ and R ¹¹ independently represent H or C _1-6 alkyl; or R ¹⁰ and R ¹¹ together represent - (CH ₂ ) _n ⁸ —X ⁶ - (CH ₂ ) _n ⁹ -, where n ⁸ and n ⁹ independently represent 2 or 3, and X ⁶ represents a bond, —CH ₂ -, O or NR ¹² , where R ¹² represents H or C _1-2 alkyl, and where the ring formed by NR ¹⁰ R ¹¹ is not substituted at the ring carbon atom.

.Preferably R ¹⁰ represents H and / or optionally R ¹¹ represents C _1-6 alkyl, for example C _1-4 alkyl, such as isopropyl. For example, - (CH ₂ ) _n ¹¹ —C (O) CO — NR ¹⁰ R ¹¹ such as —C (O) —NR ¹⁰ R ¹¹ may be

.

In an alternative preferred embodiment, if R ¹⁰ and R ¹¹ together are - (CH ₂ ) _n ⁸ —X ⁶ - (CH ₂ ) _n ⁹ -, then preferably n ⁸ is 2 and / or n ⁹ is 2. If R ¹⁰ and R ¹¹ together represent - (CH ₂ ) _n ⁸ —X ⁶ - (CH ₂ ) _n ⁹ -, which is a preferred feature of the present invention, preferably X ⁶ is a bond, —CH ₂ -, O or NR ¹² , where R ¹² is H or C _1-2 alkyl, and where the ring formed by NR ¹⁰ R ¹¹ is not substituted at the ring carbon atom.

When R ¹⁰ and R ¹¹ together are - (CH ₂ ) _n ⁸ —X ⁶ - (CH ₂ ) _n ⁹ -, preferably when the ring formed by NR ¹⁰ R ¹¹ is not substituted on the ring carbon atom or is substituted on the ring carbon atom one substituent is methyl or oxo (= O).

Most preferably, NR ¹⁰ R ¹¹ is: NH ₂ , NHMe, NMe ₂ , NHEt, NH ⁱ Pr,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

или

. (В проиллюстрированных выше наиболее предпочтительных группах и в общем в этом описании для группы или радикала, когда NH или N подчеркнуты, то это является указанием точки присоединения.)

,

,

,

,

,

or

. (In the most preferred groups illustrated above and generally in this description for a group or radical, when NH or N are underlined, this is an indication of the point of attachment.)

Even more preferably, if R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹¹ —C (O) —NR ¹⁰ R ¹¹ , —CH (C _1-2 alkyl) —C (O ) -NP ¹⁰ R ¹¹ , -CMe ₂ -C (O) -NR ¹⁰ R ¹¹ or C _3-6 cycloalkyl substituted on the carbon atom by the group -C (O) -NR ¹⁰ R ¹¹ , then preferably he / they independently represents (s) by itself - (CH ₂ ) _n ¹¹ -C (O) -NR ¹⁰ R ¹¹ (more preferably -CH ₂ -C (O) -NR ¹⁰ R ¹¹ or -C (O) -NR ¹⁰ R ¹¹ ) where NR ¹⁰ R ¹¹ is one of the most preferred NR ¹⁰ R ¹¹ groups illustrated above.

The group - (CH ₂ ) _n ¹¹ —C (O) —NR ¹⁰ R ^{11 is} preferably as defined in any one of Examples 36, 58, 84, 85-90, 95-96, 126-147 or 148-155. These Examples illustrate some of the preferred NR ¹⁰ R ¹¹ groups illustrated above, and some of these Examples provide literature references and / or commercial sources for the amines R ¹⁰ R ¹¹ NH that can be used to prepare compounds of formula (I) containing the group - ( CH ₂ ) _n ¹¹ —C (O) —NR ¹⁰ R ¹¹ as R ^X , R ^X2 , R ^Y and / or R ^Y2 .

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹² —C (O) —OR ¹³ , n ^{12 is} preferably 0 or 1, more preferably 1. In one preferred embodiment, if R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹² —C (O) —OR ¹³ , R ¹³ is H or C _1-6 alkyl. If R ¹³ is C _1-6 alkyl, then R ¹³ is preferably C _1-4 or C _1-3 alkyl, such as methyl (for example, R ^X , R ^X2 , R ^Y and / or R ^Y2 may be -CO ₂ Me) or ethyl.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹³ -C (O) -R ^13a , n ^{13 is} preferably 0 or 1, more preferably 1. If R ^X , R ^X2 , R ^Y and / or R ^Y2 represents - (CH ₂ ) _n ¹³ -C (O) -R ^13a , then suitably R ^13a represents C _1-6 alkyl, C _1-2 fluoroalkyl, C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, benzyl or phenyl (where phenyl and benzyl are independently optionally substituted on the aromatic ring with one or two of (independently) (for example, one of) fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy). More preferably, R ^13a is C _1-6 alkyl, or C _1-4 alkyl, or C _1-2 alkyl.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹⁴ Het ¹ , -CH (C _1-2 alkyl) -Het ¹ (e.g., -CH (Me) -Het ¹ ) , -CMe ₂ -Het ¹ or C _3-6 cycloalkyl (e.g., C ₃ cycloalkyl) substituted at the carbon atom by the group Het ¹ , where n ¹⁴ is 0, 1 or 2, then: (a) n ^{14 is} preferably is 0 or 1, and / or (b) - (CH ₂ ) _n ¹⁴ -Het ¹ is more preferred than -CH (Me) -Het ¹ , or -CMe ₂ -Het ¹ , or C _3-5 cycloalkyl, substituted at the connecting carbon atom by an Ar group.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹⁴ Het ¹ , -CH (C _1-2 alkyl) -He1 ¹ (e.g., -CH (Me) -Het ¹ ) , -CMe ₂ -Het ¹ or C _3-6 cycloalkyl (e.g., C ₃ cycloalkyl) substituted at the carbon atom by the group Het ¹ , where n ¹⁴ is 0, 1 or 2, and where Het ¹ is 4-, A 5-, 6- or 7-membered possibly substituted saturated heterocyclic ring containing one O or S ring atom and / or one NR ¹⁴ ring group, then a possibly substituted saturated heterocyclic ring Het ^{1 is} preferably a 4-, 5- or 6-membered more preferably 5-yl 6-membered. If Het ¹ is 6 membered, then any ring O or S atom and / or any ring group NR ¹⁴ may independently be present at the 2nd, 3rd or 4th position of the ring, preferably at the 4th position of the ring, relative connecting ring atom in Het ¹ . If a possibly substituted saturated heterocyclic ring of Het ¹ is 4-membered, then preferably the heterocyclic ring of Het ^{1 is} not possibly substituted by oxo (= O).

When R ¹⁴ and / or a possible ring substituent is C _1-4 , it is suitably C _1-2 alkyl, such as methyl. Preferably, R ¹⁴ is C _1-4 alkyl (e.g., C _1-2 alkyl), C (O) R ¹⁹ or S (O) ₂ R ¹⁹ . Preferably, R ¹⁹ is C _1-4 (e.g. methyl or isobutyl), C _3-6 cycloalkyl, such as cyclopropyl or cyclohexyl, 2-thienyl, furan-2-yl, phenyl (unsubstituted) or benzyl (unsubstituted); more preferably R ¹⁹ is C _1-4 alkyl (e.g. methyl or isobutyl).

If R ^X , R ^X2 , R ^Y and / or R ^Y2 represents - (CH ₂ ) _n ¹⁴ -Het ¹ and n ¹⁴ represents 0, and if the saturated heterocyclic ring Het ^{1 is} possibly substituted (at a position different from any position NR ¹⁴ ) C _1-4 alkyl, then preferably C _{1-4 is} substituted on the carbon atom directly connected to the 5-membered ring in the sub-formula Het (i), (ii), (iii), (iv) or ( v)

The heterocyclic ring Het ^{1 is} preferably optionally substituted (at position (s) other than any position NR ¹⁴ ) with one oxo substituent (= O) and / or one C _1-4 alkyl substituent; preferably one substituent oxo (= O). Any oxo substituent (= O) is preferably substituted at the ring carbon atom adjacent to (attached to) any ring group NR ¹⁴ present. Preferably, in Het ^1, one or two oxo substituents (= O) are present (s) only when ring group NR ^{14 is} present.

,

,

,

,

,

,

,

,

,

,

,

,

,

или позиционный изомер любого из вышеуказанного, где точка присоединения [которая соединяет с -(СН₂)_n ¹⁴-, -СН(С_1-2алкил)- или -СНМе₂- или соединяющей группировкой -С_3-5циклоалкил или соединяет с 5-членным кольцом суб-формулы (i), (ii), (iii), (iv) или (v) в Het¹ находится по разным кольцевым атомам углерода Het¹.For example, if R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹⁴ -Het ¹ , -CH (C _1-2 alkyl) -Het ¹ or -CMe ₂ -Het ¹ , 4 The 5-, 6-, or 7-membered optionally substituted saturated heterocyclic ring Het ¹ may preferably be tetrahydro-2H-pyranyl, such as tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2yl, tetrahydrofuran-3-yl,

,

,

,

,

,

,

,

,

,

,

,

,

,

or a positional isomer of any of the above, where the attachment point [which joins with - (CH ₂ ) _n ¹⁴ -, —CH (C _1-2 alkyl) - or —CHMe ₂ - or a joining group —C _3-5 cycloalkyl or The 5-membered ring of the sub-formula (i), (ii), (iii), (iv) or (v) in Het ¹ is located on different ring carbon atoms of Het ¹ .

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹⁰ —Ar, —CH (C _1-2 alkyl) —Ar (e.g. —CH (Me) —Ar), - CMe ₂ -Ar or C _3-5 cycloalkyl (e.g. C ₃ cycloalkyl) substituted at the carbon atom, Ar group, then preferably he / they independently represent (- CH ₂ ) _n ¹⁰ -Ar or -CH ( Me) -Ar, preferably - (CH ₂ ) _n ¹⁰ -Ar, such as -CH ₂ -Ar.

If R ^X , R ^X2 , R ^Y and / or R ^Y2 is - (CH ₂ ) _n ¹⁰ —Ar, then preferably n ¹⁰ is 0 or 1; more preferably n ¹⁰ is 1.

If Ar is a possibly substituted phenyl, preferably said phenyl is optionally substituted with one or two substituents (preferably one) independently representing fluoro, chloro, bromo, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy, C ₁ fluoroalkoxy , —NR ^11a R ^11b (where R ^11a is H or methyl, and R ^11b is H, C _1-2 alkyl, —C (O) Me or —S (O) ₂ Me), —C (O) —NR ^11c R ^11d (where R ^11c and R ^{11d are} independently H or methyl), —C (O) —OR ^11e , where R ^11e is H or —S (O) ₂ —R ^11f (where R ^11f is represents methyl, NH ₂ , NHMe or NMe ₂ ). If Ar is a possibly substituted phenyl, more preferably - (CH ₂ ) _n ¹⁰ -Ar may be as defined for R ^X , R ^X2 , R ^Y and / or R ^Y2 in any of Examples 49-55, 83, 103 107, 120-125, 179, 181-184, 189 or 190.

If Ar is phenyl, possibly substituted on two adjacent ring Ar atoms by two ends of the chain, which is: - (CH ₂ ) ₄ -, - (CH ₂ ) ₃ - or —CH = CH — CH = CH—, then may be, for example, naphthyl, for example 1-naphthyl or 2-naphthyl.

If Ar is a possibly substituted 5- or 6-membered heterocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms (for example 1, 2 or 3 heteroatoms) selected from O, N or S, then Ar may be optionally substituted with groups : furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, imidazolyl, oxadiazolyl (e.g., 1,3,4- or 1,2,4-or 1,2,5-oxadiazolyl), thiadiazolyl ( e.g. 1,3,4- or 1,2,4-), pyridyl, triazolyl (e.g. 1,2,3- or 1,2,4-triazolyl), tetrazolyl, triazinyl, pyridazyl, pyrimidinyl, pyrazolyl, isothiazolyl (1,2-thiazolyl) or isoxazolyl (1,2-oxazo lil). If Ar is a possibly substituted 5- or 6-membered heterocyclic aromatic ring, this ring is preferably optionally substituted with one or two independent C _1-2 alkyl groups or one OH group (including any keto-tautomer thereof); more preferably, the ring is optionally substituted with one or two independent C _1-2 alkyl groups (e.g. methyl) and even more preferably when one substituent is present or not. If Ar is a possibly substituted 5- or 6-membered heterocyclic aromatic ring, it is preferably 5-membered.

If Ar is a 5- or 6-membered heterocyclic aromatic ring, more preferably - (CH ₂ ) _n ¹⁰ -Ar may be as defined for R ^X , R ^X2 , R ^Y and / or R ^Y2 in any of Examples 71 79, 80, 97-100, 104-106, 108, 112-114, 117, 158 or 186.

, или

, или -(СН₂)_n ¹⁰-Ar может представлять собой

(например, смотри Пример 186). Предпочтительно в этих случаях -(CH₂)_n ¹⁰-Ar представляет собой -СН₂-Ar.If the heterocyclic aromatic ring Ar is substituted at two adjacent ring Ar atoms by two ends of the chain, which is: - (CH ₂ ) ₄ -, - (CH ₂ ) ₃ - or —CH = CH — CH = CH—, then, for example, Ar may be

, or

, or - (CH ₂ ) _n ¹⁰ -Ar may be

(for example, see Example 186). Preferably in these cases - (CH ₂ ) _n ¹⁰ —Ar represents —CH ₂ —Ar.

In R ⁵ , R ¹⁵ , R ⁶ , R ⁷ , R ¹⁷ , R ¹⁸ , R ⁹ , R ¹³ , R ^13a and / or R ¹⁹ , independently of one another, phenyl and / or benzyl is preferably independently possibly substituted (s) one substitute; or more preferably phenyl and / or benzyl is not substituted (s). In R ¹⁰ and / or R ¹¹ , independently of one another, phenyl, benzyl and / or —CH (C _1-2 alkyl) Ph is preferably independently possibly substituted with one substituent (s); or more preferably phenyl, benzyl and / or —CH (C _1-2 alkyl) Ph is unsubstituted (s). In Ar, the phenyl and / or heterocyclic aromatic ring is preferably independently optionally substituted (s) with one substituent; or more preferably phenyl and / or the heterocyclic aromatic ring is not substituted (s). In Het ¹ and / or Het ² , independently of one another, the saturated heterocyclic ring (s) is preferably independently possibly substituted at the ring carbon atom with one substituent; or more preferably, the saturated heterocyclic ring (s) is not substituted on the ring carbon atom (s).

If Met corresponds to sub-formula (v), then suitably R ^X2 and / or R ^Y2 independently represent (s): a hydrogen atom (H), C _1-6 alkyl (e.g. C _1-4 alkyl, such as methyl ), C _3-6 cycloalkyl, -C (O) -NR ¹⁰ R ¹¹ , -C (O) -OR ¹³ or - (CH ₂ ) _n ¹⁰ -Ar; more preferably H, C _1-6 alkyl, —C (O) —NR ¹⁰ R ¹¹ , —C (O) —OR ^13, or - (CH ₂ ) _n ¹⁰ —Ar; even more preferably H, C _1-6 alkyl (for example, C _1-4 such as methyl), —C (O) —NR ¹⁰ R ¹¹ or - (CH ₂ ) _n ¹⁰ —Ar. In this case, that is, if Het corresponds to the sub-formula (v), then Ar preferably represents a possibly substituted phenyl and / or n ¹⁰ preferably represents 0 or 1.

Preferably, R ^X1 and / or R ^Y1 independently represents (are) a hydrogen atom (H) or C _1-2 alkyl, more preferably H or methyl, even more preferably N.

Suitably, Y ⁵ may be CH ₂ or CME ₂ . More preferably, Y ⁵ is CH ₂ , that is, CR ^Y1 R ^Y , where R ^Y1 = R ^Y2 = a hydrogen atom (H).

X ⁵ may suitably be CHR ^X2 or CME ₂ , for example CHMe, CH-CO ₂ Me or CME ₂ .

Particularly preferably, when the compound of formula (I) or its salt is:

N-cyclopentyl-1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

N-cyclopentyl-1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridin-4-amine,

N-cyclopentyl-1-ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

N-cyclopentyl-1-ethyl-5- (5-methyl-1,3,4-thiadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

N-cyclopentyl-1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-thiadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridin-4-amine,

N-cyclopentyl-1-ethyl-5- (5-isopropyl-1,3,4-thiadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-N- (4-fluorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

N-cyclopentyl-5- (1,3-dimethyl-1H-1,2,4-triazol-5-yl) -1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4- amine,

N-cyclohexyl-1-ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-N-isobutyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-N-isobutyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

N-cyclohexyl-1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4- amine,

N - [(1R) -1,2-dimethylpropyl] -1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridine- 4-amine

N - [(1S) -1,2-dimethylpropyl] -1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridine- 4-amine

5- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin- 4-amine

5- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -N-cyclohexyl-1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine,

5- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -N-cyclopentyl-1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine,

5- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N-isobutyl-1H-pyrazolo [3,4-b] pyridin-4-amine,

5- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -N - [(1S) -1,2-dimethylpropyl] -1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine,

5- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -N - [(1R) -1,2-dimethylpropyl] -1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b ] pyridin-4-amine,

N-cyclohexyl-1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-N-isobutyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridin-4-amine,

N - [(1S) -1,2-dimethylpropyl] -1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4 -b] pyridin-4-amine,

N - [(1R) -1,2-dimethylpropyl] -1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4 -A] pyridin-4-amine,

1-ethyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4- amine,

1-ethyl-5- [3- (methoxymethyl) -1,2,4-oxadiazol-5-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin- 4-amine

5- {3 - [(dimethylamino) methyl] -1,2,4-oxadiazol-5-yl} -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b ] pyridin-4-amine,

1-ethyl-5- [3- (morpholin-4-ylmethyl) -1,2,4-oxadiazol-5-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4- b] pyridin-4-amine,

5- (5-cyclopropyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4- amine,

N- (1-Acetylpiperidin-4-yl) -1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4- amine,

1-ethyl-5- [5- (3-methyloxetan-3-yl) -1,3,4-oxadiazol-2-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3, 4-b] pyridin-4-amine,

1-ethyl-5- {5 - [(4-methylpiperazin-1-yl) methyl] -1,3,4-oxadiazol-2-yl} -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4-amine,

5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N-isopropyl-1,3,4-oxadiazole- 2-carboxamide

4- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole-2 -yl} -1-methylpyrrolidin-2-one,

1-ethyl-N-tetrahydro-2H-pyran-4-yl-5- (5-tetrahydro-2H-pyran-4-yl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine,

1-ethyl-5- [5- (morpholin-4-ylmethyl) -1,3,4-oxadiazol-2-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4- b] pyridin-4-amine,

5- [5- (tert-butoxymethyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4-amine or

methyl 2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxylate;

or a salt thereof, for example a pharmaceutically acceptable salt thereof.

Alternatively, the compound of formula (I) or a salt thereof may preferably be:

methyl-2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -4,5-dihydro-1,3- oxazole-4-carboxylate,

1-ethyl-5- (4-methyl-4,5-dihydro-1,3-oxazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine,

1- (n-propyl) -5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine,

1-ethyl-5- [5- (tetrahydrofuran-2-yl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine,

1-ethyl-5- [5- (dimethylamino) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- (5-methyl-1,2,4-triazol-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin- 4-amine

N- (1-Acetylpiperidin-4-yl) -1-ethyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -1H-pyrazolo [3,4-b] pyridin-4- amine or

N- (1-acetylpiperidin-4-yl) -1-ethyl-5- [3- (morpholin-4-ylmethyl) -1,2,4-oxadiazol-5-yl] -1H-pyrazolo [3,4- b] pyridin-4-amine;

or a salt thereof, for example a pharmaceutically acceptable salt thereof.

Alternatively, the compound of formula (I) or a salt thereof may preferably be:

1-ethyl-5 - [(4R) -4-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine,

1-ethyl-5 - [(4S) -4-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine,

1-ethyl-5 - [(4S) -4- (phenylmethyl) -4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5 - [(4R) -4- (phenylmethyl) -4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5 - [(4S, 5R) -5-methyl-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl ) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5 - [(5R) -5-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine,

1-ethyl-5 - [(5S) -5-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine,

5- (4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxylic acid,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (1-methylethyl) -1,3- oxazole-4-carboxamide,

1-ethyl-5- [4- (4-morpholinylcarbonyl) -1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-N-methyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine,

trans-4 - {[1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-yl] amino} cyclohexanol,

1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-3-yl) -1H-pyrazolo [3,4-b] pyridin- 4-amine

4 - {[1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-yl] amino} cyclohexanone,

1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-propyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine,

5- [5- (1,1-dimethylethyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-6-methyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-6-methyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-yl) -1,3,4-oxadiazol-2-yl ] -1H-pyrazolo [3,4-b] pyridin-4-amine,

5- (5-cyclobutyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin- 4-amine

5- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole-2 -yl} -2-pyrrolidinone,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole- 2-yl} methyl) acetamide,

1-ethyl-5- [5- (1-methyl-2-piperidinyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine,

1-ethyl-5- {5 - [(4-methyl-1,2,5-oxadiazol-3-yl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H- pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

3- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole-2 -yl} cyclopentanone,

1-ethyl-5- [5- (tetrahydro-3-furanyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine,

(4S) -4- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4 -oxadiazol-2-yl} -1,3-thiazolidin-2-one,

5- [5- (2,2-dimethylcyclopropyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole- 2-yl} methyl) -N-methylacetamide,

1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-ylmethyl) -1,3,4-oxadiazol-2-yl] -1H- pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- [5- (1-methylcyclobutyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine,

1-ethyl-5- [5- (3-methyl-5-isoxazolyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine,

1-ethyl-5- [5- (1-methyl-1H-pyrazol-5-yl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) - 1H-pyrazolo [3,4-b] pyridin-4-amine,

5- [5- (1-acetyl-4-piperidinyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine,

1-ethyl-5- {3 - [(4-methyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- [3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine or

1-ethyl-5- {3- [2-oxo-2- (1-pyrrolidinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine;

or a salt thereof, for example a pharmaceutically acceptable salt thereof. For these compounds / salts, the structures of each (s) are disclosed in Examples 49-84 below.

Alternatively, the compound of formula (I) or a salt thereof may preferably be:

2- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N-phenylacetamide,

2- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N- (1-phenylethyl) acetamide,

1-ethyl-5- {3- [2-oxo-2- (1-piperidinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

2- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N- (phenylmethyl) acetamide,

2- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N, N-dimethylacetamide,

N-ethyl-2- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4 -oxadiazol-3-yl} acetamide,

1-ethyl-5- {3- [1- (4-morpholinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

5- [3- (cyclohexylmethyl) -1,2,4-oxadiazol-5-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {3- [2-oxo-2- (1-piperidinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {3- [2- (4-methyl-1-piperazinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4 -yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (1H-1,2,3-triazol-1-ylmethyl) -1,3,4-oxadiazol-2-yl ] -1H-pyrazolo [3,4-b] pyridin-4-amine,

5- {5 - [(2,4-dimethyl-1,3-thiazol-5-yl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N- (tetrahydro-2H- pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- [5- (2-furanylmethyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine,

1-ethyl-5- [5- (3-isoxazolylmethyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine,

1-ethyl-5- (5 - {[4- (methyloxy) phenyl] methyl} -1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (1H-tetrazol-1-ylmethyl) -1,3,4-oxadiazol-2-yl] -1H-pyrazolo [ 3,4-b] pyridin-4-amine,

1-ethyl-5- [5- (5-isothiazolylmethyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine,

1-ethyl-5- {5 - [(3-methyl-5-isoxazolyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine,

5- (5 - {[4- (dimethylamino) phenyl] methyl} -1,3,4-oxadiazol-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine (1: 1),

1-ethyl-5- {5 - [(2-methyl-1,3-thiazol-4-yl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran- 4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

2- [1 - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4 -oxadiazol-2-yl} methyl) cyclopentyl] -N-methylacetamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole- 2-yl} methyl) cyclopropanecarboxamide,

1-ethyl-5- {5 - [(5-methyl-3-isoxazolyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {5 - [(5-methyl-3-isoxazolyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {5- [2- (4-methyl-1,3-thiazol-5-yl) ethyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H- pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

5- {5 - [(3,5-dimethyl-4-isoxazolyl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

N- (1- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4- oxadiazol-2-yl} ethyl) acetamide,

5- {5 - [(1-acetyl-4-piperidinyl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {5 - [(4-methylphenyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3 , 4-b] pyridin-4-amine,

1-ethyl-5- [5- (4-methylphenyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine,

5- [5- (3,4-dimethylphenyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine,

5- [5- (2,4-dimethylphenyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine,

5- {5 - [(4-bromophenyl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3 , 4-b] pyridin-4-amine,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (phenylmethyl) -1,3-oxazol- 4-carboxamide

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - {[4- (methyloxy) phenyl] methyl } -1,3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - [(2-methylphenyl) methyl] -1 3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - [(4-methylphenyl) methyl] -1 3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - [(3-methylphenyl) methyl] -1 3-oxazole-4-carboxamide,

N - [(4-chlorophenyl) methyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1 3-oxazole-4-carboxamide,

N - [(2,3-dimethylphenyl) methyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxamide,

N - [(3,5-dimethylphenyl) methyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxamide,

N - [(3,4-dimethylphenyl) methyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (1-phenylethyl) -1,3- oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - {(1R) -1- [4- (methyloxy) phenyl] ethyl} -1,3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - [(1R) -1-phenylpropyl] - 1,3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (4-methylphenyl) -1,3- oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - ({4 - [(methylsulfonyl) amino] phenyl} methyl) -1,3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - {[4- (methylsulfonyl) phenyl] methyl } -1,3-oxazole-4-carboxamide,

N- (1-acetyl-4-piperidinyl) -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] - 1,3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (tetrahydro-2H-pyran-4-yl ) -1,3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (tetrahydro-2-furanylmethyl) -1, 3-oxazole-4-carboxamide,

2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- [2- (4-methyl-1- piperazinyl) ethyl] -1,3-oxazole-4-carboxamide,

N- [1- (aminomethyl) cyclohexyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N methyl-1,3-oxazole-4-carboxamide,

N- (2,6-dimethylphenyl) -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1, 3-oxazole-4-carboxamide,

N - {[4- (aminocarbonyl) phenyl] methyl} -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl ] -1,3-oxazole-4-carboxamide,

2- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N- (tetrahydro-2H-pyran-4-yl) acetamide,

5- {3- [2- (2,6-dimethyl-4-morpholinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -1-ethyl-N- (tetrahydro-2H-pyran -4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {3- [2- (4-methyl-1-piperidinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4 -yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

2- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N- [1-methyl-2- (methyloxy) ethyl] acetamide,

5- {3- [2- (3,5-dimethyl-1-piperidinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -1-ethyl-N- (tetrahydro-2H-pyran -4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {3- [2- (3-methyl-1-piperidinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4 -yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

2- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N-3-pyridinylacetamide,

6- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole-2 -yl} -2-piperidinone,

1-ethyl-5- {5 - [(3-methyl-1H-1,2,4-triazol-5-yl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro- 2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) acetamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) benzamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-phenylacetamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} -methyl) -2-methylpropanamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -3-methylbutanamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) cyclohexanecarboxamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-furancarboxamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) methanesulfonamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) benzenesulfonamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -1-phenylmethanesulfonamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-propanesulfonamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -1-propanesulfonamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) cyclopropanesulfonamide,

N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-thiophenesulfonamide,

1 - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-pyrrolidinone,

1 - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-piperidinone,

5- {3 - [(1-acetyl-4-piperidinyl) methyl] -1,2,4-oxadiazol-5-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- (3 - {[1- (3-methylbutanoyl) -4-piperidinyl] methyl} -1,2,4-oxadiazol-5-yl) -N- (tetrahydro-2H-pyran-4- il) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- (3 - {[1- (methylsulfonyl) -4-piperidinyl] methyl} -1,2,4-oxadiazol-5-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {3- [1- (phenylsulfonyl) cyclopropyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3 , 4-b] pyridin-4-amine,

1-ethyl-5- [3- (phenylmethyl) -1,2,4-oxadiazol-5-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- [3- (1-phenylethyl) -1,2,4-oxadiazol-5-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine,

1-ethyl-5- (3 - {[4- (methyloxy) phenyl] methyl} -1,2,4-oxadiazol-5-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine,

5- (3 - {[4- (dimethylamino) phenyl] methyl} -1,2,4-oxadiazol-5-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine,

5- (3 - {[3- (dimethylamino) phenyl] methyl} -1,2,4-oxadiazol-5-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine,

5- (3 - {[4- (dimethylamino) phenyl] methyl} -1,2,4-oxadiazol-5-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {3 - [(phenyloxy) methyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4 -b] pyridin-4-amine,

1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [3- (5,6,7,8-tetrahydro [1,2,4] triazolo [4,3-a] pyridine- 3-ylmethyl) -1,2,4-oxadiazol-5-yl] -1H-pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- {3 - [(4-phenyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- (5-ethyl-1,2,4-oxadiazol-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin- 4-amine

5- (5 - {[4- (dimethylamino) phenyl] methyl} -1,2,4-oxadiazol-3-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine,

1-ethyl-5- (5 - {[4- (methyloxy) phenyl] methyl} -1,2,4-oxadiazol-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine or

5- (3,8-dioxa-1-azaspiro [4.5] dec-1-en-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine;

or a salt thereof, for example a pharmaceutically acceptable salt thereof. The structures of each of the above compounds are disclosed in Examples 85-191 below.

Preferably, the compound of formula (I) or a salt thereof is:

1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin- 4-amine (compound of Example 14),

5- (5-tert-butyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine (compound of Example 17),

1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4 -b] pyridin-4-amine (compound of Example 23),

1-ethyl-5- [5- (3-methyloxetan-3-yl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine (compound of Example 34),

1-ethyl-5- {5 - [(4-methylpiperazin-1-yl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine (compound of Example 35),

1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-yl) -1,3,4-oxadiazol-2-yl] -1H- pyrazolo [3,4-b] pyridin-4-amine (compound of Example 38),

also called: 1-ethyl-5- [5- (morpholin-4-ylmethyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine (compound of Example 39),

1-ethyl-5- [5- (tetrahydrofuran-2-yl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine (compound of Example 44),

1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-ylmethyl) -1,3,4-oxadiazol-2-yl] -1H- pyrazolo [3,4-b] pyridin-4-amine (compound of Example 77) or

1-ethyl-5- {3- [2-oxo-2- (1-pyrrolidinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine (compound of Example 84);

or its salt.

In a second aspect of the present invention, there is provided a compound of formula (1A) or a salt thereof (in particular a pharmaceutically acceptable salt thereof):

Where:

R ¹ represents C _1-4 alkyl, C _1-3 fluoroalkyl or - (CH ₂ ) ₂ OH;

R ² represents a hydrogen atom (H), methyl or C ₁ fluoroalkyl;

R ³ represents an optionally substituted branched C _3-6 alkyl, an optionally substituted C _3-8 cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group of the sub-formula (aa), (bb) or (cc):

where n ¹ and n ² independently represent 1 or 2; and Y represents O, S, SO ₂ or NR ⁴ ; if R ⁴ represents a hydrogen atom (H), C _1-2 alkyl, C _1-2 fluoroalkyl, CH ₂ C (O) NH ₂ , C (O) NH ₂ , C (O) -C _1-2 alkyl or C (O) -C ₁ fluoroalkyl;

where in R ^{3 a} possibly substituted branched C _3-6 alkyl is optionally substituted with one or two substituents representing oxo (= O), OH, C _1-2 alkoxy or C _1-2 fluoroalkoxy; and where any such substituent is not a substituent on the carbon atom R ³ connected (linked) to the group —NH— of formula (IA);

where in R ³ phenyl is optionally substituted with one substituent, which is fluoro, chloro, C _1-2 alkyl, C _1-2 fluoroalkyl C _1-2 alkoxy, C _1-2 fluoroalkoxy or cyano;

where in R ³ C _{3-8 a} cycloalkyl or heterocyclic group of a sub-formula (aa), (bb) or (cc) is possibly substituted (a) by one or two substituents representing oxo (= O), OH, C _1-2 alkoxy, C _1-2 fluoroalkoxy or C _1-2 alkyl; and where any OH, alkoxy, or fluoroalkoxy substituent is not substituted on the R ³ ring carbon atom attached to (linked) to the —NH group of formula (IA) and is not substituted on each of the R ³ ring carbon atoms attached to the Y group of the heterocyclic group (aa), (bb) or (cc);

and where Het corresponds to the sub-formula (i), (ii), (iii), (iv) or (v):

,

,

Where:

W ¹ , W ² , W ⁴ and W ⁵ are N; and W ³ represents NR ^W ;

X ¹ , X ³ and X ⁴ represent N or CR ^X , X ² represents O, S or NR ^X and X ⁵ represents CR ^X1 R ^X2 ;

Y ¹ , Y ^2, and Y ³ are CR ^Y or N; Y ⁴ represents O, S or NR ^Y ; and Y ⁵ represents CR ^Y1 R ^Y2 ;

Z ¹ and Z ⁵ represent O, S or NR ² ; and Z ² , Z ³ and Z ⁴ are N or CR ^Z ;

Where:

R ^W represents a hydrogen atom (H) or C _1-2 alkyl;

R ^X , R ^X2 , R ^Y and R ^Y1 independently represent:

hydrogen atom (H);

C _1-8 alkyl;

C _3-6 cycloalkyl optionally substituted with a C _1-2 alkyl group;

- (CH ₂ ) _n ^2a -C _3-6 cycloalkyl optionally substituted by the group - (CH ₂ ) _n ^2a - or by a C _3-6 cycloalkyl group by a C _1-2 alkyl group, where n ² represents 1, 2 or 3;

- (CH ₂ ) _n ³ —SO ₂ —R ⁵ , where n ³ is 1 or 2, and R ⁵ is C _1-3 alkyl, or —NH — C _1-2 alkyl, or phenyl;

- (CH ₂ ) _n ⁴ -NR ⁶ R ⁷ where n ⁴ represents 0, 1, 2 or 3, and R ⁶ and R ⁷ independently represent H, C _1-6 alkyl, for example C _1-6 alkyl, C _3-6 cycloalkyl, -CH ₂ -C _3-6 cycloalkyl, -C (O) -C ₁ - ₂ alkyl, -SO ₂ -C _1-2 alkyl, phenyl, or benzyl (wherein the phenyl or benzyl are independently optionally substituted by an aromatic ring with one group fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy); or R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - (CH ₂ ) _n ⁶ -, where n ⁵ and n ⁶ independently represent 2 or 3, and X ⁵ represents a bond, —CH ₂ -, O or NR ⁸ , where R ⁸ represents H or C _1-2 alkyl;

- (CH ₂ ) _n ⁷ -O-R ⁹ ; where n ⁷ represents 0, 1, 2 or 3, and R ⁹ represents H or C _1-6 alkyl; where n ⁷ represents 0 only when - (CH ₂ ) _n ⁷ -OR ⁹ is bonded to a carbon atom in the Het ring; and where n ^{7 is} not 0 when Het corresponds to the sub-formula (v) (that is, n ^{7 is} not 0 for R ^X2 and for R ^Y2 );

-C (O) -NR ¹⁰ R ¹¹ ; where R ¹⁰ and R ¹¹ independently represent H, C _1-6 alkyl, C _3-6 cycloalkyl, -CH ₂ -C _3-6 cycloalkyl, phenyl or benzyl (where phenyl or benzyl are independently possibly substituted on the aromatic ring with one fluoro group , chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy); or R ¹⁰ and R ¹¹ together represent - (CH ₂ ) _n ⁸ —X ⁶ - (CH ₂ ) n ⁹ -, where n ⁸ and n ⁹ independently represent 2 or 3, and X ⁶ represents a bond, —CH ₂ -, O or NR ¹² , where R ¹² represents H or C _1-2 alkyl;

—C (O) —OR ¹³ where R ¹³ is H, C _1-6 alkyl, C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, phenyl or benzyl (where phenyl or benzyl are independently optionally substituted by an aromatic ring with one group fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy);

—C (O) —R ^13a , where R ^13a represents a hydrogen atom (H), C _1-2 alkyl, C _1-2 fluoroalkyl, C _3-6 cycloalkyl, —CH ₂ —C _3-6 cycloalkyl, benzyl or phenyl; where phenyl or benzyl are independently possibly substituted on the aromatic ring with one group of fluoro, chloro, C _1-2 alkyl, C ₁ fluoroalkyl, C _1-2 alkoxy or C ₁ fluoroalkoxy;

A 4-, 5-, 6- or 7-membered saturated heterocyclic ring containing one O ring atom or one NR ¹⁴ ring group, where R ¹⁴ is H or C _1-2 alkyl, wherein said heterocyclic ring is optionally substituted (in position or to positions other than any position NR ¹⁴ ) with one oxo substituent (= O) and / or one C _1-4 alkyl substituent; or

- (CH ₂ ) _n ¹⁰ -Ar, where n ¹⁰ represents 0, 1 or 2, and

(1) Ar is phenyl, optionally substituted with one or two substituents representing fluoro, chloro, C _1-2 alkyl, C _1-2 fluoroalkyl, C _1-2 alkoxy, C _1-2 fluoroalkoxy or cyano;

or

(2) Ar is an optionally substituted 5- or 6-membered heterocyclic aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N or S; and where when the heterocyclic aromatic ring Ar contains 2 or 3 heteroatoms, one is selected from O, N and S, and the remaining heteroatom (s) is (are) N; and wherein the heterocyclic aromatic ring Ar is optionally substituted with one or two C _1-4 alkyl groups;

R ^X1 and R ^Y1 independently represent a hydrogen atom (H), C _1-2 alkyl or C ₁ fluoroalkyl; and

R ^Z represents a hydrogen atom (H) or C _1-2 alkyl.

Preferably in formula (IA), if R ³ is a heterocyclic group of sub-formula (bb), n ¹ is 1, and Y is NR ⁴ , then R ^{4 is} not C _1-2 alkyl C _1-2 fluoroalkyl or CH ₂ C (O) NH ₂ .

Examples 1-48 are examples of compounds or salts of the second aspect of this invention (formula (IA)).

Preferred or possible features for a compound of formula (IA) or a salt thereof are the same or similar as preferred or possible features for a compound or salt of formula (I), with all necessary changes (for example, in a formula, in R groups and / or in substitutes) to be done. In general, every time Formula (I) is mentioned here, then in alternative embodiments, the statement mentioning Formula (I) is applicable to Formula (IA) with all the necessary changes that need to be made.

