Compounds and their use as PDE4 activators - Patent application

Abstract

The present invention relates to compounds of formulas I to V and Ib to Vb, their use as activators of the long chain cyclic molecule phosphodiesterase-4 (PDE4) enzyme (isoforms), and in methods for the treatment or prevention of disorders requiring a reduction in second messenger responses mediated by cyclic 3',5'-adenosine monophosphate (cAMP).

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds as defined herein, their use as activators of long form cyclic nucleotide phosphodiesterase-4 (PDE4) enzymes (isoforms), and treatments using these compounds. In particular, the present invention relates to these compounds for use in methods for the treatment or prevention of disorders requiring a reduction in second messenger responses mediated by cyclic 3',5'-adenosine monophosphate (cAMP).

[0002] Background of the Invention Cyclic 3',5'-adenosine monophosphate (cAMP) is a critical intracellular biochemical messenger involved in the transduction of the cellular effects of various 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 and degradation rates. cAMP is generated by biosynthetic enzymes in the adenylyl 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, whereas others specifically degrade cyclic guanosine monophosphate (cGMP) or both cAMP and cGMP. The PDE4 enzyme inactivates cAMP and terminates its signaling by hydrolyzing it to 5'-AMP (Lugnier, C. Pharmacol Ther. 109: 366-398, 2006).

[0003] Four PDE4 genes (PDE4A, PDE4B, PDE4C, and PDE4D) have been identified. Each encodes many different enzyme isoforms through the use of alternative promoters and mRNA splicing. Based on their primary structure, catalytically active PDE4 splice variants can be classified as "long," "short," or "super-short" forms (Houslay, MD Prog Nucleic Acid Res Mol Biol. 69: 249-315, 2001). A "dead short" form also exists, which is not catalytically active (Houslay, MD, Baillie, GS, and Maurice, DH Circ Res. 100: 950-66, 2007). The long forms of PDE4 have two regulatory regions, called upstream conserved regions 1 and 2 (UCR1 and UCR2), located between the N-terminal portion and the catalytic domain, which are unique to these isoforms. The UCR1 region is absent from the short forms, and the ultrashort forms not only lack UCR1 but also have a truncated UCR2 region (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 within cells (Richter, W and Conti, MJ Biol. Chem. 277: 40212-40221, 2002; Bolger, GB et al., Cell. Signal. 27: 756-769, 2015). Proposed negative allosteric denaturation of the long form of PDE4 by small molecules has been reported (Burgin AB et al., Nat. Biotechnol. 28: 63-70, 2010; Gurney ME et al., Handb. Exp. Pharmacol. 204: 167-192, 2011). Summary of the Invention [Problem to be solved by the invention]

[0005] It is known in the art that PDE4 long chain forms 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 PDE4D3 by ectopic expression of a 57-amino acid protein (termed "UCR1C"), whose exact sequence reflects part of the upstream conserved region 1 of PDE4D (the sequence of UCR1C reflects amino acids 80-136, while the UCR is amino acids 17-136; numbering is based on the PDE4D3 long isoform), has recently been reported (Wang, L. et al., Cell. Signal. 27: 908-922, 2015: "UCR1C is a novel activator of the long isoform of phosphodiesterase 4 (PDE4) and attenuates cardiomyocyte hypertrophy"). The authors hypothesized that PDE4 activation might be used as a potential therapeutic strategy to prevent cardiac hypertrophy.

[0006] The first small molecule acting as an activator of the long-chain form of PDE4 has recently been described in WO2016 / 151300, WO2018 / 060704, and WO2019 / 193342. Recently, small molecule activators of the PDE4 long form have been evaluated in a cell-based model of autosomal dominant polycystic kidney disease (ADPKD) (Omar et al., PNAS 116: 13320-13329, 2019). Clinical development of small molecule activators of the PDE4 long form has not yet been reported. Additional structurally distinct small molecule activators of the PDE4 long form are still needed for potential development as therapeutic agents.

[0007] One object of the present invention is to provide at least one novel small molecule activator of the long chain form of PDE4 for use in therapy and in the treatment or prevention of certain diseases. [Means for solving the problem]

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

[0009] [ka]

[0010] One or two of Y1, Y2, and Y3 are N, and the rest are CR 3b is; Q is C or S(O); R 1 is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally one ring O heteroatom; R 1 is one or more R 4 optionally replaced by; A is R 2c , N.R. 2a R 2b OR 2f and; R 2ais a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c and R is optionally substituted with one —O— at a position other than the point of attachment of R; said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2—[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH2—O—[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 R 2c is one or more R 5 may be substituted with; R 2fis a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2f is one or more R 5 may be substituted with; Each R 3a are independently (C1-6) alkyl or fluoro, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; or two R 3a may be joined together with the atoms to which they are attached to form a 3- to 6-membered carbocyclic or heterocyclic ring containing an O heteroatom; The ring may be optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6) alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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, and when b is 2, a is 0.

[0011] In a second aspect of the present invention, there is provided a compound of formula II below, or a pharmaceutically acceptable salt or derivative thereof:

[0012] [ka]

[0013] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are each CR 3b is; Q is C or S(O); R 1a is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1a is one or more R 4 may be substituted with; A is R 2c , or NR 2a R 2b OR 2f and R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2btogether with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c with one —O— other than at the point of attachment of R; said (C3-10)alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2—[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH2—O—[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 R 2c is one or more R 5 may be substituted with; R 2f is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2f is one or more R 5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's attached to the same or adjacent carbon atoms 3a may be joined together to form a 3- to 6-membered carbocyclic or heterocyclic ring containing one O heteroatom, optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6) alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1, b is 1 or 2, and when b is 2, a is 0.

[0014] In a third aspect of the present invention, there is provided a compound of formula III or a pharmaceutically acceptable salt or derivative thereof:

[0015] [ka]

[0016] In the formula, one of Y1, Y2, and Y3 is N, and the others are each CR 3b is; Q is C or S(O); R 1b is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally a ring O heteroatom, wherein at least one ring N heteroatom is selected from the group consisting of R 1b is not at the attachment point of R 1b is one or more R 4 may be substituted with; A is R 2c , or NR 2a R 2b and optionally A is R 2c and; R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c with one —O— other than at the point of attachment of R, and said (C3-10)alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2—[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH2—O—[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 R 2c is one or more R5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's attached to the same or adjacent carbon atoms 3a may be joined together to form a 3-6 membered carbocyclic or heterocyclic ring containing an O heteroatom, optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6) alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

[0017] A fourth aspect of the present invention provides a compound of formula IV or a pharmaceutically acceptable salt or derivative thereof:

[0018] [ka]

[0019] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are each CR 3b is; Q is C or S(0); R 1 is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally one ring O heteroatom; R 1 is one or more R 4 optionally replaced by; Z is R 2e or NR 2d R 2b and; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 and R 2d teeth a) a (C5-10) alkyl group containing a cyclic moiety; R 2d is one or more R 5 or b) a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10) alkyl group (optionally a C3-10 alkyl group), which may be linear or branched; R 2d is one or more R 5 (optionally, R 5 is a halogen); R 2e teeth, a) (C3-10) alkyl groups containing cyclic moieties, wherein a C atom of the linear or cyclic moiety of said (C3-10) alkyl group is selected from the group consisting of R 2e with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2e is one or more R 5 or 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 linear or branched, wherein the C atom of the linear part of said (C3-10) alkyl group is selected from the group consisting of R 2e with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2e is one or more R 5 (possibly substituted with R 5 is a halogen); Each R 3a are independently (C1-6) alkyl optionally substituted with one or more halogens, or two R 3a may be joined together with the atoms to which they are attached to form a 3- to 6-membered carbocyclic or heterocyclic ring containing an O heteroatom, wherein said ring is optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6) alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1, b is 1 or 2, and when b is 2, a is 0.

[0020] In a fifth aspect of the present invention, there is provided a compound of formula V or a pharmaceutically acceptable salt or derivative thereof;

[0021] [ka]

[0022] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are CR 3b is; Q is C or S(O); R 1 is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally one ring O heteroatom; R 1 is one or more R 4 optionally replaced by; A is NR 2a R 2b or R 2c and; R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c with one —O— other than at the point of attachment of R, and said (C3-10)alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2—[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH2—O—[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 R 2c is one or more R 5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two Rs attached to the same or adjacent carbon atoms 3a may be joined together with the atoms to which they are attached to form a 3- to 6-membered carbocyclic or heterocyclic ring containing an O heteroatom, wherein said ring is optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6) alkyl; Each R 4are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; m is 1, 2, 3, or 4; and a is 0 or 1, b is 1 or 2, and when b is 2, a is 0.

[0023] The compounds described herein are shown in the Examples to activate the PDE4 long form enzyme. In a further aspect, the present invention provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt or derivative, and a pharmaceutically acceptable excipient. In a further aspect, the present invention provides a compound or pharmaceutical composition described herein for use in therapy. The therapy can be treatment or prevention of a disease or disorder that can be improved by activating the long isoform of PDE4. The therapy can be treatment or prevention of a disease or disorder mediated by excessive intracellular cAMP signaling. In these diseases, reducing the second messenger response mediated by cyclic 3',5'-adenosine monophosphate (cAMP) should have a therapeutic effect.

[0024] Also provided are methods for treating or preventing a disease or disorder that can be ameliorated by activation of the long isoform of PDE4, comprising administering to a patient in need thereof an effective amount of a compound or pharmaceutical composition described herein.Also provided are methods for treating or preventing a disease or disorder mediated by excessive intracellular cAMP signaling, comprising administering to a patient in need thereof an effective amount of a compound or pharmaceutical composition described herein.

[0025] Also provided is the use of a compound or pharmaceutical composition described herein in the manufacture of a medicament for treating or preventing a disease or disorder that can be ameliorated by activating the long isoform of PDE4. Also provided is the use of a compound or pharmaceutical composition described herein in the manufacture of a medicament for treating or preventing a disease or disorder mediated by excessive intracellular cAMP signaling.

[0026] In certain embodiments of the aforementioned aspects, the compounds of the present invention are provided for the treatment or prevention of cancer. In certain embodiments of the aforementioned aspects, the compounds of the present invention are provided for the treatment or prevention of a disease or disorder selected from hyperthyroidism, Janssens metaphyseal chondrodysplasia, hyperparathyroidism, familial male-limited 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 tumor, 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.

[0027] Detailed Description The present invention is based on the surprising identification of novel compounds that can activate the long-chain isoform of the PDE4 enzyme. Because these compounds are small molecules, they are expected to be easier and cheaper to manufacture and formulate into pharmaceuticals than larger biomolecules such as polypeptides, proteins, and antibodies. As shown in the examples, the compounds can be chemically synthesized.

[0028] The examples demonstrate that many compounds of formula IV and Ib-Vb can activate the long chain isoform of PDE4.The examples continue to demonstrate that certain test compounds of the present invention do not activate the short chain form of PDE4, thereby showing the selectivity for activating the long chain form of PDE4 over the short chain form of PDE4.The examples further demonstrate that the PDE4 long chain form activator of the present invention reduces cAMP-driven cyst formation in the in vitro model of ADPKD.

[0029] Various aspects and embodiments are disclosed herein, and it will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments.

[0030] The compound of formula IV shown above, or its pharmaceutically acceptable salt or derivative, is described herein.Formula IV is described herein.The compound of formula IV, or its pharmaceutically acceptable salt or derivative, can be provided for use in the treatment or prevention of diseases or disorders that can be improved by the activation of the long chain isoform of PDE4.The compound of formula IV, or its pharmaceutically acceptable salt or derivative, can be provided for use in the treatment or prevention of diseases or disorders that are mediated by excessive intracellular cAMP signaling.

[0031] Also described herein are compounds of formula Ib-Vb shown below, or pharmaceutically acceptable salts or derivatives thereof. Compounds of formula Ib-Vb, or pharmaceutically acceptable salts or derivatives thereof, can be provided for use in the treatment or prevention of diseases or disorders that can be improved by activating the long-chain isoform of PDE4. Compounds of formula Ib-Vb, or pharmaceutically acceptable salts or derivatives thereof, can be provided for use in the treatment or prevention of diseases or disorders mediated by excessive intracellular cAMP signaling.

[0032] Described herein are compounds of formula Ib, or a pharmaceutically acceptable salt or derivative thereof:

[0033] [ka]

[0034] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are CR 3b is; Q is C or S(O); 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 R 1 is one or more R 4 optionally replaced by; A is NR 2a R 2b or R 2c and; R 2ais a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; 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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c with one —O— other than at the point of attachment of R, and said (C3-10)alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's attached to the same or adjacent carbon atoms3a may be joined together with the atoms to which they are attached to form a 3- to 6-membered ring optionally further containing an O heteroatom, said ring being optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6)alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

[0035] Also provided is a compound of formula IIb, or a pharmaceutically acceptable salt or derivative thereof;

[0036] [ka]

[0037] In the formula, one or two of Y1, Y2, and Y3 are N, and the rest are each CR 3b is; Q is C or S(O); R 1a is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1a is one or more R 4 may be substituted with; A is NR 2a R 2b or R 2c and; R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; 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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; Each R 3ais independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's 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 and optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6)alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

[0038] Also provided is a compound of formula IIIb, or a pharmaceutically acceptable salt or derivative thereof:

[0039] [ka]

[0040] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are each CR 3b is; Q is C or S(O); R 1bis a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally a ring O heteroatom, wherein at least one ring N heteroatom is selected from the group consisting of R 1b Not at the attachment point of R 1b is one or more R 4 may be substituted with; A is NR 2a R 2b or R 2c and; R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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 fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is any R greater than or equal to 1 5 may be substituted with; moreover; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 may be substituted with; R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; 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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2cwith one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's 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 and optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6)alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1; If one of X1 and X2 is N and the other is S, and X3 is C, then R 1b is not a monocyclic piperazine ring.

[0041] Also provided is a compound of formula IVb, or a pharmaceutically acceptable salt or derivative thereof;

[0042] [ka]

[0043] In the formula, one or two of Y1, Y2, and Y3 are N, and the rest are each CR 3b is; Q is C or S(O); 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 R 1 is one or more R 4 optionally replaced by; Z is NR 2d R 2b or R 2e and; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 and R 2d teeth a) a (C5-10) alkyl group containing a cyclic moiety; 2d is one or more R 5 or b) a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10) alkyl group (optionally a (C3-10) alkyl group) which may be linear or branched; and R 2d is one or more R 5 (possibly substituted with R 5 is a halogen); R 2e teeth, a) a (C3-10) alkyl group containing a cyclic moiety, wherein the C atom of the linear or cyclic moiety of said (C3-10) alkyl group is R 2ewith one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2e is one or more R 5 or 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 (C3-10) alkyl group, which may be linear or branched, wherein the C atom of the linear part of said (C3-10) alkyl group is selected from the group consisting of R 2e with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2e is one or more R 5 (possibly substituted with R 5 is a halogen); Each R 3a are independently (C1-6) alkyl optionally substituted with one or more halogens; or two R 3a may be joined together with the atoms to which they are attached to form a 3- to 6-membered ring optionally further containing an O heteroatom, said ring being optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6)alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

[0044] Also provided is a compound of formula Vb, or a pharmaceutically acceptable salt or derivative thereof:

[0045] [ka]

[0046] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are CR 3b is; Q is C or S(0); 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 R 1 is one or more R 4 optionally replaced by; A is NR 2a R 2b or R 2c and; R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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 fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; 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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's attached to the same or adjacent carbon atoms 3a may be joined together with the atoms to which they are attached to form a 3 to 6 membered ring optionally further containing an O heteroatom, wherein said ring is optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6)alkyl; Each R 4are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; m is 1, 2, 3, or 4; and a is 0 or 1.

[0047] In compounds of formula I, R 1 is a 4-10 membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally one ring O heteroatom; R 1 may contain one or more R 4 The monocyclic, bridged, or bicyclic ring may be saturated or partially saturated, or in the case of a bicyclic ring, combinations thereof. It will be understood that the ring N atom in a saturated or partially saturated ring, when unsubstituted, may be NH (where valence permits). It will also be understood that there are no additional ring heteroatoms other than "at least one ring N heteroatom" (i.e., one or more ring N heteroatoms) and any "ring O heteroatoms."

[0048] In the compounds of formula Ib, R 1 is a 4-10 membered monocyclic, bridged or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and R 1 may contain one or more R 4The monocyclic, bridged, or bicyclic ring may be saturated, partially saturated, or aromatic, or in the case of a bicyclic ring, combinations thereof. It will be understood that the ring N atom in a saturated or partially saturated ring, when unsubstituted, may be NH (where valence allows). It will also be understood that there are no additional ring heteroatoms other than "at least one ring N heteroatom" (i.e., one or more ring N heteroatoms) and any "O ring heteroatoms."

[0049] In embodiment (1) of formula I or Ib, R 1 is R 1 contains at least one ring N heteroatom at a position that is not the point of attachment of R 1 (The remainder of the formula I or Ib may be as defined for any of embodiments (6)-(31) of formula I or Ib described herein, mutatis mutandis.)

[0050] In embodiment (2) of formula I or Ib, R 1 is a 4-10 membered ring that may be monocyclic, bridged, or bicyclic, containing one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom. 1 is one or more R 4 may be substituted with R 1 is R 1 and optionally, at least one ring N heteroatom other than at the point of attachment of Formula I or Ib. The remainder may be as defined for Formula I or Ib, or any of embodiments (6)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0051] In embodiment (3) of Formula I, R 1is a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom (e.g., one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom); or a 7-8 membered saturated bridged ring containing one or two ring N heteroatoms; a 9 membered saturated bridged ring containing two ring N heteroatoms and a ring O-heteroatom; or a 7-10 membered saturated, fused or spiro ring containing one or two ring N heteroatoms, optionally two ring N heteroatoms; and R 1 is an R of 1 or more 4 optionally substituted with R 1 is sometimes 1, 2 or 3 R 4 may be substituted with R 1 is R 1 may contain at least one ring N heteroatom other than the point of attachment of Formula I. The remainder may be as defined for Formula I or any of the embodiments (6)-(31) of Formula I described herein.

[0052] In embodiment (3) of formula Ib, R 1 is a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom (e.g., one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom); a 5-6 membered aromatic monocyclic ring containing one or two ring N heteroatoms; or a 7-8 membered saturated bridged ring containing one or two ring N heteroatoms; a 9 membered saturated bridged ring containing two ring N heteroatoms and one ring O-heteroatom; or a 7-10 membered saturated, fused or spiro ring containing one or two ring N heteroatoms, optionally two ring N heteroatoms; 1 is one or more R 4 and R 1 is one, two or three R 4 may be substituted with R 1 is R 1 and optionally includes at least one ring N heteroatom other than the point of attachment of Formula Ib. The remainder may be as defined for Formula Ib, or any of embodiments (6)-(31) of Formula Ib described herein, mutatis mutandis.

