Compounds and their use as PDE4 activators

Abstract

The present invention relates to compounds of formulae I to V and of formulae Ib to Vb, their use as activators of the long cyclic nucleotide phosphodiesterase-4 (PDE4) enzyme (isoform), and to the use of these compounds in methods of treating or preventing conditions requiring reduction of a second messenger response mediated by cyclic adenosine 3 ', 5'-monophosphate (cAMP).

Description

Technical Field

[0001] The present invention relates to compounds as defined herein, their use as activators of the long-form cyclic nucleotide phosphodiesterase-4 (PDE4) enzyme (isoforms) and therapies using these compounds. In particular, the present invention relates to the use of these compounds in methods for treating or preventing conditions requiring a decrease in second messenger responses mediated by cyclic 3',5'-adenosine monophosphate (cAMP). Background Art

[0002] Cyclic adenosine 3',5'-monophosphate ("cAMP") is an important intracellular biochemical messenger that is involved in the transduction of the cellular effects of a variety of hormones, neurotransmitters, and other extracellular biological factors in most animal and human cells. The intracellular concentration of cAMP is controlled by the relative balance between its production rate and degradation rate. cAMP is produced by biosynthetic enzymes of the adenylate cyclase superfamily and degraded by members of the cyclic nucleotide phosphodiesterase (PDE) superfamily. Some members of the PDE superfamily (e.g., PDE4) specifically degrade cAMP, while other members specifically degrade cyclic guanosine monophosphate (cGMP) or degrade both cAMP and cGMP. The PDE4 enzyme inactivates cAMP, thereby terminating its signaling by hydrolyzing cAMP to 5'-AMP (Lugnier, C. Pharmacol Ther. 109:366-398, 2006).

[0003] Four PDE4 genes (PDE4A, PDE4B, PDE4C, and PDE4D) have been identified, each encoding a number of different enzyme isoforms using alternative promoters and mRNA splicing. Based on their primary structure, catalytically active PDE4 splice variants can be classified as "long," "short," or "ultra-short" (Houslay, MD Prog Nucleic Acid Res Mol Biol. 69: 249-315, 2001). There is also an "ultra-short" form that is catalytically inactive (Houslay, MD, Baillie, GS, and Maurice, DH Circ Res. 100: 950-66, 2007). The long form of PDE4 has two regulatory regions, called upstream conserved region 1 and upstream conserved region 2 (UCR1 and UCR2), located between its isoform-specific N-terminal portion and the catalytic domain. The short form lacks the UCR1 domain, while the ultrashort form not only lacks UCR1 but also has a truncated UCR2 domain (Houslay, MD, Schafer, P. and Zhang, K. Drug Discovery Today 10: 1503-1519, 2005).

[0004] The long form of PDE4, but not the short form, associates into dimers in cells (Richter, W and Conti, MJ Biol. Chem. 277: 40212-40221, 2002; Bolger, GB et al., Cell. Signal. 27: 756-769, 2015). Negative allosteric regulation of the long form of PDE4 by proposed small molecules has been reported (Burgin AB et al., Nat. Biotechnol. 28: 63-70, 2010; Gumey ME et al., Handb. Exp. Pharmacol. 204: 167-192, 2011).

[0005] It is known in the art that PDE4 long form can be activated by endogenous cellular mechanisms such as phosphorylation (MacKenzie, SJ et al., Br. J. Pharmacol. 136:421-433, 2002) and phosphatidic acid (Grange et al., J. Biol. Chem. 275:33379-33387, 2000). Activation of the long form of PDE4 has been reported by ectopic expression of a 57-amino acid protein (termed "UCR1C"), the exact sequence of which reflects a portion of the upstream conserved region 1 of PDE4D (the "UCR1C" sequence reflects the sequence of amino acids 80-136, while UCR is amino acids 17-136: numbering based on the PDE4D3 long isoform) (Wang, L et al., Cell. Signal. 27:908-922, 2015: "UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy"). The authors hypothesized that PDE4 activation could be used as a potential therapeutic strategy to prevent cardiac hypertrophy.

[0006] The first small molecule acting as an activator of the long form of PDE4 was recently disclosed in WO2016 / 151300, WO2018 / 060704 and WO2019 / 193342. Small molecule activators of the long form of PDE4 were recently evaluated in a cell model of autosomal dominant polycystic kidney disease (ADPKD) (Omar et al., PNAS 116: 13320-13329, 2019). Currently, there are no reports of small molecule activators of the long form of PDE4 in clinical development. There is still a need for further, structurally unique small molecule activators of the long form of PDE4 for potential development as therapeutic agents.

[0007] One of the objects of the present invention is to provide at least one novel small molecule activator of the long form of PDE4, which is useful in methods of treatment and in the treatment or prevention of specific diseases. Summary of the Invention

[0008] In a first aspect of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt or derivative thereof for use in treating or preventing a disease or condition that can be ameliorated by activation of the long isoform of PDE4 or a disease or condition mediated by excessive intracellular cyclic AMP signaling:

[0009]

[0010] in:

[0011] One or two of Y1, Y2 and Y3 are N, and the rest are CR 3b ;

[0012] Q is C or S(O);

[0013] R 1 is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic, and wherein R 1 Optional use of one or more R 4 replace;

[0014] A is for R 2c NR 2a R 2b OR 2f ;

[0015] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0016] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0017] R 2a and R 2bTogether with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally replaced by 1 or more R 5 replace;

[0018] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0019] R 2f is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2f Optional use of one or more R 5 replace;

[0020] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0021] Two R attached to the same or adjacent carbon atoms 3a Together with the atoms to which they are attached, they may form a 3- to 6-membered carbocyclic ring or a heterocyclic ring containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0022] R 3b Each is independently H or (C1-6) alkyl;

[0023] R 4are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0024] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0025] n is 0, 1, 2, 3, or 4; and

[0026] a is 0 or 1, and b is 1 or 2, wherein when b is 2, a is 0.

[0027] In a second aspect of the present invention, there is provided a compound of formula II or a pharmaceutically acceptable salt or derivative thereof,

[0028]

[0029] in:

[0030] One or two of Y1, Y2 and Y3 are N, and the others are CR 3b ;

[0031] Q is C or S(O);

[0032] R 1a is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, and wherein R 1a Optional use of one or more R 4 replace;

[0033] A is for R 2c , or NR 2a R 2b OR 2f ;

[0034] R 2ais: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0035] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0036] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally replaced by 1 or more R 5 replace;

[0037] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0038] R 2f is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2f Optional use of one or more R 5 replace;

[0039] R 3aare each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0040] Two R attached to the same or adjacent carbon atoms 3a may be linked together to form a 3- to 6-membered carbocyclic ring or a heterocyclic ring containing an O heteroatom, which may be optionally substituted with one or more halogens;

[0041] R 3b Each is independently H or (C1-6) alkyl;

[0042] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0043] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0044] n is 0, 1, 2, 3, or 4; and

[0045] a is 0 or 1, and b is 1 or 2, wherein when b is 2, a is 0.

[0046] In a third aspect of the present invention, there is provided a compound of formula III or a pharmaceutically acceptable salt or derivative thereof,

[0047]

[0048] in:

[0049] One of Y1, Y2 and Y3 is N, and the others are CR 3b ;

[0050] Q is C or S(O);

[0051] R 1b is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic, wherein at least one ring N heteroatom is not in R 1b At the connection point, and where R 1b Optional use of one or more R 4 replace;

[0052] A is for R 2 C or NR 2a R 2b , optionally A is R 2c ;

[0053] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0054] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0055] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally replaced by 1 or more R 5 replace;

[0056] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0057] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0058] Two R attached to the same or adjacent carbon atoms 3amay be linked together to form a 3- to 6-membered carbocyclic ring or a heterocyclic ring containing an O heteroatom, which may be optionally substituted with one or more halogens;

[0059] R 3b Each is independently H or (C1-6) alkyl;

[0060] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0061] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0062] n is 0, 1, 2, 3, or 4; and

[0063] a is 0 or 1.

[0064] In a fourth aspect of the present invention, there is provided a compound of formula IV or a pharmaceutically acceptable salt or derivative thereof,

[0065]

[0066] in:

[0067] One or two of Y1, Y2 and Y3 are N, and the others are CR 3b ;

[0068] Q is C or S(O);

[0069] R 1 is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic, and wherein R 1 Optional use of one or more R 4 replace;

[0070] Z is R 2e or NR 2d R 2b ;

[0071] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R5 Replacement; and

[0072] R 2d yes

[0073] a) a (C5-10)alkyl group containing a cyclic portion; and wherein R 2d Optional use of one or more R 5 replace; or

[0074] b) a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be straight chain or branched (optionally a (C3-10)alkyl group; and wherein R 2d Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0075] R 2e yes

[0076] a) (C3-10)alkyl containing a cyclic portion, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Optional use of one or more R 5 replace; or

[0077] b) CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a (C3-10)alkyl group which may be straight-chain or branched, wherein the C atoms in the straight-chain portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0078] R 3a are each independently (C1-6)alkyl, optionally substituted with one or more halogens; or

[0079] Two R attached to the same or adjacent carbon atoms 3aTogether with the atoms to which they are attached, they may form a 3- to 6-membered carbocyclic ring or a heterocyclic ring containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0080] R 3b Each is independently H or (C1-6) alkyl;

[0081] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0082] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0083] n is 0, 1, 2, 3, or 4; and

[0084] a is 0 or 1, and b is 1 or 2, wherein when b is 2, a is 0.

[0085] In a fifth aspect of the present invention, there is provided a compound of formula V or a pharmaceutically acceptable salt or derivative thereof,

[0086]

[0087] in:

[0088] One or two of Y1, Y2 and Y3 are N, and the rest are CR 3b ;

[0089] Q is C or S(O);

[0090] R 1 is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic, and wherein R 1 Optional use of one or more R 4 replace;

[0091] A is NR 2a R 2b or R 2c ;

[0092] R 2ais: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0093] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0094] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally replaced by 1 or more R 5 replace;

[0095] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0096] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0097] Two R attached to the same or adjacent carbon atoms 3a Together with the atoms to which they are attached, they may form a 3- to 6-membered carbocyclic ring or a heterocyclic ring containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0098] R 3b Each is independently H or (C1-6) alkyl;

[0099] R 4are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0100] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0101] m is 1, 2, 3, or 4; and

[0102] a is 0 or 1, and b is 1 or 2, wherein when b is 2, a is 0.

[0103] The examples show that the compounds described herein can activate the long form of the PDE4 enzyme.

[0104] In another aspect, the present invention provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or derivative described herein, and a pharmaceutically acceptable excipient.

[0105] On the other hand, the present invention provides a compound or pharmaceutical composition as described herein for therapeutic use. The therapy can be to treat or prevent any disease or condition described herein. The therapy can be to treat or prevent a disease or condition that can be improved by activating the long isoform of PDE4. The therapy can be to treat or prevent a disease or condition mediated by excessive intracellular cAMP signaling. In these diseases, reducing the second messenger reaction mediated by cyclic 3', 5'-monophosphate (cAMP) can provide therapeutic benefits.

[0106] Also provided are methods for treating or preventing diseases or conditions that can be improved by activating the long isoform of PDE4, the methods comprising administering to a patient in need thereof an effective amount of a compound or pharmaceutical composition as described herein. Also provided are methods for treating or preventing diseases or conditions mediated by excessive intracellular cAMP signaling, the methods comprising administering to a patient in need thereof an effective amount of a compound or pharmaceutical composition as described herein.

[0107] Also provided are uses of the compounds or pharmaceutical compositions described herein in the preparation of a medicament for treating or preventing a disease or condition that can be ameliorated by activating the long isoform of PDE4. Also provided are uses of the compounds or pharmaceutical compositions described herein in the preparation of a medicament for treating or preventing a disease or condition mediated by excessive intracellular cAMP signaling.

[0108] In some embodiments of the aforementioned aspects, the compounds of the present invention are provided for use in treating or preventing cancer. In some embodiments of the aforementioned aspects, the compounds of the present invention are provided for use in treating or preventing a disease or condition selected from the group consisting of hyperthyroidism, Janssen's metaphyseal chondrodysplasia, hyperparathyroidism, familial male precocious puberty, pituitary adenoma, Cushing's disease, polycystic kidney disease, polycystic liver disease, McCune-Albright syndrome, cholera, pertussis, anthrax, tuberculosis, HIV, AIDS, common variable immunodeficiency (CVID), melanoma, pancreatic cancer, leukemia, prostate cancer, adrenocortical tumors, testicular cancer, primary pigmented nodular adrenocortical disease (PPNAD), Carney complex, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), maturity-onset diabetes of the young type 5 (MODY5), or cardiac hypertrophy. DETAILED DESCRIPTION

[0109] The present invention is based on the surprising identification of novel compounds that can activate long isoforms of the PDE4 enzyme. These compounds are small molecules and are therefore expected to be easier and cheaper to manufacture and formulate into pharmaceuticals than large biomolecules such as polypeptides, proteins or antibodies. These compounds can be chemically synthesized, as demonstrated in the Examples.

[0110] The Examples demonstrate that various compounds of Formulas I to V and Ib to Vb are capable of activating the long isoform of PDE4. The Examples further demonstrate that certain test compounds of the present invention do not activate the short form of PDE4, thereby demonstrating selective activation of the long form of PDE4 relative to the short form of PDE4. The Examples further demonstrate that the long form of PDE4 activators of the present invention reduce cAMP-driven cyst formation in an in vitro model of ADPKD.

[0111] Various aspects and embodiments are disclosed herein. It should be appreciated that features specified within each embodiment can be combined with other specified features to provide further embodiments.

[0112] Compounds of Formula I to Formula V, as described above, or pharmaceutically acceptable salts or derivatives thereof are described herein. Formulas I to Formula V are described herein. Compounds of Formula I to Formula V, or pharmaceutically acceptable salts or derivatives thereof, can be provided for treating or preventing diseases or conditions that can be ameliorated by activating the long isoform of PDE4. Compounds of Formula I to Formula V, or pharmaceutically acceptable salts or derivatives thereof, can be provided for treating or preventing diseases or conditions mediated by excessive intracellular cAMP signaling.

[0113] Also described herein are compounds of Formula Ib to Formula Vb, or pharmaceutically acceptable salts or derivatives thereof, as described below. Compounds of Formula Ib to Formula Vb, or pharmaceutically acceptable salts or derivatives thereof, can be provided for treating or preventing diseases or conditions that can be ameliorated by activating the long isoform of PDE4. Compounds of Formula Ib to Formula Vb, or pharmaceutically acceptable salts or derivatives thereof, can be provided for treating or preventing diseases or conditions mediated by excessive intracellular cAMP signaling.

[0114] Described herein are compounds of Formula Ib, or pharmaceutically acceptable salts or derivatives thereof,

[0115]

[0116] in:

[0117] One or two of Y1, Y2 and Y3 are N, and the rest are CR 3b ;

[0118] Q is C or S(O);

[0119] R 1 is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and wherein R 1 Optional use of 1 or more R 4 replace;

[0120] A is NR 2a R 2b or R 2c ;

[0121] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R5 replace;

[0122] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0123] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally substituted with 1 or more R 5 replace;

[0124] R 2c is CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0125] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0126] Two R attached to the same or adjacent carbon atoms 3a can, together with the atoms to which they are attached, form a 3- to 6-membered ring, which optionally further contains an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0127] R 3b Each is independently H or (C1-6) alkyl;

[0128] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0129] R 5are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0130] n is 0, 1, 2, 3, or 4; and

[0131] a is 0 or 1.

[0132] Also described are compounds of formula IIb, or pharmaceutically acceptable salts or derivatives thereof,

[0133]

[0134] in:

[0135] One or two of Y1, Y2 and Y3 are N, and the others are CR 3b ;

[0136] Q is C or S(O);

[0137] R 1a is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, and wherein R 1a Optional use of one or more R 4 replace;

[0138] A is NR 2a R 2b or R 2c ;

[0139] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0140] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0141] R 2a and R 2bTogether with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally substituted with 1 or more R 5 replace;

[0142] R 2c is CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0143] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0144] Two R attached to the same or adjacent carbon atoms 3a may be joined together to form a 3- to 6-membered ring, optionally further containing an O heteroatom, which is optionally substituted with one or more halogens;

[0145] R 3b Each is independently H or (C1-6) alkyl;

[0146] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0147] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0148] n is 0, 1, 2, 3, or 4; and

[0149] a is 0 or 1.

[0150] Also described are compounds of formula IIIb, or pharmaceutically acceptable salts or derivatives thereof,

[0151]

[0152] in:

[0153] One or two of Y1, Y2 and Y3 are N, and the others are CR 3b ;

[0154] Q is C or S(O);

[0155] R 1b is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic, wherein at least one ring N heteroatom is not in R 1b At the connection point, and where R 1b Optional use of one or more R 4 replace;

[0156] A is NR 2a R 2b or R 2c ;

[0157] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0158] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0159] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally substituted with 1 or more R 5 replace;

[0160] R 2cis: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0161] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0162] Two R attached to the same or adjacent carbon atoms 3a may be joined together to form a 3 to 6 membered ring, which optionally further contains an O heteroatom, which is optionally substituted with one or more halogens;

[0163] R 3b Each is independently H or (C1-6) alkyl;

[0164] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0165] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0166] n is 0, 1, 2, 3, or 4; and

[0167] a is 0 or 1;

[0168] When one of X1 and X2 is N, the other is S, and X3 is C, R 1b It is not a monocyclic piperazine ring.

[0169] Also described are compounds of formula IVb or pharmaceutically acceptable salts or derivatives thereof,

[0170]

[0171] in:

[0172] One or two of Y1, Y2 and Y3 are N, and the others are CR 3b ;

[0173] Q is C or S(O);

[0174] R 1 is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and wherein R 1 Optional use of 1 or more R 4 replace;

[0175] Z is NR 2d R 2b or R 2e ;

[0176] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 Replacement; and

[0177] R 2d yes

[0178] a) a (C5-10)alkyl group containing a cyclic portion; and wherein R 2d Optional use of one or more R 5 replace; or

[0179] b) a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be straight chain or branched (optionally a (C3-10)alkyl group; and wherein R 2d Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0180] R 2e yes

[0181] a) (C3-10)alkyl containing a cyclic portion, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Optional use of one or more R 5 replace; or

[0182] b) CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a linear or branched (C3-10) alkyl group, wherein the C atoms in the linear portion of the (C3-10) alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0183] R 3a are each independently (C1-6)alkyl, optionally substituted with one or more halogens; or

[0184] Two R attached to the same or adjacent carbon atoms 3a can form, together with the atoms to which they are attached, a 3- to 6-membered ring, optionally further containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0185] R 3b Each is independently H or (C1-6) alkyl;

[0186] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0187] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0188] n is 0, 1, 2, 3, or 4; and

[0189] a is 0 or 1.

[0190] Also described are compounds of formula Vb, or pharmaceutically acceptable salts or derivatives thereof,

[0191]

[0192] in:

[0193] One or two of Y1, Y2 and Y3 are N, and the rest are CR 3b ;

[0194] Q is C or S(O);

[0195] R 1 is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and wherein R 1 Optional use of 1 or more R 4 replace;

[0196] A is NR 2a R 2b or R 2c ;

[0197] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0198] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0199] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, optionally containing 1 additional heteroatom selected from O, and optionally with 1 or more R 5 replace;

[0200] R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5replace;

[0201] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0202] Two R3 attached to the same or adjacent carbon atoms a can form, together with the atoms to which they are attached, a 3- to 6-membered ring, optionally further containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0203] R 3b Each is independently H or (C1-6) alkyl;

[0204] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0205] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0206] m is 1, 2, 3, or 4; and

[0207] a is 0 or 1.

[0208] In the compound of formula I, R 1 is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic, and wherein R 1 Optional use of one or more R 4 substituted. A monocyclic, bridged, or bicyclic ring may be saturated or partially saturated, or, in the case of a bicyclic ring, a combination thereof. It is understood that a ring N atom in a saturated or partially saturated ring, when unsubstituted, may be NH (where valence permits). It is also understood that, other than "at least one ring N heteroatom" (i.e., one or more ring N heteroatoms) and the optional "ring O heteroatom," no additional ring heteroatoms are present.

[0209] In the compound of formula Ib, R 1is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and wherein R 1 Optional use of 1 or more R 4 Substitution. A monocyclic, bridged, or bicyclic ring may be saturated, partially saturated, or aromatic, or, in the case of a bicyclic ring, a combination thereof. It is understood that a ring N atom in a saturated or partially saturated ring, when unsubstituted, may be NH (where valence permits). It is also understood that, other than "at least one ring N heteroatom" (i.e., one or more ring N heteroatoms) and the optional "ring O heteroatom," no additional ring heteroatoms are present.

[0210] In embodiment (1) of Formula I or Formula Ib, R 1 Contains at least one not in R 1 The ring N heteroatom at the point of attachment (i.e., the ring N atom must be present in a location other than R 1 The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (6) to (31) of Formula I or Formula Ib, as described herein.

[0211] In embodiment (2) of Formula I or Formula Ib, R 1 is a 4- to 10-membered ring containing 1 ring N heteroatom, 2 ring N heteroatoms, or 1 ring N heteroatom and 1 ring O heteroatom, which may be monocyclic, bridged, or bicyclic, and wherein R 1 Optional use of one or more R 4 Replace. R 1 Can contain at least one not in R 1 The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (6) to (31) of Formula I or Formula Ib, as described herein.

[0212] In embodiment (3) of formula I, R 1 is: a 5- to 6-membered saturated monocyclic ring containing at least 1 ring N heteroatom and optional ring O heteroatom (e.g., 1 ring N heteroatom, 2 ring N heteroatoms, or 1 ring N heteroatom and 1 ring O heteroatom), or a 7- to 8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms; a 9-membered saturated bridged ring system containing 2 ring N heteroatoms and a ring O heteroatom; or a 7- to 10-membered saturated fused or spiro ring system containing 1 or 2 ring N heteroatoms, optionally 2 ring N heteroatoms; and R 1 Optional use of one or more R 4 substituted, optionally wherein R 1 Choose to use 1, 2 or 3 R 4 Replace. R 1 Can contain at least one not in R1 The remainder may be as defined mutatis mutandis for Formula I, or any of Embodiments (6) to (31) of Formula I, as described herein.

[0213] In embodiment (3) of Formula Ib, R 1 is: a 5- to 6-membered saturated monocyclic ring containing at least 1 ring N heteroatom and optional ring O heteroatom (e.g., 1 ring N heteroatom, 2 ring N heteroatoms, or 1 ring N heteroatom and 1 ring O heteroatom); a 5- to 6-membered aromatic monocyclic ring containing 1 or 2 ring N heteroatoms; or a 7- to 8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms; a 9-membered saturated bridged ring system containing 2 ring N heteroatoms and a ring O heteroatom; or a 7- to 10-membered saturated fused or spirocyclic ring system containing 1 or 2 ring N heteroatoms, optionally 2 ring N heteroatoms; and R 1 Optional use of one or more R 4 substituted, optionally wherein R 1 Choose to use 1, 2 or 3 R 4 Replace. R 1 Can contain at least one not in R 1 The remainder may be as defined mutatis mutandis for Formula Ib, or any of Embodiments (6) to (31) of Formula Ib, as described herein.

[0214] In any of Formula I or embodiments (1), (2) or (3), R 1 It may be a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom (ie, no ring O heteroatom). 1 It can be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, and R 1 Optional use of one or more R 4 Replace. R 1 It can be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, wherein at least one ring N heteroatom is not in R 1 At the connection point, and R 1 Optional use of one or more R 4 Replace. R 1 It can be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, wherein at least one ring N heteroatom is not in R 1 At the connection point, and where R 1 Optional 1 R 4 Replace. R 1It can be a 6-membered saturated monocyclic ring containing 2 ring N heteroatoms; or a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 Replace. R 1 It can be a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 Replacement, R 1 It can be a 7- to 8-membered saturated bridged ring system containing two ring N heteroatoms, for example a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octanyl, where R 1 Optional 1 R 4 The remainder may be as defined mutatis mutandis for Formula I, or any one of Embodiments (6) to (31) of Formula I, as described herein.

[0215] In any of Formula Ib or embodiments (1), (2), or (3), R 1 It may be a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom (ie, no ring O heteroatom). 1 can be a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, and R 1 Optional use of one or more R 4 Replace. R 1 It can be a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, wherein at least one ring N heteroatom is not in R 1 At the connection point, and R 1 Optional use of one or more R 4 Replace. R 1 It can be a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, wherein at least one ring N heteroatom is not in R 1 At the connection point, and where R 1 Optional 1 R 4 Replace. R 1 It can be a 6-membered saturated or aromatic monocyclic ring containing 2 ring N heteroatoms; or a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 Replace. R 1 It can be a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 Replacement, R 1It can be a 7- to 8-membered saturated bridged ring system containing two ring N heteroatoms, for example a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octyl, where R 1 Optional 1 R 4 The remainder may be as defined mutatis mutandis for Formula Ib, or any of Embodiments (6) to (31) of Formula Ib, as described herein.

[0216] In any of Formula I or embodiments (1), (2) or (3), R 1 It can be piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, azetidinyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl or 3,8-diazabicyclo[3.2.1]octyl, 3,9-diazabicyclo[3.3.1]nonyl, 3,6-diazabicyclo[3.1.1]heptyl, 4,7-diazaspiro [2.5]octyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, octahydro-4H-pyrrolo[3,2-b]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl or hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, each of which is optionally substituted with one or more R 4 substituted, preferably optionally with 1 to 3 R 4 substituted, preferably optionally with 1 R 4 Replace. R 1 It can be a group with the following structure:

[0217]

[0218] And where R 1 Optional use of one or more R 4 substituted, optionally wherein R 1 Optional 1 to 3 R 4 Replace. R 1 It may be piperidinyl, piperazinyl, pyrrolidinyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl or 3,8-diazabicyclo[3.2.1]octyl, each of which is optionally substituted with one or more R 4 substituted, preferably optionally with 1 to 3 R 4 substituted, preferably optionally with 1 R 4 Replace. R 1 It may be piperidinyl or piperazinyl, each of which may be optionally substituted with one or more R 4 substituted, preferably optionally with 1 to 3 R 4 substituted, preferably optionally with 1 R 4 Replace. R 1 Can be a structure A group wherein W is CH or N, and R 4 ' is H or R 4 . R 1 It can be a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, for example a bridged piperazine, such as The remainder may be as defined mutatis mutandis for Formula I, or any of Embodiments (6) to (31) of Formula I, as described herein.

[0219] In any of Formula Ib or embodiments (1), (2), or (3), R 1 It can be piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyridinyl, azetidinyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl or 3,8-diazabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.1.1]heptyl, 4,7-diazaspiro[2.5 ] octyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, octahydro-4H-pyrrolo[3,2-b]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl or hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, each of which is optionally substituted with one or more R 4 substituted, preferably optionally with 1 to 3 R 4 substituted, preferably optionally with 1 R 4 Replace. R 1 It can be a group with the following structure:

[0220]

[0221] And where R 1 Optional use of one or more R 4 substituted, optionally wherein R 1 Optional 1 to 3 R 4 Replace. R 1 It may be piperidinyl, piperazinyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyridinyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl or 3,8-diazabicyclo[3.2.1]octyl, each of which is optionally substituted with one or more R 4 substituted, preferably optionally with 1 to 3 R 4 substituted, preferably optionally with 1 R 4 Replace. R 1 It may be piperidinyl, piperazinyl or pyridinyl, each of which may be optionally substituted with one or more R 4 substituted, preferably optionally with 1 to 3 R 4substituted, preferably optionally with 1 R 4 Replace. R 1 Can be: with structure A group wherein W is CH or N, and R 4′ Is H or R 4 ; or optionally use 1 R 4 Substituted pyridinyl (optionally 3-pyridinyl). 1 It can be a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, for example a bridged piperazine, such as The remainder may be as defined mutatis mutandis for Formula Ib, or any of Embodiments (6) to (31) of Formula Ib, as described herein.

[0222] In embodiment (4) of Formula I or Formula Ib, R 1 is a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and an optional ring O heteroatom; or a 7- to 8-membered saturated bridged ring containing one or two ring N heteroatoms, and wherein R 1 Choose to use 1, 2 or 3 R 4 In any of the options of implementation (4), R 1 Can contain at least one not in R 1 Ring N heteroatom at the point of attachment. 1 It can be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms. 1 It can be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (6) to (31) of Formula I or Formula Ib, as described herein.

[0223] In embodiment (5) of Formula I or Formula Ib, R 1 is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, and wherein R 1 Optional use of one or more R 4 Replace. R 1 may be a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, and wherein R 1a Choose to use 1, 2 or 3 R 4 Replace. R 1 may be an optionally substituted 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (6) to (31) of Formula I or Formula Ib, as described herein.

[0224] In any of Formula I or embodiments (1)-(5), R 1 You can use one or more R 4 Replace. When R 1 When containing a substitutable ring N atom, R 1 Substitution may occur on substitutable ring N atoms. 1 You can use 1 R 4 Substitution, preferably on a ring N atom. 1 In the embodiment where R is a saturated ring, 1 You can use 1 R 4 Substitution, preferably on a ring N atom. 1 In the embodiment where the ring is a 6-membered ring, R 1 You can use 1 R 4 Replace. In R 1 In the embodiment where the ring is a 5-membered ring, R 1 You can use 1, 2 or 3 R 4 replace.