Salts, solvates, isomers, tautomeric forms, molecular weights and so on

Due to their potential use in medicine, salts of the compounds of formula (I) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts may include acid or base addition salts.

A pharmaceutically acceptable acid addition salt can be prepared by reacting a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic , benzoic, salicylic, glutamic, aspartic, para-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, such as 2-naphthalenesulfonic, or hexane acid), optionally in a suitable solvent, such as an organic solvent, to give a salt, which is usually isolated, for example, by crystallization and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) may be, for example, a hydrobromide salt, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate , aspartate, para-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate) or hexanoate. In one embodiment, the pharmaceutically acceptable acid addition salt may be hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate, tartrate, benzoate, p-toluenesulfonate, methanesulfonate or naphthalenesulfonate.

A pharmaceutically acceptable base addition salt can be prepared by reacting a compound of formula (I) with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent, such as an organic solvent, with obtaining a base addition salt, which is usually isolated, for example, by crystallization and filtration.

Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali metal or alkaline earth metal salts, such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxyl groups that may be present in the compound of formula (I).

Other non-pharmaceutically acceptable salts, for example, oxalates, can be used, for example, in the isolation of compounds of this invention, and they are included in the scope of this invention.

This invention includes in its scope all possible stoichiometric and non-stoichiometric forms of salts of the compounds of formula (I).

All solvates, hydrates, and complexes of the compounds and salts of this invention are also included within the scope of this invention.

Certain groups, substituents, compounds or salts included in the present invention may be present as isomers. The invention includes in its scope all such isomers, including racemates, enantiomers and mixtures thereof.

Some of the groups, for example, heteroaromatic ring systems included in the compounds of formula (I), or their salts, can exist in one or more of one of the tautomeric forms. The invention includes in its scope all such tautomeric forms, including mixtures. For example, if Het corresponds to the sub-formula (i) Y ¹ represents CR ^Y and X ¹ represents CR ^X , where R ^X represents OH, then the compounds of formula (I) or their salts include the keto form (K1), enol form (E1) and mixtures thereof, as shown below, unless otherwise indicated; and if Het corresponds to sub-formula (i) and Y ¹ is CR ^Y , where R ^Y is OH, then the compounds of formula (I) or their salts include the keto form (K2), enol or hydroxyimine form (E2), and mixtures thereof, as shown below, unless otherwise indicated:

Especially when it is intended for oral medical use, the compound of formula (I) may optionally have a molecular weight of 1000 or less, for example 800 or less, in particular 650 or less, or 600 or less. Molecular mass here refers to the molecular weight of a compound, which is an unsolvated "free base", that is, excluding any molecular weight introduced by any addition of salt molecules, a solvent (eg water), and so on.

The ways of synthesis

The following methods can be used to prepare the compound of formula (I). These methods are sometimes illustrated for cases where R ² represents H or Me. However, some or all of these methods are considered applicable with appropriate modifications, for example, starting materials and reagents to obtain compounds of formula (I), where R ² represents C ₁ fluoroalkyl.

Method A

Compounds of formula (I), which are compounds of formula I (ia) (i.e., compounds of formula (I) wherein Het is a sub-formula (ia)), can be prepared by cyclization by a compound of formula II, for example, in the presence of a dehydrating agent, such as phosphorus oxychloride (POCl ₃ ) or Burgess reagent (Burgess) [triethylammonium hydroxide] and / or preferably in a suitable solvent (eg, an organic solvent, preferably anhydrous) such as acetonitrile (eg, for POCl ₃ ), or THF, and / or DMF (on Example for Burgess reagent). This reaction may require heating, for example heating to a temperature of from about 70 ° C to about 150 ° C, or heating to a temperature of from about 70 ° C to about 120 ° C, or heating to a temperature of from about 70 ° C to about 90 ° C. :

For the cyclization reaction from Formula II to Formula I (ia), the conditions may, for example, be as described (a) in Examples 1-3 or 43 (POCl ₃ and acetonitrile), or (b) in Examples 32, 34-37 , 35 (alternative synthesis), 38-40, 44, 66 or 97-125 (Burgess reagent with THF and / or DMF).

Compounds of formula II themselves can be prepared by reacting a compound of formula III with a suitable substituted hydrazine derivative of formula R ^Y CONHNH ₂ under standard coupling conditions. For example, a coupling reagent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) can be used, for example, in the presence of hydroxybenzotriazole (HOBT), for example, in a suitable solvent such as DMF:

If the desired hydrazine derivative R ^Y CONHNH _{2 is} not readily available, compounds of formula II may alternatively be prepared first by reacting a compound of formula III with ROCONHNH ₂ carbazate, such as ^t ButOCONHNH ₂ tert-butyl carbazate, under coupling conditions to form a compound of formula IV. For example, you can use a coupling reagent, such as EDC, for example, in the presence of hydroxybenzotriazole, for example, in a suitable solvent, such as DMF:

Subsequent removal of the Boc protection from the obtained acid hydrazide derivative (compound of formula IV) to obtain the hydrazide derivative of formula V can be carried out using a dilute acid, such as 2 M hydrochloric acid, in an organic solvent such as dioxane.

The compound of formula V can be converted into a compound of formula II (the desired hydrazide derivative). This can be done by reacting a compound of formula V with an acid of formula R ^Y CO ₂ H under coupling conditions. For example, a coupling agent such as EDC can be used, for example, in the presence of hydroxybenzotriazole (HOBT), for example, in a suitable solvent such as DMF. Alternatively, an activated acid derivative of the formula RYCO-X ¹⁰ where X is a leaving group such as chloro (acid chloride) or —O — CO — R ³⁰ or —O — SO ₂ —R ³⁰ (where R ³⁰ may represent is, for example, R ^Y, or alkyl or aryl such as methyl, t-butyl or p-methylphenyl) to achieve formation of a hydrazide of formula II by reaction with a hydrazide derivative of formula V.

Compounds of formula III can be prepared by hydrolysis of an ester of formula VI (for example, R ^A may be C _1-2 alkyl, such as Et), for example, in accordance with the method described in Yu et. al. J. Med Chem., 2001, 44,1025-1027. This hydrolysis technique typically involves reacting with a base such as sodium hydroxide or potassium hydroxide in a solvent such as ethanol or dioxane (e.g., NaOH in EtOH), where one or both of the solvents preferably contains (at) some water:

The compounds of formula VI can be obtained, for example, in accordance with the method described in Yu et. al. J. Med Chem., 2001, 44, 1025-1027, by reacting a compound of formula VII with an amine of formula R ³ R ^3a NH. This interaction is best carried out in the presence of a base, such as triethylamine or diisopropylethylamine, in a solvent such as ethanol or dioxane (e.g. Net ₃ in EtOH), and may require heating:

Many amines of the formula R ³ R ^3a NH, for example, those amines in which R ³ R ^3a NH corresponds to the sub-formulas (a) to (t2), are commercially available, or their syntheses have been published and / or described here, or can be obtained from commercially available or synthesized compounds, for example, from other amines of the formula R ³ R ^3a NH or derivatives thereof. For amines R ³ R ^3a NH, the preparation of which and / or specific commercial sources are disclosed here, see, for example, Intermediates 21, 21A, 25, 50, 54-57 and 140-163. Compounds of formula VII are also described in the above link and can be prepared first by reacting a compound of formula VIII, for example, with diethyl (ethoxymethylene) malonate (R ² = H, to obtain R ^A = Et) or diethyl-2- (1-ethoxyethylidene ) malonate (R ² = Me, to obtain R ^A = Et), for example, by heating, followed by reaction with phosphorus oxychloride, again preferably when heated. See, for example, the synthesis of Intermediate 1 and G. Yu et. al., J. Med Chem., 2001, 44, 1025-1027 below, if R ² = H and R ¹ = ethyl; and see the synthesis of Intermediate 58 below if R ² = Me and R ¹ = ethyl:

If, for example, the desired aminopyrazole of formula VIII is not commercially available, the preparation of pyrazole of formula VIII can be carried out, for example, using the method described in Dorgan et. al. J. Chem. Soc., Perkin Trans. 1980, 1 (4), 938-42, comprising reacting cyanoethyl hydrazine with a suitable R ^1a CHO aldehyde in a solvent, such as ethanol, by heating and then reducing, for example, reducing with sodium in a solvent, such as tert-butanol. R ^1a should be chosen so that it contains one carbon atom less than in R ¹ , for example, R ^1a = methyl should give R ¹ = ethyl.

Alternatively, for example, if the desired aminopyrazole of formula VIII is not commercially available, the preparation of a compound of formula VI can be carried out from a compound of formula VII (e.g., Intermediate 1, where R ¹ = ethyl) using the general version of the reaction scheme shown in Example 43, especially that part that relates to the conversion of Intermediate 1 to Intermediate 38. In this method: 4-chloropyrazolopyridine of formula VII (eg, Intermediate 1) may be converted to 4-alkoxy- (eg C _1-2 alkoxy-, so oh as ethoxy) pyrazolopyridine (e.g., Intermediate 35); the R ¹ group is removed (to, for example, Intermediate 36, in which R ¹ is H and not alkyl), the 4-amino R ³ R ^3a N group is introduced, replacing the 4-chloro or 4-alkoxy group by reaction with R ³ R ^3a NH (e.g., up to Intermediate 37); and pyrazolopyridine is alkylated at N-1 by reacting it with R ¹ -X ⁴⁰ , where X ⁴⁰ is a group substituted with nitrogen N-1 pyrazolopyridine to reintroduce the desired R ¹ group (for example, synthesis of Intermediate 38). X ⁴⁰ may, for example, be halogen, for example Cl, Br or I; or X ⁴⁰ may be —O — SO ₂ —R ⁴⁰ , where R ⁴⁰ is C _1-4 alkyl, C _1-2 fluoroalkyl or phenyl optionally substituted with C _1-2 alkyl.

Method B

Compounds of formula (I), which are compounds of Formula I (ia) (i.e., compounds of formula (I) in which Het corresponds to sub-formula (ia)) can alternatively be prepared by reacting a compound of formula IX with an amine of formula R ³ R ^3a NH, preferably in a solvent (eg, an organic solvent) such as ethanol or acetonitrile, and / or preferably in the presence of a base such as DIPEA. This transformation may require heating:

For the interaction of the compounds of formula IX with an amine of the formula R ³ R ^3a NH to obtain the compounds of the formula I (ia), the reaction conditions, for example, solvents, molar ratios, temperatures and / or reaction times, may possibly be as described in Examples 9, 10-11 and / or 12-27.

The interaction of formula IX with R ³ R ^3a NH to give formula I (ia) can be generalized to any compound of formula (I) containing any Het group, as defined herein, starting from a compound of formula IXa:

Compounds of formula IX themselves can be prepared by cyclization of a compound of formula X, preferably in the presence of a dehydrating agent such as phosphorus oxychloride or Burgess reagent [methoxycarbonylsulfamoyl] triethylammonium], in a suitable solvent (eg, an organic solvent, preferably anhydrous) such as acetonitrile ( for example, for POCl ₃ ) or THF and / or DMF (for example, for Burgess reagent). This reaction may require heating, for example, heating to a temperature of from about 70 ° C to about 150 ° C, or heating to a temperature of from about 70 ° C to about 120 ° C, or heating to a temperature of from about 70 ° C to about 90 ° FROM:

Compounds of formula X can be prepared by first activating an acid of formula XI, for example, an amide coupling reagent such as EDC / HOBT or thionyl chloride, followed by reaction of the thus formed activated intermediate with an acid hydrazide of the formula R ^Y ONHNH ₂ :

Examples of interactions of a compound of formula XI to formula X and a compound of formula X to formula XI are provided in Intermediates 12 to 15.

The acids of formula XI themselves can be prepared by hydrolysis of an ester of formula VII (for example, as described in Method A) using a base such as potassium hydroxide in a solvent such as aqueous dioxane (dioxane / water):

Method C

Compounds of formula XII (i.e., compounds of formula (I) in which Het corresponds to sub-formula (ib)) can be prepared by reacting a compound of formula II with a sulfur-capable reagent, such as Lawesson's reagent, usually in a suitable solvent, such as acetonitrile. This interaction may require heating:

The conditions for this interaction, for example, solvents, molar ratios, temperatures and / or reaction times, may possibly be as described in Examples 4, 5 or 6.

Method D

Compounds of formula XIII [which are compounds of formula (I) in which Het corresponds to sub-formula (ic)] can be prepared by reacting a compound of formula VI (R ^A may be C _1-6 alkyl, such as Et) with an amidoxime of formula R ^X C (= NOH) NH ₂ , preferably in the presence of a base, such as sodium ethylate, and / or preferably in a suitable solvent (e.g., an anhydrous and / or organic solvent), such as ethanol, and preferably in the presence of molecular sieves (e.g. , 4-angstrom and / or powder molecule sieve) or other conditions effective to remove water. The reaction mixture may possibly be heated, for example, to a reflux temperature:

The conditions for this interaction, for example, solvents, molar ratios, temperatures and / or reaction times, may be as described in Examples 7, 28-29, 30, 31, 48, 82-84, 92, 93 and / or 178-187.

Method E

Compounds of formula XIV (which are compounds of formula (I) in which Het corresponds to a sub-formula (if)) can be prepared by reacting a compound of formula XV with a suitable acetymidate R ^X —C (= NH) OR ^E , where R ^E is C _1-6 alkyl, for example methyl (such as methylacetimidate (R ^X = Me)), preferably in the presence of a base (such as triethylamine or sodium ethylate) and / or in a suitable solvent (for example, an anhydrous and / or organic solvent) such like ethanol:

Compounds of formula XV themselves can be prepared by reacting a compound of formula III with a suitable substituted hydrazine derivative of formula R ^Z HNH ₂ under coupling conditions. For example, you can use a coupling agent, such as EDC, for example, in the presence of hydroxybenzotriazole (HOBT), in a suitable solvent, such as DMF:

Method F

To obtain a compound of formula (I) in which Het corresponds to a sub-formula (id) (optionally substituted 1,3-oxazol-2-yl), methods known to the skilled person can be used.

For example, a compound of formula III, which is 5-carboxylic acid, can be converted directly or indirectly to a compound of formula (I) in which Het corresponds to the sub-formula (id) (i.e., 5- (optionally substituted) -1,3- oxazol-2-yl) pyrazolopyridine). Alternatively or additionally, a compound of formula (I) in which Het corresponds to a sub-formula (va), wherein R ^X1 and R ^Y1 are H and R ^X1 is R ^X and R ^Y1 is R ^Y [i.e., the corresponding 5- (optionally substituted) -4,5-dihydro-1,3-oxazol-2-yl) pyrazolopyridine] can be dehydrogenated to a compound of formula (I) in which Het corresponds to a sub-formula (id), for example, by the method shown in Example 41 (DBU, CCl ₄ , CH ₃ CN, pyridine), or by a modification of this method or by a similar method, for example, using an oxidizing agent.

Dehydrogenation (oxidation) of the 4,5-dihydro-1,3-oxazol-2-yl compound of the formula (I) (wherein Het corresponds to the sub-formula (va) in which R ^X1 and R ^Y1 are H and R ^X1 is R ^X , and R ^Y1 represents R ^Y ) to the corresponding 1,3-oxazol-2-yl compound of formula (I), where Het corresponds to the sub-formula (id), can be carried out using reagents and conditions known to the person skilled in the art ( see, for example, the following reviews: TG Gant et al., Tetrahedron, 1994, 50 (8), 2297-2360; M. Reuman et al., Tetrahedron, 1985, 41 (5), 837-860; and cited therein links). An oxidizing agent such as nickel peroxide, manganese dioxide (MnO ₂ ) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is preferably used for this dehydrogenation reaction.

A compound of formula (I) in which Het corresponds to a sub-formula (va) can be prepared by cyclizing a compound of formula XXVIII, for example, in the presence of a Burgess reagent and / or preferably in a suitable solvent (e.g., an organic solvent, preferably anhydrous), such as THF

A compound of formula XXVIII can be prepared from a compound of formula III by reaction with a compound of formula XXIX under coupling conditions (e.g., EDC with or without HOBT), optionally in the presence of a base such as Et ₃ N, and preferably in a suitable solvent such as DMF.

Method G

Compounds of formula XVI (1,2,4-oxadiazoles) of this invention, which are compounds of formula (I), wherein Het corresponds to sub-formula (ic) and 14 ^x is —CH ₂ C (O) NR ¹⁰ R ¹¹ can be prepared by reacting a compound of formula XVII with an amine of formula R ¹⁰ R ¹¹ NH under coupling conditions. You can use the standard combination conditions known to the specialist. For example, a coupling agent such as TBTU can be used, preferably in the presence of hydroxybenzotriazole. However, it is more preferable when the coupling agent is oxalyl chloride, which in this reaction forms the acid chloride of the corresponding acid from the compound of formula XVII, which is a carboxylic acid; in this embodiment, it is preferable that the acid chloride is not isolated, that is, the solvent in which it is formed is preferably not substantially removed. Preferably, regardless of the coupling agent / coupling conditions, this reaction is carried out in the presence of a base, such as diisopropylethylamine, and / or in a suitable solvent (e.g., an organic solvent, preferably anhydrous), such as DMF and / or dichloromethane.

The conditions of this interaction for the conversion of Formula XVII to Formula XVI, for example, solvents, molar ratios, temperatures and / or reaction times, may be as described in Examples 85-90, 95-96 and / or 148-155.

Compounds of formula XVII themselves can be prepared by reacting a compound of formula XVIII (R ^{G is} preferably ^t Bu) with a hydrolyzing agent (for example, an acid such as trifluoroacetic acid) in a solvent such as dichloromethane:

Compounds of formula XVIII can be prepared by reacting a compound of formula VI (R ^A = H) with an amidoxime of formula P ^G OS (= O) CH ₂ C (= NOH) NH ₂ and a coupling agent, for example TBTU, preferably in the presence of hydroxybenzotriazole, preferably in the presence of base, such as diisopropylethylamine, and / or in a suitable solvent, such as DMF, followed by reaction with 1,1'-carbonyldiimidazole:

Method H

Compounds of the formula XIX, which are compounds of the formula (I) in which Het corresponds to the sub-formula (ic) and R ^x is —CH ₂ —NR ⁶ R ⁷ , where R ⁷ is C (O) R ¹⁷ , can be obtained from compounds of formula XX. For example, this may be the reaction of a compound of formula XX with a carboxylic acid R ¹⁷ COOH in the presence of a coupling agent, for example TBTU, preferably with hydroxybenzotriazole and preferably in the presence of a base such as diisopropylethylamine in a suitable solvent such as DMF. Alternatively or additionally, a compound of formula XX may be reacted with an activated derivative of the carboxyl group R ¹⁷ COOH (for example, by reaction with an acid chloride R ¹⁷ C (O) Cl), preferably in the presence of a base such as diisopropylethylamine and / or in a suitable solvent (e.g., organic) such as dichloromethane and / or chloroform.

The conditions of this interaction for the conversion of Formula XX to Formula XIX, for example, solvents, molar ratios, temperatures and / or reaction times, may be as described in any one of Examples 159-165.

Compounds of formula XX, which are compounds of formula (I) in which Het corresponds to sub-formula (ic) and R ^X is —CH ₂ —NR ⁶ R ⁷ , where R ⁷ is H, can be prepared by deprotection with a compound of formula XXI, wherein R ^H is benzyl or C _1-6 alkyl, such as ^t Bu, for example, by reaction with an acid such as trifluoroacetic acid (for example, if R ⁴ is C _1-6 alkyl, such as ^t Bu) or by hydrogenation (e.g., if R ⁴ is benzyl), preferably in a suitable solvent, taco as dichloromethane:

Compounds of formula XXI can be prepared by reacting a compound of formula VI (but where R ^A is OH) with an amidoxime of formula R ^H OC (= O) N (R ⁶ ) CH ₂ C (= NOH) NH ₂ and a coupling agent, for example TBTU, preferably in the presence of hydroxybenzotriazole and preferably in the presence of a base such as diisopropylethylamine and / or preferably in a suitable solvent such as DMF, followed by reaction with a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene:

Method I

Compounds of formula XXII, which are compounds of formula (I) in which Met corresponds to sub-formula (ic) and R ^X is —CH ₂ —NR ⁶ R ⁷ , where R ⁷ is —S (O) ₂ R ¹⁸ can be prepared from compounds of formula XX by reaction with a sulfonyl chloride R ¹⁸ S (O) ₂ Cl, preferably in the presence of a base such as triethylamine and / or pyridine, and / or preferably in a suitable solvent (eg organic) such as dichloromethane and / or chloroform:

The conditions for this interaction, for example, solvents, molar ratios, temperatures and / or reaction times, may possibly be as described in any one of Examples 166-172.

Method j

Compounds of formula XXIII are compounds of formula (I) in which Het corresponds to sub-formula (ic), and R ^x is —CH ₂ —NR ⁶ R ⁷ , where R ⁶ and R ⁷ together are - (CH ₂ ) _n- X ⁵ - (CH ₂ ) _n ⁶ -, where n ⁵ and n ⁶ independently represent 2 or 3, and where the ring formed by NR ⁶ R ⁷ is substituted with one oxo substituent (= O) at the carbon atom in (CH ₂ ) _n ⁶ , which is associated with nitrogen.

Compounds of formula XXIII can be prepared by reacting a compound of type XX, where R ⁶ = H, with acid chlorides of type X ⁵ - (CH ₂ ) _n ⁵ -X ⁵ -CH ₂ ) _(n ⁶ _-1 ) -COCl, where X ^J is is a leaving group, preferably in the presence of a base such as triethylamine, and / or preferably in a suitable solvent, for example dichloromethane or tetrahydrofuran, preferably followed by treatment with a base such as sodium hydride, in a suitable solvent such as DMF. The leaving group X ^J may, for example, be a halogen atom such as Cl, Br or I; or X ^J may, for example, be —O — SO ₂ —R ^J , where R ^J is C _1-4 , C _1-2 fluoroalkyl or phenyl optionally substituted with C _1-2 alkyl, for example 4-methylphenyl.

For examples of the reaction conditions for the conversion of formula XX to formula XXIII, see, for example, Intermediates 119 and / or 120 and / or the following Examples 173 and / or 174.

Method K

Compounds of the type of formula XXIV, which are compounds of the formula (I) in which Het corresponds to the sub-formula (iia), can be obtained from compounds of the type of the formula XXV by reaction with R ^Y C (O) X ^K , where X ^K is a leaving a group, preferably in a solvent, such as acetic acid, pyridine, diglyme and / or dichloromethane. X ^K may, for example, be chloro; or R ^Y C (O) X ^K may be an anhydride such as [R ^Y (C = O)] ₂ O; or R ^Y C (O)) X ^K may be an activated carboxylic acid derivative obtained by reacting R ^Y C (O) OH with a coupling reagent such as EDC or TBTU in the presence or absence of HOBT.

To convert Formula XXV to Formula XXIV, the conditions for this interaction may, for example, be as described in Examples 188, 189 and / or 190.

Compounds of the type of formula XXV can be prepared from compounds of the type of formula XXVI by reaction with hydroxylamine or a hydroxylamine salt, preferably in the presence of a base such as potassium carbonate, sodium alcoholate or tertiary amine, and / or preferably in a suitable solvent, such as ethanol or methanol:

Compounds of the type of formula XXVI themselves can be prepared from compounds of formula XXVII by reaction with a dehydrating agent, such as a Burgess reagent, preferably in a solvent, tetrahydrofuran:

Compounds of the type of formula XXVII can be prepared from compounds of the formula III, which are carboxylic acids, for example, by reaction with thionyl chloride and then with ammonia in a suitable solvent, such as dioxane:

Method L - Conversion of a compound of formula (I) or its salt into another compound of formula (I) or its salt

One compound of formula (I) or a salt thereof can be converted into another compound of formula (1) or a salt thereof. This conversion preferably includes or represents one or more of the following methods from L1 to L10:

L1. The method of oxidation. For example, the oxidation method may include or be the oxidation of alcohol to a ketone (for example, using Jones reagent) or the oxidation of alcohol or ketone to a carboxylic acid.

L2. A process comprising reduction, for example, reduction of a ketone or carboxylic acid to alcohol.

L3. Acylation, e.g. acylation of an amine or hydroxyl group.

L4. Alkylation, e.g. alkylation of an amine or hydroxyl group.

L5. Hydrolysis, for example, hydrolysis of an ester to the corresponding carboxylic acid or its salt, for example, in the presence of a base (e.g., an alkali metal hydroxide, preferably also in the presence of water) or in the presence of an acid (e.g., aqueous HCl or HCl in an anhydrous organic solvent such as dioxane )

The hydrolysis may, for example, be the hydrolysis of an ester compound in which R ^X , R ^X2 , R ^Y or R ^Y2 is - (CH ₂ ) _n ¹² —C (O) —OR ¹³ , where R ^{13 is} not represents a hydrogen atom (H), to the corresponding carboxylic acid, where R ¹³ represents a hydrogen atom (H). See, for example, Example 57 and Intermediate 83.

The hydrolysis may, for example, be the hydrolysis of an ester compound, where R ^{3 is} substituted with a group —C (O) OR ²³ , where R ²³ is C _1-2 alkyl (for example, NHR ³ or NR ³ R ^3a corresponds to sub formula (p8)), to the corresponding carboxylic acid or its salt, where R ²³ represents H (for example, NHR ³ or NR ³ R ^3a corresponds to the sub-formula (p7)).

L6. Deprotection, e.g., deprotection (e.g., deacylation or removal of tert-butyloxycarbonyl (BOC) or removal of benzyloxycarbonyl) from the amine group.

L7. The formation of an ester or amide, for example, from the corresponding carboxylic acid and / or an activated derivative of a carboxylic acid (for example, an acid chloride or anhydride of an acid, or a carboxylic acid activated by a coupling agent).

The amide formation can be the formation of an amide compound in which one or more of one of R ^X , R ^X2 , R ^Y and R ^Y2 is - (CH ₂ ) _n ¹¹ —C (O) —NR ¹⁰ R ¹¹ , —CH (C _1-2 alkyl) —C (O) —NR ¹⁰ R ¹¹ , —CMe ₂ —C (O) —NR ¹⁰ R ^11, or cycloalkyl substituted with —C (O) —NR ¹⁰ R ¹⁰ from the corresponding carboxylic acid and / or an activated derivative of a carboxylic acid. Examples of this amide formation are shown in Examples 58-59 and / or 126-147 for Het = sub-formula (id) and / or in Method G here for Het = sub-formula (ic) (for example, Examples 85-90, 95 -96 and / or 148-155).

The amide formation can alternatively be the formation of an amide compound in which one or more of one of R ^X , R ^X2 , R ^Y and R ^Y2 is - (CH ₂ ) _n ⁴ —NR ⁶ R ⁷ , —CH ( _1-2 alkyl) NR ⁶ R ⁷ , —CMe ₂ —NR ⁶ R ^7, or cycloalkyl substituted with NR ⁶ R ⁷ , where R ⁶ is C (O) R ¹⁷ , from the corresponding carboxylic acid and / or activated carboxylic acid derivative. One example where Het corresponds to a sub-formula (ic), see Method H and / or Examples 159-165.

L8. The conversion of ketone to the corresponding oxime or ether oxime. This may, for example, include the conversion of the oxo substituent (= O) present in R ³ , for example, NHR ³ or NR ³ R ^{3a of the} sub-formula (o), into a hydroxyimino substituent (= N-OH) or (C _{1 2} alkoxy) imino (= N-OR ²⁶ ) in R ³ , for example in NHR ³ or NR ³ R ^3a sub-formulas (o2), (o3), (o4) or (o5). This conversion can be carried out in the case of oxime (hydroxyimino, = N-OH) by reacting hydroxylamine or its salt (e.g. hydroxylamine hydrochloride) with ketone or in the case of oxime ether (C _1-4 alkoxy) imino, = N-OR ²⁶ ) by reacting C _1-2 alkoxylamine or a salt thereof (e.g., a hydrochloride salt) with a ketone. This reaction is preferably carried out in the presence of a base, such as anhydrous potassium carbonate or diisopropylethylamine, and / or in a suitable solvent, such as acetonitrile. This mixture can be heated, for example, to reflux temperature.

L9. Sulfonylation, for example, the formation of sulfonamide by reacting an amine with a sulfonyl halide, for example sulfonyl chloride (for example, see also Method I);

and / or

, в увеличенное на один кольцевой атом лактамовое соединение формулы (I), например где NHR³ или NR³R^3a соответствует суб-формуле (m3)

.L10. Rearrangement of Beckmann of one compound of formula (I) to another compound of formula (I). Preferably, cyanuric acid chloride (2,4,6-trichloro-1,3,5-triazine) is used together with formamide such as DMF, for example at room temperature (see LD Luca, J. Org. Chem., 2002, 67, 6272-6274). Beckman rearrangement may, for example, include the conversion of a (hydroxyimino) cycloalkyl compound of formula (I), for example, where NHR ³ or NHR ³ R ^3a corresponds to sub-formula (o2)

in a single ring atom enlarged lactam compound of the formula (I), for example where NHR ³ or NR ³ R ^3a corresponds to the sub-formula (m3)

.

The present invention thus also provides a method for preparing a compound of formula (I) or a salt thereof, comprising;

(a) cyclizing a compound of formula II to a compound of formula (I), wherein Het corresponds to a sub-formula (ia) (i.e., a compound of formula I (ia), i.e., a 1,3,4-oxadiazol-2-yl derivative, possibly substituted at the 5th position of the pyrazolopyridine ring system), for example, in the presence of a dehydrating agent such as phosphorus oxychloride or a Burgess reagent, or

(b) reacting a compound of formula IX and an amine of formula R ³ R ^3a NH to form a compound of formula (I), preferably in a solvent (eg, an organic solvent) and / or preferably in the presence of a base, or

(c) cyclization of a compound of formula II to a compound of formula (I), wherein Het corresponds to a sub-formula (ib) (i.e., a compound of formula XII, i.e., a 1,3,4-thiadiazol-2-yl derivative, optionally substituted with 5th position of the pyrazolopyridine ring system), for example, in the presence of an agent capable of introducing sulfur, such as Lawesson's reagent, or

(d) reacting a compound of formula VI, where R ^A is C _1-6 alkyl, such as Et, with an amidoxime of formula R ^X C (= NOH) NH ₂ or a salt thereof, preferably in the presence of a base such as sodium ethylate, and / or preferably in a suitable solvent (for example, an anhydrous and / or organic solvent) such as ethanol; or

(e) reacting a compound of formula XV with acetymidate R ^X —C (= NH) OR ^E , where R ^E is C _1-6 alkyl, to give a compound of formula (I), where Het corresponds to the sub-formula (if) (then there are compounds of formula XIV, i.e., a 1,2,4-triazol-3-yl or -5-yl derivative, optionally substituted at the 5th position of the pyrazolopyridine ring system), preferably in the presence of a base (such as triethylamine or sodium ethylate) and / or in a suitable solvent (for example, an anhydrous and / or organic solvent) such as ethanol; or

(f) (i) converting, directly or indirectly, a compound of formula III into a compound of formula (I), wherein Het corresponds to a sub-formula (id); and / or (f) (ii) dehydrogenating a compound of formula (I), wherein Het corresponds to a sub-formula (va) in which R ^X1 and R ^Y1 are H and R ^X1 is R ^X and R ^Y1 is R ^Y in the compound of formula (I), where Het corresponds to the sub-formula (id); or

(f) (iii) cyclization of a compound of formula XXVII, for example, in the presence of a Burgess reagent and / or preferably in a suitable solvent, to obtain a compound of formula (I), where Het corresponds to sub-formula (va); or

(g) reacting a compound of formula XVII with an amine of formula R ¹⁰ R ¹¹ NH under coupling conditions to give a compound of formula (I), where Het corresponds to sub-formula (ic) and R ^X is —CH ₂ C (O) NR ¹⁰ R ¹¹ (i.e., obtaining a compound of formula XVI), where this reaction is preferably carried out in the presence of a base, such as diisopropylethylamine, and / or preferably in a suitable solvent (for example, an organic solvent, preferably anhydrous), such as DMF and / or dichloromethane , and / or preferably in the presence of oxalylchlo reed; or

(h) converting a compound of formula XX into a compound of formula (1), wherein Het is a sub-formula (ic) and R ^x is —CH ₂ —NR ⁶ R ⁷ , where R ⁷ is C (O) R ¹⁷ ( that is, in a compound of formula XIX), preferably either by reacting a compound of formula XX with a carboxylic acid R ¹⁷ COOH in the presence of a coupling agent and / or by reacting a compound of formula XX with an activated derivative of the carboxyl group R ¹⁷ COOH (for example, R ¹⁷ C (O) Cl), preferably in the presence of a base and / or a suitable solvent; or

(i) reacting a compound of formula XX with sulfonyl chloride R ¹⁸ S (O) ₂ Cl to obtain a compound of formula (I), where Het corresponds to sub-formula (ic), and R ^x is —CH ₂ —NR ⁶ R ⁷ , where R ⁷ is —S (O) ₂ R ¹⁸ (i.e., to give a compound of formula XXII), preferably in the presence of a base such as triethylamine and / or pyridine, and / or preferably in a suitable solvent such as dichloromethane and / or chloroform ; or

(j) reacting a compound of formula XX, where R ⁶ = H, with an acid chloride of formula X ^J - (CH ₂ ) _n ⁵ -X ⁵ - (CH ₂ ) ( _n ⁶ _-1 ) -COCl, where X ¹ represents a leaving group (where X ^{J is} preferably a halogen atom or —O — SO ₂ —R ^J , where R ^J is C _1-4 alkyl, C _1-2 fluoroalkyl or phenyl optionally substituted with C _1-2 alkyl) to give a compound formula (I), where Het corresponds to the sub-formula (ic), and R ^X represents —CH ₂ —NR ⁶ R ⁷ , where R ⁶ and R ⁷ together represent - (CH ₂ ) _n ⁵ —X ⁵ - ( CH ₂ ) _n ⁶ -, where n ⁵ and n ⁶ independently represent 2 or 3, and where the ring formed by NR ⁶ R ⁷ is substituted with one oxo substituent (= O) at the carbon atom of (CH ₂ ) _n ⁶ , which is bonded to nitrogen (i.e., to give a compound of formula XXIII); where this interaction is preferably carried out in the presence of a base and / or in a suitable solvent and / or preferably followed by treatment with a base; or

(k) reacting a compound of formula XXV with R ^Y C (O) X ^K , where X ^K represents a leaving group, to obtain a compound of formula (I), where Het corresponds to sub-formula (iia) (i.e., to obtain a compound of formula XXIV ); or

(L) converting a compound of formula (I) or a salt thereof into another compound of formula (I) or a salt thereof;

and optionally converting a compound of formula (I) into a salt, for example a pharmaceutically acceptable salt.

Methods for preparing the salt may optionally be as described elsewhere in this specification.

Preferred features of methods (a), (b), (c), (d), (e), (f) (i), (f) (ii), (f) (iii), (9). (h), (i), (J), (k) and (L), independently of one another, are preferably as described above for Methods A, B, C, D, E, F, G, H, I, J, K and L with all the necessary changes that need to be made. For example, the conversion method (L) preferably includes or is one or more of one of the methods L1 to L10 described herein, for example, above.

In any of the methods, which comprises reacting a carboxylic acid and / or an activated carboxylic acid derivative with an amine to form an amide, this activated carboxylic acid derivative preferably contains a —C (O) X ¹¹ group instead of COOH, where X ¹¹ is a leaving group substituted amine. For example, X ¹¹ may be Cl (where activated derivative = acid chloride) or —OC (O) R (where activated derivative = anhydride). Alternatively, the activated carboxylic acid derivative may be an activated ester, wherein the leaving group X ¹¹ is

This last activated carboxylic acid derivative can be obtained from a carboxylic acid (X ¹¹ —OH) either;

(a) by reacting a carboxylic acid with a carbodiimide, such as EDC, which is 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide and is also 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, or a salt thereof for example, a hydrochloride salt, preferably followed by reaction of the resulting product with 1-hydroxybenzotriazole (HOBT); where the interaction (a) is usually carried out in the presence of a solvent (preferably anhydrous), such as dimethylformamide (DMF) or acetonitrile, and / or preferably under anhydrous conditions, and / or usually at room temperature (for example, from about 20 ° C to about 25 ° C); or:

(b) by reaction with 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or O- (7-azabenzotriazol-1-yl) -N, N, N hexafluorophosphate ', N'-tetramethyluronium (HATU), preferably in the presence of a base such as diisopropylethylamine ( ⁱ Pr ₂ NEt) = DIPEA), and usually in the presence of a solvent such as dimethylformamide (DMF) or acetonitrile, and / or preferably under anhydrous conditions , and / or usually at room temperature (for example, from about 20 ° C to about 25 ° C).

The present invention also provides: (m) a process for preparing a pharmaceutically acceptable salt of a compound of formula (I), comprising converting a compound of formula (I) or a salt thereof into its desired pharmaceutically acceptable salt.

The present invention also provides a compound of formula (I) or a salt thereof, prepared by the method as defined herein.

Medical use

The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal, such as a human. This compound or salt may be intended for use in the treatment and / or prophylaxis of any of the diseases / conditions described herein (for example, for use in the treatment and / or prophylaxis of an inflammatory and / or allergic disease in a mammal) and / or for use as an inhibitor phosphodiesterase, for example, for use as an inhibitor of phosphodiesterase-4 (PDE-4). "Therapy" may include treatment and / or prophylaxis.

Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament (eg, pharmaceutical composition) for the treatment and / or prophylaxis of any of the diseases / conditions described herein in a mammal, such as a human, for example, for treatment and / or prophylaxis an inflammatory and / or allergic disease in a mammal, such as a human.

Also provided is a method of treating and / or preventing any of the diseases / conditions described herein in a mammal (eg, a human) in need thereof, for example, a method for treating and / or preventing an inflammatory and / or allergic disease in a mammal (eg, a human) in need wherein comprising administering to a mammal (eg, a human) a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

Phosphodiesterase-4 inhibitors are considered useful in the treatment and / or prophylaxis of many different diseases / conditions, especially inflammatory and / or allergic diseases, in mammals such as humans, for example: asthma, chronic obstructive pulmonary disease (COPD) (e.g. chronic bronchitis and / or emphysema), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, non-specific ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome in adults, multiple sclerosis, cognitive disorders (for example, neurological disorders such as Alzheimer's disease), depression, or pain. Nonspecific ulcerative colitis and / or Crohn's disease are often combined under the name of inflammatory bowel disease.

In the treatment and / or prophylaxis, the inflammatory and / or allergic disease is preferably chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, or allergic rhinitis in a mammal (eg, a human). The treatment and / or prophylaxis of COPD or asthma in a mammal (e.g., human) is more preferred.