[0053] In formula I, or any of the alternatives of embodiments (1), (2) or (3), R 1 R may be a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom (i.e., no ring O heteroatoms). 1 may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms or a 7-8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms, and R 1 may contain one or more R 4 It is replaced by R 1 may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms; or a 7-8 membered saturated bridged ring containing 1 or 2 ring N heteroatoms, where at least one ring N heteroatom is R 1 does not exist at the connection point of R 1 is one or more R 4 may be substituted with R 1 may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8 membered saturated bridged ring containing 1 or 2 ring N heteroatoms, where at least one ring N heteroatom is R 1 does not exist at the connection point of R 1 is one R 4 may be substituted with R 1 may be a 6-membered saturated monocyclic ring containing two ring N heteroatoms; or a 7-8-membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one R 4 may be substituted with R 1 may be a 7-8 membered saturated bridged ring containing two ring N heteroatoms, and R 1 may contain one R 4 may be substituted with R 1 may be a 7- to 8-membered saturated bridged ring containing two ring N heteroatoms, e.g., a bridged piperazine such as 3,8-diazabicyclo[3.2.1]octanyl, and R 1 is one R 4The remainder may be as defined for Formula I, or any of embodiments (6)-(31) of Formula I described herein, mutatis mutandis.

[0054] In formula Ib, or any of the alternatives of embodiments (1), (2) or (3), R 1 R can be a 4-10 membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom (i.e., no ring O heteroatoms). 1 may be a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms, and R 1 is sometimes 1 or more R 4 It is replaced by R 1 may be a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms, at least one of which is R 1 does not exist at the attachment point of R 1 may contain one or more R 4 It is replaced by R 1 may be a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms, at least one of which is R 1 does not exist at the attachment point of R 1 may be one R 4 is replaced by R 1 can be a 6-membered saturated or aromatic monocyclic ring containing two ring N heteroatoms; or a 7-8-membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one R 4 may be substituted with R 1 may be a 7-8 membered saturated bridged ring containing two ring N heteroatoms, and R 1 may contain one R 4 may be substituted with R 1may be a 7-8 membered saturated bridged ring containing two ring N heteroatoms, for example, a bridged piperazine such as 3,8-diazabicyclo[3.2.1]octanyl, and R 1 is one R 4 The remainder may be as defined for Formula Ib, or any of embodiments (6)-(31) of Formula Ib described herein, mutatis mutandis.

[0055] In formula I, or any of the alternatives of embodiments (1), (2) or (3), R 1 is piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, azetidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl or 3,8-diazabicyclo[3.2.1]octanyl, 3,9-diazabicyclo[3.3.1]nonanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 4,7 ...6-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.1] pyrro[2.5]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 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 may be selected from the group consisting of one or more R 4 and preferably 1-3 R 4 and preferably one R 4 may be substituted with R 1 can be a radical of the structure:

[0056] [ka]

[0057] [ka]

[0058] R 1is one or more R 4 and R 1 1-3 R 4 may be substituted with R 1 may be piperidinyl, piperazinyl, pyrrolidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each of which may be one or more R 4 and preferably 1-3 of R 4 and preferably one R 4 may be substituted with R 1 is piperidinyl or piperazinyl, each of which is one or more R 4 and preferably 1-3 of R 4 and preferably one R 4 may be substituted with R 1 can be a radical of the structure:

[0059] [ka]

[0060] where W is CH or N, and R 4’ is H or R 4 R 1 is a 7-8 membered saturated bridged ring containing two ring N heteroatoms, such as the saturated bridged ring:

[0061] [ka]

[0062] For example, it can be a bridged piperazine such as:

[0063] [ka]

[0064] The remainder of the moieties may be as defined in Formula I, or any of embodiments (6)-(31) of Formula I described herein, mutatis mutandis.

[0065] In formula Ib, or any of the alternatives of embodiments (1), (2) or (3), R 1 is piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyridinyl, azetidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl or 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 4,7-diazaspiro[2. 5]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 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 selected from the group consisting of one or more R 4 and preferably 1 to 3 R 4 and preferably one R 4 Optionally substituted with R 1 can be a radical of the structure:

[0066] [ka]

[0067] [ka]

[0068] R 1 is one or more R 4 and R 1 1-3 R 4 may be substituted with R 1may be piperidinyl, piperazinyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyridinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each of which may be one or more R 4 and preferably 1-3 R 4 and preferably one R 4 is optionally replaced by R 1 is piperidinyl, piperazinyl, or pyridinyl, each of which is one or more R 4 and preferably 1-3 of R 4 and preferably one R 4 may be substituted with.

[0069] R 1 can be a group of the following structural formula:

[0070] [ka]

[0071] where W is CH or N, and R 4 ' is H or R 4 ; or possibly one R 4 R is pyridyl (optionally 3-pyridyl) substituted with 1 may be a 7- to 8-membered saturated bridged ring containing two ring N heteroatoms, such as:

[0072] [ka]

[0073] For example, it can be a bridged piperazine such as:

[0074] [ka]

[0075] The remainder may be as defined in Formula Ib, or any of embodiments (6)-(31) of Formula Ib described herein, mutatis mutandis.

[0076] In embodiment (4) of formula I or Ib, R 1 is a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; or a 7- to 8-membered saturated bridged ring containing one or two ring N heteroatoms, and R 1 is 1, 2 or 3 R 4 In any of the alternatives of embodiment (4), R 1 is R 1 R may contain at least one ring N heteroatom that is not at the point of attachment of R 1 R may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8 membered saturated bridged ring containing 1 or 2 ring N heteroatoms. 1 may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms, where R 1 is one R 4 The remainder may be as defined for Formula I or Ib, or any of embodiments (6)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0077] In embodiment (5) of formula I or Ib, R 1 is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one or more R 4 is optionally replaced by R 1 may be a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1a is one, two or three R 4 may be substituted with R 1may be an optionally substituted 7- to 8-membered saturated bridged ring containing two ring N heteroatoms. The remainder may be as defined for Formula I or Ib, or any of embodiments (6)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0078] In any of the alternatives of Formula I or embodiments (1)-(5), R 1 is one or more R 4 may be substituted with R 1 When R contains a substitutable ring N atom, 1 may be substituted on any substitutable ring N atom. 1 is one R 4 R may be substituted, preferably on the ring N atom. 1 In embodiments where R is a saturated ring 1 is one R 4 R may be substituted, preferably on the ring N atom. 1 In embodiments where R is a six-membered ring, 1 is one R 4 may be substituted with R 1 In embodiments where R is a five-membered ring, 1 is 1, 2 or 3 R 4 may be substituted with.

[0079] In any of the alternatives of formula Ib or embodiments (1)-(5), R 1 is one or more R 4 may be substituted with R 1 When R contains a substitutable ring N atom, 1 may be substituted on any substitutable ring N atom. 1 In embodiments where R is a saturated ring 1 is one R 4 R may be substituted, preferably on the ring N atom. 1 In embodiments where R is an aromatic ring, 1 is 1, 2 or 3 R 4 may be substituted with R 1 In embodiments where R is a six-membered ring, 1is one R 4 may be substituted with R 1 In embodiments where R is a five-membered ring, 1 is 1, 2 or 3 R 4 may be substituted with.

[0080] In compounds of formula I and Ib, each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and (Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy. 4 may independently represent a substituent on a carbon atom or a substituent on a substitutable N atom.

[0081] In embodiment (6) of formula I or Ib, each R 4 are independently halogen, OH, CN, (Ci_4)alkyl, (Ci_3)alkoxy, (C3_6)cycloalkyl, -(Ci_3)alkylene-(Ci_3)alkoxy, wherein the (Ci_3)alkyl, (Ci_3)alkoxy, (C3_6)cycloalkyl and -(Ci_3)alkylene-(Ci_3)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH, and (Ci_3)alkoxy. 4 may independently be F, Cl, OH, CN, (Ci_4)alkyl, methoxy, ethoxy, cyclopropyl, or -(CH)-O-(CH)-O-CH, wherein the (Ci_4)alkyl is optionally substituted with one or more substituents independently selected from halogen and OH. The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(5) or (9)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0082] In embodiment (7) of formula I or Ib, each R 4 are independently halogen, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl, and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH, and (Ci_6)alkoxy. 4 can independently be 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. 4 are independently F, Cl, OH, (C1-4) alkyl, methoxy, ethoxy, cyclopropyl, or -(CH2)2-O-(CH2)2-O-CH 3、 wherein the (Ci_4) alkyl is optionally substituted with one or more substituents independently selected from halogen and OH, and the remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(5) or (9)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0083] In embodiment (8) of formula I or Ib, each R 4 are independently halogen, CN, OH, (Ci_2)alkyl, (Ci_6)alkoxy, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_2)alkyl, (Ci_6)alkoxy, and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH, and (Ci_6)alkoxy. 4may independently be F, Cl, OH, (Ci_2)alkyl, methoxy, ethoxy, or -(CH2)2-O-(CH2)2-O-CH3, where the (Ci_2)alkyl is optionally substituted with one or more substituents independently selected from halogen and OH. The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(5) or (9)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0084] In formula I or Ib, or any of embodiments (6)-(8), R 4 When attached to a ring N atom, R independently represents a group other than halogen, CN, OH, and -(C1-6)alkoxy. 4 may be any of the options identified herein for

[0085] In the compounds of formula I, A is NR 2a R 2b , R 2c , or OR 2f and R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is selected from one or more R 5 or R 2a and R 2btogether with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 is replaced by; 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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c and R is optionally substituted with one —O— atom other than the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; R 2f is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2f is one or more R 5 may be substituted with. In the compounds of formula Ib, A is NR 2a R 2b or R 2c and R 2ais a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is selected from one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 is replaced by; 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; a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with.

[0086] In compounds of formula I and Ib, each R 5are 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 halogens or OH.

[0087] In embodiment (9) of formula I or Ib, each R 5 are independently halogen, OH, CN, (C1-4) alkyl, or (C1-4) alkoxy, wherein the (C1-4) alkyl and (C1-4) alkoxy groups are optionally substituted with one or more halogen or OH, preferably one or more fluoro or one OH. When substituted on an aliphatic group, each R 5 may independently be halogen, OH, CN, (Ci_6)alkyl, (Ci_6)alkoxy, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_6)alkyl and (Ci_6)alkoxy may be substituted with one or more halogen or OH, and when substituted on an aromatic group, each R 5 may independently be halogen, CN, (Ci_6)alkyl, (Ci_6)alkoxy, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_6)alkyl and (Ci_6)alkoxy are optionally substituted with one or more halogens or OH. 5 may independently be halogen, CN, (C1-4) alkyl, or (C1-4) alkoxy, wherein the (C1-4) alkyl and (C1-4) alkoxy groups are optionally substituted with one or more halogen or OH, preferably one or more fluoro or one OH. 5 may independently be halogen, CN, or (C1-4) alkyl, where the (C1-4) alkyl group may be substituted with one or more halogens, preferably one or more fluoros. 5 may independently be halogen (preferably fluoro), CN, or CF. 5may independently be halogen (preferably fluoro). The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(8) or (10)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0088] In embodiment (10) of formula I or Ib, R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, and R 2a is one or more R 5 is optionally replaced by R 2a is 0, 1, or 2 R 5 , preferably 0 or 1 R 5 may be substituted with R 2a is optionally substituted with halogen, CN or (C1-4) alkyl, and the (C1-4) alkyl group is optionally substituted with one or more halogens, preferably one or more fluoro. 2a is optionally substituted with halogen (preferably fluoro), CN, or CF. The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(9), (13), or (21)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0089] In embodiment (11) of formula I or Ib, R 2a is CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], and R 2a is one or more R 5 may be substituted with R 5 Substitution by R 2a It will be understood that the -CH2- linker or the aromatic or heteroaromatic ring of R 2ais 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 fluoro), 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, and the (C1-4) alkyl group is optionally substituted with one or more halogens (preferably optionally one or more fluorines). The aromatic or heteroaromatic ring may be optionally substituted with halogens (preferably fluoro), CN, or CF3. The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(9), (13), or (21)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0090] In embodiment (12) of formula I or Ib, R 2a is a (C2-10) alkyl group which may be linear, branched, or cyclic, or a combination thereof; R 2a is one or more R 5 is optionally replaced by R 2a is 0, 1, or 2 R 5 , preferably 0 or 1 R 5 may be substituted with R 2a may be a (C3-10) alkyl group which may be linear, branched, or cyclic or a combination thereof; R 2a In some cases, R 5 may be substituted with R 2a can be a (C4-10) alkyl group which may be linear, branched, or cyclic or a combination thereof; R 2a In some cases, R 5 may be substituted with R 2a can be a (C5-10) alkyl group which may be linear, branched, or cyclic or a combination thereof; R 2a In some cases, R 5 may be substituted with R 2a may be a (C5-10) alkyl group containing a cyclic moiety, where R2a is R 5 The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(9), (13), or (21)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0091] In any of embodiments (10)-(12) of formula I or Ib, R 2a is one or more R 5 can be replaced by R 5 is preferably substituted with halogen (eg fluoro).

[0092] In embodiment (13) of formula I or Ib, R 2b is H or (C1-3) alkyl, and the (C1-3) alkyl is optionally one or more R 5 is replaced by R 2b may be H, CH, or CHCH. The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(12) or (21)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0093] In embodiment (14) of formula I or Ib, R 2a and R 2b together with the N atom to which they are attached form a 5-7 membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with R 2a and R 2b may be joined together with the N atom to which they are attached to form a 5- to 7-membered non-aromatic heterocycle, and one or more R 5 R 2a and R 2b may be joined together with the N atom to which they are attached to form a 5-membered non-aromatic heterocycle, and one or more R 5 R 2a and R 2bThe ring formed by these together can contain 0 or 1 R 5 The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(9) or (21)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0094] In embodiment (15) of formula I or Ib, A is R 2c Preferably, Q is also C.

[0095] In embodiment (16) of formula I or Ib, R 2c is CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], and R 2c is one or more R 5 may be substituted with R 5 Substitution by R 2c It will be understood that the -CH2- linker or the aromatic or heteroaromatic ring of R 2c is CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], where CH2 is substituted with 1 or 2 halogens (preferably fluoro, -CHF-, or -CF2-), and the aromatic or heteroaromatic ring is optionally substituted with 1, 2, or 3 (preferably 1 or 2, preferably 1) halogen, CN, or (C1-4) alkyl, where the (C1-4) alkyl group is optionally substituted with one or more halogens (preferably one or more fluoro). The aromatic or heteroaromatic ring is optionally substituted with halogen (preferably fluoro), CN, or CF3. The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(9), (15), or (21)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0096] In embodiment (17) of formula I or Ib, R 2c is CH2-O-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], and R2c is one or more R 5 may be substituted with R 5 Substitution by R 2c It will be understood that the -CH2- linker or the aromatic or heteroaromatic ring of R 2c is 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 fluoro), 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, and the (C1-4) alkyl group is optionally substituted with one or more halogens (preferably optionally one or more fluoro). The aromatic or heteroaromatic ring is optionally substituted with halogens (preferably fluoro), CN, or CF3. The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(9), (15), or (21)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0097] In embodiment (18) of formula I or Ib, R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R 2c is one or more R 5 (e.g., one or two R 5 , where R 5 is optionally substituted with fluoro or OH, preferably fluoro). 2c is a (C3-10) alkyl group containing a cyclic moiety, and a C atom of the linear or cyclic moiety of said (C3-10) alkyl group is optionally selected from R 2cwith one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R 2c is one or more R 5 (e.g., 1 or 2 R 5 , where R 5 is fluoro or OH, preferably fluoro). 2c may be a (C3-10) alkyl group containing a cyclic moiety, and a C atom of the linear or cyclic moiety of said (C3-10) alkyl group may optionally be selected from R 2c may be substituted with one -O- at a point other than the attachment point of R 2c is one or more R 5 (e.g., one or two R 5 , where R 5 is optionally substituted with fluoro or OH, preferably fluoro). 2c may be a (C3-10) alkyl group containing a cyclic moiety, and R 2c is one or more R 5 (e.g., one or two R 5 , where R 5 is optionally substituted with fluoro or OH, preferably fluoro). 2c is preferably present on the cyclic moiety, e.g., two R 5 The remainder may be as defined for Formula I or Ib, or any of (1)-(9), (15), or (21)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0098] In embodiment (19) of formula I or Ib, R 2c is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, and R 2c is one or more R 5 is optionally replaced by R 2c is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, and R 2c is one or two R5 , for example, halogen (preferably fluoro), (C1-4)alkoxy, or (C1-4)alkyl. The (C1-4)alkyl group is optionally substituted with one or more halogens (preferably, optionally substituted with one or more fluoro). The remainder may be as defined for Formula I or Ib, or any of (1)-(9), (15), or (21)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0099] In any of embodiments (16)-(19) of formula I or Ib, R 2c is one or more R 5 can be replaced by R 5 may be halogen, for example fluoro.

[0100] In embodiment (20) of Formula I, R 2f is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; R 2f is one or more R 5 may be substituted with R 5 Substitution by R 2f It will be understood that the -CH2- linker or the aromatic or heteroaromatic ring of R 2f can be CH2-[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, cyclic, or a combination thereof; R 2f is one or more R 5 The remainder may be as defined for Formula I, or any of embodiments (1)-(9) or (21)-(31) of Formula I described herein, mutatis mutandis.

[0101] In Formula I or Ib, or any of embodiments (10)-(20) of Formula I or Ib, when substituted on a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, R 5 can independently be halogen, CN, (Ci_6)alkyl, (Ci_6)alkoxy, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_6)alkyl and (Ci_6)alkoxy are optionally substituted with one or more halogen or OH.

[0102] In compounds of formula I and Ib, each R 3a are independently (C1-6) alkyl or fluoro, 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 may be joined together with the atoms to which they are attached to form a 3- to 6-membered carbocyclic or heterocyclic ring containing an O heteroatom, wherein the ring is optionally substituted with one or more halogens. 3b are independently H or (C1-6) alkyl.

[0103] In embodiment (21) of formula I or Ib, each R 3a is independently (C1-3) alkyl or fluoro, where (C1-3) alkyl is optionally substituted with one or more halogens, and / or each R 3b is independently H or (C1-3) alkyl. 3a may be -CH3 or F. Each R 3b may be —CH or H. The remainder may be as defined mutatis mutandis for Formula I or Ib, or any of embodiments (1)-(20) or (23)-(31) of Formula I or Ib described herein.

[0104] In embodiment (22) of formula I or Ib, two R 3amay be joined together with the atoms to which they are attached to 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 may be joined together with the atoms to which they are attached to form a 3- to 6-membered ring, wherein the ring is optionally substituted with one or more halogens. 3a may be joined together with the atoms to which they are attached to form a 3- to 6-membered ring. 3a When two R 3a It is understood that when two R are attached to adjacent carbon atoms, a fused ring is formed. 3a may be joined together with the atoms to which they are attached to form a cyclopropyl ring, and the remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(20) or (23)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0105] In embodiment (23) of formula I or Ib, each R 3b may independently be H or (C1-3) alkyl. 3b may be —CH or H. Preferably, each R 3b is H. The remainder may be as defined mutatis mutandis for Formula I or Ib, or any of embodiments (1)-(22) or (24)-(31) of Formula I or Ib described herein.