[0225] In any of Formula Ib or embodiments (1)-(5), R 1 You can use one or more R 4 Replace. When R 1 When containing a substitutable ring N atom, R 1 Substitution can occur on a substitutable ring N atom. 1 In the embodiment where R is a saturated ring, 1 Can be 1 R 4 Substitution, preferably on a ring N atom. 1 In the embodiment where R is an aromatic ring, 1 You can use 1, 2 or 3 R 4 Replace. In R 1 In the embodiment where the ring is a 6-membered ring, R 1 Can be 1 R 4 Replace. In R 1 In the embodiment where the ring is a 5-membered ring, R 1 You can use 1, 2 or 3 R 4 replace.

[0226] In the compounds of Formula I and Formula Ib, R 4R is independently halogen, CN, OH, (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl or -(C1-6) alkylene-(C1-6) alkoxy, wherein the (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl and -(C1-6) alkylene-(C1-6) alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6) alkoxy. 4 Each independently may represent a substituent on a carbon atom or a substitutable N atom.

[0227] In embodiment (6) of Formula I or Formula Ib, R 4 R is independently halogen, OH, CN, (C1-4) alkyl, (C1-3) alkoxy, (C3-6) cycloalkyl or -(C1-3) alkylene-(C1-3) alkoxy, wherein the (C1-3) alkyl, (C1-3) alkoxy, (C3-6) cycloalkyl and -(C1-3) alkylene-(C1-3) alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-3) alkoxy. 4 and -(CH2)2-O-(CH2)2-O-CH3, wherein the (C1-4)alkyl radical is optionally substituted with one or more substituents independently selected from halogen and OH. The remainder may be as defined herein, mutatis mutandis, for Formula I or Formula Ib, or any of Embodiments (1)-(5) or (9)-(31) of Formula I or Formula Ib.

[0228] In embodiment (7) of Formula I or Formula Ib, R 4 R is each independently halogen, OH, (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl or -(C1-6) alkylene-(C1-6) alkoxy, wherein the (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl and -(C1-6) alkylene-(C1-6) alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6) alkoxy. 4 R may be independently halogen, OH, (C1-4) alkyl, (C1-3) alkoxy, (C3-6) cycloalkyl or -(C1-3) alkylene-(C1-3) alkoxy, wherein the (C1-3) alkyl, (C1-3) alkoxy, (C3-6) cycloalkyl and -(C1-3) alkylene-(C1-3) alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-3) alkoxy. 4and -(CH2)2-O-(CH2)2-O-CH3, wherein the (C1-4)alkyl radical is optionally substituted with one or more substituents independently selected from halogen and OH. The remainder may be as defined herein, mutatis mutandis, for Formula I or Formula Ib, or any of Embodiments (1)-(5) or (9)-(31) of Formula I or Formula Ib.

[0229] In embodiment (8) of Formula I or Formula Ib, R 4 R is each independently halogen, CN, OH, (C1-2) alkyl, (C1-6) alkoxy, or -(C1-6) alkylene-(C1-6) alkoxy, wherein the (C1-2) alkyl, (C1-6) alkoxy, and -(C1-6) alkylene-(C1-6) alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6) alkoxy. 4 and -(CH)-2-alkyl, wherein the (C)-alkyl radical is optionally substituted with one or more substituents independently selected from halogen and OH. The remainder may be as defined herein, mutatis mutandis, for Formula I or Formula Ib, or any of Embodiments (1)-(5) or (9)-(31) of Formula I or Formula Ib.

[0230] In any of Formula I or Formula Ib, or embodiments (6)-(8), when attached to a ring N atom, R 4 The R 4 OK any options.

[0231] In the compounds of formula I, A is NNR 2a R 2b 、R 2c OR 2f ,in

[0232] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0233] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0234] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, optionally containing 1 additional heteroatom selected from O, and optionally with 1 or more R 5 replace;

[0235] R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0236] R 2f is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2f Optional use of one or more R 5 replace.

[0237] In the compound of formula Ib, A is NR 2a R 2b or R 2c ,in

[0238] R 2ais: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0239] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0240] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, optionally containing 1 additional heteroatom selected from O, and optionally with 1 or more R 5 replace;

[0241] R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace.

[0242] In the compounds of Formula I and Formula Ib, R 5 Each is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups.

[0243] In embodiment (9) of Formula I or Formula Ib, R 5 Each is independently halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy, wherein the (C1-4) alkyl and (C1-4) alkoxy are optionally substituted with one or more halogen or OH, preferably optionally substituted with one or more fluorine or one OH. When substitution occurs on an aliphatic group, R5 may be independently halogen, OH, CN, (C1-6) alkyl, (C1-6) alkoxy or -(C1-6) alkylene-(C1-6) alkoxy, wherein the (C1-6) alkyl and (C1-6) alkoxy groups are optionally substituted with one or more halogens or OH; when substitution occurs on an aromatic group, R 5 R may be independently halogen, CN, (C1-6) alkyl, (C1-6) alkoxy or -(C1-6) alkylene-(C1-6) alkoxy, wherein the (C1-6) alkyl and (C1-6) alkoxy groups are optionally substituted with one or more halogens or OH. 5 R may be independently halogen, CN, (C1-4) alkyl or (C1-4) alkoxy, wherein the (C1-4) alkyl and (C1-4) alkoxy are optionally substituted with one or more halogen or OH, preferably optionally substituted with one or more fluorine or one OH. 5 R may be independently halogen, CN or (C1-4) alkyl, wherein the (C1-4) alkyl is optionally substituted with one or more halogens, preferably optionally substituted with one or more fluorines. 5 R may be independently halogen (preferably fluorine), CN or CF3. 5 and (iii) alkyl, (iv) alkyl, (v ...

[0244] In embodiment (10) of Formula I or Formula Ib, R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms, wherein R 2a Optional use of one or more R 5 Replace. R 2a You can use 0, 1 or 2 R 5 substituted, preferably with 0 or 1 R 5 Replace. R 2a It may be substituted with halogen, CN or (C1-4)alkyl, said (C1-4)alkyl being optionally substituted with one or more halogens, preferably optionally substituted with one or more fluorines. 2a It may be substituted with halogen (preferably fluorine), CN or CF3. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1) to (9), (13) or (21) to (31) of Formula I or Formula Ib as described herein.

[0245] In embodiment (11) of Formula I or Formula Ib, R 2a is CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein R 2a Optional use of one or more R5 It should be understood that R 5 The substitution can be in R 2a The -CH2- linker occurs on an aromatic ring or a heteroaromatic ring. 2a is CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein CH2 is optionally substituted with 1 or 2 halogens (preferably fluorine), and the aromatic or heteroaromatic ring is optionally substituted with 1, 2 or 3 (preferably 1 or 2, preferably 1) halogens, CN or (C1-4)alkyl, said (C1-4)alkyl being optionally substituted with 1 or more halogens (preferably optionally substituted with 1 or more fluorines). The aromatic or heteroaromatic ring may be optionally substituted with halogens (preferably fluorine), CN or CF3. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1) to (9), (13) or (21) to (31) of Formula I or Formula Ib as described herein.

[0246] In embodiment (12) of Formula I or Formula Ib, R 2a is a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein R 2a Optional use of one or more R 5 Replace. R 2a You can use 0, 1 or 2 R 5 substituted, preferably with 0 or 1 R 5 Replace. R 2a It may be a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein R 2a Optional R 5 Replace. R 2a It may be a (C4-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein R 2a Optional R 5 Replace. R 2a It may be a (C5-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein R 2a Optional R 5 Replace. R 2a It may be a (C5-10)alkyl group containing a cyclic portion, wherein R 2a Optional R 5 The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1)-(9), (13), or (21)-(31) of Formula I or Formula Ib as described herein.

[0247] In any of embodiments (10)-(12) of Formula I or Formula Ib, R 2a You can use one or more R 5 Replace. R 5 Substitution with halogen (eg fluorine) may be preferred.

[0248] In embodiment (13) of Formula I or Formula Ib, R 2b is H or (C1-3) alkyl, and wherein (C1-3) alkyl is optionally substituted with one or more R 5 Replace. R 2b and CH2CH3. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1) to (12) or (21) to (31) of Formula I or Formula Ib as described herein.

[0249] In embodiment (14) of Formula I or Formula Ib, R2 a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, optionally containing 1 additional heteroatom selected from O, and optionally with 1 or more R 5 Replace. R 2a and R 2b Together with the nitrogen atom to which they are attached, they can form a 5- to 7-membered non-aromatic heterocyclic ring, optionally with one or more R 5 Replace. R 2a and R 2b Together with the nitrogen atom to which they are attached, they can form a 5-membered non-aromatic heterocyclic ring, optionally with one or more R 5 Replace. R 2a and R 2b The rings formed together can be represented by 0 or 1 R 5 The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1)-(9) or (21)-(31) of Formula I or Formula Ib as described herein.

[0250] In embodiment (15) of Formula I or Formula Ib, A is R 2c . Preferably, Q is also C.

[0251] In embodiment (16) of Formula I or Formula Ib, R 2c is CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein R 2c Optional use of one or more R 5 It should be understood that R 5 The substitution can be in R 2c The -CH2- linker occurs on an aromatic ring or a heteroaromatic ring. 2aIt may be CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein CH2 is optionally substituted with 1 or 2 halogens (preferably fluorine, to form -CHF- or -CF2-), and the aromatic or heteroaromatic ring is optionally substituted with 1, 2 or 3 (preferably 1 or 2, preferably 1) halogens, CN or (C1-4) alkyl, said (C1-4) alkyl being optionally substituted with 1 or more halogens (preferably optionally substituted with 1 or more fluorines). The aromatic or heteroaromatic ring may be optionally substituted with halogens (preferably fluorine), CN or CF3. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1)-(9), (15) or (21)-(31) of Formula I or Formula Ib as described herein.

[0252] In embodiment (17) of Formula I or Formula Ib, R 2c is CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms], wherein R 2c Optional use of one or more R 5 It should be understood that R 5 The substitution can be in R 2c The -CH2- linker occurs on an aromatic ring or a heteroaromatic ring. 2c It may be CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein CH2 is optionally substituted with 1 or 2 halogens (preferably fluorine), and the aromatic or heteroaromatic ring is optionally substituted with 1, 2 or 3 (preferably 1 or 2, preferably 1) halogens, CN or (C1-4) alkyl, said (C1-4) alkyl being optionally substituted with 1 or more halogens (preferably optionally substituted with 1 or more fluorines). The aromatic or heteroaromatic ring may be optionally substituted with halogens (preferably fluorine), CN or CF3. The remainder may be as defined herein, mutatis mutandis, for Formula I or Formula Ib, or any of Embodiments (1) to (9), (15) or (21) to (31) of Formula I or Formula Ib.

[0253] In embodiment (18) of Formula I or Formula Ib, R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; wherein R 2c Optionally with one or more R 5 (For example, 1 or 2 R 5 , where R 5 is fluorine or OH, preferably fluorine). 2cIt may be a (C3-10)alkyl group containing a cyclic portion, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 (For example, 1 or 2 R 5 , where R 5 is fluorine or OH, preferably fluorine). 2c It may be a (C3-10)alkyl group containing a cyclic portion, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c Except for the connection point, and where R 2c Optional use of one or more R 5 (For example, 1 or 2 R 5 , where R 5 is fluorine or OH, preferably fluorine). 2c It may be a (C3-10)alkyl group containing a cyclic portion, wherein R 2c Optional use of one or more R 5 (For example, 1 or 2 R 5 , where R 5 is fluorine or OH, preferably fluorine). 2c Substitution may preferably be carried out on the cyclic moiety, for example with two R optionally on the same carbon atom. 5 The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any one of (1)-(9), (15) or (21)-(31) of Formula I or Formula Ib as described herein.

[0254] In embodiment (19) of Formula I or Formula Ib, R 2c is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms, wherein R 2c Optional use of one or more R 5 Replace. R 2c It can be a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms, wherein R 2c Optional 1 or 2 R 5 substituted, for example, halogen (preferably fluorine), (C1-4)alkoxy or (C1-4)alkyl, said (C1-4)alkyl being optionally substituted with one or more halogens (preferably optionally substituted with one or more fluorines). The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of (1) to (9), (15) or (21) to (31) of Formula I or Formula Ib as described herein.

[0255] In any of embodiments (16)-(19) of Formula I or Formula Ib, R 2c You can use one or more R 5 Replace. R 5 It may be a halogen, such as fluorine.

[0256] In embodiment (20) of Formula I, R 2f is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; and wherein R 2f Optional use of one or more R 5 It should be understood that R 5 The substitution can be in R 2f The -CH2- linker occurs on an aromatic ring or a heteroaromatic ring. 2f It can be: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or (C2-10)alkyl which can be linear, branched or cyclic or a combination thereof; and wherein R 2f Optional use of one or more R 5 The remainder may be as defined mutatis mutandis for Formula I, or any one of embodiments (1)-(9) or (21)-(31) of Formula I, as described herein.

[0257] In Formula I or Formula Ib, or any of Embodiments (10)-(20) of Formula I or Formula Ib, when substitution occurs on a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, R 5 It may independently be halogen, CN, (C1-6)alkyl, (C1-6)alkoxy or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogens or OH.

[0258] In the compounds of Formula I and Formula Ib, R3 a Each is independently (C1-6) alkyl or fluorine, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; or two R3 attached to the same or adjacent carbon atoms a can form, together with the atoms to which they are attached, a 3- to 6-membered carbocyclic ring or a heterocyclic ring containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens; and R 3b Each is independently H or (C1-6) alkyl.

[0259] In embodiment (21) of Formula I or Formula Ib, R 3aEach is independently (C1-3) alkyl or fluorine, wherein the (C1-3) alkyl is optionally substituted with one or more halogens and / or R 3b Each is independently H or (C1-3) alkyl. 3a Each of them can be -CH3 or F. 3b and -CH3 or H. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1) to (20) or (23) to (31) of Formula I or Formula Ib as described herein.

[0260] In embodiment (22) of Formula I or Formula Ib, two R 3a Together with the atoms to which they are attached, they may form a 3- to 6-membered ring, wherein the ring is optionally substituted with one or more halogens. Two R attached to the same or adjacent carbon atoms 3a Together with the atoms to which they are attached, they can form a 3- to 6-membered ring. 3a When they are attached to the same carbon atom, a spirocycle is formed. 3a When attached to adjacent carbon atoms, a fused ring is formed. 3a Together with the atoms to which they are attached, they may form a cyclopropyl ring. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1)-(20) or (23)-(31) of Formula I or Formula Ib as described herein.

[0261] In embodiment (23) of Formula I or Formula Ib, R 3b R may be independently H or (C1-3) alkyl. 3b Each of them can be -CH3 or H. Preferably, R 3b Each is H. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1)-(22) or (24)-(31) of Formula I or Formula Ib, as described herein.

[0262] In the compounds of Formula I and Formula Ib, n is 0, 1, 2, 3 or 4.

[0263] In embodiment (24) of Formula I or Formula Ib, n is 0. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of embodiments (1)-(23) or (26)-(31) of Formula I or Formula Ib, as described herein.

[0264] In embodiment (25) of Formula I or Formula Ib, n is 0, 1, 2 or 3. Preferably, n is 0, 1 or 2. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of embodiments (1) to (23) or (26) to (31) of Formula I or Formula Ib, as described herein.

[0265] In the compounds of Formula I and Formula Ib, Q is C or S(O).

[0266] In embodiment (26) of Formula I or Formula Ib, Q is C. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of embodiments (1)-(25) or (27)-(31) of Formula I or Formula Ib, as described herein.

[0267] In the compounds of Formula I and Formula Ib, one or two of Y1, Y2 and Y3 are N, and the others are CR 3b .

[0268] In embodiment (27) of Formula I or Formula Ib, one of Y1, Y2 and Y3 is N, and the others are each CR 3b The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1)-(26) or (29)-(31) of Formula I or Formula Ib as described herein.

[0269] In embodiment (28) of Formula I or Formula Ib, Y1 is N, Y2 and Y3 are CR 3b Therefore, the compound of Formula I or Formula Ib may be a compound having the following structure:

[0270]

[0271] where R 1 ,Q,A,R 3a , n, a, and b are as defined for Formula I or Formula Ib, or any of Embodiments (1)-(26) or (29)-(31) of Formula I or Formula Ib, as described herein.

[0272] In the compounds of formula I, a is 0 or 1, and b is 1 or 2, wherein when b is 2, a is 0. In the compounds of formula Ib, a is 0 or 1.

[0273] In embodiment (29) of Formula I or Formula Ib, a is 0. The compound of Formula I or Formula Ib can be:

[0274] or a pharmaceutically acceptable salt or derivative thereof. The compound may have the following formula:

[0275] or a pharmaceutically acceptable salt or derivative thereof. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any one of Embodiments (1) to (28) of Formula I or Formula Ib as described herein.

[0276] In embodiment (30) of Formula I or Formula Ib, a is 1, and the compound of Formula I or Formula Ib can be:

[0277] or a pharmaceutically acceptable salt or derivative thereof. The compound may have the following formula:

[0278] Optionally or a pharmaceutically acceptable salt or derivative thereof. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any one of Embodiments (1) to (28) of Formula I or Formula Ib as described herein.

[0279] In embodiment (31) of Formula I, a is 0, b is 2, and the compound is:

[0280] or a pharmaceutically acceptable salt or derivative thereof, optionally or a pharmaceutically acceptable salt or derivative thereof. The remainder may be as defined mutatis mutandis for Formula I, or any one of Embodiments (1) to (28) of Formula I, as described herein.

[0281] In embodiment (32) of Formula I or Formula Ib:

[0282] Q is C;

[0283] R 1 is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 replace;

[0284] A is for R 2c ;

[0285] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0286] R 3a , when present, is a methyl group;

[0287] R 4 , when present, is (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH;

[0288] R 5 , when present, is OH or a halogen; and

[0289] n is 0, 1 or 2; and optionally

[0290] b is 1. The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1) to (31) of Formula I or Formula Ib, as described herein.

[0291] In embodiment (33) of Formula I or Formula Ib, the compound is a compound having the following structure, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0292]

[0293] in:

[0294] R 1 is a 6-membered saturated monocyclic ring containing 2 ring N heteroatoms, or a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, optionally with one or more R 4 Replace; and / or

[0295] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 The remainder may be as defined, mutatis mutandis, for Formula I or Formula Ib, or any of the embodiments (1) to (31) of Formula I or Formula Ib as described herein. For example, n may be 0, R 2c It may be as defined in embodiment (18) of Formula I or Formula Ib.

[0296] Compounds of Formula I include compounds of Formulas II to V. Compounds of Formula Ib include compounds of Formulas IIb to Vb. Embodiments (1) to (24) of Formula I or Formula Ib apply mutatis mutandis to each of Formulas II to V or Formulas IIb to Vb.

[0297] Described herein are compounds of formula II, or pharmaceutically acceptable salts or derivatives thereof,

[0298]

[0299] in:

[0300] R 1a is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, and wherein R 1a Optional use of one or more R 4 replace;

[0301] And Y1, Y2, Y3, R 2a 、R 2b 、R 2c 、R 2f 、R 3a 、R 3b , A, Q, R 4 、R 5 , a, b and n are as defined above in Formula I or any one of Embodiments (6) to (31) of Formula I.

[0302] Also described herein are compounds of Formula IIb, or pharmaceutically acceptable salts or derivatives thereof,

[0303]

[0304] in:

[0305] R 1a is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, and wherein R 1a Optional use of one or more R 4 replace;

[0306] And Y1, Y2, Y3, R 2a 、R 2b 、R 2c 、R 3a 、R 3b , A, Q, R 4 、R 5 , a and n are as defined above in Formula Ib or any one of Embodiments (6) to (31) of Formula Ib.

[0307] In embodiment (1) of Formula II or Formula IIb, R 1a is a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional use of one or more R 4 substituted, for example, with 1, 2 or 3 R 4 Replace. R 1a It can be a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 Replace. R1a It may be a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octyl, where R 1a Optional 1 R 4 Replace. R 1a It may be a bridged piperazine, e.g.

[0308]

[0309] In any embodiment of Formula II or Formula IIb, or Formula II or Formula IIb, R 1a You can choose to use one or more R 4 Replace. When R 1a When containing a substitutable ring N atom, R 1a Substitution may preferably occur on a substitutable ring N atom. 1a You can use 1 R 4 The substitution preferably occurs on the ring N atom.

[0310] In embodiment (2) of Formula II or Formula IIb, the compound is a compound having the structure, or a pharmaceutically acceptable salt or derivative thereof,

[0311]

[0312] in:

[0313] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 The remainder may be as defined, mutatis mutandis, for Formula I, Formula Ib, Formula II, or Formula IIb, or any embodiment of Formula I, Formula Ib, Formula II, or Formula IIb as described herein. For example, n may be 0, R 2c It may be as defined in embodiment (18) of Formula I or Formula Ib.

[0314] Described herein are compounds of formula III, or pharmaceutically acceptable salts or derivatives thereof,

[0315]

[0316] in:

[0317] R 1bis a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic, wherein at least one ring N heteroatom is not in R 1a At the connection point, and where R 1a Optional use of one or more R 4 replace;

[0318] And Y1, Y2, Y3, R 2a 、R 2b 、R 2c 、R 2f 、R 3a 、R 3b , A, Q, R 4 、R 5 , a and n are as defined above in Formula I or any one of Embodiments (6) to (31) of Formula I.

[0319] Also described herein are compounds of Formula IIIb, or pharmaceutically acceptable salts or derivatives thereof,

[0320]

[0321] in:

[0322] R 1b is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic, wherein at least one ring N heteroatom is not in R 1a At the connection point, and where R 1a Optional use of one or more R 4 replace;

[0323] And Y1, Y2, Y3, R 2a 、R 2b 、R 2c 、R 3a 、R 3b , A, Q, R 4 、R 5 , a and n are as defined above in Formula Ib or any one of Embodiments (6) to (31) of Formula Ib.

[0324] In the compound of formula III or formula IIIb, R 1b Contains at least one not in R 1b The ring N heteroatom at the point of attachment, i.e., the ring N atom must be present in a region other than R 1b Position of the point of attachment to the ring containing Y1, Y2 and Y3.

[0325] In embodiment (1) of Formula III or Formula IIIb, R 1bis a 4- to 10-membered non-aromatic ring containing 1 ring N heteroatom, 2 ring N heteroatoms, or 1 ring N heteroatom and 1 ring O heteroatom, which may be monocyclic, bridged, or bicyclic, and wherein R 1 Optional use of one or more R 4 Replace. R 1b can be: a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and an optional ring O heteroatom (e.g., one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom); a 7- to 8-membered saturated bridged ring system containing one or two ring N heteroatoms; or a 9-membered saturated bridged ring system containing two ring N heteroatoms and a ring O heteroatom; or a 7- to 10-membered saturated fused or spirocyclic ring system containing one or two ring N heteroatoms; and wherein R 1b Optional use of one or more R 4 substituted, optionally 1, 2 or 3 R 4 .

[0326] In embodiment (2) of Formula III or Formula IIIb, R 1b is: a 5- to 6-membered saturated monocyclic ring containing at least 1 ring N heteroatom and optional ring O heteroatom (e.g., 1 ring N heteroatom, 2 ring N heteroatoms, or 1 ring N heteroatom and 1 ring O heteroatom); or a 7- to 8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms, and wherein R 1b Optional use of one or more R 4 substituted, optionally 1, 2 or 3 R 4 . R 1b It may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, optionally wherein at least one ring N heteroatom is not in R 1b At the connection point. 1b It can be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, wherein R 1b Optional 1 R 4 Replace. R 1b may be a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, and wherein R 1b Optional use of one or more R 4 substituted, optionally 1, 2 or 3 R 4 . R 1b It may be a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, such as a bridged piperazine, for example 3,8-diazabicyclo[3.2.1]octyl, where R 1b Optional 1 R 4 replace.

[0327] In any embodiment of Formula III or Formula IIIb, or Formula III or Formula IIIb, R 1bIt can be piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl or 3,9-diazabicyclo[3.3.1]nonyl, each of which is optionally substituted with one or more R 4 substituted, preferably optionally with 1 to 3 R 4 substituted, preferably optionally with 1 R 4 Replace. R 1b It can be a group with the following structure:

[0328]

[0329] And where R 1b Optional use of one or more R 4 substituted, optionally wherein R 1b Optional 1 to 3 R 4 substituted, preferably optionally with 1 R 4 Replace. R 1b It may be piperidinyl, piperazinyl, pyrrolidinyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl or 3,8-diazabicyclo[3.2.1]octyl, each of which is optionally substituted with one or more R 4 substituted, preferably optionally with 1 to 3 R 4 substituted, preferably optionally with 1 R 4 Replace. R 1b It may be piperidinyl or piperazinyl, each of which may be optionally substituted with one or more R 4 substituted, preferably optionally with 1 to 3 R 4 substituted, preferably optionally with 1 R 4 Replace. R 1b Can be a structure A group wherein W is CH or N, and R 4 ' is H or R 4 . R 1b It can be a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, for example a bridged piperazine, such as

[0330] In any embodiment of Formula III or Formula IIIb, or Formula III or Formula IIIb, R 1b You can choose to use one or more R 4 Replace. When R 1b When containing a substitutable ring N atom, R 1b Substitution may preferably occur on a substitutable ring N atom. 1b You can use 1 R 4Substitution is preferably on a ring N atom.

[0331] In any embodiment of Formula III or Formula IIIb, or Formula III or Formula IIIb, R 1b It may be a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom (ie, no ring O heteroatom), which may be monocyclic, bridged, or bicyclic. 1b It can be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, and R 1b Optional use of one or more R 4 replace.

[0332] In embodiment (3) of Formula III or Formula IIIb:

[0333] Q is C;

[0334] R 1a is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 replace;

[0335] A is for R 2c ;

[0336] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0337] R 3a , when present, is a methyl group;

[0338] R 4 , when present, is (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH;

[0339] R 5 , when present, is OH or a halogen; and

[0340] n is 0, 1 or 2; and optionally

[0341] b is 1.

[0342] In embodiment (4) of Formula III or Formula IIIb, the compound is a compound having the structure, or a pharmaceutically acceptable salt or derivative thereof,

[0343]

[0344] in:

[0345] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 The remainder may be as defined, mutatis mutandis, for Formula I, Formula Ib, Formula III, or Formula IIIb, or any embodiment of Formula I, Formula Ib, Formula III, or Formula IIIb as described herein. For example, R 1b It can be a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and an optional ring O heteroatom (e.g., one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom), wherein R 1b You can choose to use one or more R 4 Replace. R 1b It can be a 6-membered saturated monocyclic ring containing at least one ring N heteroatom (eg, one ring N heteroatom or two ring N heteroatoms), wherein R 1b You can choose to use one or more R 4 Replace. R 1b It can be a 6-membered saturated monocyclic ring containing at least one ring N heteroatom (eg, one ring N heteroatom or two ring N heteroatoms), wherein R 1b Optional 1 R 4 Replace. R 4 , when present, may be (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH. n may be 0. R 2c It may be defined as embodiment (18) of Formula I or Formula Ib.

[0346] In any embodiment of Formula III or Formula IIIb described herein, A is preferably R 2c or NR 2a R 2b , preferably R 2c .

[0347] Described herein are compounds of formula IV, or pharmaceutically acceptable salts or derivatives thereof,

[0348]

[0349] in:

[0350] Z is NR 2d R 2b or R 2e ;

[0351] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 Replacement; and

[0352] R 2d yes

[0353] a) a (C5-10)alkyl group containing a cyclic portion; and wherein R 2d Optional use of one or more R 5 replace; or

[0354] b) a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be straight chain or branched (optionally a (C3-10)alkyl group; and wherein R 2d Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0355] R 2e yes

[0356] a) (C3-10)alkyl containing a cyclic portion, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Optional use of one or more R 5 replace; or

[0357] b) CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a (C3-10)alkyl group which may be straight-chain or branched, wherein the C atoms in the straight-chain portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0358] R 3a are each independently (C1-6)alkyl, optionally substituted with one or more halogens; or

[0359] Two R attached to the same or adjacent carbon atoms 3a can form, together with the atoms to which they are attached, a 3- to 6-membered ring, optionally further containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0360] And Y1, Y2, Y3, R 1 、R 3a 、R 3b ,Q,R 4 、R 5 , a, b and n are as defined above in Formula I or any one of Embodiments (1)-(9) and (21)-(31) of Formula I.

[0361] Also described herein are compounds of Formula IVb, or pharmaceutically acceptable salts or derivatives thereof,

[0362]

[0363] in:

[0364] Z is NR 2d R 2b or R 2e ;

[0365] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 Replacement; and

[0366] R 2d yes

[0367] a) a (C5-10)alkyl group containing a cyclic portion; and wherein R 2d Optional use of one or more R 5 replace; or

[0368] b) a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be straight chain or branched (optionally a (C3-10)alkyl group; and wherein R 2d Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0369] R 2e yes

[0370] a) (C3-10)alkyl containing a cyclic portion, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Optional use of one or more R 5 replace; or

[0371] b) CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a linear or branched (C3-10) alkyl group, wherein the C atoms in the linear portion of the (C3-10) alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0372] R 3a are each independently (C1-6)alkyl, optionally substituted with one or more halogens; or

[0373] Two R attached to the same or adjacent carbon atoms 3a can form, together with the atoms to which they are attached, a 3- to 6-membered ring, optionally further containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0374] And Y1, Y2, Y3, R 1 、R 3a 、R 3b ,Q,R 4 、R 5 , a and n are as defined above in Formula Ib or any one of Embodiments (1)-(9) and (21)-(31) of Formula Ib.

[0375] In embodiment (1) of Formula IV or Formula IVb, R 2d is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms, wherein R 2d Use one or more R 5 Replace. R 2d You can use 1 or 2 R 5 Substituted, preferably with 1 R 5 Replace. R 2dIt may be substituted with halogen, CN or (C1-4)alkyl, said (C1-4)alkyl being optionally substituted with one or more halogens, preferably optionally substituted with one or more fluorines. 2d Substitution may be by halogen (preferably fluorine), CN or CF3.