PDE-4 inhibitors are considered effective in treating asthma (e.g. see MAGiembycz, Drugs, Feb. 2000, 59 (2), 193-212; Z .-, Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438; HJDyke et al., Expert Opinion on Investigational Drugs, January 2002, 11 (1), 1-13; C. Burnout et al., Current Pharmaceutical Design, 2002, 8 (14), 1255-1296; AMDoherty, Current Opinion Chem. Biol., 1999, 3 (4), 466-473; and references cited therein).

PDE-4 inhibitors are considered effective in treating COPD (e.g. see SL Wolda, Emerging Drugs, 2000, 5 (3), 309-319; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438 ; HJDyke et al., Expert Opinion on Investigational Drugs, January 2002, 11 (1), 1-13; C. Burnouf et al., Current Pharmaceutical Design, 2002, 8 (14), 1255-1296; AMDoherty, Current Opinion Chem. Biol., 1999, 3 (4), 466-473; and references cited therein). COPD is often characterized by airflow obstruction due to chronic bronchitis and / or emphysema (SL Wolda, Emerging Drugs, 2000, 5 (3), 309-319).

PDE-4 inhibitors are considered effective in the treatment of allergic rhinitis (e.g. see B.M. Schmidt et al., J. Allergy & Clinical Immunology, 108 (4), 2001, 530-536).

PDE-4 inhibitors are considered effective in treating rheumatoid arthritis and multiple sclerosis (e.g. see HJDyke et al., Expert Opinion on Investigational Drugs, January 2002, 11 (1), 1-13; C. Burnouf et al., Current Pharmaceutical Design, 2002, 8 (14), 1255-1296; and AMDoherty, Current Opinion Chem. Biol., 1999, 3 (4), 466-473; and references cited therein). See, for example, A.M. Doherty, Current Opinion Chem. Biol., 1999, 3 (4), 466-473 and references cited therein for use in atopic dermatitis.

PDE-4 inhibitors have been proposed as having analgesic properties and are thus effective in the treatment of pain (A. Kumar et al., Indian J. Exp. Biol., 2000, 38 (1), 26-30).

In the present invention, treatment and / or prophylaxis may relate to a cognitive disorder, for example a cognitive disorder in a neurological disorder such as Alzheimer's disease. For example, treatment and / or prophylaxis may include improving cognitive ability, for example, with a neurological disorder. See, for example: H.T. Zhang et al., Psychopharmacology, June 2000, 150 (3), 311-316 and Neuropsychopharmacology, 2000, 23 (2), 198-204; and T. Egawa et al., Japanese J. Pharmacol., 1997, 75 (3), 275-81.

PDE-4 inhibitors, such as rolipram, have been proposed as having antidepressant properties (e.g. J. Zhu et al ,, CNS Drug Reviews, 2001, 7 (4), 387-398; O'Donnell, Expert Opinion on Investigation al Drugs, 2000, 9 (3), 621-625; and N.T. Zhang et al., Neuropsychopharmacology, October 2002, 27 (4), 587-595).

Pharmaceutical Compositions and Dosage

For use in medicine, the compounds of this invention are usually administered in the form of a pharmaceutical composition.

Thus, the present invention provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients thereof.

The pharmaceutical composition may be intended for use in the treatment and / or prophylaxis of any of the conditions described herein.

The present invention also provides a method for the manufacture of a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients,

comprising mixing a compound or salt with one or more pharmaceutically acceptable carriers and / or excipients.

The present invention also provides a pharmaceutical composition made by this method.

The compounds of formula (I) and / or the pharmaceutical composition can be administered, for example, by oral, parenteral (e.g., intravenous, subcutaneous or intramuscular), inhalation or nasal administration. Accordingly, the pharmaceutical composition is preferably suitable for oral, parenteral (e.g., intravenous, subcutaneous or intramuscular), inhalation or nasal administration. More preferably, the pharmaceutical composition is suitable for inhalation or oral administration, for example, to a mammal, such as a human. Inhalation administration includes topical administration to the lungs, for example, by aerosol or a dry powder composition. Oral administration to humans is most preferred.

A pharmaceutical composition suitable for oral administration may be liquid or solid; for example, it may be a syrup, suspension or emulsion, tablet, capsule or lozenge.

The liquid preparation should usually consist of a suspension or solution of the compound or a pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier (s), for example, an aqueous solvent such as water, ethanol or glycerol, or a non-aqueous solvent such like polyethylene glycol or oil. The preparation may also contain a suspending agent, preservative, flavoring agent and / or coloring agent.

In one preferred embodiment, the pharmaceutical composition is presented in unit dosage form, such as a tablet or capsule for oral administration, for example, for oral administration to humans.

A pharmaceutical composition suitable for oral administration in the form of a tablet may contain one or more pharmaceutically acceptable carriers and / or excipients suitable for the preparation of tablet preparations. The carrier may, for example, be or include lactose, cellulose (e.g. microcrystalline cellulose) or mannitol. The tablet may also, or instead, contain one or more pharmaceutically acceptable excipients, for example, a binding agent, such as hydroxypropyl methylcellulose or povidone (polyvinylpyrrolidone), a lubricating agent, for example alkaline earth metal stearate, such as magnesium stearate, and / or a tablet disintegrant, such as sodium starch glycolate, croscarmellose sodium or crospovidone (cross-linked polyvinylpyrrolidone). A pharmaceutical composition comprising a tablet may be prepared by a process comprising the steps of: (1) mixing a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers and / or excipients, (2 ) compressing the resulting mixture (which is usually in powder form) into tablets, and (3) optionally coating the tablet with a film coating material.

A pharmaceutical composition suitable for oral administration in the form of a capsule can be prepared using encapsulation techniques. For example, granules or powder containing the active ingredient (s) can be prepared using a suitable pharmaceutically acceptable carrier and then filled into a hard gelatin capsule. Alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutically acceptable carrier, for example aqueous gum or oil, and this dispersion or suspension can then be filled into a soft gelatin capsule.

The parenteral composition may contain a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil. Alternatively, this solution can be lyophilized; this lyophilized parenteral pharmaceutical composition can be reconstituted with a suitable solvent immediately prior to administration.

Compositions for nasal or inhalation administration can be easily formulated as aerosols, drops, gels, or dry powders.

Aerosol preparations, for example for inhalation administration, may contain a solution or a finely divided suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol preparations may be presented in single or multiple doses in sterile form in an airtight container, which may be in the form of a cartridge or a replaceable can for use with a nebulizer or inhaler. Alternatively, the sealed container may be a single metering device, such as a single dose nasal inhaler or aerosol dispenser equipped with a metering valve (metered dose inhaler), which is intended to be used until the contents of the container are completely consumed.

If the dosage form contains an aerosol dispenser, it preferably contains a suitable propellant under pressure, such as compressed air, carbon dioxide, or an organic propellant, such as chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC). Suitable CFC propellants include dichlorodifluoromethane, trichlorofluoromethane and dichlorotetrafluoroethane. Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane. Aerosol dosage forms may also be in the form of a pumpable nebulizer.

The reduction in particle size of the compounds of formula (I) or its salt

For pharmaceutical compositions suitable and / or adapted for inhalation administration, it is preferred that the compound or salt of formula (I) is in a form with a reduced particle size and, more preferably, this form with a reduced particle size is obtained or can be obtained by micronization. In micronization, usually the compound / salt is subjected to impact and friction forces in a high-speed circular or spiral / vortex air flow, often including a cyclone component. A preferred particle size (e.g., D50 value (average particle size)) of a reduced particle size (e.g., micronized) compound or salt is from about 0.5 to about 10 microns, e.g., from about 1 to about 5 microns (e.g., as measured when using laser diffraction). For example, it is preferable for a compound or salt of formula (I) to have a particle size defined as follows: D10 from about 0.3 to about 3 microns (e.g., about 1 microns), and / or D50 from about 1 to about 5 microns (e.g. about 2-5 or about 2-3 microns), and / or D90 from about 2 to about 20 microns, or from about 3 to about 10 microns (for example, about 5-8 or about 5-6 microns); for example, as measured using laser diffraction. Laser diffraction measurement can use the dry method (suspension of the compound / salt in the air stream crosses the laser beam) or the wet method [suspension of the compound / salt in a liquid dispersion medium such as isooctane or (for example, if the compound is soluble in isooctane) in 0.1% Tween 80 in water, crosses a laser beam]. In laser diffraction, the particle size is preferably calculated using the Fraunhofer calculation and / or the Malvern Mastersizer or Sympatec is preferably used for measurement.

The following is an illustrative non-limiting example of a small scale micronization process.

Micronization Example

Purpose: Micronize a compound of formula (I) or a salt thereof, in particular one of the Examples of this invention (described below), usually in an amount of about 600-1000 mg using a Jetpharma MC1 micronizer.

The starting (non-micronized) and micronized materials are analyzed for particle size by laser diffraction and crystallinity by powder X-ray diffraction (PXRD).

Equipment and material

Equipment / Material Description and specification Micronizer Jetpharma MC ₁ Nitrogen supply: the air collector with a pipe system to 1896.5 kPa (275 lb / ⁱⁿ²⁾ Analytical balance Sartorius analytical Laboratory balance Mettler PM400 Digital micrometer Micrometer VWR Electronic Vibrating spatula Auto-spat dispenser Micronization Materials (not yet submitted)

The Jetpharma MC1 micronizer includes a horizontal disk-shaped grinding box having: a tubular inlet for connecting (for example, at an angle of about 30 degrees to the horizontal) to receive a suspension of a non-micronized compound of formula (I) or salt in a gas stream, a separate gas inlet for gas, a channel a gas outlet for exhausting gases; and a collecting vessel for collecting micronized material. The grinding box has two compartments: an external annular compartment with a gas connection with a gas inlet, where this compartment is designed to receive compressed gas (for example, air or nitrogen), an internal disk-shaped grinding compartment inside the external compartment is coaxial with it for micronization of the incoming compound / salt, where these two compartments are separated by an annular wall. The annular wall (ring R) has many small-diameter holes connecting the inner and outer compartments and spaced circumferentially at a distance around the annular wall. These openings open at an angle to the inner compartment (partly radially and partly tangentially directed) and when used act as nozzles directing compressed gas from the outer compartment to the inner compartment at high speed and in an internal spiral (vortex) around the inner compartment (cyclone). The connection inlet is in a gas connection with the internal compartment through a nozzle directed tangentially to the internal compartment, within and around the annular wall. The upper and lower exits with a large diameter go to the central axis of the internal grinding compartment, connected to (a) (lower exit) a collector vessel that has no outlet for air, and (b) (upper exit) an outlet for gas, which leads to reservoir tank, filter and gas outlet. Inside the tubular inlet for connection, a venturi inlet pipe (V) moved along it is arranged for receiving gases. The connection inlet also has a branched connection with the upstream inlet for incoming material.

In use, the narrow head of the venturi (V) inlet is preferably located lower and slightly in front of the material inlet, so that when the venturi delivers compressed gas (such as air or nitrogen), the incoming material is sucked into the gas stream through the connection inlet and accelerates into the inner grinding compartment tangentially at almost the speed of sound. Inside the grinding compartment, the material is further accelerated to supersonic speed through a system of holes / nozzles around the ring (R) (ring-shaped wall) of the grinding compartment. The nozzles are slightly angled, so that the model of acceleration of the material has the form of an inwardly directed vortex or cyclone. The material inside the grinding compartment circulates quickly, and particle collisions occur during this process, causing large particles to crush into smaller ones. The “centrifugal” vortex acceleration causes large particles to remain at the periphery, while increasingly smaller particles move toward the center until they leave the grinding compartment, usually through the lower outlet at low pressure and at low speed. Particles that exit the grinding compartment are heavier than air and settle down through the lower outlet into the collecting vessel, while the exhaust gas rises (along with a small amount of small particles of micronized material) and enters the atmosphere at low pressure and at low speed.

Methodology

Collect micronizer. The venturi protrusion distance behind the inlet port is set to 1.0 cm, respectively (for example, so that the narrow head of the venturi is lower and slightly in front of the material inlet channel) and measured with a micrometer to ensure that it is inserted correctly. The pressure in the ring (R) and the venturi (V) is set in accordance with the values indicated in the experimental design (see below in the experimental section) by adjusting the pressure gauge valves on the micronizer. The installation is checked for leaks, observing whether there are any fluctuations in the readings of the pressure gauges.

It should be noted that the pressure in the venturi (V) is maintained at least 200 kPa (2 bar) higher than the pressure in the ring (R), in order to prevent the material from projecting, for example, outward from the material inlet.

The accuracy of the balance is checked using calibration weights. A specific amount of the starting material (see the section on the experiment) is weighed in a plastic cuvette. This material is then introduced into the micronizer using a vibrating spatula (for example, V-shaped in cross section) at a specific feed rate. During the micronization process, the feed time and pressure indicators in the equipment are monitored.

At the end of the micronization cycle, the nitrogen supply is stopped and the reservoir tank is opened to allow particles to settle in the collection / regeneration vessel at the bottom of the micronizer. The collector vessel is removed and set aside. The micronized powder in the regeneration vessel (collector vessel) and cyclone (above the regeneration vessel) is collected separately in different weighed and labeled bottles. The mass of micronized material is recorded. The micronizer is disassembled and the remaining PDE-4 compounds on the inner surface of the micronizer are washed off with a mixture of isopropyl alcohol and water 70/30 and collected in a flask. The micronizer is then thoroughly cleaned and wiped with a suitable solvent and dried until subsequent cycles.

Preferred Experimental Parameters

Used scales: Sartorius analytical

Venturi tube insertion depth: 10.0 mm

Method No. The amount of material introduced (g) Pressure in venturi (V) or ring (R) (kPa, bar) Target feed rate The time required for the supply of material (min + sec) Actual feed time (g / min) one 0.8795 g V = 1000kPa 200 mg / min 4 min 0.181 (10 bar) 51 sec g / min R = 600 kPa (6 bar) 2 0.9075 g V = 800kPa 200 mg / min 4 min 192 (8 bar) 43 sec mg / min R = 550 kPa (5.5 bar)

The above preferred or possible parameters can be varied using specialist knowledge.

Yield calculations

% yield = [(Material from the vessel + Material from the cyclone) / Amount of material introduced] × 100

In general, very approximately, using this method, yields of 50-75% are achievable.

Dry Powder Inhalable Compositions

For pharmaceutical compositions suitable and / or adapted for inhalation administration, it is preferred that the pharmaceutical composition is a dry powder inhalable composition. Such a composition may contain a powder base such as lactose or starch, a compound of formula (I) or a salt thereof (preferably in a reduced particle size form, for example in micronized form) and, optionally, a property modifier such as L-leucine, mannitol, trehalose and / or magnesium stearate. Preferably, the dry powder inhalable composition comprises a dry powder mixture of lactose and a compound of formula (I) or a salt thereof. Lactose is preferably lactose hydrate, for example lactose monohydrate, and / or preferably is an inhalation grade lactose or finely divided lactose. Preferably, the lactose particle size is defined as 90% or more (by weight or volume) of lactose particles with a diameter of less than 1000 microns (micrometers) (e.g. 10-1000 microns, e.g. 30-1000 microns) and / or 50% or more particles lactose with a diameter of less than 500 microns (e.g. 10-500 microns). More preferably, the lactose particle size is defined as 90% or more of lactose particles with a diameter of less than 300 microns (for example, 10-300 microns, for example 50-300 microns) and / or 50% or more of lactose particles with a diameter of less than 100 microns in diameter . Optionally, the lactose particle size is defined as 90% or more of lactose particles with a diameter of less than 100-200 microns and / or 50% or more of lactose particles with a diameter of less than 40-70 microns. Most importantly, it is preferred that from about 3 to about 30% (e.g., about 10%) (by weight or volume) of the particles have a diameter of less than 50 microns or less than 20 microns. For example, without limitation, lactose of a suitable inhalation grade is E9334 lactose (10% fine fraction) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands),

In a dry powder inhalable composition, it is preferable that the compound of formula (I) or its salt is present in an amount of from about 0.1% to about 70% (for example, from about 1% to about 50%, for example from about 5% to about 40% , for example from about 20 to about 30%) by weight of the composition.

Illustrative non-limiting example of a dry powder inhalable composition

Dry Powder Example

Obtaining a mixture of dry lactose powder

Using a compound of formula (I) or a salt thereof in a reduced particle size form, for example micronized (for example, as made in the above Micronization Example), a dry powder mixture is prepared by mixing the required amount of the compound / salt (for example, 10 mg, 1% wt. / wt.) with lactose of the inhalation grade containing 10% fine fraction (for example, 990 mg, 99% wt./wt.) in a vessel made of Teflon ™ (polytetrafluoroethylene) in a Mikro-dismembrator ball mill (but without ball bearing) at a speed ( approximately 2000-2500 rpm) for about 4 hours for each mixture concentration. The Mikro-dismembrator (commercially available from B. Braun Biotech International, Schwarzenberger Weg 73-79, D-34212 Melsungen, Germany; www.bbraunbiotech.com) contains a base with an upwardly projecting and vibrating arm that is connected to a vessel of Teflon ™. Vibration of the handle provides mixing.

Other mixtures: 10% w / w. compounds / salts (50 mg) + 90% wt./wt. lactose (450 mg, lactose of the inhalation grade, contains 10% fine fraction).

Serial dilution of 1% wt./wt. mixtures can provide, for example, 0.1% and 0.3% wt./wt. mixtures.

Dry powder inhalation devices

It is possible, in particular, for a dry powder inhalable composition, the pharmaceutical composition for inhalation administration can be included in various sealed dosage containers (for example, containing a dry powder composition) mounted longitudinally in a strip or tape inside a suitable inhalation device. This container can be opened or removed if necessary, and a dose of, for example, a dry powder composition can be administered by inhalation using a device such as the DISKUS device available on the market from GlaxoSmithKline. The DISKUS ™ inhalation device is usually essentially the same as described in GB 2242134A, and in such a device at least one container for the pharmaceutical composition in powder form (at least one container, preferably a plurality of sealed dosage containers mounted longitudinally in a strip or tape) is installed between two parts fastened to one another with the possibility of detachment; this device comprises: means for determining an opening position for the above at least one container; means for disconnecting the parts from each other according to the position for opening the container and an outlet channel communicating with the open container through which the user can inhale the pharmaceutical composition in powder form from this open container.

Standard dosage form and dosage regimens

Preferably, the composition is in unit dosage form, such as a tablet or capsule for oral administration, for example, for oral administration to humans.

In the pharmaceutical composition, one or each dosage unit for oral or parenteral administration preferably contains from 0.01 to 3000 mg, more preferably from 0.5 to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the free base. One or each dosage unit for nasal or inhalation administration preferably contains from 0.001 to 50 mg, more preferably from 0.01 to 5 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the free base.

The pharmaceutically acceptable compound or salt of this invention is preferably administered to a mammal (eg, a human) in a daily oral or parenteral dose of from 0.001 mg to 50 mg per kg of body weight per day (mg / kg / day), for example from 0.01 to 20 mg / kg / day, or from 0.03 to 10 mg / kg / day, or from 0.1 to 2 mg / kg / day, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the free base.

The pharmaceutically acceptable compound or salt of this invention is preferably administered to a mammal (eg, a human) in a daily nasal or inhalation dose of from 0.0001 to 5 mg / kg / day or from 0.0001 to 1 mg / kg / day, for example from 0.001 to 1 mg / kg / day, or from 0.001 to 0.3 mg / kg / day, or from 0.001 to 0.1 mg / kg / day, or from 0.005 to 0.3 mg / kg / day, the compounds of formula (I ) or a pharmaceutically acceptable salt thereof, based on the free base.

The pharmaceutically acceptable compounds or salts of this invention are preferably administered in a daily dose (for an adult patient), for example, an oral or parenteral dose of from 0.01 mg to 3000 mg per day or from 0.5 to 1000 mg per day, for example from 2 to 500 mg per day, or a nasal or inhalation dose from 0.001 to 300 mg per day, or from 0.001 to 50 mg per day, or from 0.01 to 30 mg per day, or from 0.01 to 5 mg per day, or 0.02 to 2 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the free base.

Combinations

The compounds, salts and / or pharmaceutical compositions of this invention can also be used in combination with another therapeutically active agent, for example a β ₂ -adrenoreceptor agonist, antihistamine, anti-allergic or anti-inflammatory agent.

Thus, the present invention provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent, for example a β ₂ -adrenoreceptor agonist, antihistamine, anti-allergic, anti-inflammatory agent or anti-infectious agent.

Preferably, the β ₂ -adrenoreceptor agonist is salmeterol (for example, in the form of a racemate or an individual enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, phenoterol or terbutaline or a salt thereof (for example, its pharmaceutically acceptable salt), for example xinaforol salt , a sulfate salt or a free base of salbutamol or a formoterol fumarate salt. Long-acting β ₂ -adrenoreceptor agonists are preferred, especially those that have a therapeutic effect longer than a period of 12 to 24 hours, such as salmeterol or formoterol. Preferably, the β ₂ -adrenoreceptor agonist is intended for inhalation administration, for example, once a day and / or for simultaneous inhalation administration; and more preferably, the β ₂ -adrenoreceptor agonist is in a reduced particle size form, for example, as defined herein.

Preferably, the combination of a β ₂ -adrenoreceptor agonist is intended for the treatment and / or prevention of COPD or asthma. Salmeterol or a pharmaceutically acceptable salt thereof, for example salmeterol xinafoate, is preferably administered to humans in an inhaled dose of 25 to 50 micrograms twice daily (based on the free base). The combination with a β ₂ -adrenoreceptor agonist may be as described in WO 00/12078.

Preferred long-acting β ₂ -adrenoreceptor agonists include those described in WO 02 / 066422A, WO 03/024439, WO 02/070490 and WO 02/076933.

Particularly preferred long-acting β ₂ -adrenoreceptor agonists include compounds of formula (X) (described in WO 02/066422) (it should be noted that R groups are defined there independently of the corresponding R groups of formula (I)):

or their salts or solvates, where in the formula (X):

m is an integer from 2 to 8;

n is an integer from 3 to 11,

provided that m + n is from 5 to 19,

R ¹¹ represents —XSO ₂ NR ¹⁶ R ¹⁷ where X represents - (CH ₂ ) _p - or C _2-6 alkenylene;

R ¹⁶ and R ^{17 are} independently selected from hydrogen, C _1-6 alkyl, C _3-7 alkaloalkyl, C (O) NR ¹⁸ R ¹⁹ , phenyl and phenyl (C _1-4 alkyl) -,

or R ¹⁶ and R ¹⁷ together with the nitrogen to which they are attached form a 5-, 6- or 7-membered nitrogen-containing ring, and R ¹⁶ and R ^{17 are} each optionally substituted with one or two groups selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkoxy, —CO ₂ R ¹⁸ , —SO ₂ NR ¹⁸ R ¹⁹ , —CONR ¹⁸ R ¹⁹ , —NR ¹⁸ C (O) R ¹⁹ or a 5-, 6- or 7-membered heterocyclic ring;

R ¹⁸ and R ^{19 are} independently selected from hydrogen, C _1-6 alkyl, C _1-6 cycloalkyl, phenyl and phenyl (C _1-4 ) alkyl-; and

p is an integer from 0 to 6, preferably from 0 to 4;

R ¹² and R ^{13 are} independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo, phenyl and C _1-6 haloalkyl; and

R ¹⁴ and R ^{15 are} independently selected from hydrogen and C _1-4 alkyl, provided that the total number of carbon atoms in R ¹⁴ and R ¹⁵ does not exceed 4.

Preferred β ₂ -adrenoreceptor agonists disclosed in WO 02/066422 include:

3- (4 - {[6 - ({((2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide and

3- (3 - {[7 - ({((2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} amino) heptyl] oxy} propyl) benzenesulfonamide.

A preferred β ₂ -adrenoreceptor agonist disclosed in WO 03/024439 is:

4 - {(1R) -2 - [(6- {2 - [(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol.

The combination of a compound of formula (I) or a salt with an antihistamine agent is preferably intended for oral administration (for example, in the form of a combination composition, such as a combination tablet) and can be used to treat and / or prevent allergic rhinitis. Examples of antihistamines include metapyrene or H ₁ antagonists such as cetitridine, loratadine (e.g., Clarityn ™), desloratadine (e.g., Clarinex ™), or fexofenadine (e.g., APedga ™).

In a further aspect, the invention also provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic compound, for example, a muscarinic (M) receptor antagonist, in particular an M ₁ , M ₂ , M ₁ / M ₂ receptor antagonist or M ₃ receptors, more preferably with an antagonist of M ₃ receptors, even more preferably with an antagonist of M ₃ receptors, which is a selective antagonist (for example, is 10 or more times stronger antagonist) of M ₃ receptors compared with M ₁ and / or M ₂ receptors. For combinations of anticholinergic compounds / muscarinic (M) receptor antagonist with PDE-4 inhibitors see, for example, WO 03/011274 A2 and WO 02/069945 A2 / US 2002/0193393 A1 and US 2002/052312 A1, and some or all of them of these publications are examples of anticholinergic compounds / muscarinic (M) receptor antagonists that can be used with compounds of formula (I) or salts, and / or suitable pharmaceutical compositions. For example, a muscarinic receptor antagonist may include or be an ipratropium salt (e.g. ipratropium bromide), an oxytropium salt (e.g. oxytropium bromide) or more preferably a tiotropium salt (e.g. tiotropium bromide), see, for example, tiotropium in EP418716A1.

An anticholinergic compound or muscarinic receptor antagonist, for example, an M ₃ receptor antagonist, is preferably intended for inhalation administration, more preferably in a reduced particle size form, for example, as defined herein. More preferably, both the muscarinic (M) receptor antagonist and the compound of formula (I) or a pharmaceutically acceptable salt thereof are intended for inhalation. Preferably, the anticholinergic compound or muscarinic receptor antagonist and the compound of formula (I) or salt are intended for simultaneous administration. The combination with a muscarinic receptor antagonist is preferably intended for the treatment and / or prevention of COPD.

Other suitable combinations include, for example, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another anti-inflammatory agent, such as an anti-inflammatory corticosteroid; or a non-steroidal anti-inflammatory drug (NSAID), such as a leukotriene antagonist (e.g., montelukast), an INOS inhibitor (inducible NO synthase), a tryptase inhibitor, an elastase inhibitor, a beta-2 integrin antagonist, a2-adenosine antagonist, CCR3 antagonist or 5-lipoxygenase inhibitor; or with an anti-infective agent (e.g., antibiotic or antiviral). The iNOS inhibitor is preferably intended for oral administration. Suitable iNOS inhibitors (inhibitors of inducible nitric oxide synthase) include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. Suitable CCR3 inhibitors include those disclosed in WO 02/26722.

In a combination containing a compound of formula (1) or a pharmaceutically acceptable salt thereof together with an anti-inflammatory corticosteroid (which is preferably intended for the treatment and / or prevention of asthma, COPD or allergic rhinitis), the anti-inflammatory corticosteroid is preferably fluticasone, fluticasone propionate (for example, see patent US 4335121), beclomethasone, beclomethasone 17-propionate ester, beclomethasone 17.21-dipropionate ester, dexamethasone or its ester, mometasone or its ester ir, cyclesonide, budesonide, flunisolide or a compound as described in WO 02/12266 A1 (for example, as claimed in any one of claims 1 to 22 in this document), or a pharmaceutically acceptable salt of any of the above. If the anti-inflammatory corticosteroid is a compound as described in WO 02/12266 A1, then preferably it is Example 1 of this document {which is 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] - 11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioacids} or Example 41 from this document {which is 6α, 9α-difluoro-11β-hydroxy-16α- S-fluoromethyl ester methyl-17α - [(4-methyl-1,3-thiazole-6-carbonyl) oxy] -3-oxo-androsta-1,4-diene-17β-carbothioacids} or its pharmaceutically acceptable th salt. The anti-inflammatory corticosteroid is preferably intended for intranasal or inhalation administration. Fluticasone propionate is preferred and is preferably intended for inhalation administration to a person either (a) at a dose of 250 micrograms once a day, or (b) at a dose of 50 to 250 micrograms twice a day.

Also provided is a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β ₂ -adrenoreceptor agonist and anti-inflammatory corticosteroid, for example, as described in WO 03/030939 A1. Preferably, this combination is intended for the treatment and / or prophylaxis of asthma, COPD and / or allergic rhinitis. The β ₂ -adrenoreceptor agonist and / or anti-inflammatory corticosteroid may be as described above and / or as described in WO 03/030939 A1. Most preferably, in this triple combination, the β ₂ -adrenoreceptor agonist is salmeterol or a pharmaceutically acceptable salt thereof (eg, salmeterol xinafoate), and the anti-inflammatory corticosteroid is fluticasone propionate.

The combinations described above can conveniently be presented for use in the form of a pharmaceutical composition, and thus a pharmaceutical composition comprising a combination as defined above, together with one or more pharmaceutically acceptable carriers and / or excipients, is another aspect of the invention.

Individual compounds from such combinations can be administered either sequentially or simultaneously in a separate or combined pharmaceutical composition.

In one embodiment, the combination, as defined here, can be intended for simultaneous inhalation administration and is placed in a combination inhalation device. Such a combined inhalation device constitutes another aspect of the invention. Such a combined inhalation device may comprise a combined pharmaceutical composition for simultaneous inhalation administration (for example, a dry powder composition), a composition containing all individual compounds of this combination, and a composition included in a plurality of sealed dosage containers mounted longitudinally in a strip or tape inside the inhalation device, moreover, these containers can be opened or removed from them if necessary; for example, such an inhalation device may be substantially as described in GB 2242134A (DISKUS ™) and / or as described above. Alternatively, the combined inhalation device may be such that individual compounds from the combination can be administered simultaneously, but stored separately (either fully or partially stored separately for triple combinations), for example, in separate pharmaceutical compositions, for example as described in PCT / EP03 / 00598 filed January 22, 2003 (for example, as described in the claims of this document, for example in paragraph 1).

The invention also provides a method for producing a combination as defined herein, wherein

(a) preparing a separate pharmaceutical composition for administration of individual combination compounds, either sequentially or simultaneously or

(b) preparing a combination pharmaceutical composition for administering individual compounds from the combination at the same time,

where this pharmaceutical composition comprises a combination together with one or more pharmaceutically acceptable carriers and / or excipients.

The invention also provides a combination as defined herein, prepared by a method as defined herein.

METHODS OF BIOLOGICAL TESTING

Methods of primary analysis of PDE-3, PDE-4 V, PDE-40, PDE-5, PDE-6

The activity of the compounds can be measured in the assay methods shown below. Preferred compounds of the invention are selective PDE-4 inhibitors, i.e. they inhibit PDE-4 (e.g., PDE-4 B and / or PDE-40, preferably PDE-4 B) more than they inhibit PDE-3, and / or stronger than they inhibit PDE-5, and / or stronger than they inhibit PDE-6.

PDE enzyme sources and references

Human recombinant PDE-4B, in particular its 2B splicing variant (HSPDE4B2B), is disclosed in WO 94/20079, as well as in M.M. McLaughlin et al., "A low Km, rolip ram-sensitive, cAMP-specific phosphodiesterase from human brain: cloning and expression of cDNA, biochemical characterization of recombinant protein, and tissue distribution of mRNA ", J. Biol. Chem., 1993, 268, 6470-6476. Human recombinant PDE-4 B is described as being expressed in a PDE deficient strain of Saccharomyces cerevisiae GL62 yeast. The supernatant fractions of yeast cell lysates obtained at 100,000 g are described for use in collecting PDE-4 B enzyme.

Human recombinant PDE-40 (HSPDE4D3A) is disclosed in PABaecker et al., "Isolation of cDNA encoding a human rolipram-sensitive cyclic AMP phosphodiesterase (PDE IV _D )", Gene, 1994, 138, 253-256.

Human recombinant PDE-5 is disclosed in K. Loughney et al., "Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3 ', 5'-cyclic nucleotide phosphodiesterase", Gene, 1998, 216, 139 -147.

PDE-3 was purified from bovine aorta as described by H. Coste and P. Grondin, "Characterization of a novel potent and specific inhibitor of type V phosphodiesterase", Biochem. Pharmacol., 1995, 50, 1577-1585.

PDE-6 was purified from bovine retina as described in P. Catty and P. Deterre, "Activation and solubilization of the retinal cGMP-specific phosphodiesterase by limited proteolysis", Eur. J. Biochem., 1991, 199, 263-269; A. Tar et al. "Purification of bovine retinal cGMP phosphodiesterase", Methods in Enzymology, 1994, 238, 3-12 and / or D. Srivastava et al. "Effects of magnesium on cyclic GMP hydrolysis by the bovine retinal rod cGMP phosphodiesterase", Biochem. J., 1995, 308, 653-658.

Inhibition of PDE-3, PDE-4 V, PDE-40, PDE-5 or PDE-6 activity: radioactive scintillation proximity assay (SPA)

The ability of the compounds to inhibit the catalytic activity of PDE-4 B or -4D (human recombinant), PDE-3 (from the bovine aorta), PDE-5 (human recombinant) or PDE-6 (from the bovine retina) was determined by analysis of scintillation proximity (SPA) in 96-well format. Test compounds (preferably as a solution in DMSO, for example, in a volume of about 2 microliters (μl)) were pre-incubated at ambient temperature (room temperature, for example 19-23 ° C) in Wallac Isoplates (code 1450-514) with PDE enzyme in 50 mM Tris-HCl buffer, pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EGTA (ethylene bis (hydroxyethylene nitrile) -tetraacetic acid), 0.05% (w / v) bovine serum albumin in within 10-30 minutes (usually 30 minutes). The concentration of the enzyme was regulated so that in the control wells without compound during the incubation, the substrate was hydrolyzed, as defined below, by no more than 20%. For PDE-3, PDE-4V- and PDE-4D-added analysis [5 ', 8- ³ H] adenosine 3'5'-cyclic phosphate (Amersham Pharmacia Biotech, TRK.559 code or Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles, Buckinghamshire HP8 4SP, UK) yielding 0.05 mCi per well and a final concentration of -10 nM. For PDE 5 and PDE assays were added 6- [8- ³ H] guanosine 3'5'-cyclic phosphate (Amersham Pharmacia Biotech, TRK.392 code) to yield 0.05 mCi per well and a final concentration of -36 nM. Plates, for example, containing approximately 100 μl of the assay volume, were mixed on an orbital shaker for 5 minutes and incubated at ambient temperature for 1 hour. To stop the analysis, phosphodiesterase SPA granules (Amersham Pharmacia Biotech, code RPNQ 0150) (~ 1 mg per well) were added. The tablets were sealed and shaken, and then left to stand at ambient temperature for a period of time from 35 minutes to 1 hour (preferably 35 minutes) to allow granules to settle. Bound radioactive product was measured using a WALLAC TR1LUX 1450 Microbeta scintillation counter. For inhibition curves, 10 concentrations (1.5 nM - 30 μM) of each compound were analyzed. Curves were analyzed using ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU 7QB, United Kingdom). The results were expressed as pIC ₅₀ values.

As an alternative to the above radioactive SPA assay, the inhibition of PDE-4B or PDE-40 can be measured in the following fluorescence polarization analysis (FP, Fluorescence Polarization):

Inhibition of PDE-4 B or PDE-40 Activity: Fluorescence Polarization Analysis (FP)

The ability of the compounds to inhibit catalytic activity on PDE-4B (human recombinant) or PDE-40 (human recombinant) was determined by IMAP polarization of fluorescence (IMAP Explorer kit from Molecular Devices Corporation, Sunnydale, CA, USA; Molecular Devices code: R8062) in 384 well format. In IMAP FP analysis, PDE activity can be measured in the format of a homogeneous non-radioactive analysis. FP analysis uses the ability of immobilized trivalent metal cations deposited on nanoparticles (tiny granules) to bind the phosphate group FI-AMP, which is formed by hydrolysis of fluorescein-labeled (FI) cyclic adenosine monophosphate (FI-cAMP) to the non-cyclic form of FI-AMP. FI-cAMP does not bind. The binding of the FI-AMP product to granules (coated with immobilized trivalent cations) slows the rotation of the bound FI-AMP and increases the ratio of the polarization of fluorescence of parallel light to perpendicular. Inhibition of PDE reduces / inhibits this increase in signal.

Test compounds (small volume, for example from 0.5 to 1 μl, preferably about 0.5 μl, of a solution in DMSO) were pre-incubated at ambient temperature (room temperature, for example 19-23 ° C) in black 384-well microtiter plates (supplier NUNC, code 262260) with PDE enzyme in 10 mM Tris-HCl buffer, pH 7.2, 10 mM MgCl ₂ , with 0.1% (w / v) bovine serum albumin and 0.05% NaN ₃ for 10-30 minutes. The enzyme level was established experimentally, so that the reaction throughout the incubation was linear. Fluorescein-adenosine-3 ', 5'-cyclic phosphate (from Molecular Devices Corporation, Molecular Devices code: R7091) was added to give a final concentration of approximately 40 nM (final analysis volume typically of approximately 20-40 μl, preferably about 20 μl). The plates were mixed on an orbital shaker for 10 seconds and incubated at ambient temperature for 40 minutes. Added IMAP binding reagent (as described above, from Molecular Devices Corporation, Molecular Devices code: R7207) (60 μl of a 1: 400 dilution of the stock solution from the kit in binding buffer) to stop the analysis. The tablets were left to stand at ambient temperature for 1 hour. The ratio of polarization fluorescence (FP) of parallel light to perpendicular was measured using an Analyst ™ plate reader (from Molecular Devices Corporation). For inhibition curves, 10 concentrations (1.5 nM - 30 μM) of each compound were analyzed. Curves were analyzed using ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU 7QB, United Kingdom). The results were expressed as pIC ₅₀ values.

In the FP assay, all reagents were dosed using Multidrop ™ (commercially available from Thermo Labsystems Oy, Ratastie 2, PO Box 100, Vantaa 01620, Finland).

For a given PDE-4 inhibitor, the inhibition values of PDE-4 B (or PDE-40) measured using SPA and FP assays may vary slightly. However, it was found that in the regression analysis of 100 test compounds, the inhibition pIC ₅₀ values measured using SPA and FP analyzes are generally consistent within 0.5 logarithmic units for PDE-4 V and PDE-40 (linear regression coefficient of 0.966 for PDE-4 V and 0.971 for PDE-40; David R. Mobbs et al., "Comparison of the IMAP Fluorescence Polarization Assay with the Scintillation Proximity Assay for Phosphodiesterase Activity", poster presentation presented at the 2003 Molecular Devices UK & Europe User Meeting , 2 ^nd October 2003, Down Hall, Harlow, Essex, United Kingdom).

