Pyrazolo[3,4-b]Pyridine Compounds, and their Use as Phosphodiesterase Inhibitors

A compound of formula (I) or a salt thereof:

• wherein:
• R1 is C1-3alkyl C1-2fluoroalkyl or —CH2CH2OH;
• R2 is a hydrogen atom (H), methyl or C1fluoroalkyl;
• R3 is unsubstituted C6-8cycloalkyl;
• or R3 is a bicyclic group of sub-formula (ee):
• wherein Y1, Y2 and Y3 are all CH2;
• X is NR4R5 or OR5a, in which:
• R4 is a hydrogen atom (H);
• and
• R5 is a hydrogen atom (H);
• C1-8alkyl;
• C1-8 fluoroalkyl;
• C3-8cycloalkyl optionally substituted by a C1-2alkyl group;
• or —(CH2)n4—C3-8cycloalkyl optionally substituted, in the —(CH2)n4— moiety or in the C3-8cycloalkyl moiety, by a C1-2alkyl group, wherein n4 is 1, 2 or 3;
• or R5 is C2-6alkyl substituted by one or two independent substituents R11;
• wherein each substituent R11, independently of any other R11 substituent present, is:
• hydroxy (OH);
• C1-6alkoxy;
• phenyloxy;
• benzyloxy;
• —NR12R13;
• —NR15—C(O)R16;
• —NR15—C(O)—O—R16;
• —NR15—C(O)—NH—R15;
• or —NR15—SO2R16;
• and wherein any R11 substituent which is OH, alkoxy or —NR12R13 is not substituted at any carbon atom, of any R4 or R5 substituted alkyl, which is bonded to the nitrogen of NR4R5;
• or R5 is —(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;
• wherein n11 is 0, 1, 2, 3 or 4 and n12 is 1, 2, 3 or 4;
• or R5 is —(CH2)n13-Het wherein n13 is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or 7-membered saturated or partly-saturated heterocyclic ring containing one or two ring-hetero-atoms independently selected from O, S, and N;
• wherein any ring-hetero-atoms present are not bound to the —(CH2)n13— moiety when n n13 is 1 and are not bound to the nitrogen of NR4R5 when n13 is 0;
• wherein any ring-nitrogens which are present and which are not unsaturated are present as NR17 where R17 is as defined herein;
• and wherein one or two of the carbon ring-atoms independently are optionally substituted by C1-2alkyl;
• or R5 is phenyl optionally substituted with, independently, one, two or three of:
• a halogen atom;
• C1-6alkyl;
• C1-2fluoroalkyl;
• C1-4alkoxy;
• C1-2fluoroalkoxy;
• C3-6cycloalkyloxy;
• —C(O)R16a;
• —C(O)OR30;
• —S(O)2—R16a;
• R16a—S(O)2—NR15a;
• R7R8N—S(O)2—;
• C1-2alkyl-C(O)—R15aN—S(O)2—;
• C1-4alkyl-S(O)—;
• Ph-S(O)—;
• R7R8N—CO—;
• —NR15—C(O)R16;
• R7R8N;
• OH;
• C1-4alkoxymethyl;
• C1-4alkoxyethyl;
• C1-2alkyl-S(O)2—CH2—;
• R7R8N—S(O)2—CH2—;
• C1-2alkyl-S(O)2—NR15a—CH2—;
• —CH2—OH;
• —CH2CH2—OH;
• —CH2—NR7R8;
• —CH2—CH2—NR7R8;
• —CH2—C(O)OR30;
• —CH2—C(O)—NR7R8;
• —CH2—NR15a—C(O)—C1-3alkyl;
• —(CH2)n14-Het1 where n14 is 0 or 1;
• cyano (CN);
• Ar5a;
• or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
• or where two adjacent substituents, on the R5 optionally substituted phenyl, taken together are —O—(CMe2)—O— or —O—(CH2)n14—O— where n14 is 1 or 2;
• wherein R7 and R8 are independently a hydrogen atom (H);
• C1-4alkyl;
• C3-6cycloalkyl;
• or phenyl optionally substituted by one or two of:
• fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
• or R7 and R8 together are —(CH2)n6— or —C(O)—(CH2)n7— or —C(O)—(CH2)n7—C(O)— or —(CH2)n8—X7—(CH2)n9— or —C(O)—X7—(CH2)n10— in which:
• n6 is 3, 4, 5 or 6, n7 is 2, 3, 4, or 5, n8 and n9 and n10 independently are 2 or 3, and X7 is O or NR14 wherein R14 is H, C1-2alkyl or C(O)Me;
• or R5 has 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;
• 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;
• 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;
• wherein, each R6, independently of any other R6 present, is:
• a halogen atom;
• C1-6alkyl;
• C1-4fluoroalkyl;
• C1-4alkoxy;
• C1-2fluoroalkoxy;
• C3-6cycloalkyloxy;
• —C(O)R16a;
• —C(O)OR30;
• —S(O)2—R16a;
• R16a—S(O)2—NR15a—;
• R7R8N—S(O)2—;
• C1-2alkyl-C(O)—R15aN—S(O)2—;
• C1-4alkyl-S(O)—;
• Ph-S(O)—;
• R7R8N—CO—;
• —NR15—C(O)R16;
• R7R8N;
• OH;
• C1-4alkoxymethyl;
• C1-4alkoxyethyl;
• C1-2alkyl-S(O)2—CH2—;
• R7R8N—S(O)2—CH2—;
• C1-2alkyl-S(O)2—NR15a—CH2—;
• —CH2—OH;
• —CH2CH2—OH;