[0376] In embodiment (2) of Formula IV or Formula IVb, R 2d is CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein R 2d Use one or more R 5 It should be understood that R 5 The substitution can be in R 2d The -CH2- linker occurs on an aromatic ring or a heteroaromatic ring. 2d is CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein CH2 is optionally substituted with 1 or 2 halogens (preferably fluorine), and the aromatic or heteroaromatic ring is optionally substituted with 1, 2 or 3 (preferably 1 or 2, preferably 1) halogens, CN or (C1-4) alkyl, said (C1-4) alkyl being optionally substituted with 1 or more halogens (preferably optionally substituted with 1 or more fluorines). The aromatic or heteroaromatic ring may be optionally substituted with halogens (preferably fluorine), CN or CF3.

[0377] In embodiment (3) of Formula IV or Formula IVb, R 2d is a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein R 2d Use one or more R 5 Replace. R 2d You can use 1 or 2 R 5 Substituted, preferably with 1 R 5 Replace. R 2d It may be a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein R 2d Using R 5 Replace. R 2d It may be a (C4-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein R 2d Using R 5 Replace. R 2d It may be a (C5-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein R 2d Using R 5 Replace. R 2d It may be a (C5-10)alkyl group containing a cyclic portion, wherein R 2d Using R 5The remainder may be as defined mutatis mutandis for Formula I or Formula Ib, or any of Embodiments (1) to (9), (13), or (19) to (26) of Formula I or Formula Ib as described herein.

[0378] In embodiment (4) of Formula IV or Formula IVb, R 2d is a (C5-10)alkyl group containing a cyclic portion; and wherein R 2d Optional use of one or more R 5 Replacement, R 2d It may be (C5-8)cycloalkyl or CH2-[(C5-6)cycloalkyl]. 2d You can use 1 or 2 R 5 Replacement, R 5 It may preferably be halogen (eg fluorine). 2d The cyclic part can be formed by two R 5 (e.g., fluorine) substitution.

[0379] In embodiment (5) of Formula IV or Formula IVb, R 2b is H or (C1-3) alkyl, and wherein (C1-3) alkyl is optionally substituted with one or more R 5 Replace. R 2b It can be H, CH3 or CH2CH3.

[0380] In embodiment (6) of Formula IV or Formula IVb, Z is R 2e . Preferably, Q is also C.

[0381] In embodiment (7) of Formula IV or Formula IVb, R 2e is CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein R 2e Use one or more R 5 It should be understood that R 5 The substitution can be in R 2e The -CH2- linker occurs on an aromatic ring or a heteroaromatic ring. 2e It may be CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein CH2 is optionally substituted with 1 or 2 halogens (preferably fluorine), and the aromatic or heteroaromatic ring is optionally substituted with 1, 2 or 3 (preferably 1 or 2, preferably 1) halogens, CN or (C1-4) alkyl, wherein the (C1-4) alkyl group is optionally substituted with 1 or more halogens (preferably 1 or more fluorines). The aromatic or heteroaromatic ring may be optionally substituted with halogens (preferably fluorine), CN or CF3.

[0382] In embodiment (8) of Formula IV or Formula IVb, R 2eis CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms], wherein R 2e Use one or more R 5 It should be understood that R 5 The substitution can be in R 2e The -CH2- linker occurs on an aromatic ring or a heteroaromatic ring. 2e It may be CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], wherein CH2 is optionally substituted with 1 or 2 halogens (preferably fluorine), and the aromatic or heteroaromatic ring is optionally substituted with 1, 2 or 3 (preferably 1 or 2, preferably 1) halogens, CN or (C1-4) alkyl, wherein the (C1-4) alkyl group is optionally substituted with 1 or more halogens (preferably 1 or more fluorines). The aromatic or heteroaromatic ring may be optionally substituted with halogens (preferably fluorine), CN or CF3.

[0383] In embodiment (9) of Formula IV or Formula IVb, R 2e is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; wherein R 2e Use one or more R 5 (For example, 1 or 2 R 5 , where R 5 is fluorine or OH, preferably fluorine). 2e It may be a (C3-10)alkyl group containing a cyclic portion, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Use one or more R 5 (For example, 1 or 2 R 5 , where R 5 is fluorine or OH, preferably fluorine). 2e It may be a (C3-10)alkyl group containing a cyclic portion, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e Except for the connection point, and where R 2e Use one or more R 5 (For example, 1 or 2 R 5 , where R 5 is fluorine or OH, preferably fluorine).

[0384] In embodiment (10) of Formula IV or Formula IVb, R 2e is a (C5-10)alkyl group containing a cyclic portion; and wherein R 2e Optional use of one or more R 5 Replace. R 2e It may be (C5-6)cycloalkyl or (C1-2)alkylene-[(C4-6)cycloalkyl]. 2e You can use 1 or 2 R 5 Replacement, R 5 Preferably it is halogen (eg fluorine). 2e The cyclic part can be formed by two R 5 (e.g., fluorine) substitution.

[0385] In embodiment (11) of Formula IV or Formula IVb, R 2e is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms, wherein R 2e Optional use of one or more R 5 Replace. R 2e It can be a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms, wherein R 2e Optional 1 or 2 R 5 Substitution, such as halogen (preferably fluorine), (C1-4)alkoxy or (C1-4)alkyl, said (C1-4)alkyl optionally substituted with one or more halogens (preferably optionally substituted with one or more fluorines).

[0386] In embodiment (12) of Formula IV or Formula IVb, the compound is a compound having the structure, or a pharmaceutically acceptable salt or derivative thereof,

[0387]

[0388] in:

[0389] R 2e is a (C5-10)alkyl group containing a cyclic portion; and wherein R 2e Optional use of one or more R 5 The remainder may be as defined, mutatis mutandis, for Formula I, Formula Ib, Formula IV, or Formula IVb, or any embodiment of Formula I, Formula Ib, Formula IV, or Formula IVb as described herein. For example, R 1 It can be a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and an optional ring O heteroatom (e.g., one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom), wherein R 1 You can choose to use one or more R 4 Replace. R1 It can be a 6-membered saturated monocyclic ring containing at least one ring N heteroatom (eg, one ring N heteroatom or two ring N heteroatoms), wherein R 1 You can choose to use one or more R 4 Replace. R 1 It can be a 6-membered saturated monocyclic ring containing at least one ring N heteroatom (eg, one ring N heteroatom or two ring N heteroatoms), wherein R 1 Optional 1 R 4 Replace. R 4 , when present, may be (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH. n may be 0. R 2e It may be defined as embodiment (10) of Formula IV or Formula IVb.

[0390] Described herein are compounds of formula V, or pharmaceutically acceptable salts or derivatives thereof,

[0391]

[0392] in:

[0393] m is 1, 2, 3, or 4;

[0394] And Y1, Y2, Y3, R 1 、R 2a 、R 2b 、R 2b 、R 2c 、R 2f 、R 3a 、R 3b , A, Q, R 4 、R 5 , a and b are as defined above in Formula I or any one of Embodiments (1)-(23) and (26)-(31) of Formula I.

[0395] Also described herein are compounds of Formula Vb, or pharmaceutically acceptable salts or derivatives thereof,

[0396]

[0397] in:

[0398] m is 1, 2, 3, or 4;

[0399] And Y1, Y2, Y3, R 1 、R 2a 、R 2b 、R 2c 、R 3a 、R 3b , A, Q, R 4 、R 5and a is as defined above in Formula Ib or any one of Embodiments (1)-(23) and (26)-(31) of Formula Ib.

[0400] In embodiment (1) of Formula V or Formula Vb, m is 1 or 2.

[0401] In further embodiments of the compounds of Formula I to Formula V or Formula Ib to Formula Vb, or pharmaceutically acceptable salts thereof, including any of the above embodiments, one or more hydrogen atoms are replaced by 2 The remainder may be as defined mutatis mutandis for any aspect or embodiment of Formulas I to V or Ib to Vb described herein.

[0402] Compounds of Formula I to Formula V, including any embodiments thereof, may be preferred.

[0403] In one embodiment, the compound of Formula I or Formula Ib is selected from the following:

[0404] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one;

[0405] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one;

[0406] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-phenoxyethan-1-one;

[0407] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3,3-dimethylbutan-1-one;

[0408] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3-methylbutan-1-one;

[0409] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2,3-dimethylbutan-1-one;

[0410] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-phenylethan-1-one;

[0411] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4-fluorophenoxy)ethan-1-one;

[0412] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(cyclopentyl)methanone;

[0413] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4-fluorophenyl)ethan-1-one;

[0414] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2,2-difluoro-2-phenylethan-1-one;

[0415] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0416] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(pyrrolidin-1-yl)methanone;

[0417] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0418] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-ethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0419] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one;

[0420] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-cyclopentylethan-1-one;

[0421] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide;

[0422] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide;

[0423] N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide;

[0424] N-cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide;

[0425] 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-one;

[0426] 2-Cyclopentyl-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-one;

[0427] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(pyrrolidin-1-yl)methanone;

[0428] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N,N-diethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide;

[0429] N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0430] 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0431] 2-(4,4-difluorocyclohexyl)-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0432] (R)-2-cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0433] (S)-2-cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0434] 2-cyclopentyl-1-(2-(piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0435] 2-Cyclopentyl-1-(2-(1-(2-hydroxyethyl)piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0436] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(1-methylcyclopentyl)ethan-1-one;

[0437] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(phenyl)methanone;

[0438] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(2-methoxyphenyl)methanone;

[0439] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(o-tolyl)methanone;

[0440] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(4-fluorophenyl)methanone;

[0441] (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentyl-2-hydroxyethan-1-one;

[0442] 2-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid cyclopentyl ester;

[0443] Isopropyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0444] Benzyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0445] (2S)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,3-dimethylbutan-1-one;

[0446] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(1-methylcyclopentyl)ethan-1-one;

[0447] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,2-difluoro-2-phenylethan-1-one;

[0448] (R)-2-cyclopentyl-1-(2-(3-(hydroxymethyl)piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0449] (S)-2-cyclopentyl-1-(2-(3-(hydroxymethyl)piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0450] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-phenylethan-1-one;

[0451] 2-phenyl-1-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one;

[0452] 1-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-phenylethan-1-one;

[0453] 4-(2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-oxoethyl)benzonitrile;

[0454] 4-(2-Oxo-2-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethyl)benzonitrile;

[0455] 4-(2-(2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-oxoethyl)benzonitrile;

[0456] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(4-fluorophenyl)ethan-1-one;

[0457] 2-(4-Fluorophenyl)-1-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one;

[0458] 1-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(4-fluorophenyl)ethan-1-one;

[0459] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-cyclopentylethan-1-one;

[0460] 2-cyclopentyl-1-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one;

[0461] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-cyclohexylethan-1-one;

[0462] 2-cyclohexyl-1-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one;

[0463] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3,3-dimethylbutan-1-one;

[0464] (4-Fluorophenyl)(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone;

[0465] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-cyclopentylethan-1-one;

[0466] 3,3-Dimethyl-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)butan-1-one;

[0467] 1-(2-(4-ethylpiperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3,3-dimethylbutan-1-one;

[0468] 1-(2-(3,9-diazabicyclo[3.3.1]non-9-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one;

[0469] 1-(2-(3,9-diazabicyclo[3.3.1]non-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one;

[0470] 1-(2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one;

[0471] 1-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one;

[0472] 1-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one;

[0473] 1-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one;

[0474] 2-Cyclopentyl-1-(2-(7-hydroxy-3,9-diazabicyclo[3.3.1]non-9-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0475] 2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-6-((4-fluorobenzyl)sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine;

[0476] 2-(3-ethyl-3,8-diazabicyclo[3.2.1]oct-8-yl)-6-((4-fluorobenzyl)sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine;

[0477] 6-((4-fluorobenzyl)sulfonyl)-2-(piperazin-1-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine;

[0478] 2-(4-ethylpiperazin-1-yl)-6-((4-fluorobenzyl)sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine;

[0479] 6-(Benzylsulfonyl)-2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine;

[0480] 6-(Benzylsulfonyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine;

[0481] 6-(Benzylsulfonyl)-2-(piperazin-1-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine;

[0482] 6-(Benzylsulfonyl)-2-(4-ethylpiperazin-1-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine;

[0483] 2-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-N-((S)-chroman-4-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0484] N-((S)-chroman-4-yl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0485] (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0486] (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0487] N-((R)-chroman-4-yl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0488] 1-(2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4-fluorophenoxy)ethan-1-one;

[0489] 2-(4-Fluorophenoxy)-1-(2-(3-propyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0490] 2-(4-Fluorophenoxy)-1-(2-(3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0491] 2-(4-Fluorophenoxy)-1-(2-(3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0492] 2-phenyl-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0493] 2-(4-Fluorophenyl)-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0494] 1-(3-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-2-cyclopentylethan-1-one;

[0495] 1-(6-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-cyclopentylethan-1-one;

[0496] 1-(7-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-2-cyclopentylethan-1-one;

[0497] 2-(4-Fluorophenoxy)-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0498] 2-cyclopentyl-1-(2-(2-methylpyridin-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0499] 2-cyclopentyl-1-(2-(5-methylpyridin-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one;

[0500] and pharmaceutically acceptable salts thereof.

[0501] In another embodiment of the compounds of Formula I or Formula Ib, R 1 and A may be as defined above for any one of the compounds of Formula I or Formula Ib. In another embodiment of the compounds of Formula I or Formula Ib, A may be as defined above for any one of the compounds of Formula I or Formula Ib.

[0502] Further aspects and embodiments are described in the following numbered clauses.

[0503] Item 1. A compound of formula I or a pharmaceutically acceptable salt or derivative thereof,

[0504]

[0505] in:

[0506] One or two of Y1, Y2 and Y3 are N, and the rest are CR 3b ;

[0507] Q is C or S(O);

[0508] R 1 is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and wherein R 1 Optional use of 1 or more R 4 replace;

[0509] A is NR 2a R 2b or R 2c ;

[0510] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0511] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5replace; or

[0512] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, optionally containing 1 additional heteroatom selected from O, and optionally with 1 or more R 5 replace;

[0513] R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0514] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0515] Two R attached to the same or adjacent carbon atoms 3a can form, together with the atoms to which they are attached, a 3- to 6-membered ring, optionally further containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0516] R 3b Each is independently H or (C1-6) alkyl;

[0517] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0518] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0519] n is 0, 1, 2, 3, or 4; and

[0520] a is 0 or 1;

[0521] The compound is used for treating or preventing diseases or conditions that can be improved by activating the long isoform of PDE4.

[0522] Item 2. The compound for use according to Item 1, wherein the compound is a compound having the formula:

[0523]

[0524] or a pharmaceutically acceptable salt or derivative thereof.

[0525] Item 3. A compound for use according to Item 1 or 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is: a 5- to 6-membered saturated monocyclic ring containing at least 1 ring N heteroatom and an optional ring O heteroatom; a 6-membered aromatic monocyclic ring containing 1 or 2 ring N heteroatoms; a 7- to 9-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms; a 9-membered saturated bridged ring system containing 2 ring N heteroatoms and a ring O heteroatom; or a 7- to 10-membered saturated fused or spiro ring system containing 1 or 2 ring N heteroatoms; and wherein R 1 Choose to use 1, 2 or 3 R 4 replace.

[0526] Clause 4. A compound for use according to any one of the preceding clauses, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic; wherein R 1 Optional 1 R 4 replace.

[0527] Clause 5. A compound for use according to any one of clauses 1 to 3, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, optionally a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms (e.g., a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octyl), wherein R 1 Optional 1 R 4 replace.

[0528] Clause 6. A compound for use according to any one of the preceding clauses, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0529] a)R 2ais: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms]; or (C2-10)alkyl (optionally (C3-10)alkyl) which may be linear, branched or cyclic or a combination thereof; and wherein R 2a Optional use of one or more R 5 Replacement; and

[0530] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0531] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, optionally containing 1 additional heteroatom selected from O, and optionally with 1 or more R 5 replace; or

[0532] b)R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace.

[0533] Clause 7. A compound for use according to any one of the preceding clauses, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0534] a)R 2a is a (C5-10)alkyl group containing a cyclic portion; and wherein R 2a Optional use of one or more R 5 Replacement; and R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0535] b)R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms]; or a (C2-10)alkyl group (optionally a (C3-10)alkyl group) which may be straight chain or branched; and wherein R 2aOptional use of one or more R 5 substituted (optionally, wherein R 5 is halogen); and R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace.

[0536] Clause 8. A compound for use according to any one of the preceding clauses, or a pharmaceutically acceptable salt or derivative thereof, wherein R 2c yes:

[0537] a) (C3-10)alkyl containing a cyclic portion, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c , wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms;

[0538] where R 2c Optional use of one or more R 5 replace;

[0539] b) CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a linear or branched (C3-10) alkyl group, wherein the C atoms in the linear portion of the (C3-10) alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Use one or more R 5 substituted (optionally, wherein R 5 is halogen).

[0540] Clause 9. A compound for use according to any one of clauses 1 to 7, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound has the formula:

[0541]

[0542] or a pharmaceutically acceptable salt or derivative thereof.

[0543] Clause 10. A compound for use according to any one of the preceding clauses, or a pharmaceutically acceptable salt or derivative thereof, wherein R 3a Each is -CH3 or F, or two R attached to the same carbon 3a Together with the atoms to which they are attached they form a cyclopropyl ring.

[0544] Clause 11. A compound for use according to any one of the preceding clauses, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0, 1 or 2.

[0545] Clause 13. A compound for use according to any one of the preceding clauses, or a pharmaceutically acceptable salt or derivative thereof, wherein Q is C and / or A is R 2c .

[0546] Clause 14. A compound for use according to any one of the preceding clauses, or a pharmaceutically acceptable salt or derivative thereof, wherein

[0547] Q is C;

[0548] R 1 is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 replace;

[0549] A is for R 2c ;

[0550] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0551] R 3a , when present, is a methyl group;

[0552] R 4 , when present, is (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH;

[0553] R 5 , when present, is OH or a halogen; and

[0554] n is 0, 1, or 2.

[0555] Clause 15. A compound of formula IIb or a pharmaceutically acceptable salt or derivative thereof,

[0556]

[0557] in:

[0558] One or two of Y1, Y2 and Y3 are N, and the others are CR 3b ;

[0559] Q is C or S(O);

[0560] R 1a is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, and wherein R 1a Optional use of one or more R 4 replace;

[0561] A is NR 2a R 2b or R 2c ;

[0562] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0563] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0564] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, optionally containing 1 additional heteroatom selected from O, and optionally with 1 or more R 5 replace;

[0565] R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0566] R 3aare each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0567] Two R attached to the same or adjacent carbon atoms 3a may be joined together to form a 3 to 6 membered ring, which optionally further contains an O heteroatom, which is optionally substituted with one or more halogens;

[0568] R 3b Each is independently H or (C1-6) alkyl;

[0569] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0570] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0571] n is 0, 1, 2, 3, or 4; and

[0572] a is 0 or 1.

[0573] Clause 16. The compound according to Clause 15, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1a is a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms (e.g., a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octyl), wherein R 1 Optional 1 R 4 replace.

[0574] Clause 17. The compound according to any one of Clauses 15 or 16, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound has the following formula:

[0575]

[0576] or a pharmaceutically acceptable salt or derivative thereof.

[0577] Item 19. A compound of formula IIIb or a pharmaceutically acceptable salt or derivative thereof,

[0578]

[0579] in:

[0580] One or two of Y1, Y2 and Y3 are N, and the others are CR 3b ;

[0581] Q is C or S(O);

[0582] R 1b is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic, wherein at least one ring N heteroatom is not in R 1b At the connection point, and where R 1b Optional use of one or more R 4 replace;

[0583] A is NR 2a R 2b or R 2c ;

[0584] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0585] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0586] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, optionally containing 1 additional heteroatom selected from O, and optionally with 1 or more R 5 replace;

[0587] R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2cwherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0588] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0589] Two R attached to the same or adjacent carbon atoms 3a may be joined together to form a 3 to 6 membered ring, which optionally further contains an O heteroatom, which is optionally substituted with one or more halogens;

[0590] R 3b Each is independently H or (C1-6) alkyl;

[0591] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0592] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0593] n is 0, 1, 2, 3, or 4; and

[0594] a is 0 or 1.

[0595] Clause 20. The compound according to Clause 19, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1b is: a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and an optional ring O heteroatom; or a 7- to 9-membered saturated bridged ring system containing one or two ring N heteroatoms; a 9-membered saturated bridged ring system containing two ring N heteroatoms and a ring O heteroatom; or a 7- to 10-membered saturated fused or spirocyclic ring system containing one or two ring N heteroatoms; and wherein R 1b Choose to use 1, 2 or 3 R 4 replace.

[0596] Clause 21. The compound according to Clause 19 or 20, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1b is a 6-membered saturated monocyclic ring containing 2 ring N heteroatoms or a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms; wherein R 1a Optional 1 R 4 substituted, optionally wherein R 1a is a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms (e.g., a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octyl), wherein R 1b Optional 1 R 4 replace.

[0597] Clause 22. A compound according to any one of Clauses 15 to 21, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0598] a)R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring nitrogen atoms]; or (C2-10)alkyl (optionally (C3-10)alkyl) which may be linear, branched or cyclic or a combination thereof; and wherein R 2a Optional use of one or more R 5 Replacement; and

[0599] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0600] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, optionally containing 1 additional heteroatom selected from O, and optionally with 1 or more R 5 Replace; and / or

[0601] b)R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace.

[0602] Clause 23. A compound according to any one of Clauses 15 to 22, or a pharmaceutically acceptable salt or derivative thereof, wherein R 2c yes:

[0603] a) (C3-10)alkyl containing a cyclic portion, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and

[0604] where R 2c Optional use of one or more R 5 replace;

[0605] b) CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or (C3-10)alkyl which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear portion of the (C3-10)alkyl may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Use one or more R 5 substituted (optionally, wherein R 5 is halogen).

[0606] Clause 24. The compound according to any one of Clauses 15 to 23, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound has the following formula:

[0607]

[0608] or a pharmaceutically acceptable salt or derivative thereof.

[0609] Clause 25. A compound according to any one of Clauses 15 to 24, or a pharmaceutically acceptable salt or derivative thereof, wherein Q is C and / or A is R 2c .

[0610] Clause 26. A compound according to any one of Clauses 15 to 24, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0611] Q is C;

[0612] R 1a or R 1b is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1a and R 1b Optional 1 R4 replace;

[0613] A is for R 2c ;

[0614] R 2c is a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0615] R 3a , when present, is a methyl group;

[0616] R 4 , when present, is (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH;

[0617] R 5 , when present, is OH or a halogen; and

[0618] n is 0, 1, or 2.

[0619] Clause 27. A compound of formula IVb or a pharmaceutically acceptable salt or derivative thereof,

[0620]

[0621] in:

[0622] One or two of Y1, Y2 and Y3 are N, and the others are CR 3b ;

[0623] Q is C or S(O);

[0624] R 1 is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and wherein R 1 Optional use of 1 or more R 4 replace;

[0625] Z is NR 2d R 2b or R 2e ;

[0626] R 2b is H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 Replacement; and

[0627] R 2d yes

[0628] a) a (C5-10)alkyl group containing a cyclic portion; and wherein R 2d Optional use of one or more R 5 replace; or

[0629] b) a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be straight chain or branched (optionally a (C3-10)alkyl group; and wherein R 2d Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0630] R 2e yes

[0631] a) (C3-10)alkyl containing a cyclic portion, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Optional use of one or more R 5 replace; or

[0632] b) CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a linear or branched (C3-10) alkyl group, wherein the C atoms in the linear portion of the (C3-10) alkyl group may be optionally substituted with one -O-, but R 2e wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2e Use one or more R 5 substituted (optionally, wherein R 5 is a halogen);

[0633] R 3a are each independently (C1-6)alkyl, optionally substituted with one or more halogens; or

[0634] Two R attached to the same or adjacent carbon atoms 3a can form, together with the atoms to which they are attached, a 3- to 6-membered ring, optionally further containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0635] R 3b Each is independently H or (C1-6) alkyl;

[0636] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0637] R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0638] n is 0, 1, 2, 3, or 4; and

[0639] a is 0 or 1.

[0640] Clause 28. The compound according to Clause 27, or a pharmaceutically acceptable salt or derivative thereof, wherein z is R 2e .

[0641] Clause 29. The compound according to Clause 27 or 28, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is: a 5- to 6-membered saturated monocyclic ring containing at least 1 ring N heteroatom and an optional ring O heteroatom; a 6-membered aromatic monocyclic ring containing 1 or 2 ring N heteroatoms; a 7- to 9-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms; a 9-membered saturated bridged ring system containing 2 ring N heteroatoms and a ring O heteroatom; or a 7- to 10-membered saturated fused or spiro ring system containing 1 or 2 ring N heteroatoms; and wherein R 1 Choose to use 1, 2 or 3 R 4 replace.

[0642] Clause 30. A compound according to any one of Clauses 27 to 29, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which may be monocyclic, bridged, or bicyclic; wherein R 1 Optional 1 R 4 replace.

[0643] Clause 31. A compound according to any one of Clauses 27 to 30, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms (e.g., a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octyl), wherein R 1 Optional 1 R 4 replace.

[0644] Clause 32. A compound according to any one of Clauses 15 to 31, or a pharmaceutically acceptable salt or derivative thereof, wherein R 3a Each is -CH3, or two R attached to the same carbon 3a Together with the atoms to which they are attached they form a cyclopropyl ring.

[0645] Clause 33. A compound according to any one of Clauses 15 to 32, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0, 1 or 2.

[0646] Clause 34. A compound of formula Vb or a pharmaceutically acceptable salt or derivative thereof,

[0647]

[0648] in:

[0649] One or two of Y1, Y2 and Y3 are N, and the rest are CR 3b ;

[0650] Q is C or S(O);

[0651] R 1 is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and wherein R 1 Optional use of 1 or more R 4 replace;

[0652] A is NR 2a R 2b or R 2c ;

[0653] R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which may be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of one or more R 5 replace;

[0654] R 2bis H or (C1-6) alkyl, and wherein (C1-6) alkyl is optionally substituted with one or more R 5 replace; or

[0655] R 2a and R 2b Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally substituted with 1 or more R 5 replace;

[0656] R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which may be linear, branched or cyclic or a combination thereof, wherein the C atoms in the linear or cyclic portion of the (C3-10)alkyl group may be optionally substituted with one -O-, but R 2c wherein the (C3-10)alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of one or more R 5 replace;

[0657] R 3a are each independently (C1-6)alkyl or fluoro, said (C1-6)alkyl being optionally substituted with one or more halogens; or

[0658] Two R attached to the same or adjacent carbon atoms 3a can, together with the atoms to which they are attached, form a 3- to 6-membered ring, which optionally further contains an O heteroatom, wherein the ring is optionally substituted with one or more halogens;

[0659] R 3b Each is independently H or (C1-6) alkyl;

[0660] R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, and -(C1-6)alkylene-(C1-6)alkoxy groups are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-6)alkoxy groups;

[0661] R 5are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH groups;

[0662] m is 1, 2, 3, or 4; and

[0663] a is 0 or 1.

[0664] definition

[0665] The term "aromatic ring" refers to an aromatic carbocyclic ring system. The term "heteroaromatic ring" refers to an aromatic ring system in which one or more ring atoms are heteroatoms (e.g., O, S, or N). The aromatic ring can be a 6-membered aromatic ring, i.e., a benzene ring. The heteroaromatic ring can be a 6-membered heteroaromatic ring containing 1 to 3 N atoms or a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, and N. Examples of such 6-membered or 5-membered heteroaromatic rings include pyridine, pyridazine, pyrazine, pyrimidine, thiophene, furan, thiazole, thiadiazole, oxazole, oxadiazole, imidazole, triazole, and isomers thereof, including isothiazole, isothiadiazole, isoxazole, and isoxadiazole. In all of the above cases, the aromatic ring can be optionally substituted as defined herein.

[0666] The term "carbocycle" refers to a ring system that can be saturated, partially unsaturated, or aromatic, and in which all of the ring atoms are carbon. The term "heterocycle" refers to a ring system that can be saturated, partially unsaturated, or aromatic, and in which one or more of the ring atoms is a heteroatom, such as O, S, or N. A "non-aromatic carbocycle or heterocycle" can be saturated or partially unsaturated. Carbocycles and heterocycles can be bicyclic or polycyclic ring systems, such as bicyclic or polycyclic fused ring systems or bicyclic or polycyclic spiro ring systems, or combinations thereof. Each ring within a fused ring system can independently be saturated, partially unsaturated, or aromatic. Examples of such fused bicyclic ring systems include indan and chroman. Non-aromatic carbocycles or heterocycles can include: fused ring systems, in which, for example, two rings share two adjacent atoms; bridged ring systems, in which, for example, two rings share three or more adjacent atoms; or spiro ring systems, in which, for example, two rings share one adjacent atom. Examples of fused ring systems include octahydropyrrolo[1,2-a]pyrazine and octahydro-2H-pyrido[1,2-a]pyrazine. Bridged rings may include three or more rings. Examples of such bridged ring systems include 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, and 3,8-diazabicyclo[3.2.1]octane. Examples of spiro ring systems include spiro[4.3]octane and 2,6-diazaspiro[3.4]octane. In all of the above cases, the carbocyclic or heterocyclic ring may be optionally substituted as defined herein.