The biological data obtained for some compounds of Examples (PDE-4B inhibitory activity, either as a single read, or as an average of about 2-6 readings), are as follows based on the present measurements. In each of the SPA and FP analyzes, absolute measurement accuracy is not possible, and the read data is accurate only up to ± 0.5 logarithmic units inclusive, depending on the number of readings and averaged readings:

Example Number pIC50 PDE-4V (± about 0.5) 6 8.1 10 8.2 12 7.9 fourteen 7.6 23 8.1 24 8.2 35 7.5 42 8.3 7, 43, 48, 60, 61 and 64 from 6.6 to 7.2 2, 17, 26, 34, 38, 39, 44, 50, 59, 62, 63, 66, 71, 76, 77 and 84 from 7.5 to 9.1

Many, but not all, of the compounds of the Examples were tested for the inhibition of PDE-4 B. Of the compounds of the Examples tested for the inhibition of PDE-4 B, some were tested by radioactive SPA analysis, some were tested by FP analysis.

Most or essentially all of the compounds of Examples 1-45, 47-55, 57-81, 83 and 84 have inhibitory activity against PDE-4 In the range from pIC ₅₀ = about 6 (± about 0.5) to about 9 , 1 (± 0.5).

Compounds of Examples where R ³ = cyclohexyl (NHR ³ or NR ³ R ^3a = subformula (c)), tetrahydro-2H-pyran-4-yl (NHR ³ or NR ³ R ^3a = group (h)), or some others types of substituted cyclohexyl, or some heterocycles, or compounds of Examples where NHR ³ or NR ³ R ^3a = sub-formula (s) usually or often (based on data for R ¹ = ethyl) have a higher selectivity for PDE- 4 V when compared with PDE-5, as measured in the above enzyme inhibition assays, when compared with the selectivities of comparable compounds of Examples, where R ³ = cyclopropyl (NHR ³ or NR ³ R ^3a = sub-formula (b)).

Vomiting: Some known PDE-4 inhibitors may cause vomiting and / or nausea to a greater or lesser extent (e.g. see Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438, see in particular pages 433-434 and references cited there). Therefore, it would be preferable, but not essential, if the particular PDE-4 inhibiting compound or salt of this invention caused only limited or controlled emetic side effects. Vomiting side effects can, for example, be measured by the ability of a compound or salt to induce vomiting when administered to ferrets; for example, the time to occurrence, the degree, frequency and / or duration of vomiting, vomiting and / or cramps in ferrets can be measured after oral or parenteral administration of the compound or salt. See, for example, in in vivo assay 4 in the description below, a method for measuring the anti-inflammatory effect, emetic side effects and therapeutic index (TI) of a ferret. Also see, for example, A. Robichaud et al., "Emesis induced by inhibitors of [PDE IV] in the ferret", Neuropharmacology, 1999, 38, 289-297, erratum Neuropharmacology, 2001, 40, 465-465. However, it is possible that vomiting side effects and the therapeutic index (T1) in rats can be conveniently measured by monitoring perverse appetite in the eating behavior of rats after administration of the compound or salt of the invention (see in vivo assay 2 below).

Other side effects: Some known PDE-4 inhibitors may cause other side effects, such as headache and other central nervous system (CNS)-mediated side effects and / or gastrointestinal (GI) disorders. Therefore, it would be preferable, but not essential, if the particular PDE-4 inhibiting compound or salt of the invention would cause only limited or controlled side effects in one or more of one of these categories of side effects.

In vivo biological assays

The in vitro PDE-4 B enzyme inhibition assay described above should be considered as a primary test for biological activity. However, additional in vivo biological tests are described which are possible and which are not a necessary measure of effectiveness or side effects.

In vivo assay 1. LPS-induced (lipopolysaccharide) pulmonary neutrophilia in rats: effect of orally administered PDE-4 inhibitors

The influx of neutrophils into the lungs has been shown to be an important component for a family of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), which may include chronic bronchitis and / or emphysema (GFFilley, Chest. 2000; 117 (5); 251s-260s ) The purpose of this neutrophilia model is to study the potentially anti-inflammatory in vivo effects of orally administered PDE-4 inhibitors against neutrophilia induced by inhalation of aerosol lipopolysaccharide (LPS), which is a model of the neutrophilic inflammatory component (s) of COPD. For a scientific basis, see the Literature section below.

Male Lewis rats (Charles River, Raleigh, NC, USA) weighing approximately 300-400 grams are pretreated with either (a) a test compound suspended in 0.5% methylcellulose (available from Sigma-Aldrich, St. Louis, MO, USA) in water, or (b) only with a vehicle orally delivered in a dose volume of 10 ml / kg. In general, dose-response curves are obtained using the following doses of PDE-4 inhibitors: 10.0, 2.0, 0.4, 0.08 and 0.016 mg / kg. Thirty minutes after pretreatment, rats are exposed to aerosol LPS (E. coli 026: B6 serotype obtained by trichloroacetic acid extraction available from Sigma-Aldrich, St. Louis, MO, USA) formed in a nebulizer containing 100 μg / ml LPS solution. Rats are exposed to LPS aerosol at a rate of 4 L / min for 20 minutes. The LPS is carried out in a closed chamber with internal dimensions: length 45 cm × width 24 cm × height 20 cm. The nebulizer and the chamber for exposure are contained in a proven fume hood. 4 hours after exposure to LPS, rats were euthanized by an overdose of phenobarbital in an amount of 90 mg / kg administered intraperitoneally. Bronchoalveolar lavage (BAL) is performed through a blunt needle of size 14 into the exposed trachea. Five washes of 5 ml are carried out to collect a total of 25 ml of BAL fluid. BAL fluids are used to calculate the total number of cells and the difference in leukocyte counts in order to calculate the influx of neutrophils into the lung. The percent neutrophilic inhibition for each dose is calculated (compared to the carrier) and a sigmoidal slope dose response curve is obtained, usually using a Prism Graph-Pad. The dose-response curve is used to calculate the ED50 value (dose effective in 50% of cases) (in mg per kg body weight) for inhibiting LPS-induced neutrophilia by a PDE-4 inhibitor.

Results: Based on the measurement data of the compounds of Examples 14, 17, 23, 35 and 38, administered orally in the above procedure, showed ED 50 values for neutrophilia inhibition ranging from about 0.03 mg / kg to about 1 mg / kg, taking into account the errors testing.

Alternative method and results: In an alternative embodiment of this technique, rats are given single oral doses of 10 mg / kg or 1.0 mg / kg of a PDE-4 inhibitor (or vehicle), and the percent neutrophilia inhibition for this particular dose is calculated and recorded. In this embodiment, based on the present measurements, the compounds of Examples 2, 14, 23 and 38, administered orally in the above procedure in a single dose of 1.0 mg / kg, showed a percentage of neutrophilia inhibition in the range of from about 74% to about 86%, taking into account the errors testing.

Literature:

Filley G. F. Comparison of the structural and inflammatory features of COPD and asthma. Chest. 2000; 117 (5) 251s-260s.

Howell RE, Jenkins LP, Fielding LE and Grimes D. Inhibition of antigen-induced pulmonary eosinophilia and neutrophilia by selective inhibitors of phosphodiesterase types 3 and 4 in brown Norway rats. Pulmonary Pharmacology. 1995: 8: 83-89.

Spond J, Chapman R, Fine J, Jones H, Kreutner W, Kung TT, Minnicozzi M. Comparison of PDE inhibitors, Rolipram and SB 207499 (Ariflo ™) in a rat model of pulmonary neutrophilia. Pulmonary Pharmacology and Therapeutics. 2001; 14: 157-164.

Underwood DC, Osborn RR, Bochnowicz S, Webb EF, Rieman DJ, Lee JC, Romanic AM, Adams JL, Hay DWP and Griswold DE. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9 and fibrosis in lung. Am J Physio! Lung Cell Mol Physiol. 2000; 279: L895-L902.

In vivo analysis 2. Vomiting model in appetite rats

BACKGROUND: In various in vitro and in vivo models, selective PDE-4 inhibitors have been shown to inhibit inflammation by increasing intracellular cAMP levels of many immune cells (e.g., lymphocytes, monocytes). However, vomiting is a side effect of some PDE-4 inhibitors in many species. Due to the fact that many rat models of inflammation are well characterized, they were used in methods (see, for example, the above-described in vivo assay 1) to show the beneficial anti-inflammatory effects of PDE-4 inhibitors. However, rats do not have an emetic response (they do not have an emetic reflex), so it is difficult to directly investigate the relationship between the beneficial anti-inflammatory effects of PDE-4 inhibitors and vomiting directly in rats.

However, in 1991, Takeda et al. (see section Literature below) showed that the answer in the form of perverse nutrition in rats is similar to vomiting. Distorted nutrition is a behavioral response to a disease in rats in which rats eat non-nutritive substances such as earth or, in particular, clay (such as kaolin) that can help adsorb toxins. Perverse nutrition can be induced by bowel movements and chemicals (in particular chemicals that cause vomiting in humans) and can be inhibited pharmacologically by drugs that inhibit vomiting in humans. In the rat perverted appetite model, in in vivo assay 2, the rat perverted appetite response to PDE-4 inhibition at pharmacologically relevant doses can be determined in parallel with in vivo anti-inflammatory assays in (in a separate group) rats (for example, the in vivo assay described above one). The anti-inflammatory and perverted appetite analyzes of the same species together can provide data on the “therapeutic index” (TI) of the rat compounds / salts of the invention. Rat TI can, for example, be calculated as the ratio of a) a dose of ED50 of a potential emetic response in the form of a perverted appetite from analysis 2 to b) a rat anti-inflammatory dose of ED50 (for example, measured on the basis of rat neutrophilia inhibition, for example, in in vivo analysis 1), where higher TI ratios may indicate less vomiting at many anti-inflammatory doses. This may allow the selection of a non-vomiting or minimally vomiting pharmaceutical dose of the compounds or salts of the invention that has an anti-inflammatory effect. However, it is understood that the achievement of a minimally vomiting compound that is inhibitory to PDE-4 is not essential to the present invention.

Methodology: On the first day of the experiment, rats are individually placed in cells without litter or "enrichment". Rats are kept away from the floor of the cage using wire mesh. Pre-weighed feeders containing standard rat food and clay granules are placed in the cage. Clay pellets supplied by Languna Clay Co, City of Industry, CA, USA have the same size and shape as feed pellets. Rats get used to clay within 72 hours, during which time feeders and feed, as well as clay waste, are weighed daily on electronic scales capable of weighing to the nearest 0.1 gram. At the end of this 72-hour period of habituation, rats, as a rule, do not show interest in clay granules.

At the end of 72 hours, the rats are placed in clean cages and the feeders are weighed. Rats that continue to regularly consume clay are excluded from the study. Immediately before the dark cycle (the time when the animals are active and should be fed), the animals are divided into treatment groups and they are orally given the dose of the compound / salt of the invention (different doses for different treatment groups) or one vehicle in a dose volume of 2 ml / kg. At this oral dosage, the compound / salt is in the form of a suspension in 0.5% methylcellulose (supplied by Sigma-Aldrich, St. Louis, MO, USA) in water. On the next day, feed, clay feeders and feeders and cell wastes are weighed and the total clay and feed consumed by each individual animal during that night are calculated.

The response to the dose is calculated, firstly, by translating the data into a response with a finite number of possible values, where the animals have either a positive or negative response in the form of a perverted appetite. A rat is “appetite-positive” if it consumes an amount of clay that is more than or equal to 0.3 grams above the average, which is usually calculated using the logistic regression performed by the Statistica software package for processing statistical data. Then, the ED50 value of the response can be calculated as perverse appetite in mg per kg body weight.

The ED50 value of the perverted appetite response can be compared with the ED50 values of neutrophilia inhibition for the same compound administered orally to the rat (as measured by the above in vivo Analysis 1), so that the Therapeutic Index (TI) in rats can be calculated as follows:

In general, the Therapeutic Index (T1) calculated in this way often differs substantially from, for example, it can often be significantly higher than the T1 (D20 / D50) calculated in ferrets (see in vivo Analysis 4 below).

Results: Using the method described above and according to the present measurements, the compounds of Examples 14, 17, 23, 35 and 38 showed an ED50 response in the form of a perverted appetite in the range from about 2 mg / kg to a value of more than about 50 mg / kg, taking into account the test errors . Given the specific ED50 values of the perverted appetite response for these compounds, together with the specific ED50 values of rat neutrophilia inhibition measured in the in vivo analysis 1 for examples 14, 17, 23, 35 and 38, Therapeutic Index (TI) in rats for oral administration the compounds of Examples 14, 17, 23, 35 and 38 were calculated using the above equation, as being in the range from about 12 to about 470, in accordance with these measurements, taking into account testing errors.

Literature

Beavo JA, Contini, M., Heaslip, R.J. Multiple cyclic nucleotide phosphodiesterases. Mol Pharmacol. 1994; 46: 399-405.

Spond J, Chapman R, Fine J, Jones H, Kreutner W, Kung TT, Minnicozzi M. Comparison of PDE inhibitors, Rolipram and SB 207499 (Ariflo ™) in a rat model of pulmonary neutrophilia. Pulmonary Pharmacology and Therapeutics. 2001; 14: 157-164.

Takeda N, Hasegawa S, Morita M, and Matsunaga T. Pica in rats is analogous to emesis: an animal model in emesis research. Pharmacology, Biochemistry and Behavior. 1991; 45: 817-821.

Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A and Matsunaga T. Neuropharmacological mechanisms of emesis. I. Effects of antiemetic drugs on motion- and apomorphine-induced pica in rats. Meth Find Exp Clin Pharmacol. 1995; 17 (9) 589-596.

Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A and Matsunaga T. Neuropharmacological mechanisms of emesis. I. Effects of antiemetic drugs on cisplatin-induced pica in rats. Meth Find Exp Clin Pharmacol. 1995; 17 (9) 647-652.

In vivo assay 3. LPS-induced pulmonary neutrophilia in rats: effect of intratracheally administered PDE4 inhibitors

This analysis is an animal model of pulmonary inflammation - specific lipopolysaccharide-induced neutrophilia (LPS) - and allows us to investigate the alleged inhibition of such neutrophilia (anti-inflammatory effect) intratracheally (i.t.) by PDE-4 inhibitors. PDE-4 inhibitors are preferably in the form of a dry powder or liquid suspension. Intratracheal administration is one of the models of inhalation administration that enables local delivery to the lung.

Animals: Male CD rats (originating from Sprague Dawley) supplied by Charles River, Raleigh, NC, USA were kept in groups of 5 rats per cage, acclimatized after delivery for at least 7 days, regularly changing bedding / nesting material, fed SDS diet with R1 granular feed, optional, and provided with pasteurized drinking water of veterinary purity, replaced daily.

Dry Powder Injection Device: Disposable 3-channel tap between dosing needle and syringe. A 3-channel sterile valve (Vycon Ref 876.00) was weighed, then a drug mixture or inhalation-grade lactose (control carrier) was added to this valve, the valve was closed to prevent drug loss and reweighed to determine the weight of the drug in the valve. After dosing, the tap was again weighed to determine the mass of the drug that had left the tap. A Sigma Z21934-7 syringe needle 19 of size 152 mm (6 inches) with a Luer sleeve was technically cut to approximately 132 mm (5.2 inches), the end was blunted to prevent damage to the rat trachea, and the needle was weighed before and after drug delivery, to make sure that after dosing the medicine is not left in the needles.

Device for introducing a liquid suspension: This device is similar to the one described above, but a blunt dosing needle was used, the straight end of which was slightly at an angle to the axis of the needle, with a flexible plastic removable cannula inserted into the needle.

Drugs and substances: Lipopolysaccharide (LPS) (serotype: 0127: B8) (L3129 series 61K4075) is dissolved in phosphate buffered saline (PBS). PDE-4 inhibitors are used in a reduced particle size form (i.e. in micronized form), for example, in accordance with the Micronization Example above. For the administration of the drug in the form of a dry powder, the Example of a dry powder preparation described above containing a drug and inhaled lactose may be used. Commonly used lactose of the inhalation grade (Series E98L4675 Lot 845120) contains 10% fine fraction (10% of a particle size of less than 15 microns measured with a Malvern particle size analyzer).

Liquid suspensions of a drug can be prepared by adding the necessary volume of carrier to the drug; wherein the carrier used is a saline / tween mixture (0.2% tween 80). This liquid suspension is sonicated for 10 minutes before use.

Preparation and dosage of PDE-4 inhibitor: Rats were anesthetized by placing animals in an airtight Perspex chamber and exposing them to a gas mixture of isoflurane (4.5%), nitric oxide (3 liters, minute ^-1 ) and oxygen (1 liter, minute ^-1 ) Immediately after anesthesia, the animals were placed on a stainless steel support table providing intratracheal dosing. They were placed on their backs at an angle of approximately 35 °. Light was tilted to the outside of the throat to illuminate the trachea more strongly. They opened their mouths and made visible the beginning of the upper respiratory tract. The technique varies with the introduction of a liquid suspension and a dry powder of PDE-4 inhibitors as follows.

Dosing a liquid suspension: A removable cannula was inserted through a blunt metal dosing needle, which was carefully inserted into the rat trachea. Animals were given intratracheally a PDE-4 carrier or inhibitor via a dosing needle with a new internal cannula used for each different group of drugs. The drug was injected slowly (10 seconds) into the trachea using a syringe attached to a dosing needle.

Dosing of dry powder: A device with a three-channel valve and a needle was inserted into the rat trachea to a predetermined point, the location of which was set approximately 1 cm above the primary bifurcation. Another operator holds the needle in the indicated position, while 2 × 4 ml of air is delivered through a three-channel valve by squeezing syringes (ideally coinciding with the inhalation of the animal) to push the entire amount of medicine from the valve. After dosing, the needle and tap are removed from the respiratory tract and the tap is closed to prevent any residual drug from escaping from the tap.

After administering a dose of a wet suspension or dry powder, the animals are removed from the table and constantly observed until they recover from the action of anesthesia. Animals are returned to their cages for free and provided with free access to food and water; they are observed and noted by any unusual changes in behavior.

Exposure to LPS: Approximately 2 hours after intratracheal administration of a dose of a control vehicle or PDE-4 inhibitor, animals were placed in sealed Perspex containers and exposed to LPS aerosol (concentration in a nebulizer of 150 μg ml ^-1 ) for 15 minutes. LPS aerosols were obtained using a nebulizer (DeVilbiss, USA) and sent to a Perspex chamber for exposure. After a 15-minute period of exposure, LPS animals were returned to their cages for free and provided free access to both food and water.

[In an alternative embodiment, rats may be exposed to LPS less than 2 hours after intratracheal dosing. In another alternative embodiment, rats can be exposed to LPS more than 2 hours (for example, about 4 or about 6 hours) after intratracheal dosing of the carrier or PDE-4 inhibitor to check if the PDE-4 inhibitor has a long duration of action (which is not significant)].

Bronchoalveolar lavage: 4 hours after exposure to LPS, the animals were sacrificed by an overdose of sodium pentobarbitone (intraperitoneally). The trachea was cannulated with a polypropylene tube and lung lavage (rinsing) was performed with 3x5 ml heparinized (25 U ml ^-1 ) phosphate buffered saline (PBS).

Counting neutrophilic cells: Samples from bronchoalveolar lavage (BAL) were centrifuged at 1300 rpm for 7 minutes. The supernatant was removed and the resulting cell pellet was resuspended in 1 ml of PBS. A cell microscopic preparation of the resuspension liquid was prepared by placing 100 μl of the resuspended BAL liquid in the cell centrifugation holders, and then centrifuged at 5000 rpm for 5 minutes. Microscopic preparations were allowed to air dry and then stained with Leishman dye (20 minutes) to allow differential cell counting. The total number of cells was also counted from resuspension. Based on these two counts, the total neutrophil counts in the BAL were determined. To measure the inhibition of neutrophilia induced by a PDE-4 inhibitor, the number of neutrophils in rats treated with a vehicle and rats treated with PDE-4 inhibitors was compared.

By varying the dose of the PDE-4 inhibitor used at the dosing stage (for example, from 0.2 or 0.1 mg of the PDE-4 inhibitor per kg of body weight up to about 0.01 mg / kg), a dose-response curve can be obtained.

In vivo assay 4. Assessment of the therapeutic index of orally administered PDE-4 inhibitors in a conscious ferret

1.1 Materials

The following materials are used for these studies.

PDE-4 inhibitors are prepared for oral (po) administration by dissolving acetone in a fixed volume (1 ml) and then adding cremophor to 20% of the final volume. Acetone is evaporated by directing a stream of nitrogen gas to the solution. After removal of acetone, the solution was adjusted to a final volume with distilled water.

LPS is dissolved in phosphate buffered saline.

1.2 Animals

Male ferrets (Mustela Pulorius Furo, weight 1-2 kg) are transported and allowed to acclimatize for at least 7 days. The diet includes SDS diet C, with optional granular food, and Whiskers ™ cat food, given 3 times a week. The animals are provided with pasteurized drinking water of veterinary purity, which is replaced daily.

1.3 Protocol (s) of the experiment (s)

1.3.1 Dosing of PDE-4 inhibitors

PDE-4 inhibitors are administered orally (n / a) using a dose volume of 1 ml / kg. Ferrets are fasted overnight, but allow free access to water. Animals are orally given a dose of a PDE-4 carrier or inhibitor using a 15 cm dosing needle that is passed down the back of the throat into the esophagus. After dosing, animals are returned to cages equipped with Perspex doors to allow observation and free access to water. Animals are constantly monitored and recorded for any episodes of vomiting (urge to vomit and vomit) or changes in behavior. Animals are given access to food 60-90 minutes after oral dosing.

1.3.2 Impact of LPS

30 minutes after oral dosing, the ferret compound or carrier control is placed in sealed Perspex containers and exposed to LPS aerosol (30 μg / ml) for 10 minutes. LPS aerosols are obtained using a nebulizer (DeVilbiss, USA) and sent to a Perspex chamber for exposure. After a 10-minute exposure period, the animals are returned to their cages for free and given free access to water and, at a later stage, to food. General monitoring of the animals continues for at least 2.5 hours after oral dosing. All episodes of vomiting and changes in behavior are recorded.

1.3.3 Bronchoalveolar lavage and cell counts

Six hours after exposure to LPS, animals are sacrificed by an overdose of sodium pentobarbitone administered intraperitoneally. Then the trachea is cannulated with a polypropylene tube and lung lavage is performed twice in 20 ml of heparinized (10 units / ml) phosphate-buffered saline (PBS). Samples from bronchoalveolar lavage (BAL) are centrifuged at 1300 rpm for 7 minutes. The supernatant was removed and the resulting cell pellet was resuspended in 1 ml of PBS. A cell smear of the resuspended fluid is prepared and stained with a Leishman dye to allow differential cell counting. Counting the total number of cells is carried out using the remaining resuspended sample. Based on this, the total number of neutrophils in the BAL sample is determined.

1.3.4 Pharmacodynamic indicators

The following parameters are recorded:

a)% inhibition of LPS-induced pulmonary neutrophilia to determine the dose of a PDE-4 inhibitor that causes 50% inhibition (D50);

b) episodes of vomiting - count the number of vomiting and retching to determine the dose of PDE-4 inhibitor, which causes 20% of cases of vomiting (D20);

c) then, for each PDE-4 inhibitor, the therapeutic index (TI) is calculated using this analysis using the following equation:

It should be noted that the therapeutic index (TI) calculated using this in vivo assay 4 is often significantly different from, for example, often significantly lower than the TI (50/50) rats calculated using 1 + 2 analyzes of oral inflammation and food perversion in rats.

The calculation of TI using the PDE-4 inhibitor roflumilast in this analysis 4 is:

D20 for vomiting = 0.46 mg / kg p / o, D50 for neutrophilia in ferrets = 0.42 mg / kg p / o, TI in ferrets = 1.1.

All publications, including patents and patent applications cited in this description, but not limited to, are included in this description of the invention by reference, as if each individual publication was specifically and individually indicated to be included here by reference in full.

EXAMPLES

Various aspects of this invention will now be described with reference to the following examples. These examples are purely illustrative and should not be construed as limiting the scope of this invention. The “intermediates” in this section are the syntheses of intermediates intended for use in the synthesis of “Examples”.

Abbreviations Used Here

Bemp 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphazine Cdi 1,1'-carbonyldiimidazole DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DXM dichloromethane DMF dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate Et ₂ O diethyl ether Edc 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride h clock Hobt Hydroxybenzotriazole = 1-hydroxybenzotriazole Hatu O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate HBTU O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate HPLC high performance liquid chromatography JHMS liquid chromatography / mass spectroscopy Mecn acetonitrile Meoh methanol NMR nuclear magnetic resonance (in which: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, n H means that n represents the number of protons)

Dipa N, N-diisopropylethylamine ( ⁱ Pr ₂ NEt) TFE solid phase extraction TBTU tetrafluoroborate O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium THF tetrahydrofuran tret retention time (in LCMS) those thin layer chromatography Lawesson's reagent 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide Burgess reagent (methoxycarbonylsulfamoyl) triethylammonium hydroxide Room temperature = ambient temperature: it is usually in the range from about 15 ° C to about 25 ° C or from about 20 ° C to about 25 ° C.

The hardware methods used here are:

LCMS (liquid chromatography / mass spectroscopy) Waters ZQ mass spectrometer operating in the mode of electrospray of positive ions, mass range 100-1000 atomic mass units

UV wavelength: 215-330 nm

Column: 3.3 cm × 4.6 mm inner diameter (ID), 3 μm ABZ + PLUS

Flow rate: 3 ml / min

Injection volume: 5 μl

Solvent A: 95% acetonitrile + 0.05% formic acid

Solvent B: 0.1% formic acid + 10 mM ammonium acetate

Gradient: 0% A / 0.7 min, 0-100% A / 3.5 min, 100% A / 1.1 min, 100-0% A / 0.2 min

Mass Controlled Auto Preparative HPLC

The preparative column used was Supelcosil ABZplus (10 cm × 2.12 cm) (typically 10 cm × 2.12 cm × 5 μm).

UV wavelength: 200-320 nm

Flow: 20 ml / min

Injectable volume: 1 ml or more preferably 0.5 ml

Solvent A 0.1% formic acid (or 0.1% trifluoroacetic acid)

Solvent B: 95% acetonitrile + 5% (formic acid or trifluoroacetic acid) or more typically 99.95% acetonitrile + 0.05% (formic acid or trifluoroacetic acid)

Gradient: 100% A / 1 min, 100-80% A / 9 min, 80-1% A / 3.5 min, 1% AL, 4 min, 1-100% A / 0.1 min

Microwave

The CEM Discover CEM focused microwave synthesis system was used.

Intermediates and Examples

All reagents not described in detail in the text below are commercially available from well-known suppliers such as Sigma-Aldrich. The addresses of the suppliers for some of the starting materials mentioned below in the Intermediates and Examples or higher in the Analyzes are as follows:

- ABCR GmbH & CO. KG, P.O. Box 21 01 35, 76151 Karlsruhe, Germany,

- Aceto Color Intermediates (catalog name), Aceto Corporation, One Hollow Lane, Lake Success, NY, 11042-1215, USA,

- Acros Organics, A Division of Fisher Scientific Company, 500 American Road, Morris Plains, NJ 07950, USA,

- Apin Chemicals Ltd., 82 C Milton Park, Abingdon, Oxon 0X14 4RY, United Kingdom,

- Apollo Scientific Ltd., Unit 1A, Bingswood Industrial Estate, Whaley Bridge, Derbyshire SK23 PLY, United Kingdom,

- Aldrich (catalog name), Sigma-Aldrich Company Ltd., Dorset, United Kingdom, telephone: +44 1202 733114; Fax: +44 1202 715460; ukcustsv@eurnotes.sial.com; or

- Aldrich (catalog name), Sigma-Aldrich Corp., P.O. Box 14508, St. Louis, MO 63178-9916, USA; telephone: 314-771-5765; fax: 314-771-5757; custserv@sial.com; or

- Aldrich (catalog name), Sigma-Aldrich Chemie Gmbh, Munich, Germany; telephone: +498965130; Fax: +498965131169; deorders@eurnotes.sial.com.

- Alfa Aesar, A Johnson Matthey Company, 30 Bond Street, Ward Hill, MA 01835-8099, USA,

- Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles, Buckinghamshire HP8 4SP, United Kingdom,

-Array Biopharma Inc., 1885 33rd Street, Boulder, CO 80301, USA,

- AstaTech, Inc., 8301 TorresdaleAve., 19C, Philadelphia, PA 19136, USA,

- Austin Chemical Company, Inc., 1565 Barclay Blvd., Buffalo Grove, IL 60089, USA,

- Avocado Research, Shore Road, Port of Heysham Industrial Park, Heysham Lancashire LA3 2XY, United Kingdom,

- BayerAG, Business Group Basic and Fine Chemicals, D-51368 Leverkusen, Germany,

- Berk Univar pie, Berk House, P.O. Box 56, Basing View, Basingstoke, Hants RG21 2E6, United Kingdom,

- Butt Park Ltd., Braysdown Works, Peasedown St. John, Bath BA2 8LL, United Kingdom,

- Chemical Building Blocks (catalog name), Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France,

- ChemBridge Europe, 4 dark's Hill Rise, Hampton Wood, Evesham, Worcestershire WR11 6FW, United Kingdom,

- ChemService Inc., P.O. Box 3108, West Chester, PA 19381, USA,

- Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego, CA 92126, USA,

- Dynamit Nobel GmbH, Germany; Also available from: Saville Whittle Ltd (Dynamit Nobel agents in the UK), Vickers Street, Manchester M40 8EF, United Kingdom,

- E. Merck, Germany; or E. Merck (Merck Ltd), Hunter Boulevard, Magna Park, Lutterworth, Leicestershire LEI 7 4XN, United Kingdom,

- Esprit Chemical Company, Esprit Plaza, 7680 Matoaka Road, Sarasota, FL 34243, USA,

- Exploratory Library (catalog name), Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France,

- Fluka Chemie AG, Idustriestrasse 25, P.O. Box 260, CH-9471 Buchs, Switzerland,

- Fluorochem Ltd., Wesley Street, Old Glossop, Derbyshire SK13 7RY, United Kingdom,

- ICN Biomedicals, Inc., 3300 Hyland Avenue, Costa Mesa, CA 92626, USA,

- Interchim Intermediates (catalog name), Interchim, 213 Avenue Kennedy, BP 1140, Montlucon, Cedex, 03103, France,

- Key Organics Ltd., 3, Highfield Industrial Estate, Camelford, Cornwall PL32 9QZ, United Kingdom,

- Lancaster Synthesis Ltd., Newgate, White Lund, Morecambe, Lancashire LA3 3DY, United Kingdom,

- Manchester Organics Ltd., Unit 2, Ashville Industrial Estate, Sutton Weaver, Runcorn, Cheshire WA7 3PF, United Kingdom,

- Matrix Scientific, P.O. Box 25067, Columbia, SC 29224-5067, USA,

- Maybridge Chemical Company Ltd., Trevillett, Tintagel, Cornwall PL34 OHW, United Kingdom,

- Maybridge Reactive Intermediates (catalog name), Maybridge Chemical Company Ltd., Trevillett, Tintagel, Cornwall PL34 OHW, United Kingdom,

- MicroChemistry Building Blocks (catalog name), MicroChemistry-RadaPharma, Shosse Entusiastov 56, Moscow, 111123, Russia,

- Miteni S.p.A., Via Mecenate 90, Milano, 20138, Italy,

- Molecular Devices Corporation, Sunnydale, CA, USA,

- N.D. Zeiinsky Institute, Organic Chemistry, Leninsky prospect 47, 117913 Moscow B-334, Russia,

- Optimer Building Blocks (catalog name), Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA,

- Peakdale Molecular Ltd., Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak SK23 OPG, United Kingdom,

- Pfaltz & Bauer, Inc., 172 East Aurora Street, Waterbury, CT 06708, USA,

- Rare Chemicals (catalog name), Rare Chemicals GmbH, Schulstrasse 6, 24214 Gettorf, Germany,

- SALOR (catalog name) (Sigma Aldrich Library of Rare Chemicals), Aldrich Chemical Company Inc, 1001 West Saint Paul Avenue, Milwaukee, Wl 53233, USA,

- Sigma (catalog name), Sigma-Aldrich Corp., P.O. Box 14508, St. Louis, MO 63178-9916, USA; see "Aldrich" above for other addresses outside the US and other contact details,

- SIGMA-RBI, One Strathmore Road, Natick, MA 01760-1312, USA,

- Synchem OHG Heinrich-Plett-Strasse 40, Kassel, D-34132, Germany,

- Syngene International Pvt Ltd, Hebbagodi, Hosur Road, Bangalore, India,

- TCI America, 9211 North Harborgate Street, Portland, OR 97203, USA,

- TimTec Building Blocks A, TimTec, Inc., P 0 Box 8941, Newark, DE 19714-8941, USA,

- Trans World Chemicals, Inc. 14674 Southlawn Lane, Rockville, MD 20850, USA,

- Ubichem PLC, Mayflower Close, Chandlers Ford Industrial Estate, Eastleigh, Hampshire S053 4AR, United Kingdom,

- Ultrafine (UFC Ltd.), Synergy House, Guildhall Close, Manchester Science Park, Manchester M15 6SY, United Kingdom.

Intermediate 1: Ethyl 4-chloro-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylate

Prepared from commercially available 5-amino-1-ethylpyrazole as described in G. Yu et. al. J. Med Chem., 2001,44,1025-1027:

Intermediate 2: Ethyl 4- (cyclopentylamino) -1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylate

Intermediate 1 (0.051 g) and cyclopentylamine (0.019 g) were suspended in ethanol (2 ml) and triethylamine (0.14 ml) was added. This mixture was stirred under a nitrogen atmosphere and heated at 80 ° C. for 16 hours. After cooling to room temperature, ethanol was removed by evaporation in a stream of nitrogen and the residue was partitioned between DCM and water. The organic layer was applied directly to a TFE cartridge (silica, 5 g) and was eluted sequentially when used; (1) DCM, (2) DCM: Et ₂ O (2: 1), (3) DCM: Et ₂ O (1: 1), (4) Et ₂ O, (5) EtOAc, and (6) MeOH. Fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 2 (0.074 g). LCMS showed MH ⁺ = 303; T _RET = 3.45 min.

Intermediate 3: 4- (cyclopentylamino) -1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid

A solution of Intermediate 2 (2.2 g) in ethanol: water (95: 5, 16.85 ml) was treated with sodium hydroxide (1.2 g) and heated at 50 ° C. for 16 hours. This mixture was concentrated in vacuo and the residue was redissolved in water (0.85 ml). This solution was acidified to pH 4 using acetic acid and the resulting white precipitate was collected by filtration and dried in vacuo to give Intermediate 3 (1.9 g). LCMS showed MH ⁺ = 275; T _RET = 2.65 min.

Intermediate 4: N'-Acetyl-4- (cyclopentylamino) -1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carbohydrazide

Intermediate 3 (0.066 g), EDC (0.06 g) and HOBT (0.035 g) were suspended in DMF (2 ml) and this mixture was stirred for 15 minutes. Then, acetic hydrazide (0.02 g) was added and the mixture was stirred under nitrogen for 18 hours. The solvents were removed by concentration in vacuo and the residue was partitioned between DCM and water. The layers were separated and the organic phase was washed with saturated aqueous sodium bicarbonate, then concentrated and applied to a TFE cartridge (aminopropyl, 1 g) which was eluted with methanol. Concentration in vacuo gave Intermediate 4 (0.043 g). LCMS showed MH ⁺ = 331; T _RET = 2.38 min.

Intermediate 5: 4- (cyclopentylamino) -1-ethyl-N '- [(methylsulfonyl) acetyl] -1H-pyrazolo [3,4-b] pyridine-5-carbohydrazide

Intermediate 3 (0.12 g), EDC (0.12 g) and HOBT (0.072 g) were suspended in DMF (2 ml) and stirred for 15 minutes. Then, intermediate 8 (0.082 g) was added and the mixture was stirred under nitrogen for 18 hours. The reaction was incomplete, so an additional portion of Intermediate 8 (0.040 g) was added and stirring was continued for an additional 66 hours. Solvents were removed in vacuo and the residue was partitioned between DXM and water. The aqueous phase was further extracted with DCM and the combined organic layers were applied onto a TFE cartridge (silica, 5 g), which was eluted successively with a gradient of Et ₂ O: MeOH (1: 0, 9: 1, 8: 2, 7: 3 and 6: 4 ) Fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 5 (0.154 g). LCMS showed MH ⁺ = 409; T _RET = 2.42 min.

Intermediate 6: Ethyl 4- (4-fluorophenylamino) -1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylate

Intermediate 1 (0.051 g) and 4-fluoroaniline (0.024 g) were suspended in ethanol (2 ml) and triethylamine (0.14 ml) was added. This mixture was stirred under a nitrogen atmosphere and heated at 80 ° C. for 16 hours. After cooling to room temperature, ethanol was removed by evaporation in a stream of nitrogen and the residue was partitioned between DCM and water. The organic layer was applied directly to a TFE cartridge (silica, 5 g) and was eluted sequentially using: (1) DCM, (2) DCM: Et ₂ O (2: 1), (3) DCM: Et ₂ O (1: 1), (4) Et ₂ O, (5) EtOAc, (6) MeOH. Fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 6 (0.077 g), LCMS showed MH ⁺ = 328; T _RET = 3.36 min.

Intermediate 7: 4- (cyclopentylamino) -1-ethyl-N- [methyl] -1H-pyrazolo [3,4-b] pyridine-5-carbohydrazide

Intermediate 3 (0.10 g) was dissolved in DMF (2 ml) and treated with HBTU (0.136 g) and DIPEA (0.116 g). A separate portion of Intermediate 3 (0.10 g) was dissolved in DMF (2 ml) and treated with EDC (0.096 g) and HOBT (0.058 g). Both of the resulting suspensions were stirred in a nitrogen atmosphere for 15 minutes, then methylhydrazine (0.017 g) was added to each, and stirring was continued in a nitrogen atmosphere for 18 hours. These mixtures were independently concentrated in vacuo and the residues were partitioned between DCM and water. The organic layers were concentrated and each was applied onto a TFE cartridge (aminopropyl, 2 g), which was eluted with methanol and then 10% ammonia in methanol. Thus obtained, two portions of Intermediate 7 were combined (0.16 g). LCMS showed MH ⁺ = 303; T _RET = 2.22 min.

Intermediate 8: Methanesulfonylacetic Acid Hydrazide

Prepared from commercially available ethyl methylsulfonyl acetate as described by D.E. Bays et. al. in EP 50407:

Intermediate 9: Acetamidoxime

Can be obtained from aqueous hydroxylamine and acetonitrile as described by J.J. Sahbari et. al. in WO 00/032565.

