Pyrazolo '3,4-B! Pyridine Compounds And Their Use As Phosphodiesterase Type 4(Pde4) Inhibitors

The present invention relates to pyrazolo[3,4-b]pyridine compounds, processes for their preparation, intermediates usable in these processes, and pharmaceutical compositions containing the compounds. The invention also relates to the use of the pyrazolo[3,4-b]pyridine compounds in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.

BACKGROUND TO THE INVENTION

U.S. Pat. No. 3,979,399, U.S. Pat. No. 3,840,546, and U.S. Pat. No. 3,966,746 (E.R. Squibb & Sons) disclose 4-amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxamides wherein the 4-amino group NR₃R₄can be an acyclic amino group wherein R₃and R₄may each be hydrogen, lower alkyl (e.g. butyl), phenyl, etc.; NR₃R₄can alternatively be a 3-6-membered heterocyclic group such as pyrrolidino, piperidino and piperazino. The compounds are disclosed as central nervous system depressants useful as ataractic, analgesic and hypotensive agents.

U.S. Pat. No. 3,925,388, U.S. Pat. No. 3,856,799, U.S. Pat. No. 3,833,594 and U.S. Pat. No. 3,755,340 (E.R. Squibb & Sons) disclose 4-amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxylic acids and esters. The 4-amino group NR₃R₄can be an acyclic amino group wherein R₃and R₄may each be hydrogen, lower alkyl (e.g. butyl), phenyl, etc.; NR₃R₄can alternatively be a 5-6-membered heterocyclic group in which an additional nitrogen is present such as pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl. The compounds are mentioned as being central nervous system depressants useful as ataractic agents or tranquilisers, as having antiinflammatory and analgesic properties. The compounds are mentioned as increasing the intracellular concentration of adenosine-3′,5′-cyclic monophosphate and for alleviating the symptoms of asthma.

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

CA 1003419, CH 553 799 and T. Denzel, Archiv der Pharmazie, 1974, 307(3), 177-186 disclose 4,5-disubstituted 1H-pyrazolo[3,4-b]pyridines unsubstituted at the 1-position.

Japanese laid-open patent application JP-2002-20386-A (Ono Yakuhin Kogyo K K) published on 23 Jan. 2002 discloses pyrazolopyridine compounds of the following formula:

wherein R¹denotes 1) a group —OR⁶, 2) a group —SR⁷, 3) a C2-8 alkynyl group, 4) a nitro group, 5) a cyano group, 6) a C1-8 alkyl group substituted by a hydroxy group or a C1-8 alkoxy group, 7) a phenyl group, 8) a group —C(O)R⁸, 9) a group —SO₂NR⁹R¹⁰, 10) a group —NR¹¹SO₂R¹², 11) a group —NR¹³C(O)R¹⁴or 12) a group —CH═NR¹⁵. R⁶and R⁷denote i) a hydrogen atom, ii) a C1-8 alkyl group, iii) a C1-8 alkyl group substituted by a C1-8 alkoxy group, iv) a trihalomethyl group, v) a C3-7 cycloalkyl group, vi) a C1-8 alkyl group substituted by a phenyl group or vii) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms. R²denotes 1) a hydrogen atom or 2) a C1-8 alkoxy group. R³denotes 1) a hydrogen atom or 2) a C1-8 alkyl group. R⁴denotes 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group substituted by a C3-7 cycloalkyl group, 5) a phenyl group which may be substituted by 1-3 halogen atoms or 6) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms. R⁵denotes 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group substituted by a C3-7 cycloalkyl group or 5) a phenyl group which may be substituted by 1-3 substituents. In group R³, a hydrogen atom is preferred. In group R⁴, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl are preferred. The compounds of JP-2002-20386-A are stated as having PDE4 inhibitory activity and as being useful in the prevention and/or treatment of inflammatory diseases and many other diseases,

1,3-Dimethyl-4-(arylamino)-pyrazolo[3,4-b]pyridines with a 5-C(O)NH₂substituent similar or identical to those in JP-2002-20386-A were disclosed as orally active PDE4 inhibitors by authors from Ono Pharmaceutical Co. in: H. Ochiai et al., Bioorg. Med. Chem. Lett., 5th Jan. 2004 issue, vol. 14(1), pp. 29-32 (available on or before 4th Dec. 2003 from the Web version of the journal: “articles in press”).

EP 0 076 035 A1 (ICI Americas) discloses pyrazolo[3,4-b]pyridine derivatives as central nervous system depressants useful as tranquilisers or ataractic agents for the relief of anxiety and tension states.

The compound cartazolate, ethyl 4-(n-butylamino)-1-ethyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylate, is known. J. W. Daly et al., Med. Chem. Res., 1994, 4, 293-306 and D. Shi et al., Drug Development Research, 1997, 42, 41-56 disclose a series of 4-(amino)substituted 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives, including ethyl 4-cyclopentylamino-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, and their affinities and antagonist activities at A₁- and A_2A-adenosine receptors, and the latter paper discloses their affinities at various binding sites of the GABA_A-receptor channel. 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 Oct. 2002, allegedly published on Web Sep. 24, 2002), pp. 4875-4887 disclose a series of 4-amino-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esters as A₁-adenosine receptor ligands.

WO 02/060900 A2 appears to disclose, as MCP-1 antagonists for treatment of allergic, inflammatory or autoimmune disorders or diseases, a series of bicyclic heterocyclic compounds with a —C(O)—NR⁴—C(O)—NR⁵R⁶substituent, including isoxazolo[5,4-b]pyridines and 1H-pyrazolo[3,4-b]pyridines (named as pyrazolo[5,4-b]pyridines) with the —C(O)—NR⁴—C(O)—NR⁵R⁶group as the 5-substituent and optionally substituted at the 1-, 3-, 4-, and/or 6-positions. Bicyclic heterocyclic compounds with a —C(O)NH₂substituent instead of the —C(O)—NR⁴—C(O)—NR⁵R⁶substituent are alleged to be disclosed in WO 02/060900 as intermediates in the synthesis of the —C(O)—NR⁴—C(O)—NR⁵R⁶substituted compounds.

WO 00/15222 (Bristol-Myers Squibb) discloses inter alia pyrazolo[3,4-b]pyridines having inter alia a C(O)—X₁group at the 5-position and a group E₁at the 4-position of the ring system. Amongst other things, X₁can for example be —OR₉, —N(R₉)(R₁₀) or —N(R₅)(-A₂-R₂), and E₁can for example be —NH-A₁-cycloalkyl, —NH-A₁-substituted cycloalkyl, or —NH-A₁-heterocyclo; wherein A₁is an alkylene or substituted alkylene bridge of 1 to 10 carbons and A₂can for example be a direct bond or an alkylene or substituted alkylene bridge of 1 to 10 carbons. The compounds are disclosed as being useful as inhibitors of cGMP phosphodiesterase, especially PDE type V, and in the treatment of various cGMP-associated conditions such as erectile dysfunction. Compounds with a cycloalkyl or heterocyclo group directly attached to —NH— at the 4-position of the pyrazolo[3,4-b]pyridine ring system and/or having PDE4 inhibitory activity do not appear to be disclosed in WO 00/15222.

Copending patent application PCT/EP03/11814, filed on 12 Sep. 2003 in the name of Glaxo Group Limited, and incorporated herein by reference, discloses pyrazolo[3,4-b]pyridine compounds or salts thereof with a 4-NHR³group and a 5-C(O)—X group, according to this formula (I):

wherein:

R¹is C_1-4alkyl, C_1-3fluoroalkyl, —CH₂CH₂OH or —CH₂CH₂CO₂C_1-2alkyl;

R²is a hydrogen atom (H), methyl or C₁fluoroalkyl;

R³is optionally substituted C_3-8cycloalkyl or optionally substituted mono-unsaturated-C_5-7cycloalkenyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc);

in which n¹and n²independently are 1 or 2; and in which Y is O, S, SO₂, or NR¹⁰;

or R³is a bicyclic group (dd) or (ee): (dd) (ee):

and wherein X is NR⁴R⁵or OR^5a.

In PCT/EP03/11814, R⁴is a hydrogen atom (H); C_1-6alkyl; C_1-3fluoroalkyl; or C_2-6alkyl substituted by one substituent R¹¹.

In PCT/EP03/11814, R⁵can be: a hydrogen atom (H); C_1-8alkyl; C_1-8fluoroalkyl; C_3-8cycloalkyl optionally substituted by a C_1-2alkyl group; —(CH₂)_n⁴—C_3-8cycloalkyl optionally substituted, in the —(CH₂)_n⁴— moiety or in the C_3-8cycloalkyl moiety, by a C_1-2alkyl group, wherein n⁴is 1, 2 or 3; C_2-6alkyl substituted by one or two independent substituents R¹¹; —(CH₂)_n¹¹—C(O)R¹⁶; —(CH₂)_n¹²—C(O)NR¹²R¹³; —CHR¹⁹—C(O)NR¹²R¹³; —(CH₂)_n¹²—C(O)OR¹⁶; —(CH₂)_n¹²—C(O)OH; —CHR¹⁹—C(O)OR¹⁶; —CHR¹⁹—C(O)OH; —(CH₂)_n¹²—SO₂—NR¹²R¹³; —(CH₂)_n¹²—SO₂R¹⁶; or —(CH₂)_n¹²—CN; —(CH₂)_n¹³-Het; or optionally substituted phenyl.

Alternatively, in PCT/EP03/11814, R⁵can have the sub-formula (x), (y), (y1) or (z):

wherein in sub-formula (x), n=0, 1 or 2; in sub-formula (y) and (y1), m=1 or 2; and in sub-formula (z), r=0, 1 or 2; and wherein in sub-formula (x) and (y) and (y1), none, one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N⁺—O⁻) provided that no more than one of A, B, D, E and F is nitrogen-oxide, and the remaining of A, B, D, E and F are independently CH or CR⁶; and provided that when n is 0 in sub-formula (x) then one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N⁺—O⁻) and no more than one of A, B, D, E and F is nitrogen-oxide;

In PCT/EP03/11814, each R⁶, independently of any other R⁶present, is: a halogen atom; C_1-6alkyl; C_1-4fluoroalkyl; C_1-4alkoxy; C_1-2fluoroalkoxy; C_3-6cycloalkyloxy; —C(O)R^16a; —C(O)OR³⁰; —S(O)₂—R^16a; R^16a—S(O)₂—NR^15a—; R⁷R⁸N—S(O)₂—; C_1-2alkyl-C(O)—R^15aN—S(O)₂—; C_1-4alkyl-S(O)—; Ph-S(O)—; R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH; C_1-4alkoxymethyl; C_1-4alkoxyethyl; C_1-2alkyl-S(O)₂—CH₂—; R⁷R⁸N—S(O)₂—CH₂—; C_1-2alkyl-S(O)₂—NR^15a—CH₂—; —CH₂—OH; —CH₂CH₂—OH; —CH₂—NR⁷R⁸; —CH₂—CH₂—NR⁷R⁸; —CH₂—C(O)OR³⁰; —CH₂—C(O)—NR⁷R⁸; —CH₂—NR^15a—C(O)—C_1-3alkyl; —(CH₂)_n¹⁴-Het¹where n¹⁴is 0 or 1; cyano (CN); Ar^5b; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, C_1-2alkyl, C₁fluoroalkyl, C_1-2alkoxy or C₁fluoroalkoxy;

or two adjacent R⁶taken together can be —O—(CMe₂)-O— or —O—(CH₂)_n¹⁴—O— where n¹⁴is 1 or 2.

In PCT/EP03/11814, in sub-formula (z), G is O or S or NR⁹wherein R⁹is a hydrogen atom (H), C_1-4alkyl or C_1-4fluoroalkyl; none, one, two or three of J, L, M and Q are nitrogen; and the remaining of J, L, M and Q are independently CH or CR⁶where R⁶, independently of any other R⁶present, is as defined therein.

The pyrazolo[3,4-b]pyridine compounds of formula (I) and salts thereof disclosed in PCT/EP03/11814 are disclosed as being inhibitors of phosphodiesterase type IV (PDE4), and as being useful for the treatment and/or prophylaxis of an inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, or allergic rhinitis.

The Invention

We have now found new pyrazolo[3,4-b]pyridine compounds, having a —C(O)—NH—W substituent at the 5-position of the pyrazolo[3,4-b]pyridine ring system, which compounds inhibit phosphodiesterase type IV (PDE4).

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

wherein:

W is Ar, —CR⁴R⁵Ar or a group (y) or (y1) wherein:

wherein m=1 or 2

R¹is C_1-4alkyl, C_1-3fluoroalkyl, or —CH₂CH₂OH;

R²is C_2-6alkyl, C_3-6cycloalkyl or —(CH₂)_n⁴C_3-6cycloalkyl, wherein n⁴is 1 or 2;

R³is optionally substituted C_3-8cycloalkyl or optionally substituted mono-unsaturated-C_5-7cycloalkenyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc);

in which n¹and n²independently are 1 or 2; and in which Y is O, S, SO₂, or NR¹⁰; where R¹⁰is a hydrogen atom (H), C_1-2alkyl, C_1-2fluoroalkyl, CH₂C(O)NH₂, C(O)NH₂, C(O)NHMe, C(O)—C_1-2alkyl, C(O)—C₁fluoroalkyl or —C(O)—CH₂O—C_1-2alkyl;

and wherein in R³the C_3-8cycloalkyl or the heterocyclic group of sub-formula (aa), (bb) or (cc) is optionally substituted on a ring carbon with one or two substituents independently being oxo (═O); OH; C_1-2alkoxy; C_1-2fluoroalkoxy; NHR²¹wherein R²¹wherein R²¹is a hydrogen atom (H) or C_1-4straight-chain alkyl; C_1-2alkyl; C_1-2fluoroalkyl; —CH₂OH; —CH₂CH₂OH; —CH₂NHR²²wherein R²²is H or C_1-2alkyl; —C(O)OR²³wherein R²³is H or C_1-2alkyl; —C(O)NHR²⁴wherein R²⁴is H or C_1-2alkyl; —C(O)R²⁵wherein R²⁵is C_1-2alkyl; fluoro; hydroxyimino (═N—OH); or (C_1-4alkoxy)imino (═N—OR²⁶where R²⁶is C_1-4alkyl); and wherein any OH, alkoxy, fluoroalkoxy or NHR²¹substituent is not substituted at the R³ring carbon attached (bonded) to the —NH— group of formula (I) and is not substituted at either R³ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc);

and wherein, when R³is optionally substituted mono-unsaturated-C_5-7cycloalkenyl, then the cycloalkenyl is optionally substituted with one substituent being fluoro or C_1-2alkyl or two substituents independently being fluoro or methyl, and the R³ring carbon bonded to the —NH— group of formula (I) does not partake in the cycloalkenyl double bond;

or R³is a bicyclic group of sub-formula (ee):

wherein Y¹, Y²and Y³independently are CH₂or oxygen (O) provided that no more than one of Y¹, Y²and Y³is oxygen (O);

and wherein:

R⁴and R⁵are independently a hydrogen atom (H), methyl, ethyl, n-propyl, isopropyl, C_1-2fluoroalkyl, cyclopropyl, —CH₂OR^4a, —CH(Me)OR^4a, or —CH₂CH₂OR^4a, wherein R^4ais a hydrogen atom (H), methyl (Me), or C₁fluoroalkyl such as CF₃or CHF₂.

and wherein, in sub-formula (x) (y) and (y1):