[0106] In compounds of formula I and Ib, n is 0, 1, 2, 3 or 4.

[0107] In embodiment (24) of Formula I or Ib, n is 0. The remainder of the moieties may be as defined for Formula I or Ib, or any of embodiments (1)-(23) or (26)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0108] In embodiment (25) of Formula I or Ib, n is 0, 1, 2, or 3. Preferably, n is 0, 1, or 2. The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(23) or (26)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0109] In compounds of formula I and Ib, Q is C or S(O).

[0110] In embodiment (26) of Formula I or Ib, Q is C. The remainder of the moieties may be as defined for Formula I or Ib, or any of embodiments (1)-(25) or (27)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0111] In the compounds of formula I and Ib, one or two of Y1, Y2 and Y3 are N and the others are CR 3b is.

[0112] In embodiment (27) of formula I or Ib, one of Y1, Y2, and Y3 is N and the others are each CR 3b The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(26) or (29)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0113] In embodiment (28) of formula I or Ib, Y1 is N and Y2 and Y3 are CR 3b Thus, a compound of formula I or Ib can be a compound of the following structure:

[0114] [ka]

[0115] In the formula, R 1 , Q, A, R 3a, n, a, and b are as defined for Formula I or Ib, or any of embodiments (1)-(26) or (29)-(31) of Formula I or Ib described herein.

[0116] In compounds of formula I, a is 0 or 1, b is 1, or 2, and when b is 2, a is 0. In compounds of formula Ib, a is 0 or 1.

[0117] In embodiment (29) of Formula I or Ib, a is 0. The compound of Formula I or Ib, or a pharmaceutically acceptable salt or derivative thereof, can be the following compound, or a pharmaceutically acceptable salt or derivative thereof:

[0118] [ka]

[0119] The compound or a pharmaceutically acceptable salt or derivative thereof may be the following compound or a pharmaceutically acceptable salt or derivative thereof:

[0120] [ka]

[0121] The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(28) of Formula I or Ib described herein, mutatis mutandis.

[0122] In embodiment (30) of Formula I or Ib, a is 1 and the compound of Formula I or Ib, or a pharmaceutically acceptable salt or derivative thereof, can be the following compound, or a pharmaceutically acceptable salt or derivative thereof:

[0123] [ka]

[0124] The compound or a pharmaceutically acceptable salt or derivative thereof may be the following compound or a pharmaceutically acceptable salt or derivative thereof:

[0125] [ka]

[0126] The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(28) of Formula I or Ib described herein, mutatis mutandis.

[0127] In embodiment (31) of Formula I, a is 0 and b is 2, and the compound, or a pharmaceutically acceptable salt or derivative thereof, can be the following compound, or a pharmaceutically acceptable salt or derivative thereof:

[0128] [ka]

[0129] Alternatively, the compound or a pharmaceutically acceptable salt or derivative thereof may be the following compound or a pharmaceutically acceptable salt or derivative thereof:

[0130] [ka]

[0131] The remainder may be as defined for Formula I, or any of embodiments (1)-(28) of Formula I described herein, mutatis mutandis.

[0132] In embodiment (32) of formula I or Ib: Q is C; R 1 is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one R 4 may be substituted with; A is R 2c and; R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; R 3a is methyl, if present; R 4 is, if present, (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH; R 5 is, if present, OH or halo; and n is 0, 1, or 2; and optionally b is 1. The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(31) of Formula I or Ib described herein, mutatis mutandis.

[0133] In embodiment (33) of Formula I or Ib, the compound or a pharmaceutically acceptable salt or derivative thereof can be a compound of the following structure, or a pharmaceutically acceptable salt or derivative thereof:

[0134] [ka]

[0135] In the formula, R 1 is a 6-membered saturated monocyclic ring containing two ring N heteroatoms or a 7-9-membered saturated bridged ring containing two ring N heteroatoms, optionally containing one or more R 4 and / or R 2cis a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(31) of Formula I or Ib described herein, mutatis mutandis. For example, n may be 0, and R 2c may be as defined according to embodiment (18) of formula I or Ib.

[0136] Compounds of formula I include compounds of formulas II-V. Compounds of formula Ib include compounds of formulas IIb-Vb. Embodiments (1)-(24) of formula I or Ib can be applied mutatis mutandis to formulas II-V or IIb-Vb, respectively.

[0137] Provided herein are compounds of Formula II, or pharmaceutically acceptable salts or derivatives thereof:

[0138] [ka]

[0139] In the formula, R 1a is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1a is one or more R 4 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 in Formula I or in the description of embodiments (6)-(31) of Formula I above.

[0140] Provided herein are compounds of formula IIb, or pharmaceutically acceptable salts or derivatives thereof:

[0141] [ka]

[0142] R 1a is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1a is one or more R 4 may be substituted with; 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 for Formula 1b or any of embodiments (6)-(31) of Formula Ib above.

[0143] In embodiment (1) of formula II or IIb, R 1a is a 7-8 membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one or more R 4 may be substituted with, for example, 1, 2 or 3 R 4 may be substituted with R 1a is a 7-8 membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one R 4 may be substituted with R 1a may be a bridged piperazine such as 3,8-diazabicyclo[3.2.1]octanyl, and R 1a is one R 4 may be substituted with R 1a may also be a bridged piperazine such as:

[0144] [ka]

[0145] In any of Formula II or IIb, or embodiments of Formula II or IIb, R 1a is one or more R 4 may be optionally substituted with R 1a When R contains a substitutable ring N atom, 1a R may be substituted preferably on a substitutable ring N atom. 1a is one R 4 It may be substituted by, preferably on the ring N atom.

[0146] In embodiment (2) of Formula II or IIb, the compound or a pharmaceutically acceptable salt or derivative thereof is a compound of the following structure, or a pharmaceutically acceptable salt or derivative thereof:

[0147] [ka]

[0148] R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c at any point other than the point of attachment of R to R, and said (C3-10) alkyl group may be substituted with one -O-, and said (C3-10) alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 The remainder may be as defined for Formula I, Ib, II, or IIb, or any embodiment of Formula I, Ib, II, or IIb described herein, mutatis mutandis. For example, n may be 0, and R 2c may be as defined according to embodiment (18) of formula I or Ib.

[0149] Also provided herein are compounds of Formula III, or pharmaceutically acceptable salts or derivatives thereof:

[0150] [ka]

[0151] In the formula, R 1b is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally a ring O heteroatom, wherein at least one ring N heteroatom is selected from the group consisting of R 1a is not at the attachment point of R 1a is one or more R 4 may be substituted with; 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 for Formula I or any of embodiments (6)-(31) of Formula I above.

[0152] Also provided is a compound of formula IIIb, or a pharmaceutically acceptable salt or derivative thereof:

[0153] [ka]

[0154] In the formula, R 1b is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally a ring O heteroatom, wherein at least one ring N heteroatom is selected from the group consisting of R 1a is not at the attachment point of R 1a is one or more R 4 may be substituted with; 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 for Formula Ib or any of embodiments (6)-(31) of Formula Ib above.

[0155] In the compounds of formula III or IIIb, R 1b is R 1b contains at least one ring N heteroatom that is not the point of attachment to R, i.e., the ring N atom is not the point of attachment to the ring containing Y, Y, and Y 1b must be located at a position that is not the attachment point of

[0156] In embodiment (1) of formula III or IIIb, R 1b is a 4-10 membered non-aromatic ring that may be monocyclic, bridged, or bicyclic containing one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom; R 1 In some cases, R is 1 or more 4 is replaced by

[0157] R 1b may be a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a 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 containing one or two ring N heteroatoms; or a 9-membered saturated bridged ring containing two ring N heteroatoms and a ring O-heteroatom; or a 7- to 10-membered saturated, fused, or spirocyclic ring containing one or two ring N heteroatoms; R 1b is an R of 1 or more 4 , possibly 1, 2 or 3 R 4 may be substituted with.

[0158] In embodiment (2) of formula III or II1b, R 1bis a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom (e.g., one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom); or a 7- to 8-membered saturated bridged ring containing one or two ring N heteroatoms; R 1b is one or more R 4 , possibly 1, 2 or 3 R 4 may be substituted with R 1b may be a 6-membered saturated monocyclic ring containing one or two ring N heteroatoms, and optionally at least one ring N heteroatom is R 1b It is not at the connection point of R 1b can be a 6-membered saturated monocyclic ring containing one or two ring N heteroatoms, and R 1b is one R 4 may be substituted with R 1b may be a 7-8 membered saturated bridged ring containing one or two ring N heteroatoms, and R 1b is one or more R 4 , possibly 1, 2 or 3 R 4 may be substituted with R 1b may be a 7- to 8-membered saturated bridged ring containing two ring N heteroatoms, for example, a bridged piperazine such as 3,8-diazabicyclo[3.2.1]octanyl, where R 1b may be one R 4 is replaced by .

[0159] In Formula III or IIIb, or any of the embodiments of Formula III or IIIb, R 1b may be piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, or 3,9-diazabicyclo[3.3.1]nonanyl, each of which may be one or more R 4 and preferably 1 to 3 R 4 and preferably one R 4 It is replaced by R 1bcan be a radical of the structure:

[0160] [ka]

[0161] [ka]

[0162] In the formula, R 1b is an R of 1 or more 4 and R 1b 1-3 R 4 and preferably one R 4 may be substituted with R 1b may be piperidinyl, piperazinyl, pyrrolidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each of which may be selected from the group consisting of one or more R 4 Optionally substituted with, preferably 1-3 of R 4 and preferably one R 4 is optionally replaced by R 1b may be piperidinyl or piperazinyl, each of which may contain one or more R 4 and preferably 1-3 of R 4 and preferably one R 4 may be substituted with R 1b can have the following structure:

[0163] [ka]

[0164] where W is CH or N, and R 4’ is H or R 4 R 1bmay also be a 7-8 membered saturated bridged ring containing two ring N heteroatoms, such as:

[0165] [ka]

[0166] For example, it can be a bridged piperazine such as:

[0167] [ka]

[0168] In Formula III or IIIb, or any of the embodiments of Formula III or IIIb, R 1b is one or more R 4 may be optionally substituted with R 1b When R contains a substitutable ring N atom, 1b is preferably substituted on a substitutable ring N atom. 1b is one R 4 It may be substituted by, preferably on the ring N atom.

[0169] In Formula III or IIIb, or any of the embodiments of Formula III or IIIb, R 1b R can be a 4-10 membered non-aromatic ring that may be monocyclic, bridged, or bicyclic containing at least one ring N heteroatom (i.e., no ring O heteroatoms). 1b may be a 6-membered saturated monocyclic ring containing one or two ring N heteroatoms or a 7- to 8-membered saturated bridged ring containing one or two ring N heteroatoms, and R 1b may contain one or more R 4 is replaced by .

[0170] In embodiment (3) of Formula III or 111b: Q is C; R 1ais a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one R 4 may be substituted with; A is R 2c and; R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c at any point other than the point of attachment of R to R, and said (C3-10) alkyl group may be substituted with one -O-, and said (C3-10) alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; R 3a is methyl, if present; R 4 is, if present, (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH; R 5 is, if present, OH or halo; and n is 0, 1, or 2; and optionally b is 1.

[0171] In embodiment (4) of Formula III or IIIb, the compound or a pharmaceutically acceptable salt or derivative thereof is a compound of the following structure, or a pharmaceutically acceptable salt or derivative thereof:

[0172] [ka]

[0173] R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2cwith one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 The remainder may be as defined for Formula I, Ib, III or IIIb, or any embodiment of Formula I, Ib, III or IIIb described herein, mutatis mutandis. For example, R 1b can be a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom (e.g., one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom), where R 1b is one or more R 4 may be substituted with R 1b can be a 6-membered saturated monocyclic ring containing at least one ring N heteroatom (e.g., one ring N heteroatom or two ring N heteroatoms), and R 1b is one or more R 4 R 1b may be a 6-membered saturated monocyclic ring containing at least one ring N heteroatom (e.g., one ring N heteroatom or two ring N heteroatoms), and R 1b is one R 4 may be substituted with R 4 If there is R 4 may be (C1-6) alkyl optionally substituted with OH, or (C1-2) alkyl optionally substituted with OH. n may be 0. R 2c may be as defined according to embodiment (18) of formula I or Ib.

[0174] In the embodiments of formula III or IIIb described herein, A is preferably R 2c or NR 2a R 2b , preferably R 2c is.

[0175] Provided herein are compounds of formula IV or pharmaceutically acceptable salts or derivatives thereof:

[0176] [ka]

[0177] In the formula, Z is NR 2d R 2b or R 2e and; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is selected from one or more R 5 and R 2d teeth a) a (C5-10) alkyl group containing a cyclic moiety; R 2d is one or more R 5 or b) a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10) alkyl group (optionally a (C3-10) alkyl group) which may be linear or branched; R 2d is one or more R 5 (possibly substituted with R 5 is a halogen); R 2e teeth, a) a (C3-10) alkyl group containing a cyclic moiety, wherein the C atom of the linear or cyclic moiety of said (C3-10) alkyl group is R 2e with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R 2e is one or more R 5 or 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 linear or branched, wherein the C atom of the linear part of said (C3-10) alkyl group is selected from the group consisting of R 2e with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R 2e is one or more R 5 (possibly substituted with R 5 is a halogen); Each R 3a are independently (C1-6) alkyl optionally substituted with one or more halogens, or two R 3a may be joined together with the atoms to which they are attached to form a 3 to 6 membered ring optionally further containing an O heteroatom, wherein said ring is optionally substituted with one or more halogens; Y1, Y2, Y3, R 1 , R 3a , R 3b , Q, R 4 , R 5 , a, b and n are as defined according to Formula I or embodiments (1)-(9) and (21)-(31) of Formula I above.

[0178] The present specification also provides a compound of formula IVb, or a pharmaceutically acceptable salt or derivative thereof:

[0179] [ka]

[0180] In the formula, Z is NR 2d R 2b or R 2e and; R 2bis H or (C1-6) alkyl, and the (C1-6) alkyl is selected from one or more R 5 is optionally replaced by, and R 2d teeth a) a (C5-10) alkyl group containing a cyclic moiety; R 2d is one or more R 5 or b) a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10) alkyl group (optionally a (C3-10) alkyl group) which may be linear or branched; and R 2d is one or more R 5 (possibly substituted with R 5 is a halogen); R 2e teeth, a) a (C3-10) alkyl group containing a cyclic moiety, wherein the C atom of the linear or cyclic moiety of said (C3-10) alkyl group is R 2e with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R 2e is one or more R 5 or 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 (C3-10) alkyl group which may be linear or branched, wherein the C atom of the linear part of said (C3-10) alkyl group is selected from the group consisting of R 2e with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R 2e is one or more R 5 (possibly substituted with R 5 is a halogen); Each R 3aare independently (C1-6) alkyl optionally substituted with one or more halogens; or two R attached to the same or adjacent carbon atoms 3a may be joined together with the atoms to which they are attached to form a 3- to 6-membered ring optionally further containing an O heteroatom; said ring may be optionally substituted with one or more halogens; Y1, Y2, Y3, R 1 , R 3a , R 3b , Q, R 4 , R 5 , a, and n are as defined for Formula 1b or any of embodiments (1)-(9) and (21)-(31) of Formula Ib above.

[0181] In embodiment (1) of formula IV or IVb, R 2d is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, and R 2d is an R of 1 or more 5 It is replaced by R 2d is one or two R 5 , preferably one R 5 may be substituted with R 2d is optionally substituted with halogen, CN or (C1-4) alkyl, and the (C1-4) alkyl group is optionally substituted with one or more halogens, preferably one or more fluoro. 2d may be substituted with halogen (preferably fluoro), CN or CF3.

[0182] In embodiment (2) of formula IV or IVb, R 2d is CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], and R 2d is one or more R 5 It is replaced by R 5 Substitution by R 2d It will be understood that the -CH2- linker or the aromatic or heteroaromatic ring of R 2dis 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 fluoro), 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, and the (C1-4) alkyl group is optionally substituted with one or more halogens (preferably optionally one or more fluoro). The aromatic or heteroaromatic ring is optionally substituted with halogens (preferably fluoro), CN, or CF3.

[0183] In embodiment (3) of formula IV or IVb, R 2d is a (C2-10) alkyl group which may be linear, branched, or cyclic, or a combination thereof; R 2d is one or more R 5 is replaced by R 2d is one or two R 5 , preferably one R 5 may be substituted with R 2d can be a (C3-10) alkyl group which may be linear, branched, or cyclic or a combination thereof; R 2d is R 5 It is replaced by R 2d can be a (C4-10) alkyl group which may be linear, branched, or cyclic or a combination thereof; R 2d is R 5 It is replaced by R 2d can be a (C5-10) alkyl group which may be linear, branched, or cyclic or a combination thereof; R 2d is R 5 It is replaced by R 2d may be a (C5-10) alkyl group containing a cyclic moiety, and R 2d is R 5 The remainder may be as defined for Formula I or Ib, or any of embodiments (1)-(9), (13), or (19)-(26) of Formula I or Ib described herein, mutatis mutandis.

[0184] In embodiment (4) of formula IV or IVb, R 2d is a (C5-10) alkyl group containing a cyclic moiety, and R 2d is one or more R 5 and R 2d may be a (C5-8)cycloalkyl group or CH2-[(C5-6)cycloalkyl group]. R 2d is one or two R 5 may be substituted with R 5 is preferably halogen (e.g., fluoro). 2d The cyclic moiety of 5 (e.g., fluoro).

[0185] In embodiment (5) of formula IV or IVb, R 2b is H or (C1-3) alkyl, and the (C1-3) alkyl is one or more R 5 may be substituted with R 2b may be H, CH3 or CH2CH3.

[0186] In embodiment (6) of formula IV or IVb, Z is R 2e Preferably, Q is also C.

[0187] In embodiment (7) of formula IV or IVb, R 2e is CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], and R 2e is one or more R 5 It is replaced by R 5 Substitution by R 2e It will be understood that the -CH2- linker or the aromatic or heteroaromatic ring of R 2emay be CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], where CH2 is optionally substituted with 1 or 2 halogens (preferably fluoro), 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, and the (C1-4) alkyl group is optionally substituted with 1 or more halogens (preferably 1 or more fluoro). The aromatic or heteroaromatic ring is optionally substituted with halogens (preferably fluoro), CN, or CF3.

[0188] In embodiment (8) of formula IV or IVb, R 2e is CH2-O-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], and R 2e is one or more R 5 It is replaced by R 5 Substitution by R 2e It will be understood that the -CH2- linker or the aromatic or heteroaromatic ring of R 2e 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 fluoro), 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, and the (C1-4) alkyl group is optionally substituted with one or more halogens (preferably optionally one or more fluoro). The aromatic or heteroaromatic ring may optionally be substituted with halogens (preferably fluoro), CN, or CF3.