Intermediate 10: 4- (Cyclopentylamino) -1-ethyl-N'-isobutyryl-1H-pyrazolo [3,4-b] pyridine-5-carbohydrazide

Intermediate 3 (0.060 g), EDC (0.06 g) and HOBT (0.035 g) were suspended in DMF (2 ml) and stirred under nitrogen for 15 minutes. Then, isobutyric acid hydrazide (0.027 g) was added and the mixture was stirred under nitrogen for 18 hours. The solvents were removed in vacuo and the residue was partitioned between DCM and water. The organic phase was washed with saturated aqueous sodium bicarbonate, then concentrated in vacuo and applied to a TFE cartridge (aminopropyl, 1 g), which was eluted with methanol. Concentration in vacuo afforded Intermediate 10. LCMS showed MH ⁺ = 359; T _RET = 2.70 min.

Intermediate 11: 4-Chloro-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid

A solution of Intermediate 1 (3.5 g) in dioxane (28 ml) was treated with potassium hydroxide (6.3 g) as a solution in water (20 ml). This mixture was stirred for 2 hours, then concentrated in vacuo, acidified to pH 3 with 2 M aqueous hydrochloric acid and extracted with ethyl acetate. The layers were separated, the organic layer was dried over sodium sulfate, then concentrated in vacuo to give Intermediate 11 as a white solid (2.4 g). LCMS showed MH ⁺ = 226; T _RET = 2.62 min.

Intermediate 12: 4-Chloro-1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridine

Intermediate 11 (0.4 g) was dissolved in thionyl chloride (3 ml) and this mixture was heated at reflux (95 ° C) with stirring for 1 h. After cooling to room temperature, the excess thionyl chloride was removed by evaporation under reduced pressure and the resulting solid the substance was dissolved in anhydrous acetonitrile (2 ml). This solution was added to a solution of acetic hydrazide (0.145 g) and diisopropylethylamine (0.465 ml) in anhydrous acetonitrile (2 ml) and this mixture was stirred for an additional 2 hours. The mixture was concentrated in vacuo and the residue was directly treated with phosphorus oxychloride (4 ml). The resulting solution was stirred and heated at reflux (120 ° C) for 0.5 h, then left to cool and purified on Biotage (silica, 40 g), eluting with cyclohexane: EtOAc (1: 1) to give Intermediate 12 (0.32 g). LCMS showed MH ⁺ = 264; T _RET = 2.55 min.

Intermediate 13: 4-Chloro-1-ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridine

Intermediate 11 (0.05 g) was dissolved in thionyl chloride (1 ml) and this mixture was heated at reflux (95 ° C) with stirring for 1 h. After cooling to room temperature, the excess thionyl chloride was removed by evaporation under reduced pressure and the resulting solid the substance was dissolved in anhydrous acetonitrile (0.5 ml). This solution was added to a solution of isobutyric acid hydrazide (0.025 g) and diisopropylethylamine (0.058 ml) in anhydrous acetonitrile (1 ml) and this mixture was stirred for an additional 1.5 hours. The mixture was concentrated in vacuo and the residue was directly treated with phosphorus oxychloride (2 ml). The resulting solution was stirred and heated at reflux (120 ° C) for 2 hours, then left to cool and concentrated in vacuo. The residue was applied to a TFE cartridge (silica, 5 g), which was eluted successively with a gradient of EtOAc: cyclohexane (1) 1:16, (2) 1: 8, (3) 1: 4, (4) 1: 2, (5 ) 1: 1 and (6) 1: 0. Fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 13 (0.049 g). LCMS showed MH ⁺ = 29.2; T _RET = 2.96 min.

Intermediate 14: 5- (5-tert-Butyl-1,3,4-oxadiazol-2-yl) -4-chloro-1-ethyl-1H-pyrazolo [3,4-b] pyridine

Intermediate 11 (0.40 g) was dissolved in thionyl chloride (3 ml) and this mixture was heated at reflux (95 ° C) with stirring for 1 h. After cooling to room temperature, the excess thionyl chloride was removed by evaporation under reduced pressure and the resulting solid the substance was dissolved in anhydrous acetonitrile (2 ml). This solution was added to a solution of pivalic acid hydrazide (0.228 g) and diisopropylethylamine (0.465 ml) in anhydrous acetonitrile (2 ml) and this mixture was stirred for an additional 1.5 hours. The mixture was concentrated in vacuo and the residue was directly treated with phosphorus oxychloride (5 ml). The resulting solution was stirred and heated at reflux (120 ° C) for 1.5 h, then left to cool, concentrated in vacuo and purified on Biotage (silica, 40 g), eluting with a mixture of petroleum ether (40/60): EtOAc ( 1: 1) to give Intermediate 14 (0.388 g). LCMS showed MH ⁺ = 306; T _RET = 3.14 min.

Intermediate 15: 4-Chloro-1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridine

Intermediate 11 (0.68 g) was dissolved in thionyl chloride (4 ml) and this mixture was heated at reflux (95 ° C) with stirring for 1 h. After cooling to room temperature, excess thionyl chloride was removed by evaporation under reduced pressure and the resulting solid the substance was dissolved in anhydrous acetonitrile (3 ml). This solution was added dropwise over 5 minutes to a solution of Intermediate 8 (0.504 g) and diisopropylethylamine (0.787 ml) in anhydrous acetonitrile (12 ml) and this mixture was then stirred for another 1 hour. The mixture was concentrated in vacuo and the residue was directly treated with phosphorus oxychloride. (8 ml). The resulting solution was stirred and heated at reflux (120 ° C) for 2.5 h, then left to cool, concentrated in vacuo and purified on Biotage (silica, 40 g), eluting first with petroleum ether (40/60): EtOAc ( 2: 1), then petroleum ether (40/60): EtOAc (1: 1). Fractions containing the desired material were combined, concentrated in vacuo, and the residue was further purified by trituration with diethyl ether to give Intermediate 15 (0.41 g). LCMS showed MH ⁺ = 342; T _RET = 2.46 min.

Intermediate 16: Ethyl-1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carboxylate

Intermediate 1 (0.20 g) and triethylamine (0.55 ml) were suspended in ethanol (8 ml) and 4-aminotetrahydropyran was added (Intermediate 21, 0.088 g). This mixture was stirred under nitrogen, heated at 80 ° C for 16 hours, then concentrated in vacuo. The residue was partitioned between DCM and water. The layers were separated and the organic layer was applied directly to a TFE cartridge (silica, 5 g), which was eluted sequentially using: (1) DCM, (2) DCM: Et ₂ O (2: 1), (3) DCM: Et ₂ O (1: 1), (4) Et ₂ O and (5) EtOAc. Fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 16 (0.21 g). LCMS showed MH ⁺ = 319; T _RET = 2.93 min.

Intermediate 17: 1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid

A solution of Intermediate 16 (0.21 g) in ethanol: water (95: 5, 10 ml) was treated with sodium hydroxide (0.12 g). This mixture was heated at 50 ° C for 8 hours, then concentrated in vacuo, dissolved in water and acidified to pH 4 with acetic acid. The resulting white solid was removed by filtration and dried in vacuo to give Intermediate 17 as an off-white solid (0.16 g). LCMS showed MH ⁺ = 291; T _RET = 2.11 min.

An alternative preparation of Intermediate 17 is as follows.

A solution of Intermediate 16 (37.8 g) in ethanol: water (4: 1, 375 ml) was treated with sodium hydroxide (18.9 g). This mixture was heated at 50 ° C for 5 hours, then concentrated in vacuo, dissolved in water and acidified to pH 2 with aqueous hydrochloric acid (2 M). The resulting white solid was removed by filtration and dried in vacuo to give Intermediate 17 as an off-white solid (29.65 g). LCMS showed MH ⁺ = 291; T _RET = 2.17 min.

Intermediate 18: tert-Butyl-2 - {[1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] carbonyl} hydrazinecarboxylate

A suspension of Intermediate 17 (1.48 g), EDC (1.34 g) and HOBT (0.83 g) in DMF (20 ml) was stirred at room temperature for 30 minutes. Then, tert-butyl carbazate (0.68 g) was added and stirring was continued under nitrogen for an additional 66 hours. This mixture was concentrated in vacuo and the residue was partitioned into two portions for purification. Each portion was applied to a TFE cartridge (aminopropyl, 10 g), which was eluted with methanol, and the combined eluates were concentrated in vacuo. Additional purification was carried out on Biotage (silica, 40 g) with elution with a mixture of cyclohexane: ethyl acetate (1: 4). Fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 18 (1.39 g). LCMS showed MH ⁺ = 405; T _RET = 2.64 min.

Intermediate 19: 1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carbohydrazide dihydrochloride

Intermediate 18 (1.39 g) was treated with 4 M hydrochloric acid in dioxane (8 ml) and this mixture was stirred under nitrogen for 1 h. Concentration in vacuo gave Intermediate 19 as a white solid (1.17 g) ) LCMS showed MH ⁺ = 305; T _RET = 2.04 min.

Intermediate 20: LH- (cyclopropylcarbonyl) -1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-carbohydrazide

A solution of Intermediate 19 (0.045 g) in THF (2 ml) was treated with DIPEA (0.045 ml), then cyclopropylcarbonyl chloride (0.013 g) and stirred at room temperature for 16 hours. This mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and water. The layers were separated and the organic layer was concentrated in vacuo, then applied to a TFE cartridge (aminopropyl, 1 g). The column was eluted with methanol to give Intermediate 20 as a white solid (0.02 g). LCMS showed MH ⁺ = 373; T _RET = 2.15 min.

Intermediate 21: 4-Aminotetrahydropyran

Available from Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego, CA 92126. CAS (Chemical) Registry Number 38041-19-9.

Intermediate 21A: Tetrahydro-2H-pyran-4-amine hydrochloride = 4-Aminotetrahydropyran hydrochloride

Stage 1: N, N-dibenzyltetrahydro-2H-pyran-4-amine

Dibenzylamine (34.5 g) and acetic acid (6.7 ml) were added to a stirred solution of tetrahydro-4H-pyran-4-one (16.4 g, commercially available, for example, from Aldrich) in dichloromethane (260 ml) at temperatures from 0 ° C to 5 ° C. After 2.5 hours at a temperature of 0 ° C. to 5 ° C., sodium triacetoxyborohydride (38.9 g) was added portionwise and the mixture was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction mixture was washed successively with 2 M sodium hydroxide (200 ml and 50 ml), water (2 × 50 ml) and brine (50 ml), then dried and evaporated to give a yellow oil (45 g) . This oil was stirred with methanol (50 ml) at 4 ° C for 30 minutes to give the product as a white solid (21.5 g). LCMS showed MH ⁺ = 282; T _RET = 1.98 min.

Stage 2: Tetrahydro-2H-pyran-4-amine N, N-Dibenzyltetrahydro-2H-pyran-4-amine hydrochloride (20.5 g) was dissolved in ethanol (210 ml) and hydrogenated over the catalyst with 10% palladium on carbon (4 g) at a pressure of 690 kPa (100 psi) for 72 hours at room temperature. This reaction mixture was filtered and the filtrate was adjusted to pH 1 with 2 M hydrogen chloride in diethyl ether. Evaporation of the solvents gave a solid which was triturated with diethyl ether to give the product as a white solid (9.23 g). ¹ H-NMR (400 MHz, d _6- DMSO, δ ppm) 8.24 (br, s, 3H), 3.86 (dd, 12, 4 Hz, 2H), 3.31 (dt, 2, 12 Hz, 2H ), 3.20 (m, 1H), 1.84 (m, 2H), 1.55 (dq, 4, 12 Hz, 2H).

Intermediate 22: N'-Hydroxy-2-methoxy-ethanimidamide

A solution of methoxyacetonitrile (12.26 g) in ethanol (220 ml) was treated with hydroxylamine hydrochloride (11.95 g) and then potassium carbonate (22.9 g) and refluxed for 2 days. This mixture was concentrated in vacuo, then partitioned between ethyl acetate and water. The organic layer was concentrated in vacuo to give Intermediate 22 as a colorless liquid (7.6 g). ¹ H-NMR (CDCl ₃ ) 7.16 (3H, s), 7.67 (s, 2H), 9.32 (brs, 2H), 13.08 (1H, s).

Intermediate 23: 2- (Dimethylamino) -N'-hydroxyethanimidamide

Can be obtained analogously to Intermediate 9, starting with dimethylaminoacetonitrile.

Intermediate 24: N'-Hydroxy-2-morpholin-4-ylethanimidamide

Can be prepared analogously to Intermediate 9, starting with morpholinoacetonitrile (commercially available from TCI America, 9211 North Harborgate Street, Portland, OR 97203, USA).

Intermediate 25: 1-Acetyl-4-aminopiperidine hydrochloride

Prepared from commercially available M1-benzyl-4-aminopiperidine as described by Yamada et al. at WO 00/42011:

Intermediate 26: 3-Methyloxetane-3-carboxylic acid

Can be obtained by oxidation of 3-methyl-3-oxetanomethanol (commercially available, for example, from Fluka, CAS (Chemical Abstracts) Registry Number 3143-02-0) in accordance with the method described by H. Fiege et. al. in DE3618142.

Intermediate 27: (4-Methylpiperazin-1-yl) acetic acid

Available from ChemPacific USA Sales Marketing and Research Center, 6200 Freeport Center, Baltimore, MD 21224, USA (CAS Registry Number 54699-92-2).

Intermediate 28: (Isopropylamino) (oxo) acetic acid

Commercially available from Austin Chemical Company, Inc., 1565 Barclay Blvd., Buffalo Grove, IL 60089, USA. CAS (Chemical Abstracts) Registry Number 3338-22-5.

Intermediate 29: 1-Methyl-5-oxopyrrolidine-3-carboxylic acid

Available from MicroChemistry-RadaPharma, Shosse Entusiastov 56, Moscow 111123, Russia. CAS (Chemical Abstracts) Registry Number 4,2346-68-9.

Intermediate 30: Tetrahydro-2H-pyran-4-carboxylic acid

Available from Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego, CA 92126, USA. CAS (Chemical Abstracts) Registry Number 5337-03-1. Intermediate 31: Morpholin-4-ylacetic acid

Can be obtained from ethyl bromoacetate as described by Z. Dega-Szafran et. al. in J. Molecular Structure, 2001, 560, 261-273.

Intermediate 32: tert-butoxyacetic acid

A suspension of sodium tert-butylate (24.1 g) in tert-butanol (150 ml) was cooled in a water bath and treated dropwise with a solution of chloroacetic acid (11.4 g) in tert-butanol (30 ml). This mixture was heated under reflux for 5 hours, then concentrated in vacuo. The resulting white solid was dried in vacuo for 16 hours, then water (100 ml) was added and this mixture was filtered. The filtrate was treated with diethyl ether (150 ml), then cooled in an ice bath, stirred and acidified with 2 N. sulfuric acid to pH 1. The layers were separated and the aqueous layer was further extracted with diethyl ether. The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give Intermediate 32 (11.1 g). ¹ H-NMR (400 MHz, CDCl ₃ , δ ppm) 1.27 (9H, s), 4.04 (2H, s).

Intermediate 33: Methyl- (2S) -2 - ({[1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] carbonyl } amino) -3-hydroxypropanoate

Interaction Scheme:

Intermediate 17 (0.1 g, 0.34 mmol), EDC (0.066 g, 0.34 mmol) and HOBT (0.05 g, 0.37 mmol) were suspended in DMF (2 ml) and stirred at room temperature in a nitrogen atmosphere for 15 minutes. L-serine methyl ester hydrochloride (0.054 g, 0.34 mmol) and triethylamine (0.036 g, 0.36 mmol) were added and the mixture was stirred at room temperature under nitrogen for 18 hours. Solvents were removed in vacuo and the residue was partitioned between DCM and water. The organic layer was concentrated in vacuo and applied to a TFE cartridge (aminopropyl, 5 g), which was eluted with methanol. Concentration in vacuo gave a contaminated residue, which was further purified on a TFE cartridge (silica, 5 g), eluting with ethyl acetate and then with 5% methanol / ethyl acetate. The desired fractions were concentrated in vacuo to give Intermediate 33 (0.055 g). LCMS showed MH ⁺ = 393; T _RET = 2.22 min.

Intermediate 34: 1-Ethyl-N- (2-hydroxy-1-methylethyl) -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-carboxamide

Intermediate 17 (0.1 g, 0.34 mmol), EDC (0.066 g, 0.34 mmol) and HOBT (0.05 g, 0.37 mmol) were suspended in DMF (2 ml) and stirred at room temperature in a nitrogen atmosphere for 15 minutes 2-aminopropan-1-ol (0.026 g, 0.34 mmol) and triethylamine (0.036 g, 0.36 mmol) were added and the mixture was stirred at room temperature under nitrogen for 6 hours. Solvents were removed in vacuo and the residue was partitioned between DCM and water. The organic layer was concentrated and applied to a TFE cartridge (aminopropyl, 5 g), which was eluted with methanol. Concentration in vacuo gave Intermediate 34 (0.095 g). LCMS showed MH ⁺ = 348, T _RET = 2.15 min.

Intermediate 35: Ethyl 4-ethoxy-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylate

Sodium (0.55 g, 23.7 mmol) was added portionwise to anhydrous ethanol (25 ml) at 20 ° C. under a nitrogen atmosphere. After stirring for 1 hour, this solution was added to Intermediate 1 (4.622 g, 18.22 mmol) and the reaction mixture was heated at reflux for 2 hours. This mixture was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified on a TFE cartridge (silica, 4 × 20 g), eluting with dichloromethane, ethyl acetate: petroleum ether (1: 4, 1: 2, then 1: 1) and then ethyl acetate. The appropriate fractions were combined and evaporated in vacuo to give Intermediate 35 as a white solid (4.33 g). LCMS showed MH ⁺ = 264, T _RET = 2.77 min.

Intermediate 36: Ethyl 4-ethoxy-1H-pyrazolo [3,4-b] pyridine-5-carboxylate

A mixture of Intermediate 35 (1.0 g, 3.8 mmol) and N-bromosuccinimide (NBS, 1.49 g, 8.4 mmol) in carbon tetrachloride (35 ml) was heated at reflux for 3 hours. The reaction mixture was cooled in an ice bath and the precipitate was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in tetrahydrofuran (12.5 ml). Water (3.5 ml) and saturated sodium carbonate solution (3 ml) were added, and this mixture was stirred at 20 ° C. for 18 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified on a TFE cartridge (silica, 20 g), eluting with dichloromethane, chloroform, then with a mixture of chloroform: methanol (99: 1, 49: 1, 19: 1, then 9: 1). The appropriate fractions were combined and evaporated in vacuo to give Intermediate 36 as an off-white solid (0.45 g). LCMS showed MH ⁺ = 236, T _RET = 2.46 min.

Intermediate 37: Ethyl 4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carboxylate

Method 1: Intermediate 36 (0.035 g) was placed in Reactivial ™ and treated with 4-aminotetrahydropyran (0.05 ml). This mixture was heated at 90 ° C for 1.5 hours, then was allowed to cool to room temperature and partitioned between chloroform (2 ml) and water (1 ml). The layers were separated and the organic phase was concentrated. The crude product was purified by mass-controlled autopreparative HPLC to give Intermediate 37 as an off-white solid (0.011 g). LCMS showed MH ⁺ = 291; T _RET = 2.08 min.

Alternative Method 2: Intermediate 36 (2 g) was suspended in 4-aminotetrahydropyran (2 g) and this mixture was heated at 90 ° C. for 6 hours. The residual mixture was allowed to cool to room temperature and partitioned between chloroform (50 ml) and water (50 ml). The phases were separated and the organic phase was evaporated to dryness. The residue was triturated with Et ₂ O (30 ml) and the insoluble solid was collected and dried to give Intermediate 37 as a cream solid (2.24 g). LCMS showed MH ⁺ = 291; T _RET = 2.19 min.

Intermediate 38: Ethyl-1-n-propyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carboxylate

Sodium hydride (0.067 g, 60% dispersion in oil) was added to a stirred solution of Intermediate 37 (0.47 g) in DMF (19 ml) and then n-propyl iodide (0.17 ml) was added. This mixture was stirred at 23 ° C. for 16 hours, then concentrated, diluted with chloroform (30 ml) and washed with a 1: 1 brine / water mixture (30 ml), separated, and the organic layer was concentrated. The residue was purified on a TFE cartridge (silica, 10 g) with elution with volumes of 10 ml of dichloromethane, a mixture of diethyl ether: cyclohexane 1: 1 and diethyl ether. The combined fractions of a mixture of diethyl ether: cyclohexane 1: 1 and diethyl ether were concentrated to give Intermediate 38 as a clear gum (0.23 g). LCMS showed MH ⁺ = 333; T _RET = 3.14 min.

Intermediate 39: 1-n-Propyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid

A 2 M sodium hydroxide solution (0.7 ml) was added to a stirred suspension of Intermediate 38 (0.23 g) in ethanol (5 ml) and water (1.5 ml). After stirring overnight at room temperature, an additional amount of a 2 M sodium hydroxide solution (0.7 ml) was added, and this reaction mixture was heated at 43 ° C. for 2.5 hours. This reaction solution was concentrated, diluted with water (5 ml) and acidified with 2 M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give Intermediate 39 as a white solid (0.14 g). LCMS showed MH ⁺ = 305; T _RET = 2.42 min.

Intermediate 40: N'-Acetyl-1-n-propyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-carbohydrazide

Intermediate 40 can be prepared from Intermediate 39 in a manner similar to that described for Intermediate 4, for example, using the same or the same number of moles of reactants and / or volumes of solvents.

Intermediate 41: Ethyl 4 - [(1-acetyl-4-piperidinyl) amino] -1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylate

Intermediate 1 (0.079 g, 0.56 mmol), Intermediate 25 (0.129 g, 0.51 mmol) and diisopropylethylamine (0.45 ml, 2.55 mmol) in acetonitrile (2 ml) were heated at 85 ° C. within 36 hours. This reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and water. The phases were separated using a hydrophobic frit (Whatman). The organic phase was evaporated in vacuo and the residue was applied to a TFE cartridge (silica, 5 g). The cartridge was eluted using EtOAc and then DCM / MeOH (1: 1). Fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 41 (0.1 g), LCMS showed MH ⁺ = 360; T _RET = 2.63 min.

Intermediate 42: 1-Ethyl-N [(1R) -2-hydroxy-1-phenylethyl] -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5 carboxamide

Intermediate 17 (0.25 g, 0.86 mmol), EDC (0.23 g, 1.2 mmol) and HOBT (0.139 g, 1.03 mmol) were suspended in DMF (5 ml) and this suspension was stirred at room temperature. After 25 minutes, (2R) -2-amino-2-phenylethanol (0.13 g, 0.95 mmol, commercially available from Aldrich) was added and the mixture was stirred at room temperature for 20 hours. The solvents were removed in vacuo and the residue was dissolved in DCM (50 ml) and washed successively with water (25 ml) and 5% sodium bicarbonate solution (25 ml). The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml) and applied to a TFE cartridge (silica, 10 g), which was eluted with a gradient of ethyl acetate - petroleum ether (1: 2, 1: 1 and 1: 0). Fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 42 as a white foam (0.318 g). LCMS showed MH ⁺ = 410; T _RET = 2.55 min.

Intermediate 43: 1-Ethyl-N - [(15) -2-hydroxy-1-phenylethyl] -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin- 5-carboxamide

Intermediate 43 was prepared from Intermediate 17 and (25) -2-amino-2-phenylethanol (commercially available from Lancaster Synthesis) using a method similar to that for Intermediate 42. LCMS showed MH ⁺ = 410; T _RET = 2.55 min.

Intermediate 44: 1-Ethyl-N - [(15) -2-hydroxy-1- (phenylmethyl) ethyl] -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b ] pyridine-5-carboxamide

Intermediate 44 was prepared from Intermediate 17 and (25) -2-amino-3-phenyl-1-propanol (commercially available from AIdrich) using a method similar to that for Intermediate 42. LCMS showed MH ⁺ = 424; T _RET = 2.60 min.

Intermediate 45: 1-Ethyl-N - [(1R) -2-hydroxy-1- (phenylmethyl) ethyl] -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b ] pyridine-5-carboxamide

Intermediate 45 was prepared from Intermediate 17 and (2R) -2-amino-3-phenyl-1-propanol (commercially available from Aldrich) using a method similar to that for Intermediate 42. LCMS showed MH ⁺ = 424; T _RET = 2.59 min.

Intermediate 46: 1-Ethyl-N - [(1S, 2S) -2-hydroxy-1-phenylpropyl] -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carboxamide

Intermediate 46 was prepared from Intermediate 17 and (1S, 2R) -1-amino-1-phenyl-2-propanol hydrochloride (commercially available from Arch Corporation, 100 Jersey Avenue, Building D, New Brunswick, NJ 08901, USA) using a method similar to that for Intermediate 42. LCMS showed MH ⁺ = 424; T _RET = 2.58 min.

Intermediate 47: 1-Ethyl-N - [(2R) -2-hydroxy-2-phenylethyl] -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin- 5-carboxamide

Intermediate 47 was prepared from Intermediate 17 and (1R) -2-amino-1-phenylethanol (commercially available from Aldrich) using a method similar to that for Intermediate 42. LCMS showed MH ⁺ = 410; T _RET = 2.62 min.

Intermediate 48: 1-Ethyl-N - [(25) -2-hydroxy-2-phenylethyl] -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin- 5-carboxamide

Intermediate 48 was prepared from Intermediate 17 and (1S) -2-amino-1-phenylethanol (commercially available from Fluka) using a method similar to that for Intermediate 42. LCMS showed MH ⁺ = 410; T _RET = 2.62 min.

Intermediate 49: 1-Ethyl-N- (2-hydroxy-1,1-dimethylethyl) -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5- carboxamide

Intermediate 49 was prepared from Intermediate 17 and 2-amino-2-methyl-1-propanol (commercially available from Aldrich) using a method similar to that for Intermediate 42. LCMS showed MH ⁺ = 362; T _RET = 2.28 min.

Intermediate 50: N-methyltetrahydro-2H-pyran-4-amine

Can be obtained from tetrahydro-4H-pyran-4-one (commercially available, for example, from Sigma Aldrich; CAS (Chemical Abstracts) Registry Number 29943-42-8) in accordance with the method described by H. Hashimoto et al. in Organic Process Research and Development 2002, G, 70.

Intermediate 51: Ethyl-1-ethyl-4- [methyl (tetrahydro-2H-pyran-4-yl) amino] -1H-pyrazolo [3,4-b] pyridine-5-carboxylate

Intermediate 1 (1.2 g, 4.76 mmol), Intermediate 50 (0.79 g, 5.2 mmol) and diisopropylethylamine (4 ml, 24 mmol) in MeCN (8 ml) were heated at 70 ° C. within 24 hours. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic phase was concentrated in vacuo and the residue was chromatographed on silica (50 g), eluting with a mixture of cyclohexane: ethyl acetate (2: 1, then 1: 1 and then 1: 2). The appropriate fractions were combined and evaporated to give Intermediate 51 as a brown oil (1.21 g). LCMS showed MH ⁺ = 334; T _RET = 2.61 min.

Intermediate 52: 1-Ethyl-4- [methyl (tetrahydro-2H-pyran-4-yl) amino] -1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid

Sodium hydroxide (0.43 g, 10.8 mmol) was added to a solution of Intermediate 51 in ethanol (10 ml, 95%). This reaction mixture was heated at 50 ° C for 18 hours. The solvent was evaporated in vacuo and the residue was dissolved in water and acidified to pH 3 by the addition of aqueous hydrochloric acid. This solution was extracted with DCM. The organic phase was separated using a hydrophobic frit (Whatman PTFE Folter Media with a polypropylene support with a pore size of 5 μm) and the solvent was evaporated in vacuo to give Intermediate 52 as a white solid (0.65 g). LCMS showed MH ⁺ = 305; T _RET = 1.97 min.

Intermediate 53: N'-Acetyl-1-ethyl-4- [methyl- (tetrahydro-2H-pyran-4-yl) amino] -1H-pyrazolo [3,4-b] pyridin-5-carbohydrazide

Intermediate 53 was prepared from Intermediate 52 using a method similar to that for Intermediate 4. LCMS showed MH ⁺ = 361; T _RET = 1.91 min.

Intermediate 54: trans-4-aminocyclohexanol

Available, for example, from Acros. CAS (Chemical Abstracts) Registry Number 27489-62-9.

Intermediate 55: Tetrahydro-2H-pyran-3-amine hydrochloride

Received as described in Anales De Quimica, 1988, 84, 148. Intermediate 56: 4-Aminocyclohexanone hydrochloride

A solution of hydrogen chloride in dioxane (0.5 ml, 2.0 mmol, 4M) was added to a stirred solution of tert-butyl-4-oxocyclohexylcarbamate (0.043 g, 0.20 mmol, commercially available from Astatech Inc., Philadelphia, USA) in dioxane (0.5 ml) and this mixture was stirred at room temperature. After 1 h, the reaction mixture was evaporated to give Intermediate 56 as a cream solid (34 mg). ¹ H-NMR (400 MHz in d ₆ -DMSO, 27 ° C, δ ppm) 8.09 (br, s, 3H), 3.51 (tt, 11, 3.5 Hz, 1H), 2.45 (m, 2H, partially hidden), 2.29 (m, 2H), 2.16 (m, 2H), 1.76 (m, 2H).

Intermediate 57: N-Propyltetrahydro-2H-pyran-4-amine

Can be obtained from tetrahydro-4H-pyran-4-one (commercially available, for example, from Sigma Aldrich CAS 29943-42-8), as described by C. Zagar et al. in WO 99/07702.

Intermediate 58: Ethyl 4-chloro-1-ethyl-6-methyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylate

A mixture of 5-amino-1-ethylpyrazole (1.614 g, 14.5 mmol) and diethyl 2- (1-ethoxyethylidene) malonate (3.68 g, 16.0 mmol, as described in PPTSah, J. Amer, Chem. Soc., 1931, 53, 1836) was heated at 150 ° C under Dean Stark conditions for 5 hours. Phosphorus oxychloride (25 ml) was carefully added to this mixture and the resulting solution was heated at 130 ° C under reflux for 18 hours. This mixture was concentrated in vacuo, then the residual oil was carefully added while cooling to water (100 ml). The resulting mixture was extracted using DCM (3 × 100 ml) and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residual oil was purified by Biotage chromatography (silica, 90 g), eluting with ethyl acetate-gasoline (1:19). Fractions containing the desired product were combined and concentrated in vacuo to give Intermediate 58 (1.15 g). LCMS showed MH ⁺ = 268; T _RET = 3.18 min.

Intermediate 59: Ethyl 1-ethyl-6-methyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carboxylate

4-aminotetrahydropyran hydrochloride (Intermediate 21, 0.413 g, 3.0 mmol) was added to a mixture of Intermediate 58 (0.268 g, 1.0 mmol) and N, N-diisopropylethylamine (0.87 ml, 5.0 mmol) in acetonitrile (3 ml). The resulting mixture was heated at 85 ° C for 24 hours. Volatiles were removed in vacuo and the residue was dissolved in chloroform (1.5 ml) and applied to a TFE cartridge (silica, 5 g). The cartridge was eluted sequentially using Et ₂ O, EtOAc and EtOAc-MeOH (9/1). Fractions containing the desired product were combined and concentrated in vacuo to give the desired product contaminated with the starting material (Intermediate 51). Further purification using a TFE cartridge (silica, 5 g) while eluting with ethyl acetate-cyclohexane (1: 3) gave Intermediate 59 (0.248 g). LCMS showed MH ⁺ = 333; T _RET = 2.75 min.

Intermediate 60: 1-Ethyl-6-methyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid

A 2 M solution of sodium hydroxide (0.75 ml, 1.5 mmol) was added to Intermediate 59 (0.248 g, 0.75 mmol) in ethanol (2 ml), and this mixture was heated at reflux for 16 hours. The reaction mixture was concentrated, diluted with water (1 ml) and acidified with 2 M hydrochloric acid (0.75 ml) to precipitate a solid which was collected by filtration to obtain Intermediate 60 (0.168 g). LCMS showed MH ⁺ = 305; T _RET = 1.86 min.

Intermediate 61: N '- (2,2-Dimethylpropanoyl) -1-ethyl-6-methyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5 carbohydrazide

The intermediate compound 60 (0.255 g, 0.84 mmol), EDC (0.225 g, 1.17 mmol) and HOBT (0.136 g, 1.0 mmol) in DMF (5 ml) was stirred at 20 ° C for 75 minutes, pivalic acid hydrazide (0.107 g, 0.92 mmol) was added and stirring was continued for 18 hours. This reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and water. The organic phase was washed with aqueous sodium bicarbonate, then evaporated in vacuo to give Intermediate 61 as a white solid (0.27 g). LCMS showed MH ⁺ = 403; T _RET = 2.13 min.

Intermediate 62: 11-Dimethylethyl-2 - {[1-ethyl-6-methyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -carbonyl} hydrazinecarboxylate

Intermediate 60 (0.253 g, 0.83 mmol), EDC (0.223 g, 1.17 mmol) and HOBT (0.135 g, 1.0 mmol) in DMF (5 ml) was stirred at 20 ° C. for 30 minutes. Tert-butyl carbazate (0.110 g, 0.83 mmol) was added and stirring was continued for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in DMF (5 ml) and additional EDC (0.159 g) and HOBT (0.112 g) were added. After 30 minutes, tert-butyl carbazate (0.019 g) was added and stirring was continued for 18 hours. This reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and water. The organic phase was washed with aqueous sodium bicarbonate, then evaporated in vacuo. This material was applied to a TFE cartridge (silica, 10 g) and eluted with a cyclohexane: ethyl acetate mixture (1: 1, then 2: 1) to give Intermediate 62 as a white solid (0.19 g). LCMS showed MH ⁺ = 419; T _RET = 2.35 min.

Intermediate 63: 1-Ethyl-6-methyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carbohydrazide hydrochloride

Intermediate 62 (0.19 g, 0.46 mmol) was dissolved in 4 M hydrogen chloride in dioxane (5 ml) and this reaction mixture was stirred overnight at 20 ° C. Concentration in vacuo gave Intermediate 63 as a white solid (0.161 g). LCMS showed MH ⁺ = 319; T _RET = 1.72 min.

Intermediate 64: 1-Ethyl-6-methyl-4- (tetrahydro-2H-pyran-4-ylamino) -N '- (tetrahydro-2H-pyran-4-ylcarbonyl) -1H-pyrazolo [3,4-b ] pyridine-5-carbohydrazide

Intermediate 30 (0.06 g, 0.45 mmol) and TBTU (0.146 g, 0.45 mmol) in DMF (5 ml) were stirred at 20 ° C. for 30 minutes. A mixture of Intermediate 63 (0.16 g, 0.45 mmol) and diisopropylethylamine (0.32 ml, 1.82 mmol) in DMF (1 ml) was added and the reaction mixture was stirred overnight under nitrogen. This reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and water. The phases were separated using a hydrophobic frit (Whatman PTFE Folter Medium with a polypropylene substrate, pore size 5 μm) and the organic phase was evaporated in vacuo. The residue was applied to a TFE cartridge (aminopropyl, 10 g) and eluted using MeOH. The appropriate fractions were concentrated in vacuo, then applied to an additional TFE cartridge (silica, 2 g), which was eluted successively with a MeOH gradient in DCM (1) 2%, (2) 4%, (3) 6% and (4) 10% . Fractions containing the desired material were combined and concentrated in vacuo to give Intermediate 64 as a white solid (0.048 g). LCMS showed MH ⁺ = 431; T _RET = 1.87 min.

Intermediate 65: N '- (cyclobutylcarbonyl) -1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-carbohydrazide

TBTU (0.050 g, 0.15 mmol) and diisopropylethylamine (0.04 ml, 0.26 mmol) in DMF (0.5 ml) were added to cyclobutyl carboxylic acid (R ^Y COOH, 0.015 g, 0.15 mmol). This reaction mixture was stirred for 40 minutes at 20 ° C. A mixture of Intermediate 19 (0.045 g, 0.13 mmol) and diisopropylethylamine (0.04 ml, 0.26 mmol) in DMF (0.5 ml) was added and the reaction mixture was stirred for 18 hours. The solvent was removed in vacuo and the residue was applied to a TFE cartridge (aminopropyl, 2 g). The cartridge was eluted with methanol to give Intermediate 65 (0.052 g). LCMS showed MH ⁺ = 387; T _RET = 2.28 min.

The following compounds were similarly prepared using the same or similar amounts of moles of reactants and / or volumes of solvents:

R ^Y COOH Acid source Mh ⁺ T _RET (min) The intermediate connection 66

Sigma-alldrich 416 2.03 The intermediate connection 67

Sigma-alldrich 404 2.01 The intermediate connection 68

Salt with HCl, Maybridge, or DE10008089 430 1.89 The intermediate connection 69

Interchim intermediates 429 2,35 Intermediate 70

Sigma-Aldrich, or J. Org. Chem., 1997.62.5144 415 2.12 The intermediate connection 71

Sigma-alldrich 403 2.11 The intermediate connection 72

Sigma-alldrich 434 2.15 The intermediate connection 73

Chempacific 401 2.46 The intermediate connection 74

Sigma-alldrich 418 2.06 The intermediate connection 75

Astatech, or J.Med. Chem., 1993,36,2300 431 2.18 The intermediate connection 76

Synthesis, 1971, 258; or WO 03/082190 401 2,35 Intermediate 77

Eur. J. Med. Chem., 1992 37,581 414 2,30 The intermediate connection 78

Indian J. Chemistry, 2002, 41B, 1093 413 2.24 The intermediate connection 79

Lancaster synthesis 458 2.18

Intermediate 80: (1E / Z) -N-hydroxy-2- (4-methyl-1-piperazinyl) ethanamide

(4-Methyl-1-piperazinyl) acetonitrile (1.08 g, 7.7 mmol) (J. Med. Chem., 1999, 42, 2870) was added to a suspension of potassium carbonate (3.2 g, 23.1 mmol ) and hydroxylamine hydrochloride (1.06 g, 15.4 mmol) in ethanol (10 ml). This reaction mixture was heated at reflux for 9 hours, then allowed to cool. The reaction mixture was filtered and the solvent was evaporated in vacuo to give Intermediate 80 (1.53 g). ¹ H-NMR (400 MHz in d _6- DMSO, 27 ° C, δ ppm) 9.02 (br s, 1H), 5.17 (brs, 2H), 2.78 (s, 2H), 2.31 (brs, 8H ), 2.13 (s, 3H).

Intermediate 81: 4-Fluoro-N-hydroxybenzene-carboximidamide

Available from Sigma-Aldrich, CAS (Chemical Abstracts) Registry Number 22179-78-8.

Intermediate 82: (1E / Z) -N-hydroxy-3-oxo-3- (1-pyrrolidinyl) propanimidamide

Available from Maybridge Chemical Company, CAS (Chemical Abstracts) Registry Number 57399-51-6.