A is C—R^6A, nitrogen (N) or nitrogen-oxide (N⁺—O⁻)), B is C—R^6B, nitrogen (N) or nitrogen-oxide (N⁺—O⁻)), D is C—R^6D, nitrogen (N) or nitrogen-oxide (N⁺—O⁻)), E is C—R^6E, nitrogen (N) or nitrogen-oxide (N⁺—O⁻)), F is C—R^6F, nitrogen (N) or nitrogen-oxide (N⁺—O⁻)),

wherein, R^6A, R^6B, R^6D, R^6Eand R^6Findependently are: a hydrogen atom (H), a halogen atom; C_1-6alkyl (e.g. C_1-4alkyl or C_1-2alkyl); C_1-4fluoroalkyl (e.g. C_1-2fluoroalkyl); C_3-6cycloalkyl; C_1-4alkoxy (e.g. C_1-2alkoxy); C_1-2fluoroalkoxy; C_3-6cycloalkyloxy; —C(O)R^16a; —C(O)OR³⁰; —S(O)₂—R^16a(e.g. C_1-2alkyl-S(O)₂—); R^16a—S(O)₂—NR^15a— (e.g. C_1-2alkyl-S(O)₂—NH—); R⁷R⁸N—S(O)₂—; C_1-2alkyl-C(O)—R^15aN—S(O)₂—; C_1-4alkyl-S(O)—, Ph-S(O)—, R⁷R⁸N—CO—; —NR¹⁵—C(O)R^16a; R⁷R⁸N; nitro(—NO₂); OH (including any tautomer thereof); C_1-4alkoxymethyl; C_1-4alkoxyethyl; C_1-2alkyl-S(O)₂—CH₂—; R⁷R⁸N—S(O)₂—CH₂—; C_1-2alkyl-S(O)₂—NR^15a—CH₂—; —CH₂—OH; —CH₂CH₂—OH; —CH₂—R⁷R⁸; —CH₂—CH₂—NR⁷R⁸; —CH₂—C(O)OR³⁰; —CH₂—C(O)—NR⁷R⁸; —CH₂—NR^15a—C(O)—C_1-3alkyl; —(CH₂)_n¹⁴-Het¹where n¹⁴is 0 or 1; cyano(—CN); Ar^5b; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, C_1-2alkyl, C₁fluoroalkyl, C_1-2alkoxy or C₁fluoroalkoxy;

and/or two adjacent groups selected from R^6A, R^6B, R^6D, R^6Eand R^6Fare taken together and are: —CH═CH—CH═CH₂—, —(CH₂)_n^14a— where n^14ais 3, 4 or 5 (e.g. 3 or 4), —O—(CMe₂)—O—, —O—(CH₂)_n^14b—O— where n^14bis 1 or 2; —CH═CH—NR^15b—; —N═CH—NR^15b—; —CH═N—NR^15b—; —N═N—NR^15b—; —CH═CH—O—; —N═CH—O—; —CH═CH—S—; or —N═CH—S—; wherein R^15bis H or C_1-2alkyl;

provided that:

- two or more of A, B, D, E and F are independently C—H (carbon-hydrogen), C—F (carbon-fluorine), nitrogen (N), or nitrogen-oxide (N⁺—O⁻));
- and no more than two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N⁺—O⁻)),
- and no more than one of A, B, D, E and F is nitrogen-oxide (N⁺—O⁻));

and wherein, in sub-formula (z):

G is O or S or NR⁹wherein R⁹is a hydrogen atom (H), C_1-4alkyl, or C_1-2fluoroalkyl; J is C—R^6J, C-[connection point to formula (I)], or nitrogen (N), L is C—R^6L, C-[connection point to formula (I)], or nitrogen (N), M is C—R^6M, C-[connection point to formula (I)], or nitrogen (N), Q is C—R^6Q, C-[connection point to formula (I)], or nitrogen (N),

wherein, R^6J, R^6L, R^6Mand R^6Qindependently are: a hydrogen atom (H), a halogen atom; C_1-4alkyl (e.g. C_1-2alkyl); C_1-3fluoroalkyl (e.g. C_1-2fluoroalkyl); C_3-6cycloalkyl; C_1-4alkoxy (e.g. C_1-2alkoxy); C_1-2fluoroalkoxy; C_3-6cycloalkyloxy; OH (including any tautomer thereof); or phenyl optionally substituted by one or two substituents independently being fluoro, chloro, C_1-2alkyl, C₁fluoroalkyl, C_1-2alkoxy or C₁fluoroalkoxy;

provided that:

- two or more of J, L, M and Q are independently C—H, C—F, C—C_1-2alkyl (e.g. C-Me), C-[connection point to formula (I)], or nitrogen (N);
- and no more than three of J, L, M and Q are nitrogen (N);
  
  and wherein:

R⁷and R⁸are independently a hydrogen atom (H); C_1-4alkyl (e.g. C_1-2alkyl such as methyl); C_3-6cycloalkyl; or phenyl optionally substituted by one or two substituents independently being: fluoro, chloro, C_1-2alkyl, C₁fluoroalkyl, C_1-2alkoxy or C₁fluoroalkoxy;

or R⁷and R⁸together are —(CH₂)_n⁶— or —C(O)—(CH₂)_n⁷— or —C(O)—(CH₂)_n¹⁰—C(O)— or —(CH₂)_n⁸—X⁷—(CH₂)_n⁹— or —C(O)—X⁷—(CH₂)_n¹⁰— in which: n⁶is 3, 4, 5 or 6 (suitably n⁶is 4 or 5), n⁷is 2, 3, 4, or 5 (suitably n⁷is 3 or 4), n⁸and n⁹and n¹⁰independently are 2 or 3 (suitably independently 2), and X⁷is O or NR¹⁴;

R^7ais a hydrogen atom (H) or C_1-4alkyl (suitably H or C_1-2alkyl, more suitably H or methyl);

R^8ais a hydrogen atom (H) or methyl (suitably H);

R¹⁴, R¹⁷and R^17aindependently are: a hydrogen atom (H); C_1-4alkyl (e.g. C_1-2alkyl); C_1-2fluoroalkyl (e.g. CF₃); cyclopropyl; —C(O)—C_1-4alkyl (e.g. —C(O)Me);

—C(O)NR^7aR^8a(e.g. —C(O)NH₂); or —S(O)₂—C_1-4alkyl (e.g. —S(O)₂Me) (preferably, R¹⁴, R¹⁷and/or R^17aindependently is/are: H; C_1-2alkyl; or —C(O)Me);

R^15a, independent of other R^15a, is a hydrogen atom (H) or C_1-4alkyl (e.g. H, ^tBu or C_1-2alkyl such as methyl; preferably R^15ais H or C_1-2alkyl, more preferably H);

R^16ais:

C_1-6alkyl (e.g. C_1-4alkyl or C_1-2alkyl);

C_3-6cycloalkyl (e.g. C_5-6cycloalkyl) optionally substituted by one oxo (═O), OH or C_1-2alkyl substituent (e.g. optionally substituted at the 3- or 4-position of a C_5-6cycloalkyl ring; and/or preferably unsubstituted C_3-6cycloalkyl);

C_3-6cycloalkyl-CH₂— (e.g. C_5-6cycloalkyl-CH₂—);

pyridinyl (e.g. pyridin-2-yl) optionally substituted on a ring carbon atom by one of: a halogen atom, C_1-2alkyl, C₁fluoroalkyl, C_1-2alkoxy or C₁fluoroalkoxy;

Ar^5c;

phenyl optionally substituted by one or two substituents independently being: a halogen atom, C_1-2alkyl, C₁fluoroalkyl, C_1-2alkoxy or C₁fluoroalkoxy;

benzyl optionally substituted on its ring by one or two substituents independently being: a halogen atom, C_1-2alkyl, C₁fluoroalkyl, C_1-2alkoxy or C₁fluoroalkoxy; or

a 4-, 5-, 6- or 7-membered saturated heterocyclic ring connected at a ring-carbon and containing one or two ring-hetero-atoms independently selected from O, S, and N;

wherein any ring-nitrogens which are present are present as NR²⁷where R²⁷is H, C_1-2alkyl or —C(O)Me; and wherein the ring is optionally substituted at carbon by one C_1-2alkyl or oxo (═O) substituent, provided that any oxo (═O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen;

R³⁰, independent of other R³⁰, is a hydrogen atom (H), C_1-4alkyl or C_3-6cycloalkyl;

Ar^5band Ar^5cindependently is/are a 5-membered aromatic heterocyclic ring containing one O, S or NR^15ain the 5-membered ring, wherein the 5-membered ring can optionally additionally contain one or two N atoms, and wherein the heterocyclic ring is optionally substituted on a ring carbon atom by one of: a halogen atom, C_1-2alkyl, C₁fluoroalkyl, —CH₂OH, —CH₂—OC_1-2alkyl, OH (including the keto tautomer thereof) or —CH₂—NR²⁸R²⁹wherein R²⁸and R²⁹independently are H or methyl; and

Het¹, is a 4-, 5-, 6- or 7-membered saturated heterocyclic ring connected at a ring-carbon and containing one or two ring-hetero-atoms independently selected from O, S, and N; wherein any ring-nitrogens which are present are present as NR³¹where R³¹is H, C_1-2alkyl or —C(O)Me; and wherein the ring is optionally substituted at carbon by one C_1-2alkyl or oxo (═O) substituent, provided that any oxo (═O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen.

In compounds, for example in the compounds of formula (I) (or formula (IA) or formula (IB), see later), an “alkyl” group or moiety may be straight-chain or branched. Alkyl groups, for example C_1-8alkyl or C_1-6alkyl or C_1-4alkyl or C_1-3alkyl or C_1-2alkyl, which may be employed include C_1-6alkyl or C_1-4alkyl or C_1-3alkyl or C_1-2alkyl such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl or any branched isomers thereof such as isopropyl, t-butyl, sec-butyl, isobutyl, 3-methylbutan-2-yl, 2-ethylbutan-1-yl, or the like.

A corresponding meaning is intended for “alkoxy”, “alkylene”, and like terms derived from alkyl. For example, “alkoxy” such as C_1-6alkoxy or C_1-4alkoxy or C_1-2alkoxy includes methoxy, ethoxy, propyloxy, and oxy derivatives of the alkyls listed above. “Alkylsulfonyl” such as C_1-4alkylsulfonyl includes methylsulfonyl (methanesulfonyl), ethylsulfonyl, and others derived from the alkyls listed above. “Alkylsulfonyloxy” such as C_1-4alkylsulfonyloxy includes methanesulfonyloxy (methylsulfonyloxy), ethanesulfonyloxy, et al. “Cycloalkyl”, for example C_3-8cycloalkyl, includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably, a C_3-8cycloalkyl group is C_3-6cycloalkyl or C_5-6cycloalkyl, that is contains a 3-6 membered or 5-6 membered carbocyclic ring.

“Fluoroalkyl” includes alkyl groups with one, two, three, four, five or more fluorine substituents, for example C_1-4fluoroalkyl or C_1-3fluoroalkyl or C_1-2fluoroalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl (CF₃CH₂—), 2,2-difluoroethyl (CHF₂CH₂—), 2-fluoroethyl (CH₂FCH₂—), etc. “Fluoroalkoxy” includes C_1-4fluoroalkoxy or C_1-2fluoroalkoxy such as trifluoromethoxy, pentafluoroethoxy, monofluoromethoxy, difluoromethoxy, etc. “Fluoroalkylsulfonyl” such as C_1-4fluoroalkylsulfonyl includes trifluoromethanesulfonyl, pentafluoroethylsulfonyl, etc. A halogen atom (“halo”) present in compounds, for example in the compounds of formula (I), means a fluorine, chlorine, bromine or iodine atom (“fluoro”, “chloro”, “bromo” or “iodo”), for example fluoro, chloro or bromo.

When the specification states that atom or moiety A is “bonded” or “attached” to atom or moiety B, it means that atom/moiety A is directly bonded to atom/moiety B usually by means of a covalent bond or a double covalent bond, and excludes A being indirectly attached to B via one or more intermediate atoms/moieties (e.g. excludes A-C-B); unless it is clear from the context that another meaning is intended.

When R¹is C_1-4alkyl or C_1-3fluoroalkyl, it can be straight-chained or branched. Where R¹is C_1-4alkyl then it can for example be methyl, ethyl, n-propyl, isopropyl or n-butyl. When R¹is C_1-3fluoroalkyl, then R¹can for example be C₁fluoroalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl; or R¹can be C₂fluoroalkyl such as pentafluoroethyl or more preferably C₁fluoroalkyl-CH₂— such as 2,2,2-trifluoroethyl(CF₃CH₂—), 2,2-difluoroethyl(CHF₂CH₂—), or 2-fluoroethyl(CH₂FCH₂—).

Preferably, R¹is C_1-3alkyl (e.g. methyl, ethyl or n-propyl), C_1-3fluoroalkyl or —CH₂CH₂OH. R¹is more preferably C_1-3alkyl, C_1-2fluoroalkyl, or —CH₂CH₂OH. Still more preferably, R¹is C_2-3alkyl (e.g. ethyl or n-propyl), C₂fluoroalkyl (e.g. C₁fluoroalkyl-CH₂— such as CF₃—CH₂—) or —CH₂CH₂OH; in particular ethyl, n-propyl or —CH₂CH₂OH. Yet more preferably, R¹is C₂alkyl or C₂fluoroalkyl. R¹is most preferably ethyl.

Representative examples of R¹include ethyl.

In another aspect of the invention R²is C_2-4alkyl, C_3-5cycloalkyl or —CH₂cyclopropyl.

Representative examples of R²include ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclopropylmethyl.

Preferably, in R³there is one substituent or no substituent.

In one embodiment, R³is the optionally substituted C_3-8cycloalkyl or the optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc).

In one optional embodiment, when R³is optionally substituted C_3-8cycloalkyl, it is not unsubstituted C₅cycloalkyl, i.e. not unsubstituted cyclopentyl. In this case, more suitably, R³is optionally substituted C_6-8cycloalkyl.

When R³is optionally substituted C_3-8cycloalkyl, it is more preferably optionally substituted C_6-7cycloalkyl or optionally substituted C₆cycloalkyl (i.e. cyclohexyl).

Suitably, when R³is optionally substituted C_3-8cycloalkyl, then R³is C_3-8cycloalkyl (e.g. C_6-7cycloalkyl) optionally substituted with one or two substituents independently being oxo (═O); OH; C₁alkoxy; C₁fluoroalkoxy (e.g. trifluoromethoxy or difluoromethoxy); NHR²¹wherein R²¹is a hydrogen atom (H) or C_1-2alkyl (more preferably R²¹is H); C_1-2alkyl such as methyl; C₁fluoroalkyl such as —CH₂F or —CHF₂; —CH₂OH; —CH₂NHR²²wherein R²²is H; —C(O)OR²³wherein R²³is H or methyl; —C(O)NHR²⁴wherein R²⁴is H or methyl; —C(O)R²⁵wherein R²⁵is methyl; fluoro; hydroxyimino (═N—OH); or (C_1-4alkoxy)imino(—N—OR²⁶where R²⁶is C_1-4alkyl); and wherein any OH, alkoxy, fluoroalkoxy or NHR²¹substituent is not substituted at the R³ring carbon attached (bonded) to the —NH— group of formula (I) and is not substituted at either R³ring carbon bonded to the Y group of the heterocyclic group (aa), (bb) or (cc).

Preferably, when R³is optionally substituted C_3-8cycloalkyl, then R³is C_3-8cycloalkyl (e.g. C_6-7cycloalkyl) optionally substituted with one or two substituents independently being oxo (═O); OH; NHR²¹wherein R²¹is a hydrogen atom (H); C_1-2alkyl such as methyl; C₁fluoroalkyl such as —CH₂F or —CHF₂; —C(O)OR²³wherein R²³is H or methyl; —C(O)NHR²⁴wherein R²⁴is H or methyl; fluoro; hydroxyimino (═N—OH); or (C_1-2alkoxy)imino (═N—OR²⁶where R²⁶is C_1-2alkyl).

More preferably, when R³is optionally substituted C_3-8cycloalkyl, then R³is C_3-8cycloalkyl (e.g. C_6-7cycloalkyl) optionally substituted with one or two substituents independently being oxo (═O); OH; NHR²¹wherein R²¹is a hydrogen atom (H); methyl; —CH₂F; —CHF₂; —C(O)OR²³wherein R²³is H; —C(O)NHR²⁴wherein R²⁴is H or methyl (preferably H); fluoro; hydroxyimino (═N—OH); or methoxyimino (═N—OR²⁶where R²⁶is methyl).