[0667] When it is indicated herein that a ring contains specified ring heteroatoms, it is understood that no other ring heteroatoms besides those specified are present.

[0668] "Monocyclic, bridged or bicyclic" includes monocyclic, bridged and bicyclic ring systems. Unless otherwise defined, "monocyclic, bridged or bicyclic" rings may be saturated, partially unsaturated or aromatic. These may be aromatic, heteroaromatic, carbocyclic or heterocyclic rings or combinations thereof. Bicyclic ring systems may include fused rings and spirocyclic rings.

[0669] Unless otherwise defined, the term "alkyl" as used herein refers to a saturated hydrocarbon that can be straight-chain, branched, cyclic, or a combination thereof. Alkyl includes straight-chain, branched, or cyclic alkyl groups and their hybrids, such as (cycloalkyl)alkyl. The term "(C1-6)alkyl" as used herein refers to an alkyl group having 1 to 6 carbon atoms, which can be branched or unbranched and optionally contain a ring. Examples of (C1-6)alkyl groups include hexyl, cyclohexyl, pentyl, cyclopentyl, butyl, isobutyl, cyclobutyl, tert-butyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, ethyl, and methyl. The term "(C1-4)alkyl" as used herein refers to a branched or unbranched alkyl group having 1 to 4 carbon atoms, optionally containing a ring. Examples of (C1-4)alkyl groups include butyl, isobutyl, cyclobutyl, tert-butyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, ethyl, and methyl. The (C1-4)alkyl group mentioned herein may preferably be a (C1-2)alkyl group. When specified in the above formula, (C1-4) alkyl may be substituted, for example, by 1 to 3 fluorines. A particularly preferred example of a substituted (C1-4) alkyl is trifluoromethyl. Alternatively, (C1-4) alkyl may be unsubstituted.

[0670] As used herein, the term "alkylene" refers to a divalent alkyl group.

[0671] The term "cycloalkyl" refers to a cyclic alkyl group, for example cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl. A cycloalkyl group may be substituted as defined herein.

[0672] The term "alkoxy" refers to -O-alkyl, wherein alkyl has the meaning as defined above. Examples of (C1-4)alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy. The (C1-4)alkoxy mentioned herein may preferably be (C1-2)alkoxy. When specified in the above formula, the (C1-4)alkoxy may be substituted, for example, by 1 to 3 fluorines. A particularly preferred example of a substituted (C1-4)alkoxy is trifluoromethoxy. Alternatively, the (C1-4)alkoxy may be unsubstituted. In the present invention, the alkoxy is connected to the rest of the molecule via the "oxygen-containing" portion.

[0673] As used herein, a group referred to as "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a C or N atom) is replaced by a permitted substituent (e.g., a substituent that produces a stable compound when the substitution occurs), such as a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, when more than one substituent is present, the substituents may be the same or different at each occurrence. Unless otherwise stated, a "substituted" group has one or more substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents at each position may be the same or different.

[0674] As used herein, the term "may" should be interpreted as optional. When a feature is mentioned as "may" be present, the feature is optionally present. For example, when a moiety is described as "may be substituted," the moiety is optionally substituted, i.e., it is either unsubstituted or substituted as described.

[0675] The term "halogen" refers to F, Cl, Br or I. F and Cl are particularly preferred, and F is most preferred.

[0676] Activation of the long PDE4 isoform

[0677] The long isoform of PDE4 has two regulatory regions, upstream conserved region 1 (UCR1) and upstream conserved region 2 (UCR2). These are located between the isoform-specific N-terminal portion and the catalytic domain. The short isoform lacks the UCR1 domain, while the ultrashort isoform not only lacks UCR1 but also has an N-terminal truncated UCR2 domain (Houslay, MD, Schafer, P. and Zhang, K. Drug Discovery Today 10: 1503-1519, 2005).

[0678] There are four families of PDE4: PDE4A, PDE4B, PDE4C, and PDE4D. The present invention relates to compounds that can activate one or more of the long isoforms from one or more of these four families. Thus, the long isoform PDE4 can be long isoform PDE4A, long isoform PDE4B, long isoform PDE4C, or long isoform PDE4D. For the avoidance of doubt, the long isoform PDE4 comprises the UCR1 region. In some embodiments, the long isoform PDE4 referred to herein is human. UCR1 is conserved across mammalian species (Houslay, MD, Sullivan, Mand Bolger GB Adv. Pharmacol. 44: 225-342, 1998), so in other embodiments, the long isoform PDE4 can be from a non-human mammal.

[0679] Without wishing to be bound by theory, compounds as described herein can serve as PDE4 long-form activators. Compounds as described herein are small molecules that are thought to directly bind to PDE4 long-form and induce structural changes to increase, stabilize, reveal and / or maintain the catalytic activity of these enzymes. Without wishing to be bound by theory, the activation of PDE4 long-form by PDE4 long-form activators may be sensitive to the regulatory state of the enzyme, including post-translational modification (e.g., phosphorylation) or using a protein-protein complex relevant to a specific physiological location or a cell or biochemical analysis background. PDE4 long-form activators can show activation of the enzyme under one or more states but not necessarily all states.

[0680] In the field of pharmacology, and as used herein, small molecules are defined as low molecular weight organic compounds that can act as regulatory factors for biological processes. Preferred small molecule activators according to the present invention have a molecular weight of less than or equal to 700 Daltons. This enables rapid diffusion across the cell membrane and reaching the site of action within the cell (Veber, DF et al., J. Med. Chem. 45: 2615-2623, 2002). Particularly preferred small molecule activators according to the present invention have a molecular weight greater than or equal to 250 Daltons and less than or equal to 500 Daltons (Lipinski, CA, Rug Discovery Today: Technologies 1: 337-341, 2004).

[0681] A suitable method for testing whether a compound is able to act as an activator of the long form of PDE4 is to use the two-step radioassay procedure described in Experiment 1. In summary, this method involves the long form of PDE4 being exposed to a test small molecule activator and [ 3 The reaction mixture was incubated with [H]-labeled cAMP to assess changes in the breakdown of cAMP into 5′-adenosine monophosphate (5′-AMP) products. A sample of the reaction mixture from this incubation was subsequently treated with snake venom 5′-nucleotidase to convert the nucleotide [ 3 H]-labeled 5'-AMP is converted to uncharged nucleosides [ 3 [H]-labeled adenosine, which can be isolated and quantified to assess PDE4 activity and the effects of test compounds (Thompson, WJ and Appleman, MM Biochemistry 10:311-316, 1971, as described in Marchmont, RJ and Houslay, MD Biochem J. 187:381-92, 1980 with some modifications).

[0682] Using the above assay procedures, preferred compounds described herein can increase the background activity of one or more long forms of PDE4 by more than 20% or more than 30% at a test compound concentration of 100 micromolar or less, as described in detail in Experiment 1. Particularly preferred compounds described herein can increase the background activity of one or more long forms of PDE4 by more than 20% or more than 30% at a test compound concentration of 10 micromolar or less (e.g., 3 micromolar).

[0683] The compounds described herein may be selective for the long form of the PDE4 enzyme and therefore do not act or act to a lesser extent as activators of short or ultrashort isoforms of the PDE4 enzyme. A short or ultrashort isoform of PDE4 may be a short or ultrashort isoform of PDE4A, a short or ultrashort isoform of PDE4B, a short or ultrashort isoform of PDE4C, or a short or ultrashort isoform of PDE4D. For the avoidance of doubt, short and ultrashort isoforms of PDE4 lack the UCR1 domain. Ultrashort isoforms are characterized by a truncated UCR2 domain and the lack of the UCR1 domain. Short or ultrashort isoforms of PDE4 are, for example, human, but may also be from other mammalian species (where UCR2 is conserved, see Houslay, MD, Sullivan, M and Bolger GB Adv. Pharmacol. 44: 225-342, 1998).

[0684] Under the same assay conditions, as described in Experiment 1, the compounds described herein may increase background activity of short or ultrashort PDE4A, PDE4B, PDE4C or PDE4D enzymes by less than 30% or less than 20% at test compound concentrations of 100 micromolar or less.

[0685] Thus, the compounds described herein can provide a positive result in an activation assay for the long form of PDE4 and a negative result in an activation assay for the short (or ultrashort) form of PDE4.

[0686] PDE4 long isoforms include those now known as PDE4A4, PDE4A4 / 5, PDE4A5, PDE4A8, PDE4A10, PDE4A11, PDE4B1, PDE4B3, PDE4B4, PDE4C1, PDE4C2, PDE4C3, PDE4C4, PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9, and PDE4D11. Other long isoforms can be or have been identified or named by any of the four PDE4 subfamilies using different nomenclature.

[0687] PDE4 short and ultrashort isoforms include PDE4A1, PDE4B2, PDE4B5, PDE4D1, PDE4D2, PDE4D6, and PDE4D 10. Other short and ultrashort isoforms can be or have been identified or named by any of the four PDE4 subfamilies using different nomenclatures.

[0688] The following examples illustrate the activity of the compounds described herein in an activation assay of the long isoform of human PDE4D5, and the lack of activity in an activation assay of the short isoform of human PDE4B2. Detailed information on these isoforms and many other known isoforms, including GenBank accession numbers, is provided in Tables A to D below.

[0689] Table A: Examples of known PDE4A isoforms

[0690]

[0691] *Note that PDE4A4B is correctly cloned, while PDE4A4A is a cloning artifact and PDE4A4C is a truncation artifact.

[0692] **Note that both the C-terminus and N-terminus are truncated in this species.

[0693] Table B: Examples of known PDE4B isoforms

[0694]

[0695] Table C: Examples of known PDE4C isoforms

[0696]

[0697] Table D: Examples of known PDE4D isoforms

[0698]

[0699] Decreased cAMP levels

[0700] Without wishing to be bound by theory, the compounds described herein may work by reducing cAMP levels in one or more intracellular compartments. Thus, the PDE4 long-form activators described herein may provide a means for regulating certain cellular processes that depend on cAMP. Excessive intracellular cAMP signaling mediates many diseases and conditions. Therefore, it is expected that the compounds described herein may be used to treat diseases associated with abnormally elevated cAMP levels, abnormally increased cAMP-mediated signaling, and / or abnormally reduced cAMP elimination (enzymatic or otherwise, for example, via efflux). Treatment is typically directed to humans, but may also be directed to non-human animals, such as non-human mammals (e.g., veterinary treatment).

[0701] In one aspect, the invention provides compounds described herein (ie, small molecule activators of the long form of PDE4) for use in a method of treating or preventing a condition requiring reduction of a second messenger response mediated by cyclic 3',5'-adenosine monophosphate (cAMP).

[0702] For example, gain-of-function genetic mutations in proteins involved in driving cAMP signaling upstream of adenylate cyclase, such as GPCRs and Gsα, can lead to abnormally excessive cAMP activity and produce pathological consequences (Lania A, Mantovani G, Spada A. Ann Endocrinol (Paris). 73:73-75, 2012.; Thompson, MD et al., Methods Mol. Biol. 448:109-137, 2008; Weinstein LS, Liu J, Sakamoto A, Xie T, Chen M. Endocrinology. 145:5459-5464, 2004; Lania A, Mantovani G, Spada A. Eur J Endocrinol. 145:543-559, 2001). The PDE4 long form activators described herein have the ability to accelerate the termination of cAMP action and are therefore expected to be effective in treating, preventing or partially managing diseases characterized by undesirably high cAMP levels or activity, as described in detail below.

[0703] The treatment or prevention described herein can be treatment and prevention of diseases or conditions that can be improved by activating the long isoform of PDE4. The treatment or prevention described herein can be treatment or prevention of diseases or conditions mediated by excessive intracellular cAMP signaling. In these diseases, reducing the second messenger response mediated by cyclic 3', 5'-monophosphate (cAMP) will provide therapeutic benefits.

[0704] Diseases that are ameliorated by activation of the long isoform of PDE4 or are characterized by elevated cAMP levels

[0705] Hyperthyroidism

[0706] Stimulation of the thyroid-stimulating hormone (TSH) receptor (TSHR) leads to increased production and release of the thyroid hormones, thyroxine and triiodothyronine, through a cAMP-dependent signaling mechanism involving Gsα-mediated activation of adenylate cyclase. It has been reported that gain-of-function mutations in TSHR are associated with the development of hyperthyroidism (Duprez, L et al., Nat. Genet. 7: 396-401, 1994; Biebermann, H. et al., J. Clin. Endocrinol. Metab. 86: 4429-4433, 2001; Karges, B. et al., J. Endocrinol. 186: 377-385, 2005). Activating mutations of TSHR and Gsα have also been found in goiters and thyroid adenomas (Armri, F. et al., Exp. Clin. Endocrinol. Diabetes 106: 234-236, 1998). It has been reported that increased cAMP activity in thyroid adenomas due to activating TSHR or Gsα mutations can produce a protective adaptive increase in PDE4 activity to offset the abnormal increase in cAMP levels and signal transduction (Persani, L et al. al., J. Clin. Endocrinol. Metab. 85:2872-2878, 2000).

[0707] The most common cause of hyperthyroidism is Graves' disease, an autoimmune disorder in which antibodies mimic the actions of TSH at the TSHR, leading to excessive cAMP activity in thyroid follicular cells and a hyperthyroid state.

[0708] Therefore, it is expected that the PDE4 long form activators described herein may be effective in treating, preventing or partially controlling hyperthyroidism. In one embodiment, the hyperthyroidism is associated with Graves' disease.

[0709] Janssen's metaphyseal chondrodysplasia

[0710] Jansen's metaphyseal chondrodysplasia (JMC) is a very rare disease caused by gain-of-function mutations in the parathyroid hormone (PTH) receptor 1 (PTHR1) (Thompson, MD et al., Methods Mol. Biol. 448: 109-137, 2008). Constitutive activation of PTHR1, an effector coupled to adenylate cyclase, is associated with excessive cAMP signaling, primarily in the bones and kidneys, leading to ion homeostasis disorders characterized by hypercalcemia and hypophosphatemia (Calvi, LM and Schipani, EJ Endocrinol. Invest. 23: 545-554, 2000), as well as developmental (e.g., short stature) and physiological (e.g., proptosis) abnormalities. Therefore, the long-form PDE4 activators described herein are expected to be effective in treating, preventing, or partially managing JMC.

[0711] Hyperparathyroidism

[0712] Hyperparathyroidism (HPT) is characterized by excessive secretion of PTH by the parathyroid glands, which regulates plasma calcium and phosphate concentrations via PTHR1 receptors in the kidneys, bones, and gastrointestinal tract. The resulting overstimulation of these receptors leads to a disruption of plasma ion homeostasis, with patients exhibiting hypercalcemia and hypophosphatemia. Primary HPT is caused by parathyroid hyperplasia or dysfunction, while secondary HPT is associated with underlying medical conditions, primarily chronic kidney disease. If left untreated, HPT can lead to a variety of debilitating symptoms and can be life-threatening.

[0713] The PDE4 long-form activators described herein are expected to be effective in treating, preventing, or partially controlling hyperparathyroidism by downregulating the excess cAMP produced by sustained PTH signaling.

[0714] Familial male precocious puberty (testicular toxicity)

[0715] Familial male precocious puberty (FMPP), also known as familial precocious puberty or non-gonadotropin-dependent testicular toxicity, is a disorder in which boys typically show signs of early puberty in early childhood.

[0716] Due to the rapid progression of epiphyseal maturation, boys may have a short spine length. FMPP is an autosomal dominant disorder in which a constitutively activating mutation in the luteinizing hormone (LH) receptor occurs, resulting in increased cAMP production, which is associated with Leydig cell hyperplasia and low sperm counts (Latronico, AC et al., J Clin. Endocrinol. Metab. 80: 2490-2494, 1995; Kosugi, S. et al., Hum. Mol. Genet. 4: 183-188, 1995). Therefore, the long-form PDE4 activators described herein are expected to be effective in treating, preventing, or partially controlling FMPP.

[0717] Pituitary adenoma and Cushing's disease

[0718] Non-cancerous tumors of the pituitary gland are collectively referred to as pituitary adenomas, which can lead to excessive secretion of pituitary hormones (such as growth hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and adrenocorticotropic hormone), which act through GPCRs and cAMP generation coupled to Gs. Therefore, pituitary adenomas can lead to a state of enhanced cAMP-mediated signaling in multiple endocrine tissues, which can lead to multiple hormonal disorders, such as acromegaly (primarily due to excessive secretion of growth hormone), Cushing's disease (due to excessive secretion of adrenocorticotropic hormone (ACTH) and subsequent hypercortisolemia), and / or general hyperpituitarism (associated with excessive release of multiple anterior pituitary hormones). Current treatment options for pituitary adenomas include treatment with dopamine receptor agonists, which reduce tumor size and reduce pituitary hormone output by a mechanism that reduces intracellular cAMP levels. The long-form PDE4 activators described herein can also be expected to attenuate the pathological effects of pituitary hormones in their target tissues (such as the adrenal glands).

[0719] In Cushing's disease, pituitary adenoma-associated ACTH overproduction can lead to hypercortisolemia through overactivation of the melanocortin 2 receptor (MC2) and subsequent cAMP-mediated stimulation of steroidogenesis and release of cortisol from the adrenal cortex (Tritos, NA and Biller, BMD Scov Med. 13: 171-179, 2012). Therefore, it is expected that the long-form PDE4 activators described herein may be effective in treating, preventing, or partially controlling Cushing's disease.

[0720] Polycystic kidney disease

[0721] Polycystic kidney disease (PKD) is an inherited kidney disease characterized by the development of pathological cysts that damage kidney structure and impair kidney function (Takiar, V. and Caplan, MJ Biochim. Biophys. Acta. 1812:1337-1343, 2011; Masoumi, A. et al., Drugs 67:2495-2510, 2007). There are two types of PKD: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). ADPKD affects 0.1% to 0.2% of the global population and is characterized by progressive cyst development and kidney enlargement. Approximately 50% of people with this disease will develop end-stage renal disease, usually between the ages of 40 and 70, requiring dialysis or a kidney transplant. ARPKD affects approximately 1 in 20,000 live births and is usually discovered within the first few weeks of life. Lung hypoplasia results in a 30-50% mortality rate in neonates with ARPKD.

[0722] Defects in two genes are thought to cause ADPKD. In approximately 85% of patients, the development of ADPKD may be associated with mutations in the gene PKD1, which encodes polycystin-1 (PC-1); approximately 15% of patients have mutations in PKD2, which encodes polycystin 2 (PC-2). Cyclic AMP has been identified as an important stimulator of proliferation and cyst expansion in polycystic kidney cells, but not in normal human kidney cells (Yamaguchi, T. et al., Kidney Int. 57:1460-1471, 2000). There is now a large body of evidence that cAMP is an important promoter of renal cyst development (Masoumi, A. et al., Drugs 67:2495-2510, 2007; Wallace, DP Biochim. Biophys. Acta. 1812:1291-1300, 2011). Consistent with a role for cAMP in cyst formation, agents that reduce cAMP levels, such as the vasopressin V2 receptor antagonist and the somatostatin receptor agonist octreotide, have shown efficacy in rodent models of PKD (Torres, VE et al., Nat. Med. 10:363-364, 2004; Gattone, VH2 ndet al., Nat. Med. 9: 1323-1326, 2003; Belibi, FA and Edelstein, CL Expert Opin. Investig. Drugs. 19: 315-328, 2010). In zebrafish embryos, depletion of the cAMP-hydrolyzing PDE enzyme isoform PDE1A leads to the formation of a cystic phenotype, while overexpression of PDE1A partially rescues the cystic phenotype caused by PC2 depletion (Sussman, CR, Ward, CJ, Leightner, AC, Smith, JL, Agarwal, R., Harris, PC, Torres, VEJ Am. Soc. Nephrol. 25: 2222-2230, 2014). Phosphodiesterase activation has been suggested as a therapeutic strategy for the treatment of PKD (Sun, Y., Zhou, H. and Yang, BX. Acta Pharmacologica Sinica 32:805-816, 2011).

[0723] Therefore, it is expected that the PDE4 long form activators described herein may be effective in treating, preventing or partially managing polycystic kidney disease.

[0724] Polycystic liver disease

[0725] Polycystic liver disease (PLD) is a rare genetic disorder associated with the development of liver cysts (generally defined as more than 20 cysts) and is often associated with ADPKD (Strazzabosco, M. and Somlo, S. Gastroenterology 140:1855-1859, 2011; Gevers, T.J. and Drenth, J.P. Curr. Opin. Gastroenterol. 27:294-300, 2010). PLD may have a different genetic pathology than ADPKD, driven by mutant proteins associated with the endoplasmic reticulum and cilia. Increased bile duct cell proliferation, neovascularization, and fluid secretion drive liver cyst formation through dysregulation of multiple signaling pathways, including cAMP-mediated signaling. Elevated hepatic cAMP levels stimulate cAMP-dependent chloride and fluid secretion in biliary epithelial cells and increase bile duct cell proliferation (Janssen, M.J. et al., J. Hepatol. 52:432-440, 2010). Somatostatin acts through a Gi-coupled mechanism to reduce cAMP levels, reducing bile duct cell proliferation and fluid secretion (Gong, AY et al., Am. J. Physiol. Cell. Physiol. 284: C1205-1214, 2003). In addition, the synthetic somatostatin analog octreotide has shown efficacy in PLD animal models through a mechanism involving reduced cAMP signaling (Masyuk, TV et al., Gastroenterology 132: 1104-1116, 2007). Therefore, the PDE4 long-form activators described herein are effective in treating, preventing, or partially controlling polycystic liver disease, which is at least partially caused by cAMP.

[0726] Maturity-onset diabetes of the young type 5 (MODY5)

[0727] MODY5 is a non-insulin-dependent form of diabetes mellitus associated with renal cysts. It is an autosomal dominant disorder caused by mutations in the gene encoding hepatocyte nuclear factor-1β (HNF-1β). The main clinical feature of patients affected by MODY5 is renal dysfunction, which is often diagnosed before the onset of diabetes. In some patients, HNF-1β mutations can lead to additional phenotypic features such as pancreatic atrophy, liver dysfunction, and reproductive tract abnormalities. Studies in mice have shown that the mechanism of renal cyst formation associated with HNF-1β mutations involves severe defects in PKD2 transcriptional activation in addition to effects on the uromodulin (UMOD) and PKD1 genes. Downregulation of PKD1 and PKD2 is associated with cAMP-driven renal cyst formation (Mancusi, S. et al., J. Nephrol. 26:207-12, 2013). HNF-1β also binds to the PDE4C promoter and regulates the expression of PDE4C (Ma et al., PNAS 104: 20386, 2007).

[0728] Therefore, it is expected that the PDE4 long form activators described herein may be effective in treating, preventing or partially managing the symptoms of MODY5.

[0729] Cardiac hypertrophy, heart failure, and arrhythmias

[0730] Local regulation and integration of cAMP signaling are crucial for normal cardiac function, and disruption of this signaling can lead to heart failure. Following chronic β-adrenergic receptor stimulation, elevated cAMP and activation of its downstream effectors, including PKA and Epac, induce cardiomyocyte hypertrophy (Wang, Let al., Cell. Signal. 27:908-922, 2015, and references therein). Cardiomyocyte hypertrophy increases the risk of heart failure and arrhythmias.

[0731] Therefore, the PDE4 long form activators described herein are effective in treating, preventing or partially controlling cardiac hypertrophy, heart failure and / or arrhythmias.

[0732] Diseases associated with enhanced cAMP-mediated signaling

[0733] Conditions associated with activating mutations in G. gamma protein alpha subunit (GNAS1)

[0734] G proteins (Gs) act as transducers for GPCRs, stimulating adenylate cyclase activity and exerting their biological effects by increasing intracellular cAMP levels. Gs is a heterotrimeric protein composed of α, β, and γ subunits. Mutations that activate the α subunit gene, GNAS1, have been identified, leading to abnormal cAMP signaling in multiple tissues and causing a range of pathologies.

[0735] McCune-Albright syndrome

[0736] McCune-Albright syndrome (MAS) is a rare genetic disorder typically characterized by three main features: precocious puberty, fibrous dysplasia, and café au lait spots. The underlying molecular pathology of MAS involves activating mutations in the GNAS1 gene (Diaz, A. Danon, M. and Crawford, J. Pediatr Endocrinol. Metab. 20:853-880, 2007). Therefore, the long-form PDE4 activators described herein are expected to be effective in treating, preventing, or partially managing conditions associated with activating mutations in GNAS1, including McCune-Albright syndrome.

[0737] Improves toxin-induced increase in adenylate cyclase activity in infectious diseases

[0738] Adenylate cyclase is an enzyme responsible for producing cAMP and is considered to be a key biological target involved in mediating the effects of many bacterial toxins (Ahuja et al., Critical Reviews in Microbiology, 30: 187-196, 2004). These toxins act by increasing cAMP levels by enhancing the activity of adenylate cyclases associated with host immune cells and / or pathogens. Therefore, by reducing cAMP levels, the PDE4 long-form activators described herein are expected to be useful in treating or partially controlling the symptoms of infectious diseases associated with elevated cAMP activity. The following are some examples of such infectious diseases:

[0739] cholera

[0740] Vibrio cholerae produces cholera toxin, which activates host cell adenylate cyclase and produces cAMP through adenosine diphosphate ribosylation of the α-subunit of Gs. Cholera toxin-induced diarrhea is thought to result from excessive accumulation of cAMP in gastrointestinal cells.

[0741] pertussis

[0742] Bordetella pertussis is the pathogen that causes whooping cough in children. The B. pertussis toxin stimulates adenosine diphosphate ribosylation of the α-subunit of Gi and indirectly increases cAMP levels in target cells. The bacterium also secretes an invasive adenylate cyclase that generates toxic cAMP levels and impairs host immune defenses.

[0743] anthrax

[0744] Anthrax, caused by Bacillus anthracis, is primarily an animal disease but can be transmitted to humans through contact. Anthrax infection is associated with widespread edema, the development of which is thought to be driven by edema toxin, an adenylate cyclase that is activated by host calmodulin, producing abnormally high levels of cAMP that are toxic to host immune cells.

[0745] Tuberculosis

[0746] Mycobacterium tuberculosis expresses a large and diverse set of adenylate cyclases that play a role in virulence and the development of disease pathology. One adenylate cyclase isoform, RV0386, has been shown to enter host macrophages and elevate intracellular cAMP to induce toxicity (Agarwal et al., Nature, 460:98-102, 2009).

[0747] Therefore, the long-form PDE4 activators described herein can effectively treat, prevent or partially control infectious diseases such as cholera, pertussis, anthrax and tuberculosis.

[0748] Diseases that depend on activation of PKA by elevated cAMP

[0749] In eukaryotes, cAMP activates protein kinase A (PKA), also known as cAMP-dependent protein kinase. PKA is a normally inactive tetrameric holoenzyme composed of two catalytic units and two regulatory units, where the regulatory units block the catalytic centers of the catalytic units. cAMP binds to specific sites on the PKA regulatory units, causing dissociation between the regulatory and catalytic units, thereby activating the catalytic units. The active catalytic units catalyze the transfer of phosphate from ATP to specific residues on protein substrates, which can regulate the functions of these protein substrates.

[0750] Activation of the long form of PDE4 reduces cAMP levels and cAMP-mediated activation of PKA. Thus, it is expected that the long form activators of PDE4 described herein can be used to treat or partially control conditions for which PKA inhibitors show therapeutic benefit.

[0751] Disorders that rely on cAMP to activate PKA can be identified by their response to PKA inhibitors, such as Rp-8-Br-cAMPS, a cAMP analog that occupies the cAMP binding site of PKA, preventing its dissociation and activation.

[0752] HIV infection and AIDS

[0753] T cells from HIV-infected patients have elevated cAMP levels and are more sensitive to inhibition by Rp-8-Br-cAMPS than normal T cells. Excessive activation of PKA by cAMP is associated with progressive T cell dysfunction in HIV infection (Aandahl, E.M. et al., FASEB J. 12: 855-862, 1998). In addition, in vivo administration of Rp-8-Br-cAMPS has been shown to restore T cell responses in retrovirally infected mice (Nayjib, B. et al., The Open Immunology Journal, 1: 20-24, 2008). Therefore, it is expected that the long-form PDE4 activators described herein may be useful for treating, preventing, or partially controlling HIV infection and AIDS.

[0754] Common variable immunodeficiency (CVID)

[0755] In vitro administration of Rp-8-Br-cAMPS has been shown to correct the impaired secretion of the cytokine IL-10 by T cells from patients with common variable immunodeficiency (CVID) (Holm, AM et al., J. Immunol. 170: 5772-5777, 2003). Therefore, it is expected that the long-form PDE4 activators described herein may be useful for treating, preventing, or partially managing CVID.

[0756] Diseases that rely on elevated cAMP to activate either or both Epac1 and Epac2

[0757] In addition to PKA, cAMP also activates another intracellular receptor called exchange protein directly activated by cAMP (Epac). Epac has two isoforms, Epac1 and Epac2, both of which consist of a regulatory region that binds cAMP and a catalytic region that promotes the exchange of GDP for GTP on the Ras family small G proteins Rap1 and Rap2. In addition, Epac proteins exert their functions by interacting with many other cellular partners at specific cellular sites. Pathophysiological changes in Epac signaling are associated with a variety of diseases (Breckler, M. et al., Cell. Signal. 23: 1257-1266, 2011).

[0758] Conditions dependent on cAMP activation of the Epac protein can be identified by their response to Epac inhibitors, such as ESI-09, a novel acyclic nucleotide Epac1 and Epac2 antagonist that specifically blocks Epac-mediated Rap1 activation and Akt phosphorylation in cells, as well as Epac-mediated insulin secretion in pancreatic β cells (Almahariq, M. et al., Mol. Pharmacol. 83:122-128, 2013).