Intermediates 83 and 84

The structures of Intermediates 83 and 84 and their preparation are as follows:

Intermediate 83: {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole -3-yl} -acetic acid

Anhydrous hydrogen chloride in dioxane (8 ml, 4 M solution) was added to Intermediate 84 (0.807 g, 1, 88 mmol). This reaction mixture was stirred overnight at room temperature, then evaporated in vacuo. The residue was suspended in ether and the mixture was filtered to give Intermediate 83 as a brown solid (0.525 g). LCMS showed MH ⁺ = 373; T _RET = 2.62 min.

Intermediate 84: 1,1-Dimethylethyl- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1 2,4-oxadiazol-3-yl} acetate

Diisopropylethylamine (8.3 ml, 47.5 mmol) was added to a mixture of Intermediate 17 (2.76 g, 9.5 mmol), TBTU (3.050 g, 9.5 mmol) and hydroxybenzotriazole (1.28 g, 9, 5 mmol) in N, N-dimethylformamide (40 ml) at room temperature. After stirring for 10 minutes, Intermediate 85 (2.318 g, 13.3 mmol) was added. The reaction mixture was stirred for 50 minutes, then 1,1'-carbonyldiimidazole (1.54 g, 9.5 mmol) was added thereto, and the reaction mixture was heated at 100 ° C. for 16 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was washed with aqueous sodium bicarbonate (5%), then dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by chromatography using a Biotage system (100 g, silica), eluting with a cyclohexane: ethyl acetate mixture (1: 1). Intermediate 84 was obtained as a brown solid (0.97 g). LCMS showed MH ⁺ = 429; T _RET = 3.26 min.

Intermediate 85: 1,1-Dimethylethyl- (3-E / Z) -3- (hydroxyamino) -3-iminopropanoate

The interaction scheme is shown below:

Available from Aldrich Intermediate 85

A solution of sodium methylate in methanol (50 ml, 0.5 M) was added to hydroxylamine hydrochloride (1.78 g, 25.62 mmol) at room temperature. After stirring for 15 minutes, the solution was filtered and the filtrate was added to tert-butyl cyanoacetate (3.0 g, 21.25 mmol, commercially available from Aldrich). This solution was refluxed for 1.75 hours, then cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (MgSO ₄ ) and evaporated in vacuo. The residue was suspended in cyclohexane: ether (1: 1), then filtered to give Intermediate 85 as a white solid (1.883 g). ¹ H-NMR (400 MHz in CDCl ₃ , 27 ° C, δ ppm) 8.34 (brs, 1H), 5.05 (brs, 2H), 3.09 (s, 2H), 1.47 (s, 9H).

Intermediate 86: N "- {[1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] carbonyl} -N, N, N'N'-tetramethylcarbonohydrazone diamide

Intermediate 19 (0.1 g, 0.29 mmol), TBTU (0.094 g, 0.29 mmol) and diisopropylethylamine (0.204 ml, 1.17 mmol) in N, N-dimethylformamide (1 ml) were stirred at room temperature within 1 hour. The solvent was evaporated in vacuo and the residue was dissolved in methanol and applied to a TFE cartridge (aminopropyl, 5 g). The cartridge was eluted with methanol and the appropriate fractions were evaporated in vacuo to give Intermediate 86 as a yellow solid (0.113 g). LCMS showed MH ⁺ = 403; T _RET = 1.99 min.

Intermediate 87: Ethyl- (2-methyl-1,3-thiazol-4-yl) acetate

Received as described in K. Arakawa et. al., Chem Pharm Bull, 1972, 20 (5), 1041.

Intermediate 88: 2-Methyl-1,3-thiazol-4-yl-acetic acid

To a solution of Intermediate 87 (6 g, 32.4 mmol) in dioxane (15 ml) was added a solution of lithium hydroxide monohydrate (1.53 g, 36.4 mmol) in water (15 ml). This mixture was stirred for 17 hours, then washed with diethyl ether (20 ml), then ethyl acetate (20 ml) and acidified with concentrated hydrochloric acid under ethyl acetate (50 ml). The combined aqueous phases were adjusted to pH 2.7 by adding sodium bicarbonate and extracted with additional ethyl acetate (2 × 50 ml). The combined organic phases were washed with water (20 ml) and saturated brine (20 ml), then concentrated in vacuo to give Intermediate 88 as a white solid (1.69 g). ¹ H-NMR (400 MHz in CDCl ₃ , 27 ° C, δ ppm) 2.74 (s, 3H), 3.85 (s, 2H). 5.8-6.2 (br, s, 1H); 7.02 (s, 1H).

Intermediate 89: 1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -N '- (1H-1,2,3-triazol-1-ylacetyl) -1H-pyrazolo [3,4-b ] pyridine-5-carbohydrazide

General Procedure for Intermediates 89-114:

A mixture of carboxylic acid R ^Y CO ₂ H (0.2 mmol), diisopropylethylamine (0.105 ml, 0.6 mmol) and TBTU (0.071 g, 0.22 mmol) in N, N-dimethylformamide (0.5 ml) was left standing for 10 minutes. A mixture of Intermediate 19 (0.2 mmol) and diisopropylethylamine (0.035 ml, 0.2 mmol) in N, N-dimethylformamide (0.5 ml) was added. After stirring, this reaction mixture was left to stand for 16 hours. The solvent was removed in vacuo and the residue was applied to a TFE cartridge (aminopropyl, 0.5 g). The cartridge was eluted with chloroform, ethyl acetate: chloroform (1: 1), ethyl acetate, ethyl acetate: methanol (9: 1, 2 ml). The appropriate fractions were evaporated in vacuo to give Intermediates indicated below.

Intermediate Number R ^y Carboxylic acid source R ^Y CO ₂ H Mh ⁺ T _RET (min) 89

Chem Pacific Ltd 413 2.17 90

SPECS Fleminglaan 16 2289 CP Rijswijk, The Netherlands 457 2,3 91

Advanced Synthesis P.O. Box 437920 San Ysidro, California 92173 United States 412 2,4 92

Microchemistry Ltd, Shosse Entusiastov 56, Moscow 111123, Russia 413 2.25 93

Alldrich 452 2.59 94

Maybridge Chemical Company Ltd., Trevillett, Tintagel, Cornwall PL34 OHW, United Kingdom 414 2.2 95

Described in R. Raap et. al., US3271407A 429 2,33 96

Alldrich 427 2,32 97

Alldrich 465 2.21 98

The intermediate connection 88 443 2,33 99

Peakdale Molecular Ltd, Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak SK23 OPG, UK 485 2.47 one hundred

J. Chem. Soc., Perkin Trans II, 1993, 4, 741-8 429 2.19 101

Lancaster synthesis 413 2.42 102

J. Chem. Soc. Perkin Trans. 1, 1976, 9, 994-7 427 2,35 103

Microchemistry Ltd, Shosse Entusiastov 56, Moscow 1111123, Russia 457 2,32 104

Microchemistry Ltd, Shosse Entusiastov 56, Moscow 1111123, Russia 429 2.13 105

Microchemistry Ltd, Shosse Entusiastov 56, Moscow 1111123, Russia 427 2.11 106

Microchemistry Ltd, Shosse Entusiastov 56, Moscow 1111123, Russia 441 2,35 107

Sigma chemical company 417 2.11 108

T. J. Guziet.al., WO 03/022835 471 2.22 109

Alldrich 437 2.7 110

Alldrich 423 2.6 111

Alldrich 437 2,8 112

Alldrich 437 2.7 113

ACB Blocks Ltd or described in Rzeszotarski, W.J., WO 93/05772 451 2.7 114

Alldrich 501/503 2,8

Intermediate 115: 4- (Aminomethyl) benzamide

Can be obtained in accordance with the methodology described in L.W. Jones et. al. WO 02/085860.

Intermediate 116: 1,1-Dimethylethyl - [(2Z) -2- (hydroxyamino) -2-iminoethyl] carbamate

Prepared from commercially available N- (tert-butoxycarbonyl) -2-aminoacetonitrile as described by M. Schwarz et. al. in WO 02/102799.

Intermediate 117: 1,1-Dimethylethyl - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] - 1,2,4-oxadiazol-3-yl} methyl) carbamate

Diisopropylethylamine (6.0 ml, 34.4 mmol) was added to the stirred mixture of Intermediate 17 (2.0 g, 6.89 mmol), TBTU (2.212 g, 6.89 mmol) and HOBT (0.931 g, 6.89 mmol) in anhydrous dimethylformamide (45 ml). After 10 minutes, the resulting clear solution was treated with Intermediate 116 (1.89 g, 10 mmol). The reaction mixture was stirred at room temperature for 2 hours. DBU (5.14 ml, 34.5 mmol) was added and the reaction mixture was heated at 80 ° C. After 3.5 hours at 80 ° C., the reaction mixture was evaporated in vacuo and the residue was dissolved in dichloromethane (150 ml) and washed successively with 5% sodium bicarbonate (50 ml) and water (50 ml). The organic solution was dried over anhydrous sodium sulfate and evaporated to give a crude product. Purification by Biotage chromatography (silica, 100 g), eluting with ethyl acetate-petroleum ether (1: 1), gave Intermediate 117 as a white solid (2.70 g). LCMS showed MH ⁺ = 444, T _RET = 3.06 min.

Intermediate 118: 5- [3- (Aminomethyl) -1,2,4-oxadiazol-5-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine

Trifluoroacetic acid (5 ml) was added to a stirred solution of Intermediate 117 (1.774 g, 4.0 mmol) in anhydrous dichloromethane (20 ml) at 0 ° C. After 2 hours, this reaction mixture was neutralized by carefully adding a 5% solution of sodium bicarbonate (150 ml) and solid sodium bicarbonate. The resulting mixture was extracted with chloroform (2 × 100 ml). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to give Intermediate 118 as a white solid (1.358 g). LCMS showed MH ⁺ = 344, T _RET = 1.95 min.

Intermediate 119: 4-Chloro-N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] - 1,2,4-oxadiazol-3-yl} methyl) butanamide

4-Chlorobutanoyl chloride (0.12 mmol) was added to a stirred solution of Intermediate 118 (0.1 mmol) and diisopropylethylamine (0.3 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 hours, this reaction mixture was applied to a TFE cartridge (aminopropyl, 2 g), and the cartridge was eluted successively with chloroform, ethyl acetate and methanol. Fractions containing the desired product were combined and purged under nitrogen. The resulting residue was further purified on a TFE cartridge (silica, 1 g), eluting with a gradient of 30-100% ethyl acetate in petroleum ether to give Intermediate 119 as a white solid (45 mg). LCMS showed MH ⁺ = 448, T _RET = 2.77 min.

Intermediate 120: 5-Chloro-N - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] - 1,2,4-oxadiazol-3-yl} methyl) pentanamide

5-Chloropentanoyl chloride (0.12 mmol) was added to a stirred solution of Intermediate 118 (0.1 mmol) and diisopropylethylamine (0.3 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 hours, this reaction mixture was applied to a TFE cartridge (aminopropyl, 2 g), and the cartridge was eluted successively with chloroform, ethyl acetate and methanol. Fractions containing the desired product were combined and purged under nitrogen. The resulting residue was further purified on a TFE cartridge (silica, 1 g), eluting with a gradient of 30-100% ethyl acetate in petroleum ether to give Intermediate 120 as a white solid (46 mg). LCMS showed MH ⁺ = 462, T _RET = 2.86 min.

Intermediate 121: (1E / Z) -N-hydroxy-2- (4-morpholinyl) propanimidamide

Obtained from α-methyl-4-morpholinacetonitrile using a process similar to that described for any of Intermediates 9, 22 or 80, using the same or the same amount of moles of reagents and / or volumes of solvents. ¹ H-NMR (27 ° C, d _4- MeOH) 3.70-3.60 (m, 5H), 3.13-3.07 (m, 2H), 2.83-2.76 (m, 2H), 1.84 (d, J = 5 Hz, 3H)

α-Methyl-4-morpholinacetonitrile can be prepared according to the procedure described in H. R. Henze et. at. J. Am. Chem. Soc 1957, 79, 6230.

Intermediate 122: (1E / Z) -2-cyclohexyl-N-hydroxyethanimidamide

It can be obtained from cyclohexylacetic acid (commercially available, for example, from Aldrich) in accordance with the procedure described in T.R. Alessi et al., US 4,895,860.

Intermediate 123: 1,1-Dimethylethyl-4 - [(2Z) -2- (hydroxyamino) -2-iminoethyl] -1-piperidinecarboxylate

Prepared from 1,1-dimethylethyl-4- (cyanomethyl) -1-piperidinecarboxylate using a process similar to that described for any of Intermediates 9, 22 or 80, using the same or the same number of moles of reactants and / or volumes of solvents.

1,1-Dimethylethyl-4- (cyanomethyl) -1-piperidinecarboxylate can be obtained from commercially available 1,1-dimethylethyl-4-oxo-1-piperidinecarboxylate in accordance with the procedure described in A.M. Wilson, WO 00/006159.

Intermediate 124: 1,1-Dimethylethyl-4 - ({5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl ] -1,2,4-oxadiazol-3-yl} methyl) -1-piperidinecarboxylate

A mixture of Intermediate 16 (0.064 g, 0.2 mmol), Intermediate 80 (0.257 g, 1 mmol), a solution of sodium ethylate in EtOH (0.19 ml, 21% solution) and 4Å molecular sieve powder (0, 38 g) in EtOH (2 ml) was stirred at 82 ° C. under nitrogen for 18 hours. Additional sodium ethoxide in ethanol (0.19 ml, 21% solution), molecular sieves (0.38 g) and ethanol (4 ml) were added and this reaction mixture was heated for an additional 72 hours. The reaction mixture was filtered, the solvent was evaporated in vacuo, and the residue was applied to a TFE cartridge (silica, 2 g). The cartridge was eluted with a mixture of cyclohexane: ethyl acetate (4: 1, 2: 1, 1: 1), then with ethyl acetate to give Intermediate 124 as a colorless oil (0.052 g). LCMS showed MH ⁺ = 512; T _RET = 3.51 min.

Intermediate 125: 1-Ethyl-5- [3- (4-piperidinylmethyl) -1,2,4-oxadiazol-5-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine hydrochloride

A solution of hydrogen chloride in dioxane (1 ml) was added to Intermediate 124 (0.052 g, 0.1 mmol) and this reaction mixture was stirred at 20 ° C for 2 hours. The solution was evaporated in vacuo to give Intermediate 125 as a yellow solid (0.047 g). LCMS showed MH ⁺ = 412, T _RET = 2.21 min.

Intermediate 126: N-Hydroxy-1- (phenylsulfonyl) cyclopropanecarboximidamide

Prepared from 1- (phenylsulfonyl) cyclopropanecarbonitrile (commercially available from Menai Organics Ltd, Menai Technology Center, Deiniol Roas, Bangor, Gwynedd, Wales, LL57 UP, United Kingdom, or described in Bull. Chem. Soc. Jpn. 1985 58 ( 2), 765) using a process similar to that described for any of Intermediates 9, 22 or 80 using the same or the same amount of moles of reagents and / or volumes of solvents. LCMS showed MH ⁺ = 241; T _RET = 1.71 min.

Intermediate 127: (1E / Z) -N-Hydroxy-2-phenylethanimidamide

Available from Maybridge Chemical Company Ltd, Trevillett, Tintagel, Cornwall, PL34 OHW, United Kingdom.

Intermediate 128: (1E / Z) -N-Hydroxy-2-phenylpropanimidamide

Can be obtained from α-methylphenylacetonitrile in accordance with the procedure described in J. Rheineimer EP 323864.

Intermediate 129: (1E / Z) -N-Hydroxy-2- [4- (methyloxy) phenyl] ethanimidamide

Available from the Exploratory Library, Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France.

Intermediate 130: (1E / Z) -N-Hydroxy-2- [3- (methyloxy) phenyl] ethanimidamide

Can be obtained in accordance with the method described in S. Borg et. al, European J. Med Chem. 1993, 28 (10,) 801.

Intermediate 131: (1E / Z) -2- [4- (Dimethylamino) phenyl] -N-hydroxyethanimidamide

Prepared from 4- (dimethylamino) benzeneacetonitrile (described in Borovicka et at. Collect. Czech. Chem. Commun. 1955, 20, 437) using a process similar to that described for any of Intermediates 9, 22 or 80, using a similar or such the same number of moles of reagents and / or volumes of solvents. LCMS showed MH ⁺ = 194; T _RET = 0.38 min.

Intermediate 132: (1E / Z) -2- [3- (Dimethylamino) phenyl] -N-hydroxyethanimidamide

Prepared from 3- (dimethylamino) benzeneacetonitrile (described in ML Sznaidman et al. Bioorganic Medical Chemistry Letters 1996, 6 (5), 565) using a process similar to that described for any of Intermediates 9, 22 or 80, using a similar or the same number of moles of reagents and / or volumes of solvents. LCMS showed MH ⁺ = 194; T _RET = 0.46 min.

Intermediate 133: (1E / Z) -N-Hydroxy-2- (phenyloxy) ethanimidamide

Available from Pfaltz & Bauer Inc.

Intermediate 134: (1E / Z) -N-hydroxy-2- (5,6,7,8-tetrahydro [1,2,4] triazolo [4,3-a] pyridin-3-yl) ethanimidamide

Prepared from 5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyridin-3-acetonitrile (commercially available from Interchim, 213 Avenue Kennedy, BP 1140, Montlucon, Cedex 03103, France, or Exploratory Library, Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France) using a process similar to that described for any of Intermediates 9, 22 or 80, using the same or the same amount of molar reagents and / or volumes of solvents. LCMS showed MH ⁺ = 198; T _RET = 0.32 min.

Intermediate 135: (1E / Z) -N-Hydroxy-2- (4-phenyl-1-piperazinyl) ethanimidamide

Prepared from 4-phenyl-1-piperazinacetonitrile (commercially available from Interchim, 213 Avenue Kennedy, BP 1140, Montlucon, Cedex 03103, France, or Exploratory Library, Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France) at using a process similar to that described for any of Intermediates 9, 22 or 80, using the same or the same amount of moles of reagents and / or volumes of solvents. LCMS showed MH ⁺ = 235; T _RET = 1.09 min.

Intermediate 136: 1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridine-5-carboxamide

A solution of Intermediate 17 (3.263 g, 11.25 mmol) in thionyl chloride (17 ml) was heated at 60 ° C. for 2 hours. This solution was concentrated in vacuo and then evaporated with dichloromethane. The residue was suspended in a solution of ammonia in dioxane (45 ml, 0.5 M solution) and the resulting mixture was stirred for 18 hours. After concentration in vacuo, the residue was again suspended in ammonia in dioxane (45 ml, 0.5 M) and stirred for another 16 hours. The solvent was removed in vacuo and the solid was suspended in a mixture of dichloromethane (40 ml) and water (40 ml), the solid was filtered, washed with water and dried in vacuum over P ₂ O ₅ to give Intermediate 136 as a cream solid (2, 50 g). LCMS showed MH ⁺ = 290; T _RET = 2.12 min.

Intermediate 137: 1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-carbonitrile

Burgess reagent (4.53 g, 19.0 mmol) was added to a suspension of Intermediate 136 (5.0 g, 17.3 mmol) in THF (80 ml). This reaction mixture was stirred at room temperature for 18 hours, then an additional portion of Burgess reagent (0.9 g, 1.8 mmol) was added and stirring was continued for 5 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was washed with water, dried and evaporated in vacuo to give Intermediate 137 as an off-white solid (4.43 g). LCMS showed MH ⁺ = 272; T _RET = 2.40 min.

Intermediate 138: 1-Ethyl-N-hydroxy-4- (tetrahydro-2H-pyran-4-ylamino) -N-pyrazolo [3,4-b] pyridin-5-carboximidamide

Intermediate 137 (3.50 g, 12.9 mmol), hydroxylamine hydrochloride (3.30 g, 47.8 mmol) and sodium bicarbonate (4.01 g, 47.8 mmol) in EtOH (45 ml) were heated at 45 ° C for 1.5 hours then at 50 ° C for 2.5 hours. This suspension was concentrated in vacuo and the solid was stirred in dichloromethane (80 ml) for 0.5 hours. This mixture was filtered and the solid was stirred in EtOH, the resulting mixture was filtered and the filtrate was evaporated. The solid was then washed with dichloromethane three times to give Intermediate 138 as a white solid (1.62 g). LCMS showed MH ⁺ = 305; T _RET = 1.85 min.

Intermediate 139: 1-Ethyl-N- [4- (hydroxymethyl) -tetrahydro-2H-pyran-4-yl] -4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4- b] pyridine-5-carboxamide

Intermediate 139 was prepared from Intermediate 17 and (4-aminotetrahydro-2H-pyran-4-yl) methanol (commercially available from PharmaCore Inc., 4170 Mendenhall Oaks Pkwy, Suite 140, High point, NC, USA) using the method similar to that for Intermediate 42. LCMS showed MH ⁺ = 404, T _RET = 2.19 min.

Intermediate 140: (R) - (+) - 3-Aminotetrahydrofuran-4-toluenesulfonate

Available from Fluka Chemie AG, Germany (CAS 111769-27-8).

Intermediate 141: (S) - (-) - 3-Aminotetrahydrofuran-4-toluenesulfonate

Available from E. Merck, Germany; or from E. Merck (Merck Ltd), Hunter Boulevard, Magna Park, Lutterworth, Leicestershire LE17 4XN, United Kingdom (CAS 104530-80-5).

Intermediate 142: Tetrahydro-2H-thiopyran-4-amine

Prepared from commercially available tetrahydrothiopyran-4-one as described in Subramanian et. al., J. Org. Chem., 1981, 46, 4376-4383. Subsequent preparation of the hydrochloride salt can be carried out in a conventional manner.

Intermediate 143: Tetrahydro-3-thiophenamine

Prepared analogously to Intermediate 142 from commercially available tetrahydrothiophen-4-one. Oxime formation is described in Grigg et.al., Tetrahedron, 1991, 47, 4477-4494, and oxime reduction in Unterhalt et. al., Arch. Pharm., 1990,317-318.

Intermediate 144: tetrahydro-3-thiophenamine 1,1-dioxide hydrochloride

Available from the Sigma Aldrich Library of Rare Chemicals (SALOR) (CAS-6338-70-1). The preparation of the amine salt of the hydrochloride salt can be carried out in a conventional manner.

Intermediate 145: Tetrahydro-2H-thiopyran-4-amine-1,1-dioxide hydrochloride

Prepared in the same manner as Intermediate 11 from commercially available tetrahydrothiophen-4-one. Oxidation to 1,1-dioxo-tetrahydro-1λ ⁶ -thiopyran-4-one is described in Rule et. al., J. Org. Chem., 1995, 60, 1665-1673. Oxime formation is described in Truce et.al., J. Org. Chem., 1957, 617, 620, and oxime reduction is described in Barkenbus et. al., J. Am. Chem. Soc., 1955, 77, 3866. The subsequent preparation of the hydrochloride amine salt can be carried out in a conventional manner.

Intermediate 146: 1,1-Dimethylethyl- (4,4-difluorocyclohexyl) carbamate

(Diethylamino) sulfur trifluoride (DAST), (0.06 ml, 0.47 mmol) was added to a stirred solution of 1,1-dimethylethyl (4-oxocyclohexyl) carbamate (250 mg, 1.17 mmol, commercially available from AstaTech Inc., Philadelphia, USA) in anhydrous dichloromethane (5 ml) and this mixture was stirred under nitrogen at 20 ° C. After 22 hours, the reaction mixture was cooled to 0 ° C, treated with saturated sodium bicarbonate solution (4 ml), and then allowed to warm to ambient temperature. The phases were separated by passing through a hydrophobic frit and the aqueous phase was further extracted using DCM (5 ml). The combined organic phases were concentrated in vacuo to give an orange solid (369 mg), which was further purified by chromatography using a TFE cartridge (silica, 10 g) while eluting with DCM to give Intermediate 62 (140 mg) containing 20% 1.1 -dimethylethyl- (4-fluoro-3-cyclohexen-1-yl) carbamate. ¹ H-NMR (400 MHz in COCl ₃ , 27 ° C, δ ppm):

Minor component: δ 5.11 (dm, 16 Hz, 1H), 4.56 (br, 1H), 3.80 (br, 1H) 2.45-1.45 (m's, 6H excess), 1.43 (s, 9H). Main component: δ 4.43 (br, 1H), 3.58 (br, 1H), 2.45-1.45 (m's, 8H excess), 1.45 (s, 9H).

Intermediate 147: (4,4-Difluorocyclohexyl) amine hydrochloride

A solution of hydrogen chloride in dioxane (4 M, 1.6 ml) was added at 20 ° C. to a stirred solution of Intermediate 146 (140 mg, 0.6 mmol) in dioxane (1.6 ml). After 3 hours, this reaction mixture was concentrated in vacuo to give Intermediate 147 (96.5 mg) containing 4-fluoro-3-cyclohexene-1-amine. ¹ H-NMR (400 MHz in d _6- DMSO, 27 ° C, δ ppm): minor component: δ 8.22 (br, 3H excess), 5.18 (dm, 16 Hz, 1H), 3.28-3.13 ( m, 1H excess), 2.41-1.53 (m's, 6H excess); main component: δ 8.22 (br, 3H excess), 3.28-3.13 (m, 1H excess), 2.41-1.53 (m's, 8H excess). Impurities are also present.

Intermediates 148 to 163: different types of R ³ R ^3a NH

Intermediate Number R ³ R ^3a NH Source R ³ R ^3a NH 148

J. Chem. Soc., Perkin Trans. 1, 1994,537 148A as Intermediate 148, but in the form of a racemic cis isomer, i.e. a racemic cis (3-hydroxy-cyclohex-1-yl) -amine J. Chem. Soc., Perkin Trans. 1, 1994,537 149

Aldrich; or TCI-America 150

US 4219660 151

Alldrich 152

Alldrich 153

Alldrich 154

Pfaltz-bauer 155

J. Org. Chem., 1985, 50 (11), 1859 156

WO 99/12933 157

EP 1,188,744 158

Sigma-Aldrich Company Ltd 159 *

J. Med. Chem., 1994, 37 (17), 2360 160 *

Alldrich 161 *

Alldrich 162 *

Alldrich 163 *

Peakdale Molecular Ltd * For R ³ R ^3a NH in Intermediates 159-163, R ³ R ^3a NH is the cis or trans isomer, if indicated. For Intermediates 161-163, R ³ R ^3a NH is usually 3-amino or 2-amino-cyclohex-1-ylamine in racemic form.

Table of Examples Example Number Title one N-cyclopentyl-1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 2 N-cyclopentyl-1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridin-4-amine 3 N-cyclopentyl-1-ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine four N-cyclopentyl-1-ethyl-5- (5-methyl-1,3,4-thiadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 5 N-cyclopentyl-1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-thiadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridin-4-amine 6 N-cyclopentyl-1-ethyl-5- (5-isopropyl-1,3,4-thiadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 7 1-Ethyl-N- (4-fluorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 8 N-cyclopentyl-5- (1.3-dimethyl-1H-1,2,4-triazol-5-yl) -1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine 9 1-Ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4- amine 10 N-cyclohexyl-1-ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine eleven 1-Ethyl-N-isobutyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 12 1-Ethyl-N-isobutyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 13 N-cyclohexyl-1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine fourteen 1-Ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4- amine; also called: 1-Ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-amine fifteen N - [(1R) -1,2-dimethylpropyl] -1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridine- 4-amine 16 N - [(1S) -1,2-dimethylpropyl] -1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridine- 4-amine 17 5- (5-tert-Butyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin- 4-amine; also called: 5- [5- (1,1-Dimethylethyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine eighteen 5- (5-tert-Butyl-1,3,4-oxadiazol-2-yl) -N-cyclohexyl-1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine 19 5- (5-tert-Butyl-1,3,4-oxadiazol-2-yl) -N-cyclopentyl-1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine twenty 5- (5-tert-Butyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N-isobutyl-1H-pyrazolo [3,4-b] pyridin-4-amine 21 5- (5-tert-Butyl-1,3,4-oxadiazol-2-yl) -N - [(1S) -1,2-dimethylpropyl] -1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine 22 5- (5-tert-Butyl-1,3,4-oxadiazol-2-yl) -N - [(1R) -1,2-dimethylpropyl] -1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine 23 1-Ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b ] pyridin-4-amine 24 N-cyclohexyl-1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridin-4-amine 25 1-Ethyl-N-isobutyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridin-4-amine 26 N - [(1S) -1,2-dimethylpropyl] -1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4 -b] pyridin-4-amine 27 N - [(1R) -1,2-dimethylpropyl] -1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-oxadiazol-2-yl} -1H-pyrazolo [3,4 -b] pyridin-4-amine 28 1-Ethyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4- amine 29th 1-Ethyl-5- [3- (methoxymethyl) -1,2,4-oxadiazol-5-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin- 4-amine thirty 5- {3 - [(Dimethylamino) methyl] -1,2,4-oxadiazol-5-yl} -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b ] pyridin-4-amine 31 1-Ethyl-5- [3- (morpholin-4-ylmethyl) -1,2,4-oxadiazol-5-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4- b] pyridin-4-amine 32 5- (5-Cyclopropyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4- amine 33 N- (1-Acetylpiperidin-4-yl) -1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4- amine 34 1-Ethyl-5- [5- (3-methyloxetan-3-yl) -1,3,4-oxadiazol-2-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3, 4-b] pyridin-4-amine 35 1-Ethyl-5- {5 - [(4-methylpiperazin-1-yl) methyl] -1,3,4-oxadiazol-2-yl} -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4-amine; also called; 1-Ethyl-5- {5 - [(4-methyl-1-piperazinyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine 36 5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N-isopropyl-1,3,4-oxadiazole- 2-carboxamide 37 4- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole-2 -yl} -1-methylpyrrolidin-2-one 38 1-Ethyl-N-tetrahydro-2H-pyran-4-yl-5- (5-tetrahydro-2H-pyran-4-yl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine; also called: 1-Ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-yl) -1,3,4-oxadiazol-2-yl] -1H-pyrazolo [3,4-b] pyridin-4-amine 39 1-Ethyl-5- [5- (morpholin-4-ylmethyl) -1,3,4-oxadiazol-2-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4- b] pyridin-4-amine; also called: 1-Ethyl-5- [5- (morpholin-4-ylmethyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 40 5- [5- (tert-butoxymethyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4-amine 40A Methyl-2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -4,5-dihydro-1,3- oxazole-4-carboxylate 41 Methyl-2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxylate 42 1-Ethyl-5- (4-methyl-4,5-dihydro-1,3-oxazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine 43 1- (n-Propyl) -5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine 44 1-Ethyl-5- [5- (tetrahydrofuran-2-yl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine 45 1-Ethyl-5- [5- (dimethylamino) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 46 1-Ethyl-5- (5-methyl-1,2,4-triazol-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin- 4-amine 47 N- (1-Acetylpiperidin-4-yl) -1-ethyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -1H-pyrazolo [3,4-b] pyridin-4- amine 48 N- (1-Acetylpiperidin-4-yl) -1-ethyl-5- [3- (morpholin-4-ylmethyl) -1,2,4-oxadiazol-5-yl] -1H-pyrazolo [3,4- b] pyridin-4-amine 49 1-Ethyl-5 - [(4R) -4-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine fifty 1-Ethyl-5 - [(4S) -4-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine 51 1-Ethyl-5 - [(4S) -4- (phenylmethyl) -4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine 52 1-Ethyl-5 - [(4R) -4- (phenylmethyl) -4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine 53 1-Ethyl-5 - [(4S, 5R) -5-methyl-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl ) -1H-pyrazolo [3,4-b] pyridin-4-amine 54 1-Ethyl-5 - [(5R) -5-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 55 1-Ethyl-5 - [(5S) -5-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine 56 5- (4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine 57 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxylic acid 58 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (1-methylethyl) -1,3 - oxazole-4-carboxamide 59 1-Ethyl-5- [4- (4-morpholinylcarbonyl) -1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 60 1-Ethyl-N-methyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine 61 trans-4 - {[1-Ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-yl] amino} cyclohexanol 62 1-Ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-3-yl) -1H-pyrazolo [3,4-b] pyridin- 4-amine 63 4 - {[1-Ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-yl] amino} cyclohexanone 64 1-Ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-propyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine 65 5- [5- (1,1-Dimethylethyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-6-methyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine 66 1-Ethyl-6-methyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-yl) -1,3,4-oxadiazol-2-yl ] -1H-pyrazolo [3,4-b] pyridin-4-amine 67 5- (5-Cyclobutyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin- 4-amine 68 5- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole-2 -yl} -2-pyrrolidinone 69 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole- 2-yl} methyl) acetamide 70 1-Ethyl-5- [5- (1-methyl-2-piperidinyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine 71 1-Ethyl-5- {5 - [(4-methyl-1,2,5-oxadiazol-3-yl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H- pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 72 3- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole-2 -yl} cyclopentanone 73 1-Ethyl-5- [5- (tetrahydro-3-furanyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo (3, 4-b] pyridin-4-amine 74 (4S) -4- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4 -oxadiazol-2-yl} -1,3-thiazolidin-2-one 75 5- [5- (2,2-Dimethylcyclopropyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine 76 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole- 2-yl} methyl) -N-methylacetamide 77 1-Ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-ylmethyl) -1,3,4-oxadiazol-2-yl] -1H- pyrazolo [3,4-b] pyridin-4-amine 78 1-Ethyl-5- [5- (1-methylcyclobutyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine 79 1-Ethyl-5- [5- (3-methyl-5-isoxazolyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine 80 1-Ethyl-5- [5- (1-methyl-1H-pyrazol-5-yl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) - 1H-pyrazolo [3,4-b] pyridin-4-amine 81 5- [5- (1-Acetyl-4-piperidinyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine 82 1-Ethyl-5- {3 - [(4-methyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine 83 1-Ethyl-5- [3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine 84 1-Ethyl-5- {3- [2-oxo-2- (1-pyrrolidinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 85 2- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N-phenylacetamide 86 2- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N- (1-phenylethyl) acetamide 87 1-Ethyl-5- {3- [2-oxo-2- (1-piperidinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 88 2- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N- (phenylmethyl) acetamide 89 2- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N, N-dimethylacetamide 90 N-Ethyl-2- {5- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4 -oxadiazol-3-yl} acetamide 92 1-Ethyl-5- {3- [1- (4-morpholinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 93 5- [3- (Cyclohexylmethyl) -1,2,4-oxadiazol-5-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 95 1-Ethyl-5- {3- [2-oxo-2- (1-piperidinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 96 1-Ethyl-5- {3- [2- (4-methyl-1-piperazinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4 -yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 97 1-Ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (1H-1,2,3-triazol-1-ylmethyl) -1,3,4-oxadiazol-2-yl ] -1H-pyrazolo [3,4-b] pyridin-4-amine 98 5- {5 - [(2,4-Dimethyl-1,3-thiazol-5-yl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N- (tetrahydro-2H- pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine formate 99 1-Ethyl-5- [5- (2-furanylmethyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine formate one hundred 1-Ethyl-5- [5- (3-isoxazolylmethyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine formate 103 1-Ethyl-5- (5 - {[4- (methyloxy) phenyl] methyl} -1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine trifluoroacetate 104 1-Ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (1H-tetrazol-1-ylmethyl) -1,3,4-oxadiazol-2-yl] -1H-pyrazolo [ 3,4-b] pyridin-4-amine formate 105 1-Ethyl-5- [5- (5-isothiazolylmethyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine 106 1-Ethyl-5- {5 - [(3-methyl-5-isoxazolyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine formate 107 5- (5 - {[4- (Dimethylamino) phenyl] methyl} -1,3,4-oxadiazol-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine (1: 1) 108 1-Ethyl-5- {5 - [(2-methyl-1,3-thiazol-4-yl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran- 4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine formate 109 2- [1 - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4 -oxadiazol-2-yl} methyl) cyclopentyl] -N-methylacetamidate trifluoroacetate 111 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole- 2-yl} methyl) -cyclopropanecarboxamide 112 1-Ethyl-5- {5 - [(5-methyl-3-isoxazolyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine formate 113 1-Ethyl-5- {5 - [(5-methyl-3-isoxazolyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine 114 1-Ethyl-5- {5- [2- (4-methyl-1,3-thiazol-5-yl) ethyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H- pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine formate 117 5- {5 - [(3,5-Dimethyl-4-isoxazolyl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine trifluoroacetate 118 N- (1- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4- oxadiazol-2-yl} ethyl) acetamide 119 5- {5 - [(1-acetyl-4-piperidinyl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine trifluoroacetate 120 1-Ethyl-5- {5 - [(4-methylphenyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3 , 4-b] pyridin-4-amine 121 1-Ethyl-5- [5- (4-methylphenyl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine 122 5- [5- (3,4-Dimethylphenyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine 123 5- [5- (2,4-Dimethylphenyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-amine 125 5- {5 - [(4-Bromophenyl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3 , 4-b] pyridin-4-am.in 126 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (phenylmethyl) -1,3-oxazol- 4-carboxamide 127 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - {[4- (methyloxy) phenyl] methyl } -1,3-oxazole-4-carboxamide 128 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - [(2-methylphenyl) methyl] -1 3-oxazole-4-carboxamide 129 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - [(4-methylphenyl) methyl] -1 3-oxazole-4-carboxamide 130 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - [(3-methylphenyl) methyl] -1 3-oxazole-4-carboxamide 131 N - [(4-Chlorophenyl) methyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1 3-oxazole-4-carboxamide 132 N - [(2,3-Dimethylphenyl) methyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxamide 133 N - [(3,5-Dimethylphenyl) methyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxamide 134 N - [(3,4-Dimethylphenyl) methyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxamide 135 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (1-phenylethyl) -1,3- oxazole-4-carboxamide 136 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - {(1R) -1- [4- (methyloxy) phenyl] ethyl} -1,3-oxazole-4-carboxamide 137 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - [(1R) -1-phenylpropyl] - 1,3-oxazole-4-carboxamide 138 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (4-methylphenyl) -1,3- oxazole-4-carboxamide 139 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - ({4 - [(methylsulfonyl) amino] phenyl} methyl) -1,3-oxazole-4-carboxamide 140 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N - {[4- (methylsulfonyl) phenyl] methyl } -1,3-oxazole-4-carboxamide 141 N- (1-Acetyl-4-piperidinyl) -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] - 1,3-oxazole-4-carboxamide 142 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (tetrahydro-2H-pyran-4-yl ) -1,3-oxazole-4-carboxamide 143 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (tetrahydro-2-furanylmethyl) -1, 3-oxazole-4-carboxamide 144 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- [2- (4-methyl-1- piperazinyl) ethyl] -1,3-oxazole-4-carboxamide 145 N- [1- (Aminomethyl) cyclohexyl] -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N methyl-1,3-oxazole-4-carboxamide 146 N- (2,6-Dimethylphenyl) -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1, 3-oxazole-4-carboxamide 147 N - {[4- (Aminocarbonyl) phenyl] methyl} -2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl ] -1,3-oxazole-4-carboxamide 148 2- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N- (tetrahydro-2H-pyran-4-yl) acetamide 149 5- {3- [2- (2,6-Dimethyl-4-morpholinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -1-ethyl-N- (tetrahydro-2H-pyran -4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 150 1-Ethyl-5- {3- [2- (4-methyl-1-piperidinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4 -yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 152 2- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N- [1-methyl-2- (methyloxy) ethyl] acetamide 153 5- {3- [2- (3,5-Dimethyl-1-piperidinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -1-ethyl-N- (tetrahydro-2H-pyran -4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 154 1-Ethyl-5- {3- [2- (3-methyl-1-piperidinyl) -2-oxoethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4 -yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 155 2- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole-3 -yl} -N-3-pyridinylacetamide 157 6- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4-oxadiazole-2 -yl) -2-piperidinone 158 1-Ethyl-5- {5 - [(3-methyl-1H-1,2,4-triazol-5-yl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro- 2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 159 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) acetamide 160 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) benzamide 161 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-phenylacetamide 162 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-methylpropanamide 163 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -3-methylbutanamide 164 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} -methyl) cyclohexanecarboxamide 165 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-furancarboxamide 166 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) methanesulfonamide 167 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) benzenesulfonamide 168 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -1-phenylmethanesulfonamide 169 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-propanesulfonamide 170 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -1-propanesulfonamide 171 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} -methyl) cyclopropanesulfonamide 172 N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-thiophenesulfonamide 173 1 - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-pyrrolidinone 174 1 - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4-oxadiazole- 3-yl} methyl) -2-piperidinone 175 5- {3 - [(1-Acetyl-4-piperidinyl) methyl] -1,2,4-oxadiazol-5-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine 176 1-Ethyl-5- (3 - {[1- (3-methylbutanoyl) -4-piperidinyl] methyl} -1,2,4-oxadiazol-5-yl) -N- (tetrahydro-2H-pyran-4- il) -1H-pyrazolo [3,4-b] pyridin-4-amine 177 1-Ethyl-5- (3 - {[1- (methylsulfonyl) -4-piperidinyl] methyl} -1,2,4-oxadiazol-5-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 178 1-Ethyl-5- {3- [1- (phenylsulfonyl) cyclopropyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3 , 4-b] pyridin-4-amine 179 1-Ethyl-5- [3- (phenylmethyl) -1,2,4-oxadiazol-5-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine 180 1-Ethyl-5- [3- (1-phenylethyl) -1,2,4-oxadiazol-5-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4- b] pyridin-4-amine 181 1-Ethyl-5- (3 - {[4- (methyloxy) phenyl] methyl} -1,2,4-oxadiazol-5-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine 182 5- (3 - {[4- (Dimethylamino) phenyl] methyl} -1,2,4-oxadiazol-5-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine 183 5- (3 - {[3- (Dimethylamino) phenyl] methyl} -1,2,4-oxadiazol-5-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine 184 5- (3 - {[4- (Dimethylamino) phenyl] methyl} -1,2,4-oxadiazol-5-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine 185 1-Ethyl-5- {3 - [(phenyloxy) methyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4 -b] pyridin-4-amine 186 1-Ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [3- (5,6,7,8-tetrahydro [1,2,4] triazolo [4,3-a] pyridine- 3-ylmethyl) -1,2,4-oxadiazol-5-yl] -1H-pyrazolo [3,4-b] pyridin-4-amine 187 1-Ethyl-5- {3 - [(4-phenyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine 188 1-Ethyl-5- (5-ethyl-1,2,4-oxadiazol-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin- 4-amine 189 5- (5 - {[4- (Dimethylamino) phenyl] methyl} -1,2,4-oxadiazol-3-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine 190 1-Ethyl-5- (5 - {[4- (methyloxy) phenyl] methyl} -1,2,4-oxadiazol-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H- pyrazolo [3,4-b] pyridin-4-amine 191 5- (3,8-dioxa-1-azaspiro [4,5] dec-1-en-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [ 3,4-b] pyridin-4-amine

Example 1: N-cyclopentyl-1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

Intermediate 4 (0.043 g) was dissolved in acetonitrile (2 ml), then treated with phosphorus oxychloride (0.101 g) and stirred in nitrogen atmosphere and heated at 90 ° C for 2 hours. This mixture was concentrated in vacuo and the residue was partitioned between DCM and saturated aqueous sodium bicarbonate. The organic layer was concentrated in vacuo and applied onto a TFE cartridge (aminopropyl, 1 g), which was eluted with methanol. Concentration in vacuo gave the compound of Example 1 (0.032 g). LCMS showed MH ⁺ = 313; T _RET = 3.13 min.