Still more preferably, when R³is optionally substituted C_3-8cycloalkyl, then R³is C_3-8cycloalkyl (e.g. C_6-7cycloalkyl) optionally substituted with one or two substituents independently being oxo (═O); OH; methyl; —C(O)NHR²⁴wherein R²⁴is H; fluoro; hydroxyimino (═N—OH); or methoxyimino (═N—OR²⁶where R²⁶is methyl).

Yet more preferably, when R³is optionally substituted C_3-8cycloalkyl, then R³is C_3-8cycloalkyl (e.g. C_6-7cycloalkyl) optionally substituted with one or two substituents independently being OH; —C(O)NHR²⁴wherein R²⁴is H; oxo (═O) or hydroxyimino (═N—OH).

In one optional embodiment, in R³, the C_3-8cycloalkyl can be unsubstituted.

When R³is optionally substituted C_3-8cycloalkyl or optionally substituted C_5-7cycloalkenyl, e.g. optionally substituted C_5-8cycloalkyl or C_5-7cycloalkyl, such as optionally substituted C₆cycloalkyl (optionally substituted cyclohexyl) or optionally substituted cyclohexenyl, the one or two optional substituents if present suitably can comprise a substituent (for example is or are substituent(s)) at the 3-, 4- and/or 5-position(s), e.g. at the 3- and/or 4-position(s), of the R³cycloalkyl or cycloalkenyl ring. (In this connection and generally herein, the l-position of the R³ring, e.g. of the R³cycloalkyl or cycloalkenyl ring is deemed to be the connection point to the —NH— in formula (I)=the ring atom connecting to the —NH— in formula (I)).

Suitably, for R³, and in particular when R³is optionally substituted C_3-8cycloalkyl or optionally substituted C_5-7cycloalkenyl, R³is not substituted (other than optionally by alkyl or fluoroalkyl) at the ring atom connecting to the —NH— in formula (I), and R³is not substituted (other than optionally by alkyl, fluoroalkyl or NHR²¹) at the two ring atoms either side of (bonded to) the connecting atom. For example, suitably, for R³, and in particular when R³is optionally substituted C_3-8cycloalkyl or optionally substituted C_5-7cycloalkenyl, R³is not substituted at the ring atom connecting to the —NH— in formula (I), and R³is not substituted at the two ring atoms either side of (bonded to) the connecting atom.

Suitably, for R³, and in particular when R³is optionally substituted C_3-8cycloalkyl or optionally substituted C_5-7cycloalkenyl, the one or two optional R³substituents if present can comprise a substituent (for example is or are substituent(s)):

(a) at the 3-position of a R³cyclobutyl ring, or
(b) at the 3- and/or 4-position(s) of a R³cyclopentyl or cyclopentenyl ring, or
(c) at the 3-, 4- and/or 5-position(s) of a R³cyclohexyl or cyclohexenyl ring, or
(d) at the 3-, 4-, 5- and/or 6-position(s) of a R³cycloheptyl or cycloheptenyl ring, or
(e) at the 3-, 4-, 5-, 6- and/or 7-position(s) of a R³cyclooctyl ring, and/or
(f) at the 1-, 2- and/or highest-numbered-position(s) of a R³cycloalkyl or cycloalkenyl ring, for alkyl or fluoroalkyl substituent(s), and/or
(g) at the 2- and/or highest-numbered-position(s) of a R³cycloalkyl or cycloalkenyl ring, for NHR²¹or fluoro substituent(s).

When R³is optionally substituted C_3-8cycloalkyl, any OH, alkoxy, fluoroalkoxy, —CH₂CH₂OH or —CH₂NHR²²substituent (particularly any OH substituent) is suitably at the 3-, 4- or 5-position, e.g. 3- or 5-position, of the R³cycloalkyl (e.g. C_6-8cycloalkyl) ring. Optionally, any OH, alkoxy, fluoroalkoxy, —CH₂CH₂OH or —CH₂NHR²²substituent (particularly any OH substituent) can be: at the 3-position of a R³cyclobutyl ring; or at the 3- or 4-position of a R³C₅cycloalkyl (cyclopentyl) ring; or at the 3-, 4- or 5-position, of a R³C₆cycloalkyl (cyclohexyl) ring e.g. at the 3- or 5-position of a R³cyclohexyl ring especially for any OH substituent; or at the 3-, 4-, 5- or 6-position of a R³cycloheptyl ring, or at the 3-, 4-, 5-, 6- or 7-position of a R³cyclooctyl ring. Suitably, any OH, alkoxy, fluoroalkoxy, —CH₂CH₂OH or —CH₂NHR²²substituent (particularly any OH substituent) is at the 3- or 4-position of a R³C₅cycloalkyl (cyclopentyl) ring; or more suitably at the 3-, 4- or 5-position, still more suitably at the 3- or 5-position, of a R³C₆cycloalkyl(cyclohexyl) ring.

Suitably, when R³is optionally substituted C_3-8cycloalkyl or optionally substituted C_5-7cycloalkenyl, any —C(O)OR²³, —C(O)NHR²⁴, —C(O)R²⁵, —CH₂OH, or fluoro substituent is: at the 3-position of a R³cyclobutyl ring; or at the 3- or 4-position of a R³C₅cycloalkyl(cyclopentyl) or cyclopentenyl ring; or at the 3-, 4- or 5-position, preferably at the 4-position, of a R³C₆cycloalkyl(cyclohexyl) or cyclohexenyl ring; or at the 3-, 4-, 5- or 6-position of a R³cycloheptyl or cycloheptenyl ring, or at the 3-, 4-, 5-, 6- or 7-position of a R³cyclooctyl ring. Any —C(O)OR²³, —C(O)NHR²⁴, —C(O)R²⁵, —CH₂OH, or fluoro substituent, e.g. any —C(O)NHR²⁴or fluoro substituent, is suitably at the 3-, 4- or 5-position, more suitably at the 4-position, of a R³C₆cycloalkyl(cyclohexyl) or cyclohexenyl ring. It is particularly preferable for any —C(O)NHR²⁴substituent to be at the 4-position of a R³cyclohexyl ring.

When R³is optionally substituted C_3-8cycloalkyl, any NHR²¹substituent is at any position other than the 1-position (the ring atom connecting to the —NH— in formula (I)), e.g. at the 3-, 4-, 5-, 6-, 7- or 8-position. Preferably, any NHR²¹substituent is at the 2-, 3-, 5- or 6-position, or more preferably at the 3- or 5-position, of a R³cyclohexyl ring.

When R³is optionally substituted C_3-8cycloalkyl or optionally substituted C_5-7cycloalkenyl, any alkyl or fluoroalkyl substituent can for example be at the 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-position, for example at the 1-, 2-, 3-, 5- or 6-position, e.g. the 1-position, of the R³ring. Preferably, any alkyl or fluoroalkyl substituent is at the 1-, 2-, 3-, 5- or 6-position, or more preferably at the 1-, 3- or 5-position, of a R³cyclohexyl or cyclohexenyl ring.

When R³is optionally substituted C_3-8cycloalkyl, any oxo (═O), hydroxyimino (═N—OH); or (C_1-4alkoxy)imino (═N—OR²⁶) substituent is suitably at the 3-, 4- or 5-position, e.g. at the 4-position, of the R³cycloalkyl (e.g. C_6-8cycloalkyl e.g. cyclohexyl) ring. Preferably any such substituent is at the 4-position of a R³cyclohexyl ring.

When R³is optionally substituted C_3-8cycloalkyl (e.g. C_6-7cycloalkyl), R³is preferably cyclohexyl (i.e. unsubstituted); or cycloheptyl (i.e. unsubstituted); or cyclohexyl substituted by one substituent being oxo (═O), OH, NHR²¹, C_1-2alkyl, C_1-2fluoroalkyl, —CH₂OH, —C(O)OR²³, —C(O)NHR²⁴, —C(O)R²⁵, fluoro, hydroxyimino (═N—OH), or (C_1-4alkoxy)imino (═N—OR²⁶); or cyclohexyl substituted by two fluoro substituents. More preferably, R³is cyclohexyl (i.e. unsubstituted); or cycloheptyl (i.e. unsubstituted); or cyclohexyl substituted by one substituent being oxo (═O), OH, NHR²¹, C_1-2alkyl, C_1-2fluoroalkyl, —C(O)OR²³, —C(O)NHR²⁴, fluoro, hydroxyimino (═N—OH), or (C_1-2alkoxy)imino (═N—OR²⁶wherein R²⁶is C_1-2alkyl); or cyclohexyl substituted by two fluoro substituents. Still more preferably R³is cyclohexyl (i.e. unsubstituted) or cyclohexyl substituted by one oxo (═O), hydroxyimino (═N—OH), —C(O)NH₂, methyl or OH substituent. The optional substituent can for example be at the 3- or 4-position, of the R³cyclohexyl ring. Preferably, any OH substituent is preferably at the 3-position of a R³cyclohexyl ring, and/or any oxo (═O), hydroxyimino (═N—OH), (C_1-4alkoxy)imino (═N—OR²⁶) or —C(O)NH₂substituent is preferably at the 4-position of a R³cyclohexyl ring, and/or any alkyl or fluoroalkyl substituent is preferably at the 1-, 3- or 5-position of a R³cyclohexyl ring.

When R³is optionally substituted C_6-7cycloalkyl, R³can for example be 4-hydroxy-cyclohexyl (i.e. 4-hydroxycyclohexan-1-yl), 4-methylcyclohexyl, 3-fluorocyclohexyl, 2-aminocyclohexyl, 3-(HO(O)C)cyclohexyl or 3-oxocyclohexyl, but R³is more preferably cyclohexyl (i.e. unsubstituted), cycloheptyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-1-yl) (e.g. in a cis configuration), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-1-yl), 4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan-1-yl), 4-(C_1-2alkoxyimino)cyclohexyl, 4-(aminocarbonyl)cyclohexyl (i.e. 4-(aminocarbonyl)cyclohexan-1-yl) (e.g. in a cis configuration), 1-methylcyclohexyl, 3-methylcyclohexyl, 4,4-(difluoro)cyclohexyl, or 3-aminocyclohexyl.

When R³is optionally substituted C_6-7cycloalkyl, R³is most preferably cyclohexyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e. 3-hydroxycyclohexan-1-yl) (e.g. in a cis configuration), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-1-yl), 4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan-1-yl), or 4-(aminocarbonyl)cyclohexyl (i.e. 4-(aminocarbonyl)cyclohexan-1-yl) (e.g. in a cis configuration).

When R³is optionally substituted C₅cycloalkyl (optionally substituted cyclopentyl), R³can for example be cyclopentyl (i.e. unsubstituted) or more suitably 3-hydroxy-cyclopentyl.

When R³is optionally substituted mono-unsaturated-C_5-7cycloalkenyl, preferably it is optionally substituted mono-unsaturated-C_5-6cycloalkenyl, more preferably optionally substituted mono-unsaturated-C₆cycloalkenyl (i.e. optionally substituted mono-unsaturated-cyclohexenyl=optionally substituted cyclohexenyl). For example, the R³cyclohexenyl can be optionally substituted cyclohex-3-en-1-yl.

When R³is optionally substituted mono-unsaturated-C_5-7cycloalkenyl, in one optional embodiment the R³cycloalkenyl is optionally substituted with one or two substituents independently being fluoro or methyl. Preferably, in this embodiment, if there are two substituents then they are not both methyl.

In another optional embodiment, the R³cycloalkenyl (e.g. cyclohexenyl) is optionally substituted with one substituent being fluoro or C_1-2alkyl (preferably fluoro or methyl); more preferably the R³cycloalkenyl (e.g. cyclohexenyl) is substituted with one fluoro substituent or is unsubstituted. For example, the R³optionally substituted cycloalkenyl can be cyclohex-3-en-1-yl (i.e. unsubstituted) or 4-fluoro-cyclohex-3-en-1-yl.

For R³cycloalkenyl, the optional substituent(s) can for example be at the 1-, 2-, 3-, 4-, 5- or 6-position(s) of the cycloalkenyl ring.

When R³is the heterocyclic group of sub-formula (aa), (bb) or (cc), then Y is preferably O or NR¹⁰, most preferably O.

Suitably, R¹⁰is a hydrogen atom (H), methyl, ethyl, C(O)NH₂, C(O)—C_1-2alkyl or C(O)—C₁fluoroalkyl. Preferably, R¹⁰is not C_1-2alkyl or C_1-2fluoroalkyl. Suitably R¹⁰is not CH₂C(O)NH₂.

More preferably, R¹⁰is a hydrogen atom (H), C(O)NH₂, C(O)—C_1-2alkyl (e.g. C(O)methyl) or C(O)—C₁fluoroalkyl (e.g. C(O)—CF₃). Still more preferably R¹⁰is H, C(O)NH₂or C(O)methyl; for example C(O)NH₂.

When R³is the heterocyclic group of sub-formula (aa), (bb) or (cc), then it is preferable that R³is the heterocyclic group of sub-formula (aa) or (bb), more preferably of sub-formula (bb).

In sub-formula (bb), n¹is preferably 1. In sub-formula (cc), n²is preferably 1. That is, six-membered rings are preferred in the R³heterocyclic group.

Suitably, in R³, the heterocyclic group of sub-formula (aa), (bb) or (cc) is unsubstituted on a ring carbon. (In this connection, where Y is NR¹⁰, R¹⁰is not a substituent on a ring carbon).

In the R³heterocyclic group of sub-formula (aa), (bb) or (cc), the one or two optional substituents preferably comprise (e.g. is or independently are) OH; oxo (═O); C_1-2alkyl (e.g. methyl) or C_1-2fluoroalkyl (e.g. C₁fluoroalkyl such as —CH₂F or —CHF₂). More preferably, in the R³heterocyclic group of sub-formula (aa), (bb) or (cc), the one or two optional substituents comprise (e.g. is or independently are) C_1-2alkyl (e.g. methyl) or oxo; most preferably the one or two optional substituents comprise (e.g. is or are) oxo (═O).

In the R³heterocyclic group of sub-formula (aa), (bb) or (cc), any oxo (═O) substituent is preferably on a carbon atom bonded (adjacent) to Y, e.g. is on a carbon atom bonded (adjacent) to Y only when Y is O or NR¹⁰.

In the R³heterocyclic group of sub-formula (aa), (bb) or (cc), any oxo (═O) substituent can suitably be at the 2-, 3-, 4-, 5- or 6-position of the R³heterocyclic ring. For example any oxo (═O) substituent(s) can be: at the 2-, 4- or 5-position(s) (e.g. 2-position or 4-position, or two oxo substituents at 2- and 4-positions) of a R³heterocyclic group of sub-formula (aa), at the 2-, 4-, 5- or 6-position(s) (e.g. 4-position) of a six-membered R³heterocyclic group of sub-formula (cc) wherein n²is 1, at the 2-, 3-, 5-, 6- or 7-position(s) (e.g. 5-position) of a seven-membered R³heterocyclic group of sub-formula (bb) wherein n¹is 2, or at the 2-, 4-, 5-, 6- or 7-position(s) (e.g. 2-position) of a seven-membered R³heterocyclic group of sub-formula (cc) wherein n²is 2.

(In this connection and generally herein, the 1-position of the R³heterocyclic ring is deemed to be the connection point to the —NH— in formula (I)=the ring atom connecting to the —NH— in formula (I), and the remaining positions of the ring are then numbered so that the ring heteroatom takes the lowest possible number).

In the R³heterocyclic group of sub-formula (aa), (bb) or (cc), any alkyl or fluoroalkyl substituent can for example be at the 1-, 2-, 3-, 4-, 5- or 6-position, e.g. the 1-position, of the R³heterocyclic ring, for example at the 1-, 3- or 5-position of a six-membered R³heterocyclic ring.

In the R³heterocyclic group of sub-formula (aa), (bb) or (cc), any OH substituent can be: at the 5-position of a six-membered R³heterocyclic group of sub-formula (cc) wherein n²is 1; at the 5- or 6-position of a seven-membered R³heterocyclic group of sub-formula (cc) wherein n²is 2; or at the 6-position of a seven-membered R³heterocyclic group of sub-formula (bb) wherein n¹is 2.