[0759] Melanoma

[0760] Epac1 is involved in promoting the migration and metastasis of melanoma (Baljinnyam, E. et al., Pigment Cell Melanoma Res. 24: 680-687, 2011 and references cited therein).

[0761] Therefore, it is expected that the PDE4 long form activators described herein may be useful in the treatment, prevention or partial management of melanoma.

[0762] pancreatic cancer

[0763] It has recently been shown that Epac1 is significantly elevated in human pancreatic cancer cells compared to normal pancreas or surrounding tissues (Lorenz, R. et al., Pancreas 37:102-103, 2008).

[0764] Pancreatic cancer is generally resistant to treatments that are usually effective for other types of cancer. Using the Epac inhibitor ESI-09, a functional role of Epac1 overexpression in pancreatic cancer cell migration and invasion was demonstrated (Almahariq, M. et al., Mol. Pharmacol. 83:122-128, 2013). These findings are consistent with results based on RNAi silencing technology, suggesting that inhibiting Epac1 signaling may be an effective therapeutic strategy for pancreatic cancer.

[0765] Therefore, it is expected that the PDE4 long form activators described herein may be used to treat, prevent or partially manage pancreatic cancer.

[0766] Diseases that rely on the regulation of cAMP-gated ion channels by cAMP elevation

[0767] In addition to activating PKA and Epac, another effect pathway of elevated cAMP is the activation of cAMP-gated ion channels. Therefore, it is expected that the PDE4 long-form activators described herein can be used to treat diseases for which inhibitors of cAMP-gated ion channels show therapeutic effects.

[0768] Diseases associated with increased cAMP response element binding protein activity

[0769] cAMP response element binding protein (CREB) is an important transcription factor involved in the regulation of various cellular functions, such as cell proliferation, differentiation, survival and apoptosis (Cho et al., Crit Rev Oncog, 16: 37-46, 2011). CREB activity is regulated by kinase-dependent phosphorylation through a series of extracellular signals (such as stress, growth factors and neurotransmitters). Phosphorylation leads to CREB dimerization and, together with other co-activator partner proteins, enables it to bind to the promoter region of target genes containing cAMP response elements (CRE sites) and initiate transcriptional activity. The cAMP pathway (e.g., phosphorylation mediated by cAMP-dependent protein kinases) is an important positive regulator of CREB-mediated biological activities. Therefore, it is expected that the PDE4 long-form activators described herein can be used to treat, prevent or partially control conditions associated with increased CREB activity.

[0770] leukemia

[0771] Bone marrow cells from patients with acute lymphoblastic and myeloid leukemia have been reported to overexpress CREB protein and mRNA (Crans-Vargas et al., Blood, 99:2617-9, 2002; Cho et al., Crit Rev Oncog, 16:37-46, 2011). Furthermore, increased CREB levels have been associated with poor clinical responses in subjects with acute myeloid leukemia (Crans-Vargas et al., Blood, 99:2617-9, 2002; Shankar et al., Cancer Cell, 7:351-62, 2005). Upregulation of CREB has been associated with stimulation of human leukemia cell growth, whereas downregulation inhibits myeloid cell proliferation and survival. The long-form PDE4 activators described herein are expected to reduce CREB activity and function by attenuating cAMP-mediated CREB stimulation and are therefore expected to be useful in treating, preventing, or partially controlling acute lymphoblastic and myeloid leukemia.

[0772] Prostate cancer

[0773] Abnormal excess androgen activity is an important driver of prostate cancer development because it stimulates the development of intraepithelial neoplasia (Merkle et al., Cellular Signaling, 23: 507-515, 2011). This is strongly supported by the use of androgen ablation methods (including chemical or surgical castration) in the treatment of prostate cancer. Cyclic AMP-elevating agents (such as forskolin) can enhance androgen receptor activity through a variety of intracellular mechanisms, including activation of androgen receptors by phosphorylation and / or interaction with CREB. Epac1 activation has also been implicated in promoting cell proliferation in prostate cancer (Misra, UK and Pizzo, SVJ Cell. Biochem. 108: 998-1011, 2009; Misra, UK and Pizzo, SVJ Cell. Biochem. 113: 1488-1500, 2012). Therefore, it is expected that the long-form PDE4 activators described herein can be used to treat, prevent or partially control prostate cancer.

[0774] Diseases associated with decreased cAMP hydrolyzing PDE enzyme activity

[0775] Loss-of-function mutations in genes for cAMP-hydrolyzing PDE isoforms other than PDE4 (e.g., PDE8 and PDE11) have been detected in a variety of diseases (Vezzosi, D. and Bertherat, J., Eur J. Endocrinol. 165: 177-188, 2011; Levy, I. et al., Curr. Opin. Pharmacol. 11: 689-697, 2011; Azevedo, MF and Stratakis, CA Endocr Pract. 17 Suppl 3: 2-7, 2011). These mutations can lead to abnormally high cAMP levels and / or duration of cAMP action, with the pathological consequences described in detail below. Therefore, it is expected that the long-form PDE4 activators described herein can be used to treat, prevent, or partially control these diseases, such as adrenocortical tumors, testicular cancer, PPNAD, and Carney complex.

[0776] Adrenal cortical tumors

[0777] Adrenocortical tumors associated with inactivating point mutations in the gene encoding PDE11A4 have reduced PDE11A4 expression and increased cAMP levels (Horvath, A. et al., Nat Genet. 38:794-800, 2006; Horvath, A. et al., Cancer Res. 66:11571-11575, 2006; Libé, R., et al., Clin. Cancer Res. 14:4016-4024, 2008).

[0778] testicular cancer

[0779] Mutations that reduce PDE11A activity and increase cAMP levels have been observed in certain types of testicular cancer (Horvath. A. et al., Cancer Res. 69: 5301-5306. 2009).

[0780] Primary pigmented nodular adrenocortical disease (PPNAD)

[0781] Mutations in the PDE8B gene have also been identified as inducible factors for PPNAD, and the mutant protein exhibits a reduced ability to degrade cAMP (Horvath, A., Mericq, V. and Stratakis, CAN Engl. J. Med. 358:750-752, 2008; Horvath, A. et al., Eur. J. Hum. Genet. 16:1245-1253, 2008).

[0782] Carney complex

[0783] In Carney complex (CNC) caused by PRKAR1A mutations, some patients also have PDE11A deficiency, which may play a synergistic role to enhance the abnormal activation of the cAMP signaling pathway, leading to adrenal cancer and testicular cancer (Libé, R. et al., J. Clin. Endocrinol. Metab. 96: E208-214, 2011).

[0784] Treatment and dosimetry

[0785] As used herein, "treatment" refers to treatment by therapy, whether of a human or non-human animal (e.g., in veterinary applications), typically a non-human mammal, in which some desired therapeutic effect on a condition is achieved; for example, inhibiting the progression of a condition, including reducing the rate of progression, halting the rate of progression, ameliorating the condition, or curing the condition. Treatment as a preventative measure is also included. References to prevention or prophylaxis herein do not imply or require complete prevention of a condition; rather, its manifestations may be reduced or delayed by prophylaxis or prophylaxis according to the present invention.

[0786] When used to prevent or treat a condition, the compounds or compositions described herein can be administered in an "effective amount," which may also be referred to as a "therapeutically effective amount." A "therapeutically effective amount" herein refers to an amount of one or more compounds described herein, or a pharmaceutical formulation comprising such one or more compounds, that is effective to produce such a therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0787] It should be understood that the appropriate dosage of the compounds described herein may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit with any risks or adverse side effects of the treatment of the present invention. The dosage level selected will depend on a variety of factors, including the activity of the specific compound, the route of administration, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds or materials used in combination, and the patient's age, sex, weight, condition, general health and medical history. The amount of the compound and the route of administration will ultimately be determined by the physician, but generally the dosage will achieve local concentrations at the site of action to achieve the desired effect. In vivo administration can be achieved continuously or intermittently in a single dose throughout the course of treatment. Methods for determining the most effective mode of administration and dosage are well known to those skilled in the art and will vary with the formulation used for treatment, the purpose of treatment, the target cell being treated and the subject being treated. Single or multiple administrations can be performed, and the dosage level and pattern are selected by the treating physician.

[0788] In general, a suitable dosage of one or more compounds described herein can be in the range of about 0.001 mg to 50 mg per kg of subject body weight per day, preferably 0.01 mg to 25 mg per kg of body weight per day, for example, 0.01 mg, 0.05 mg, 0.10 mg, 0.25 mg, 0.50 mg, 1.0 mg, 2.5 mg, 10 mg or 25 mg per kg per day. When the compound is a salt, solvate, prodrug, etc., the dosage can be calculated based on the parent compound, so the actual weight used can be increased proportionally.

[0789] Combination therapy

[0790] The compounds described herein may also be used to mimic or enhance the effects of drugs known to produce their therapeutic effects by reducing intracellular cAMP levels.

[0791] Many therapeutically useful drugs have a primary mode of action involving the activity of reducing intracellular cAMP levels and / or cAMP mediation, as described below. Since PDE4 long-form activators as herein described will also play a role in reducing cAMP levels, it is expected that these agents will simulate and / or enhance the pharmacological properties and therapeutic effectiveness of the drug that works by lowering the signal transduction of cAMP mediation. Therefore, in some embodiments, compound as herein described is provided together with another agent that reduces intracellular cAMP levels and / or cAMP mediation activity as a part of conjoint therapy. Conjoint therapy can be used simultaneously, over the same period, in sequence or separately. In one embodiment, compound as herein described and independent cAMP reducers are provided as single compositions, as described in more detail below. Conjoint therapy can include one or more of as herein described and following:

[0792] (i) a presynaptic alpha-2 adrenergic receptor agonist, optionally clonidine, dexmedetomidine, or guanfacine;

[0793] (ii) a beta-1 adrenergic receptor antagonist ("beta-blocker"), optionally atenolol, metoprolol, bisoprolol, acebutolol or betaxolol.

[0794] Combination with alpha-2 adrenergic receptor agonists

[0795] It is known that alpha-2 adrenergic receptor stimulation can i PDE4 is a steroid hormone that is regulated by the α-2 adrenergic receptor agonist Clonidine. It ... Furthermore, the PDE4 long-form activators described herein can be expected to enhance the pharmacodynamic effects of alpha-2 adrenergic receptor agonists when used in combination.

[0796] Combination with beta-1 adrenergic receptor antagonists

[0797] Beta-1 adrenergic receptor antagonists are used to treat a range of cardiovascular indications, including hypertension, arrhythmias, and cardioprotection after myocardial infarction. Their primary mechanism of action involves reducing the effects of excess circulating adrenaline and sympathetic nerve activity mediated by norepinephrine, specifically at cardiac beta-1 adrenergic receptors. Endogenous and synthetic beta-1 adrenergic receptor agonists act through G s Activation stimulates adenylate cyclase activity and increases intracellular cAMP levels in various tissues, including the heart and kidney. Therefore, drugs that block β-1 adrenergic receptor-mediated activity exert their pharmacological effects by attenuating increases in cAMP-mediated signaling. Given that activation of the long form of PDE4 will also reduce cAMP concentrations and transduction in cardiac tissue, the long form of PDE4 activators described herein are expected to be useful in the treatment or partial management of hypertension, arrhythmias, congestive heart failure, and cardioprotection. Additional non-cardiovascular therapeutic benefits are expected in conditions such as post-traumatic stress disorder, anxiety disorders, essential tremor, and glaucoma, which are also responsive to treatment with β-1 adrenergic antagonists. Furthermore, when used in combination, the long form of PDE4 activators described herein are expected to enhance the pharmacodynamic effects of β-1 adrenergic receptor antagonists.

[0798] Treatment

[0799] The compounds described herein can be used to treat or prevent diseases or conditions that can be improved by activating the long isoform of PDE4. The compounds described herein can be used to treat or prevent diseases or conditions mediated by excessive intracellular cyclic AMP signaling. The compounds described herein can be used to treat or prevent diseases or conditions that can be improved by activating the long isoform of PDE4, wherein the disease or condition that can be improved by activating the long isoform of PDE4 is a disease or condition mediated by excessive intracellular cyclic AMP signaling. On the other hand, the present invention provides small molecule activators of the long form of PDE4 as described herein, which are used to treat or prevent diseases or conditions in patients in need of such therapy. The present invention also provides methods for treating or preventing diseases or conditions in patients in need thereof, comprising administering an effective amount of a compound as described herein to a patient in need thereof. The present invention provides a method for treating or preventing a disease or condition that can be improved by activating the long isoform of PDE4, comprising administering a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt or derivative to a patient in need thereof. The present invention provides a method for treating or preventing a disease or condition mediated by excessive intracellular cyclic AMP signaling, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt or derivative described herein. The disease or condition can be any disease or condition described herein, including: diseases associated with increased cAMP production and signaling (e.g., hyperthyroidism, Janssen's metaphyseal chondrodysplasia, hyperparathyroidism, familial male precocious puberty, pituitary adenoma, Cushing's disease, polycystic kidney disease, polycystic liver disease, MODY5, and cardiac hypertrophy); diseases known to be associated with increased cAMP-mediated signaling, including conditions associated with activating mutations in the alpha subunit of G protein (GNAS1) (e.g., McCune-Albright syndrome); improving increased adenylate cyclase activity caused by toxins in infectious diseases (e.g., cholera, pertussis, anthrax, and tuberculosis); treating diseases known to be dependent on elevated cAMP for activation of PKA (e.g., H1 V infection and AIDS and common variable immunodeficiency (CVID)); treatment of diseases known to depend on elevated cAMP for activation of one or both of Epac1 and Epac2 (e.g., melanoma and pancreatic cancer); treatment of diseases known to depend on regulation of cAMP-gated ion channels by elevated cAMP; treatment of diseases known to be associated with increased activity of cAMP response element binding protein (e.g., leukemia and prostate cancer); treatment of diseases known to be associated with decreased activity of cAMP-hydrolyzing PDE enzymes (e.g., adrenocortical tumors, testicular cancer, primary pigmented nodular adrenocortical disease (PPNAD), and Carney complex); and mimicking or enhancing the effects of drugs known to produce their therapeutic effects by reducing intracellular cAMP levels.

[0800] As used herein, the terms "compounds of the present invention," "compounds of the present disclosure," "compounds described herein," and "compounds of Formula I," etc., include pharmaceutically acceptable salts and derivatives thereof, as well as polymorphs, isomers (e.g., stereoisomers and tautomers), and isotopically labeled variants thereof. For example, reference to a compound of Formula I includes pharmaceutically acceptable salts thereof. Reference to a compound of Formula Ib includes pharmaceutically acceptable salts thereof. Furthermore, these terms include all sub-embodiments of those compounds disclosed herein, including compounds of Formulas II through V, and IIb through Vb, and all embodiments thereof.

[0801] The compounds described herein may be provided as solvates, such as hydrates.

[0802] Pharmaceutically acceptable derivatives of the compounds described herein include pharmaceutically acceptable esters, amides, prodrugs (e.g., pyridine N-oxides) or isotopically labeled variants thereof. The present invention also provides pharmaceutical compositions comprising: compounds described herein (including pharmaceutically acceptable salts, solvates, esters, hydrates, or amides thereof) and pharmaceutically acceptable excipients and optional other therapeutic agents admixed therewith. The term "acceptable" refers to being compatible with the other ingredients of the composition and harmless to its receptor. Compositions include, for example, compositions suitable for oral, sublingual, subcutaneous, intravenous, epidural, intrathecal, intramuscular, transdermal, intranasal, pulmonary, topical, local or rectal administration, and are typically administered in unit dosage form.

[0803] The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and bases. Compounds containing basic groups (e.g., amino groups) are capable of forming pharmaceutically acceptable salts with acids. Examples of pharmaceutically acceptable acid addition salts of the compounds described herein include acid addition salts formed with the following acids: organic carboxylic acids, such as acetic acid, lactic acid, tartaric acid, maleic acid, citric acid, pyruvic acid, oxalic acid, fumaric acid, oxaloacetic acid, isethionic acid, lactobionic acid, and succinic acid; organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid.

[0804] Compounds containing acidic groups (e.g., carboxyl groups) are capable of forming pharmaceutically acceptable salts with bases. Pharmaceutically acceptable basic salts of the compounds described herein include, but are not limited to, metal salts, such as alkali metal salts or alkaline earth metal salts (e.g., sodium salts, potassium salts, magnesium salts, or calcium salts) and zinc or aluminum salts, and salts formed with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamine (e.g., diethanolamine), benzylamine, N-methyl-glucamine, amino acids (e.g., lysine), or pyridine.

[0805] Hemisalts of acids and bases can also be formed, for example hemisulphates.

[0806] Pharmaceutically acceptable salts of the compounds described herein can be prepared by methods well known in the art. For a review of pharmaceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0807] Prodrug

[0808] The compounds described herein may be provided as prodrugs. Prodrugs are derivatives of the compounds described herein (which may themselves have little or no pharmacological activity) that are converted to the compounds described herein when administered in vivo.

[0809] Prodrugs can be prepared, for example, by replacing functional groups present in the compounds described herein with appropriate moieties that are metabolized in vivo to form the compounds described herein. The design of prodrugs is well known in the art, as discussed in Bundgaard, Design of Prodrugs 1985 (Elsevier), The Practice of Medicinal Chemistry 2003, 2nd ed., 561-585 and Leinweber, Drug Metab. Res. 1987, 18: 379.

[0810] The in vivo metabolism of the prodrugs of the compounds described herein may involve, for example, hydrolysis, oxidative metabolism, or reductive metabolism of the prodrug. Examples of prodrugs of the compounds described herein are amides and esters of those compounds that can be hydrolyzed in vivo. For example, when the compounds described herein contain a carboxylic acid group (-COOH), the hydrogen atom of the carboxylic acid group may be substituted to form an ester (e.g., the hydrogen atom may be replaced by a C 1-6 When the compound contains an alcohol group (-OH), the hydrogen atom of the alcohol group may be substituted to form an ester (for example, the hydrogen atom may be replaced by -C(O)C 1-6 Other examples of prodrugs of the compounds described herein include pyridine N-oxides, which can be reductively metabolized in vivo to form compounds described herein containing a pyridine ring.

[0811] Solvates

[0812] It may be convenient or desirable to prepare, purify and / or process corresponding solvates of the compounds described herein, which may be used in any of the uses / methods. As used herein, the term solvate refers to a complex of a solute (e.g., a compound or a salt of a compound) and a solvent. If the solvent is water, the solvate may be referred to as a hydrate, such as a monohydrate, dihydrate, trihydrate, etc., depending on the number of water molecules present per substrate molecule.

[0813] Isomers

[0814] It should be understood that the compounds described herein can exist in various isomeric forms, and the compounds described herein include all stereoisomeric forms and mixtures thereof, including enantiomers and racemic mixtures. The present invention includes within its scope the use of any such stereoisomeric forms or mixtures of stereoisomers, including individual enantiomers of the compounds described herein and complete or partial racemic mixtures of such enantiomers. Where appropriate, isomers can be separated from their mixtures by applying or improving known methods (such as chromatography techniques and recrystallization techniques). Where appropriate, isomers can be prepared by applying or improving known methods (such as asymmetric synthesis). In addition, it should be understood that in some cases, the compounds described herein can exist in tautomeric forms, and the compounds described herein include all tautomers and mixtures thereof.

[0815] isotope

[0816] The compounds described herein include pharmaceutically acceptable isotopically-labeled compounds wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0817] Examples of isotopes included in the compounds described herein include isotopes of hydrogen, e.g. 2 H and 3 H, isotopes of carbon, e.g. 11 C. 13 C and 14 C, isotopes of chlorine, e.g. 36 Cl, isotopes of fluorine, e.g. 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O. 17 O and 18 O, isotopes of sulfur, such as 35 Certain isotopically-labeled compounds, for example, those incorporating radioactive isotopes, are useful in drug and / or substrate tissue distribution studies. 3 H and 14 C is particularly useful for this purpose because it is easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. 2 H] Isotopic substitution of carbon-bonded hydrogen atoms can positively affect the ADME properties of drug candidates by slowing CYP-mediated metabolism [for review, see Nat. Rev. Drug Discov. 15(4): 219-21 (2016)].

[0818] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0819] Pharmaceutical composition

[0820] The pharmaceutical composition may comprise any compound as described herein or a pharmaceutically acceptable salt or derivative and a pharmaceutically acceptable excipient. The pharmaceutical composition as described herein may comprise one or more pharmaceutically acceptable excipients, such as pharmaceutically acceptable carriers, diluents, preservatives, solubilizers, stabilizers, disintegrants, adhesives, lubricants, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts, buffers, coating agents, and antioxidants. Suitable excipients and techniques for preparing pharmaceutical compositions are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, 20th edition, edited by A. Gennaro, Lippincott Williams & Wilkins, 2000). Suitable excipients include, but are not limited to, pharmaceutical grades of starch, mannitol, lactose, corn starch, magnesium stearate, stearic acid, alginic acid, sodium saccharin, talc, cellulose, cellulose derivatives (e.g., hydroxypropyl methylcellulose, carboxymethyl cellulose), glucose, sucrose (or other sugars), sodium carbonate, calcium carbonate, magnesium carbonate, sodium phosphate, calcium phosphate, gelatin, agar, pectin, liquid paraffin, olive oil, alcohol, detergents, emulsifiers, or water (preferably sterile).

[0821] The pharmaceutical composition may further comprise an adjuvant and / or one or more additional therapeutically active agents.

[0822] The pharmaceutical composition can be provided in unit dosage form, usually in a sealed container and can be provided as part of a kit. Such a kit usually (but not necessarily) includes instructions for use. It can include a plurality of said unit dosage forms.

[0823] The pharmaceutical composition may be suitable for administration by any appropriate route, for example, by oral, buccal or sublingual routes or parenteral routes, including subcutaneous, intramuscular, intravenous, intraperitoneal and intradermal, rectal and topical administration and inhalation. Such compositions may be prepared by any method known in the pharmaceutical art, for example by admixing the active ingredient with an excipient under sterile conditions.

[0824] For oral administration, the active ingredient may be presented as discrete units such as tablets, capsules, powders, granules, solutions, suspensions, and the like.

[0825] Formulations suitable for oral administration can also be designed to deliver the compounds described herein in an immediate release manner or in a sustained rate manner, wherein the release profile can be delayed, pulsatile, controlled, sustained, or delayed and sustained, or modified in a manner to optimize the therapeutic efficacy of the compound. Methods for delivering compounds in a sustained rate manner are known in the art and include slow-release polymers that can be formulated with the compound to control its release.

[0826] Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the compound by diffusion or a combination of diffusion and polymer erosion. Examples of rate-sustaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthan gum, polymethacrylates, polyethylene oxide, and polyethylene glycol.

[0827] Liquid (including multiphase and dispersed systems) preparations include emulsions, suspensions, solutions, syrups and elixirs. Such preparations can exist as fillers in soft or hard capsules (e.g., made of gelatin or hydroxypropyl methylcellulose) and typically include a carrier, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared by reconstitution of a solid (e.g., from a pouch).

[0828] The compounds described herein may also be used in fast dissolving, fast disintegrating dosage forms, such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents 2001, 11(6):981-986.

[0829] The formulation of tablets is discussed in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets 1980, vol. 1 (Marcel Dekker, New York).

[0830] For intranasal or inhalation administration, the active ingredient may be presented in the form of a dry powder from a dry powder inhaler or in the form of an aerosol spray of a solution or suspension from a pressurized container, pump, sprayer, nebulizer or atomizer.

[0831] For parenteral administration, the pharmaceutical compositions of the present invention may be presented in unit-dose or multi-dose containers, e.g., pre-measured injection solutions, such as sealed vials and ampoules, and may be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, e.g., water, prior to use.

[0832] For parenteral administration, the compounds described herein can be administered directly into the bloodstream, into subcutaneous tissue, into muscle, or into an internal organ. Suitable modes of administration include intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous. Suitable administration devices include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.

[0833] Parenteral formulations are typically aqueous or oily solutions. When the solution is aqueous, excipients such as sugars (including but not limited to glucose, mannitol, sorbitol, etc.), salts, carbohydrates, and buffers (preferably pH 3 to 9) may be used. For some applications, the compounds described herein may be more suitably formulated as sterile non-aqueous solutions or formulated as dry forms for use in combination with suitable solvents such as sterile pyrogen-free water (WFI).

[0834] Parenteral formulations may include implants derived from degradable polymers such as polyesters (e.g., polylactic acid, polylactide, polylactide-co-glycolide, polycaprolactone, polyhydroxybutyrate), polyorthoesters, and polyanhydrides. These formulations can be administered through a surgical incision into the subcutaneous tissue, muscle tissue, or directly into a specific organ.

[0835] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, is readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0836] The solubility of the compounds described herein for use in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of cosolvents and / or solubility enhancers, such as surfactants, micellar structures and cyclodextrins.

[0837] The active agent can be compressed into solid dosage units, such as pills, tablets, or processed into capsules, suppositories or patches, mixed with such pharmaceutically acceptable excipients, for example as described in the standard reference text Gennaro, A R et al, Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005, see in particular Section 5: Pharmaceutical Manufacturing. The active agent can be administered as a liquid composition, for example as an injectable preparation or as an aerosol spray, in the form of a solution, suspension or emulsion by means of a pharmaceutically acceptable liquid.

[0838] In order to prepare solid dosage units, conventional additives such as fillers, colorants, polymer binders, etc. are contemplated. In general, any pharmaceutically acceptable additive that does not interfere with the function of the active compound can be used. Suitable carriers for administration as solid compositions with the active agents described herein include lactose, starch, cellulose derivatives, etc., or mixtures thereof, used in appropriate amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions, and sterile injectable solutions containing pharmaceutically acceptable dispersants and / or wetting agents such as propylene glycol or butylene glycol can be used.

[0839] The present invention also includes a pharmaceutical composition as described above in combination with packaging material suitable for use with said composition, said packaging material including instructions for use of the composition for use as described above.

[0840] In some embodiments, one or more compounds described herein can be used in combination therapy for treating the conditions, i.e., in combination with other therapeutic agents. For active compounds combined with other therapies, two or more treatment methods can be administered in separate different dosage regimens and by different routes.

[0841] The combination of the above-listed agents with the compounds described herein will be at the discretion of the physician, who will select the amounts using his or her general knowledge and dosing regimens known to skilled artisans.

[0842] When the compounds described herein are administered in combination therapy with one, two, three, four or more, preferably one or two, preferably one, other therapeutic agent, the compounds can be administered simultaneously or sequentially. When administered sequentially, they can be administered closely spaced (e.g., within 5-10 minutes) or at longer intervals (e.g., 1 hour, 2 hours, 3 hours, 4 hours or more, or longer intervals as needed), the precise dosage regimen being commensurate with the nature of the therapeutic agent.

[0843] In one embodiment, the present invention provides a product comprising a compound as described herein and another therapeutic agent as a combined preparation for simultaneous, separate or sequential use in treatment. In one embodiment, the therapy is to treat or prevent a condition requiring reduction of a second messenger response mediated by cyclic 3', 5'-adenosine monophosphate (cAMP). Products provided as combined preparations include compositions comprising a compound as described herein and other therapeutic agents in the same pharmaceutical composition, or a compound as described herein and other therapeutic agents in separate form (e.g., in the form of a kit).

[0844] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.

[0845] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition comprises a compound as described herein. In one embodiment, the kit includes a device for separately retaining the compositions, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, which is commonly used to package tablets, capsules, and the like.

[0846] The kits of the invention can be used to administer different dosage forms, e.g., oral and parenteral, for administering the separate compositions at different dosing intervals, or for titrating the separate compositions relative to each other. To facilitate compliance, the kits of the invention typically include instructions for administration.

[0847] In the combination therapies of the present invention, the compounds described herein and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. In addition, the compounds described herein and the other therapeutic agent may be combined to form a combination therapy: (i) before the combination product is issued to the physician (e.g., in the case of a kit containing the compounds described herein and the other therapeutic agent); (ii) by the physician himself (or under the guidance of the physician) shortly before administration; (iii) by the patient himself, for example, during the sequential administration of the compounds described herein and the other therapeutic agent.

[0848] Preparation method and treatment method

[0849] The present invention also provides the use of a compound described herein in the preparation of a medicament for treating or preventing a condition requiring reduction of a second messenger response mediated by cyclic 3′,5′-adenosine monophosphate (cAMP), wherein the medicament is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent in the preparation of a medicament for treating a disease or condition mediated by cAMP, wherein the medicament is used to treat or prevent a condition requiring reduction of a second messenger response mediated by cAMP, wherein the medicament is prepared for administration with a compound described herein.

[0850] The present invention also provides compounds as described herein for use in treating or preventing conditions requiring reduction of second messenger reactions mediated by cAMP, wherein the compounds as described herein are prepared for administration together with another therapeutic agent. The present invention also provides another therapeutic agent for use in treating or preventing conditions requiring reduction of second messenger reactions mediated by cAMP, wherein the another therapeutic agent is prepared for administration together with the compounds as described herein. The present invention also provides compounds as described herein for use in treating or preventing conditions requiring reduction of second messenger reactions mediated by cAMP, wherein the compounds as described herein are administered together with another therapeutic agent. The present invention also provides another therapeutic agent for use in treating or preventing conditions requiring reduction of second messenger reactions mediated by cAMP, wherein the another therapeutic agent is administered together with the compounds as described herein.

[0851] The present invention also provides the use of a compound as described herein in the preparation of a medicament for treating or preventing a condition requiring reduction of a second messenger response mediated by cAMP, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent in the preparation of a medicament for treating or preventing a condition requiring reduction of a second messenger response mediated by cAMP, wherein the patient has previously (e.g., within 24 hours) been treated with a compound as described herein.