Similarly obtained, for example, without limitation, using the same or similar amount of moles of reagents and / or volumes of solvents, but with increased reaction time (see table):

R ^y Starting material Interaction time MH ⁺ ion T _RET (min) Example 2

Intermediate 5 3 h 391 2.88

Example 3: N-cyclopentyl-1-ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

Intermediate 10 was dissolved in acetonitrile (2 ml), then treated with phosphorus oxychloride (0.101 g) and stirred under nitrogen at 90 ° C. for 3.5 hours. This mixture was concentrated in vacuo and the residue was partitioned between DCM and saturated aqueous bicarbonate solution. sodium. The organic layer was concentrated in vacuo and the residue was applied to a TFE cartridge (silica, 5 g), which was eluted with a mixture of cyclohexane: Et ₂ O (1: 2). Fractions containing the desired material were combined and concentrated in vacuo to give the compound of Example 3 (0.034 g). LCMS showed MH ⁺ = 341; T _RET = 3.39 min.

Example 4: N-cyclopentyl-1-ethyl-5- (5-methyl-1,3,4-thiadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

A solution of Intermediate 4 (0.09 g) in acetonitrile (5 ml) was stirred under nitrogen and treated with Lawesson's reagent (0.116 g). This mixture was heated at 65 ° C for 16 hours, then concentrated in vacuo. The residue was applied to a TFE cartridge (silica, 5 g) and was suirable gradient of a mixture of cyclohexane: Et ₂ O (1: 2, then 1: 3, 1: 4, 1: 5, 0: 1). Fractions containing the desired material were combined and concentrated in vacuo. Additional purification was carried out using mass-controlled self-preparative HPLC to give the compound of Example 4 (0.002 g). LCMS showed MH ⁺ = 339; T _RET = 3.23 min.

Example 5: N-cyclopopentyl-1-ethyl-5- {5 - [(methylsulfonyl) methyl] -1,3,4-thiadiazol-2-yl} -1H-pyrazolo [3,4-b] pyridin-4- amine

A solution of Intermediate 5 (0.07 g) in acetonitrile (3 ml) was stirred under a nitrogen atmosphere and treated with Lawesson's reagent (0.085 g). This mixture was heated at 65 ° C for 136 hours, then concentrated in vacuo. The residue was partitioned between DCM and water and the organic layer was concentrated in vacuo. Additional purification was carried out using mass-controlled self-preparative HPLC to give the compound of Example 5 (0.008 g). LCMS showed MH ⁺ = 407; T _RET = 2.98 min.

Example 6: N-cyclopentyl-1-ethyl-5- (5-isopropyl-1,3,4-thiadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

Intermediate 10 was dissolved in acetonitrile (5 ml), then treated with Lawesson's reagent (0.125 g) and heated under nitrogen at 65 ° C for 66 hours. Volatiles were removed in vacuo and the residue was purified by mass-controlled self-preparative HPLC to give Example compound 6. LCMS showed MH ⁺ = 357; T _RET = 3.59 min.

Example 7: 1-Ethyl-N- (4-fluorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

A solution of Intermediate 6 (0.04 g) in ethanol (1 ml) was stirred over 4Å molecular sieve powder (0.290 g) and treated with Intermediate 9 (0.045 g) and then sodium ethylate (0.020 g). This mixture was heated at reflux for 18 hours, then cooled and filtered. After the filtrate was concentrated in vacuo, the residue was applied to a TFE cartridge (silica, 5 g), which was eluted with a mixture of cyclohexane: Et ₂ O (1: 1). Fractions containing the desired material were combined and concentrated in vacuo to give the compound of Example 7 (0.017 g). LCMS showed MH ⁺ = 339; T _RET = 3.23 min.

Example 8: N-cyclopentyl-5- (1,3-dimethyl-1H-1,2,4-triazol-5-yl) -1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-amine

A solution of Intermediate 7 (0.06 g) in ethanol (2 ml) was treated with triethylamine (0.101 g) and then methylacetimidate hydrochloride (0.033 g), and this mixture was heated under reflux (80 ° C) for 42 hours. The reaction was incomplete, therefore, an additional portion of methylacetimidate hydrochloride (0.033 g) was added and stirring was continued under reflux for 6 days. This mixture was concentrated in vacuo and the residue was partitioned between DCM and 2 M aqueous HCI. The organic layer was concentrated in vacuo and purified by mass-controlled self-preparative chromatography to give the compound of Example 8 (0.003 g). LCMS showed MH ⁺ = 326; T _RET = 2.66 min.

Example 9: 1-Ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridine -4-amine

Intermediate 13 (0.016 g) was dissolved in anhydrous acetonitrile (1 ml). 4-aminotetrahydropyran hydrochloride (Intermediate 21A, 0.008 g) was added and then diisopropylethylamine (0.05 ml) was added and the mixture was stirred under nitrogen at 75 ° C for 19 hours. An additional portion of 4-aminotetrahydropyran (0.002 g) was added and stirring continued at 85 ° C. for 16 hours. The mixture was concentrated in vacuo and partitioned between DCM and water. The organic phase was concentrated in vacuo and applied onto a TFE cartridge (silica, 1 g), which was eluted successively with a gradient of EtOAc: cyclohexane (1) 1: 8, (2) 1: 4, (3) 1: 2, (4) 1 : 1 and (5) 1: 0. Fractions containing the desired material were combined and concentrated in vacuo to give the compound of Example 9 (0.013 g). LCMS showed MH ⁺ = 357; T _RET = 2.89 min.

Example 10: N-cyclohexyl-1-ethyl-5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

Intermediate 13 (0.016 g, 0.055 mmol) was dissolved in anhydrous acetonitrile (1 ml). Then cyclohexylamine (0.007 ml, 0.061 mmol) and then diisopropylethylamine (0.05 ml, 0.29 mmol) were added and the mixture was stirred under nitrogen at 75 ° C for 16 hours. The mixture was concentrated in vacuo and partitioned between DCM and water . The organic phase was concentrated in vacuo and applied onto a TFE cartridge (silica, 1 g), which was eluted successively with a gradient of EtOAc: cyclohexane (1) 1:16, (2) 1: 8, (3) 1: 4, (4) 1 : 2 and (5) 1: 1. Fractions containing the desired material were combined and concentrated in vacuo to give the compound of Example 10 (0.015 g). LCMS showed MH ⁺ = 355; T _RET = 3.59 min.

Similarly obtained using the same or a similar amount of moles of reagents and volumes of solvents:

NR3R33 Starting amine MH ⁺ ion T _RET (min) Example 11

Isobutylamine 329 3.40

Example 12: 1-Ethyl-N-isobutyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

Intermediate 12 (0.026 g, 0.1 mmol) was dissolved in ethanol (1.5 ml) and treated with a solution of isobutylamine (0.007 g, 0.1 mmol), also in ethanol (1 ml). This mixture was then treated with diisopropylethylamine (0.075 ml, 0.4 mmol, 4 mol equivalents) and stirred at 75 ° C. for 16 hours. This mixture was concentrated in vacuo and applied to a TFE cartridge (silica, 0.5 g), which was eluted sequentially with (1) chloroform, (2) Et ₂ O and (3) methanol. Fractions containing the desired material were combined and concentrated in vacuo to give the compound of Example 12 (0.024 g). LCMS showed MH ⁺ = 301; T _RET = 2.90 min.

Similarly obtained using the same or a similar amount of moles of reagents and volumes of solvents:

R ^y NR ³ R ³³ Raw material Reagent amine MH ⁺ ion T _RET (min) Example 13 Me

Intermediate 12 cyclohexylamine 327 3.12 Example 14 Me

Intermediate 12 4-amino-tetrahydropyran 329 2.49 Example 15 Me

Intermediate 12 (R) - (-) - 3-methyl-2-butylamine 315 3.00 Example 16 Me

Intermediate 12 (S) - (-) - 3-methyl-2-butylamine 315 3.00 Example 17 ^t Bu

The intermediate connection 14 4-amino-tetrahydropyran 371 2.99 Example 18 ^t Bu

The intermediate connection 14 Cyclohexylamine 369 3.64 Example 19 ^t Bu

The intermediate connection 14 Cyclopentylamine 355 3.48 Example 20 ^t Bu

The intermediate connection 14 Isobutylamine 343 3.43 Example 21 ^t Bu

The intermediate connection 14 (S) - (-) - 3-methyl-2-butylamine 357 3.53 Example 22 ^t Bu

The intermediate connection 14 (R) - (-) - 3-methyl-2-butylamine 357 3.53 Example 23

The intermediate connection 15 4-amino-tetrahydropyran 407 2.44 Example 24

The intermediate connection 15 cyclohexylamine 405 3.00 Example 25

The intermediate connection 15 Isobutylamine 379 2.81 Example 26

The intermediate connection 15 (S) - (-) - 3-methyl-2-butylamine 393 2.90 Example 27

The intermediate connection 15 (R) - (-) - 3-methyl-2-butylamine 393 2.91

Example 14: 1-Ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-amine

The following describes an alternative method of obtaining the compound of Example 14:

To Intermediate 17 (1.10 g, 3.80 mmol) in N, N'-dimethylformamide (10 ml) was added EDC (0.823 g, 5.3 mmol) and HOBT (0.614 g, 4.55 mmol). This mixture was stirred for 1.5 hours, then acetic hydrazide (0.421 g, 5.7 mmol) (commercially available from, for example, Aldrich) was added and this reaction mixture was stirred at 20 ° C. for 48 hours. The reaction mixture was evaporated and the residue was partitioned between chloroform and water. The aqueous phase was extracted with chloroform and the combined organic phases were washed with a saturated aqueous solution of sodium chloride, then dried (Na ₂ SO ₄ ) and evaporated. Phosphorus oxychloride (10 ml) was added to the residue, and this mixture was heated at 120 ° C. for 0.5 hours. This reaction mixture was evaporated in vacuo and the residue was applied to a TFE cartridge (silica, 20 g). The cartridge was eluted with dichloromethane, a mixture of cyclohexane: ethyl acetate (2: 1, then 1: 1), ethyl acetate, a mixture of chloroform: methanol (19: 1, then 9: 1). Fractions containing the desired compounds were combined and evaporated in vacuo. The residue was then chromatographed on Biotage (silica, 50 g) using a mixture of cyclohexane: ethyl acetate (2: 1, then 1: 1), ethyl acetate and then a mixture of ethyl acetate: ethanol (19: 1, 9: 1, then 9: 2). The residue was partitioned between dichloromethane and an aqueous solution of sodium bicarbonate. The organic phase was dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the compound of Example 14 as a pale yellow solid (0.93 g). LCMS showed MH ⁺ = 329, T _RET = 2.54 min. ¹ H-NMR (400 MHz in CDCl ₃ , 27 ° C, δ ppm) 9.12 (br m, 1H), 8.72 (s, 1H), 8.01 (s, 1H), 4.52 (q, 2H), 4.24 (m, 1H), 4.08 (m, 2H), 3.67 (m, 2H), 2.65 (s, 3H), 2.20 (m, 2H), 1.86 (m, 2H), 1.53 (t, 3H).

Example 17: 5- [5- (1,1-Dimethylethyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

The following describes an alternative method of obtaining the compound of Example 17:

To Intermediate 17 (1.40 g, 4.83 mmol) in N, N'-dimethylformamide (20 ml) was added EDC (1.30 g, 6.76 mmol) and HOBT (0.782 g, 5.80 mmol) . This mixture was stirred for 0.5 hours, then pivalic acid hydrazide (0.616 g, 5.3 mmol) was added to it (commercially available from Fluorochem Ltd, Wesley Street, Glossop, Derbyshire SK13 9RY, United Kingdom, or may be prepared in accordance with the methodology of K. Ohmoto et al., J. Med. Chem., 2001, 44 (8), 1268) and the reaction mixture was stirred at 20 ° C for 18 hours. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic phase was washed with water, saturated aqueous sodium hydrogen carbonate and then with saturated aqueous sodium chloride, then evaporated in vacuo. Phosphorus oxychloride (10 ml) was added to the residue, and this mixture was heated at 120 ° C for 3 hours. The reaction mixture was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was washed with an aqueous sodium hydrogen carbonate solution, then dried and evaporated in vacuo. The residue was applied to a TFE cartridge and eluted with cyclohexane: ethyl acetate (3: 1, then 7: 3). The solvent was evaporated in vacuo to give the compound of Example 17 as a white solid (0.65 g). LCMS showed MH ⁺ = 371, T _RET = 3.05 min. ¹ H-NMR (400 MHz in CDCl ₃ , 27 ° C, 6 ppm) 9.18 (br m, 1H), 8.75 (s, 1H), 8.01 (s, 1H), 4.52 (q, 2H), 4.25 (m, 1H), 4.08 (m, 2H), 3.67 (m, 2H), 2.20 (m, 2H), 1.84 (m, 2H), 1.57-1.49 (m, 12H).

Example 28: 1-Ethyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridine -4-amine

A solution of Intermediate 16 (0.05 g, 0.157 mmol) in ethanol (2 ml) was stirred over a 4Å molecular sieve powder (0.30 g) and treated with a solution of Intermediate 9 (0.059 g, 0.8 mmol) and sodium ethylate ( 0.027 g, 0.4 mmol) in ethanol (1 ml). This mixture was heated at reflux for 18 hours under nitrogen, then cooled and filtered. After the filtrate was concentrated in vacuo, the residue was applied to a TFE cartridge (silica, 5 g), which was eluted with a mixture of cyclohexane: EtOAc (1: 1). Fractions containing the desired material were combined and concentrated in vacuo to give the compound of Example 28 (0.024 g). LCMS showed MH ⁺ = 329; T _RET = 2.86 min.

Similarly, when using the same or a similar amount of moles of reagents and volumes of solvents, the following was obtained:

R ^x Starting amidoxime MH ⁺ ion T _RET (MIN) Example 29 CH ₂ OMe The intermediate connection 22 359 2.78

Example 30: 5- {3 - [(Dimethylamino) methyl] -1,2,4-oxadiazol-5-yl} -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3, 4-b] pyridin-4-amine

A solution of Intermediate 16 (0.05 g) in ethanol (2 ml) was stirred over 4Å molecular sieve powder (0.30 g) and treated with a solution of Intermediate 23 (0.094 g) and sodium ethylate (0.027 g) in ethanol (1 ml ) This mixture was heated at reflux for 18 hours under nitrogen, then cooled and filtered. After the filtrate was concentrated in vacuo, the residue was applied to a TFE cartridge (silica, 5 g), which was eluted with 2-5% methanol in DCM. Fractions containing the desired material were combined and concentrated in vacuo, then applied to an additional TFE cartridge (aminopropyl, 1 g), which was eluted with methanol to give the compound of Example 30 (0.02 g). LCMS showed MH ⁺ = 372; T _RET = 2.10 min.

Example 31: 1-Ethyl-5- [3- (morpholin-4-ylmethyl) -1,2,4-oxadiazol-5-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3 , 4-b] pyridin-4-amine

A solution of Intermediate 16 (0.05 g) in ethanol (2 ml) was stirred over a 4Å molecular sieve powder (0.30 g) and treated with a solution of Intermediate 24 (0.128 g) and sodium ethylate (0.027 g) in ethanol (1 ml ) This mixture was heated at reflux for 18 hours under nitrogen, then cooled and filtered. After the filtrate was concentrated in vacuo, the residue was applied to a TFE cartridge (silica, 5 g), which was eluted with 2-5% methanol in DCM. Fractions containing the desired material were combined and concentrated in vacuo to give the compound of Example 31 (0.025 g). LCMS showed MH ⁺ = 415; T _RET = 2.46 min.

Example 32: 5- (5-cyclopropyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridine -4-amine

A solution of Intermediate 20 (0.020 g) in THF (0.2 ml) was treated with a Burgess reagent (0.026 g) and heated with microwaves at 120 ° C (100 W) for 5 minutes. This mixture was concentrated by evaporation in a stream of nitrogen and the residue was applied to a TFE cartridge (silica, 1 g), which was eluted with 2% methanol in DCM to give Example 32 as a white solid (0.014 g). LCMS showed MH ⁺ = 355; T _RET = 2,78 min.

Example 33: N- (1-Acetylpiperidin-4-yl) -1-ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridine -4-amine

Intermediate 12 (0.03 g) was dissolved in acetonitrile (2 ml) and treated with DIPEA (0.1 ml) and Intermediate 25 (0.022 g). This mixture was stirred at 85 ° C for 18 hours, then concentrated in vacuo and partitioned between DCM and water. The layers were separated and the organic layer was concentrated in vacuo, then purified by mass-controlled self-preparative HPLC to give Example 33 (0.01 g). LCMS showed MH ⁺ = 370; T _RET = 2.48 min.

Example 34: 1-Ethyl-5- [5- (3-methyloxetan-3-yl) -1,3,4-oxadiazol-2-yl] -N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo [3,4-b] pyridin-4-amine

A solution of Intermediate 19 (0.05 g, 0.133 mmol), TBTU (0.045 g, 0.14 mmol) and DIPEA (0.1 ml, approximately 0.5 mmol) in DMF (1 ml) was stirred at room temperature in the atmosphere nitrogen for 5 min. Then, a solution of Intermediate 26 (0.024 g, 0.21 mmol) in DMF (1 ml) is added and stirring is continued for 18 hours. The reaction after this time may not be complete, so an additional portion of Intermediate 26 (0.012 g, 0, 10 mmol) and stirring was continued under nitrogen for an additional 18 hours. This mixture was concentrated in vacuo, then the residue was applied to a TFE cartridge (aminopropyl, 2 g), which was eluted with methanol (2 × 3 ml). Fractions containing the desired material are concentrated in vacuo.

The partially purified intermediate is taken further without further characterization and dissolved in THF (0.5 ml), then treated with a Burgess reagent (0.025 g, approximately 0.1 mmol). This mixture is heated under microwave conditions at 120 ° C (120 W) for 5 minutes. The mixture was then concentrated in vacuo and purified by mass-controlled self-preparative HPLC to give the compound of Example 34.

In accordance with an alternative and more preferred embodiment, this interaction was carried out as follows. A solution of the carboxylic acid Intermediate 26 (0.024 g, 0.21 mmol) was mixed with TBTU (0.045 g, 0.14 mmol) and DIPEA (0.1 ml, approximately 0.5 mmol) in DMF (1 ml ) at room temperature in a nitrogen atmosphere for 5 minutes Then a solution of Intermediate 19 (0.05 g, 0.133 mmol) in DMF (1 ml) was added and stirring was continued for 18 hours. It was found that the reaction after this time was incomplete, therefore, an additional portion of Intermediate 26 (0.012 g) was added. , 0.10 mmol) and stirring was continued under nitrogen for an additional 18 hours. This mixture was concentrated in vacuo, then the residue was applied to a TFE cartridge (aminopropyl, 2 g), which was eluted with methanol (2 × 3 ml). Fractions containing the desired material were concentrated in vacuo. The partially purified intermediate was taken further without further characterization and dissolved in THF (0.5 ml), then treated with a Burgess reagent (0.025 g, approximately 0.1 mmol). This mixture was heated under microwave conditions at 120 ° C (120 W) for 5 minutes. The mixture was then concentrated in vacuo and purified by mass-controlled self-preparative HPLC to give Example 34 (0.006 g). LCMS showed MH ⁺ = 385; T _RET = 2.65 min.

Similarly obtained using the above original or alternative embodiment, and using the same or similar amount of moles of reagents and volumes of solvents, the following:

R ^y Starting carboxylic acid (instead of Intermediate 26) MH ⁺ ion T _RET (min) Example 35

The intermediate connection 27 427 2.14 Example 36

The intermediate connection 28 400 2.87 Example 37

The intermediate connection 29 412 2,39

Example 35: 1-Ethyl-5- {5 - [(4-methyl-1-piperazinyl) methyl] -1,3,4-oxadiazol-2-yl} -N- (tetrahydro-2H-pyran-4-yl ) -1H-pyrazolo [3,4-b] pyridin-4-amine

The following describes an alternative method of obtaining the compound of Example 35:

A solution of Intermediate 27 (0.463 g, 2.93 mmol), TBTU (0.941 g, 2.93 mmol) and DIPEA (1.53 ml, 8.79 mmol) in anhydrous dimethylformamide (7 ml) was stirred at room temperature for 15 minutes. Then a solution of Intermediate 19 (1.0 g, 2.93 mmol) in anhydrous dimethylformamide (5 ml) was added and stirring was continued for 1 hour. This mixture was concentrated in vacuo and the residue was dissolved in methanol (5 ml) and applied in equal parts to two TFE cartridge (aminopropyl, South). Cartridges were eluted with methanol. The product fractions were combined and evaporated to give a yellow oil (1.56 g), which was dissolved in dichloromethane (10 ml) and applied to a TFE cartridge (silica, 10 g). The cartridge was eluted with chloroform-methanol-triethylamine (9/0, 2/0, 1). Fractions containing the desired product were combined and evaporated to give a pale yellow foam (1.17 g). This product was suspended in anhydrous tetrahydrofuran (45 ml) and treated with a Burgess reagent (1.244 g, 5.22 mmol) at room temperature under a nitrogen atmosphere. The resulting solution was heated at 70 ° C. After 2 hours, the reaction mixture was evaporated and the residual oil was dissolved in dichloromethane (5 ml) and applied to a TFE cartridge (silica, 20 g). The cartridge was eluted with chloroform-methanol-triethylamine (9/0, 2/0, 1). Fractions containing the desired material were combined and evaporated to give a creamy solid. Further purification by passing through an SCX cartridge (20 g) while eluting with methanol and then 10% ammonia in methanol gave the compound of Example 35 as a dark yellow solid (0.72 g). LCMS showed MH ⁺ = 427, T _RET = 2.02 min. ¹ H-NMR (400 MHz in CDCl ₃ , 27 ° C, δ ppm) 9.11 (d, 7 Hz, 1H), 8.76 (s, 1H), 8.01 (s, 1H), 4.52 (q, 2H ), 4.24 (m, 1H), 4.08 (m, 2H), 3.93 (s, 2H) 3.66 (m, 2H), 2.8-2.5 (br m's, 4H), 2.31 (s, 3H), 2.20 (m, 2H), 1.85 (m, 2H), 1.52 (t, 3H).

Example 38: 1-Ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-yl) -1,3,4-oxadiazol-2-yl] -1H-pyrazolo [3,4-b] pyridin-4-amine

A solution of Intermediate 19 (0.05 g, 0.133 mmol), TBTU (0.045 g, 0.14 mmol) and DIPEA (0.1 ml, approximately 0.5 mmol) in DMF (1 ml) was stirred at room temperature in the atmosphere nitrogen for 5 min. Then, a solution of Intermediate 30 (0.018 g, 0.14 mmol) in DMF (1 ml) is added and stirring is continued for 18 hours. The reaction after this time may not be complete, so an additional portion of Intermediate 30 (0.009 g, 0, 07 mmol) and stirring was continued under nitrogen for an additional 18 hours. This mixture was concentrated in vacuo, then the residue was applied to a TFE cartridge (aminopropyl, 2 g), which was eluted with methanol (2 × 3 ml). Fractions containing the desired material are concentrated in vacuo. The partially purified intermediate is taken further without further characterization and dissolved in THF (0.5 ml), then treated with a Burgess reagent (0.025 g, approximately 0.1 mmol). This mixture is heated under microwave conditions at 120 ° C (120 W) for 5 minutes. The interaction may be incomplete, so add an additional portion of the Burgess reagent (0.012 g, approximately 0.05 mmol) and heat the mixture under microwave conditions at 140 ° C (120 W) for an additional 10 minutes. This mixture was then concentrated in vacuo and purified by mass-controlled self-preparative HPLC to give the compound of Example 38.

In accordance with an alternative and more preferred embodiment, this interaction was carried out as follows. A solution of the carboxylic acid Intermediate 30 (0.018 g, 0.14 mmol) was mixed with TBTU (0.045 g, 0.14 mmol) and DIPEA (0.1 ml, approximately 0.5 mmol) in DMF (1 ml ) at room temperature in a nitrogen atmosphere for 5 minutes Then a solution of Intermediate 19 (0.05 g, 0.133 mmol) in DMF (1 ml) was added and stirring was continued for 18 hours. It was found that the reaction after this time was incomplete, so an additional portion of Intermediate 30 (0.009 g) was added. , 0.07 mmol) and stirring was continued under nitrogen for an additional 18 hours. This mixture was concentrated in vacuo, then the residue was applied to a TFE cartridge (aminopropyl, 2 g), which was eluted with methanol (2 × 3 ml). Fractions containing the desired material were concentrated in vacuo. The partially purified intermediate was taken further without further characterization and dissolved in THF (0.5 ml), then treated with a Burgess reagent (0.025 g, approximately 0.1 mmol). This mixture was heated under microwave conditions at 120 ° C (120 W) for 5 minutes. The interaction was incomplete, so an additional portion of Burgess reagent (0.012 g, approximately 0.05 mmol) was added and the mixture was heated under microwave conditions at 140 ° C (120 W) for an additional 10 minutes This mixture was then concentrated in vacuo and purified by mass-controlled self-preparative HPLC to give Example 38 (0.006 g). LCMS showed MH ⁺ = 399; T _RET = 2.64 min.

Similarly obtained using the above original or alternative embodiment, and using the same or similar amount of moles of reagents and volumes of solvents, the following:

R Starting carboxylic acid (instead of Intermediate 30) MH ⁺ ion T _RET (min) Example 39

The intermediate connection 31 414 2.44 Example 40 CH ₂ O ^t Bu The intermediate connection 32 401 2.98

Example 38: 1-Ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-yl) -1,3,4-oxadiazol-2-yl] -1H-pyrazolo [3,4-b] pyridin-4-amine

The following describes an alternative method of obtaining the compound of Example 38:

A mixture of Intermediate 30 (0.325 g, 2.5 mmol), TBTU (0.803 g, 2.5 mmol) and DIPEA (1.75 ml, 10.04 mmol) in N, N-dimethylformamide (10 ml) was stirred at 20 ° C for 20 minutes. A suspension of Intermediate 19 (1.024 g, 3.00 mmol) in N, N-dimethylformamide was added and the reaction mixture was stirred for 18 hours. The solvent was evaporated and the residue was applied to TFE cartridges (2 × 50 g, aminopropyl). The cartridge was eluted with dichloromethane: methanol (0-100% methanol for 17 minutes at 25 ml / min). The appropriate fractions were evaporated in vacuo and the residue was dissolved in tetrahydrofuran (10 ml). Burgess reagent (0.746 g, 3.13 mmol) was added and the reaction mixture was heated at reflux for 2.5 hours. An additional Burgess reagent (0.284 g) was added and heating continued for 1.5 hours. The solvent was evaporated in vacuo. The residue was applied to a TFE cartridge (silica, 100 g) and was eluted with a mixture of cyclohexane: ethyl acetate (gradient from 0 to 100% ethyl acetate for 25 minutes at 25 ml / min) and then with ethyl acetate, then with a mixture of ethyl acetate: methanol (4: 1) . The appropriate fractions were combined and evaporated to give the compound of Example 38 as a white solid (0.503 g). MH ⁺ = 399, T _RET = 2.67 min. ⁺ H-NMR (400 MHz in CDCl ₃ , 27 ° C, δ ppm) 9.14 (br m, 1H), 8.72 (s, 1H), 8.01 (s, 1H), 4.52 (q, 2H), 4.24 (m, 2H), 4.10 (m, 4H), 3.64 (m, 4H), 3.27 (m, 1H), 2.25-1.96 (m, 6H), 1.85 (m, 2H), 1.53 (t, 3H) .

Example 40A: Methyl-2- [1-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -4,5-dihydro-1 3-oxazole-4-carboxylate

Intermediate 33 (0.055 g, 0.14 mmol) and Burgess reagent (0.037 g, 0.16 mmol) were suspended in THF (2 ml) and heated at reflux for 4 hours. The solvents were removed in vacuo and the residue was applied to a TFE cartridge (silica, 2 g), which was eluted with a mixture of cyclohexane: ethyl acetate (1: 2). Concentration in vacuo gave the compound of Example 40A (0.03 g). LCMS showed MH ⁺ = 374, T _RET = 2.78 min.

Example 41: Methyl-2 41-ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxylate

The compound of Example 41 was synthesized using the following pathways, reagents, and solvents:

In one embodiment, a suitable detailed procedure for the first two steps is given above in “Intermediate 33” and “Example 40A”. In one embodiment, a suitable detailed procedure for the synthesis of the compound of Example 41 from Example 40A is as follows:

The compound of Example 40A (0.023 g, 0.062 mmol) and DBU (0.028 g, 0.18 mmol) was dissolved in a mixture of carbon tetrachloride / acetonitrile / pyridine (2: 3: 3, 1.6 ml) and stirred at room temperature in a nitrogen atmosphere within 48 hours. The solvents were removed in vacuo and the residue was purified by mass-controlled self-preparative HPLC to give Example 41 (0.0017 g). LCMS showed MH ⁺ = 372, T _RET = 9.24 min.

Example 42: 1-Ethyl-5- (4-methyl-4,5-dihydro-1,3-oxazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3 , 4-b] pyridin-4-amine

Intermediate 34 (0.095 g, 0.27 mmol) and Burgess reagent (0.071 g, 0.30 mmol) were dissolved in THF (2 ml) and heated at reflux for 4 hours. The solvents were removed in vacuo and the residue was applied to TFE (silica, 5 g), which was eluted with ethyl acetate to give the compound of Example 42 (0.045 g). LCMS showed MH ⁺ = 330, T _RET = 2.84 min.

Example 43: 1-n-Propyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4 -b] pyridin-4-amine

The compound of Example 43 was synthesized in accordance with the following interaction scheme:

Detailed conditions that can be used for the first six interactions from Intermediate 1 to Intermediate 40 are given above in the syntheses of “Intermediates” for Intermediates 35, 36, 37, 38, 39 and 40.

The compound of Example 43 can be obtained from Intermediate 40 using a process similar to that described for Example 1, 2, 3, using the same or the same number of moles of reactants and / or volumes of solvents. LCMS showed MH ⁺ = 343, T _RET = 2.70 min.

Example 44: 1-Ethyl-5- [5- (tetrahydrofuran-2-yl) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

A solution of tetrahydro-2-furoic acid = 2- (tetrahydrofuran) carboxylic acid (commercially available from Sigma-Aldrich) (0.012 ml, 0.12 mmol), TBTU (0.039 g, 0.12 mmol) and DIPEA (0.084 ml , 0.48 mmol) in DMF (2 ml) was stirred at room temperature in a nitrogen atmosphere. Intermediate 19 (0.045 g, 0.12 mmol) was added and the reaction mixture was stirred for 2 days. This mixture was concentrated in vacuo, then the residue was applied to a TFE cartridge (aminopropyl, 5 g), which was eluted with methanol. Fractions containing the desired material were concentrated in vacuo. Half of the partially purified material was dissolved in THF (0.1 ml) and treated with a Burgess reagent (0.015 g, 0.06 mmol). This mixture was heated under microwave conditions at 120 ° C (100 W) for 5 minutes. The mixture was then concentrated in vacuo and applied to a TFE cartridge (silica, 0.5 g). The cartridge was eluted with dichloromethane: methanol (19: 1), the fractions containing the desired material were concentrated in vacuo. The sample was then partitioned between dichloromethane and water, the organic phase was evaporated to give the compound of Example 44 (0.0065 g). LCMS showed MH ⁺ = 385, T _RET = 2.69 min.

Example 45: 1-Ethyl-5- [5- (dimethylamino) -1,3,4-oxadiazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4 -b] pyridin-4-amine

Intermediate 86 (0.113 g, 0.28 mmol) and Burgess reagent (0.133 g, 0.56 mmol) in THF (1 ml) were heated with microwaves for 5 minutes at 120 ° C. in a SmithCreator Microwave. The sample was evaporated in vacuo and the residue was purified by mass-controlled self-preparative HPLC. LCMS showed MH ⁺ = 358; T _RET = 2.57 min.

Example 46: 1-Ethyl-5- (5-methyl-1,2,4-triazol-3-yl) -N- (tetrahydro-2M-pyran-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-amine

A solution of Intermediate 19 (0.1 g, 0.29 mmol), diisopropylethylamine (0.3 ml, 1.74 mmol) and methylacetamidate hydrochloride (0.095 g, 0.87 mmol, commercially available from Aldrich) in ethanol (3 ml) was heated under reflux. After 17 hours, this reaction mixture was evaporated to a residue as an oil, which was partitioned between dichloromethane (10 ml) and water (2 ml). The phases were separated and the organic phase was dried over anhydrous sodium sulfate and evaporated to a waxy solid (0.053 g). Purification of a portion of this solid (0.025 g) by mass-controlled self-preparative HPLC gave the compound of Example 46 (0.005 g). LCMS showed MH ⁺ = 328; T _RET = 2.25 min.

Example 47: N- (1-Acetylpiperidin-4-yl) -1-ethyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -1H-pyrazolo [3,4-b] pyridine -4-amine

A mixture of Intermediate 41 (0.049 mg, 0.14 mmol), Intermediate 9 (0.051 g, 0.68 mmol), sodium ethylate (0.13 ml, 21% solution in ethanol, commercially available from Aldrich) and 4Å molecular sieve powder (0.3 g) in ethanol (2 ml) was heated at 80 ° C. for 16 hours under nitrogen. This mixture was cooled and filtered, and the filtrate was concentrated in vacuo. The residue was applied to a TFE cartridge (silica, 5 g) and was suirable cyclohexane, a mixture of cyclohexane: ethyl acetate (1: 1) and then ethyl acetate. The desired fractions were combined and evaporated to give the compound of Example 47 (0.005 g). LCMS showed MH ⁺ = 370; T _RET = 2.77 min.

Example 48: N- (1-Acetylpiperidin-4-yl) -1-ethyl-5- [3- (morpholin-4-ylmethyl) -1,2,4-oxadiazol-5-yl] -1H-pyrazolo [3 , 4-b] pyridin-4-amine

The compound of Example 48 was obtained from Intermediate 41 and Intermediate 24 using a method similar to that for Example 47. LCMS showed MH ⁺ = 455; T _RET = 2.59 min.