Any other substituents of the R³heterocyclic group can optionally be positioned on the R³heterocyclic ring at numerical positions as described herein for when R³is optionally substituted C_5-7cycloalkyl, all necessary changes to the wording being made.

In the R³heterocyclic group of sub-formula (aa), (bb) or (cc), preferably, only C_1-2alkyl, C_1-2fluoroalkyl, fluoro or oxo (═O) substitution or no substitution is allowed independently at each of the 2- and highest-numbered-positions of the R³heterocyclic ring (e.g. at each of the 2- and 6-positions of a six-membered R³heterocyclic ring), and/or only C_1-2alkyl, C_1-2fluoroalkyl or fluoro substitution or no substitution is allowed at the 1-position of the R³heterocyclic ring.

When R³is the heterocyclic group of sub-formula (aa) and Y is NR¹⁰, then R¹⁰is not C(O)—C_1-2alkyl, C(O)—C₁fluoroalkyl or —C(O)—CH₂O—C_1-2alkyl. According to one optional embodiment when R³is the heterocyclic group of sub-formula (aa) and Y is NR¹⁰then R¹⁰is optionally not C(O)NHMe, C(O)—C_1-2alkyl, C(O)—C₁fluoroalkyl or —C(O)—CH₂O—C_1-2alkyl.

In one preferable embodiment, Y is O, S, SO₂or NH when R³is the heterocyclic group of sub-formula (aa).

When R³is the heterocyclic group of sub-formula (bb), n¹is 1, and Y is NR¹⁰(e.g. when NHR³is

then R¹⁰is not C_1-2alkyl or C_1-2fluoroalkyl. More preferably, when R³is the heterocyclic group of sub-formula (bb) wherein n¹is 1 or 2 and Y is NR¹⁰, then R¹⁰is preferably not C_1-2alkyl or C_1-2fluoroalkyl.

In one embodiment, when R³is the heterocyclic group of sub-formula (bb), then preferably Y is O, S, SO₂or NR¹⁰wherein R¹⁰is H, C(O)NH₂, C(O)—C_1-2alkyl (e.g. C(O)methyl) or C(O)—C₁fluoroalkyl (e.g. C(O)—CF₃), or more preferably R¹⁰is H, C(O)NH₂or C(O)Me, for example C(O)NH₂or C(O)Me most preferably CONH₂.

In one optional embodiment, when R³is the heterocyclic group of sub-formula (cc), then optionally Y is O, S, SO₂or NR¹⁰wherein R¹⁰is H, C(O)NH₂, C(O)—C_1-2alkyl (e.g. C(O)methyl) or C(O)—C₁fluoroalkyl (e.g. C(O)—CF₃). In this case R¹⁰can for example be H, C(O)NH₂or C(O)Me, for example H.

Optionally, for sub-formula (bb) and/or for sub-formula (cc), Y is O or NR¹⁰.

When R³is optionally substituted C_3-8cycloalkyl (e.g. C_6-7cycloalkyl) or optionally substituted mono-unsaturated-C_5-7cycloalkenyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc), then a substituent can be in the cis or trans configuration with respect to the —NH— group of formula (I) to which R³is attached (bonded); this includes mixtures of configurations wherein the stated configuration is the major component. For example, an OH or —C(O)NHR²⁴substituent on C_6-7cycloalkyl can for example be in the cis configuration and/or a NHR²¹substituent on C_6-7cycloalkyl can for example be in the cis or trans configuration, with respect to the —NH— group of formula (I) to which R³is attached (bonded), including mixtures of configurations wherein the stated configuration is the major component.

When R³is a bicyclic group of sub-formula (ee), then preferably Y¹, Y²and Y³are all CH₂.

Preferably, NHR³is of sub-formula (a), (a1), (b), (c), (c 1), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (g), (g1), (g2), (g3), (g4), (h), (i), (j), (k), (k1), (k2), (L), (m), (m1), (m2), (m3), (m5), (n), (o), (o1), (o2), (o3), (p), (p1), (p2), (p3), (p4), (p5), (p6), (p7), (p8), (p9), (p10), (p11) or (q):

In the sub-formulae (a) to (q) etc above, the —NH— connection point of the NHR³group to the 4-position of the pyrazolopyridine of formula (I) is underlined.

Preferably, NHR³is of sub-formula (c), (c1), (c 2), (c 3), (c 4), (c 5), (c 6), (c 7), (d), (e), (f), (g1), (g4), (h), (i), (j), (k), (k1), (k2), (L), (m), (m1), (m2), (m3), (m5), (n), (o), (o1), (o2), (o3), (p), (p2), (p5), (p6), (p7), (p9), (p10), (p11) or (q). More preferably, NHR³is of sub-formula (c), (c1), (c 4), (c 5), (h), (i), (j), (k), (k2), (m1), (m2), (n), (o), (o2), (o3), (p2), (p5), (16), (p9), (p11) or (q). NHR³can for example be of sub-formula (c), (p11), (h), (k), (k2), (n), (o), (o2) or (p9); or still more preferably (c), (p11), (h), (k2), (n), (o), (o2) or (p9). Most preferably, R³is tetrahydro-2H-pyran-4-yl or 1-(aminocarbonyl)-4-piperidinyl; that is NHR³is most preferably of sub-formula (h) or (k2), as shown above.

In another aspect of the invention R³is C_3-8cycloalkyl (e.g. C_6-7cycloalkyl) optionally substituted with one or two substituents independently being oxo (═O); OH; methyl; —C(O)NHR²⁴wherein R²⁴is H; fluoro; hydroxyimino (—N—OH); or methoxyimino(═N—OR²⁶where R²⁶is methyl).

In another aspect of the invention R³is a 4-(aminocarbonyl)cyclohexyl (i.e. 4-(aminocarbonyl)cyclohexan-1-yl) group of sub-formula (aa), or an N-aminocarbonyl-piperidinyl or an N-aminocarbonyl-pyrrolidinyl or a tetrahydropyranyl group of sub-formula (bb);

wherein Y is O or NCONH₂and n¹is 0 or 1;

and wherein the cyclohexyl group of sub-formula (aa) or the piperidinyl, pyrrolidinyl or tetrahydropyranyl groups of sub-formula (bb) may be further optionally substituted with one or two substituents independently selected from C_1-2alkyl; C_1-2fluoroalkyl; CH₂OH; —C(O)OR²³wherein R²³is H or C_1-2alkyl; —C(O)NHR²³; or fluoro; on any ring carbon; as well as, on the C2, C3, C5 and C6 of the cyclohexyl group of (aa), the C2 or C6 of the piperidinyl ring or the C5 of the pyrrolidinyl ring of (bb), a substituent selected from OH; C_1-2alkoxy; C_1-2fluoroalkoxy; or alkoxy.

Representative examples of R³include tetrahydro-2H-pyran-4-yl.

When NHR³is of sub-formula (n), then preferably it is in the cis configuration, i.e. preferably it is a cis-(3-hydroxycyclohexan-1-yl)amino group, e.g. in any enantiomeric form or mixture of forms such as a racemic mixture.

When NHR³is of sub-formula (p9), then preferably it is in the cis configuration, i.e. preferably it is a cis-[4-(aminocarbonyl)cyclohexan-1-yl]amino group.

Where R⁴is C_1-2fluoroalkyl, then it can be C₁fluoroalkyl such as monofluoromethyl, difluoromethyl or trifluoromethyl.

R^4acan suitably be a hydrogen atom (H) or methyl (Me), more suitably H.

R⁴can for example be a hydrogen atom (H); methyl, ethyl, C₁fluoroalkyl, —CH₂OH, —CH(Me)OH, —CH₂CH₂OH, or −CH₂OMe; or preferably a hydrogen atom (H), methyl, ethyl, —CH₂OH, or —CH₂OMe. More preferably, R⁴is H, methyl, ethyl, —CH₂OH, or —CH₂OMe.

Representative examples of R⁴include H, methyl and ethyl.

In another aspect of the invention, R⁵is a hydrogen atom (H), methyl, ethyl, n-propyl, or iso-propyl.

Representative examples of R⁵include H.

In another aspect of the invention, in sub-formulae (y) and (y1) m is 1, A is C—R^6A, B is C—R^6B, D is C—R^6Dand E is C—R^6E.

Representative examples of (y) include 2,3-dihydro-1H-inden-2-yl.

It is preferable that Ar has the sub-formula (x).

Preferably, in sub-formula (x), two or more (more preferably three or more) of A, B, D, E and F are independently C—H (carbon-hydrogen), C—F (carbon-fluorine) or nitrogen (N).

Preferably, in sub-formula (x), three or more of A, B, D, E and F are independently C—H (carbon-hydrogen), C—F (carbon-fluorine), nitrogen (N), or nitrogen-oxide (N⁺—O⁻)).

Preferably, in sub-formula (x), two or more (e.g. three or more) of A, B, D, E and F are independently C—H (carbon-hydrogen), C—F (carbon-fluorine), or nitrogen (N); and one or more (e.g. two or more) others of A, B, D, E and F are independently C—H (carbon-hydrogen), C—F (carbon-fluorine), C—Cl (carbon-chlorine), C-Me, C—OMe, or nitrogen (N). More preferably, in sub-formula (x), two or more (e.g. three or more) of A, B, D, E and F are C—H (carbon-hydrogen); and one or more (e.g. two or more) others of A, B, D, E and F are independently C—H (carbon-hydrogen), C—F (carbon-fluorine), C—Cl (carbon-chlorine), C-Me, C—OMe, or nitrogen (N).

Preferably, in sub-formula (x), two or more (e.g. three or more, e.g. four or more) of A, B, D, E and F are C—H.

Preferably, in sub-formula (x), no more than one (more preferably none) of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N⁺—O⁻)).

Preferably, in sub-formula (x), none of A, B, D, E and F are nitrogen-oxide (N⁺—O⁻)).

Preferably, Ar has the sub-formula (x) which is sub-formula (x1), (x2), (x3), (x4), (x5), (x6), (x7), (x8), (x9), (x10), (x11), (x12), (x13), (x14), (x15) or (x16):

More preferably, Ar has the sub-formula (x) which is sub-formula (x1), (x2), (x3), (x8), (x13), or (x14). Still more preferably, Ar has the sub-formula (x) which is sub-formula (x1), (x8), (x13), or (x14). Most preferably, Ar has the sub-formula (x) which is sub-formula (x1).

In sub-formula (x), preferably, R^6A, R^6B, R^6D, R^6Eand/or R^6F, independently of each other, is or are: a hydrogen atom (H), a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, C₄alkyl, trifluoromethyl, —CH₂OH, methoxy, ethoxy, n-propoxy, isopropoxy, C₁fluoroalkoxy (e.g. trifluoromethoxy or difluoromethoxy), cyclohexyloxy; cyclopentyloxy; nitro (—NO₂), OH, C_1-3alkylS(O)₂— (such as MeS(O)₂—), C_1-3alkylS(O)₂—NH— such as Me-S(O)₂—NH—, Me₂N—S(O)₂—, H₂N—S(O)₂—, —CONH₂, —CONHMe, —C(O)OH, cyano (—CN), NMe₂, or C_1-2alkyl-S(O)₂—CH₂— such as Me-S(O)₂—CH₂—.

More preferably, R^6A, R^6B, R^6D, R^6Eand/or R^6F, independently of each other, is or are: a hydrogen atom (H), a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, isobutyl, trifluoromethyl, —CH₂OH, methoxy, ethoxy, n-propoxy, isopropoxy, C₁fluoroalkoxy (e.g. trifluoromethoxy or difluoromethoxy), nitro (—NO₂), OH, C_1-3alkylS(O)₂— such as MeS(O)₂—, C_1-2alkylS(O)₂—NH— such as Me-S(O)₂—NH—, —CONH₂, cyano (—CN), or C_1-2alkylS(O)₂—CH₂— such as Me-S(O)₂—CH₂.

Still more preferably, R^6A, R^6B, R^6D, R^6Eand/or R^6F, independently of each other, is or are: a hydrogen atom (H), a fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, —CH₂OH, methoxy, ethoxy, n-propoxy, difluoromethoxy, OH or MeS(O)₂—.

When two adjacent groups selected from R^6A, R^6B, R^6D, R^6Eand R^6Fare taken together, then, preferably, when taken together they are: —CH═CH—CH═CH₂—, —(CH₂)_n^14a— where n^14ais 3, 4 or 5 (e.g. 3 or 4), —O—(CMe₂)-O—, —O—(CH₂)_n^14b—O— where n^14bis 1 or 2; —CH═CH—NR^15b—; —N═CH—NR^15b—; —N═N—NR^15bwherein R^15bis H or C_1-2alkyl (preferably R^15bis H). More preferably, in this embodiment, two adjacent groups selected from R^6A, R^6B, R^6D, R^6Eand R^6Fare taken together and are: —CH═CH—CH═CH₂— or —(CH₂)_n^14a— where n^14ais 3, 4 or 5 (e.g. 3 or 4).

In sub-formula (x), e.g. in sub-formula (x1), suitably, one, two or three of R^6B, R^6Dand R^6Eare other than a hydrogen atom (H).

In sub-formula (x), e.g. in sub-formula (x1), preferably, one or both of R^6Aand R^6Fare independently a hydrogen atom (H), a fluorine atom (F), or methyl. For example, one or both of R^6Aand R^6Fcan be a hydrogen atom (H).

In sub-formula (x), e.g. in sub-formula (x1), suitably the ring or ring system is unsubstituted, monosubstituted, disubstituted or trisubstituted, preferably the ring or ring system is monosubstituted or disubstituted. In sub-formula (x), e.g. in sub-formula (x1), for monosubstitution of the ring or ring system, then the one substituent selected from R^6A, R^6B, R^6D, R^6Eand R^6Fis suitably present at the 3- or 4-position with respect to the —(CR⁴R⁵)— side-chain (i.e. D is CR^6Dwhere R^6Dis other than H), or is a 2-methyl 2-ethyl, 2-fluoro or 2-chloro substituent. In sub-formula (x), e.g. in sub-formula (x1), for disubstitution of the ring or ring system, then 3,4-disubstitution, 2,4-disubstitution, 2,3-disubstitution or 3,5-disubstitution is suitable.

In one preferable embodiment, Ar has the sub-formula (x1) and is: phenyl, monoalkyl-phenyl-, mono(fluoroalkyl)-phenyl-, monohalo-phenyl-, monoalkoxy-phenyl-, mono(fluoroalkoxy)-phenyl-, mono(N,N-dimethylamino)-phenyl-, mono(methyl-SO₂—NH-)-phenyl-, mono(methyl-SO₂-)-phenyl-, dialkyl-phenyl-, monoalkyl-monohalo-phenyl-, mono(fluoroalkyl)-monohalo-phenyl-, dihalo-phenyl-, dihalo-monoalkyl-phenyl-, dihalo-mono(hydroxymethyl)-phenyl- (e.g. 2,3-dichloro-6-(hydroxymethyl)-phenyl-), or dialkoxy-phenyl- such as 3,4-dimethoxy-phenyl-. The substituents can preferably be further defined, as defined in preferable embodiments herein.

In one preferable embodiment, Ar is of sub-formula (x1) and is: monoalkyl-phenyl-, mono(fluoroalkyl)-phenyl-, monohalo-phenyl-, monoalkoxy-phenyl-, mono(fluoroalkoxy)-phenyl-, dialkyl-phenyl-, monoalkyl-monohalo-phenyl-, dihalo-phenyl- or dihalo-monoalkyl-phenyl-.