[0852] In one embodiment, the additional therapeutic agent is:

[0853] (i) a presynaptic alpha-2 adrenergic receptor agonist, optionally clonidine, dexmedetomidine, or guanfacine;

[0854] (ii) a beta-1 adrenergic receptor antagonist ("beta-blocker"), optionally atenolol, metoprolol, bisoprolol, acebutolol or betaxolol.

[0855] Example

[0856] The present invention will now be further described by the following non-limiting examples and in conjunction with the tables:

[0857] Table 1 shows the structures of the small molecule PDE4 long-form activators according to the present invention.

[0858] Table 2 shows the enzyme assay data for PDE4D5 (PDE4 long form) and PDE4B2 (PDE4 short form).

[0859] Table 3 shows the reduction of cAMP levels in 3D cultures of m-IMCD3 kidney cells treated with compounds of the invention.

[0860] Table 4 shows the inhibition of PGE2-stimulated cyst formation in 3D cultures of m-IMCD3 renal cells treated with compounds of the invention.

[0861] General experimental details

[0862] The chromatographic analysis was performed by thin layer chromatography (Merck Millipore TLC Silica Gel 60 F 254 ) to monitor the reaction. Flash column chromatography was performed using prepacked silica gel columns in Biotage or Büchi The NMR spectra were recorded on a Bruker X2 flash chromatography system. NMR spectra were recorded using a Bruker 300 or 400 MHz spectrometer, using the residual signal of the deuterated solvent as an internal reference at 25°C (unless otherwise stated). In some cases, 1 No exchangeable NH and OH residues could be identified in the H NMR spectrum.

[0863] UPLC method:

[0864] Method A: Instrument: Agilent 1290 Infinity II, 1290 G7120A binary pump, 1290 G7167B multisampler, 1290 MCT G7116B column compartment, 1290 G7117B DAD (210-320 nm), PDA (210-320 nm), G6135BMSD (ESI positive / negative), mass range: 90-1500, chromatographic column: XSelect CSH XP C18 (50×2.1 mm, 2.5 μm), flow rate: 0.8 mL / min, column temperature: 40°C, eluent A: 0.1% formic acid in water, eluent B: 0.1% formic acid in acetonitrile, gradient: t=0 min 5% B, t=0.5 min 5% B, t=4.5 min 98% B, t=5 min 98% B, post run: 0.5 min.

[0865] Method B: Instrument: Agilent 1290 Infinity II, 1290 G7120A binary pump, 1290 G7167B multisampler, 1290 MCT G7116B column compartment, 1290 G7117B DAD (210-320 nm), PDA (210-320 nm), G6135BMSD (ESI positive / negative), mass range: 90-1500, chromatographic column: XSelect CSH XP C18 (50×2.1 mm, 2.5 μm), flow rate: 0.8 mL / min, column temperature: 25, eluent A: 10 mM ammonium bicarbonate aqueous solution (pH 9.5), eluent B: acetonitrile, gradient: t=0 min 5% B, t=0.5 min 5% B, t=4.5 min 98% B, t=5 min 98% B, post run: 0.5 min.

[0866] Method C: Instrument: Agilent 1290 Infinity II, 1290 G7120A binary pump, 1290 G7167B multisampler, 1290 MCT G7116B column compartment, 1290 G7117B DAD (210, 210-320 nm), PDA (210-320 nm), G6135B MSD (ESI positive / negative), mass range: 90-1500, column: Atlantis T3 (100×3.0 mm, 3 μm), flow rate: 0.8 mL / min, column temperature: 40°C, eluent A: 0.1% formic acid in water, eluent B: 0.1% formic acid in acetonitrile, gradient: t=0 min 5% B, t=1 min 5% B, t=10 min 98% B, t=12 min 98% B, post run: 2.5 min.

[0867] Method D: Instrument: Agilent 1290 Infinity II, 1290 G7120A binary pump, 1290 G7167B multisampler, 1290 MCT G7116B column compartment, 1290 G7117B DAD (210, 210-320 nm), PDA (210-320 nm), G6135B MSD (ESI positive / negative), mass range: 90-1500, column: Atlantis T3 (100×2.1 mm, 1.7 μm), flow rate: 0.8 mL / min, column temperature: 40°C, eluent A: 0.1% formic acid in water, eluent B: 0.1% formic acid in acetonitrile, gradient: t=0 min 2% B, t=2 min 2% B, t=10 min 30% B, t=12 min 30% B, post run: 2.5 min.

[0868] LCMS method

[0869] Method A: Instruments: Agilent 1260 Infinity II, 1260 G7112B binary pump, 1260 G7167A multisampler, 1290 MCT G7116B column oven, 1260 G7115A DAD (210, 220, and 210-320 nm), PDA (210-320 nm), G6135B MSD (ESI positive / negative), mass range 90-1500, 1290 G7102A ELSD (evaporation: 50 °C, nebulization: 50 °C, gas flow rate: 1.3 mL / min), chromatographic column: XSelect CSH C18 (30 × 2.1 mm 3.5 μm), flow rate: 1 mL / min, column temperature: 40°C, eluent A: 0.1% formic acid in water, eluent B: 0.1% formic acid in acetonitrile, gradient: t=0 min 5% B, t=1.6 min 98% B, t=3 min 98% B, post-run: 1.3 min.

[0870] Method B: Instrument: Agilent 1260 Infinity, 1260 G1312B binary pump, 1260 G1367E WPS, 1260 TCC G1316A column oven, 1260 G1315C DAD (210-320 nm, 210 and 220 nm), PDA (210-320 nm), G6130B MSD (ESI positive / negative), mass range: 100-1000, chromatographic column: Waters XSelect CSH C18 (30×2.1 mm, 3.5 μm), flow rate: 1 mL / min, column temperature: 25, eluent A: 10 mM ammonium bicarbonate aqueous solution (pH=9), eluent B: acetonitrile, gradient: t=0 min 5% B, t=1.6 min 98% B, t=3 min 98% B, post run: 1.4 min.

[0871] abbreviation:

[0872] name CAS number RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl 787618-22-8 <![CDATA[Pd(Ph3P)4]]> Tetrakis(phenylphosphine)palladium(0) 14221-01-3 Xantphos 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene 161265-03-8 <![CDATA[Pd2(dba)3]]> Tris(dibenzylideneacetone)dipalladium(0) 51364-51-3 XPhos 2-Dicyclohexylphosphino-2′,4′,6-triisopropylbiphenyl 564483-18-7 <![CDATA[( t This)PhCPhos]]> 2-[(tert-Butyl)phenylphosphino]-2′,6′-bis(N,N)dimethylamino)biphenyl 1660153-91-2 <![CDATA[PdCl2(dppf)-CH2Cl2]]> [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane 95464-05-4

[0873] The following abbreviations may also be used in experimental details: CDI (1,1′-carbonyldiimidazole), DCM (dichloromethane), DIPEA (N,N-diisopropylethylamine), DMF (N,N-dimethylformamide), EDC (N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide), h (hour), HOBt (hydroxybenzotriazole), MW (microwave), rt (room temperature), SEM [2-(trimethylsilyl)ethoxymethyl], TBDPS (tert-butyldiphenylsilyl), THF (tetrahydrofuran). The following abbreviations are used in NMR signal attributions: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), app. (approximately), br. (broad), dd (two doublets), dt (two triplets), td (three doublets).

[0874] Synthesis procedure of key intermediates:

[0875] Intermediate 1: Synthesis of Benzyl 3,8-Diazabicyclo[3.2.1]octane-3-carboxylate

[0876]

[0877] Under a nitrogen atmosphere, tert-butyl 3,8-diazabicyclo [3.2.1] octane -8-carboxylate (5.00g, 23.6mmol) and triethylamine (6.57mL, 47.1mmol) were dissolved in dichloromethane (100mL), and benzyl chlorocarboxylate (3.7mL, 26mmol) was slowly added. The mixture was stirred at room temperature for 30 minutes, poured into a saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude oil was purified by silica gel column chromatography (0% to 50% ethyl acetate in n-heptane) and concentrated in vacuo to give 8- (tert-butyl) 3,8-diazabicyclo [3.2.1] octane -3,8-dicarboxylic acid 3-benzyl ester (8.15g, 85%) as a colorless oil.

[0878] To a solution of 8-(tert-butyl) 3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylic acid 3-benzyl ester (8.15g, 20.0mmol) in 1,4-dioxane (40mL) was added a 1,4-dioxane solution (40mL, 160mmol) of 4M hydrochloric acid, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and distributed between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give 3,8-diazabicyclo [3.2.1] octane-3-carboxylic acid benzyl ester (4.95g, 95%, intermediate 1) as a light yellow oil.1 H-NMR: δ H (400MHz, CDCl3) 7.39-7.28 (5H, m), 5.13 (2H, s), 3.89-3.72 (2H, m), 3.57-3.41 (2H, m), 3.13-2.97 (2H, m), 1.86 (1H, s), 1.80-1.66 (4H, m).

[0879] Intermediate 4: Synthesis of 8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester hydrochloride

[0880]

[0881] Under an argon atmosphere, Pd2(dba)3 (50 mg, 0.06 mmol) was added to a solution of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (199 mg, 0.74 mmol), benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (275 mg, 1.12 mmol, intermediate 1), XPhos (27 mg, 0.06 mmol) and cesium carbonate (620 mg, 1.90 mmol) in 1,4-dioxane (5 mL). The mixture was heated to 100 ° C in a sealed vial for 21 hours. The mixture was cooled to room temperature and distributed between saturated aqueous sodium bicarbonate solution and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a brown oil. The oil was purified by silica gel column chromatography (2% to 75% ethyl acetate in n-heptane) and concentrated in vacuo to provide tert-butyl 2-(3-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (187 mg, 35%) as an off-white solid.

[0882] To a solution of tert-butyl 2-(3-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (187 mg, 0.39 mmol) in methanol (5 mL) was added a 4M hydrochloric acid solution in 1,4-dioxane (0.5 mL, 2.00 mmol), and the mixture was stirred at room temperature for 22 hours. The mixture was concentrated in vacuo to give 8-(5,6,7,8-tetrahydro-1,6-naphthyridine-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate benzyl ester hydrochloride (188 mg, 96%, intermediate 4) as a yellow solid. LCMS (method A): t R1.28min, 90%, MS (ESI) 379.2 (M+H) + .

[0883] Example 39: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one

[0884]

[0885] To a solution of 8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester hydrochloride (76 mg, 0.18 mmol, intermediate 4) and cyclopentyl acetic acid (26 μL, 0.21 mmol) in N,N-dimethylformamide (2 mL) was added triethylamine (80 μL, 0.58 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol) and 1-hydroxy-7-azabenzotriazole (3.5 mg, 0.026 mmol), and the reaction was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by preparative reverse phase chromatography (Waters XSelect TM The reaction mixture was purified by CSHC18 column, aqueous ammonium bicarbonate / acetonitrile to give benzyl 8-(6-(2-cyclopentylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (58 mg, 65%).

[0886] To a solution of 8-(6-(2-cyclopentylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (58 mg, 0.12 mmol) in acetic acid (2.5 mL) was added 33% hydrogen bromide in acetic acid (0.3 mL, 1.71 mmol), and the reactants were stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, the residue was transferred to an SCX- column, the product was eluted with 2N ammonia in methanol, and the resulting solution was concentrated. The residue was lyophilized to give 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethyl-1-one (36 mg, 86%, Example 39) as a white solid. 1 H-NMR: δ H(400 MHz, CDCl3, mixture of rotamers) 7.21 (0.6H, d, J 8.5), 7.17 (0.4H, d, J 8.4), 6.53-6.40 (1H, m), 4.82-4.38 (4H, m), 3.88 (0.8H, t, J 5.9), 3.74 (1.2H, t, J 6.0), 3.14 (2H, m), 2.95-2.77 (2H, m), 2.64 (2H, m), 2.43 (2H, m), 2.38-2.23 (1H, m), 2.13-1.83 (6H, m), 1.70-1.49 (4H, m), 1.33-1.07 (2H, m); UPLC (method C): t R 3.58min, 100%, MS(ESI)355.2(M+H) + .

[0887] The following examples (40-49) were prepared using a similar procedure to Example 39 using appropriate starting materials.

[0888] Example 40: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one

[0889]

[0890] Prepared using 2-(4,4-difluorocyclohexyl)acetic acid as the acid component.

[0891] 1 H-NMR: δ H (400MHz, DMSO-d6) 7.29 (1H, d, J 8.4), 6.56 (1H, t, J 8.0), 4.53-4.42 (2H, m), 4.34 (2H, brs), 3.72 (2H, m), 2.85 (2H, m), 2.72 (1H, t, J 5.9), 2.62 (1H, t, J 6.0), 2.45 (2H, dd, J 12.2, 2.2), 2.36 (2H, t, J 7.1), 2.06-1.94 (2H, m), 1.92-1.65 (10H, m), 1.29-1.14 (2H, m); UPLC (Method A): t R 1.33min, 97%, MS(ESI)405.4(M+H) + .

[0892] Example 41: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-phenoxyethan-1-one

[0893]

[0894] Prepared using phenoxyacetic acid as the acid component.

[0895] 1 H-NMR: δ H 3H, m), 4.74-4.83 (2H, m), 4.72-4.69 (2H, m), 4.43-5.87 (2H, br s), 3.88-3.01 (2H, m), 3.84-3.06 (2H, m), 3.13-3.07 (2H, m), 2.97-2.79 (2H, m), 2.64-3.06 (2H, m); UPLC (method C): t R 3.39min, 100%, MS(ESI)379.2(M+H) + .

[0896] Example 42: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3,3-dimethylbutan-1-one

[0897]

[0898] Prepared using 3,3-dimethylbutyric acid as the acid component.

[0899] 1 H-NMR: δ H(400 MHz, CDCl3, mixture of rotamers) 7.21 (0.6H, d, J 8.5), 7.15 (0.4H, d, J 8.5), 6.46-6.39 (1H, m), 4.61 (1.2H, s), 4.52 (0.8H, s), 4.43 (2H, br s), 3.89 (0.8H, t, J 6.0), 3.77 (1.2H, t, J 6.0), 3.18-3.10 (2H, m), 2.89-2.77 (2H, m), 2.68-2.60 (2H, m), 2.38-2.32 (2H, m), 2.06-1.90 (4H, m), 1.09 (5.4H, s), 1.05 (3.6H, s); UPLC (method C): t R 3.37min, 100%, MS(ESI)343.2(M+H) + .

[0900] Example 43: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3-methylbutan-1-one

[0901]

[0902] Prepared using isovaleric acid as the acid component.

[0903] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.21 (0.6H, d, J 8.5), 7.17 (0.4H, d, J 8.5), 6.43 (1H, m), 4.61 (1H, s), 4.49 (1H, s), 4.44 (2H, br s), 3.88 (0.8H, t, J 6.0), 3.74 (1.2H, t, J 5.9), 3.15 (2H, d, J 12.2), 2.88-2.77 (2H, m), 2.67 (2H, d, J 11.5), 2.30 (2H, m), 2.18 (1H, m), 2.05-1.94 (4H, m), 0.98 (6H, m); UPLC (Method C): t R 3.09min, 100%, MS(ESI)329.2(M+H) + .

[0904] Example 44: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2,3-dimethylbutan-1-one

[0905]

[0906] Prepared using 2,3-dimethylbutyric acid as the acid component.

[0907] 1 H-NMR: δ H δ 1.57 (2H, d, J 1.0), 1.44 (2H, d, J 1.0), 1.27 (2H, m, d, J 1.1), 1.22 (2H, d, J 1.0), 1.49 (2H, d, J 1.1), 2.13 (2H, d, J 1.0), 1.27 (2H, m, d, J 1.1), 1.26 (2H, d, J 1.0), 1.24 (2H, d, J 1.1), 1.25 (2H, d, J 1.1), 1.24 (2H, d, J 1.1), 1.26 (2H, d, J 1.1), 1.28 (2H, d, J 1.1), 1.29 (2H, d, J 1.2), 1.34 (2H, d, J 1.1), 1.43 (2H, d, J 12.4), 2.57-2.46 (1H, m), 2.06-1.89 (5H, m), 1.16-1.06 (3H, m), 0.99-0.84 (6H, m); UPLC (method C): t R 3.31min, 98%, MS (ESI) 343.2 (M+H) + .

[0908] Example 45: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-phenylethan-1-one

[0909]

[0910] Prepared using 2-phenylacetic acid as the acid component.

[0911] 1 H-NMR: δ H δ 1.57 (0.4H, d, J 8.7), 1.44 (0.4H, d, J 8.9), 1.27 (0.6H, d, J 8.1), 1.26 (0.8H, s, 4.11 (2H, s), 3.91 (0.8H, t, J 6.0), 3.70 (2H, m), 3.14 (2H, d, J 6.0), 3.15 (2H, d, J 8.7), 3.54 (2H, s, 4.16 (2H, s, 4.14), 3.57 (2H, t, J 6.0), 3.13 (2H, d, J 8.9), 3.17 (2H, d, J 8.1), 3.19 (2H, d, J 12.3), 2.82 (0.8H, m), 2.68-2.58 (3.2H, m), 2.05-1.90 (4H, m); UPLC (method A): tR 1.17min, 100%, MS(ESI)363.2(M+H) + .

[0912] Example 46: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4-fluorophenoxy)ethan-1-one

[0913]

[0914] Prepared using 2-(4-fluorophenoxy)acetic acid as the acidic component.

[0915] 1 H-NMR: δ H δ 1.57 (2H, d, J 1.0), 2.47 (2H, t, J 6.0), 2.20 (0.6H, d, J 8.6), 2.71 (0.4H, d, J 8.6), 2.87 (1H, m, J 6.0), 2.65 (2H, d, J 6.0), 2.94 (2H, t, J 6.0), 3.15 (2H, d, J 12.0), 3.54 (2H, t, J 6.0), 3.57 (1.2H, t, J 6.0), 3.10 (2H, d, J 12.0), 3.59 (2H, t, J 6.0), 3.63 (2H, d, J 12.0), 3.96 (2H, t, J 6.0), 3.60 (2H, d, J 12.0), 3.61 (2H, d, J 12.2), 2.00-1.90 (4H, m); UPLC (method A): t R 1.28min, 100%, MS(ESI)397.4(M+H) + .

[0916] Example 47: Synthesis of (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(cyclopentyl)methanone

[0917]

[0918] Prepared using cyclopentanecarboxylic acid as the acid component.

[0919] 1 H-NMR: δ H(400 MHz, CDCl3, mixture of rotamers) 7.25-7.07 (1H, m), 6.50-6.34 (1H, m), 4.61 (1.2H, s), 4.54 (0.8H, s), 4.43 (2H, br s), 3.94-3.75 (2H, s), 3.20-3.11 (2H, m), 3.06-2.92 (1H, m), 2.92-2.72 (2H, m), 2.69-2.60 (2H, m), 2.10-1.73 (10H, m), 1.64-1.53 ​​(2H, m); UPLC (method A): t R 1.12min, 99%, MS(ESI)341.2(M+H) +

[0920] Example 48: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4-fluorophenyl)ethan-1-one

[0921]

[0922] Prepared using 2-(4-fluorophenyl)acetic acid as the acid component.

[0923] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.26-7.17 (3H, m), 7.08-6.95 (2H, m), 6.42 (0.6H, d, J 8.4), 6.38 (0.4H, d, J 8.5), 4.62 (1.2H, s), 4.47 (0.8H, s), 4.41 (2H, br s), 3.89 (0.8H, t, J 6.0), 3.81-3.75 (2H, m), 3.71 (1.2H, t, J 6.0), 3.16-3.08 (2H, m), 2.85-2.78 (0.8H, m), 2.71-2.58 (3.2H, m), 2.04-1.90 (4H, m); UPLC (method A): t R 0.61min, 99%, MS (ESI) 381.7 (M+H) + .

[0924] Example 49: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2,2-difluoro-2-phenylethan-1-one

[0925]

[0926] Prepared using 2,2-difluoro-2-phenylacetic acid as the acid component.

[0927] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.65-7.36 (5H, m), 7.20 (0.7H, d, J 8.6), 6.90 (0.3H, d, J 8.6), 6.43 (0.7H, d, J 8.5), 6.31 (0.3H, d, J 8.4), 4.68 (1.4H, s), 4.46 (0.6H, s), 4.40 (2H, br s), 3.95 (0.6H, t, J 6.0), 3.71 (1.4H, t, J 5.9), 3.14-3.07 (2H, m), 2.90-2.84 (0.6H, m), 2.64-2.56 (3.4H, m), 2.03-1.88 (4H, m); UPLC (method A): t R 0.74min, 100%, MS(ESI)399.7(M+H) + .

[0928] Example 59: Synthesis of 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0929]

[0930] Under an argon atmosphere, diphenylphosphoryl azide (75 μL, 0.35 mmol) was added to a toluene (2.5 mL) solution of 4,4-difluorocyclohexanecarboxylic acid (57 mg, 0.35 mmol) and triethylamine (49 μL, 0.35 mmol), and the mixture was heated to 85 ° C for 2 hours. The mixture was cooled to room temperature and added to a toluene (1 mL) and N, N-dimethylformamide (0.5 mL) solution of 8- (5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylic acid benzyl ester hydrochloride (84 mg, 0.20 mmol, intermediate 4) and triethylamine (57 μL, 0.41 mmol). The reactants were stirred at room temperature for 16 hours under an argon atmosphere. The mixture was distributed between a saturated sodium bicarbonate aqueous solution and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (30% to 100% ethyl acetate in n-heptane) and concentrated in vacuo to give 8-(6-((4,4-difluorocyclohexyl)carbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (59 mg, 50%) as a colorless gum. LCMS (Method A): t R 1.70min, 98%, MS(ESI)540.4(M+H) + .

[0931] To a solution of benzyl 8-(6-((4,4-difluorocyclohexyl)carbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (59 mg, 0.11 mmol) in acetic acid (2.5 mL) was added 33% hydrogen bromide in acetic acid (290 μL, 1.66 mmol) and the reaction was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and purified by SCX (ion exchange) chromatography (washing with methanol and eluting with 3.5 M ammonia in methanol) to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-carboxamide (39 mg, 88%, Example 59) as a white solid. 1 H-NMR: δ H(400MHz, CDCl3): 7.18 (1H, d, J 8.5), 6.42 (1H, d, J 8.6), 4.43 (2H, br s), 4.39 (2H, s), 4.30 (1H, d, J 7.5), 3.84 (1H, d, J 9.8), 3.64 (2H, t, J 5.9), 3.13 (2H, dd, J 12.4, 1.8), 2.84 (2H, t, J 5.9), 2.63 (2H, dd, J 12.2, 2.3), 2.12-1.80 (10H, m), 1.57-1.46 (2H, m); UPLC (Method A): t R 1.11min, 99%, MS(ESI)406.2(M+H) + .

[0932] Example 61: Synthesis of (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(pyrrolidin-1-yl)methanone

[0933]

[0934] To a solution of 8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester hydrochloride (76 mg, 0.18 mmol, intermediate 4) in dichloromethane (3 mL) and diisopropylethylamine (96 μL, 0.55 mmol) was added 1-pyrrolidinecarbonyl chloride (40 μL, 0.36 mmol) at 0° C., and the mixture was stirred at 0° C. for 10 minutes. The mixture was concentrated in vacuo, and the residue was purified by preparative reverse phase chromatography (Waters XSelect TM CSH C18 column, aqueous ammonium bicarbonate / acetonitrile) and lyophilized to give benzyl 8-(6-(pyrrolidine-1-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (59 mg, 67%) as a white solid. LCMS (Method A): t R 1.62min, 98%, MS(ESI)476.4(M+H) + .

[0935] To a solution of benzyl 8-(6-(pyrrolidine-1-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (58 mg, 0.12 mmol) in acetic acid (2 mL) was added 33% hydrogen bromide in acetic acid (290 μL, 1.66 mmol) and the reaction was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and purified by SCX (ion exchange) chromatography (washing with methanol and eluting with 3.5 M ammonia in methanol) to give (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(pyrrolidin-1-yl)methanone (38 mg, 92%, Example 61) as an off-white solid. 1 H-NMR: δ H (400MHz, CDCl3) 7.17 (1H, d, J 8.5), 6.41 (1H, d, J 8.6), 4.46-4.39 (2H, m), 4.30 (2H, s), 3.55 (2H, t, J 5.9), 3.46-3.38 (4H, m), 3.14 (2H, dd, J12.2, 1.8), 2.86 (2H, t, J 5.8), 2.63 (2H, dd, J 12.4, 2.4), 2.06-1.96 (2H, m), 1.96-1.88 (2H, m), 1.87-1.80 (4H, m). UPLC (method D): t R 4.01min, 99%, MS(ESI)342.2(M+H) + .

[0936] Example 63: Synthesis of 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0937]

[0938] To a solution of 8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester hydrochloride (76 mg, 0.18 mmol, intermediate 4) and diisopropylethylamine (80 μL, 0.46 mmol) in dichloromethane (3 mL) was added triphosgene (38 mg, 0.13 mmol) at 0°C and the reaction was stirred at 0°C for 30 minutes. Next, N-methylcyclopentylamine (158 μL, 0.13 mmol) was added and the reaction was heated to 40°C for 2 days. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% to 100% ethyl acetate in n-heptane) and concentrated in vacuo to give benzyl 8-(6-(cyclopentyl(methyl)carbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (65 mg, 70%) as a colorless gum. LCMS (Method A): t R 1.76min, 99%, MS(ESI)504.4(M+H) + .

[0939] To a solution of benzyl 8-(6-(cyclopentyl(methyl)carbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (65 mg, 0.13 mmol) in acetic acid (2 mL) was added 33% hydrobromic acid in acetic acid (340 μL, 1.94 mmol) and the reaction was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and purified by SCX (ion exchange) chromatography (washing with methanol and eluting with 3.5 M ammonia in methanol) to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-carboxamide (38 mg, 81%, Example 63) as an off-white solid. 1 H-NMR: δ H (400MHz, CDCl3) 7.17 (1H, d, J 8.5), 6.41 (1H, d, J8.5), 4.43 (2H, m), 4.24 (2H, s), 4.23-4.13 (1H, m), 3.50 (2H, t, J 5.8), 3.15 (2H, m), 2.87 (2H, m), 2.76 (3H, s), 2.64 (2H, m), 2.06-1.89 (4H, m), 1.88-1.80 (2H, m), 1.71-1.64 (2H, m), 1.62-1.52 (4H, m); UPLC (Method A): t R1.27min, 99%, MS(ESI)370.2(M+H) + .

[0940] Example 64: Synthesis of 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-ethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0941]

[0942] To a solution of benzyl 8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate hydrochloride (66 mg, 0.16 mmol, Intermediate 4) and triethylamine (66 μL, 0.48 mmol) in dichloromethane (2 mL) was added cyclopentyl isocyanate (22 μL, 0.20 mmol), and the reaction was stirred at room temperature for 16 hours.

[0943] The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (0% to 5% methanol in dichloromethane) and concentrated in vacuo to give 8-(6-(cyclopentyl(ethyl)carbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (49 mg, 62%) as a colorless gum. LCMS (Method A): t R 1.68min, 99%, MS(ESI)490.4(M+H) + .

[0944] To a solution of 8-(6-(cyclopentylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (44 mg, 0.09 mmol) in N,N-dimethylformamide (1.5 mL) was added a 60% sodium hydride solution in mineral oil (26 mg, 1.08 mmol) and the mixture was stirred for 5 minutes. Next, iodoethane (172 μL, 2.15 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with methanol (5 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% to 100% ethyl acetate in n-heptane) and concentrated in vacuo to afford benzyl 8-(6-(cyclopentyl(ethyl)carbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (33 mg, 62%) as a yellow solid. LCMS (Method A): t R 1.83min, 93%, MS(ESI)518.4(M+H)+ .

[0945] To a solution of benzyl 8-(6-(cyclopentyl(ethyl)carbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (33 mg, 0.06 mmol) in acetic acid (2 mL) was added 33% hydrobromic acid in acetic acid (167 μL, 0.95 mmol) and the reaction was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and purified by SCX (ion exchange) chromatography (washing with methanol and eluting with 3.5 M ammonia in methanol) to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-ethyl-7,8-dihydro-1,6-naphthyridin-6(5H)-carboxamide (12 mg, 50%, Example 64) as a white solid. 1 H-NMR: δ H (400MHz, CDCl3) 7.18 (1H, d, J 8.5), 6.41 (1H, d, J 8.6), 4.44 (2H, br s), 4.26 (2H, br s), 4.01-3.94 (1H, m), 3.52 (2H, t, J 5.9), 3.21-3.11 (4H, m), 2.86 (2H, t, J 6.0), 2.68-2.61 (2H, m), 2.04-1.83 (6H, m), 1.65-1.49 (6H, m), 1.10 (3H, t, J7.0); UPLC (Method A): t R 1.41min, 93%, MS (ESI) 384.4 (M+H) + .

[0946] Example 87: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one

[0947]

[0948] To a solution of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (120 mg, 0.63 mmol), 2-(4,4-difluorocyclohexyl)acetic acid (134 mg, 0.75 mmol) and triethylamine (0.19 mL, 1.38 mmol) in acetonitrile (4 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol) and 1-hydroxy-7-azabenzotriazole (8.55 mg, 0.06 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was added to a 4% acetonitrile solution of 1% acetic acid (100 mg, 0.75 mmol). The mixture was filtered, washed with dichloromethane and concentrated in vacuo. The residue was dissolved in dichloromethane (3 mL), purified by silica gel column chromatography (0% to 100% ethyl acetate in n-heptane) and concentrated in vacuo to give 1-(2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one (140 mg, 71%) as a white solid.

[0949] Under argon atmosphere, RuPhos (44 mg, 0.10 mmol) and Pd2(dba)3 (39 mg, 0.04 mmol) were suspended in 1,4-dioxane (0.3 mL) and heated to 80 ° C for 5 minutes. The mixture was cooled to room temperature and transferred to a stirred solution of 1-(2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one (134 mg, 0.43 mmol), 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (117 mg, 0.55 mmol) and cesium carbonate (347 mg, 1.06 mmol) in 1,4-dioxane (1.2 mL) under argon atmosphere, and the mixture was heated to 100 ° C for 16 hours. The mixture was stirred for 16 hours. The mixture was filtered, washed with acetonitrile and concentrated in vacuo. The residue was purified by silica gel column chromatography (0% to 100% ethyl acetate in n-heptane) and concentrated in vacuo to give 8-(6-(2-(4,4-difluorocyclohexyl)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (193 mg, 91%) as an orange foam.

[0950] To a solution of tert-butyl 8-(6-(2-(4,4-difluorocyclohexyl)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (190 mg, 0.39 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.30 mL, 3.87 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, dissolved in methanol (2.5 mL) and 7N ammonia in methanol (0.5 mL), and purified by preparative reverse phase chromatography (Waters XSelect TMThe mixture was purified by HPLC-MS / MS (using 5-nitropropane-2-yl)-4-nitropropane-2-yl)-2-nitropropane-1-one (500 mg, 44.77%) using a CSHC18 column, aqueous ammonium bicarbonate / acetonitrile) and lyophilized to give 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one (109 mg, 72%, Example 87) as a white solid. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.42-7.28 (1H, m), 6.52-6.41 (1H, m), 4.74-4.58 (4H, m), 4.43-4.39 (2H, m), 3.20-3.05 (2H, m), 2.71-2.56 (2H, m), 2.32-2.28 (2H, m), 2.15-1.67 (11H, m), 1.40-1.26 (2H, m); UPLC (method C): t R 4.17min, 99%, MS (ESI) 391.2 (M+H) + .

[0951] The following Example (88) was prepared using a similar procedure to Example 87 using appropriate starting materials.

[0952] Example 88: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-cyclopentylethan-1-one

[0953]

[0954] Prepared using cyclopentyl acetic acid as the acid component.

[0955] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.40-7.28 (1H, m), 6.51-6.41 (1H, m), 4.74-4.61 (4H, m), 4.50-4.34 (2H, m), 3.17-3.06 (2H, m), 2.69-2.57 (2H, m), 2.41-2.35 (3H, m), 2.10-1.99 (2H, m), 1.99-1.84 (4H, m), 1.70-1.49 (4H, m), 1.27-1.13 (2H, m); UPLC (method C): t R 4.11min, 100%, MS(ESI)341.2(M+H) + .

[0956] Example 89: Synthesis of 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide

[0957]

[0958] To a solution of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (128 mg, 0.67 mmol) and triethylamine (0.11 mL, 0.80 mmol) in dichloromethane (2 mL) was added 1,1-difluoro-4-isocyanatocyclohexane (130 mg, 0.80 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was applied to The product was purified by silica gel column chromatography (0% to 100% ethyl acetate in n-heptane) and concentrated in vacuo to afford 2-chloro-N-(4,4-difluorocyclohexyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (218 mg, 95%) as a white solid.

[0959] Under argon atmosphere, RuPhos (50 mg, 0.11 mmol) and Pd2(dba)3 (44 mg, 0.05 mmol) were suspended in 1,4-dioxane (0.3 mL) and heated to 80 ° C for 5 minutes. The mixture was cooled to room temperature and transferred to a stirred solution of 2-chloro-N-(4,4-difluorocyclohexyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (153 mg, 0.49 mmol), tert-butyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (134 mg, 0.63 mmol) and cesium carbonate (395 mg, 1.21 mmol) in 1,4-dioxane (1.5 mL) under argon atmosphere, and the mixture was heated to 100 ° C for 16 hours. The mixture was stirred for 16 hours. The mixture was filtered, washed with acetonitrile and concentrated in vacuo. The residue was purified by silica gel column chromatography (0% to 100% ethyl acetate in n-heptane) and concentrated in vacuo to give 8-(6-((4,4-difluorocyclohexyl)carbamoyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (279 mg, 80%) as an orange solid.

[0960] To a solution of tert-butyl 8-(6-((4,4-difluorocyclohexyl)carbamoyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (270 mg, 0.55 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.42 mL, 5.49 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, dissolved in methanol (3 mL) and 7N ammonia in methanol (0.5 mL), and purified by preparative reverse phase chromatography (Waters XSelect TM CSH C18 column, aqueous ammonium bicarbonate / acetonitrile) and lyophilized to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (162 mg, 75%, Example 89) as a white solid. 1 H-NMR: δ H (400MHz, CDCl3) 7.34 (1H, d, J 8.5), 6.46 (1H, d, J 8.6), 4.58 (2H, s), 4.51 (2H, s), 4.42 (2H, t, J 3.5), 4.13 (1H, d, J 7.6), 3.87 (1H, d, J 8.4), 3.20-3.08(2H,m), 2.68-2.57(2H,m), 2.18-1.99(6H,m), 1.99-1.78(4H,m), 1.54(2H,m); UPLC (Method A): t R 2.07min, 99%, MS (ESI) 392.2 (M+H) + .

[0961] The following example (90) was prepared using a similar procedure to Example 89 using appropriate starting materials.

[0962] Example 90: Synthesis of 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide

[0963]

[0964] Prepared using cyclopentyl isocyanate as the isocyanate component.

[0965] 1 H-NMR: δ H(400MHz, CDCl3)7.34(1H,d,J 8.5), 6.45(1H,d,J 8.6), 4.64-4.55(2H,m), 4.55-4.46(2H,m), 4.46-4.37(2H,m), 4.26-4.13(2H,m), 3.18-3.07(2H,m), 2.68-2.56(2 H, m), 2.11-1.98 (4H, m), 1.98-1.89 (2H, m), 1.70-1.65 (2H, m), 1.65-1.55 (2H, m), 1.47-1.33 (2H, m); UPLC (Method A): t R 1.88min, 99%, MS(ESI)342.2(M+H) + .

[0966] Example 91: Synthesis of N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide

[0967]

[0968] To a solution of 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (132 mg, 0.34 mmol, Example 89) and potassium carbonate (117 mg, 0.84 mmol) in dichloromethane (2 mL) was added methyl iodide (63 μL, 1.01 mmol), and the mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was purified by preparative reverse phase chromatography (Waters XSelect TM CSH C18 column, aqueous ammonium bicarbonate / acetonitrile) and lyophilized to give N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (92 mg, 67%, Example 91) as a white solid. 1 H-NMR: δ H(400MHz, CDCl3) 7.33 (1H, d, J 8.6), 6.46 (1H, d, J 8.6), 4.58 (2H, s), 4.49 (4H, d, J14.2), 4.12 (1H, d, J 7.7), 3.87 (1H, d, J 7.5), 2.68-2.56 (2H, m), 2.40-2.28 (2H, m), 2.19 (3H, s), 2.15-2.03 (4H, m), 2.03-1.79 (6H, m), 1.59-1.47 (2H, m); UPLC (Method B): t R 1.26min, 100%, MS(ESI)406.7(M+H) + .

[0969] The following examples (92-94) were prepared using a similar procedure to Example 91 using appropriate starting materials.

[0970] Example 92: Synthesis of N-cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide

[0971]

[0972] Prepared using Example 90 as starting reagent.

[0973] 1 H-NMR: δ H (400MHz, CDCl3) 7.33 (1H, d, J 8.5), 6.45 (1H, d, J 8.5), 4.65-4.54 (2H, m), 4.54-4.42 (4H, m), 4.18-4.05 (2H, m), 2.61 (2H, dd, J 11.0, 2.5), 2.35 (2H, dd, J 11.0, 1.8), 2.18 (3H, s), 2.10-1.97 (4H, m), 1.97-1.90 (2H, m), 1.75-1.60 (4H, m), 1.45-1.35 (2H, m); UPLC (Method A): t R 1.90min, 100%, MS(ESI)356.2(M+H) + .

[0974] Example 93: Synthesis of 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-one

[0975]

[0976] Prepared using Example 87 as starting reagent.

[0977] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.40-7.28 (1H, m), 6.54-6.38 (1H, m), 4.75-4.56 (4H, m), 4.47 (2H, s), 2.68-2.56 (2H, m), 2.36-2.32 (2H, m), 2.29-2.24 (2H, m), 2.19 (3H, s), 2.08 (3H, m), 2.03-1.67 (8H, m), 1.42-1.27 (2H, m); UPLC (method B): t R 1.41min, 99%, MS(ESI)405.7(M+H) + .

[0978] Example 94: Synthesis of 2-cyclopentyl-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-one

[0979]

[0980] Prepared using Example 88 as starting reagent.

[0981] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.39-7.27 (1H, m), 6.51-6.41 (1H, m), 4.73-4.62 (4H, m), 4.46 (2H, m), 2.68-2.54 (2H, m), 2.44-2.29 (5H, m), 2.19 (3H, s), 2.06-1.83 (6H, m), 1.76-1.55 (2H, m), 1.58-1.54 (2H, m), 1.28-1.13 (2H, m); UPLC (method B): t R 2.67min, 99%, MS(ESI)355.2(M+H) + .

[0982] Example 95: Synthesis of (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(pyrrolidin-1-yl)methanone

[0983]

[0984] 1-Pyrrolidinecarbonyl chloride (0.09mL, 0.79mmol) is added to a solution of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (125mg, 0.65mmol) and triethylamine (0.24mL, 1.70mmol) in dichloromethane (3mL), and the mixture is stirred at room temperature for 1 hour. The mixture is concentrated in vacuo, suspended in methanol (1mL) and diluted with water. The precipitate is collected by filtration, washed thoroughly with water and dried to give (2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl) (pyrrolidin-1-yl) ketone (93mg, 57%) as a pink solid.

[0985] Under argon atmosphere, RuPhos (31 mg, 0.07 mmol) and Pd2(dba)3 (27 mg, 0.03 mmol) were suspended in 1,4-dioxane (1 mL) and heated to 80 ° C for 5 minutes. The mixture was cooled to room temperature and transferred to a stirred solution of (2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(pyrrolidin-1-yl)methanone (93 mg, 0.37 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (102 mg, 0.48 mmol) and cesium carbonate (301 mg, 0.92 mmol) in 1,4-dioxane (3 mL) under argon atmosphere, and the mixture was heated to 100 ° C for 16 hours. The mixture was stirred for 16 hours. The mixture was filtered, washed with acetonitrile and concentrated in vacuo. The residue was purified by silica gel column chromatography (0% to 100% ethyl acetate in n-heptane) to give 8-(6-(pyrrolidine-1-carbonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (40 mg, 24%) as a light yellow solid.

[0986] To a solution of tert-butyl 8-(6-(pyrrolidine-1-carbonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (40 mg, 0.09 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.180 mL, 2.34 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, redissolved in methanol (2.5 mL) and 7N ammonia in methanol (0.5 mL), and purified by preparative reverse phase chromatography (Waters XSelect TMCSH C18 column, aqueous ammonium bicarbonate / acetonitrile) and lyophilized to give (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(pyrrolidin-1-yl)methanone (21 mg, 68%, Example 95) as a white solid. 1 H-NMR: δ H (400MHz, CDCl3) 7.33 (1H, d, J 8.5), 6.44 (1H, d, J 8.5), 4.74-4.60 (4H, m), 4.43 (2H, d, J 4.6), 3.53-3.41(4H,m), 3.20-3.09(2H,m), 2.69-2.59(2H,m), 2.08-1.98(2H,m), 1.98-1.91(2H,m), 1.91-1.84(4H,m); UPLC (Method A): t R 1.70min, 99%, MS(ESI)328.2(M+H) + .

[0987] The following example (96) was prepared using a similar procedure to Example 95 using appropriate starting materials.

[0988] Example 96: Synthesis of 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N,N-diethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide

[0989]

[0990] Prepared using diethylcarbamoyl chloride.

[0991] 1 H-NMR: δ H (400MHz, CDCl3) 7.32 (1H, d, J 8.5), 6.44 (1H, d, J 8.5), 4.70-4.66 (2H, m), 4.62-4.58 (2H, m), 4.48-4.36 (2H, m), 3.28 (4H, q, J 7.1), 3.20-3.08 (2H, m), 2.69-2.56 (2H, m), 2.08-1.98 (2H, m), 1.98-1.89 (2H, m), 1.19 (6H, t, J 7.1H); UPLC (Method A): t R 1.91min, 99%, MS(ESI)330.2(M+H) + .

[0992] Example 105: Synthesis of N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0993]

[0994] To a solution of 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide (18.7 mg, 0.05 mmol, Example 59) in methanol (1 mL) was added 37% wt aqueous formaldehyde solution (17 μL, 0.23 mmol) and formic acid (9 μL, 0.24 mmol). The mixture was heated to 45° C. and maintained for 16 hours, and then the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (Waters XSelect TM CSH C18 column, aqueous ammonium bicarbonate / acetonitrile, followed by Phenomenex LUNA C18 column, aqueous formic acid / acetonitrile) and lyophilization gave N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide (12 mg, 62%, Example 105) as a white solid. 1 H-NMR: δ H (400MHz, CDCl3) 7.17 (1H, d, J 8.5), 6.42 (1H, d, J 8.5), 4.47 (2H, s), 4.39 (2H, s), 4.30 (1H, d, J 7.5), 3.90-3.78 (1H, m), 3.64 (2H, t, J 5.9), 2.84(2H,t,J 5.9), 2.67-2.57(2H,m), 2.39-2.31(2H,m), 2.19(3H,s), 2.15-1.78(11H,m), 1.54-1.45(2H,m); UPLC (Method B): t R 2.46min, 99%, MS(ESI)420.2(M+H) + .

[0995] The following Example (106) was prepared using a similar procedure to Example 105 using appropriate starting materials.

[0996] Example 106: Synthesis of 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one

[0997]

[0998] Prepared using Example 40 as starting reagent.

[0999] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.20 (0.6H, d, J 8.6), 7.15 (0.4H, d, J 8.6), 6.47-6.40 (1H, m), 4.63-4.44 (4H, m), 3.88 (0.8H, t, J 6.0), 3.72 (1.2H, t, J 6.0), 2.88-2.77 (2H, m), 2.66-2.57 (2H, m), 2.39-2.29 (4H, m), 2.19 (3H, s), 2.13-1.66 (11H, m), 1.40-1.24 (2H, m); UPLC (method B): 2.73 min, 99%, MS (ESI) 419.4 (M+H) + .

[1000] Example 111: Synthesis of 2-(4,4-difluorocyclohexyl)-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one

[1001]

[1002] To a stirred solution of 2-(4,4-difluorocyclohexyl)acetic acid (1.00 g, 5.61 mmol) in DCM (15 mL) was added DIPEA (4.90 mL, 28.1 mmol) and n-propylphosphonic anhydride (cyclic trimer) (50% ethyl acetate solution; 3.57 g, 5.61 mmol) at 0 ° C. After 15 minutes, 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (1.15 g, 5.61 mmol) was added. The mixture was stirred at room temperature for 16 hours, then diluted with water (10 mL) and extracted with 5% MeOH in DCM (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0% to 100% ethyl acetate in petroleum ether to give 1-(2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one (1.68 g, 91%) as an off-white solid.

[1003] Under continuous nitrogen flow, to a mixture of degassed 1-(2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one (1.10g, 3.35mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.25g, 6.69mmol) in toluene (10mL) was added sodium tert-butoxide (0.965g, 10.0mmol), XPhos (0.319g, 0.669mmol) and Pd2(dba)3 (0.306g, 0.335mmol). The mixture was stirred at 100°C for 16 hours in a sealed vial and then concentrated under reduced pressure. The residue was diluted with a 10% MeOH solution in DCM (40mL) and filtered. In the mixture of 4- (6- (2- (4,4- difluorocyclohexyl) acetyl) -5,6,7,8- tetrahydro -1,6- naphthyridin-2-yl) piperazine -1- carboxylic acid tert-butyl ester (1.3g, 81%), it is a pale yellow solid.

[1004] To a stirred solution of tert-butyl 4-(6-(2-(4,4-difluorocyclohexyl)acetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperazine-1-carboxylate (5.00 g, 10.45 mmol) in DCM (10 mL) was added HCl (4 M in 1,4-dioxane; 13.1 mL, 52.2 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was dissolved in water (50 mL) and washed with EtOAc (2×15 mL). The separated aqueous layer was basified with 10% sodium bicarbonate solution (10 mL) and extracted with 15% MeOH in DCM (3×50 mL). The combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was washed with 20% EtOAc in petroleum ether (20 mL), then dissolved in MeCN:water (7:3 ratio, 10 mL) and lyophilized to give 2-(4,4-difluorocyclohexyl)-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one (2.5 g, 63%, Example 111) as an off-white solid. 1 H-NMR: δ H(400MHz, DMSO-d6, 80℃) 7.36 (1H, d, J 8.8), 6.67 (1H, d, J 8.8), 4.51 (2H, br s), 3.74 (2H, t, J 6.0), 3.49-3.46(4H,m), 2.91-2.89(4H,m), 2.74-2.68(2H,m), 2.38-2.36(2H,m), 2.00-1.92(3H,m), 1.78-1.75(4H,m), 1.32-1.23(2H,m).

[1005] Example 112: Synthesis of (R)-2-cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one

[1006]

[1007] To a solution of 2-cyclopentylacetic acid (5.00 g, 39.0 mmol) in DCM (20 mL) was added DIPEA (34.0 mL, 195 mmol), n-propylphosphonic anhydride (cyclic trimer) (50% in ethyl acetate; 45.6 mL, 78.0 mmol) and 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (9.60 g, 46.8 mmol) at 0 ° C. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure, diluted with water (50 mL), and extracted with 10% methanol in DCM (3×50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0% to 50% ethyl acetate in petroleum ether to give 1-(2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one (10.2 g, 94%) as a light yellow solid.

[1008] To a stirred solution of 1-(2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one (200 mg, 0.717 mmol) in toluene (10 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (181 mg, 1.44 mmol), sodium tert-butoxide (207 mg, 2.15 mmol), and X-Phos (68.4 mg, 0.143 mmol) under continuous nitrogen flow. After stirring at room temperature for 5 minutes, Pd2(dba)3 (65.7 mg, 0.072 mmol) was added, and the mixture was stirred in a sealed tube at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL) and extracted with 10% methanol in DCM (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic method). The fractions containing the product were combined, concentrated under reduced pressure, alkalized with saturated NaHCO solution (20 mL), and extracted with a DCM solution of 10% methanol (2 × 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R) -2- cyclopentyl -1- (2- (hexahydropyrrolo [1,2-a] pyrazine -2 (1H) -yl) -7,8- dihydro -1,6- naphthyridine -6 (5H) -yl) ethyl -1- ketone (58 mg, 22%, Example 112), which was a gummy solid. 1 H-NMR: δ H (400MHz, DMSO-d6)7.35(1H,d,J 8.4), 6.73-6.69(1H,m), 4.52-4.50(2H,m), 4.46-4.42(1H,m), 4.31-4.33(1H,m), 3.72-3.70(2H,m), 3.03-3.01(2H,m), 2.77-2.74(2H, m), 2.68-2.64(1H,m), 2.45-2.41(3H,m), 2.34-2.02(3H,m), 1.78-1.69(6H,m), 1.59-1.48(4H,m), 1.16-1.14(1H,m), 1.13-1.11(2H,m).

[1009] The following example (113) was prepared using a similar procedure to Example 112 using appropriate starting materials.

[1010] Example 113: Synthesis of (S)-2-cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one

[1011]

[1012] Prepared using (S)-octahydropyrrolo[1,2-a]pyrazine instead of (R)-octahydropyrrolo[1,2-a]pyrazine. 1 H-NMR: δ H (400MHz, DMSO-d6)7.34(1H,d,J 8.8), 6.72-6.69(1H,m), 4.52-4.50(2H,m), 4.42-4.44(1H,m), 4.31-4.33(1H,m), 3.72-3.70(2H,m), 3.03-3.01(2H,m), 2.77-2.74(2H, m), 2.68-2.64(1H,m), 2.45-2.41(3H,m), 2.34-2.02(3H,m), 1.78-1.69(6H,m), 1.59-1.48(4H,m), 1.16-1.14(1H,m), 1.13-1.11(2H,m).

[1013] Example 114: Synthesis of 2-cyclopentyl-1-(2-(piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one

[1014]

[1015] To a stirred solution of 1-(2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one (2 g, 7.17 mmol) in 1,4-dioxane (18 mL) and water (2 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.33 g, 10.8 mmol), Cs2CO3 (7.01 g, 21.5 mmol) and PdCl2(dppf)-CH2Cl2 complex (0.586 g, 0.717 mmol) under continuous nitrogen flow. The reaction mixture was heated to 100° C. and stirred for 16 hours, then diluted with water (50 mL) and extracted with 5% MeOH in DCM (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, eluted with a DCM solution of 0% to 20% methanol to give 4- (6- (2- cyclopentylacetyl) -5,6,7,8- tetrahydro -1,6- naphthyridin-2-yl) -3,6- dihydropyridine -1 (2H) -carboxylic acid tert-butyl ester (2.5 g, 82%) as a pale white solid.

[1016] To a stirred solution of tert-butyl 4-(6-(2-cyclopentylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.00 g, 7.05 mmol) in MeOH (50 mL) was added Pd / C (10%, dry; 300 mg) under nitrogen. The mixture was stirred at room temperature under H2 balloon pressure for 16 hours and then filtered. Filtered, washed with methanol (50 mL) and concentrated under reduced pressure to give crude tert-butyl 4-(6-(2-cyclopentylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperidine-1-carboxylate (2.9 g, 95%), which was used in the next step without further purification.

[1017] To a stirred solution of tert-butyl 4-(6-(2-cyclopentylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperidine-1-carboxylate (300 mg, 0.702 mmol) in DCM (5 mL) at 0 ° C., a dioxane solution of HCl (4 M; 1.0 mL, 4.0 mmol) was added. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-cyclopentyl-1-(2-(piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one (50 mg, 22%, Example 114) as a gum. 1 H-NMR: δ H (400MHz, DMSO-d6)7.52(1H,d,J 8.0), 7.10-7.07(1H,m), 4.60-4.70(2H,m), 3.78-3.75(2H,m), 2.99-2.91(2H,m), 2.90-2.80(1H,m), 2.60-2.78(1H,m), 2.56- 2.51(2H,m), 2.50-2.41(3H,m), 2.19-2.16(1H,m), 1.76-1.68(4H,m), 1.61-1.57(4H,m), 1.48-1.49(2H,m), 1.14-1.10(2H,m).

[1018] Example 115: Synthesis of 2-cyclopentyl-1-(2-(1-(2-hydroxyethyl)piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one

[1019]

[1020] To a solution of 2-cyclopentyl-1-(2-(piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one (Example 114; 700 mg, 2.14 mmol) in acetonitrile (30 mL) was added 2-bromoethan-1-ol (321 mg, 2.57 mmol) and potassium carbonate (886 mg, 6.41 mmol). The mixture was stirred at 80 ° C for 16 hours and then concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with 10% MeOH in DCM (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-cyclopentyl-1-(2-(1-(2-hydroxyethyl)piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one (120 mg, 38%, Example 115) as a light yellow gel. 1 H-NMR: δ H (400MHz, DMSO-d6)7.52(1H,d,J 8.0), 7.13-7.09 (1H, m), 4.60-4.70 (2H, m), 4.36 (1H, m), 3.78-3.75 (2H, m), 3.53-3.48(2H, m), 2.97-2.91(2H, m), 2.89-2.79(1H, m), 2.78(1H, m), 2.57-2.52(1H,m), 2.43-2.39(4H,m), 2.17(1H,m), 2.07-2.01(2H,m), 1. 77-1.71(6H,m), 1.69-1.59(2H,m), 1.49-1.48(2H,m), 1.15-1.12(2H,m).

[1021] The following examples (119-124) were prepared using a similar procedure to Example 39 using appropriate starting materials.

[1022] Example 119: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(1-methylcyclopentyl)ethan-1-one

[1023]

[1024] Prepared using 2-(1-methylcyclopentyl)acetic acid as the acid component.

[1025] 1 H-NMR: δ H(400 MHz, CDCl3, mixture of rotamers); 7.21 (0.6H, d, J 8.5), 7.16 (0.4H, d, J 8.5), 6.46-6.40 (1H, m), 4.61 (1.2H, s), 4.52 (0.8H, s), 4.44 (2H, s), 3.88 (0.8H, t, J 6.0), 3.76 (1.2H, t, J 5.9), 3.14 (2H, m), 2.89-2.77 (2H, m), 2.68-2.61 (2H, m), 2.48-2.42 (2H, m), 2.07-1.91 (4H, m), 1.64-1.54 (5H, m), 1.54-1.46 (2H, m), 1.09 (1.8H, s), 1.06 (1.2H, s). UPLC (method A): t R 1.45min, 100%, MS(ESI)369.2(M+H) + .

[1026] Example 120: Synthesis of (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(phenyl)methanone

[1027]

[1028] Prepared using benzoic acid as the acid component.

[1029] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.50-7.37 (5H, m), 7.26-6.31 (2H, m), 4.84-4.39 (4H, m), 4.11-3.59 (2H, m), 3.14 (2H, d, J 12.2), 3.01-2.75 (2H, m), 2.63 (2H, d, J 2.2), 2.07-1.87 (4H, m); UPLC (method A): t R 1.05min, 100%, MS(ESI)349.2(M+H) + .

[1030] Example 121: Synthesis of (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(2-methoxyphenyl)methanone

[1031]

[1032] Prepared using 2-methoxybenzoic acid as the acid component.

[1033] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.40-7.26 (2H, m), 7.26-7.23 (1H, m), 7.03-6.91 (2H, m), 6.49-6.34 (1H, m), 4.87-4.72 (1H, m), 4.52-4.39 (2H, m), 4.35-4.19 (1H, m), 3.94-3.73 (3H, m), 3.61-3.44 (1H, m), 3.20-3.07 (2H, m), 2.97-2.70 (2H, m), 2.69-2.61 (2H, m), 2.07-1.90 (4H, m); UPLC (method A): t R 1.09min, 100%, MS(ESI)379.2(M+H) + .

[1034] Example 122: Synthesis of (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(o-tolyl)methanone

[1035]

[1036] Prepared using 2-methylbenzoic acid as the acid component.

[1037] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.33-7.26 (2H, m), 7.24-6.92 (3H, m), 6.52-6.32 (1H, m), 4.99-3.45 (6H, m), 3.18-3.09 (2H, m), 2.99-2.68 (2H, m), 2.66-2.59 (2H, m), 2.35-2.21 (3H, m), 2.06-1.89 (4H, m); UPLC (method A): t R 1.19min,100%,MS(ESI)363.2(M+H) + .

[1038] Example 123: Synthesis of (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(4-fluorophenyl)methanone

[1039]

[1040] Prepared using 4-fluorobenzoic acid as the acid component.

[1041] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.53-7.41 (2H, m), 7.26-6.87 (3H, m), 6.54-6.30 (1H, m), 4.85-4.36 (4H, m), 4.15-3.58 (2H, m), 3.14 (2H, d, J 12.2), 2.99-2.76 (2H, m), 2.65 (2H, d, J 2.3), 2.06-1.91 (4H, m); UPLC (method A): t R 1.12min, 99%, MS(ESI)367.2(M+H) + .

[1042] Example 124: Synthesis of (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentyl-2-hydroxyethan-1-one

[1043]

[1044] Prepared using (2R)-2-cyclopentyl-2-hydroxyacetic acid as the acid component.

[1045] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.19 (1H, dd, J 16.5, 8.5), 6.44 (1H, t, J 7.6), 4.70-4.56 (1H, m), 4.56-4.39 (4H, m), 4.03-3.63 (3H, m), 3.13 (2H, d, J 12.1), 2.91-2.74 (2H, m), 2.63 (2H, dd, J 12.4, 2.2), 2.17-1.86 (5H, m), 1.82-1.61 (4H, m), 1.54-1.31 (4H, m); UPLC (Method A): t R 1.15min, 99%, MS(ESI)371.2(M+H) + .

[1046] Example 125: Synthesis of cyclopentyl 2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[1047]

[1048] At 0 ° C, to a solution of 8- (5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylic acid benzyl ester (50 mg, 0.13 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dichloromethane (1.0 mL) was added cyclopentyl chloroformate (36 μL, 0.30 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and dried in vacuo. The residue was purified by silica gel column chromatography (0% to 50% ethyl acetate in n-heptane) and concentrated in vacuo to give cyclopentyl 2-(3-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (65 mg, quantitative) as a clear solid. UPLC (Method B): t R 2.31min, 94%, MS (ESI) 491.2 (M+H) + .

[1049] Under nitrogen atmosphere, 10% palladium on carbon (7 mg, 6.7 μmol) was added to a solution of cyclopentyl 2-(3-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (33 mg, 67 μmol) in dichloromethane (1 mL) and methanol (1 mL). A hydrogen atmosphere was introduced and the mixture was stirred at room temperature for 3 hours. The mixture was washed with water and then dried over a medium temperature. Filter, concentrate in vacuo, and analyze by preparative reverse phase chromatography (Waters XSelect TM CSH C18 column, aqueous ammonium bicarbonate / acetonitrile) and lyophilized to give cyclopentyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (8 mg, 36%, Example 125) as a beige solid. 1 H-NMR: δ H (400MHz, CDCl3)7.17(1H,d,J 8.6), 6.42(1H,d,J 8.6), 5.19-5.12 (1H, m), 4.50-4.39 (4H, m), 3.71 (2H, m), 3.17-3.09 (2H, m), 2.84-2.75 (2H, m), 2.66-2.58 (2H, m), 2.04-1.82 (6H, m), 1.80-1.69 (4H, m), 1.65-1.59 (2H, m); UPLC (Method D): t R 2.21min, 99%, MS(ESI)357.2(M+H)+ .

[1050] The following example (126) was prepared using a similar procedure to Example 125 using appropriate starting materials.

[1051] Example 126: Synthesis of 2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid isopropyl ester

[1052]

[1053] Prepared using isopropyl chloroformate.

[1054] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.17 (1H, d, J 8.6), 6.42 (1H, d, J 8.5), 4.97 (1H, hept, J 6.4), 4.50-4.38 (4H, m), 3.77-3.67 (2H, m), 3.18-3.08 (2H, m), 2.85-2.76 (2H, m), 2.67-2.58 (2H, m), 2.06-1.88 (4H, m), 1.27 (6H, d, J 6.3); UPLC (Method A): t R 1.92min, 95%, MS(ESI)331.2(M+H) + .

[1055] Example 127: Synthesis of Benzyl 2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[1056]

[1057] To a solution of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (500 mg, 1.86 mmol) in 1,4-dioxane (5 mL) was added a 4M solution of hydrochloric acid in 1,4-dioxane (5.0 mL, 20 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated to give 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (225 mg, 53%) as a yellow solid. LCMS (Method V): t R 1.34min, 89%, MS(ESI)169.1(M+H) + .

[1058] To a solution of 2-chloro-7,8-dihydro-1,6-naphthyridine-6 ​​(5H)-carboxylic acid benzyl ester (417 mg, 1.17 mmol) and triethylamine (382 μL, 2.74 mmol) in 1,4-dioxane (5 mL) was added benzyl chlorocarboxylate (172 μL, 1.21 mmol), and the mixture was stirred at room temperature for 3 days. The mixture was concentrated, distributed between dichloromethane and a saturated aqueous sodium bicarbonate solution, and the layers were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate and concentrated to give 2-chloro-7,8-dihydro-1,6-naphthyridine-6 ​​(5H)-carboxylic acid benzyl ester (417 mg, quantitative) as a light yellow jelly. LCMS (method B): t R 2.02min, 84%, MS(ESI)303.1(M+H) + .

[1059] Under nitrogen atmosphere, a solution of a mixture of 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid benzyl ester (208 mg, 583 μmol), 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (186 mg, 874 μmol), cesium carbonate (342 mg, 1.05 mmol), 2-dicyclohexylphosphine-2′,6′-diisopropoxybiphenyl (15 mg, 32.0 μmol) and Pd2(dba)3 (26 mg, 29 μmol) in 1,4-dioxane (5 mL) was heated at 90° C. for 16 hours. The mixture was passed through Filter and concentrate in vacuo. The residue was purified by silica gel column chromatography (0% to 50% ethyl acetate in n-heptane) and concentrated in vacuo to give 2-(3-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid benzyl ester (138 mg, 48%) as a viscous, transparent solid. LCMS (Method B): t R 2.29min, 97%, MS(ESI)479.2(M+H) + .

[1060] To a solution of benzyl 2-(3-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (69 mg, 0.14 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL, 19 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and analyzed by preparative reverse phase chromatography (Waters XSelect TMCSH C18 column, aqueous ammonium bicarbonate / acetonitrile) and lyophilized to give benzyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (38 mg, 69%, Example 127) as a yellow solid. 1 H-NMR: δ H (400MHz, CDCl3, 7.42-7.29 (5H, m), 7.18 (1H, s), 6.42 (1H, d, J 8.5), 5.18 (2H, s), 4.52 (2H, s), 4.48-4.41 (2H, m), 3.77 (2H, t, J 6.0), 3.20-3.12(2H,m), 2.87-2.76(2H,m), 2.73-2.65(2H,m), 2.13-1.92(4H,m); UPLC (Method A): t R 1.97min, 97%, MS(ESI)379.2(M+H) +

[1061] The following examples (128-130) were prepared using a similar procedure to Example 87 using appropriate starting materials.

[1062] Example 128: Synthesis of (2S)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,3-dimethylbutan-1-one

[1063]

[1064] Prepared using (S)-2,3-dimethylbutyric acid as the acid component.

[1065] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.41-7.29 (1H, m), 6.49-6.44 (1H, m), 4.88-4.36 (7H, m), 3.14 (2H, d, J 12.2), 2.64 (2H, dd, J 12.3, 2.2), 2.43-2.28 (1H, m), 2.10-1.90 (5H, m), 1.15 (3H, d, J 6.7), 1.00-0.91 (6H, m); UPLC (method C): t R 1.79min, 100%, MS(ESI)329.2(M+H) + .

[1066] Example 129: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(1-methylcyclopentyl)ethan-1-one

[1067]

[1068] Prepared using 2-(1-methylcyclopentyl)acetic acid as the acid component.

[1069] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.54-7.38 (1H, m), 6.61-6.42 (1H, m), 4.82-4.52 (6H, m), 3.30 (2H, d, J 12.3), 3.04 (2H, d, J 12.4), 2.40 (2H, d, J 4.5), 2.31-2.14 (4H, m), 1.80-1.46 (9H, m), 1.13 (3H, s); UPLC (method C): t R 2.09min, 100%, MS(ESI)355.2(M+H) + .

[1070] Example 130: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,2-difluoro-2-phenylethan-1-one

[1071]

[1072] Prepared using 2,2-difluoro-2-phenylacetic acid as the acid component.

[1073] 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.73-7.62 (2H, m), 7.58-7.30 (5H, m), 6.51-6.39 (1H, m), 4.85-4.66 (4H, m), 4.41 (2H, d, J 14.1), 3.10 (2H, dd, J 12.4, 5.6), 2.63 (2H, d, J 12.3), 2.131.89 (4H, m); UPLC (method A): t R 1.69min, 98%, MS(ESI)385.2(M+H) + .

[1074] Example 131 and Example 132: Synthesis of Two Enantiomers of 2-Cyclopentyl-1-(2-(3-(hydroxymethyl)piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one (TFA Salt)

[1075]

[1076] Under continuous nitrogen flow, sodium tert-butoxide (207mg, 2.15mmol) and XPhos (68mg, 0.14mmol) were added to a stirred solution of 1-(2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2-cyclopentylethyl-1-one (200mg, 0.717mmol) and 2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester (474mg, 1.44mmol) in toluene (10mL). After 5 minutes, Pd2(dba)3(65mg, 0.072mmol) was added and the resulting mixture was heated at 100°C for 16 hours. After completion of the reaction, which was monitored by TLC, the reaction mixture was concentrated to obtain a residue, which was diluted with water (15mL) and extracted with a 20% MeOH solution in DCM (20mL×2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography using a solution of petroleum ether (0 to 100%) of EtOAc as eluent to give the desired product, 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(6-(2-cyclopentylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (570 mg, 69%), as a yellow jelly.

[1077] At 0 ° C, to a DCM (10 mL) stirred solution of tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(6-(2-cyclopentylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperazine-1-carboxylate (470 mg, 0.820 mmol) was added TFA (3.14 mL, 41.0 mmol), and the resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by reverse phase preparative HPLC. The fractions were concentrated and the enantiomers were separated by chiral preparative SFC. The two fractions were collected and lyophilized to give fraction-1 (30 mg, Example 131) and fraction-2 (36 mg, Example 132), respectively.

[1078] First eluting isomer (Example 131): 1 H-NMR: δ H(400 MHz, DMSO-d6, mixture of rotamers) 9.12-9.01 (1H, m), 8.69-8.62 (1H, m), 7.47-7.44 (1H, m), 6.82-6.80 (1H, m), 5.45 (1H, brs), 4.55-4.41 (2H, m), 4.28-4.21 (2H, m), 3.74-3.72 (2H, m), 3.69-3.61 (1H, m), 3.59-3.58 (2H, m), 3.07-3.04 (2H, m), 2.91-2.77 (1H, m), 2.68-2.60 (2H, m), 2.55-2.41 (2H, m) , 2.39-2.33(2H,m), 1.81-1.75(2H,m), 1.59-1.48(4H,m), 1.26-1.12(2H,m); MS(ESI)359.2(M+H) + .

[1079] Second eluting isomer (Example 132): 1 H-NMR: δ H (400 MHz, DMSO-d6, mixture of rotamers) 9.12-9.01 (1H, m), 8.69-8.62 (1H, m), 7.47-7.44 (1H, m), 6.82-6.80 (1H, m), 5.45 (1H, brs), 4.55-4.41 (2H, m), 4.28-4.21 (2H, m), 3.74-3.61 (4H, m), 3.59- 3.58(2H,m), 3.07-3.04(2H,m), 2.91-2.77(1H,m), 2.68-2.55(2H,m), 2.39-2.33(2H,m), 2.3 3-2.11(1H, m), 1.81-1.75(2H, m), 1.59-1.48(4H, m), 1.26-1.12(m, 2H); MS(ESI)359.2(M+H) + .

[1080] Example 133: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-phenylethan-1-one

[1081]

[1082] At 0 ° C, to a solution of 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (400 mg, 2.36 mmol) in DCM (7 mL) was added n-propylphosphonic anhydride (cyclic trimer) (50% in EtOAc) (2.25 mL, 7.07 mmol) and DIPEA (1.92 mL, 11.8 mmol). After 15 minutes, 2-phenylacetic acid (642 mg, 4.72 mmol) was added and stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water (15 mL) and extracted with 5% MeOH in DCM (15 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-phenylethan-1-one (1.8 g, 60%) as an off-white solid.

[1083] To a stirred solution of 1-(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-phenylethan-1-one (1.8 g, 6.26 mmol) in n-butanol (10 mL) was added ter...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt or derivative thereof, in: One or two of Y1, Y2 and Y3 are N, and the rest are CR 3b ; Q is C or S(O); R 1 is a 4- to 10-membered non-aromatic ring containing at least 1 ring N heteroatom and optionally a ring O heteroatom, which can be monocyclic, bridged or bicyclic, and wherein R 1 Optional use of 1 or more R 4 replace; A is for R 2C NR 2a R 2b OR 2f ; R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which can be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, which is optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of 1 or more R 5 replace; R 2b is H or (C1-6) alkyl, and wherein the (C1-6) alkyl is optionally substituted with one or more R 5 replace; or R 2a and R 2b Together with the N atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally substituted with 1 or more R 5 replace; R 2c is a (C3-10) alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10) alkyl group can be optionally substituted by 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of 1 or more R 5 replace; R 2f is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which can be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, which is optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2f Optional use of 1 or more R 5 replace; R 3a are each independently (C1-6)alkyl or fluorine, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R attached to the same or adjacent carbon atoms 3a can, together with the atoms to which they are attached, form a 3- to 6-membered carbocyclic ring or a heterocyclic ring containing O heteroatoms, wherein the ring is optionally substituted with 1 or more halogens; R 3b Each is independently H or (C1-6) alkyl; R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; R 5 Each is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogen or OH; n is 0, 1, 2, 3 or 4; and a is 0 or 1, b is 1 or 2, wherein when b is 2, a is 0; The compound or a pharmaceutically acceptable salt or derivative thereof is used for treating or preventing a disease or condition that can be improved by activating the long isoform of PDE4 or a disease or condition mediated by excessive intracellular cyclic AMP signaling.

2. The compound for use according to claim 1, wherein the compound is a compound having the following formula: or a pharmaceutically acceptable salt or derivative thereof.

3. The compound for use according to claim 1 or 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is: a 5- to 6-membered saturated monocyclic ring containing at least 1 ring N heteroatom and an optional ring O heteroatom; a 7- to 9-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms; a 9-membered saturated bridged ring system containing 2 ring N heteroatoms and a ring O heteroatom; or a 7- to 10-membered saturated fused or spirocyclic ring system containing 1 or 2 ring N heteroatoms; and wherein R 1 Optionally substituted with 1, 2 or 3 R4.

4. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is a 4- to 10-membered non-aromatic ring containing at least 1 ring N heteroatom and optionally a ring O heteroatom, which can be monocyclic, bridged or bicyclic; wherein R 1 Optionally substituted with 1 R4.

5. The compound for use according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, optionally a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, for example a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octyl, wherein R 1 Optional 1 R 4 replace.

6. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein when substitution occurs on an aliphatic group, R 5 are each independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy groups are optionally substituted with one or more halogen or OH; and when substitution occurs on an aromatic group, R 5 Each is independently halogen, CN, (C1-6)alkyl, (C1-6)alkoxy or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogen or OH.

7. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein: a) R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or (C2-10)alkyl, which can be linear, branched or cyclic or a combination thereof, optionally (C3-10)alkyl; and wherein R 2a Optional use of 1 or more R 5 Replacement; and R 2b is H or (C1-6) alkyl, and wherein the (C1-6) alkyl is optionally substituted with one or more R 5 replace; or R 2a and R 2b Together with the N atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally substituted with 1 or more R 5 replace; or b) R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group can be optionally substituted with 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of 1 or more R 5 replace; or c) R 2f is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which can be linear, branched or cyclic or a combination thereof; and wherein R 2f Optional use of 1 or more R 5 replace.

8. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein: a) R 2a is a (C5-10)alkyl group containing a cyclic portion; and wherein R 2a Optional use of 1 or more R 5 Replacement; and R 2b is H or (C1-6) alkyl, and wherein the (C1-6) alkyl is optionally substituted with one or more R 5 replace; or b) R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which can be linear or branched, optionally a (C3-10)alkyl group; and wherein R 2a Optional use of 1 or more R 5 substituted, optionally wherein R 5 is halogen; and R 2b is H or (C1-6) alkyl, and wherein the (C1-6) alkyl is optionally substituted with one or more R 5 replace.

9. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein R 2c yes: a) a (C3-10) alkyl group containing a cyclic portion, wherein the C atom in the linear or cyclic portion of the (C3-10) alkyl group can be optionally substituted by one -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and Where R 2c Optional use of 1 or more R 5 replace; b) CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a (C3-10) alkyl group which can be straight chain or branched, wherein the C atom in the straight chain part of the (C3-10) alkyl group can be optionally substituted by 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Use one or more R 5 substituted, optionally wherein R 5 It is a halogen.

10. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound is a compound having the formula, or a pharmaceutically acceptable salt or derivative thereof.

11. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein R 3a Each is -CH3 or F, or two R attached to the same carbon 3a Together with the atoms to which they are attached they form a cyclopropyl ring.

12. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0, 1 or 2.

13. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0.

14. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein Q is C and / or A is R 2c .

15. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein Q is C; R 1 is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1 Optional 1 R 4 replace; A is for R 2c ; R 2c is a (C3-10) alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10) alkyl group can be optionally substituted by 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of 1 or more R 5 replace; R 3a , when present, is a methyl group; R 4 , when present, is (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH; R 5 , when present, is OH or a halogen; and n is 0, 1 or 2.

16. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein one of Y1, Y2 and Y3 is N and the others are each CR 3b .

17. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein a is 1 and b is 1.

18. A compound for use according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound is a compound having the formula, or a pharmaceutically acceptable salt or derivative thereof, optionally wherein: R1 is a 6-membered saturated monocyclic ring containing 2 ring N heteroatoms or a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, which is optionally substituted with one or more R 4 Replace; and / or R 2c is a (C3-10) alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10) alkyl group can be optionally substituted by 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of 1 or more R 5 replace.

19. A compound of formula II or a pharmaceutically acceptable salt or derivative thereof, in: One or two of Y1, Y2 and Y3 are N, and the others are CR 3b ; Q is C or S(O); R 1a is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, and wherein R 1a Optional use of 1 or more R 4 replace; A is for R 2c NR 2a R 2b OR 2f ; R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which can be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, which is optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of 1 or more R 5 replace; R 2b is H or (C1-6) alkyl, and wherein the (C1-6) alkyl is optionally substituted with one or more R 5 replace; or R 2a and R 2b Together with the N atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally substituted with 1 or more R 5 replace; R 2c is a (C3-10) alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10) alkyl group can be optionally substituted by 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of 1 or more R 5 replace; R 2f is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which can be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, which is optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2f Optional use of 1 or more R 5 replace; R 3a are each independently (C1-6)alkyl or fluorine, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R attached to the same or adjacent carbon atoms 3a can be linked together to form a 3- to 6-membered carbocyclic ring or a heterocyclic ring containing an O heteroatom, which is optionally substituted with one or more halogens; R 3b Each is independently H or (C1-6) alkyl; R 4 are each independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; R 5 Each is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogen or OH; n is 0, 1, 2, 3 or 4; and a is 0 or 1, and b is 1 or 2, wherein when b is 2, a is 0.

20. The compound according to claim 18 or a pharmaceutically acceptable salt or derivative thereof, wherein R 1a is a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, such as a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octyl, wherein R 1 Optional 1 R 4 replace.

21. A compound according to any one of claims 18 or 19 or a pharmaceutically acceptable salt or derivative thereof, wherein the compound is a compound having the formula, or a pharmaceutically acceptable salt or derivative thereof.

22. The compound according to any one of claims 18 to 20, or a pharmaceutically acceptable salt or derivative thereof, wherein one of Y1, Y2 and Y3 is N, and the others are each CR 3b .

23. A compound of formula III or a pharmaceutically acceptable salt or derivative thereof, in: One of Y1, Y2 and Y3 is N, and the others are CR 3b ; Q is C or S(O); R 1b is a 4- to 10-membered non-aromatic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, which can be monocyclic, bridged or bicyclic, wherein at least one ring N heteroatom is not in R 1b At the connection point, and where R 1b Optional use of 1 or more R 4 replace; A is for R 2c or NR 2a R 2b ; R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C2-10)alkyl group which can be linear, branched or cyclic or a combination thereof; a (C5-7)cycloalkyl group fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, which is optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2a Optional use of 1 or more R 5 replace; R 2b is H or (C1-6) alkyl, and wherein the (C1-6) alkyl is optionally substituted with one or more R 5 replace; or R 2a and R 2b Together with the N atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally substituted with 1 or more R 5 replace; R 2c is a (C3-10) alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10) alkyl group can be optionally substituted by 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of 1 or more R 5 replace; R 3a are each independently (C1-6)alkyl or fluorine, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R attached to the same or adjacent carbon atoms 3a can be linked together to form a 3- to 6-membered carbocyclic ring or a heterocyclic ring containing an O heteroatom, which is optionally substituted with one or more halogens; R 3b Each is independently H or (C1-6) alkyl; R4 is each independently halogen, CN, OH, (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl or -(C1-6) alkylene-(C1-6) alkoxy, wherein the (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl and -(C1-6) alkylene-(C1-6) alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6) alkoxy; R 5 Each is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogen or OH; n is 0, 1, 2, 3 or 4; and a is 0 or 1.

24. The compound according to claim 22, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1b is: a 5- to 6-membered saturated monocyclic ring containing at least 1 ring N heteroatom and an optional ring O heteroatom; or a 7- to 9-membered saturated bridged ring system containing 1 or 2 ring N heteroatoms; a 9-membered saturated bridged ring system containing 2 ring N heteroatoms and a ring O heteroatom; or a 7- to 10-membered saturated fused or spirocyclic ring system containing 1 or 2 ring N heteroatoms; and wherein R 1b Choose to use 1, 2 or 3 R 4 replace.

25. The compound according to claim 22 or 23, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1b is a 6-membered saturated monocyclic ring containing 2 ring N heteroatoms or a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms; wherein R 1a Optional 1 R 4 substituted, optionally wherein R 1a is a 7- to 8-membered saturated bridged ring system containing 2 ring N heteroatoms, such as a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octyl, wherein R 1b Optional 1 R 4 replace.

26. A compound according to any one of claims 18 to 24, or a pharmaceutically acceptable salt or derivative thereof, wherein a is 1, and b, when present, is 1.

27. A compound according to any one of claims 18 to 25, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound is a compound having the formula, or a pharmaceutically acceptable salt or derivative thereof, optionally wherein the compound is a compound of formula III, and wherein: R 1b is a 6-membered saturated monocyclic ring containing 2 ring N heteroatoms or a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, which is optionally substituted with one or more R 4 Replace; and / or R 2c is a (C3-10) alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10) alkyl group can be optionally substituted by 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of 1 or more R 5 replace.

28. A compound according to any one of claims 18 to 25, or a pharmaceutically acceptable salt or derivative thereof, wherein: a) R 2a is: a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or (C2-10)alkyl, which can be linear, branched or cyclic or a combination thereof, optionally (C3-10)alkyl; and wherein R 2a Optional use of 1 or more R 5 Replacement; and R 2b is H or (C1-6) alkyl, and wherein the (C1-6) alkyl is optionally substituted with one or more R 5 replace; or R 2a and R 2b Together with the N atom to which they are attached, they form a 5- to 7-membered non-aromatic heterocyclic ring, which optionally contains 1 additional heteroatom selected from O and is optionally substituted with 1 or more R 5 replace; or b) R 2c is: CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; or a (C3-10)alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10)alkyl group can be optionally substituted with 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of 1 or more R 5 replace.

29. A compound according to any one of claims 18 to 27, or a pharmaceutically acceptable salt or derivative thereof, wherein R 2c yes: a) a (C3-10) alkyl group containing a cyclic portion, wherein the C atom in the linear or cyclic portion of the (C3-10) alkyl group can be optionally substituted by one -O-, but R 2c , wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and Where R 2c Optional use of 1 or more R 5 replace; b) CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; CH2-O-[a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms]; a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a (C3-10)alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic part of the (C3-10)alkyl group can be optionally substituted with 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Use one or more R 5 substituted, optionally wherein R 5 It is a halogen.

30. A compound according to any one of claims 18 to 28, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound is a compound having the formula, or a pharmaceutically acceptable salt or derivative thereof.

31. A compound according to any one of claims 18 to 29, or a pharmaceutically acceptable salt or derivative thereof, wherein Q is C and / or A is R 2c .

32. A compound according to any one of claims 18 to 29, or a pharmaceutically acceptable salt or derivative thereof, wherein: Q is C; R 1a or R 1b is a 7- to 9-membered saturated bridged ring system containing 2 ring N heteroatoms, wherein R 1a and R 1b Optional 1 R 4 replace; A is for R 2c ; R 2c is a (C3-10) alkyl group which can be linear, branched or cyclic or a combination thereof, wherein the C atom in the linear or cyclic portion of the (C3-10) alkyl group can be optionally substituted by 1 -O-, but R 2c wherein the (C3-10)alkyl group can be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and wherein R 2c Optional use of 1 or more R 5 replace; R 3a , when present, is a methyl group; R 4 , when present, is (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH; R 5 , when present, is OH or a halogen; and n is 0, 1 or 2.

33. A compound according to any one of claims 18 to 31, or a pharmaceutically acceptable salt or derivative thereof, wherein each R3a is -CH3, or two R3a attached to the same carbon 3a Together with the atoms to which they are attached they form a cyclopropyl ring.

34. A compound according to any one of claims 18 to 32, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0, 1 or 2.

35. A compound according to any one of claims 18 to 33, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0.

36. A compound selected from: 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-phenoxyethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3,3-dimethylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3-methylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2,3-dimethylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-phenylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4-fluorophenoxy)ethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(cyclopentyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4-fluorophenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2,2-difluoro-2-phenylethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(pyrrolidin-1-yl)methanone; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-ethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-cyclopentylethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide; N-cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide; 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-one; 2-Cyclopentyl-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(pyrrolidin-1-yl)methanone; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N,N-diethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; (R)-2-cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; (S)-2-cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-Cyclopentyl-1-(2-(piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-Cyclopentyl-1-(2-(1-(2-hydroxyethyl)piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(1-methylcyclopentyl)ethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(2-methoxyphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(o-tolyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(4-fluorophenyl)methanone; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentyl-2-hydroxyethan-1-one; 2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid cyclopentyl ester; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid isopropyl ester; Benzyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; (2S)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,3-dimethylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(1-methylcyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,2-difluoro-2-phenylethan-1-one; (R)-2-cyclopentyl-1-(2-(3-(hydroxymethyl)piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; (S)-2-cyclopentyl-1-(2-(3-(hydroxymethyl)piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-phenylethan-1-one; 2-phenyl-1-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-phenylethan-1-one; 4-(2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-oxoethyl)benzonitrile; 4-(2-Oxo-2-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethyl)benzonitrile; 4-(2-(2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-oxoethyl)benzonitrile; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(4-fluorophenyl)ethan-1-one; 2-(4-Fluorophenyl)-1-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(4-fluorophenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-cyclopentylethan-1-one; 2-cyclopentyl-1-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-cyclohexylethan-1-one; 2-cyclohexyl-1-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3,3-dimethylbutan-1-one; (4-Fluorophenyl)(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-cyclopentylethan-1-one; 3,3-Dimethyl-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)butan-1-one; 1-(2-(4-ethylpiperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3,3-dimethylbutan-1-one; 1-(2-(3,9-diazabicyclo[3.3.1]non-9-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,9-diazabicyclo[3.3.1]non-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one; 1-(2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one; 1-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one; 1-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one; 2-Cyclopentyl-1-(2-(7-hydroxy-3,9-diazabicyclo[3.3.1]non-9-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-6-((4-fluorobenzyl)sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 2-(3-ethyl-3,8-diazabicyclo[3.2.1]oct-8-yl)-6-((4-fluorobenzyl)sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 6-((4-fluorobenzyl)sulfonyl)-2-(piperazin-1-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 2-(4-ethylpiperazin-1-yl)-6-((4-fluorobenzyl)sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 6-(Benzylsulfonyl)-2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 6-(Benzylsulfonyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]oct-8-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 6-(Benzylsulfonyl)-2-(piperazin-1-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 6-(Benzylsulfonyl)-2-(4-ethylpiperazin-1-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-((S)-chroman-4-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; N-((S)-Chroman-4-yl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; N-((R)-chroman-4-yl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; 1-(2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4-fluorophenoxy)ethan-1-one; 2-(4-Fluorophenoxy)-1-(2-(3-propyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-(4-Fluorophenoxy)-1-(2-(3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-(4-Fluorophenoxy)-1-(2-(3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-phenyl-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-(4-Fluorophenyl)-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 1-(3-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-2-cyclopentylethan-1-one; 1-(6-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-cyclopentylethan-1-one; 1-(7-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-2-cyclopentylethan-1-one; 2-(4-Fluorophenoxy)-1-(2-(piperazin-1-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; or a pharmaceutically acceptable salt or derivative thereof.

37. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or derivative as defined in any one of claims 1 to 35, and a pharmaceutically acceptable excipient.

38. A compound or pharmaceutically acceptable salt or derivative as claimed in any one of claims 18 to 35 for use in therapy.

39. Use of a compound or pharmaceutically acceptable salt or derivative according to any one of claims 18 to 35, or a pharmaceutical composition according to claim 36, for treating or preventing a disease or condition that can be ameliorated by activation of the long isoform of PDE4 or a disease or condition mediated by excessive intracellular cyclic AMP signaling.

40. A compound or pharmaceutically acceptable salt or derivative for use according to any one of claims 1 to 17, or a compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to claim 38, for use in treating or preventing a disease or condition mediated by excessive intracellular cyclic AMP signaling.

41. A method of treating or preventing a disease or condition that can be ameliorated by activation of the long isoform of PDE4 or a disease or condition mediated by excessive intracellular cyclic AMP signaling, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt or derivative as defined in any one of claims 1 to 35.

42. Use of a compound or pharmaceutically acceptable salt or derivative as defined in any one of claims 1 to 35 for the preparation of a medicament for treating or preventing a disease or condition that can be ameliorated by activation of the long isoform of PDE4 or a disease or condition mediated by excessive intracellular cyclic AMP signalling.

43. The method of claim 40 or the use of claim 41, wherein the disease or condition that can be ameliorated by activation of the long isoform of PDE4 is a disease or condition mediated by excessive intracellular cyclic AMP signaling.

44. The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to claim 39, or the method or use according to any one of claims 40 to 42, wherein the excessive intracellular cyclic AMP signaling is caused by: a. The adenoma produces too high a level of hormones; bGain-of-function mutations in G protein-coupled receptors (GPCRs); c. Activating mutations in the GNAS1 gene, which encodes the G protein G s α-subunit of d. Bacterial toxins.

45. A compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to any one of claims 1 to 17 or 38, 39 or 43, or a method or use according to any one of claims 40 to 43, wherein the disease is cancer, optionally wherein the cancer is prostate cancer.

46. ​​A compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to any one of claims 1 to 17 or 38, 39 or 43, or a method or use according to any one of claims 40 to 43, wherein the disease is: a. Pituitary adenoma, Cushing's disease, polycystic kidney disease or polycystic liver disease; b. Hyperthyroidism, Janssen's metaphyseal chondrodysplasia, hyperparathyroidism or familial male precocious puberty; c.McCunn-Albright syndrome; d. Cholera, whooping cough, anthrax or tuberculosis; e. HIV, AIDS or common variable immunodeficiency disease (CVID); f. Melanoma, pancreatic cancer, leukemia, prostate cancer, adrenal cortical tumor, testicular cancer, primary pigmented nodular adrenocortical disease (PPNAD), or Carney complex; g. Autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD); or h. Maturity-onset diabetes of youth type 5 (MODY5); or i. Cardiac hypertrophy.

47. The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to claim 45, the method or use, wherein the disease is: a. Autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD); or b. Hyperparathyroidism.

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