• —CH2—NR7R8;
• —CH2—CH2—NR7R8;
• —CH2—C(O)OR30;
• —CH2—C(O)—NR7R8;
• —CH2—NR15a—C(O)—C1-3alkyl;
• —(CH2)n14-Het1 where n14 is 0 or 1;
• cyano (CN);
• Ar5b;
• or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
• or where two adjacent R6 taken together are —O—(CMe2)—O— or —O—(CH2)n14—O— where n14 is 1 or 2;
• wherein R7 and R8 are as herein defined;
• wherein sub-formula (y) and (y1), independently, are optionally substituted by oxo (═O) at a ring carbon adjacent the 6-membered aromatic ring;
• wherein in sub-formula (z), G is O or S or NR9 wherein R9 is a hydrogen atom (H), C1-4alkyl or C1-4fluoroalkyl;
• 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 CR6 where R6, independently of any other R6 present, is as defined herein;
• and
• R5a is C1-8alkyl;
• C1-8 fluoroalkyl;
• C3-8cycloalkyl;
• —(CH2)n4a—C3-6cycloalkyl wherein n4a is 1 or 2;
• phenyl optionally substituted with one or two of:
• a halogen atom, C1-2alkyl, trifluoromethyl, C1-2alkoxy or trifluoromethoxy;
• or R5a has the sub-formula (x), (y), (y1) or (z) as defined herein;
• R12 and R13 independently are H;
• C1-5alkyl;
• C3-6cycloalkyl;
• or phenyl optionally substituted by one or two of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
• or R12 and R13 together are —(CH2)n6— or —C(O)—(CH2)n7— or —C(O)—(CH2)n7—C(O)— or —(CH2)n8—X12—(CH2)n9— or —C(O)—X12—(CH2)n10— in which:
• n6 is 3, 4, 5 or 6, n7 is 2, 3, 4, or 5, n8 and n9 and n10 independently are 2 or 3 and X12 is O or NR14a wherein R14a is H, C1-2alkyl or C(O)Me;
• R15 is a hydrogen atom (H);
• C1-4alkyl;
• C3-6cycloalkyl;
• or phenyl optionally substituted by one or two of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
• R15a, independent of other R15a, is a hydrogen atom (H) or C1-4alkyl;
• R16 and R16a independently are:
• C1-6alkyl;
• C3-6cycloalkyl optionally substituted by one oxo (═O), OH or C1-2alkyl substituent;
• C3-6cycloalkyl-CH2—;
• pyridinyl optionally substituted on a ring carbon atom by one of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
• Ar5c;
• phenyl optionally substituted by one or two of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
• benzyl optionally substituted at an aromatic carbon atom by one or two of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy 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 NR27 where R27 is H, C1-2alkyl or —C(O)Me;
• and wherein the ring is optionally substituted at carbon by one C1-2alkyl or oxo (═O) substituent, provided that any oxo (═O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen;
• wherein Ar5a, Ar5b and Ar5c independently is/are a 5-membered aromatic heterocyclic ring containing one O, S or NR15a in 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, C1-2alkyl, C1fluoroalkyl, —CH2OH, —CH2—OC1-2alkyl, OH (including the keto tautomer thereof) or —CH2—NR28R29 wherein R28 and R29 independently are H or methyl;
• and R17 is a hydrogen atom (H);
• C1-4alkyl;
• C1-2fluoroalkyl;
• C3-6cycloalkyl;
• —(CH2)p6—C(O)R16 wherein p6 is 0, 1, 2 or 3;
• —(CH2)p6—C(O)NR12R13;
• —(CH2)p6—C(O)OR16;
• —(CH2)p6—C(O)OH;
• —SO2R16;
• —C(O)—CH2—NR12R13;
• —C(O)—CH2—NR15a—C(O)—C1-3alkyl;
• —C(O)—CH2—O—C1-3alkyl;
• or phenyl or benzyl wherein the phenyl or benzyl is optionally substituted at an aromatic carbon atom by one or two of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy or C1fluoroalkoxy;
• R19 is C1-4alkyl;
• —(CH2)n20—OR20 wherein n20 is 1, 2, 3 or 4 and R20 is a hydrogen atom (H) or C1-4alkyl;
• —CH(Me)-OH;
• —CH2—SH;
• —CH2—CH2—S-Me;
• benzyl;
• or (4-hydroxyphenyl)methyl;
• and
• R30, independent of other R30, is a hydrogen atom (H), C1-4alkyl or C3-6cycloalkyl;
• and
• Het1, independent of other 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 NR31 where R31 is H, C1-2alkyl or —C(O)Me;
• and wherein the ring is optionally substituted at carbon by one C1-2alkyl or oxo (═O) substituent, provided that any oxo (═O) substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen.