Pyrazolo[3,4-b]pyridine compounds, and their use as PDE4 inhibitors

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

• wherein:
• R1 is ethyl, n-propyl, isopropyl, C1-2fluoroalkyl, or —CH2CH2OH;
• R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, C1-2fluoroalkyl, cyclopropyl or (cyclopropyl)methyl-;
• NHR3 has the sub-formula (nhr3):
• wherein, in sub-formula (nhr3), the —NH— connection point of the NHR3 group to the bicyclic ring system of formula (I) is underlined, and wherein
• R3a is methyl or ethyl;
• R3b is hydrogen, methyl or ethyl,
• R3c is hydrogen, methyl or ethyl,
• R3d is hydrogen, methyl or ethyl, and
• R3e is hydrogen or methyl,
• provided that:
• (a) R3b is methyl or ethyl;
• and (b) R3c and R3d are independently methyl or ethyl;
• and provided that:
• (c) when R3c is ethyl and when R3d is ethyl and when R3e is methyl, then:
• R3a is methyl and R3b is hydrogen or methyl;
• and wherein:
• R5 is C3-8alkyl;
• 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;
• C1-6alkoxy;
• phenyloxy;
• benzyloxy;
• —NR12R13;
• —NR15—C(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 the carbon atom, of any R5 substituted alkyl, which is bonded to the nitrogen of NHR5;
• or R5 is —(CH2)n12—SO2—NR12R13 or —(CH2)n12—SO2R16;
• wherein n12 is 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 n13 is 1 and are not bound to the nitrogen of NHR5 when n13 is 0;
• wherein any ring-nitrogens which are present and which are saturated are present as NR17;
• and wherein one or two of the carbon ring-atoms independently are optionally substituted by C1-2alkyl;
• or R5 has the sub-formula (x), (xa), (y), (y1), (z) or (za):
• 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 sub-formula (y) and (y1), independently, are optionally substituted by oxo at a ring carbon adjacent the 6-membered aromatic ring;
• and wherein, in sub-formula (xa) and (za):
• R4a is hydrogen;
• methyl, ethyl, n-propyl, isopropyl, C1-2fluoroalkyl, cyclopropyl, —CH2OR4aa, —CH(Me)OR4aa, or —CH2CH2OR4aa, wherein R4aa is hydrogen, methyl, or C1fluoroalkyl;
• and
• R5a is-hydrogen;
• C1-8alkyl;
• C1-3fluoroalkyl;
• C3-8cycloalkyl optionally substituted by a C1-2alkyl group;
• or —(CH2)n4a—C3-8cycloalkyl optionally substituted, in the —(CH2)n4a- moiety or in the C3-8-cycloalkyl moiety, by a C1-2alkyl group, wherein n4a is 1 or 2;
• or R5a is C1-4alkyl substituted by one substituent R11a;
• wherein R11a is:
• hydroxy (OH);
• C1-6alkoxy;
• C1-2fluoroalkoxy;
• phenyloxy;
• (monofluoro- or difluoro-phenyl)oxy;
• (monomethyl- or dimethyl-phenyl)oxy;
• benzyloxy;
• —NR12R13;
• —NR15—C(O)R16;
• —NR15—C(O)—NH—R15;
• or —NR15—S(O)2R16;
• or R5a is C2-4alkyl substituted on different carbon atoms by two hydroxy substituents;
• or R5a is —(CH2)n11a—C(O)R16;
• —(CH2)n11a—C(O)NR12R13;
• —CHR19a—C(O)NR12R13;
• —(CH2)n11a—C(O)OR16;
• —(CH2)n11a—C(O)OH;
• —CHR19a—C(O)OR16;
• —CHR19a—C(O)OH;
• —(CH2)n11a—S(O)2—NR12R13;
• —(CH2)n11a—S(O)2R16;
• or —(CH2)n11a—CN;
• wherein n11a is 0, 1, 2 or 3 wherein for each R5a group n11a is independent of the value of n11a in other R5a groups;
• and wherein R19a is C1-2alkyl;
• or R5a is —(CH2)n13a-HetA, wherein n13a is 0, 1 or 2 and HetA is a 4-, 5-, 6- or 7-membered saturated or unsaturated heterocyclic ring, other than —NR12R13, 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)n13a moiety when n13a is 0;
• wherein any ring-nitrogens which are present and which are saturated and which are not connecting nitrogens are present as NR17a;
• and wherein one or two of the carbon ring-atoms are independently optionally substituted by C1-2alkyl;
• or R5a is phenyl, —CH2-Ph, —CHMe-Ph, —CHEt-Ph, CMe2Ph, or —CH2CH2-Ph, wherein the phenyl ring is optionally substituted with one or two substituents independently selected from the group consisting of a halogen atom;
• C1-4alkyl;
• C1-2fluoroalkyl;
• C1-4alkoxy;
• C1-2fluoroalkoxy;
• cyclopropyl;
• cyclopropyloxy;
• —C(O)—C1-4alkyl;
• —C(O)OH;
• —C(O)—OC1-4alkyl;
• C1-4alkyl-S(O)2—;
• C1-4alkyl-S(O)2—NR8a—;
• R7aR8aN—S(O)2—;
• R7aR8aN—C(O)—;
• —NR8a—C(O)—C1-4alkyl;
• R7aR8aN;
• OH;
• nitro (—NO2);
• and cyano (—CN);
• or R4a and R5a taken together are —(CH2)p1— or —(CH2)p3—X5—(CH2)p4—, in which:
• X5 is O or NR17a;
• p1=2, 3, 4, 5 or 6, and p3 and p4 independently are 1, 2 or 3 provided that if p3 is 3 then p4 is 1 or 2 and if p4 is 3 then p3 is 1 or 2;
• provided that at least one of R4a and R5a is not hydrogen;
• and wherein, in sub-formula (x) and in sub-formula (xa):
• A is C—R6A, nitrogen or nitrogen-oxide,
• B is C—R6B, nitrogen or nitrogen-oxide,
• D is C—R6D, nitrogen or nitrogen-oxide,
• E is C—R6E, nitrogen or nitrogen-oxide,
• F is C—R6F, nitrogen or nitrogen-oxide,
• wherein, R6A, R6B, R6D, R6E and R6F independently are:
• hydrogen, a halogen atom;
• C1-6alkyl;
• C1-4fluoroalkyl;
• C3-6cycloalkyl;
• 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—;
• —NR15a—C(O)R16a;
• R7R8N;
• nitro;
• 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;
• Ar5b;
• or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two substituents selected from the group consisting of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy and C1fluoroalkoxy;
• and two adjacent groups are selected from the group consisting of R6A, R6B, R6D, R6E and R6F, and are:
• —CH═CH—CH═CH2—, —(CH2)n14a— where n14a is 3, 4 or 5, —O—(CMe2)—O—, —O—(CH2)n14b—O— where n14b is 1 or 2;
• —CH═CH—NR15b—;
• —N═CH—NR15b—;
• —CH═N—NR15b—;
• —N═N—NR15b—;
• —CH═CH—O—;
• —N═CH—O—;
• —CH═CH—S—;
• or —N═CH—S—;
• wherein R15b is H or C1-2alkyl;
• provided that:
• at least two of A, B, D, E and F are independently C—H, C—F, nitrogen, or nitrogen-oxide;
• and no more than two of A, B, D, E and F are independently nitrogen or nitrogen-oxide,
• and no more than one of A, B, D, E and F is nitrogen-oxide;
• and wherein, in sub-formula (z) and in sub-formula (za):
• G is O or S or NR9 wherein R9 is hydrogen, C1-4alkyl, or C1-2fluoroalkyl;
• J is C—R6J, C-[connection point to formula (I)], or nitrogen,
• L is C—R6L, C-[connection point to formula (I)], or nitrogen,
• M is C—R6M, C-[connection point to formula (I)], or nitrogen,
• Q is C—R6Q, C-[connection point to formula (I)], or nitrogen,
• wherein, R6J, R6L, R6M and R6Q independently are:-hydrogen, a halogen atom;
• C1-4alkyl;
• C1-3fluoroalkyl;
• C3-6cycloalkyl;
• C1-4alkoxy;
• C1-2fluoroalkoxy;
• C3-6cycloalkyloxy;
• OH (including any tautomer thereof);
• or phenyl optionally substituted by one or two substituents independently selected from the group consisting of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy and C1fluoroalkoxy;
• provided that:
• at least two of J, L, M and Q are independently C—H, C—F, C—C1-2alkyl, C-[connection point to formula (I)], or nitrogen;
• and no more than three of J, L, M and Q are nitrogen;
• and wherein:
• R7 and R8 are independently hydrogen;
• C1-4alkyl;
• C3-6cycloalkyl;
• or phenyl optionally substituted by one or two substituents independently selected from the group consisting of:
• fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy and C1fluoroalkoxy;
• or R7 and R8 together 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:
• 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;
• R7a is hydrogen or C1-4alkyl;
• R8a is hydrogen or methyl;
• R12 and R13, independent of any other R12 or R13 independently are H;
• C1-4alkyl;
• C3-6cycloalkyl;
• or phenyl optionally substituted by one or two substituents independently selected from the group consisting of fluoro, chloro, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy and C1fluoroalkoxy;
• or R12 and R13, independent of any other R12 or R13, together are —(CH2)n6a— or —C(O)—(CH2)n7a— or —C(O)—(CH2)n10a—C(O)— or —(CH2)n8a—X12—(CH2)n9a— or —C(O)—X12—(CH2)n10a— in which:
• n6a is 3, 4, 5 or 6, n7a is 2, 3, 4, or 5, n8a and n9a and n10a independently are 2 or 3 and X12 is O or NR14a;
• R14, R14a and R17a, independent of any other R14, R14a or R17a, independently are:
• hydrogen;
• C1-4alkyl;
• C1-2fluoroalkyl;
• cyclopropyl;
• —C(O)—C1-14alkyl;
• —C(O)NR7aR8a;
• or —S(O)2—C1-4alkyl;
• R15, independent of any other R15, is hydrogen;
• C1-4alkyl;
• C3-6cycloalkyl;
• or phenyl optionally substituted by one or two substituents independently selected from the group consisting of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy and C1fluoroalkoxy;
• R15a, independent of any other R15a, is hydrogen or C1-4alkyl;
• R16, independent of any other R16, is:
• C1-4alkyl;
• C3-6cycloalkyl;
• C3-6cycloalkyl-CH2—;
• or phenyl or benzyl, wherein the phenyl and benzyl are independently optionally substituted by one or two substituents independently selected from the group consisting of fluoro, chloro, methyl, C1fluoroalkyl, methoxy and C1fluoroalkoxy;
• R16a, independent of any other R16a, is:
• C1-6alkyl;
• C3-6cycloalkyl optionally substituted by one oxo, 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 substituents independently selected from the group consisting of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy and C1fluoroalkoxy;
• benzyl optionally substituted on its ring by one or two substituents independently selected from the group consisting of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy, 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 the group consisting of 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 substituent, provided that any oxo substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen;
• R17, independent of any other R17, is hydrogen;
• 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)—C1-3 alkyl;
• —C(O)—CH2—O—C1-3alkyl;
• or phenyl or benzyl wherein the phenyl or benzyl is optionally substituted on their ring by one or two substituents independently selected from the group consisting of:
• a halogen atom, C1-2alkyl, C1fluoroalkyl, C1-2alkoxy and C1fluoroalkoxy;
• R30, independent of any other R30, is hydrogen, C1-4alkyl or C3-6cycloalkyl;
• Ar5b and Ar5c independently are a 5-membered aromatic heterocyclic ring containing one O, S or NR15a, the ring can optionally additionally contain one or two N atoms, and wherein the heterocyclic ring is optionally substituted on a ring carbon atom by a substituent selected from the group consisting of:
• halo, C1-2alkyl, C1fluoroalkyl, —CH2OH, —CH2—OC1-2alkyl, OH, and —CH2—NR28R29 wherein R28 and R29 independently are H or methyl;
• and
• Het1, independent of any 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 the group consisting of 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 substituent, provided that any oxo substituent is substituted at a ring-carbon atom bonded to a ring-nitrogen.