More preferably, in this embodiment, Ar is:

monoC_1-4alkyl-phenyl- or monoC_1-3alkyl-phenyl- such as 4-C_1-4alkyl-phenyl- (e.g. 4-C_1-3alkyl-phenyl-) or 2-C_1-2alkyl-phenyl-;

monoC₁fluoroalkyl-phenyl- such as 4-C₁fluoroalkyl-phenyl-;

monoC_1-3alkoxy-phenyl- such as 4-C_1-3alkoxy-phenyl- or 3-C_1-3alkoxy-phenyl-;

mono(C₁fluoroalkoxy)-phenyl- such as 4-C₁fluoroalkoxy-phenyl-;

diC_1-3alkyl-phenyl- or diC_1-2alkyl-phenyl- or dimethyl-phenyl- such as 3,4-dimethyl-phenyl-, 2,4-dimethyl-phenyl-, 3,5-dimethyl-phenyl-, 2,3-dimethyl-phenyl- or 2,5-dimethyl-phenyl-; for example 3,4-dimethyl-phenyl-, 2,4-dimethyl-phenyl-, 2,3-dimethyl-phenyl- or 3,5-dimethyl-phenyl-;

monoC_1-3alkyl-monohalo-phenyl-, such as monoC_1-2alkyl-monohalo-phenyl- and/or monoC_1-3alkyl-monochloro-phenyl- or monoC_1-3alkyl-monofluoro-phenyl-, for example 4-methyl-3-chloro-phenyl-, 3-methyl-4-chloro-phenyl-, or 2-methyl-4-chloro-phenyl-;

dihalo-phenyl- such as 2-chloro-4-fluorophenyl- or 2,4-difluoro-phenyl- or 4-bromo-2-fluorophenyl- or preferably 4-chloro-2-fluorophenyl-; for example dichloro-phenyl- such as 3,4-dichloro-phenyl- or 2,4-dichloro-phenyl- or 2,6-dichloro-phenyl- or preferably 2,3-dichloro-phenyl-; or

dihalo-monoC_1-2alkyl-phenyl- e.g. 2,4-dichloro-6-methyl-phenyl-.

In an alternative embodiment, Ar has the sub-formula (z).

Preferably, in sub-formula (z), three or more (for example all) of J, L, M and Q are independently C—H, C—F, C—C_1-2alkyl (e.g. C-Me), C-[connection point to formula (I)], or nitrogen (N).

Preferably, in sub-formula (z), no more than two (for example no more than one) of J, L, M and Q are nitrogen (N).

Suitably, Q is C-[connection point to formula (I)].

Suitably, R⁹is a hydrogen atom (H) or methyl.

Suitably, R^6J, R^6L, R^6Mand/or R^6Qindependently is or are: a hydrogen atom (H); fluoro; chloro; C_1-2alkyl (e.g. methyl); C₁fluoroalkyl (e.g. CF₃); C_1-2alkoxy(methoxy); C₁fluoroalkoxy (e.g. CF₂HO—); OH (including any tautomer thereof); or phenyl optionally substituted by one substituent being fluoro, methyl, C₁fluoroalkyl, methoxy or C₁fluoroalkoxy. More Suitably R^6J, R^6L, R^6Mand/or R^6Qindependently is or are H, OH (including any keto tautomer thereof), or more preferably C_1-2alkyl (e.g. methyl) or C₁fluoroalkyl.

When Ar has the sub-formula (z), then sub-formula (z) can suitably be one of the following:

In another aspect of the invention Ar is phenyl and R^6A, R^6B, R^6D, R^6Eand R^6Fare independently H, C_1-2alkyl, C_1-2alkoxy or halogen.

Representative examples of Ar include 4-chloro-2-methylphenyl, 4-methoxyphenyl, 3,4-dimethylphenyl, 4-chlorophenyl, and phenyl.

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

Formula (IA) means that more than 50% of the compound or salt present has the stereochemistry shown at the carbon atom bearing the R⁴and R⁵groups.

Preferably, the stereochemistry at the carbon atom bearing the R⁴and R⁵groups is such that there is an enantiomeric excess (e.e.) of 50% or more at the carbon atom bearing the R⁴and R⁵groups (ignoring the stereochemistry at any other carbon atoms). More preferably, the enantiomeric excess (e.e.) is 70% or more or 80% or more, still more preferably 90% or more, yet more preferably 95% or more, at the carbon atom bearing the R⁴and R⁵groups (ignoring the stereochemistry at any other carbon atoms).

“Enantiomeric excess” (e.e.) is defined as the percentage of the major isomer present minus the percentage of the minor isomer present. For example, if 95% of major isomer is present and 5% of the minor isomer is present, then the e.e. would be 90%.

In another aspect of the invention in formula (IA) R⁴is not a hydrogen atom (H). In this aspect in formula (IA), R⁴can for example be methyl, ethyl, C₁fluoroalkyl (such as CF₃), —CH₂OH, or —CH₂OMe.

In another aspect of the invention in formula (IA) R⁵is a hydrogen atom (H) and R⁴is not a hydrogen atom (H).

It is particularly preferred that the compound of formula (I) or the salt thereof is:

N-[(4-chloro-2-methylphenyl)methyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclopropyl-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclopropyl-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclopropyl-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[1-(4-chlorophenyl)ethyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[1-(4-chlorophenyl)propyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

1-ethyl-N-(phenylmethyl)-6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[(4-chloro-2-methylphenyl)methyl]-1-ethyl-6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[(3,4-dimethylphenyl)methyl]-1-ethyl-6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

1,6-diethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

1,6-diethyl-N-{[4-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[(3,4-dimethylphenyl)methyl]-1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-(2,3-dihydro-1H-inden-2-yl)-1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[1-(4-chlorophenyl)propyl]-1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclobutyl-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclobutyl-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-(cyclopropylmethyl)-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclobutyl-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[(4-chloro-2-methylphenyl)methyl]-6-cyclobutyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[1-(4-chlorophenyl)ethyl]-6-cyclobutyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[1-(4-chlorophenyl)propyl]-6-cyclobutyl-1 ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-(cyclopropylmethyl)-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-(cyclopropylmethyl)-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran 4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-(cyclopropylmethyl)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[1-(4-chlorophenyl)ethyl]-6-(cyclopropylmethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclopentyl-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; or

6-cyclopentyl-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide.

or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.

The structures of these specific compounds are given in Examples 1 to 29 hereinafter.

Alternatively, it is particularly preferred that the compound of formula (I) or the salt thereof is one of Examples 1 to 29, as a compound or a salt thereof, e.g. a pharmaceutically acceptable salt thereof. The structures of these specific compounds are given in Examples 1 to 29 hereinafter, and their names are given in the Examples section.

In a further aspect the invention provides a compound of formula (I) or a salt thereof selected from the group consisting of:

N-[(4-chloro-2-methylphenyl)methyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclopropyl-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclopropyl-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

6-cyclopropyl-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[1-(4-chlorophenyl)ethyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; or

N-[1-(4-chlorophenyl)propyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.

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

A pharmaceutically acceptable acid addition salt can be formed by reaction of 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, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate) or hexanoate salt.

A pharmaceutically acceptable base addition salt can be formed by reaction of 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, to give the base addition salt which is usually isolated for example by crystallisation 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 carboxylic acid moieties that may be present in the the compound of formula (I).

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

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

Also included within the scope of the invention are all solvates, hydrates and complexes of compounds and salts of the invention.

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

In the compounds or salts, pharmaceutical compositions, uses, methods of treatment/prophylaxis, methods of preparing, etc. according to the present invention, where a defined isomeric configuration e.g. stereochemical configuration is described or claimed, the invention includes a mixture comprising (a) a major component of the compound or salt which is in the described or claimed configuration, together with (b) one or more minor components of the compound or salt which is/are not in the described or claimed configuration. Preferably, in such a mixture, the major component of the compound or salt which is in the described or claimed configuration represents 70% or more, or 75% or more, more preferably 85% or more, still more preferably 90% or more, yet more preferably 95% or more, yet more preferably 98% or more, of the total amount of compound or salt present in the mixture on a molarity basis.

The percentage of one isomeric/stereochemical component in a mixture of different isomeric/stereochemical components, and if appropriate enantiomeric and/or diastereomeric excesses, can be measured using techniques known in the art. Such methods include the following:

(1) Measurement using NMR (e.g. ¹H NMR) spectroscopy in the presence of chiral agent. One can measure a nuclear magnetic resonance (NMR) spectrum (preferably a ¹H NMR spectrum, and/or a solution-phase NMR spectrum e.g. in CDCl₃or D6-DMSO solvent) of the compound/salt mixture in the presence of a suitable chiral agent which “splits” the NMR peaks of a given atom in different isomers into different peak positions. The chiral agent can be: i) an optically pure reagent which reacts with the compound/salt e.g. to form a mixture of diastereomers, ii) a chiral solvent, iii) a chiral molecule which forms a transient species (e.g. diastereomeric species) with the compound/salt, or iv) a chiral shift reagent. See e.g. J. March, “Advanced Organic Chemistry”, 4th edn., 1992, pages 125-126 and refs. 138-146 cited therein. A chiral shift reagent can be a chiral lanthanide shift reagent such as tris[3-trifluoroacetyl-d-camphorato]europium-(III) or others as described in Morrill, “Lanthanide Shift Reagents in Stereochemical Analysis”, VCH, New York, 1986. Whatever the chiral agent is that is used, usually, the relative integrals (intensities) for the NMR peaks of a given atom or group in different isomers can provide a measurement of the relative amounts of each isomer present.

(2) Measurement using chiral chromatography, especially on an analytical scale. A suitable chiral column which separates the different isomeric components can be used to effect separation, e.g. using gas or liquid chromatography such as HPLC, and/or e.g. on an analytical scale. The peaks for each isomer can be integrated (area under each peak); and a comparison or ratio of the integrals for the different isomers present can give a measurement of the percentage of each isomeric component present. See for example: “Chiral Chromatography”, Separation Science Series Author: T. E. Beesley and R. P. W. Scott, John Wiley & Sons, Ltd., Chichester, UK, 1998, electronic Book ISBN: 0585352690, Book ISBN: 0471974277.

(3) Separation of pre-existing diastereomeric mixtures which are compounds/salts of the invention can be achieved (usually directly, without derivatisation) using separation techniques such as gas or liquid chromatography. Diastereomeric ratios and/or excesses can thereby be derived e.g. from the relative peak areas or relative separated masses.

(4) Conversion with a chiral/optically-active agent and subsequent separation of the resulting isomers, e.g. diastereomers. Conversion can be via derivatisation of a derivatisable group (e.g. —OH, —NHR) on the compound/salt with an optically-active derivatising group (e.g. optically active acid chloride or acid anhydride); or can be via formation of an acid or base addition salt of the compound by treatment of the compound with an optically-active acid or base, such as + or − di-para-toluoyl tartaric acid. After derivatisation, separation of the resulting isomers e.g. diastereomers, can be using gas or liquid chromatography (usually non-chiral); or (especially with isomeric salts) can be by selective crystallisation of a single isomeric e.g. diastereoisomeric salt. Determination of isomeric ratios and/or excesses can be using chromatography peak areas or measurement of mass of each separated isomer.

See e.g. J. March, “Advanced Organic Chemistry”, 4th edn., 1992, pages 120-121 and 126, and refs. 105-115 and 147-149 cited therein.

(5) Measurement of optical activity [alpha] of mixture and comparison with optical activity of pure isomer [alpha]_maxif available (e.g. see J. March, “Advanced Organic Chemistry”, 4th edn., 1992, page 125 and refs. 138-139 cited therein). This assumes a substantially linear relationship between [alpha] and concentration.

Certain of the groups, e.g. heteroaromatic ring systems, included in compounds of formula (I) or their salts may exist in one or more tautomeric forms. The present invention includes within its scope all such tautomeric forms, including mixtures.

Especially when intended for oral medicinal use, the compound of formula (I) can optionally have a molecular weight of 1000 or less, for example 800 or less, in particular 650 or less or 600 or less. Molecular weight here refers to that of the unsolvated “free base” compound, that is excluding any molecular weight contributed by any addition salts, solvent (e.g. water) molecules, etc.

The following processes can be used to make the compounds of the invention:

Process A

To form a compound of formula (I) wherein W═—CR⁴R⁵Ar, a carboxylic acid of formula (II) can be converted into an activated compound of formula (III) wherein X¹=a leaving group substitutable by an amine (as defined below) and subsequently the activated compound can be reacted with an amine of formula ArCR⁴R⁵NH₂:

For example, the activated compound (the compound of formula (III)) can be the acid chloride. This can be formed from the carboxylic acid (II) e.g. by reaction with thionyl chloride, either in an organic solvent such as chloroform or without solvent. Alternatively, the activated compound (the compound of formula (III)) can be an activated ester wherein the leaving group X¹is

The latter activated compound of formula (III) can be formed from the carboxylic acid (II) either:

(a) by reaction of the 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 e.g. hydrochloride salt, preferably followed by reaction of the resulting product with 1-hydroxybenzotriazole (HOBT); reaction (a) usually being carried out in the presence of a solvent (preferably anhydrous) such as dimethyl formamide (DMF) or acetonitrile and/or preferably under anhydrous conditions and/or usually at room temperature (e.g. about 20 to about 25° C.); or:

(b) by reaction with 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), in the presence of a base such as diisopropylethylamine (ⁱPr₂NEt=DIPEA), and usually in the presence of a solvent such as dimethyl formamide (DMF) or acetonitrile and/or preferably under anhydrous conditions and/or usually at room temperature (e.g. about 20 to about 25° C.).

Compounds of formula (II) can be prepared by hydrolysis of an ester of formula (IV). This procedure preferably involves reaction of (IV) with either:

- (a) a base such as sodium hydroxide or potassium hydroxide in a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane or
- (b) an acid such as hydrochloric acid in a solvent e.g. an aqueous solvent such as aqueous dioxane:

Compounds of formula (IV) can be prepared according to a method, for example as described by Yu et. al. in J. Med Chem., 2001, 44, 1025-1027, by reaction of a compound of formula (V) with an amine of formula R³NH₂. The reaction is preferably carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, dioxane, 1-methyl-2-pyrrolidinone (NMP) or acetonitrile. The reaction may require heating e.g. to ca. 60-180° C., for example ca. 140-160° C.:

Compounds of formula (V) are also described in the above reference and can be prepared by reaction of a compound of formula (VI) with, for example, diethyl[chloro(cyclopropyl)methylene]malonate (VII) (where X³=Et) with heating, followed by reaction with phosphorous oxychloride, again with heating:

Compounds of formula (VII) are also described in the above reference and can be prepared by reaction of a malonate derivative, for example diethyl(cyclopropylcarbonyl)malonate (VIII), with phosphorus oxychloride in the presence of a base such as tributylamine. The reaction may require heating, e.g. to ca 80-130° C., for example ca. 100-120° C.:

Compounds of formula (VII) are also described in the above reference and can be prepared by reaction of diethyl malonate (IX) with magnesium powder followed by an acid chloride, for example cyclopropylcarbonyl chloride (X).

Where the desired amino pyrazole of formula (VI) is not commercially available, preparation can be achieved using methods described by Dorgan et. al. in J. Chem. Soc., Perkin Trans. 1, (4), 938-42; 1980, by reaction of cyanoethylhydrazine with a suitable aldehyde of formula R⁴⁰CHO in a solvent such as ethanol, with heating, followed by reduction with, for example sodium in a solvent such as t-butanol. R⁴⁰should be chosen so as to contain one less carbon atom than R¹, for example R⁴⁰=methyl will afford R¹=ethyl.

In an alternative embodiment of Process A, the 4-chloro substituent in the compound of formula (V) can be replaced by another halogen atom, such as a bromine atom, or by another suitable leaving group which is displaceable by an amine of formula R³NH₂. The leaving group can, for example, be an alkoxy group —OR³⁵such as —OC_1-4alkyl (in particular —OEt) or a group —O—S(O)₂—R³⁷, wherein R³⁷is C_1-8alkyl (e.g. C_1-4alkyl or C_1-2alkyl such as methyl), C_1-6fluoroalkyl (e.g. C_1-4fluoroalkyl or C_1-2fluoroalkyl such as CF₃or C₄F₉), or phenyl wherein the phenyl is optionally substituted by one or two of independently C_1-2alkyl, halogen or C_1-2alkoxy (such as phenyl or 4-methyl-phenyl). The reaction may be carried out with or without solvent and may require heating.

Process B

Compounds of formula (I) can be prepared by reaction of a compound of formula (XI) with an amine of formula R³NH₂. The reaction is preferably carried out in the presence of a base, such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, THF, dioxane or acetonitrile. The reaction may require heating, e.g. to ca. 60-100° C. or ca. 80-90° C., for example for 8-48 or 12-24 hours:

Compounds of formula (XI) can be prepared in a two step procedure as described by Bare et. al. in J. Med. Chem. 1989, 32, 2561-2573. This process involves, first, reaction of a compound of formula (XII) with thionyl chloride (or another agent suitable for forming an acid chloride from a carboxylic acid), either in an organic solvent such as chloroform or THF, or as a neat solution. This reaction may require heating and the thus-formed intermediate may or may not be isolated. Step two involves reaction with an amine of formula WNH₂, in an organic solvent such as THF or chloroform and may also involve the use of a base such as triethylamine or diisopropylethylamine:

Compounds of formula (XII) can be prepared by hydrolysis of an ester of formula (V) according to the method described by Yu et. al. in J. Med Chem., 2001, 44, 1025-1027. This procedure preferably involves reaction with a base such as sodium hydroxide or potassium hydroxide in a solvent e.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane:

In an alternative embodiment of Process B, the 4-chloro substituent in the compound of formula (IV) can be replaced by another halogen atom, such as a bromine atom.

Process C

Compounds of formula (IV) can be prepared by reaction of a compound of formula (XIII) with an alkylating agent of formula R¹—X⁴, where X⁴is a leaving group displaceable by the 1-position pyrazolopyridine nitrogen atom of the compound of formula (XIII):

A suitable alkylating agent of formula R¹—X⁴can be used. For example, X⁴can be a halogen atom such as a chlorine atom or more preferably a bromine or iodine atom, or X³can be —O—S(O)₂—R³⁶wherein R³⁶is C_1-8alkyl (e.g. C_1-4alkyl or C_1-2alkyl such as methyl), C_1-6fluoroalkyl (e.g. C_1-4fluoroalkyl or C_1-2fluoroalkyl such as CF₃or C₄F₉), or phenyl wherein the phenyl is optionally substituted by one or two of independently C_1-2alkyl, halogen or C_1-2alkoxy (such as phenyl or 4-methyl-phenyl). The reaction is preferably carried out in the presence of a base; the base can for example comprise or be potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, or a basic resin or polymer such as polymer-bound 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine. The reaction is preferably carried out in the presence of a solvent, e.g. an organic solvent such as DMF; the solvent is preferably anhydrous. Compounds of formula (XIII) can be prepared, using a method analogous to that used for the preparation of compounds (IV), by reaction of a compound of formula (V) (R¹═H) with an amine of formula R³NH₂. The reaction is preferably carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine, and/or in an organic solvent such as ethanol, dioxane or acetonitrile. The reaction may require heating e.g. to ca. 60-100° C., for example ca. 80-90° C.:

Process D: Conversion of One Compound of Formula (I)-(IV) or Salt thereof into Another Compound of Formula (I)-(IV) or Salt thereof

One compound of formula (I)-(IV) or salt thereof can be converted into another compound of formula (I)-(IV) or salt thereof. This conversion preferably comprises or is one or more of the following processes D1 to D7:

D1. Conversion of a ketone into the corresponding oxime.
D2. An oxidation process. For example, the oxidation process can comprise or be oxidation of an alcohol to a ketone (e.g. using Jones reagent) or oxidation of an alcohol or a ketone to a carboxylic acid.
D3. A reduction process, for example reduction of a ketone or a carboxylic acid to an alcohol.
D4. Alkylation, for example alkylation of an amine or of a hydroxy group.
D5. Hydrolysis, e.g. hydrolysis of an ester to the corresponding carboxylic acid or salt thereof.
D6. Deprotection, e.g. deprotection (e.g. deacylation or t-butyloxycarbonyl (BOC) removal) of an amine group.
D7. Formation of an ester or amide, for example from the corresponding carboxylic acid.

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. The compound or salt can be for use in the treatment and/or prophylaxis of any of the diseases/conditions described herein (e.g. for use in the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal) and/or for use as a phosphodiesterase inhibitor e.g. for use as a phosphodiesterase 4 (PDE4) inhibitor. “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 (e.g. pharmaceutical composition) for the treatment and/or prophylaxis of any of the diseases/conditions described herein in a mammal such as a human, e.g. for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human.

Also provided is a method of treatment and/or prophylaxis of any of the diseases/conditions described herein in a mammal (e.g. human) in need thereof, e.g. a method of treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal (e.g. human) in need thereof, which method comprises administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I) as herein defined or a pharmaceutically acceptable salt thereof.

Phosphodiesterase 4 inhibitors are thought to be useful in the treatment and/or prophylaxis of a variety of 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, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, multiple sclerosis, cognitive impairment (e.g. in a neurological disorder such as Alzheimer's disease), depression, or pain. Ulcerative colitis and/or Crohn's disease are collectively often referred to as 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 (e.g. human). More preferably, the treatment and/or prophylaxis is of COPD or asthma in a mammal (e.g. human).

PDE4 inhibitors are thought to be effective in the treatment of asthma (e.g. see M. A. Giembycz, Drugs, February 2000, 59(2), 193-212; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438; H. J. Dyke 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; A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473; and references cited in the aforementioned publications).

PDE4 inhibitors are thought to be effective in the treatment of COPD. For example, see S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438; H. J. Dyke 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; A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473; and references cited in the aforementioned publications; and G. Krishna et al., Expert Opinion on Investigational Drugs, 2004, 13(3), 255-267 (see especially pp. 259-261 and refs. 102-111 and 201 therein). COPD is often characterised by the presence of airflow obstruction due to chronic bronchitis and/or emphysema (e.g., see S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319).

PDE4 inhibitors are thought to be effective in the treatment of allergic rhinitis (e.g. see B. M. Schmidt et al., J. Allergy & Clinical Immunology, 108(4), 2001, 530-536).

PDE4 inhibitors are thought to be effective in the treatment of rheumatoid arthritis and multiple sclerosis (e.g. see H. J. Dyke 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 A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473; and references cited in these publications). See e.g. A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473 and references cited therein for atopic dermatitis use.

PDE4 inhibitors have been suggested as having analgesic properties and thus being effective in the treatment of pain (A. Kumar et al., Indian J. Exp. Biol., 2000, 38(1), 26-30).

In the invention, the treatment and/or prophylaxis can be of cognitive impairment e.g. cognitive impairment in a neurological disorder such as Alzheimer's disease. For example, the treatment and/or prophylaxis can comprise cognitive enhancement e.g. in a neurological disorder. See for example: H. T. Zhang et al. in: 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.

PDE4 inhibitors such as rolipram have been suggested as having antidepressant properties (e.g. J. Zhu et al., CNS Drug Reviews, 2001, 7(4), 387-398; O'Donnell, Expert Opinion on Investigational Drugs, 2000, 9(3), 621-625; and H. T. Zhang et al., Neuropsychopharmacology, October 2002, 27(4), 587-595).

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

The present invention therefore 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.

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

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

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

The invention also provides a pharmaceutical composition prepared by said method.

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

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

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.

A pharmaceutical composition suitable for oral administration being a tablet can comprise one or more pharmaceutically acceptable carriers and/or excipients suitable for preparing tablet formulations. The carrier can for example be or include lactose, cellulose (for example microcrystalline cellulose), or mannitol. The tablet can also or instead contain one or more pharmaceutically acceptable excipients, for example a binding agent such as hydroxypropylmethylcellulose or povidone (polyvinylpyrollidone), a lubricant e.g. an alkaline earth metal stearate such as magnesium stearate, and/or a tablet disintegrant such as sodium starch glycollate, croscarmellose sodium, or crospovidone (cross-linked polyvinylpyrollidone). The pharmaceutical composition being a tablet can be prepared by a method comprising the steps of: (i) mixing the compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof, with the one or more pharmaceutically acceptable carriers and/or excipients, (ii) compressing the resulting mixture (which is usually in powder form) into tablets, and (iii) optionally coating the tablet with a tablet film-coating material.

A pharmaceutical composition suitable for oral administration being a capsule can be prepared using encapsulation procedures. For example, pellets or powder containing the active ingredient 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 an aqueous gum or an oil and the dispersion or suspension then filled into a soft gelatin capsule.

Preferably the composition is in unit dose form such as a tablet or capsule for oral administration, e.g. for oral administration to a human.

A parenteral composition can comprise a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil. Alternatively, the solution can be lyophilised; the lyophilised parenteral pharmaceutical composition can be reconstituted with a suitable solvent just prior to administration.

Compositions for nasal or inhaled administration may conveniently be formulated as aerosols, drops, gels or dry powders.

Aerosol formulations, e.g. for inhaled administration, can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide, or an organic propellant such as a 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. The aerosol dosage forms can also take the form of a pump-atomiser.

For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is preferred that the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation. Micronisation usually involves subjecting the compound/salt to collisional and/or abrasional forces in a fast-flowing circular or spiral/vortex-shaped airstream often including a cyclone component. The preferable particle size of the size-reduced (e.g. micronised) compound or salt is defined by a D50 value of about 0.5 to about 10 microns, e.g. about 1 to about 7 microns (e.g. as measured using laser diffraction). For example, it is preferable for the compound or salt of formula (I) to have a particle size defined by: a D10 of about 0.3 to about 3 microns (e.g. about 0.5 to about 2 microns, or about 1 micron), and/or a D50 of about 0.5 to about 10 microns or about 1 to about 7 microns (e.g. about 2 to about 5 microns or about 2 to about 4 microns), and/or a D90 of about 1 to about 30 microns or about 2 to about 20 microns or about 3 to about 15 microns (e.g. about 5 to about 15 microns or about 5 to about 10 microns); for example as measured using laser diffraction.

In particle size measurements, D90, D50 and D10 respectively mean that 90%, 50% and 10% of the material is less than the micron size specified. D50 is the median particle size. DV90, DV50 and DV10 respectively mean that 90%, 50% and 10% by volume of the material is less than the micron size specified. DM90, DM50 and DM10 respectively mean that 90%, 50% and 10% by weight of the material is less than the micron size specified.

Laser diffraction measurement of particle size can use a dry method (wherein a suspension of the compound/salt in an airflow crosses the laser beam) or a wet method [wherein a suspension of the compound/salt in a liquid dispersing medium, such as isooctane or (e.g. if compound is soluble in isooctane) 0.1% Tween 80 in water, crosses the laser beam]. With laser diffraction, particle size is preferably calculated using the Fraunhofer calculation; and/or preferably a Malvern Mastersizer or Sympatec apparatus is used for measurement. For example, particle size measurement and/or analysis by laser diffraction can use any or all of (preferably all of) the following: a Malvern Mastersizer longbed version, a dispersing medium of 0.1% Tween 80 in water, a stir rate of ca. 1500 rpm, ca. 3 mins sonification prior to final dispersion and analysis, a 300 RF (Reverse Fourier) lens, and/or the Fraunhofer calculation with Malvern software.

For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is preferred that the pharmaceutical composition is a dry powder inhalable composition. Such a composition can comprise a powder base such as lactose or starch, the compound of formula (I) or salt thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine, mannitol, trehalose and/or magnesium stearate. Preferably, the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of formula (I) or salt thereof. The lactose is preferably lactose hydrate e.g. lactose monohydrate and/or is preferably inhalation-grade and/or fine-grade lactose. Preferably, the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 300 microns (e.g. 10-300 microns e.g. 50-300 microns) in diameter, and/or 50% or more of the lactose particles being less than 100 microns in diameter. Optionally, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40-70 microns in diameter. Most importantly, it is preferable that about 3 to about 30% (e.g. about 10%) (by weight or by volume) of the particles are less than 50 microns or less than 20 microns in diameter. For example, without limitation, a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 J D Zwolle, Netherlands).

In the dry powder inhalable composition, preferably, the compound of formula (I) or salt thereof is present in about 0.1% to about 70% (e.g. about 1% to about 50%, e.g. about 5% to about 40%, e.g. about 20 to about 30%) by weight of the composition.

An illustrative non-limiting example of a dry powder inhalable composition follows:

Dry Powder Formulation Example—Dry Powder Lactose Blend Preparation

Using a size-reduced e.g. micronised form of the compound of formula (I) or salt thereof, the dry powder blend is prepared by mixing the required amount of the compound/salt (e.g. 10 mg, 1% w/w) with inhalation-grade lactose containing 10% fines (e.g. 990 mg, 99% w/w) in a Teflon™ (polytetrafluoroethene) pot in a Mikro-dismembrator ball-mill (but without a ball bearing) at 3/4 speed (ca. 2000-2500 rpm) for about 4 hours at each blend concentration. The Mikro-dismembrator (available from B. Braun Biotech International, Schwarzenberger Weg 73-79, D-34212 Melsungen, Germany; www.bbraunbiotech.com) comprises a base with an upwardly-projecting and sidewardly-vibratable arm to which is attached the Teflon™ pot. The vibration of the arm achieves blending.

Other blends: 10% w/w compound/salt (50 mg)+90% w/w lactose (450 mg, inhalation-grade lactose containing 10% fines).

Serial dilution ofthe 1% w/w blend can achieve e.g. 0.1% and 0.3% w/w blends.

Optionally, in particular for dry powder inhalable compositions, a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device. The container is rupturable or peel-openable on demand and the dose, e.g. of the dry powder composition, can be administered by inhalation via a device such as the DISKUS™ device, marketed by GlaxoSmithKline. The DISKUS™ inhalation device is usually substantially as described in GB 2,242,134 A. In such device at least one container for the pharmaceutical composition in powder form (the at least one container preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: means defining an opening station for the said at least one container; means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the pharmaceutical composition in powder form from the opened container.

Preferably the composition is in unit dose form such as a tablet or capsule for oral administration, e.g. for oral administration to a human.

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

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

A pharmaceutically acceptable compound or salt of the invention is preferably administered to a mammal (e.g. human) in a daily nasal or inhaled dose of: 0.0001 to 5 mg/kg/day or 0.0001 to 1 mg/kg/day, e.g. 0.001 to 1 mg/kg/day or 0.001 to 0.3 mg/kg/day or 0.001 to 0.1 mg/kg/day or 0.005 to 0.3 mg/kg/day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.

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

The compounds, salts and/or pharmaceutical compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a β₂adrenoreceptor agonist, an anti-histamine, an anti-allergic or an anti-inflammatory agent.

The invention thus 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 β₂-adrenoreceptor agonist, an anti-histamine, an anti-allergic, an anti-inflammatory agent or an antiinfective agent.

Preferably, the β₂-adrenoreceptor agonist is salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline, or a salt thereof (e.g. pharmaceutically acceptable salt thereof), for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting β₂-adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 12-24 hour period such as salmeterol or formoterol. Preferably, the β₂-adrenoreceptor agonist is for inhaled administration, e.g. once per day and/or for simultaneous inhaled administration; and more preferably the β₂-adrenoreceptor agonist is in particle-size-reduced form e.g. as defined herein. Preferably, the β₂-adrenoreceptor agonist combination is for treatment and/or prophylaxis of COPD or asthma. Salmeterol or a pharmaceutically acceptable salt thereof, e.g. salmeterol xinofoate, is preferably administered to humans at an inhaled dose of 25 to 50 micrograms twice per day (measured as the free base). The combination with a β₂-adrenoreceptor agonist can be as described in WO 00/12078.

Preferred long acting β₂-adrenoreceptor agonists include those described in WO 02/066422A, WO 03/024439, WO 02/070490 and WO 02/076933.

Especially preferred long-acting β₂-adrenoreceptor agonists include compounds of formula (XX) (described in WO 02/066422):

or a salt or solvate thereof, wherein in formula (XX):

m^Xis an integer of from 2 to 8;

n^Xis an integer of from 3 to 11,

with the proviso that m^X+n^Xis 5 to 19,

R^11Xis —XSO₂NR^16XR^17Xwherein X is —(CH₂)_p^x— or C_2-6alkenylene;

R^16Xand R^17Xare independently selected from hydrogen, C_1-6alkyl, C_3-7cycloalkyl, C(O)NR^18XR^19X, phenyl, and phenyl (C_1-4alkyl)-,

or R^16Xand R^17X, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring, and R^16Xand R^17Xare each optionally substituted by one or two groups selected from halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, hydroxy-substituted C_1-6alkoxy, —CO₂R^18X, —SO₂NR^18XR^19X, —CONR^18XR^19X, —NR^18XC(O)R^19X, or a 5-, 6- or 7-membered heterocyclic ring;

R^18Xand R^19Xare independently selected from hydrogen, C_1-6alkyl, C_3-6cycloalkyl, phenyl, and phenyl (C_1-4alkyl)-; and

p^Xis an integer of from 0 to 6, preferably from 0 to 4;

R^12Xand R^13Xare independently selected from hydrogen, C_1-6alkyl, C_1-6alkoxy, halo, phenyl, and C_1-6haloalkyl; and

R^14Xand R^15Xare independently selected from hydrogen and C_1-4alkyl with the proviso that the total number of carbon atoms in R^14Xand R^15Xis not more than 4.

Preferred β₂-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 β₂-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.

A combination of a compound of formula (I) or salt together with an anti-histamine is preferably for oral administration (e.g. as a combined composition such as a combined tablet), and can be for treatment and/or prophylaxis of allergic rhinitis. Examples of anti-histamines include methapyrilene, or H1 antagonists such as cetirizine, loratadine (e.g. Clarityn™), desloratadine (e.g. Clarinex™) or fexofenadine (e.g. Allegra™).

The invention also provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic compound, e.g. a muscarinic (M) receptor antagonist in particular an M₁, M₂, M₁/M₂, or M₃receptor antagonist, more preferably a M₃receptor antagonist, still more preferably a M₃receptor antagonist which selectively antagonises (e.g. antagonises 10 times or more strongly) the M₃receptor over the M₁and/or M₂receptor. For combinations of anticholinergic compounds/muscarinic (M) receptor antagonist with PDE4 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 these publications give examples of anticholinergic compounds/muscarinic (M) receptor antagonists which may be used with the compounds of formula (I) or salts, and/or suitable pharmaceutical compositions. For example, the muscarinic receptor antagonist can comprise or be an ipratropium salt (e.g. ipratropium bromide), an oxitropium salt (e.g. oxitropium bromide), or more preferably a tiotropium salt (e.g. tiotropium bromide); see e.g. EP 418 716 A1 for tiotropium.

The anticholinergic compound or muscarinic (M) receptor antagonist, e.g. M₃receptor antagonist, is preferably for inhaled administration, more preferably in particle-size-reduced form e.g. as defined herein. More preferably, both the muscarinic (M) receptor antagonist and the compound of formula (I) or the pharmaceutically acceptable salt thereof are for inhaled administration. Preferably, the anticholinergic compound or muscarinic receptor antagonist and the compound of formula (I) or salt are for simultaneous administration. The muscarinic receptor antagonist combination is preferably for treatment and/or prophylaxis 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, a tryptase inhibitor, a elastase inhibitor, a beta-2 integrin antagonist, a adenosine 2a agonist, a CCR3 antagonist, or a 5-lipoxogenase inhibitor; or an antiinfective agent (e.g. an antibiotic or an antiviral). An iNOS inhibitor is preferably for oral administration. Suitable iNOS inhibitors (inducible nitric oxide synthase inhibitors) 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 comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anti-inflammatory corticosteroid (which is preferably for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis), then preferably the anti-inflammatory corticosteroid is fluticasone, fluticasone propionate (e.g. see U.S. Pat. No. 4,335,121), beclomethasone, beclomethasone 17-propionate ester, beclomethasone 17,21-dipropionate ester, dexamethasone or an ester thereof, mometasone or an ester thereof, ciclesonide, budesonide, flunisolide, or a compound as described in WO 02/12266 A1 (e.g. as claimed in any of claims 1 to 22 therein), 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 therein {which is 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester} or Example 41 therein {which is 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester}, or a pharmaceutically acceptable salt thereof. The anti-inflammatory corticosteroid is preferably for intranasal or inhaled administration. Fluticasone propionate is preferred and is preferably for inhaled administration to a human either (a) at a dose of 250 micrograms once per day or (b) at a dose of 50 to 250 micrograms twice per day.

Also provided is a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with β₂-adrenoreceptor agonist and an anti-inflammatory corticosteroid, for example as described in WO 03/030939 A1. Preferably this combination is for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis. The β₂-adrenoreceptor agonist and/or the anti-inflammatory corticosteroid can be as described above and/or as described in WO 03/030939 A1. Most preferably, in this “triple” combination, the β₂-adrenoreceptor agonist is salmeterol or a pharmaceutically acceptable salt thereof (e.g. salmeterol xinafoate) and the anti-inflammatory corticosteroid is fluticasone propionate.

The combinations referred to above may 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 represent a further aspect of the invention.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical composition.

In one embodiment, the combination as defined herein can be for simultaneous inhaled administration and is disposed in a combination inhalation device. Such a combination inhalation device is another aspect of the invention. Such a combination inhalation device can comprise a combined pharmaceutical composition for simultaneous inhaled administration (e.g. dry powder composition), the composition comprising all the individual compounds of the combination, and the composition being incorporated into a plurality of sealed dose containers mounted longitudinally in a strip or ribbon inside the inhalation device, the containers being rupturable or peel-openable on demand; for example such inhalation device can be substantially as described in GB 2,242,134 A (DISKUS™) and/or as described above. Alternatively, the combination inhalation device can be such that the individual compounds of the combination are administrable simultaneously but are stored separately (or wholly or partly stored separately for triple combinations), e.g. in separate pharmaceutical compositions, for example as described in PCT/EP03/00598 filed on 22 Jan. 2003, published as WO 03/061743 (e.g. as described in the claims thereof e.g. claim 1).

The invention also provides a method of preparing a combination as defined herein,

- the method comprising either
- (a) preparing a separate pharmaceutical composition for administration of the individual compounds of the combination either sequentially or simultaneously, or
- (b) preparing a combined pharmaceutical composition for administration of the individual compounds of the combination simultaneously,
- wherein the pharmaceutical composition comprises the 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.

Biological Test Methods

PDE 3, PDE 4B, PDE 4D, PDE 5, PDE 6 Primary Assay Methods

The activity of the compounds can be measured in the assay methods shown below. Preferred compounds of the invention are selective PDE4 inhibitors, i.e. they inhibit PDE4 (e.g. PDE4B and/or PDE4D, preferably PDE4B) more strongly than they inhibit PDE3 and/or more strongly than they inhibit PDE5 and/or more strongly than they inhibit PDE6.

PDE Enzyme Sources and Literature References

Human recombinant PDE4B, in particular the 2B splice variant thereof (HSPDE4B2B), is disclosed in WO 94/20079 and also M. M. McLaughlin et al., “A low Km, rolipram-sensitive, cAMP-specific phosphodiesterase from human brain: cloning and expression of cDNA, biochemical characterisation of recombinant protein, and tissue distribution of mRNA”, J. Biol. Chem., 1993, 268, 6470-6476. For example, in Example 1 of WO 94/20079, human recombinant PDE4B is described as being expressed in the PDE-deficient yeast Saccharomyces cerevisiae strain GL62, e.g. after induction by addition of 150 uM CuSO₄, and 100,000×g supernatant fractions of yeast cell lysates are described for use in the harvesting of PDE4B enzyme.

Human recombinant PDE4D (HSPDE4D3A) is disclosed in P. A. Baecker et al., “Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phoshodiesterase (PDE IV_D)”, Gene, 1994, 138, 253-256.

Human recombinant PDE5 is disclosed in K. Loughney et al., “Isolation and characterisation of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3′,5′-cyclic nucleotide phosphodiesterase”, Gene, 1998, 216, 139-147.

PDE3 can be purified from bovine aorta, e.g. as described by H. Coste and P. Grondin, “Characterisation of a novel potent and specific inhibitor of type V phosphodiesterase”, Biochem. Pharmacol., 1995, 50, 1577-1585.

PDE6 can be purified from bovine retina, e.g. as described by: 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 cyclic GMP phosphodiesterase”, Biochem. J., 1995, 308, 653-658.

Inhibition of PDE 3, PDE 4B, PDE 4D, PDE 5 or PDE 6 Activity: Radioactive Scintillation Proximity Assay (SPA)

The ability of compounds to inhibit catalytic activity at PDE4B or 4D (human recombinant), PDE3 (from bovine aorta), PDE5 (human recombinant) or PDE6 (from bovine retina) is determined by Scintillation Proximity Assay (SPA) in 96-well format. Test compounds (as a solution in DMSO, preferably about 2 microlitre (ul) volume of DMSO solution) are preincubated at ambient temperature (room temperature, e.g. 19-23° C.) in Wallac Isoplates (code 1450-514) with PDE enzyme in 50 mM Tris-HCl buffer pH 7.5, 8.3 mM MgCl₂, 1.7 mM EGTA, 0.05% (w/v) bovine serum albumin for 10-30 minutes (usually 30 minutes). The enzyme concentration is adjusted so that no more than 20% hydrolysis of the substrate defined below occurs in control wells without compound, during the incubation. For the PDE3, PDE4B and PDE4D assays, [5′,8-³H]Adenosine 3′,5′-cyclic phosphate (Amersham Pharmacia Biotech, code TRK.559; or Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles, Buckinghamshire HP8 4SP, UK) is added to give 0.05 uCi per well and ˜10 nM final concentration. For the PDE5 and PDE6 assays, [8-³H]Guanosine 3′,5′-cyclic phosphate (Amersham Pharmacia Biotech, code TRK.392) is added to give 0.05 uCi per well and ˜36 nM final concentration. Plates containing assay mixture, preferably approx. 100 ul volume of assay mixture, are mixed on an orbital shaker for 5 minutes and incubated at ambient temperature for 1 hour. Phosphodiesterase SPA beads (Amersham Pharmacia Biotech, code RPNQ 0150) are added (˜1 mg per well) to terminate the assay. Plates are sealed and shaken and allowed to stand at ambient temperature for 35 minutes to 1 hour (preferably 35 minutes) to allow the beads to settle. Bound radioactive product is measured using a WALLAC TRILUX 1450 Microbeta scintillation counter. For inhibition curves, 10 concentrations (1.5 nM -30 uM) of each compound are assayed. Curves are analysed using ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kingdom) Results are expressed as pIC₅₀values.

In an alternative to the above radioactive SPA assay, PDE4B or PDE4D inhibition can be measured in the following Fluorescence Polarisation (FP) assay:

Inhibition of PDE4B or PDE4D Activity: Fluorescence Polarisation (FP) Assay

The ability of compounds to inhibit catalytic activity at PDE4B (human recombinant) or PDE4D (human recombinant) is determined by IMAP Fluorescence Polarisation (FP) assay (IMAP Explorer kit, available from Molecular Devices Corporation, Sunnydale, Calif., USA; Molecular Devices code: R8062) in 384-well format. The IMAP FP assay is able to measure PDE activity in an homogenous, non-radioactive assay format. The FP assay uses the ability of immobilised trivalent metal cations, coated onto nanoparticles (tiny beads), to bind the phosphate group of Fl-AMP that is produced on the hydrolysis of fluorescein-labelled (Fl) cyclic adenosine mono-phosphate (Fl-cAMP) to the non-cyclic Fl-AMP form. Fl-cAMP does not bind. Binding of Fl-AMP product to the beads (coated with the immobilised trivalent cations) slows the rotation of the bound Fl-AMP and leads to an increase in the fluorescence polarisation ratio of parallel to perpendicular light. Inhibition of the PDE reduces/inhibits this signal increase.

Test compounds (small volume, e.g. ca. 0.5 to 1 ul, preferably ca. 0.5 ul, of solution in DMSO) are preincubated at ambient temperature (room temperature, e.g. 19-23° C.) in black 384-well microtitre plates (supplier: NUNC, code 262260) with PDE enzyme in 10 mM Tris-HCl buffer pH 7.2, 11 mM MgCl₂, 0.1% (w/v) bovine serum albumin, and 0.05% NaN₃for 10-30 minutes. The enzyme level is set by experimentation so that reaction is linear throughout the incubation. Fluorescein adenosine 3′,5′-cyclic phosphate (from Molecular Devices Corporation, Molecular Devices code: R7091) is added to give about 40 nM final concentration (final assay volume usually ca. 20-40 ul, preferably ca. 20 ul). Plates are mixed on an orbital shaker for 10 seconds and incubated at ambient temperature for 40 minutes. IMAP binding reagent (as described above, from Molecular Devices Corporation, Molecular Devices code: R7207) is added (60 ul of a 1 in 400 dilution in binding buffer of the kit stock solution) to terminate the assay. Plates are allowed to stand at ambient temperature for 1 hour. The Fluorescence Polarisation (FP) ratio of parallel to perpendicular light is measured using an Analyst™ plate reader (from Molecular Devices Corporation). For inhibition curves, 10 concentrations (1.5 nM -30 uM) of each compound are assayed. Curves are analysed using ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kingdom). Results are expressed as pIC₅₀values.

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

For a given PDE4 inhibitor, the PDE4B (or PDE4D) inhibition values measured using the SPA and FP assays can differ slightly. However, in a regression analysis of 100 test compounds (not necessarily compounds of the invention), the pIC₅₀inhibition values measured using SPA and FP assays have been found generally to agree within 0.5 log units, for PDE4B and PDE4D (linear regression coefficient 0.966 for PDE4B and 0.971 for PDE4D; David R. Mobbs et al., “Comparison of the IMAP Fluorescence Polarisation Assay with the Scintillation Proximity Assay for Phosphodiesterase Activity”, poster presented at 2003 Molecular Devices UK & Europe User Meeting, 2 Oct. 2003, Down Hall, Harlow, Essex, United Kingdom).

Biological Data obtained for some of the Examples (PDE4B inhibitory activity, either as one reading or as an average of ca. 2-6 readings) are as follows, based on current measurements only. In each of the SPA and FP assays, absolute accuracy of measurement is not possible, and the readings given are accurate only up to about ±0.5 of a log unit, depending on the number of readings made and averaged:

All of the Examples have been tested for PDE4B inhibition using the radioactive SPA assay or the FP assay or in a similar assay. All of the Examples tested have PDE4B inhibitory activities in the range of pIC₅₀=about 7 (±about 0.5) to about 9 (±about 0.5).

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

EXAMPLES

The various aspects of the invention will now be described by reference to the following examples. These examples are merely illustrative and are not to be construed as a limitation of the scope of the present invention. In this section, “Intermediates” represent syntheses of intermediate compounds intended for use in the synthesis of the “Examples”.

Abbreviations Used Herein:

CCl₄carbon tetrachloride

DCM dichloromethane

DMF dimethyl formamide

DIPEA diisopropylethyl amine (ⁱPr₂NEt)

EtOAc ethyl acetate

Et₂O diethyl ether

Et₃N triethylamine

EtOH ethanol

HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

HCl hydrogen chloride/hydrochloric acid

Na₂SO₄sodium sulfate

NaHCO₃sodium bicarbonate

NMP 1-methyl-2-pyrrolidinone

PhCH₃toluene

PPA polyphosphoric acid

HPLC high pressure liquid chromatography

SPE solid phase extraction

NMR nuclear magnetic resonance (in which: s=singlet, d=doublet, t=triplet, q=quartet, dd=doublet of doublets, m=multiplet, H=no. of protons)

LCMS liquid chromatography/mass spectroscopy

TLC thin layer chromatography

h hours

T_RETretention time

Room temperature this is usually in the range of about 20 to about 25° C.

General Experimental Details

Machine Methods Used Herein:

LCMS (Liquid Chromatography/Mass Spectroscopy)

Waters ZQ mass spectrometer operating in positive ion electrospray mode, mass range 100-1000 amu.