Example 49: 1-Ethyl-5 - [(4R) -4-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine

Burgess reagent (0.189 g, 0.79 mmol) was added portionwise over 3 min to a stirred solution of Intermediate 42 (0.293 g, 0.72 mmol) in anhydrous tetrahydrofuran (13 ml) at room temperature under a nitrogen atmosphere. The resulting solution was heated at 70 ° C. under nitrogen for 4 hours. This reaction mixture was evaporated to give a whitish solid, which was dissolved in dichloromethane (5 ml) and applied to a TFE cartridge (silica, 10 g). The cartridge was eluted sequentially with a gradient of ethyl acetate-petroleum ether (1: 8, 1: 4, 1: 2, 1: 1, 1: 0). Fractions containing the desired product were combined and evaporated to give the compound of Example 49 as a white crystalline solid (0.169 g). LCMS showed MH ⁺ = 392; T _RET = 3.31 min.

Example 50: 1-Ethyl-5 - [(4S) -4-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine

The compound of Example 50 was obtained from Intermediate 43 using a method similar to that for Example 49. LCMS showed MH ⁺ = 392; T _RET = 3.32 min.

Example 51: 1-Ethyl-5 - [(4S) -4- (phenyl methyl) -4,5-dihydro-1.3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) - 1H-pyrazolo [3,4-b] pyridin-4-amine

The compound of Example 51 was obtained from Intermediate 44 using a method similar to that for Example 49. LCMS showed MH ⁺ = 406; T _RET = 3.38 min.

Example 52: 1-Ethyl-5 - [(4R) -4- (phenylmethyl) -4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

The compound of Example 52 was obtained from Intermediate 45 using a method similar to that for Example 49. LCMS showed MH ⁺ = 406; T _RET = 3.38 min.

Example 53: 1-Ethyl-5 - [(4S, 5R) -5-methyl-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran- 4-yl) -1R-pyrazolo [3,4-b] pyridin-4-amine

The compound of Example 53 was obtained from Intermediate 46 using a method similar to that for Example 49. LCMS showed MH ⁺ = 406; T _RET = 3.37 min.

Example 54: 1-Ethyl-6 - [(5R) -5-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine

The compound of Example 54 was obtained from Intermediate 47 using a method similar to that for Example 49. LCMS showed MH ⁺ = 392; T _RET = 3.29 min.

Example 55: 1-Ethyl-5 - [(55) -5-phenyl-4,5-dihydro-1,3-oxazol-2-yl] -N- (tetrahydro-2M-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine

The compound of Example 55 was obtained from Intermediate 48 using a method similar to that for Example 49. LCMS showed MH ⁺ = 392; T _RET = 3.29 min.

Example 56: 5- (4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

The compound of Example 56 was obtained from Intermediate 49 using a method similar to that for Example 49. LCMS showed MH ⁺ = 344; T _RET = 2.95 min.

Example 57: 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3-oxazole-4-carboxylic acid

A solution of lithium hydroxide (0.12 g, 5.2 mmol) in water (6 ml) was added to a suspension of the compound of Example 41 (0.48 g, 1.3 mmol) in methanol (20 ml) and the resulting mixture was heated at 50 ° C for 2 hours. The solvent was evaporated in vacuo and the residue was dissolved in water (50 ml), cooled in an ice bath and acidified to pH 3 by the addition of aqueous hydrochloric acid. The precipitate was filtered off, washed with water and dried in vacuo at 40 ° C to obtain the compound of Example 57 as a white solid (0.3 g). LCMS showed MH ⁺ = 358; T _RET = 2.62 min.

Example 58: 2- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (1-methylethyl) -1 3-oxazole-4-carboxamide

A mixture of the compound of Example 57 (0.05 g, 0.14 mmol), HOBT (0.023 g, 0.17 mmol), EDC (0.038 g, 0.2 mmol) in DMF (2 ml) was stirred at 20 ° C for 20 minutes. Isopropylamine (0.013 ml, 0.15 mmol) was added and the reaction mixture was stirred overnight. The solvent was concentrated in vacuo and the residue was dissolved in DCM. The organic phase was washed with water, then with an aqueous solution of sodium bicarbonate. The aqueous phases were extracted using DCM and the combined organic phases were concentrated in vacuo. The residue was applied to a TFE cartridge (aminopropyl, 2 g) and eluted using MeOH, the appropriate fractions were combined and evaporated in vacuo. The residue was further purified by chromatography on TFE (silica, 0.5 g), eluting with a cyclohexane: ethyl acetate mixture (2: 1 and then 1: 1) to obtain the compound of Example 58 as a white solid (0.012 g). LCMS showed MH ⁺ = 399; T _RET = 2.78 min.

Similarly, when using the same or similar amounts of moles of reagents and / or volumes of solvents, the following were obtained:

Nfw Starting amine Mh ⁺ T _RET (min) Example 59

Morpholine 426 2,56

Example 60: 1-Ethyl-N-methyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3 , 4-b] pyridin-4-amine

Intermediate 53 (0.076 g, 0.21 mmol) in phosphorus oxychloride (3 ml) was heated at 120 ° C. for 3 hours, then evaporated in vacuo. The residue was partitioned between DCM and water and the organic phase was concentrated in vacuo. The residue was purified by mass-controlled autopreparative HPLC to give Example 60 (0.027 g). LCMS showed MH ⁺ = 343; T _RET = 2.34 min.

Example 61: trans-4 - {[1-Ethyl-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-pyrazolo [3,4-b] pyridin-4-yl] amino } cyclohexanol

Intermediate 54 (0.072 g, 0.63 mmol), Intermediate 12 (0.150 g, 0.57 mmol) and diisopropylethylamine (0.51 ml) in acetonitrile (3 ml) were heated at 85 ° C. for 18 hours, then evaporated in vacuo. The residue was partitioned between DCM and water and the organic phase was concentrated in vacuo. The residue was purified by mass-controlled autopreparative HPLC to give the compound of Example 61 (0.004 g). LCMS showed MH ⁺ = 343; T _RET = 2.48 min.

Similarly, when using the same or similar amounts of moles of reagents and / or volumes of solvents, the following were obtained:

Nfw Amine FWNH (instead of Intermediate 54) Mh ⁺ T _RET (min) Example 62

The intermediate connection 55 329 2.59 Example 63

The intermediate connection 56 341 2,53 Example 64

The intermediate connection 57 371 2.60

Example 65: 5- [5- (1,1-Dimethylethyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-6-methyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

Intermediate 61 (0.266 g, 0.56 mmol) in phosphorus oxychloride (10 ml) was heated at 120 ° C. for 1.5 hours, then evaporated in vacuo. The residue was partitioned between DCM and water and the organic phase was concentrated in vacuo. The residue was purified on a TFE cartridge (silica, 5 g) with elution with a mixture of cyclohexane: ethyl acetate (2: 1, 1: 1, then 2: 3) to obtain the compound of Example 65 (0.042 g). LCMS showed MH ⁺ = 385; T _RET = 3.05 min.

Example 66: 1-Ethyl-6-methyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-yl) -1,3,4-oxadiazole- 2-yl] -1H-pyrazolo [3,4-b] pyridin-4-amine

Intermediate 64 (0.05 g, 0.11 mmol) and Burgess reagent (0.053 g, 0.22 mol) in a THF / DMF mixture (1 ml, 1: 1) were heated under microwave conditions at 120 ° C (120 W) ) for 5 minutes. This reaction mixture was heated at 150 ° C for four 10-minute intervals with an additional portion of Burgess reagent (0.025 g), which was added after the first and third periods of additional microwave heating. The reaction mixture was concentrated in vacuo and purified on TFE (silica, 0.5 g), eluting with cyclohexane, a mixture of cyclohexane: ethyl acetate (2: 3, then 1: 4), then ethyl acetate. Fractions containing the desired material were evaporated in vacuo to give the compound of Example 66 (0.010 g). LCMS showed MH ⁺ = 413; T _RET = 2.63 min.

Example 67: 5- (5-Cyclobutyl-1,3,4-oxadiazol-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-amine

Intermediate 65 (0.05 g, 0.13 mmol) and Burgess reagent (0.07 g, 0.3 mmol) in THF (2 ml) were heated at 80 ° C. for 7 hours. This reaction mixture was concentrated in vacuo and an additional portion of Burgess reagent (0.07 g, 0.3 mmol) in THF (0.5 ml) was added and this reaction mixture was refluxed for 18 hours. The reaction mixture was concentrated in vacuo and partitioned between DCM and water. The phases were separated using a hydrophobic frit (Whatman PTFE Filter Media with polypropylene substrate, pore size 5 μm). The organic phase was concentrated in vacuo and the residue was purified by mass-controlled self-preparative HPLC to give Example 67 (0.018 g). LCMS showed MH ⁺ = 369; T _RET = 3.03 min.

Similarly, when using the same or similar amounts of moles of reagents and / or volumes of solvents, the following were obtained:

R ^y Starting Intermediate Mh ⁺ T _RET (min) Example 68

The intermediate connection 66 398 2,34 Example 69

The intermediate connection 67 386 2.29 Example 70

The intermediate connection 68 412 2.03 Example 71

The intermediate connection 69 411 2.92 Example 72

Intermediate 70 397 2.67 Example 73

The intermediate connection 71 385 2.65 Example 74

The intermediate connection 72 416 2.59 Example 75

The intermediate connection 73 383 3.22 Example 76

The intermediate connection 74 400 2,38 Example 77

The intermediate connection 75 413 2.79 Example 78

The intermediate connection 76 383 3.22 Example 79

Intermediate 77 396 2.88 Example 80

The intermediate connection 78 395 2.91

Example 77: 1-Ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (tetrahydro-2H-pyran-4-ylmethyl) -1,3,4-oxadiazol-2-yl] -1H-pyrazolo [3,4-b] pyridin-4-amine

Alternative technique:

Burgess reagent (0.168 g, 0.74 mmol) was added to a solution of Intermediate 75 (0.141 g, 0.33 mmol) in tetrahydrofuran (2 ml). This reaction mixture was heated at reflux for 1.5 hours, then evaporated. The residue was applied to a TFE cartridge (silica, 10 g) and was eluted with a mixture of cyclohexane: ethyl acetate (gradient from 0 to 100% ethyl acetate for 15 minutes at 15 ml / min) and then with ethyl acetate, then with a mixture of ethyl acetate: methanol (4: 1) . The appropriate fractions were combined and evaporated to give the compound of Example 77 as a white solid (0.099 g). LCMS showed MH ⁺ = 413, T _RET = 2.72 min. ¹ H-NMR (400 MHz in CDCl ₃ , 27 ° C, δ ppm) 9.12 (br m, 1H), 8.72 (s, 1H), 8.01 (s, 1H), 4.52 (q, 2H), 4.245 (m, 1H), 4.08 (m, 2H), 4.00 (m, 2H), 3.67 (m, 2H), 3.44 (m, 2H). 2.91 (m, 2H), 2.20 (m, 3H), 1.93-1.70 (m, 4H), 1.57-1.40 (m, 5H).

Example 81: 5- [5- (1-Acetyl-4-piperidinyl) -1,3,4-oxadiazol-2-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H -pyrazolo [3,4-b] pyridin-4-amine

Intermediate 79 (0.18 mmol) and Burgess reagent (0.14 g, 0.6 mmol) in THF (0.75 ml) were heated at 80 ° C. under nitrogen for 16 hours. This reaction mixture was concentrated in a stream of nitrogen and the residue was dissolved in DCM (8 ml). This solution was mixed with water and the phases were separated using a hydrophobic frit (Whatman). The organic phase was concentrated in vacuo and this material was purified by mass-controlled self-preparative HPLC to give Example 81 (0.005 g). LCMS showed MH ⁺ = 440; T _RET = 2.52 min.

Example 82: 1-Ethyl-5- {3 - [(4-methyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl ) -1H-pyrazolo [3,4-b] pyridin-4-amine

A mixture of Intermediate 16 (0.064 g, 0.2 mmol), Intermediate 80 (0.172 g, 1 mmol), a solution of sodium ethylate in EtOH (0.19 ml, 21% solution) and a 4Å molecular sieve powder (0, 38 g) in EtOH (2 ml) was stirred at 82 ° C. under nitrogen for 18 hours. This reaction mixture was filtered, the solvent was evaporated in vacuo and the residue was applied to a TFE cartridge (silica, 2 g). The cartridge was eluted with (1) cyclohexane, (2) a mixture of cyclohexane: ethyl acetate (4: 1, 3: 2, 1: 1, 2: 3, 1: 4), (3) EtOAc, (4) MeOH and (5) 10 % aqueous solution of NH ₃ in MeOH to give the compound of Example 82 as a white solid (0.038 g). LCMS showed MH ⁺ = 427; T _RET = 2.10 min.

Similarly, the following were prepared from intermediate 16 using the same or similar amounts of moles of reactants and / or volumes of solvents:

R ^x Starting Intermediate (instead of Intermediate 80) Mh ⁺ T _RET (min) Example 83

The intermediate connection 81 398 2,34 Example 84

The intermediate connection 82 426 2.6

Examples 85 to 96 are various 5- {3- [substituted] -1,2,4-oxadiazol-5-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amines

The compounds of Examples 85 to 96 can be obtained from Intermediate 16 using the same methods as described for any of Examples 28-31 or 82-84, using the same or the same number of moles of reagents and / or volumes of solvents.

Alternatively, the compounds of Examples 85-90 and Examples 95-96 (all amides) can be obtained from the corresponding carboxylic acid, which is Intermediate 83, by activation of a carboxyl group (for example, using a coupling agent such as EDC, HATU or, more preferably, TBTU) and by reacting the activated carboxylic acid with the corresponding amine R ¹⁰ R ¹¹ NH. This reaction, preferred reagents, and the structure of Intermediate 83 is shown in the following scheme (Intermediate 83 has the same structure as the compound of Example 84, but the 1,2,4-oxadiazole side-chain R ^x is -CH ₂ -C (O )IT):

As shown in the diagram above, Intermediate 83 can be prepared by hydrolysis of the corresponding tert-butyl ether of Intermediate 84 (where the 1,2,4-oxadiazole side chain R ^x is —CH ₂ —C (O) —OO ^t Bu). Intermediate 84 can be obtained from Intermediate 17 and Intermediate 85, as shown in the scheme above. The preparation of Intermediate 85 has been shown previously.

In an alternative embodiment, the compounds of Examples 85-90 and Examples 95-96 can be prepared by reacting a carboxylic acid, which is Intermediate 83, with R ¹⁰ R ¹¹ NH, as shown above, but Intermediate 83 (where 1,2,4- the oxadiazole side chain R ^x represents —CH ₂ —C (O) OH) can be prepared from the compound of Example 84 by hydrolysis of the amide bond in R ^X in Example 84 to form a carboxylic acid, which is Intermediate 83.

The numbers of examples and corresponding structures of the compounds of Examples 85-96 are indicated below:

Example 85: 2- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4- oxadiazol-3-yl} -N-phenylacetamide

General Procedure for Examples 85-90:

N, N-Dimethylformamide (0.1) was added dropwise to a stirred mixture of Intermediate 83 (0.525 g, 1.40 mmol) and oxalyl chloride (0.18 ml, 2.1 mmol) in dichloromethane (15 ml) at 0 ° C in an atmosphere of nitrogen. The resulting mixture was stirred at 0 ° C for 1 hour.

An aliquot of the above solution (1.1 ml) was added to a solution of the amine R ¹⁰ R ¹¹ NH (0.6 mmol) in dichloromethane (0.5 ml). The reaction mixture was allowed to stand at room temperature for 2 hours, then it was applied to a TFE cartridge (aminopropyl, 2 g). The cartridge was eluted with chloroform, then with ethyl acetate / methanol (9: 1). The fractions containing the product were concentrated and the residue was purified on a TFE cartridge (silica, 5 g), eluting with dichloromethane, ether, ethyl acetate, then with ethyl acetate / methanol (9: 1). The desired fractions were concentrated to obtain the following compounds of Examples.

Example Number NR ¹⁰ R ¹¹ Source of the amine R ¹⁰ R ¹¹ NH Mh ⁺ T _RET (min) 85

Sigma-alldrich 448 2.98 86

Sigma-alldrich 476 2.97 87

Sigma-alldrich 440 2.81 88

Sigma-alldrich 461 2.90 89

Sigma-alldrich 400 2,51 90

Sigma-alldrich 400 2,51

Example 92: 1-Ethyl-5- {3- [1- (4-morpholinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4-yl) - 1H-pyrazolo [3,4-b] pyridin-4-amine

A mixture of intermediate 16 (0.059 g, 0.2 mmol), Intermediate 121 (0.161 g, 1.54 mmol), a solution of sodium ethylate in EtOH (0.21 ml, 21% solution) and a 4 Å molecular sieve powder ( 0.43 g) in EtOH (1.5 ml) was stirred at 82 ° C. under nitrogen for 18 hours. This reaction mixture was filtered and the residue was purified by mass-controlled self-preparative HPLC to give Example 92 (0.007 g). LCMS showed MH ⁺ = 428; T _RET = 2.46 min.

Example 93: 5- [3- (cyclohexylmethyl) -1,2,4-oxadiazol-5-yl] -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4 -b] pyridin-4-amine

A mixture of Intermediate 16 (0.098 g, 0.31 mmol), Intermediate 122 (0.24 g, 0.93 mmol), a solution of sodium ethylate in EtOH (0.21 ml, 21% solution) and molecular sieve powder 4Å (0.43 g) in EtOH (1.5 ml) was stirred at 82 ° C. under nitrogen for 18 hours. This reaction mixture was filtered and the residue was purified by mass-controlled self-preparative HPLC to give Example 93 (0.079 g). LCMS showed MI-T = 411; T _RET = 3.80 min.

Example 95: 1-Ethyl-5- {3- [2-oxo-2- (1-piperidinyl) ethyl] -1,2,4-oxadiazol-5-yl} -N- (tetrahydro-2H-pyran-4 -yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

General Procedure for Examples 95-96:

N, N-Dimethylformamide (0.1 ml) was added dropwise to a stirred mixture of Intermediate 83 (0.525 g, 1.40 mmol) and oxalyl chloride (0.18 ml, 2.1 mmol) in dichloromethane (15 ml) at 0 ° C in nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 1 hour.

An aliquot of the above solution (1.1 ml) was added to a solution of the amine R ¹⁰ R ¹¹ NH (0.6 mmol) in dichloromethane (0.5 ml). This reaction mixture was allowed to stand at room temperature for 2 hours, then it was applied to a TFE cartridge (aminopropyl, 2 g). The cartridge was eluted with chloroform, then with ethyl acetate / methanol (9: 1). The fractions containing the product were concentrated and the residue was purified on a TFE cartridge (silica, 5 g), eluting with dichloromethane, ether, ethyl acetate, then with ethyl acetate / methanol (9: 1). The desired fractions were concentrated to obtain the following compounds of Examples.

Example Number NR ¹⁰ R ¹¹ Source of the amine R ¹⁰ R ¹¹ NH Mh ⁺ T _RET (min) 95

Sigma-alldrich 442 2,51 96

Sigma-alldrich 455 2.08

Examples 97 to 125 - various 5- {5- [substituted] -1,3,4-oxadiazol-2-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amines

The compounds of Examples 97-125 can be obtained using the same methods as described for any of Examples 9, 14, 32-40, 44-45, 60-64, 65-66 and 67-81, using a similar or the same amounts of moles of reagents and / or volumes of solvents.

Example 97: 1-Ethyl-N- (tetrahydro-2H-pyran-4-yl) -5- [5- (1H-1,2,3-triazol-1-ylmethyl) -1,3,4-oxadiazole- 2-yl] -1H-pyrazolo [3,4-b] pyridin-4-amine

General procedure for preparing the compounds of Examples 97-125:

A mixture of diacyl hydrazide, which is an Intermediate (one of Intermediates 89-114), and a Burgess reagent (2 equivalents) in N, N-dimethylformamide (1 ml) was heated in microwaves for 10 minutes at 120 ° C at 150 watts. The resulting solution was concentrated in vacuo and partitioned between chloroform and water. The organic phase was separated using a hydrophobic frit (Whatman PTFE Filer Media with a polypropylene support, pore size 5 μm), then concentrated. The residue was purified by mass-controlled autopreparative HPLC.

Since either mass formic HPLC procedure uses either formic acid or trifluoroacetic acid in solvents (see "Hardware Methods" above), some of the compounds of the Examples were isolated as formate salt or trifluoroacetate salt, as shown below.

The numbers of Examples and corresponding structures of the compounds of Examples 97-125 are indicated below:

Example Number R ^y Diacyl Hydrazide Intermediate Number MH ⁺ T _RET (min) 97

89 396 2.47 98 (as formate salt)

90 440 2.79 99 (as formate salt)

91 395 2.97 100 (as formate salt)

92 396 2.69 103 (as trifluoroacetate salt)

93 435 3.15 104 (as formate salt)

94 397 2,51 105

95 412 2.79 106 (as salt formate)

96 410 2.77 107

97 448 3.01 108 (as formate salt)

98 426 2.76 109 (as trifluoroacetate salt)

99 468 2.85 111

one hundred 412 2,53 1.12 (as formate salt)

101 396 3.03 113

102 410 2.81 114 (as formate salt)

103 440 2.79 117 (as trifluoroacetate salt)

106 424 2.80 118

107 400 2.43 119 (as trifluoroacetate salt)

108 454 2.63 120

109 419 3.20 121

110 405 3.41 122

111 419 3.53 123

112 419 3.65 125

114 3.30 483/485

Examples 126 to 147 are various 5- {4- [substituted] -oxazol-2-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-amines

The compounds of Examples 126-147 (all amides) can be obtained by reacting the compound of Example 57 and the corresponding amine to form an amide bond using a method similar to that described for Example 58, except that HATU instead of EDC is preferably used as the coupling agent, and when using the same or the same number of moles of reagents and / or volumes of solvents, as in Example 58.

Example 126: 2- [1-Ethyl-4- {tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -N- (phenylmethyl) -1.3 -oxazole-4-carbroxamide

General procedure for Examples 126-147:

A mixture of the compound of Example 57 (0.014 g, 0.04 mmol), diisopropylethylamine (0.0017 ml, 0.096 mmol) and HATU (0.016 g, 0.042 mmol) in N, N-dimethylformamide (0.4 ml) was allowed to stand for 10 minutes. The resulting solution was added to the corresponding amine R ¹⁰ R ¹¹ NH (0.05 mmol) and this mixture was stirred by sonication. After settling for 18 hours, the solvent was removed in vacuo. The residue was applied to a TFE cartridge (aminopropyl, 0.5 g) and the cartridge was eluted with chloroform (1.5 ml) and then with ethyl acetate: methanol (9: 1, 2 ml). The appropriate fractions were evaporated in vacuo and the residue was purified by mass-controlled self-preparative HPLC.

The numbers of Examples and the corresponding structure of the compounds of Examples 126-147 are indicated below:

Example Number NR ¹⁰ R ¹¹ Source of the amine R ¹⁰ R ¹¹ NH Mh ⁺ T _RET (min) 126

Sigma-alldrich 447 3.14 127

Sigma-alldrich 477 3.16 128

Sigma-alldrich 461 3.26 129

Sigma-alldrich 461 3.36 130

Sigma-alldrich 461 3.23 131

Sigma-alldrich 481 3.35 132

Matrix Scientific or Maybridge 475 3.57 133

Matrix Scientific 475 3,55 134

Matrix Scientific or Pfaulz-Bauer 475 3.46 135

Sigma-alldrich 461 3.21 136

Pfaulz-bauer 491 3.22 137 Sigma-alldrich 475 3.32 138

Sigma-alldrich 447 3.42 139

J. Med. Chem. 2003, 46 (14), 3116 540 2.87 140

WO 02/016318 525 2.86 141

The intermediate connection 25 482 2,55 142

The intermediate connection 21 441 2.68 143

Sigma-alldrich 441 2.89 144

J. Med. Chem. 1999.42 (15), 2870 or Matrix Scientific 483 2.21 145

WO 96/05166 482 3.32 146

Sigma-alldrich 461 3.23 147

The intermediate connection 115 490 2,58

Example 148: 2- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4- oxadiazol-3-yl} -N- (tetrahydro-2H-pyran-4-yl) acetamide

General procedure for Examples 148-155 and for an alternative preparation of the compound of Example 84:

N, N-Dimethylformamide (0.1 ml) was added dropwise to a stirred mixture of Intermediate 83 and oxalyl chloride (0.18 ml, 2.1 mmol) in dichloromethane (15 ml) at 0 ° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 1 hour.

An aliquot of the above solution (1.1 ml) was added to a solution of the amine R ¹⁰ R ¹¹ NH (0.6 mmol) in dichloromethane (0.5 ml). This reaction mixture was allowed to stand at room temperature for 2 hours, then applied to a TFE cartridge (aminopropyl, 2 g). The cartridge was eluted with chloroform, then with ethyl acetate / methanol (9: 1). The fractions containing the product were concentrated and the residue was purified on a TFE cartridge (silica, 5 g), eluting with dichloromethane, ether, ethyl acetate, then with ethyl acetate / methanol (9: 1). The desired fractions were concentrated to obtain the following compounds of Examples.

Example Number NR ¹⁰ R ¹¹ Amine source R ¹⁰ R ¹¹ NH Mh ⁺ T _RET (min) 148

The intermediate connection 21 456 2.49 149

Sigma-Aldrich (mixture of isomers) 470 2.66, 2.71 150

Sigma-alldrich 454 2.96 152

Sigma-alldrich 444 2,57 153

Sigma-alldrich 468 3.13 154

Sigma-alldrich 454 2.96 155

Sigma-alldrich 449 2,51 84 (alternative receipt)

Sigma-alldrich 426 2.63

Example 157: 6- {5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,3,4- oxadiazol-2-yl} -2-piperidinone

General procedure for Examples 157-158:

A mixture of diacyl hydrazide Intermediate 104 or 105 and Burgess reagent (2 equivalents) in N, N-dimethylformamide (1 ml) was heated in microwaves for 10 minutes at 120 ° C at 150 watts. The resulting solution was concentrated in vacuo and partitioned between chloroform and water. The organic phase was separated using a hydrophobic frit (Whatman PTFE Filter Media with a polypropylene substrate, pore size 5 μm), then concentrated. The residue was purified by mass-controlled autopreparative HPLC.

Example Number R ^y The diacyl hydrazide intermediate Mh ⁺ T _RET (min) 157

The intermediate connection 104 411 2.45 158

The intermediate connection 105 409 2,38

Example 159: N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4 -oxadiazol-3-yl} methyl) acetamide

General Procedure for Examples 159-165:

The corresponding carboxylic acid chloride R ¹⁷ C (O) Cl (0.12 mmol) was added to a stirred solution of an amine of Intermediate 118 (0.1 mmol) and diisopropylethylamine (0.3 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 hours, this reaction mixture was applied to a TFE cartridge (aminopropyl, 2 g), and the cartridge was eluted successively with chloroform, ethyl acetate and methanol. Fractions containing the desired product were combined and purged under nitrogen.

The resulting residue was further purified on a TFE cartridge (silica, 1 g) with elution with a gradient of 30-100% ethyl acetate in petroleum ether. The appropriate fractions were combined and the solvents were evaporated to give the product.

Example Number R ¹⁷ Source of acid chloride R ¹⁷ C (O) Cl Mh ⁺ T _RET (min) 159 CH ₃ Sigma-alldrich 386 2,38 160

Sigma-alldrich 448 2.82 161

Sigma-alldrich 462 2.85 162

Sigma-alldrich 414 2.66 163

Sigma-alldrich 428 2.79 164

Sigma-alldrich 454 2.99 165

Lancaster 438 2.68

Example 166: N - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4 -oxadiazol-3-yl} methyl) methanesulfonamide

General procedure for Examples 166-172:

The corresponding sulfonyl chloride R ¹⁸ S (O) ₂ Cl (0.12 mmol) was added to a stirred solution of the amine, which was Intermediate 118, (0.1 mmol) and pyridine (0.2 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 hours, this reaction mixture was applied to a TFE cartridge (aminopropyl, 2 g), and the cartridge was eluted successively with chloroform, ethyl acetate and methanol. Fractions containing the desired product were combined and purged under nitrogen. The resulting residue was further purified on a TFE cartridge (silica, 1 g) with elution with a gradient of 30-100% ethyl acetate in petroleum ether. The appropriate fractions were combined and the solvents were evaporated to give the product.

Example Number R18 Source of sulfonyl chloride R ¹⁸ (O) ₂ Cl Mh ⁺ T _RET (min) 166 CH ₃ Sigma-alldrich 422 2.59 167

Sigma-alldrich 484 3.00 168

Sigma-alldrich 498 3.04 169

Sigma-alldrich 450 2.79 170

Sigma-alldrich 450 2.83 171

Array Biopharma Inc 448 2.69 172

Avocado 490 2.93

Example 173: 1 - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4 -oxadiazol-3-yl} methyl) -2-pyrrolidinone

A solution of Intermediate 119 (45 mg, 0.1 mmol) in anhydrous dimethylformamide (2 ml) was added to sodium hydride (60% dispersion in mineral oil, 4.4 mg, 0.11 mmol) and the resulting mixture was stirred at room temperature. After 16 hours, this reaction mixture was diluted with water (2 ml) and extracted with chloroform (3 × 5 ml). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to give a crude product. Purification of the crude product on a TFE cartridge (silica, 2 g) using a gradient of ethyl acetate in petroleum ether gave the compound of Example 173. LCMS showed MH ⁺ = 412, T _RET = 2.59 min.

Example 174: 1 - ({5- [1-Ethyl-4- (tetrahydro-2H-pyran-4-ylamino) -1H-pyrazolo [3,4-b] pyridin-5-yl] -1,2,4 -oxadiazol-3-yl} methyl) -2-piperidinone

A solution of Intermediate 120 (46 mg, 0.1 mmol) in anhydrous dimethylformamide (2 ml) was added to sodium hydride (60% dispersion in mineral oil, 4.4 mg, 0.11 mmol) and the resulting mixture was stirred at room temperature. After 16 hours, the reaction mixture was diluted with water (2 ml) and extracted with chloroform (3 × 5 ml). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to give a crude product. Purification of the crude product on a TFE cartridge (silica, 2 g) using a gradient of ethyl acetate in petroleum ether gave the compound of Example 174. LCMS showed MH ⁺ = 426, T _RET = 2.66 min.

Example 175: 5- {3 - [(1-Acetyl-4-piperidinyl) methyl] -1,2.4-oxadiazol-5-yl} -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) - 1H-pyrazolo [3,4-b] pyridin-4-amine

Acetyl chloride (0.04 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and diisopropylethylamine (0.1 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 1.5 hours, an additional amount of acetyl chloride (0.04 mmol) and diisopropylethylamine (0.1 mmol) were added to this reaction mixture. After 3.5 hours, the reaction mixture was applied to a TFE cartridge (aminopropyl, 1 g) and the cartridge was eluted successively with chloroform, ethyl acetate and methanol. Fractions containing the desired product were combined and purged under nitrogen. The resulting residue was further purified on a TFE cartridge (silica, 1 g), eluting with a gradient of 30-100% ethyl acetate in petroleum ether to give the compound of Example 175. LCMS showed MH ⁺ = 454, T _RET = 2.79 min.

Example 176: 1-Ethyl-5- (3 - {[1- (3-methylbutanoyl) -4-piperidinyl] methyl} -1,2,4-oxadiazol-5-yl) -N- (tetrahydro-2H- pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

Isovaleryl chloride (0.04 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and diisopropylethylamine (0.1 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 1.5 hours, this reaction mixture was applied to a TFE cartridge (aminopropyl, 1 g) and the cartridge was eluted successively with chloroform, ethyl acetate and methanol. Fractions containing the desired product were combined and purged under nitrogen. The resulting residue was further purified on a TFE cartridge (silica, 1 g), eluting with a gradient of 30-100% ethyl acetate in petroleum ether to give the compound of Example 176. LCMS showed MH ⁺ = 496, T _RET = 3.17 min.

Example 177: 1-Ethyl-5- (3 - {[1- (methylsulfonyl) -4-piperidinyl] methyl} -1,2,4-oxadiazol-5-yl) -N- (tetrahydro-2H-pyran- 4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

Methanesulfonyl chloride (1.16 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and pyridine (0.5 ml) in chloroform (1 ml) at room temperature. After stirring at room temperature for 31 h, this reaction mixture was applied to a TFE cartridge (aminopropyl, 5 g) and the cartridge was eluted successively with chloroform, ethyl acetate and methanol. Fractions containing the desired product were evaporated in vacuo. The resulting residue was further purified on a TFE cartridge (silica, 1 g), eluting with a gradient of 30-100% ethyl acetate in petroleum ether to give the compound of Example 176. LCMS showed MH ⁺ = 490, T _RET = 2.97 min.

Example 178:

A mixture of Intermediate 16 (0.067 g, 0.26 mmol), amidoxime, which is Intermediate 126 (0.255 g, 1.06 mmol), a solution of sodium ethoxide in EtOH (0.87 ml, 21% solution) and 4 Å molecular sieve powder (0.68 g) in EtOH (2 ml) was stirred at 82 ° C. under nitrogen for 12 hours. This reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was applied to a TFE cartridge (silica, 5 g) and was eluted with ethyl acetate: cyclohexane (0 to 70% in increments of 10%). The appropriate fractions were combined and evaporated, the residue was further purified by mass-controlled self-preparative HPLC to give the compound of Example 178 (0.011 g). LCMS showed MH ⁺ = 495; T _RET = 3.2 min.

Similarly, when using the same or similar amounts of moles of reagents and / or volumes of solvents, the following were obtained:

Example Number R ^x Amidoxime, which is an Intermediate number (instead of Intermediate 126) Mh ⁺ T _RET (min) 179

127 405 3.35 180

128 419 3.44 181

129 435 3.34 182

130 435 3.35 183

132 448 3.2 184

131 448 3.30 185

133 421 3.35 186

134 450 2.47 187

135 489 3.01

Example 188: 1-Ethyl-5- (5-ethyl-1,2,4-oxadiazol-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-amine

Propionic anhydride (0.015 ml, 0.12 mmol) was added to Intermediate 138 (0.030 g, 0.1 mmol) in glacial acetic acid (1.5 ml). This reaction mixture was stirred at room temperature for 2 hours, then heated at 80 ° C. for 5 hours. The solvent was concentrated in vacuo and the residue was applied to a TFE cartridge (silica, 1 g). The cartridge was eluted with cyclohexane, then with a mixture of cyclohexane: ethyl acetate (7: 3). The appropriate fractions were combined and evaporated to give the compound of Example 188 as a white solid (0.015 g). LCMS showed MH ⁺ = 343; T _RET = 2.92 min.

Example 189: 5- (5 - {[4- (Dimethylamino) phenyl] methyl} -1,2,4-oxadiazol-3-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

4- (Dimethylamino) phenylacetic acid (0.09 g, 0.504 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.097 g, 0.51 mmol) in dichloromethane (1 ml) were stirred at room temperature for 3 hours. This reaction mixture was concentrated, then Intermediate 138 (0.07 g, 0.23 mmol) and diglyme (1 ml) were added. After stirring at 20 ° C for 18 hours, glacial acetic acid (0.07 ml) and an additional amount of diglyme (0.5 ml) were added and this mixture was heated at 60 ° C for 2 hours, then at 75 ° C for 4 hours. The reaction mixture was applied to a TFE cartridge (SCX, 2 g) and the cartridge was eluted with methanol, then with 10% ammonia in methanol. The methanol-ammonia fractions were evaporated in vacuo and the residue was purified by mass-controlled self-preparative HPLC to give Example 189 as a beige solid (0.004 g). LCMS showed MH ⁺ = 448; T _RET = 3.24 min.

Example 190: 1-Ethyl-5- (5 - {[4- (methyloxy) phenyl] methyl} -1,2,4-oxadiazol-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

Prepared from Intermediate 138 and 4-methoxyphenylacetic acid using the same method as described for Example 189 using the same or the same amount of moles of reagents and / or volumes of solvents. LCMS showed MH ⁺ = 435; T _RET = 3.26 min.

Example 191: 5- (3,8-dioxa-1-azaspiro [4.5] dec-1-en-2-yl) -1-ethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

The compound of Example 191 was obtained from Intermediate 139 using a method similar to that for Example 49. LCMS showed MH ⁺ = 386, T _RET = 2.71 min.

Claims (17)

1. The compound representing 5- {5 - [(2,4-dimethyl-1,3-thiazol-5-yl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N - (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridin-4-amine

where R ^Y represents

or a pharmaceutically acceptable salt thereof. 2. The compound representing 5- {5 - [(2,4-dimethyl-1,3-thiazol-5-yl) methyl] -1,3,4-oxadiazol-2-yl} -1-ethyl-N - (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-6] pyridin-4-amine

where R ^Y represents

3. The compound or its pharmaceutically acceptable salt according to claim 1 or 2 for use as an inhibitor of PDE4 (phosphodiesterase 4) in humans. 4. The compound or its pharmaceutically acceptable salt according to claim 1 or 2 for the treatment and / or prevention of depression in humans. 5. The compound or its pharmaceutically acceptable salt according to claim 1 or 2 for the treatment and / or prevention of cognitive disorders in humans. 6. The compound or its pharmaceutically acceptable salt according to claim 5, where the cognitive impairment occurs in a neurological disorder. 7. The compound or its pharmaceutically acceptable salt according to claim 6, where the neurological disorder is Alzheimer's disease. 8. The use of the compound or its pharmaceutically acceptable salt according to claim 1 or 2 in the manufacture of a medicament for the treatment and / or prevention of depression in humans. 9. The use of the compound or its pharmaceutically acceptable salt according to claim 1 or 2 in the manufacture of a medicament for the treatment and / or prevention of a cognitive disorder in humans. 10. The use of the compound or its pharmaceutically acceptable salt according to claim 9, where the cognitive impairment occurs in a neurological disorder. 11. The use of a compound or a pharmaceutically acceptable salt thereof of claim 10, wherein the neurological disorder is Alzheimer's disease. 12. A pharmaceutical composition for inhibiting PDE4, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and one or more pharmaceutically acceptable carriers and / or excipients. 13. The pharmaceutical composition according to item 12, which is suitable and / or adapted for oral administration. 14. The pharmaceutical composition according to item 12 for the treatment and / or prevention of depression in humans. 15. The pharmaceutical composition according to item 12 for the treatment and / or prevention of cognitive disorders in humans. 16. The pharmaceutical composition according to clause 15, where the cognitive disorder occurs with a neurological disorder. 17. The pharmaceutical composition according to clause 16, where the neurological disorder is Alzheimer's disease.