UV wavelength: 215-330 nM

Column: 3.3cm×4.6mm 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 mMolar ainmonium acetate

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

It should be noted that retention times (T_RET) quoted herein may vary slightly (±0.1 min.) when samples were run on different Waters machines, even though the same type of column and identical flow rates, injection volumes, solvents and gradients were used.

Mass Directed Autoprep HPLC

The prep column used was a Supelcosil ABZplus (10 cm×2.12 cm) (usually 10 cm×2.12 cm×5 μm).

UV wavelength: 200-320 nM

Flow: 20 ml/min

Injection Volume: 1 ml; or more preferably 0.5 ml

Solvent A: 0.1% formic acid

Solvent B: 95% acetonitrile+5% formic acid; or more usually 99.95% acetonitrile+0.05% formic acid

Gradient: 100% A/1 min, 100-80% A/9 min, 80-1% A/3.5 min, 1% A/1.4 min, 1-100% A/0.1 min

Intermediates and Examples

All reagents not detailed in the text below are corumercially available from established suppliers such as Sigma-Aldrich. The addresses of the suppliers for some of the starting materials mentioned in the Intermediates and Examples below or the Assays above are as follows:

- Aldrich (catalogue name), Sigma-Aldrich Company Ltd., Dorset, United Kingdom, telephone: +44 1202 733114; Fax: +44 1202 715460; ukcustsv@eurnotes.sial.com; or
- Aldrich (catalogue 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 (catalogue name), Sigma-Aldrich Chemie Gmbh, Munich, Germany; telephone: +49 89 6513 0; Fax: +49 89 6513 1169; deorders@eurnotes.sial.com.
- Bionet Research Ltd; Highfield Industrial Estate, Camelford, Cornwall PL32 9QZ UK
- Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego, Calif. 92126, USA (CAS 38041-19-9)
- Lancaster Synthesis Ltd., Newgate, White Lund, Morecambe, Lancashire LA3 3DY, United Kingdom
- Matrix Scientific, P.O. Box 25067, Columbia, S.C. 29224-5067, USA

Trans World Chemicals, Inc., 14674 Southlawn Lane, Rockville, Md. 20850, USA

Table of IntermediatesInter-mediateNumberName1Diethyl (cyclopropylcarbonyl)malonate2Diethyl (cyclopentylcarbonyl) malonate3Diethyl (propylcarbonyl)malonate4Diethyl (ethylcarbonyl)malonate5Diethyl (cyclobutylcarbonyl)malonate6Diethyl (cyclopropylmethylcarbonyl)malonate7Diethyl [chloro(cyclopropyl)methylene]malonate8Diethyl [chloro(propyl)methylene] malonate9Diethyl [chloro(ethyl)methylene] malonate10Diethyl [chloro(cyclobutyl)methylene] malonate11Diethyl [chloro(cyclopropylmethyl)methylene] malonate12Ethyl 4-chloro-6-cyclopropyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate13Ethyl-4-chloro-6-propyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate14Ethyl-4-chloro-6-ethyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate15Ethyl-4-chloro-6-cyclobutyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate16Ethyl-4-chloro-6-cyclopropylmethyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate17Ethyl-4-chloro-6-cyclopentyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate184-Aminotetrahydropyran19Ethyl 6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate20Ethyl 6-propyl- 1-ethy1-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate21Ethyl 6-ethyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate22Ethyl 6-cyclobutyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate23Ethyl 6-cyclopropylmethyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate24Ethyl 6-cyclopentyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate256-Cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid266-propyl- 1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid276-Ethyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid286-Cyclobutyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-6]pyridine-5-carboxylic acid296-Cyclopropylmethyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid306-Cyclopentyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

Cyclopropylacetyl Chloride

Prepared from cyclopropyl acetic acid according to the procedure outlined in: Bouzoubaa, Mohamed; Leclerc, Gerard; Decker, Nicole; Schwartz, Jean; Andermann, Guy; J. Med. Chem; 1984, 27 (10); 1291-1294.

Intermediate 1: Diethyl(cyclopropylcarbonyl)malonate

A solution of diethyl malonate (6 ml) in EtOH (20 ml) was added to solid magnesium powder (1 g) and CCl₄(1 ml) at such a rate as to maintain a constant reflux. Et₂O (20 ml) was added and the mixture was heated under reflux for 2 h. The solvents were removed under reduced pressure and the residue was azeotroped with PhCH₃(2×10 ml). The solid residue was dissolved in Et₂O (40 ml) and the solution was added to a cooled solution of cylopropane carbonyl chloride (3.6 ml), maintaining the temperature between 0 and 5° C. The mixture was allowed to warm slowly to room temperature and stirred for 16 hours. The mixture was treated with 5% aqueous sulphuric acid solution (100 ml), with stirring. The organic phase was separated, washed with saturated aqueous NaHCO₃(2×75 ml), dried over anhydrous Na₂SO₄, filtered and the filtrate evaporated to dryness to leave Intermediate 1 as a colourless oil (7.74 g). LCMS showed MH⁺=229; T_RET=2.79 min.

Similarly prepared from diethyl malonate were the following:

MH⁺T_RETX⁵ion(min)Intermediate 22573.2Intermediate 32313.09Intermediate 42172.81Intermediate 52433.07Intermediate 62433.07

Intermediates 7-11

These intermediates were prepared using a modification of the procedure developed by O. E. O. Hormi and described in Synthetic Commun; 1986, 16 997-1002.

Intermediate 7: Diethyl[chloro(cyclopropyl)methylene]malonate

A mixture of Intermediate 1 (1 g), phosphorus oxychloride (10 ml) and tributylamine (1.1 ml) was stirred at 110° C. for 5 h. The volatile organics were removed under reduced pressure. The mixture was dissolved in Et₂O (20 ml) and n-hexane was added until two layers formed. The top layer was collected. More n-hexane was added until two layers formed again. This procedure was repeated once more. The combined Et₂O extracts were washed with dilute aqueous HCl (1M, 2×50 ml), dilute aqueous NaOH (1M, 2×50 ml) and water (2×50 ml), dried over anhydrous Na₂SO₄, filtered and evaporated to give Intermediate 7 as a pale yellow oil (0.87 g). LCMS showed MH⁺=249; T_RET=3.49 min.

Similarly prepared from Intermediates 3-6 were the following:

T_RETPrecursorR²MH⁺ ion(min)Intermediate 8Intermediate 32493.45Intermediate 9Intermediate 42353.21Intermediate 10Intermediate 52613.44Intermediate 11Intermediate 62613.23

Intermediate 12: Ethyl 4-chloro-6-cyclopropyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of intermediate 7 (6.75 g), Et₃N (2.88 ml) and 5-amino-1-ethyl pyrazole (3.28 g) in PhCH₃(40 ml) was heated at reflux for 16 hours. The solvent was removed under reduced pressure and the residue was treated with phosphorus oxychloride (50 ml). The reaction mixture was heated at 110° C. for 16 hours. The phosphorus oxychloride was removed under reduced pressure and the residue was partitioned between EtOAc (50 ml) and saturated aqueous NaHCO₃(50 ml). The organic layer was collected, dried (Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a 50 g SiO₂SPE cartridge, eluting with 5% EtOAc: 95% cyclohexane, to give Intermediate 12 as a yellow oil (1.53 g). LCMS showed MH⁺=294; T_RET=3.4 min.

Similarly prepared from Intermediates 8-11 were the following:

T_RETPrecursorR²MH⁺ ion(min)Intermediate 13Intermediate 82963.63Intermediate 14Intermediate 92823.4Intermediate 15Intermediate 103083.71Intermediate 16Intermediate 113083.71

Intermediate 17: Ethyl-4-chloro-6-cyclopentyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of Intermediate 2 (1.6 g) and 5-amino-i-ethyl pyrazole (0.69 g) in PPA (12 ml) was heated at 120° C. for 3 h. The mixture was poured into water (50 ml) and extracted with Et₂O (3×75 ml). The organic extracts were combined, dried (Na₂SO₄), filtered and the filtrate concentrated to leave a yellow oil. Phosphorus oxychloride (50 ml) was added to the oil. The mixture was heated at 110° for 16 h. The phosphorus oxychloride was removed and the residue was partitioned between EtOAc (50 ml) and saturated aqueous NaHCO₃(25 ml). The organic layer was collected, dried (Na₂SO₄), filtered and the filtrate was concentrated to leave Intermediate 17 as a tan solid (100 mg). LCMS showed MH⁺=322; T_RET=3.96 min.

Intermediate 18: 4-Aminotetrahydropyran

Commercially available from Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego, Calif. 92126, USA (CAS 38041-19-9)

Intermediate 19: Ethyl 6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A solution of Intermediate 12 (0.76 g), Intermediate 18 (0.36 g) and DIPEA (0.65 ml) in NMP (8 ml) was heated at 150° C. for 16 h. The mixture was allowed to cool and partitioned between EtOAc (100 ml) and water (20 ml). The organic layer was collected, dried (Na₂SO₄), filtered and concentrated to give a dark gum. The gum was purified on a 20 g SiO₂SPE cartridge, eluting with 10% EtOAc:90% Cyclohexane to give Intermediate 18 as a pale yellow solid (0.35 g). LCMS showed MH⁺=359; T_RET=3.43 min.

Similarly prepared from Intermediates 13-17 were the following:

T_RETPrecursorR²MH⁺ ion(min)Intermediate 20Intermediate 133613.16Intermediate 21Intermediate 143473.05Intermediate 22Intermediate 153733.57Intermediate 23Intermediate 163733.35Intermediate 24Intermediate 173873.78

Intermediate 25: 6-Cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic Acid

A solution of intermediate 19 (0.35 g) in EtOH (60 ml) was treated with a solution of NaOH (0.75 g) in water (20 ml) and the reaction mixture was heated at 60° C. for 16 h. The solvents were removed under reduced pressure, the residue was suspended in water (5 ml) and the pH of the solution was adjusted to 3 (1M HCl). The resultant suspension was extracted with EtOAc (2×30 ml). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure to give Intermediate 25 as a white solid (0.30 g). LCMS showed MH⁺=331; T_RET=2.41 min

Similarly prepared from Intermediates 21-25 were the following:

T_RETPrecursorR²MH⁺ ion(min)Intermediate 26Intermediate 213332.06Intermediate 27Intermediate 223191.9Intermediate 28Intermediate 233452.61Intermediate 29Intermediate 243452.12Intermediate 30Intermediate 253592.72

Table of Examples

Example

Number
Name

1
N-[(4-chloro-2-methylphenyl)methyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-

2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

2
6-cyclopropyl-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-

ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

3
6-cyclopropyl-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-

pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

4
6-cyclopropyl-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-

pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

5
N-[1-(4-chlorophenyl)ethyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-

4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

6
N-[1-(4-chlorophenyl)propyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-

pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

7
1-ethyl-N-(phenylmethyl)-6-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-

1H-pyrazolo[3,4-b]pyridine-5-carboxamide

8
1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-6-propyl-4-(tetrahydro-2H-

pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

9
N-[(4-chloro-2-methylphenyl)methyl]-1-ethyl-6-propyl-4-(tetrahydro-2H-

pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

10
N-[(3,4-dimethylphenyl)methyl]-1-ethyl-6-propyl-4-(tetrahydro-2H-pyran-

4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

11
N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-6-propyl-4-(tetrahydro-2H-pyran-4-

ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

12
1,6-diethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-

pyrazolo[3,4-b]pyridine-5-carboxamide

13
1,6-diethyl-N-{[4-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-

ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

14
N-[(3,4-dimethylphenyl)methyl]-1,6-dithyl-4-(tetrahydro-2H-pyran-4-

ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

15
N-(2,3-dihydro-1H-inden-2-yl)-1,6-diethyl-4-(tetrahydro-2H-pyran-4-

ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

16
N-[1-(4-chlorophenyl)propyl]-1,6-diethyl-4-(tetrahydro-2H-pyran-4-

ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

17
6-cyclobutyl-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-

ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

18
6-cyclobutyl-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-

pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

19
6-(cyclopropylmethyl)-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-

(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-

carboxamide

20
6-cyclobutyl-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-

pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

21
N-[(4-chloro-2-methylphenyl)methyl]-6-cyclobutyl-1-ethyl-4-(tetrahydro-

2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

22
N-[1-(4-chlorophenyl)ethyl]-6-cyclobutyl-1-ethyl-4-(tetrahydro-2H-pyran-

4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

23
N-[1-(4-chlorophenyl)propyl]-6-cyclobutyl-1-ethyl-4-(tetrahydro-2H-pyran-

4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

24
6-(cyclopropylmethyl)-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-

4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

25
6-(cyclopropylmethyl)-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-

(tetraliydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-

carboxamide

26
6-(cyclopropylmethyl)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-

(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-

carboxamide

27
N-[1-(4-chlorophenyl)ethyl]-6-(cyclopropylmethyl)-1-ethyl-4-(tetrahydro-

2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

28
6-cyclopentyl-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-

ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

29
6-cyclopentyl-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-

pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 1
N-[(4-chloro-2-methylphenyl)methyl]-6-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A solution of Intermediate 20 (30 mg) in DMF (2 ml) was treated with HATU (35 mg) and DIPEA (100 μL). The solution was allowed to stand at 22° C. for 10 min. then treated with 2-methyl-4-chloro benzylamine (supplier: Matrix Scientific) (14 mg) and allowed to stand at 22° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (5 ml) and saturated aqueous NaHCO₃(2 ml). The organic phase was collected through a hydrophobic frit and evaporated. The residue was purified by mass directed autoprep. HPLC to give Example 1 as a white solid (14.9 mg). LCMS showed MH⁺=468; T_RET=3.45 min.

The following Examples 2-6 were prepared from Intermediate 20 and the appropriate amine WNH₂using a similar procedure to that used for the preparation of Example 1:

Exam-Source of amineMH⁺T_RETple No.NHWreagent WNH₂ion(min)2Aldrich4203.023Aldrich4502.994Trans World Chemicals4483.275Bionet Research4683.396J. Pharm. Pharmacol; 1997, 49 (1), 10- 154823.51

The following Examples 7-11 were prepared from Intermediate 21 and the appropriate amine WNH₂using a similar procedure to that used for the preparation of Example 1:

Exam-Source of amineMH⁺T_RETple No.NHWreagent WNH₂ion(min)7Aldrich4222.718Aldrich4522.79Matrix Scientific4703.0910Trans World Chemicals4502.9911Aldrich4482.86

The following Examples 12-16 were prepared from Intermediate 22 and the appropriate amine WNH₂using a similar procedure to that used for the preparation of Example 1:

Exam-Source of amineMH⁺T_RETple No.NHWreagent WNH₂ion(min)12Aldrich4082.4313Aldrich4382.4414Trans World Chemicals4362.7515Aldrich4342.616J. Pharm. Pharmacol; 1997, 49 (1), 10- 154702.94

The following examples 17-23 were prepared from Intermediate 23 and the appropriate amine WNH₂using a similar procedure to that used for the preparation of Example 1:

Exam-Source of amineMH⁺T_RETple No.NHWreagent WNH₂ion(min)17Aldrich4343.1718Aldrich4643.1419Trans World Chemicals4623.4220Aldrich4603.3421Matrix Scientific4823.5122Bionet Research4823.4523J. Pharm. Pharmacol; 1997, 49 (1), 10- 154963.57

The following examples 24-27 were prepared from Intermediate 24 and the appropriate amine WNH₂using a similar procedure to that used for the preparation of Example 1:

Exam-Source of amineMH⁺T_RETple No.NHWreagent WNH₂ion(min)24Aldrich4342.7725Trans World Chemicals4623.0426Aldrich4602.9327Bionet Research4823.09

The following Examples 28-29 were prepared from Intermediate 24 and the appropriate amine WNH₂using a similar procedure to that used for the preparation of Example 1:

Source of amineMH⁺T_RETExample No.NHWreagent WNH₂ion(min)28Aldrich4483.3329Aldrich4743.45

Pyrazolo '3,4-B! Pyridine Compounds And Their Use As Phosphodiesterase Type 4(Pde4) Inhibitors

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