[0189] In embodiment (9) of formula IV or IVb, R 2e is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and the C atoms of the linear or cyclic portion of said (C3-10) alkyl group are 2emay be substituted with one -O- other than at the point of attachment of R, and said (C3-10) alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2e is one or more R 5 (e.g., one or two R 5 , where R 5 is substituted with fluoro or OH, preferably fluoro). 2e may be a (C3-10) alkyl group containing a cyclic moiety, wherein a C atom of the linear or cyclic moiety of said (C3-10) alkyl group is optionally selected from R 2e and optionally substituted with one —O— other than at the point of attachment of R; said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2e is one or more R 5 (e.g., 1 or 2 R 5 , R 5 is fluoro or OH, preferably fluoro). 2e may be a (C3-10) alkyl group containing a cyclic moiety, wherein a C atom of the linear or cyclic moiety of said (C3-10) alkyl group is optionally selected from R 2e may be substituted with one -O- at a position other than the point of attachment of R 2e is one or more R 5 (e.g., one or two R 5 , where R 5 is substituted with fluoro or OH, preferably fluoro).

[0190] In embodiment (10) of formula IV or IVb, R 2e is a (C5-10) alkyl group containing a cyclic moiety, and R 2e is one or more R 5 may be substituted with R 2e may be a (C5-6)cycloalkyl group or a (C1-2)alkylene-[(C4-6)cycloalkyl group]; R 2e is 1 or 2 R 5 may be substituted with R 5is preferably halogen (e.g., fluoro). 2e The cyclic moiety of 5 (e.g., fluoro).

[0191] In embodiment (11) of formula IV or IVb, R 2e is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, and R 2e is one or more R 5 is optionally replaced by R 2e may be a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, and R 2e is one or two R 5 , for example, by halogen (preferably fluoro), (C1-4)alkoxy or (C1-4)alkyl, wherein the (C1-4)alkyl group is optionally substituted with one or more halogens (preferably optionally substituted with one or more fluoro).

[0192] In embodiment (12) of Formula IV or IVb, the compound, or a pharmaceutically acceptable salt or derivative thereof, is a compound of the following structure, or a pharmaceutically acceptable salt or derivative thereof:

[0193] [ka]

[0194] R 2e is a (C5-10) alkyl group containing a cyclic moiety, and R 2e is one or more R 5 The remainder may be as defined for Formula I, Ib, IV or IVb, or any embodiment of Formula I, Ib, IV or IVb described herein, mutatis mutandis. For example, R 1can be a 5-6 membered saturated monocyclic ring having at least one ring N heteroatom and optionally a ring O heteroatom (e.g., one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom), and R 1 is one or more R 4 may be substituted with R 1 can be a 6-membered saturated monocyclic ring containing at least one ring N heteroatom (e.g., one ring N heteroatom or two ring N heteroatoms), and R 1 is one or more R 4 R 1 may be a 6-membered saturated monocyclic ring containing at least one ring N heteroatom (e.g., one ring N heteroatom or two ring N heteroatoms), and R 1 is one R 4 may be substituted with R 4 If there is R 4 may be (C1-6) alkyl optionally substituted with OH, or may be (C1-2) alkyl optionally substituted with OH. n may be 0. R 2e may be as defined according to embodiment (10) of formula IV or IVb.

[0195] Described herein are compounds of formula V or pharmaceutically acceptable salts or derivatives thereof:

[0196] [ka]

[0197] wherein m is 1, 2, 3, or 4; Y1, Y2, Y3, R 1 , R 2a , R 2b , R 2c , R 2f , R 3a , R 3b , A, Q, R 4 , R 5, a and b are as defined for Formula I or any of embodiments (1)-(23) and (26)-(31) of Formula I above.

[0198] Described herein are compounds of formula Vb or a pharmaceutically acceptable salt or derivative thereof:

[0199] [ka]

[0200] wherein m is 1, 2, 3, or 4; Y1, Y2, Y3, R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , A, Q, R 4 , R 5 , a is as defined for Formula Ib or any of embodiments (1)-(23) and (26)-(31) of Formula Ib above.

[0201] In embodiment (1) of formula V or Vb, m is 1, or 2.

[0202] In further embodiments of the compound of Formula IV or Ib-Vb or a pharmaceutically acceptable salt thereof, including any of the above embodiments, one or more hydrogen atoms are 2 H, and the remainder may be as defined in any aspect or embodiment of formula IV or Ib-Vb described herein, mutatis mutandis.

[0203] Compounds of formula IV (including any embodiment thereof) are preferred. In one embodiment, the compound of Formula I or Formula Ib is 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;

[0204] (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;

[0205] 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; Cyclopentyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; Isopropyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; 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;

[0206] 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]octan-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;

[0207] 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]nonan-9-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,9-diazabicyclo[3.3.1]nonan-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]heptan-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]heptan-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]nonan-9-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-((4-fluorobenzyl)sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-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]octan-8-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 6-(benzylsulfonyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine;

[0208] 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;

[0209] 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; 2-Cyclopentyl-1-(2-(2-methylpyridin-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-Cyclopentyl-1-(2-(5-methylpyridin-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; and pharmaceutically acceptable salts or derivatives thereof.

[0210] In a further embodiment of the compound of Formula I or Ib, R 1 can be as defined above in any of the compounds of formula I or Ib. In further embodiments of compounds of formula I or Ib, A can be as defined above in any of the compounds of formula I or Ib.

[0211] Further aspects and embodiments are described in the following numbered paragraphs. Section 1. A compound of formula I or a pharmaceutically acceptable salt or derivative thereof for use in the treatment or prevention of a disease or disorder that can be ameliorated by activation of the long isoform of PDE4:

[0212] [ka]

[0213] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are CR 3b is; Q is C or S(O); 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 R 1 is one or more R 4 optionally replaced by; A is NR 2a R 2b or R 2c and; R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; 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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's attached to the same or adjacent carbon atoms 3a may be joined together with the atoms to which they are attached to form a 3 to 6 membered ring optionally further containing an O heteroatom, said ring being optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6)alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

[0214] Item 2. The compound for use in item 1, or a pharmaceutically acceptable salt or derivative thereof, is a compound of the following formula:

[0215] [ka]

[0216] Paragraph 3: A compound or a pharmaceutically acceptable salt or derivative thereof for use according to paragraph 1 or 2, R 1 is a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; a 6 membered aromatic monocyclic ring containing one or two ring N heteroatoms; a 7-9 membered saturated bridged ring containing one or two ring N heteroatoms; a 9 membered saturated bridged ring containing two ring N heteroatoms and a ring O heteroatom; or a 7-10 membered saturated fused or spirocyclic ring containing one or two ring N heteroatoms; 1 is one, two or three R 4 may be substituted with.

[0217] Item 4. The compound or a pharmaceutically acceptable salt or derivative thereof according to any one of items 1 to 3 for use, R 1 is a 4- to 10-membered non-aromatic ring which may be monocyclic, bridged, or bicyclic containing at least one ring N heteroatom and an optional ring O heteroatom; R 1 is one R 4 is optionally replaced by

[0218] Item 5. The compound or a pharmaceutically acceptable salt or derivative thereof according to any one of items 1 to 3 for use, R 1is a 7- to 9-membered saturated bridged ring containing two ring N heteroatoms, and optionally a 7-8-membered saturated bridged ring containing two ring N heteroatoms (e.g., a bridged piperazine such as 3,8-diazabicyclo[3.2.1]octanyl), where R 1 is one R 4 may be substituted with.

[0219] Item 6. A compound or a pharmaceutically acceptable salt or derivative thereof for use according to any of the preceding items, a)R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10)alkyl group (optionally a (C3-10)alkyl group) which may be linear, branched, or cyclic, or a combination thereof; R 2a is one or more R 5 may be substituted with; and R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; 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 may be linear, branched, or cyclic or a combination thereof, wherein a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c and optionally substituted with one —O— other than at the point of attachment of R; said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R2c is one or more R 5 may be substituted with.

[0220] Paragraph 7: A compound for use according to any of the preceding paragraphs, or a pharmaceutically acceptable salt or derivative thereof, a)R 2a is a (C5-10) alkyl group containing a cyclic moiety, and R 2a is one or more R 5 may be substituted with R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or b)R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10) alkyl group (optionally a (C3-10) alkyl group) which may be linear or branched; R 2a is one or more R 5 (possibly substituted with R 5 is a halogen); R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 may be substituted with.

[0221] Paragraph 8. A compound for use according to any of the preceding paragraphs, or a pharmaceutically acceptable salt or derivative thereof, R 2c but: a) a (C3-10) alkyl group containing a cyclic moiety, wherein the C atom of the linear or cyclic moiety of said (C3-10) alkyl group is R 2c and optionally substituted with one —O— other than at the point of attachment of R; said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2c is one or more R 5 may be substituted with; 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 (C3-10) alkyl group, which may be linear or branched, wherein the C atom of the linear part of said (C3-10) alkyl group is selected from the group consisting of R 2 and optionally substituted with one —O— other than at the point of attachment of R; said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2c is one or more R 5 (possibly substituted with R 5 is a halogen).

[0222] Section 9. A compound for use according to any one of sections 1 to 7, or a pharmaceutically acceptable salt or derivative thereof, having the following formula:

[0223] [ka]

[0224] Item 10. A compound for use according to any of the preceding items, or a pharmaceutically acceptable salt or derivative thereof, Each R 3a is -CH3 or F, or two R 3a together with the atom to which it is attached form a cyclopropyl ring.

[0225] Item 11. The compound for use according to any of the preceding items, wherein n is 0, 1, or 2, or a pharmaceutically acceptable salt or derivative thereof.

[0226] Section 13 Q is C and / or A is R 2c 10. The compound for use according to any of the preceding claims, which is, or a pharmaceutically acceptable salt or derivative thereof:

[0227] Item 14. A compound for use according to any of the preceding items, or a pharmaceutically acceptable salt or derivative thereof, Q is C; R 1 is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one R 4 may be substituted with; A is R 2c and R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c with one —O— other than at the point of attachment of R, and said (C3-10)alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; R 3a is methyl, if present; R 4 is, if present, (C1-6)alkyl optionally substituted with OH, and is (C1-2)alkyl optionally substituted with OH; R 5 is, if present, OH or halo; and n is 0, 1, or 2.

[0228] Item 15. A compound of formula IIb or a pharmaceutically acceptable salt or derivative thereof:

[0229] [ka]

[0230] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are each CR 3b is; Q is C or S(O); R 1ais a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1a is one or more R 4 may be substituted with; A is NR 2a R 2b or R 2c and; R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; 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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c and optionally substituted with one —O— other than at the point of attachment of R; said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2cis one or more R 5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's attached to the same or adjacent carbon atoms 3a are joined together to form a 3- to 6-membered ring optionally further containing an O heteroatom and optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6)alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

[0231] Item 16. A compound according to item 15, or a pharmaceutically acceptable salt or derivative thereof, R 1a is a 7-8 membered saturated bridged ring containing two ring N heteroatoms (e.g., a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octanyl), and R 1 is one R 4 may be substituted with.

[0232] Item 17. A compound according to item 15 or 16, or a pharmaceutically acceptable salt or derivative thereof, The compound is of the formula:

[0233] [ka]

[0234] Item 19. A compound of formula 111b or a pharmaceutically acceptable salt or derivative thereof:

[0235] [ka]

[0236] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are each CR 3b is; Q is C or S(O); R 1b is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally a ring O heteroatom, wherein at least one ring N heteroatom is selected from the group consisting of R 1b Not at the connection point of R 1b is one or more R 4 may be substituted with; A is NR 2a R 2b or R 2c and; R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl 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 heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2ais one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; 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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c may be substituted with one -O- other than at the point of attachment of R; said (C3-10) alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R 2c is one or more R 5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's 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 and optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6)alkyl; Each R 4are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

[0237] Item 20: A compound according to item 19, or a pharmaceutically acceptable salt or derivative thereof, R 1b is a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; or a 7- to 9-membered saturated bridged ring containing one or two ring N heteroatoms; a 9-membered saturated bridged ring containing two ring N heteroatoms and a ring O-heteroatom; or a 7- to 10-membered saturated, fused, or spiro-membered ring containing one or two ring N heteroatoms; 1b is one, two or three R 4 may be substituted with.

[0238] Item 21: A compound according to item 19 or 20, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1b is a 6-membered saturated monocyclic ring containing two ring N heteroatoms or a 7-9-membered saturated bridged ring containing two ring N heteroatoms; R 1a may be one R 4 and optionally R 1ais a 7-8 membered saturated bridged ring containing two ring N heteroatoms (e.g., a bridged piperazine, e.g., 3,8-diazabicyclo[3.2.1]octanyl), and R 1b is one R 4 may be substituted with.

[0239] Item 22: A compound according to any one of items 15-21, or a pharmaceutically acceptable salt or derivative thereof, a)R 2a is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10)alkyl group (optionally a (C3-10)alkyl group) which may be linear, branched, or cyclic, or a combination thereof; and R 2a is one or more R 5 may be substituted with; and R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 and / 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 may be linear, branched, or cyclic or a combination thereof, wherein a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5may be substituted with.

[0240] Item 23: A compound according to any one of items 15-22, or a pharmaceutically acceptable salt or derivative thereof, R 2c but, a) a (C3-10) alkyl group containing a cyclic moiety, wherein the C atom of the linear or cyclic moiety of said (C3-10) alkyl group is R 2c wherein said (C3-10)alkyl group is optionally substituted with one -O- other than at the point of attachment of R, said (C3-10)alkyl group being optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; 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 (C3-10) alkyl group which may be linear, branched, or cyclic or a combination thereof, wherein a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 (possibly substituted with R 5 is a halogen).

[0241] Item 24. The compound of any of items 15-23, or a pharmaceutically acceptable salt or derivative thereof, which is a compound of the following formula:

[0242] [ka]

[0243] Section 25 Q is C and / or A is R 2c25. The compound according to any one of paragraphs 15-24, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0244] Item 26: A compound according to any one of items 15-24, or a pharmaceutically acceptable salt or derivative thereof, Q is C; R 1a or R 1b is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R 1a and R 1b is one R 4 may be substituted with; A is R 2c and R 2c is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic portion of said (C3-10) alkyl group is optionally selected from R 2c with one —O— other than at the point of attachment of R, and said (C3-10)alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; R 3a If there is R 3a is methyl; R 4 when present, is (C1-6)alkyl optionally substituted with OH, and is (C1-2)alkyl optionally substituted with OH; R 5 is, if present, OH or halo; and n is 0, 1, or 2.

[0245] Item 27. A compound of formula IVb or a pharmaceutically acceptable salt or derivative thereof:

[0246] [ka]

[0247] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are each CR 3b is; Q is C or S(O); 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 R 1 is one or more R 4 optionally replaced by; Z is NR 2d R 2b or R 2e and; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 may be substituted with; and R 2d teeth a) a (C5-10) alkyl group containing a cyclic moiety, R 2d is one or more R 5 or b) a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10) alkyl group (optionally a (C3-10) alkyl group) which may be linear or branched; 2d is one or more R 5 (possibly substituted with R 5 is a halogen); R 2e teeth, a) (C3-10) alkyl groups containing cyclic moieties, wherein a C atom of the linear or cyclic moiety of said (C3-10) alkyl group is selected from the group consisting of R 2e and R is optionally substituted with one -O- at any point other than the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2e is one or more R 5 or 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 (C3-10) alkyl group which may be linear or branched, wherein the C atom of the linear part of said (C3-10) alkyl group is selected from the group consisting of R 2e with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2e is one or more R 5 (possibly substituted with R 5 is a halogen); Each R 3a are independently (C1-6) alkyl optionally substituted with one or more halogens; or two R 3a may be joined together with the atoms to which they are attached to form a 3 to 6 membered ring optionally further containing an O heteroatom, said ring being optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6) alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

[0248] Section 28 Z is R 2e 28. The compound of claim 27, wherein:

[0249] Item 29. A compound according to item 27 or 28, or a pharmaceutically acceptable salt or derivative thereof, R 1 is a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; a 6-membered aromatic monocyclic ring containing one or two ring N heteroatoms; a 7- to 9-membered saturated bridged ring containing one or two ring N heteroatoms; a 9-membered saturated bridged ring containing two ring N heteroatoms and a ring O-heteroatom; or a 7- to 10-membered saturated, fused, or spirocyclic ring containing one or two ring N heteroatoms; 1 is one, two or three R 4 may be substituted with.

[0250] Item 30. A compound according to any one of items 27-29, or a pharmaceutically acceptable salt or derivative thereof, R 1 is a 4- to 10-membered non-aromatic ring which may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally a ring O heteroatom; R 1 is one R 4 may be substituted with.

[0251] Item 31. A compound according to any one of items 27-30, or a pharmaceutically acceptable salt or derivative thereof, R 1 is a 7- to 9-membered saturated bridged ring containing two ring N heteroatoms (e.g., a bridged piperazine, e.g., 3,8-diazabicyclo[3.2.1]octanyl), and R 1 is one R 4 may be substituted with.

[0252] Item 32. A compound according to any one of items 15-31, or a pharmaceutically acceptable salt or derivative thereof, Each R 3a is -CH3 or two R 3a are joined together with the atoms to which they are attached to form a cyclopropyl ring.

[0253] Item 33: The compound according to any one of items 15-32, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0, 1, or 2.

[0254] Item 34. A compound of formula Vb or a pharmaceutically acceptable salt or derivative thereof:

[0255] [ka]

[0256] In the formula, one or two of Y1, Y2 and Y3 are N, and the rest are CR 3b is; Q is C or S(O); 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 R 1 is one or more R 4 optionally replaced by; A is NR 2a R 2b or R 2c and; R 2ais a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2-[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R 2a is one or more R 5 may be substituted with; R 2b is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R 5 or R 2a and R 2b together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R 5 may be substituted with; 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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R 2c with one —O— other than at the point of attachment of R, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2c is one or more R 5 may be substituted with; Each R 3a is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two R's attached to the same or adjacent carbon atoms3a may be joined together with the atoms to which they are attached to form a 3- to 6-membered ring optionally further containing an O heteroatom, said ring being optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6) alkyl; Each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; Each R 5 are 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 halogens or OH; m is 1, 2, 3, or 4; and a is 0 or 1.

[0257] definition 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 of the ring-forming atoms is a heteroatom such as O, S, or N. The aromatic ring may be a six-membered aromatic ring, i.e., a phenyl ring. The heteroaromatic ring may be a six-membered heteroaromatic ring containing one to three N atoms or a five-membered heteroaromatic ring containing one to three heteroatoms selected from O, S, and N. Examples of such six- or five-membered heteroaromatic rings include pyridine, pyridazine, pyrazine, pyrimidine, thiophene, furan, thiazole, thiadiazole, oxazole, oxadiazole, imidazole, triazole, and their isomers, including isothiazole, isothiadiazole, isoxazole, and isoxadiazole. In all of the above cases, the aromatic ring may be optionally substituted as defined herein.

[0258] The term "carbocycle" refers to a ring system in which all ring atoms are carbon, which may be saturated, partially unsaturated, or aromatic. The term "heterocycle" refers to a ring system in which one or more ring atoms are a heteroatom, such as O, S, or N. A "non-aromatic carbocycle or heterocycle" may be saturated or partially unsaturated. Carbocycles and heterocycles may 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 may independently be saturated, partially unsaturated, or aromatic. Examples of such fused bicyclic ring systems include indane and chroman. Non-aromatic carbocycles or heterocycles may include fused ring systems, for example, in which two rings share two adjacent atoms; bridged ring systems, for example, in which two rings share three or more adjacent atoms; or spiro ring systems, for example, in which 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 contain 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 rings include spiro[4.3]octane and 2,6-diazaspiro[3.4]octane. In all of the above examples, the carbocyclic or heterocyclic ring may be optionally substituted as defined herein. When a ring is referred to herein as containing a particular ring heteroatom, it will be understood that there are no additional ring heteroatoms beyond the particular one.

[0259] "Monocyclic, bridged, or bicyclic ring" includes monocyclic, bridged, and bicyclic ring systems. "Monocyclic, bridged, or bicyclic rings" may be saturated, partially unsaturated, or aromatic, unless otherwise specified. They may be aromatic, heteroaromatic, carbocyclic, or heterocyclic, or combinations thereof. Bicyclic ring systems may include fused and spiro rings.

[0260] Unless otherwise defined, the term "alkyl" refers to a saturated hydrocarbon which can be linear, branched, cyclic, or a combination thereof. Alkyl groups include linear, branched, and cyclic alkyl groups, or combinations thereof, such as (cycloalkyl)alkyl groups. As used herein, the term "(C1-6)alkyl" refers to a branched or unbranched alkyl having 1-6 carbon atoms, which can optionally include a ring. Examples of (C1-6)alkyl include hexyl, cyclohexyl, pentyl, cyclopentyl, butyl, isobutyl, cyclobutyl, tert-butyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, ethyl, and methyl. The term "(C1-4)alkyl" refers to a branched or unbranched alkyl having 1-4 carbon atoms, which can optionally include a ring. Examples of (C1-4)alkyl include butyl, isobutyl, cyclobutyl, tert-butyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, ethyl, and methyl. When specified in the above formula, (C1-4)alkyl can preferably be (C1-2)alkyl. As specified in the above formula, (C1-4) alkyl may be substituted, for example, with one to three fluoro groups. A particularly preferred example of a substituted (C1-4) alkyl is trifluoromethyl. Alternatively, the (C1-4) alkyl may be unsubstituted.

[0261] As used herein, the term "alkylene" refers to a divalent alkyl group. The term "cycloalkyl" refers to a cyclic alkyl group such as cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl, or cyclopropyl. Cycloalkyl may be optionally substituted as defined herein.

[0262] The term "alkoxy" means -O-alkyl, where alkyl has the meaning defined above. Examples of (C1-4)alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy. The (C1-4)alkoxy referred to herein may preferably be (C1-2)alkoxy. When specified in the above formula, the (C1-4)alkoxy may be substituted, for example, with 1-3 fluoro. 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 attached to the rest of the molecule by the "oxy" moiety.

[0263] As used herein, a group referred to as "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a C or N atom) is replaced with an acceptable substituent. For example, substitution refers to a substituent that results in a stable compound, e.g., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, when two or more substituents are present, the substituents can be the same or different at each occurrence. Unless otherwise specified, a "substituted" group has one or more substituents at one or more substitutable positions of the group, and when two or more positions in any given structure are substituted, the substituents can be the same or different at each position.

[0264] As used herein, the term "can be" is to be construed as optional. When a feature is expressed as "potentially present," the feature is optionally present. For example, when a moiety is described as "optionally substituted," the moiety is optionally substituted, i.e., either unsubstituted or substituted as described.

[0265] The term "halogen" means F, Cl, Br or I. F and Cl are particularly preferred, with F being most preferred.

[0266] Activation of PDE4 long isoforms PDE4 long isoforms have two regulatory regions, upstream conserved region 1 (UCR1) and upstream conserved region 2 (UCR2), which are located between the isoform-specific N-terminal portion and the catalytic region. The UCR1 region is absent in short forms. The ultrashort forms not only lack UCR1 but also have an N-terminal truncated UCR2 region (Houslay, MD, Schafer, P. and Zhang, K. Drug Discovery Today 10: 1503-1519, 2005).

[0267] There are four PDE4 families: PDE4A, PDE4B, PDE4C, and PDE4D. The present invention relates to compounds that can activate one or more long-chain isoforms of one or more of these four families. Thus, the long-chain isoform PDE4 can be long-chain isoform PDE4A, long-chain isoform PDE4B, long-chain isoform PDE4C, or long-chain isoform PDE4D. For the avoidance of doubt, the long-chain isoform PDE4 comprises a UCR1 region. In some embodiments, the long-chain isoform PDE4 is human. UCR1 is conserved among mammalian species (Houslay, MD, Sullivan, M, and Bolger GB Adv Pharmacol. 1998;44:225-34). Thus, in other embodiments, the long-chain isoform PDE4 can be from a mammal other than human.

[0268] Without wishing to be bound by theory, the compounds described herein may act as PDE4 long-chain form activators. The compounds described herein are small molecules that are believed to directly bind to PDE4 long-chain forms and induce conformational changes that increase, stabilize, exert, and / or maintain the catalytic activity of these enzymes. Without being bound by theory, activation of PDE4 long-chain form by PDE4 long-chain form activators may be sensitive to the regulatory status of the enzyme, such as post-translational modifications (e.g., phosphorylation), specific physiological locations, or the introduction of protein-protein complexes associated with the context of cellular or biochemical assays. PDE4 long-chain form activators may exhibit enzyme activation in one or more states, but not necessarily in all states. In the field of pharmacology, as used herein, a small molecule is defined as a low molecular weight organic compound capable of regulating biological processes. Preferred small molecule activators according to the present invention have a molecular weight of 700 daltons or less, which allows for rapid diffusion across cell membranes and allows them to reach the intracellular site of action (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 of 250 daltons or more and 500 daltons or less (Lipinski, CA Drug Discovery Today: Technologies 1: 337-341, 2004).

[0269] One suitable method to detect whether a compound can serve as an activator of the PDE4 long chain form is using the two-step radioanalysis procedure described in Experiment 1. In summary, the method involves comparing the test small molecule activator with the PDE4 long chain form [ 3 This involves incubating with [H]-labeled cAMP to assess the breakdown of cAMP into its 5'-adenosine monophosphate (5'-AMP) product. Samples of the reaction mixture from such incubations are subsequently treated with snake venom 5'-nucleotidase to produce the nucleotide [ 3H] labeled uncharged nucleoside of 5'-AMP [ 3 This allows for the conversion of [H] to labeled adenosine, which can be separated and quantified to assess PDE4 activity and the effects of test compounds (Thompson, WJ and Appleman, MM Biochemistry 10: 311-316, 1971, with some modifications as described in Marchmont, RJ and Houslay, MD Biochem J. 187: 381-92, 1980).

[0270] Using the assay procedures described above, as detailed in Experiment 1, preferred small molecule activators of the present invention produce an increase in background activity of one or more PDE4 long form(s) by 20% or more or 30% or more at test compound concentrations of 100 micromolar or less. Particularly preferred compounds according to the present invention produce an increase in background activity of one or more PDE4 long form(s) by 20% or more or 30% or more at concentrations of 10 micromolar or less, e.g., 3 micromolar.

[0271] The compound of the present invention is selective for the long chain form of PDE4 enzyme, and does not act as an activator of the short chain isoform or the very short chain isoform of PDE4 enzyme, or only acts to a lesser extent.Therefore, the short chain or the very short chain isoform PDE4 can be the short chain or the very short chain isoform PDE4A, the short chain or the very short chain isoform PDE4B, the short chain or the very short chain isoform PDE4C, or the short chain or the very short chain isoform PDE4D.For the avoidance of doubt, the short chain and the very short chain isoform of PDE4 lack UCR1 region.The very short chain isoform is characterized by truncated UCR2 region and lack of UCR1 region. Short or ultrashort isoform PDE4 can be, for example, human, but also from other mammalian species (where UCR2 is conserved; see Houslay, MD, Sullivan, M and Bolger GB Adv Pharmacol. 44:225-34, 1998).

[0272] Under the same assay conditions, as described in Experiment 1, compounds of the present invention produce less than a 30% or less than a 20% increase in background activity of the short or ultrashort forms of the PDE4A, PDE4B, PDE4C, or PDE4D enzymes at test compound concentrations of 100 micromolar or less.

[0273] Thus, the compounds of the present invention provide negative results in assays for activation of the short (or ultrashort) form of PDE4 and positive results in assays for activation of the long form of PDE4.

[0274] PDE4 long chain isoforms include PDE4A4, PDE4A4 / 5, PDE4A5, PDE4A8, PDE4A10, PDE4A11, PDE4B1, PDE4B3, PDE4B4, PDE4C1, PDE4C2, PDE4C3, PDE4C4, PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9 and PDE4D11. Furthermore, long chain isoforms have been identified or can be referred to by nomenclature distinct from any of the four PDE4 subfamilies.

[0275] PDE4 short and very short isoforms include PDE4A1, PDE4B2, PDE4B5, PDE4D1, PDE4D2, PDE4D6, and PDE4D10. Additionally, short and very short isoforms have been identified or can be referred to by nomenclature distinct from any of the four PDE4 subfamilies.

[0276] The following examples illustrate the analysis of compound activity of the human PDE4D5 long isoform and the lack of activity of the human PDE4B2 short isoform. Details of these isoforms, as well as the numbers of many other known isoforms, including GenBank accession numbers, are provided in Tables AD below. Table A - Examples of known PDE4A isoforms

[0277] [Table 1]

[0278] *Note that the PDE4A4B clone is correct, whereas PDE4A4A has a cloning artifact and PDE4A4C is a truncation artifact. **Note that this species is C- and N-terminally truncated

[0279] Table B - Examples of known PDE4B isoforms

[0280] [Table 2]

[0281] Table C - Examples of known PDE4C isoforms

[0282] [Table 3]

[0283] Table D - Examples of known PDE4D isoforms

[0284] [Table 4]

[0285] Reduced cAMP levels Without being bound by theory, the compounds of the present invention may function by lowering cAMP levels in one or more intracellular compartments. The PDE4 long form activators of the present invention may thus provide a means of regulating certain cAMP-dependent cellular processes. Excessive intracellular cAMP signaling mediates many diseases and disorders. Therefore, the compounds of the present invention are expected to be useful in treating diseases associated with abnormally high cAMP levels, increased cAMP-mediated signaling, and / or reduced cAMP loss, enzymes, or other (e.g., efflux) pathways. While such treatment is typically administered to humans, it can also be administered to non-human animals (e.g., non-human mammals) (e.g., veterinary treatment).

[0286] In one aspect, the present invention provides compounds described herein (i.e., small molecule activators of the PDE4 long chain form), which are useful in methods for the treatment or prevention of conditions requiring reduction of second messenger responses mediated by cyclic 3',5'-adenosine monophosphate (cAMP).

[0287] For example, gain-of-function genetic mutations in adenylyl cyclase, a protein involved in driving cAMP signaling upstream of GPCRs and Gsα, can lead to abnormal, excessive cAMP activity with 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). Therefore, the PDE4 long chain form activators of the present invention, which possess the ability to accelerate the end of cAMP action, are expected to be useful in treating, preventing, or partially controlling diseases characterized by undesirably high cAMP levels or activity, as described in detail below.

[0288] The treatment or prevention described herein can be the treatment or prevention of diseases or disorders that can be improved by activating the long chain isoform of PDE4.The treatment or prevention described herein can be the treatment or prevention of diseases or disorders that are mediated by excessive intracellular cAMP signaling.In these diseases, reducing the second messenger response mediated by cyclic 3',5'-adenosine monophosphate (cAMP) should have a therapeutic effect.

[0289] Diseases that are ameliorated by activation of the long isoform of PDE4 or that are characterized by elevated cAMP levels

[0290] Hyperthyroidism Stimulation of the thyroid-stimulating hormone (TSH) receptor (TSHR) leads to increased production and release of thyroid hormones, thyroxine and triiodothyronine, through a cAMP-dependent signaling mechanism involving Gsα-mediated activation of adenylyl cyclase. Gain-of-function mutations in the TSHR have been reported to be 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 in both TSHR and Gsα have also been found in goitre and thyroid adenomas (Arturi, F. et al., Exp. Clin. Endocrinol. Diabetes 106: 234-236, 1998). Increased cAMP activity in goitre has been reported to be the result of activating mutations in TSHR or Gsα, producing a protective adaptive increase in PDE4 activity that counteracts the abnormal elevation in cAMP levels and signaling (Persani, L. et al., J. Clin. Endocrinol. Metab. 85: 2872-2878, 2000).

[0291] The most common cause of hyperthyroidism is Graves' disease, an autoimmune disorder that mimics TSH action on the TSHR, leading to excessive cAMP activity in thyroid follicular cells, resulting in the hyperthyroid state. Therefore, the PDE4 long form activators of the present invention are expected to be effective in treating, preventing, or partially controlling hyperthyroidism. In one embodiment, the hyperthyroidism is associated with Graves' disease.

[0292] Jansen's Metaphyseal Chondrodysplasia Janssen metaphyseal chondrodysplasia (JMC) is an extremely rare disease caused by gain-of-function mutations in parathyroid hormone (PTH) receptor 1 (PTHR1) (Thompson, MD et al., Methods Mol. Biol. 448: 109-137, 2008). Constitutive activation of PTHR1, coupled with adenylyl cyclase as an effector, is associated with excessive cAMP signaling, primarily in bone and kidney, leading to dysregulation of ion homeostasis 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 physical abnormalities (e.g., protruding eyes). Therefore, PDE4 long-chain form activators described herein are expected to be effective in treating, preventing, or partially controlling JMC.

[0293] Hyperparathyroidism Hyperparathyroidism (HPT) is characterized by excessive PTH secretion from the parathyroid glands, which regulates plasma calcium and phosphate concentrations via PTHR1 receptors in the kidneys, bones, and gastrointestinal tract. The resulting excessive stimulation of these receptors causes disruption of plasma ion homeostasis, leading patients to develop hypercalcemia and hypophosphatemia. While primary HPT is caused by parathyroid hyperplasia or dysfunction, secondary HPT is associated with underlying conditions, primarily chronic kidney disease. Left untreated, HPT can lead to a variety of debilitating symptoms, which can become life-threatening.

[0294] The PDE4 long form activators described herein are expected to be effective in treating, preventing, or partially controlling hyperparathyroidism by acting to downregulate excess cAMP produced by sustained PTH signaling.

[0295] Familial male precocious puberty (testotoxemia) Familial male-limited precocious puberty (FMPP), also known as familial precocious sexual puberty or gonadotropin-independent testicular toxicosis, is a condition in which boys typically show signs of precocious puberty during early childhood.

[0296] The length of the vertebral column in boys may be shortened due to the rapid progression of epiphyseal maturation. FMPP is an autosomal dominant condition with a constitutively activating mutation in the luteinizing hormone (LH) receptor, associated with Leydig cell hyperplasia and low sperm cell counts (Latronico, AC et al., J. Clin. Endocrinol. Metab. 80: 2490-2494, 1995; Kosugi, S. et al., Hum. Mol. Genet. 4: 183-188, 1995). This leads to increased cAMP production. Therefore, the PDE4 long form activator of the present invention is expected to be effective in treating, preventing, or partially controlling FMPP.

[0297] Pituitary adenoma and Cushing's disease Noncancerous tumors of the pituitary gland, collectively called pituitary adenomas, can lead to hypersecretion of adenospirillary hormones (e.g., growth hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and adrenocorticotropic hormone), which exert their actions through the interaction of GPCRs with Gs and cAMP production. Thus, pituitary adenomas can lead to a state of elevated cAMP-mediated signaling within various endocrine cells that can promote a number of hormonal disorders, such as acromegaly (primarily due to growth hormone hypersecretion), Cushing's disease (overproduction of adrenocorticotropic hormone (ACTH) and subsequent hypercortisolemia), and / or general hyperpituitarism (related to the excessive release of multiple anterior pituitary hormones). Current treatment options for pituitary adenomas include treatment with dopamine receptor agonists, which reduce tumor size and pituitary hormone production by mechanisms involving a reduction in intracellular cAMP levels. The PDE4 long form activators of the present invention are expected to reduce the pathological effects of pituitary hormones in their target tissues (e.g., the adrenal gland).

[0298] In Cushing's disease, pituitary adenomas are associated with excessive ACTH production, which can lead to hypercortisolism through overactivation of the melanocortin 2 receptor (MC2), cAMP-mediated stimulation of steroidogenesis, and release of cortisol from the adrenal cortex (Tritos, NA and Biller, BM Discov. Med. 13: 171-179, 2012). Therefore, the PDE4 long-chain form activators of the present invention are expected to be effective in treating, preventing, or partially controlling Cushing's disease.

[0299] Polycystic kidney disease Polycystic kidney disease (PKD) is a genetic disease of the kidney characterized by the development of cysts. This leads to damage to renal structure and a decline in 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 between 0.1% and 0.2% of the population worldwide and is characterized by the gradual development of cysts and enlarged kidneys. Approximately 50% of people with this disease will develop end-stage renal disease, usually between the ages of 40 and 70, and will require dialysis or a kidney transplant. ARPKD affects 1:20,000 newborns and is typically identified in the first few weeks after birth. Pulmonary hypoplasia results in a 30-50% mortality rate among newborns with ARPKD.

[0300] Defects in two genes appear to cause ADPKD. In approximately 85% of patients, the development of ADPKD can be linked to mutations in the gene PKD1, encoding polycystin-1 (PC-1); approximately 15% of patient mutations in PKD2, encoding polycystin-2 (PC-2), are involved. Cyclic AMP has been identified as an important stimulus for proliferation and cyst expansion of polycystic kidney disease cells, but not normal human kidney cells (Yamaguchi, T. et al., Kidney Int. 57: 1460-1471, 2000). A significant body of evidence has implicated cAMP as a key facilitator of renal cystogenesis (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, drugs that lower cAMP levels (e.g., vasopressin V2 receptor antagonists 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, VH 2nd et 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 subtype (PDE1A) resulted in the development of a cystic phenotype. On the other hand, PDE1A overexpression partially rescued the cystic phenotype caused by PC2 wasting (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 strategy for treating PKD (Sun, Y., Zhou, H. and Yang, BX. Acta Pharmacologica Sinica 32: 805-816, 2011).

[0301] Therefore, the PDE4 long form activators of the present invention are expected to be effective in treating, preventing or partially controlling polycystic kidney disease.

[0302] Polycystic liver disease Polycystic liver disease (PLD) is a rare genetic condition associated with hepatic cystogenesis (usually defined as a number of cysts exceeding 20). It often occurs together with ADPKD (Strazzabosco, M. and Somlo, S. Gastroenterology 140: 1855-1859, 2011; Gevers, TJ and Drenth, JP Curr. Opin. Gastroenterol. 27: 294-300, 2010). Compared with ADPKD, PLD may have a distinct genetic pathology driven by mutated proteins associated with the endoplasmic reticulum and cilia. Increased cholangiocyte proliferation, angiogenesis, and high flow secretion act to drive hepatic 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 cholangiocyte proliferation (Janssen, MJ et al., J. Hepatol. 52: 432-440, 2010). Somatostatin, which reduces cAMP levels via a Gi-coupled mechanism, reduces cholangiocyte proliferation and fluid secretion (Gong, AY et al., Am. J. Physiol. Cell. Physiol. 284: C1205-1214, 2003). Furthermore, the synthetic somatostatin analog, octreotide, has shown efficacy in an animal model of PLD through a mechanism involving reduction of cAMP signaling (Masyuk, TV et al., Gastroenterology 132: 1104-1116, 2007). Thus, the PDE4 long form activators of the present invention may be useful in treating, preventing or partially controlling polycystic liver disease, which is caused at least in part by cAMP.

[0303] Adult-onset early-onset type 5 (MODY5) MODY5 is a form of non-insulin-dependent 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 predominant clinical manifestation in patients affected by MODY5 is renal dysfunction, frequently diagnosed before the onset of diabetes. In some patients, HNF-1β mutations can result in additional phenotypic features (e.g., pancreatic atrophy, abnormal liver function, and reproductive tract abnormalities). Studies in mice suggest that the mechanism underlying renal cyst formation associated with HNF-1β mutations involves a critical defect in the transcriptional activation of PKD2, in addition to effects on the uromodulin (UMOD) and PKD1 genes. Downregulation of PKD1 and PKD2 is associated with cAMP-driven formation of renal cysts (Mancusi, S. et al., J. Nephrol. 26: 207-12, 2013). HNF-1β binds to the PDE4C promoter and regulates the expression of PDE4C (Ma et al., PNAS 104: 20386, 2007). Therefore, the PDE4 long chain form activators of the present invention are expected to be effective in treating, preventing or partially controlling the symptoms of MODY5.

[0304] Cardiac hypertrophy, heart failure, and arrhythmias Local regulation and integration of cAMP signaling are important for proper cardiac function, and perturbations in this signaling can lead to heart failure. Upon chronic β-adrenergic receptor stimulation, cardiomyocyte hypertrophy is caused by elevated cAMP and activation of its downstream effectors, including PKA and Epac (Wang, L. et al., Cell. Signal. 27: 908-922, 2015 and references therein). Cardiomyocyte hypertrophy increases the risk of heart failure and arrhythmias. Therefore, the PDE4 long form activators of the present invention may be useful in the treatment, prevention or partial control of cardiac hypertrophy, heart failure and / or arrhythmias.

[0305] Diseases associated with increased cAMP-mediated signaling Diseases associated with activating mutations in the alpha subunit of the G protein (GNAS1) The G protein Gs acts as a transducer for GPCRs, which exert their biological effects by stimulating adenylyl cyclase activity and increasing intracellular cAMP levels. Gs is a heterotrimeric protein composed of α, β, and γ subunits. Activating mutations in the gene for the α subunit, GNAS1, have been recognized to lead to aberrant cAMP signaling in various tissues, resulting in a range of diseases.

[0306] McCune-Albright syndrome McCune-Albright syndrome (MAS) is a rare genetic disease typically characterized by three major features: precocious puberty, fibrous dysplasia, and cafe au lait lesions. The underlying molecular pathology for MAS involves activating mutations in the GNAS1 gene (Diaz, A. Danon, M. and Crawford, JJ Pediatr. Endocrinol. Metab. 20: 853-880, 2007). Therefore, the PDE4 long form activator of the present invention is expected to be effective in treating, preventing, or partially controlling diseases associated with activating mutations in GNAS1, including McCune-Albright syndrome.

[0307] Amelioration of toxin-induced increases in adenylyl cyclase activity during infection Adenylyl cyclase (the enzyme responsible for the production of cAMP) is a key biological target believed to be involved in mediating the effects of many bacterial toxins (Ahuja et al., Critical Reviews in Microbiology, 30: 187-196, 2004). These toxins produce their effects by increasing cAMP levels through the enhancement of adenylyl cyclase activity associated with host immune cells and / or pathogens. Therefore, by lowering cAMP levels, the PDE4 long form activators of the present invention 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:

[0308] cholera Vibrio cholerae produces cholera toxin, which activates host cell adenylyl cyclase and cAMP production by adenosine diphosphate ribosylation of the α subunit of Gs. Diarrhea caused by cholera toxin is thought to result from excessive cAMP accumulation in gastrointestinal cells.

[0309] whooping cough Bordetella pertussis is the causative agent of the childhood disease whooping cough. B. pertussis toxin stimulates adenosine diphosphate ribosylation of the α subunit of Gi, indirectly increasing cAMP levels in target cells. The bacterium also secretes an invasive adenylyl cyclase, which produces toxic cAMP levels and impairs host immune defenses.

[0310] anthrax disease Anthrax is caused by Bacillus anthracis. It is primarily a livestock disease but can be transmitted to humans by contact. Anthrax infection is accompanied by extensive edema, the development of which is thought to be driven by edema toxin, an adenylyl cyclase that is activated by host calmodulin to produce abnormally high levels of cAMP, which exerts a toxic effect on host immune cells.

[0311] tuberculosis Mycobacterium tuberculosis expresses adenylyl cyclase in large amounts and in multiple regions, which may play a role in virulence and pathogenesis of the disease. One adenylyl cyclase subtype (RV0386) has been demonstrated to enter host macrophages and elevate intracellular cAMP, causing toxicity (Agarwal et al., Nature, 460: 98-102, 2009). Therefore, the PDE4 long chain activators of the present invention are effective in treating, preventing or partially controlling infectious diseases (cholera, whooping cough, anthrax and tuberculosis).

[0312] Diseases dependent on PKA activation by elevated cAMP In eukaryotes, cAMP activates protein kinase A (PKA), also known as cAMP-dependent protein kinase. PKA is normally inactive as a tetrameric holoenzyme, consisting of two catalytic units and two regulatory units, with the regulatory units blocking the catalytic center of the catalytic units. cAMP binds to a specific site on the regulatory units of PKA, causing dissociation between the regulatory and catalytic units and 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 function of those protein substrates.

[0313] Activation of the PDE4 long form reduces cAMP levels and reduces cAMP-mediated activation of PKA. Thus, the PDE4 long form activators of the present invention would be expected to be useful in treating or partially controlling diseases in which inhibitors of PKA show evidence of therapeutic efficacy.

[0314] Diseases dependent on the activation of PKA by cAMP can be identified by their response to PKA inhibitors (e.g., Rp-8-Br-cAMPS), an analog of cAMP that occupies the cAMP binding site of PKA, preventing its dissociation and activation.

[0315] HIV infection and AIDS T cells from HIV-infected individuals have increased levels of cAMP and are more sensitive to inhibition by Rp-8-Br-cAMPS than normal T cells. Excessive activation of PKA by cAMP is associated with the progressive T cell dysfunction in HIV infection (Aandahl, EM et al., FASEB J. 12: 855-862, 1998). Furthermore, in vivo administration of Rp-8-Br-cAMPS has been shown to restore T cell responses in retrovirus-infected mice (Nayjib, B. et al., The Open Immunology Journal, 1: 20-24, 2008). Therefore, the PDE4 long form activators of the present invention are expected to be useful for treating, preventing, or partially controlling HIV infection and AIDS.

[0316] Unclassifiable immunodeficiency (CVID) In vitro application of Rp-8-Br-cAMPS has been shown to correct 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, the PDE4 long form activators of the present invention are expected to be useful for treating, preventing, or partially controlling CVID.

[0317] Diseases dependent on activation of either or both Epac1 and Epac2 by elevated cAMP In addition to PKA, cAMP activates another intracellular receptor known as the cAMP-directly activated exchange protein (Epac). Epac has two isoforms, Epac1 and Epac2, both of which consist of a regulatory domain that binds cAMP and a catalytic domain that promotes the exchange of GDP for GTP with the small GTP-dependent Ras family of small GTP proteins, Rap1 and Rap2. Furthermore, Epac proteins exert their functions through interactions with numerous other cellular partners at specific cellular loci. Altered pathophysiology of Epac signaling has been implicated in a wide range of diseases (Breckler, M. et al., Cell. Signal. 23: 1257-1266, 2011).

[0318] Diseases dependent on cAMP-mediated activation of Epac protein have been identified by their response to Epac inhibitors. For example, ESI-09, a novel acyclic nucleotide Epac1 and Epac2 antagonist, can specifically block 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).

[0319] melanoma Epac1 is involved in promoting migration and metastasis in melanoma (Baljinnyam, E. et al., Pigment Cell Melanoma Res. 24: 680-687, 2011, and references cited therein). Therefore, the PDE4 long form activators of the present invention are expected to be useful in treating, preventing, or partially controlling melanoma.

[0320] Pancreatic cancer It has recently been shown that Epac1 is significantly increased in human pancreatic cancer cells compared with normal pancreas or surrounding tissues (Lorenz, R. et al., Pancreas 37: 102-103, 2008).

[0321] Pancreatic cancer is often resistant to treatments typically effective against other types of cancer. Using the Epac inhibitor ESI-09, a functional role for Epac1 overexpression in pancreatic cancer cell migration and invasion was demonstrated (Almahariq, M. et al., Mol. Pharmacol. 83: 122-128, 2013). These results are consistent with those based on RNAi silencing techniques, suggesting that suppression of Epac1 signaling may be an effective therapeutic strategy for pancreatic cancer. Therefore, the PDE4 long form activators of the present invention are expected to be useful in the treatment, prevention or partial control of pancreatic cancer.

[0322] Diseases that depend on modulation of cAMP-gated ion channels by elevated cAMP In addition to activation of PKA and Epac, another effector pathway for elevated cAMP is activation of cAMP-gated ion channels. Therefore, the PDE4 long form activators of the present invention would be expected to be useful in treating diseases in which inhibitors of cAMP-gated ion channels show evidence of therapeutic efficacy.

[0323] Diseases associated with hyperactivity of cAMP response element binding protein cAMP response element-binding protein (CREB) is a key transcription factor involved in regulating 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 via a range of extracellular signals, including stress, growth factors, and neurotransmitters. Phosphorylation leads to CREB dimerization, allowing it to bind, together with other coactivator partner proteins, to promoter regions of target genes containing cAMP response elements (CRE sites), initiating transcriptional activation. The cAMP pathway (e.g., via cAMP-dependent protein kinase-mediated phosphorylation) is an important positive modulator of CREB-mediated biological activity. Therefore, the PDE4 long form activators of the present invention are expected to be useful in treating, preventing, or partially controlling diseases associated with elevated CREB activity.

[0324] leukemia Bone marrow cells from patients with acute lymphoid 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 are associated with poor clinical response 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 is associated with stimulation of human leukemia cell proliferation, while downregulation suppresses myeloid cell proliferation and survival. The PDE4 long form activators of the present invention are expected to reduce CREB activity and function by attenuating cAMP-mediated stimulation of CREB, and therefore are expected to be useful in the treatment, prevention, or partial control of acute lympho-myeloid leukemia.

[0325] prostate cancer Abnormal androgen activity is a key driver in prostate cancer progression 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 approaches, such as chemotherapy or surgical castration, in the treatment of prostate cancer. Cyclic AMP-increasing agents, such as forskolin, can enhance androgen receptor activity through multiple intracellular mechanisms, including androgen receptor activation via 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 PDE4 long form activators of the present invention will be useful in treating, preventing or partially controlling prostate cancer.

[0326] Diseases associated with reduced activity of cAMP-hydrolyzing PDE enzymes Loss-of-function mutations in genes for cAMP-hydrolyzing PDE isoforms other than PDE4, such as PDE8 and PDE11, have been detected in many 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 may lead to abnormally high cAMP levels and / or persistent cAMP activity, resulting in pathological consequences, as detailed below. Therefore, the PDE4 long form activators of the present invention are expected to be useful in the treatment, prevention, or partial control of these diseases (adrenal cortical tumors, testicular cancer, PPNAD, and cancer complex).

[0327] Adrenal cortical tumors Adrenal cortical tumors associated with inactivating point mutations in the PDE11A4-encoding gene 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; Libe, R., et al., Clin. Cancer Res. 14: 4016-4024, 2008).

[0328] Testicular cancer Mutations that reduce PDE11A activity and increase cAMP levels have been observed in some forms of testicular cancer (Horvath, A. et al., Cancer Res. 69: 5301-5306, 2009).

[0329] Primary pigmented nodular adrenal cortical lesions (Primary pigmented nodular adrenocortical diseases (PPNAD)) Mutations in the PDE8B gene have also been identified as a predisposing factor for PPNAD, and mutant proteins exhibit reduced cAMP degradation capacity (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).

[0330] Carney Complex In Cancer Complex (CNC) caused by PRKAR1A mutations, some patients have defects in PDE11A, which may have a synergistic effect of enhancing the abnormal activation of the cAMP signaling pathway, further leading to adrenal and testicular cancer (Libe, R. et al., J. Clin. Endocrinol. Metab. 96: E208-214, 2011).

[0331] Treatment and Posology "Treatment" refers to therapeutic treatment, whether in humans or non-human animals (e.g., in veterinary applications), typically mammals other than humans, to achieve some desired therapeutic effect on a condition. For example, inhibiting the progression of a condition, including slowing the rate of progression, halting the rate of progression, ameliorating the condition, or curing symptoms. Preventative treatment is also included. Prevention does not refer to or require complete prevention of a condition; its onset may instead be reduced or delayed by prevention in accordance with the present invention.

[0332] When used to prevent or treat a disorder, the compounds or compositions described herein can be administered in an "effective amount," also referred to as a "therapeutically effective amount." As used herein, a "therapeutically effective amount" refers to an amount of one or more compounds described herein, or a pharmaceutical formulation containing such one or more compounds, effective to produce such a therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0333] It will be recognized that appropriate doses of the compounds of the present invention may vary from patient to patient. Determining the optimal amount will generally require balancing the level of therapeutic benefit against any risk or deleterious side effects of the treatment of the present invention. The selected dosage will depend on various factors, including the activity of the specific compound, the route of administration, the time of application, the time it takes for the compound to be excreted, the duration of treatment, other drugs, compounds or substances used in combination, and the patient's age, sex, weight, symptoms, health status, and medical history. Generally, the dosage and route of administration will be ultimately determined by the physician, but will generally be designed to achieve a local concentration at the site of action that achieves the desired results. Administration can be achieved in vivo in a single dose, continuously, or intermittently throughout the course of treatment. Methods for determining the most effective means and amount of administration are known to those skilled in the art and will vary depending on the formulation used in the therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple applications can be used, with the dosage level and pattern selected by the treating physician.

[0334] In general, a suitable dosage of one or more compounds of the present invention can range from about 0.001 to 50 mg / kg of body weight per day, preferably 0.01-25 mg / kg of body weight per day, e.g., 0.01, 0.05, 0.10, 0.25, 0.50, 1.0, 2.5, 10, or 25 mg / kg. Where the compound is a salt, solvate, prodrug, or the like, the amount applied is calculated on the basis of the parent compound and the actual weight used may be increased proportionately.

[0335] Use in combination The compounds of the present invention may further be adapted to mimic or enhance the effects of drugs known to produce their therapeutic effect through the reduction of intracellular cAMP levels.

[0336] Many therapeutically beneficial drugs have a primary mode of action that includes reducing intracellular cAMP levels and / or reducing cAMP-mediated activity, as summarized below. Because the PDE4 long form activators of the present invention also act to reduce cAMP levels, these agonists may mimic and / or enhance the pharmacological properties and therapeutic efficacy of drugs that downregulate cAMP-mediated signaling. In one embodiment, therefore, the compounds of the present invention are provided as part of a combination with another agonist that reduces intracellular cAMP levels and / or reduces cAMP-mediated activity. The combination may be administered simultaneously, contemporaneously, sequentially, or separately. In one embodiment, as described in more detail below, the compounds of the present invention and a separate cAMP-lowering agonist are provided as a single composition. The combination may include the compounds of the present invention and one or more of the following compounds: (i) a presynaptic alpha-2 adrenergic receptor agonist, optionally clonidine, dexmedetomidine, or guanfacine; (ii) a beta-1 adrenergic receptor antagonist ("beta-blocker"), optionally atenolol, metoprolol, bisoprolol, acebutolol, or betaxolol.

[0337] Combination with alpha-2 adrenergic receptor agonists Alpha-2 adrenergic receptor stimulation is known to decrease cAMP levels in a wide range of tissues through Gi protein-mediated inhibition of adenylyl cyclase activity. In noradrenergic neurons in the brain and limbic sympathetic nervous system, presynaptic alpha-2 adrenergic receptor activation inhibits noradrenaline release and noradrenergic activity. Drugs that act as agonists at these receptors (e.g., clonidine, dexmedetomidine, and guanfacine) are effective in treating a variety of clinical conditions. Clonidine (the prototypical agonist) has been shown to be useful in treating hypertension, neuropathic pain, opioid detoxification, insomnia, ADHD, Tourette syndrome, sleep hyperhidrosis, addiction (opioid, alcohol, and nicotine withdrawal), migraine, hyperarousal, and anxiety, as well as in veterinary anesthetics. The reduction in cAMP levels due to activation of the long chain PDE4 is expected to produce results similar to those of drugs that act via alpha-2 adrenergic receptor stimulation. Furthermore, when the long chain PDE4 activators of the present invention are used in combination with alpha-2 adrenergic receptor agonists, the pharmacodynamic effects are expected to be enhanced.

[0338] Combination with a beta-1 adrenergic receptor antagonist Beta-1 adrenergic receptor antagonists are used in a range of cardiovascular treatments, including hypertension, cardiac dysrhythmias, and cardioprotection after myocardial infarction. Their primary mechanism of action involves counteracting the effects of excessive circulating adrenaline and sympathetic activity, particularly mediated by the cardiac beta-1 adrenergic receptor, noradrenaline. Endogenous and synthetic beta-1 adrenergic receptor agonists stimulate adenylyl cyclase activity through Gs activation, increasing intracellular cAMP levels in various tissues (e.g., heart and kidney). Therefore, agents that block beta-1 adrenergic receptor-mediated activity exert their pharmacological effects by attenuating the increase in cAMP-mediated signaling. Given that PDE4 long form activation also reduces cAMP concentration and transduction in cardiac tissue, the PDE4 long form activators of the present invention are expected to be useful in treating or partially controlling hypertension, cardiac dysrhythmias, congestive heart failure, and cardioprotection. Additional non-cardiovascular therapeutic benefits are expected in the treatment of conditions that respond to beta-1 adrenergic antagonists, such as post-traumatic stress-related conditions, anxiety, essential tremor, and glaucoma. Furthermore, the PDE4 long form activators of the present invention can be expected to enhance the pharmacodynamic effects when used in combination with beta-1 adrenergic receptor antagonists.

[0339] Treatment method The compounds described herein can be used to treat or prevent diseases or disorders that can be improved by activating the long-chain isoform of PDE4.The compounds described herein can be used to treat or prevent diseases or disorders mediated by excessive intracellular cyclic AMP signaling.The compounds described herein can be used to treat or prevent diseases or disorders that can be improved by activating the long-chain isoform of PDE4, where the disease or disorder is a disease or disorder mediated by excessive intracellular cyclic AMP signaling.In a further aspect, the present invention provides a small molecule activator of the long-chain isoform of PDE4 described herein for use in a method for treating or preventing a disease or disorder in a patient in need of treatment.The present invention also provides a method for treating or preventing a disease or disorder in a patient in need thereof, comprising administering an effective amount of a compound described herein to the patient in need thereof.The present invention also provides a method for treating or preventing a disease or disorder that can be improved by activating the long-chain isoform of PDE4, comprising administering a therapeutically effective amount of any compound described herein or a pharmaceutically acceptable salt or derivative to the patient in need thereof. The present invention provides a method for treating or preventing a disease or disorder mediated by excessive intracellular cyclic AMP signaling, comprising administering to a patient in need thereof a therapeutically effective amount of any of the compounds described herein, or a pharmaceutically acceptable salt or derivative.The diseases or disorders include diseases associated with increased cAMP production and signaling (e.g., hyperthyroidism, Janssen's metaphyseal chondrodysplasia, hyperparathyroidism, familial male-limited precocious puberty, pituitary adenoma, Cushing's disease, polycystic kidney disease, polycystic liver disease, MODY5, cardiac hypertrophy); diseases known to be associated with increased cAMP-mediated signaling, including diseases associated with activating mutations in the α subunit of G protein (GNAS1), such as McCune-Albright syndrome; ameliorating toxin-induced increases in adenylyl cyclase activity in infectious diseases (e.g., cholera, pertussis, anthrax, tuberculosis); treating diseases known to depend on PKA activation by cAMP elevation (e.g., HIV infection, AIDS, common variable immunodeficiency (CVID)); treating diseases known to depend on activation of Epac1 and / or Epac2 by cAMP elevation (e.g., melanoma and pancreatic cancer); and treating diseases dependent on the regulation of cAMP-gated ion channels by cAMP elevation. Treatment of diseases known to be associated with increased activity of cAMP response element binding proteins (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); mimicking or enhancing the effects of drugs known to produce their therapeutic effect through a reduction in intracellular cAMP levels.

[0340] As used herein, the terms "compounds of the invention," "disclosed compounds," "compounds described herein," "compounds of Formula I," and the like, encompass pharmaceutically acceptable salts, derivatives, polymorphs, isomers (e.g., stereoisomers and tautomers), and isotopically labeled variations thereof. For example, compounds of Formula I encompass pharmaceutically acceptable salts thereof. Furthermore, these terms encompass sub-embodiments of the disclosed compounds, including Formulas II-V, IIb-Vb, and embodiments thereof.

[0341] The compounds described herein may be provided as solvates, for example, hydrates.

[0342] Acceptable derivatives of the compounds of the present invention include pharmaceutically acceptable esters, amides, prodrugs (e.g., pyridine N-oxides), and isotopically labeled variations thereof. The present invention further provides pharmaceutical compositions comprising the compounds of the present invention, including pharmaceutically acceptable salts, solvates, esters, hydrates, or amides thereof, and further including mixtures with pharmaceutically acceptable excipients and any other therapeutic agents. The term "acceptable" means compatible with the other ingredients of the composition and not deleterious to the recipient. Compositions include, for example, those suitable for oral, sublingual, subcutaneous, intravenous, epidural, intrathecal, intramuscular, transdermal, intranasal, pulmonary, topical, local, or rectal application, typically in unit dosage form for administration.

[0343] The term "pharmaceutically acceptable salts" includes salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and bases. Compounds of the present invention that contain a basic group, such as an amino group, can form pharmaceutically acceptable salts with acids. Examples of pharmaceutically acceptable acid addition salts of compounds of the present invention include acid addition salts made with 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.

[0344] Compounds of the present invention that contain an acidic group, such as a carboxy group, can form pharmaceutically acceptable salts with bases. Pharmaceutically acceptable base salts of compounds of the present invention include, but are not limited to, metal salts, such as alkali metal or alkaline earth metal salts (e.g., sodium, potassium, magnesium, or calcium salts), zinc or aluminum salts, and salts formed with ammonia or pharmaceutically acceptable organic amines or heterocyclic salts, such as ethanolamines (e.g., diethanolamine), benzylamine, N-methyl-glucamine, amino acids (e.g., lysine), or pyridine. Hemisalts of acids and bases may also be formed, such as hemisulfates.

[0345] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by methods known in the art. For a discussion of pharmaceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0346] Prodrug The compounds of the present invention can be provided as prodrugs. Prodrugs are derivatives of the compounds described herein (which may themselves have little or no pharmacological activity) and are compounds that can be converted into the compounds described herein when applied in vivo.

[0347] Prodrugs can be produced, for example, by substituting a functional group in a compound described herein at a suitable site that is metabolized in vivo to form a compound described herein. The design of prodrugs is 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.

[0348] In vivo metabolism of prodrugs of the compounds described herein includes, 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, which are hydrolyzed in vivo. For example, if a compound described herein contains a carboxylic acid group (—COOH), a hydrogen atom of the carboxylic acid group can be substituted to form an ester group (e.g., replacing the hydrogen atom with C 1-6 If the compound contains an alcohol group (-OH), the hydrogen atom of the alcoholic group can be substituted to form an ester (e.g., the hydrogen atom can be substituted with -C(O)C 1-6 (substituted with alkyl). Additionally, examples of prodrugs of the compounds described herein include pyridine N-oxides, which are reductively metabolized in vivo to form compounds described herein having a pyridine ring.

[0349] solvate It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of a compound, which can be used in any of the uses / methods described herein. The term "solvate" is used to refer to a complex of a solute (e.g., a compound or a salt of a compound) and a solvent. When the solvent is water, the solvate can be referred to as a hydrate (e.g., a monohydrate, a dihydrate, a trihydrate, etc., depending on the number of water molecules present per molecule of substrate).

[0350] Isomers It will be appreciated that the compounds of the present invention may exist in various stereoisomeric forms. The compounds of the present invention include all stereoisomeric forms, including enantiomers and racemic mixtures. The present invention includes within its scope the use of any stereoisomer of the compounds described herein, or mixtures of stereoisomers, individual enantiomers, or wholly or partially racemic mixtures of such enantiomers, wherein appropriate isomers can be separated from such mixtures by the use or adaptation of known methods (e.g., chromatographic and recrystallization techniques). wherein appropriate isomers can be prepared by the use or adaptation of known methods (e.g., asymmetric synthesis). Furthermore, in some instances, the compounds of the present invention may exist in deuterated isomeric forms, and the compounds of the present invention herein encompass deuterated isomers and mixtures thereof.

[0351] isotope The present invention includes pharmaceutically acceptable isotopically labeled compounds of compounds of Formula I in which 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 normally found in nature.

[0352] Examples of isotopes suitable for incorporation into compounds of the invention include isotopes of hydrogen, e.g. 2 H and 3 H, carbon, e.g. 11 C. 13 C and 14 C, chlorine, e.g. 36 Cl, fluoro, e.g. 18 F, iodine, e.g. 123 I and 125 I, nitrogen, e.g. 13 N and 15 N, oxygen, e.g. 15 O. 17 O and 18 O, as well as sulfur, e.g. 35For example, isotopically labeled compounds, e.g., those incorporating radioisotopes, are useful for drug and / or substrate biodistribution studies. 3 H and 14 C is particularly useful for this purpose given the ease of detection and means of incorporation. 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as N is useful in positron emission topography (PET) studies to examine substrate receptor occupancy. 2 It is well known in the art that isotopic substitution with [H] can positively impact the ADME properties of drug candidates by slowing CYP-mediated metabolism [for review, see Nat. Rev. Drug Discov. 15(4): 219-21 (2016)].

[0353] Isotopically labeled compounds can generally be prepared by processes known to those skilled in the art or described herein or analogous thereto, substituting an appropriate isotopically labeled reagent for an unlabeled reagent.

[0354] Pharmaceutical Composition Pharmaceutical compositions can comprise any compound described herein or its pharmaceutically acceptable salt or derivative and pharmaceutically acceptable excipient.Pharmaceutical compositions described herein can comprise one or more pharmaceutically acceptable excipients, such as pharmaceutically acceptable carriers, diluents, preservatives, solubilizers, stabilizers, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts, buffers, coating agents, antioxidants.Suitable excipients and techniques for formulating pharmaceutical compositions are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000).

[0355] 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., hydroxypropylmethylcellulose, carboxymethylcellulose), glucose, sucrose (or other sugars), sodium carbonate, calcium carbonate, magnesium carbonate, sodium phosphate, calcium phosphate, gelatin, agar, pectin, liquid paraffin oil, olive oil, alcohol, detergent, emulsifier, or water (preferably sterile).

[0356] The pharmaceutical composition may further comprise an adjuvant and / or one or more additional therapeutically active agents.

[0357] The pharmaceutical composition may be provided in unit dosage form, generally in a hermetically sealed container, and may be provided as part of a kit. Such a kit will usually (but not necessarily) include instructions for use. It may include a plurality of said unit dosage forms.

[0358] The pharmaceutical compositions can be adapted for administration by any suitable route, including, for example, oral, buccal or sublingual routes, or parenteral routes, such as subcutaneous, intramuscular, intravenous, intraperitoneal and intradermal, rectal and topical administration, and inhalation. Such compositions can be prepared by any method known in the art of pharmacy, for example, by mixing the active ingredient with an excipient under sterile conditions.

[0359] For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions, and the like.

[0360] Formulations suitable for oral administration may also be designed to deliver the compounds of the present invention in an immediate-release or sustained-release manner, where the release profile can be delayed, pulsed, controlled, sustained, delayed and sustained, or modified in a manner that optimizes the therapeutic efficacy of the compound. Means of delivering compounds in a sustained-release manner are known in the art and can be formulated with the compounds and slow-release polymers to control their release.

[0361] Examples of rate-sustaining polymers include degradable or 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 hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, polymethacrylate, polyethylene oxide, and polyethylene glycol.

[0362] Liquid preparations (including multiple phases and dispersed systems) include emulsions, suspensions, solutions, syrups and elixirs.Such preparations can be provided as fillers in soft or hard capsules (for example, made from gelatin or hydroxypropylmethylcellulose), and typically contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and contain one or more emulsifiers and / or suspending agents.Liquid preparations can also be prepared by reconstituting solids, for example, from sachets.

[0363] The compounds of the present invention may be used in fast dissolving, fast disintegrating dosage forms, for example as described in (Liang and Chen, Expert Opinion in Therapeutic Patents 2001, 11(6): 981-986).

[0364] Tablet formulations are discussed in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets 1980, vol. 1 (Marcel Dekker, New York).

[0365] For intranasal or inhalation administration, the active ingredient can be 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 pack, pump, spray, atomizer or nebulizer.

[0366] For parenteral administration, the pharmaceutical compositions of the invention may be presented in unit-dose or multi-dose packaged containers, for example, as a predetermined amount of injection liquid in sealed vials and ampoules, and may be stored in a lyophilized (freeze-dried) form requiring only the addition of a sterile liquid carrier, e.g., water, prior to use.

[0367] For parenteral administration, the compounds of the present invention may be applied directly to the blood stream, subcutaneous tissue, muscle, or an internal organ. Suitable means of application include intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable devices for application include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.

[0368] Parenteral formulations are typically aqueous or oily solutions. If 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) can be used. For some applications, the compounds of the present invention are preferably formulated as sterile non-aqueous solutions, or can be prepared as a dry form for use with an appropriate vehicle (e.g., sterile, pyrogen-free water (WFI)).

[0369] 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 applied via a surgical incision into subcutaneous tissue, muscle tissue, or directly into specific organs.

[0370] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0371] The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the addition of cosolvents and / or solubility-enhancing agents, e.g., surfactants, micellar structures, and cyclodextrins.

[0372] In admixture with such pharmaceutically acceptable excipients, such as those described in Gennaro, AR et al, Remington: The Science and Practice of Pharmacy (21st Edition, Lippincott Williams & Wilkins, 2005, see especially Part 5: Pharmaceutical Manufacturing), the active agent is compressed into a solid dosage unit, such as a pill, tablet, or processed into a capsule, suppository, or patch. With a pharmaceutically acceptable liquid, the active agent can be applied as a fluid composition, for example, in the form of an injection, an aerosol spray, or a solution, suspension, or emulsion.

[0373] To prepare solid dosage units, conventional additives such as fillers, colorants, polymeric binders, etc. are contemplated. Generally, any pharmaceutically acceptable additive that does not interfere with the function of the active compound can be used. Suitable carriers that can be used in appropriate amounts with the active agents of the present invention in solid compositions include lactose, starch, cellulose derivatives, and the like, or mixtures thereof. For parenteral administration, aqueous suspensions containing pharmaceutically acceptable dispersants and / or wetting agents (propylene glycol or butylene glycol), isotonic saline solutions, and sterile injectable solutions can be used.

[0374] The above-mentioned compositions of the present invention can also be used with suitable packaging materials for the compositions. The packaging materials can include instructions for using the above-mentioned compositions. In some embodiments, one or more compounds of the present invention can be used with other therapeutic agents, i.e., other therapeutic agents, used to treat the above-mentioned conditions. In the case of an active compound combined with other therapies, the two or more therapeutic agents can be administered via individual dosage schedules and different routes.

[0375] Combinations of the compounds of the present invention with the above-listed agents can be determined by a physician using general knowledge and using dosage regimens known to skilled practitioners.

[0376] When a compound of the invention is applied in combination with one, two, three, or more, preferably one or two, preferably one therapeutic agent, the other therapeutic agents and the compound of the invention can be applied simultaneously or sequentially. When applied sequentially, they can be administered at closely spaced intervals (e.g., 5-10 minutes apart), or at longer intervals (e.g., 1, 2, 3, or 4 hours or more apart, or even longer if necessary). The exact dosing regimen will depend on the characteristics of the therapeutic agents.

[0377] In one embodiment, the present invention provides an article of manufacture comprising a compound described herein and another therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is treatment or prevention of a disorder in which a decrease in second messenger responses mediated by cyclic 3',5'-adenosine monophosphate (cAMP) is indicated. Articles of manufacture provided as combined preparations include compositions comprising a compound described herein and another therapeutic agent together in the same pharmaceutical composition, or compositions comprising a compound described herein and another therapeutic agent in separate forms, e.g., in the form of a kit.

[0378] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent. Optionally, the pharmaceutical composition may contain pharmaceutically acceptable excipients, as described above.

[0379] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the present invention. In one embodiment, the kit comprises a means for separately holding the compositions, such as a package, a divided bottle, or a divided foil packet. One example of such a kit is a blister pack, typically used for packaging tablets, capsules, and the like.

[0380] The kits of the invention are used to apply different dosage forms, for example, when administering oral and parenteral dosage forms, when administering separate compositions at different dosing intervals, or when titrating individual compositions together. To aid in compliance, the kits of the invention typically include directions for application.

[0381] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent can be produced and / or formulated by the same or different manufacturers. Additionally, the compound of the present invention and the other therapeutic agent can be used together in the combination therapy: (i) prior to providing a combination product to a physician (e.g., in the case of a kit containing a compound of the invention and another therapeutic agent); (ii) by a physician (or under a physician's guidance) immediately prior to application; (iii) by the patient themselves, for example, during sequential administration of a compound of the invention and another therapeutic agent.

[0382] Manufacturing methods and treatments The present invention further provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of a disease in which a reduction in a second messenger response mediated by cyclic 3',5'-adenosine monophosphate (cAMP) is indicated, wherein the medicament is formulated for application in combination with another therapeutic agent. The present invention further provides the use of another therapeutic agent in the manufacture of a medicament for the treatment or prevention of a disease in which a reduction in a second messenger response mediated by cyclic 3',5'-adenosine monophosphate (cAMP) is indicated, wherein the medicament is formulated for application in combination with a compound of the present invention.

[0383] The present invention also provides a compound described herein for use in the treatment or prevention of a disorder requiring a reduction in a second messenger response mediated by cAMP, wherein the compound described herein is prepared for administration with another therapeutic agent. The present invention also provides another therapeutic agent for use in the treatment or prevention of a disorder requiring a reduction in a second messenger response mediated by cAMP, wherein the other therapeutic agent is prepared for administration with the compound described herein. The present invention also provides a compound described herein for use in the treatment or prevention of a disorder requiring a reduction in a second messenger response mediated by cAMP, wherein the compound described herein is administered with another therapeutic agent. The present invention also provides another therapeutic agent for use in the treatment or prevention of a disorder in which a reduction in a second messenger response mediated by cAMP is required, wherein the other therapeutic agent is administered together with a compound described herein.

[0384] The invention also provides the use of a compound described herein in the manufacture of a medicament for the treatment or prevention of a disorder requiring a reduction in a cAMP-mediated second messenger response, where a patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent in the manufacture of a medicament for the treatment or prevention of a disorder requiring a reduction in a cAMP-mediated second messenger response, where a patient has previously (e.g., within 24 hours) been treated with a compound described herein.

[0385] In one embodiment, the other therapeutic agent is: (i) a presynaptic α-2 adrenergic receptor agonist, optionally clonidine, dedexmedetomidine, or guanfacine; (ii) a beta-1 adrenergic receptor antagonist ("beta-blocker"), optionally atenolol, metoprolol, bisoprolol, acebutolol, or betaxolol.

[0386] Example The invention will now be further described by the following non-limiting examples with reference to the Tables. Table 1 shows the structures of small molecule PDE4 long chain conformation activators according to the present invention. Table 2 shows enzyme assay data for PDE4D5, the long form of PDE4, and PDE4B2, the short form of PDE4. Table 3 shows the reduction in cAMP levels in 3D cultures of m-IMCD3 kidney cells treated with compounds of the invention. Table 4 shows the inhibition of PGE2-stimulated cyst formation in 3D cultures of m-IMCD3 kidney cells treated with compounds of the invention.

[0387] General Experimental Details The reaction was analyzed by thin layer chromatography (Merck Millipore TLC Silicagel 60 F 254 ) were monitored. Flash column chromatography was performed on a Biotage Isolera® or Buchi Reveleris® X2 flash chromatography system using prepacked silica gel columns. NMR spectra were recorded using a Bruker 300 or 400 MHz spectrometer at 25 °C using the residual signal of the deuterated solvent as the internal standard (unless otherwise stated). Exchangeable NH and OH residues were occasionally 1 The H-NMR spectrum did not allow identification.

[0388] UPLC method: Method A: Instrument: Agilent 1290 Infinity II, 1290 G7120A Bin Pump, 1290 G7167B Multisampler, 1290 MCT G7116B Column Configuration, 1290 G7117B DAD (210-320 nm), PDA (210-320 nm), G6135B MSD (ESI pos / neg). Mass Range: 90-1500. Column: XSelect CSH XP C18 (50x2.1 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. B, Post-run: 0.5 min

[0389] Method B: Instrument: Agilent 1290 Infinity II, 1290 G7120A Bin Pump, 1290 G7167B Multisampler, 1290 MCT G7116B Column Configuration, 1290 G7117B DAD (210-320 nm), PDA (210-320 nm), G6135B MSD (ESI pos / neg). Mass Range: 90-1500. Column: XSelect CSH XP C18 (50x2.1 mm, 2.5 μm). Flow Rate: 0.8 mL / min. Column Temperature: 25°C. Eluent A: 10 mM ammonium bicarbonate (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. B, Post-run: 0.5 min

[0390] Method C: Instrument: Agilent 1290 Infinity II, 1290 G7120A Bin Pump, 1290 G7167B Multisampler, 1290 MCT G7116B Column Configuration, 1290 G7117B DAD (210, 210-320 nm), PDA (210-320 nm), G6135B MSD (ESI pos / neg). Mass Range: 90-1500. Column: Atlantis T3 (100x3.0 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. B, Post-run: 2.5 min

[0391] Method D: Instrument: Agilent 1290 Infinity II, 1290 G7120A Bin Pump, 1290 G7167B Multisampler, 1290 MCT G7116B Column Configuration, 1290 G7117B DAD (210, 210-320 nm), PDA (210-320 nm), G6135B MSD (ESI pos / neg). Mass Range: 90-1500. Column: Atlantis T3 (100x2.1 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. B, Post-run: 2.5 min

[0392] LCMS method Method A: Instrument: Agilent 1260 Infinity II, 1260 G7112B Bin Pump, 1260 G7167A Multisampler, 1290 MCT G7116B Column Configuration: 1260 G7115A DAD (210, 220, and 210-320 nm), PDA (210-320 nm), G6135B MSD (ESI pos / neg) Mass Range: 90-1500, 1290 G7102A ELSD (Evap: 50°C, Neb: 50°C, Gas Flow: 1.3 mL / min), Column: XSelect CSH C18 (30x2.1 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% in acetonitrile Formic acid, gradient: t = 0 min 5% B, t = 1.6 min 98% B, t = 3 min 98% B, post-run: 1.3 min

[0393] Method B: Instrument: Agilent 1260 Infinity, 1260 G1312B Bin Pump, 1260 G1367E WPS, 1260 TCC G1316A Column Configuration: 1260 G1315C DAD (210-320 nm, 210 and 220 nm), PDA (210-320 nm), G6130B MSD (ESI pos / neg). Mass Range: 100-1000. Column: Waters XSelect CSH C18 (30x2.1 mm, 3.5 μm). Flow Rate: 1 mL / min. Column Temperature: 25°C. Eluent A: 10 mM ammonium bicarbonate (pH 9). Eluent B: acetonitrile. Gradient: t = 0 min 5% B, t = 1.6 min 98% B, t = 3 min 98% B. B, Postrun: 1.4 min The following compound abbreviations are used:

[0394] [Table 5]

[0395] Abbreviation: The following abbreviations may also be used in the 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 for NMR signal assignments: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), app. (approximate), br. (broad), dd (double doublet), dt (double triplet), td (triple doublet). In the chemical formula, "Example" means "Example" and "Intermediate" means "Intermediate."

[0396] Synthetic procedures for key intermediates: Intermediate 1: Synthesis of benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0397] [ka]

[0398] Under a nitrogen atmosphere, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.00 g, 23.6 mmol) and triethylamine (6.57 mL, 47.1 mmol) were dissolved in dichloromethane (100 mL), and benzyl chloroformate (3.7 mL, 26 mmol) was slowly added. The mixture was stirred at room temperature for 30 minutes, poured into saturated aqueous sodium bicarbonate, 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 column chromatography (0%-50% ethyl acetate in n-heptane) and concentrated in vacuo to give 3-benzyl 8-(tert-butyl)3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (8.15 g, 85%) as a colorless oil. To a solution of 3-benzyl 8-(tert-butyl)3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (8.15 g, 20.0 mmol) in 1,4-dioxane (40 mL) was added 4 M hydrochloric acid in 1,4-dioxane (40 mL, 160 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. 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 benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (4.95 g, 95%, Intermediate 1) as a pale yellow oil. 1 H-NMR: δ H (400 MHz, 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).

[0399] Intermediate 4: Synthesis of benzyl 8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate hydrochloride

[0400] [ka]

[0401] 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 in a sealed vial at 100 °C for 21 h. The mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate 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 column chromatography (2%-75% ethyl acetate in n-heptane) and concentrated in vacuo to give 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. To a solution of 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, 0.39 mmol) in methanol (5 mL) was added a 4 M solution of hydrochloric acid 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 benzyl 8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate hydrochloride (88 mg, 96%, Intermediate 4) as a yellow solid. LCMS (Method A): t R 1.28 minutes, 90%, MS(ESI) 379.2(M+H) + .

[0402] 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

[0403] [ka]

[0404] 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 (76 mg, 0.18 mmol, Intermediate 4) and cyclopentylacetic 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® CSH C18 column, ammonium bicarbonate in water / 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%). To a solution of 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, 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 reaction was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, and the residue was transferred to an SCX cartridge. 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-cyclopentylethan-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, 8.4), 6.53 - 6.40(1 H, 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(1 H, m), 2.13 - 1.83(6H, m), 1.70 - 1.49(4H, m), 1.33 - 1.07(2H, m); UPLC (Method C): t R 3.58 minutes, 100%, MS(ESI) 355.2(M+H) + .

[0405] The following examples (40-49) were prepared using procedures similar to those of Example 39, using the appropriate starting materials.

[0406] 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

[0407] [ka]

[0408] It is prepared using 2-(4,4-difluorocyclohexyl)acetic acid as the acid component. 1 H-NMR: δ H(400 MHz, DMSO-d6) 7.29(1 H, d, J 8.4), 6.56(1 H, t, J 8.0), 4.53 - 4.42(2H, m), 4.34(2H, br s), 3.72(2H, m), 2.85(2H, m), 2.72(1H, t, J 5.9), 2.62(1 ​​H, t, J6.0), 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 1.33 minutes, 97%, MS(ESI) 405.4(M+H) + . 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

[0409] [ka]

[0410] It is prepared using phenoxyacetic acid as the acid component. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.33 - 7.27(2H, m), 7.20(0.6H, d, J 8.5), 7.16(0.4H, d, J 8.5), 7.12 - 6.93(3H, m), 6.43(1 H, d, J 8.6), 4.90 - 4.74(2H, m), 4.70 - 4.58(2H, m), 4.43(2H, br s), 3.88(1 H, t, J 5.9), 3.84(1 H, t, J 5.8), 3.13(2H, m), 2.97 - 2.79(2H, m), 2.64(2H, m), 2.09 - 1.91(4H, m); UPLC (Method C): t R3.39 minutes, 100%, MS(ESI) 379.2(M+H) + .

[0411] 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

[0412] [ka]

[0413] It is prepared using 3,3-dimethylbutanoic acid as the acid component. 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(1 H, 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 3.37 minutes, 100%, MS(ESI) 343.2(M+H) + .

[0414] 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

[0415] [ka]

[0416] It is produced using isovaleric acid as the acid component. 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(1 H, m), 4.61(1H, s), 4.49(1 H, 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 3.09 minutes, 100%, MS(ESI) 329.2(M+H) + .

[0417] 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

[0418] [ka]

[0419] It is prepared using 2,3-dimethylbutanoic acid as the acid component. 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(1 H, d, J 8.5), 4.62(1.2H, d, J 8.7), 4.55(0.8H, d, J 8.7), 4.43(2H, br s), 3.93 - 3.86(0.8H, m), 3.84 - 3.75(1.2H, m), 3.14(2H, dd, J 12.3, 1.8), 2.90 - 2.77(2H, m), 2.63(2H, d, J 12.4), 2.57 - 2.46(1 H, m), 2.06 - 1.89(5H, m), 1.16 - 1.06(3H, m), 0.99 - 0.84(6H, m); UPLC(Method C): t R 3.31 minutes, 98%, MS(ESI) 343.2(M+H) + .

[0420] 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

[0421] [ka]

[0422] It is prepared using 2-phenylacetic acid as the acid component. 1 H-NMR: δ H(400 MHz, CDCl3, mixture of rotamers) 7.35 - 7.22(5H, m), 7.20(0.6H, d, J 8.5), 7.05(0.4H, d, J 8.5), 6.42(0.6H, d, J 8.6), 6.37(0.4H, d, J 8.6), 4.63(1 ,2H, s), 4.46(0.8H, s), 4.41(2H, s), 3.90(0.8H, t, J 6.0), 3.82(2H, m), 3.70(1.2H, t, J 6.0), 3.11(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): t R 1.17 minutes, 100%, MS(ESI) 363.2(M+H) + .

[0423] 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

[0424] [ka]

[0425] It is prepared using 2-(4-fluorophenoxy)acetic acid as the acid component. 1 H-NMR: δ H(400 MHz, CDCl3, mixture of rotamers) 7.20(0.6H, d, J 8.6), 7.17(0.4H, d, J 8.6), 7.02 - 6.87(4H, m), 6.43(1 H, d, J 8.6), 4.76 - 4.70(2H, m), 4.64 - 4.56(2H, m), 4.43(2H, br s), 3.88(0.8H, t, J 6.0), 3.82(1.2H, t, J 6.0), 3.13(2H, d, J 12.0), 2.87(1.2H, t, J 6.0), 2.82(0.8H, t, J 6.0), 2.65(2H, d, J 12.2), 2.00 -1.90(4H, m); UPLC(Method A): t R 1.28 minutes, 100%, MS(ESI) 397.4(M+H) + .

[0426] 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

[0427] [ka]

[0428] It is prepared using cyclopentanecarboxylic acid as the acid component. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.25 - 7.07(1 H, m), 6.50 - 6.34(1 H, 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(1 H, 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): tR 1.12 minutes, 99%, MS(ESI) 341.2(M+H) + .

[0429] 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

[0430] [ka]

[0431] It is prepared using 2-(4-fluorophenyl)acetic acid as the acid component. 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 0.61 min, 99%, MS(ESI) 381.7(M+H) + .

[0432] 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

[0433] [ka]

[0434] It is prepared using 2,2-difluoro-2-phenylacetic acid as the acid component. 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 0.74 min, 100%, MS(ESI) 399.7(M+H) + .

[0435] 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

[0436] [ka]

[0437] Under an argon atmosphere, diphenylphosphoryl azide (75 μL, 0.35 mmol) was added to a solution of 4,4-difluorocyclohexanecarboxylic acid (57 mg, 0.35 mmol) and triethylamine (49 μL, 0.35 mmol) in toluene (2.5 mL), and the mixture was heated at 85° C. for 2 hours. The mixture was cooled to room temperature and added 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 (84 mg, 0.20 mmol, Intermediate 4) and triethylamine (57 μL, 0.41 mmol) in toluene (1 mL) and N,N-dimethylformamide (0.5 mL). The reaction was stirred at room temperature under an argon atmosphere for 16 hours. The mixture was partitioned between saturated aqueous sodium bicarbonate 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 column chromatography (30%-100% ethyl acetate in n-heptane) and concentrated in vacuo to give 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, 50%) as a colorless gum. LCMS (Method A): R 1.70 min, 98%, MS(ESI)540.4(M+H) + . 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 (washed with methanol and eluted 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-naphthyridine-6(5H)-carboxamide (39 mg, 88%, Example 59) as a white solid. 1 H-NMR: δ H (400 MHz, CDCl3): 7.18(1 H, d, J 8.5), 6.42(1 H, d, J 8.6), 4.43(2H, br s), 4.39(2H, s), 4.30(1 H, d, J 7.5), 3.84(1 H, 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 1.11 minutes, 99%, MS(ESI) 406.2(M+H) + .

[0438] 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

[0439] [ka]

[0440] 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 (76 mg, 0.18 mmol, Intermediate 4) in dichloromethane (3 mL) and diisopropylethylamine (96 μL, 0.55 mmol) at 0° C., 1-pyrrolidinecarbonyl chloride (40 μL, 0.36 mmol) was added, and the mixture was stirred at 0° C. for 10 minutes. The mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (Waters XSelect® CSH C18 column, ammonium bicarbonate in water / 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 1.62 minutes, 98%, MS(ESI) 476.4(M+H) + .

[0441] 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 (washed with methanol and eluted 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(400 MHz, CDCl3) 7.17(1 H, d, J 8.5), 6.41(1 H, 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, J 12.2, 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 4.01 min, 99%, MS(ESI) 342.2(M+H) + .

[0442] 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

[0443] [ka]

[0444] 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 (76 mg, 0.18 mmol, Intermediate 4) and diisopropylethylamine (80 μL, 0.46 mmol) in dichloromethane (3 mL) at 0 °C was added triphosgene (38 mg, 0.13 mmol), and the reaction was stirred at 0 °C for 30 min. Next, N-methylcyclopentanamine (158 μL, 0.13 mmol) was added, and the reaction was heated at 40 °C for 2 days. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica column chromatography (20%-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): R 1.76 minutes, 99%, MS(ESI)504.4(M+H) + . 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% hydrogen bromide 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 (washed with methanol and eluted 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(400 MHz, CDCl3) 7.17(1 H, d, J 8.5), 6.41(1 H, d, J 8.5), 4.43(2H, m), 4.24(2H, s), 4.23 - 4.13(1 H, 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 R 1.27 minutes, 99%, MS(ESI) 370.2(M+H) + .

[0445] 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

[0446] [ka]

[0447] 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 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica column chromatography (0% to 5% methanol in dichloromethane) and concentrated in vacuo to give 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 (49 mg, 62%) as a colorless gum. LCMS (Method A): tR 1.68 min, 99%, MS(ESI) 490.4(M+H) + .

[0448] To a solution of benzyl 8-(6-(cyclopentylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (44 mg, 0.09 mmol) in N,N-dimethylformamide (1.5 mL) was added 60% sodium hydride in mineral oil (26 mg, 1.08 mmol), and the mixture was stirred for 5 min. Next, iodoethane (172 μL, 2.15 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was quenched with methanol (5 mL) and concentrated in vacuo. The residue was purified by silica column chromatography (20%-100% ethyl acetate in n-heptane) and concentrated in vacuo to give 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): R 1.83 min, 93%, MS(ESI)518.4(M+H) + .

[0449] 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% hydrogen bromide 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 (washed with methanol and eluted 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. 1H-NMR: δ H (400 MHz, CDCl3) 7.18(1 H, d, J 8.5), 6.41(1 H, d, J 8.6), 4.44(2H, br s), 4.26(2H, br s), 4.01 - 3.94(1 H, m), 3.52(2H, t, J 5.9), 3.21 - 3.11(4H, m), 2.86(2H, t, J6.0), 2.68 - 2.61(2H, m), 2.04 - 1.83(6H, m), 1.65 - 1.49(6H, m), 1.10(3H, t, J 7.0); UPLC (Method A): t R 1.41 min, 93%, MS(ESI) 384.4(M+H) + .

[0450] 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

[0451] [ka]

[0452] 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 filtered through Celite®, washed with dichloromethane, and concentrated in vacuo. The residue was dissolved in dichloromethane (3 mL), purified by silica column chromatography (0%-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. RuPhos (44 mg, 0.10 mmol) and Pd(dba) (39 mg, 0.04 mmol) were suspended in 1,4-dioxane (0.3 mL) under an argon atmosphere and heated at 80 °C for 5 min. 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), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (117 mg, 0.55 mmol), and cesium carbonate (347 mg, 1.06 mmol) in 1,4-dioxane (1.2 mL) under an argon atmosphere, and the mixture was heated at 100 °C for 16 h. The mixture was filtered through Celite®, washed with acetonitrile, and concentrated in vacuo. The residue was purified by silica column chromatography (0%-100% ethyl acetate in n-heptane) and concentrated in vacuo to give 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 (193 mg, 91%) as an orange foam. 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), purified by preparative reverse-phase chromatography (Waters XSelect® CSH C18 column, ammonium bicarbonate in water / 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(1 H, m), 6.52 - 6.41(1 H, 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(11 H, m), 1.40 - 1.26(2H, m); UPLC(Method C): t R 4.17 minutes, 99%, MS(ESI) 391.2(M+H) + .

[0453] The following example (88) was prepared using a procedure similar to that of Example 87 using the appropriate starting materials.

[0454] 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

[0455] [ka]

[0456] It is prepared using cyclopentylacetic acid as the acid component. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.40 - 7.28(1 H, m), 6.51 - 6.41(1 H, 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 4.11 minutes, 100%, MS(ESI) 341.2(M+H) + .

[0457] 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

[0458] [ka]

[0459] 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 coated on Celite® and purified by silica column chromatography (0%-100% ethyl acetate in n-heptane) and concentrated in vacuo to give 2-chloro-N-(4,4-difluorocyclohexyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (218 mg, 95%) as a white solid. Under an argon atmosphere, RuPhos (50 mg, 0.11 mmol) and Pd(dba) (44 mg, 0.05 mmol) were suspended in 1,4-dioxane (0.3 mL) and heated at 80 °C for 5 min. 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 an argon atmosphere, and the mixture was heated at 100 °C for 16 h. The mixture was filtered through Celite®, washed with acetonitrile, and concentrated in vacuo. The residue was purified by silica column chromatography (0% to 100% ethyl acetate in n-heptane) and concentrated under reduced pressure to give 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 (279 mg, 80%) as an orange solid. 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), purified by preparative reverse-phase chromatography (Waters XSelect® CSH C18 column, ammonium bicarbonate in water / 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 (400 MHz, CDCl3) 7.34(1 H, d, J 8.5), 6.46(1 H, d, J 8.6), 4.58(2H, s), 4.51(2H, s), 4.42(2H, t, J 3.5), 4.13(1 H, d, J 7.6), 3.87(1 H, 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 2.07 minutes, 99%, MS(ESI) 392.2(M+H) + .

[0460] The following example (90) was prepared using a procedure similar to that of Example 89 using the appropriate starting materials.

[0461] 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

[0462] [ka]

[0463] It is prepared using cyclopentyl isocyanate as the isocyanate component. 1 H-NMR: δ H (400 MHz, CDCl3) 7.34(1H, d, J 8.5), 6.45(1 H, 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(2H, 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 1.88 min, 99%, MS(ESI) 342.2(M+H) + .

[0464] 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

[0465] [ka]

[0466] 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® CSH C18 column, ammonium bicarbonate in water / 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 (400 MHz, CDCl3) 7.33(1 H, d, J 8.6), 6.46(1 H, d, J 8.6), 4.58(2H, s), 4.49(4H, d, J 14.2), 4.12(1 H, d, J 7.7), 3.87(1 H, 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 1.26 minutes, 100%, MS(ESI) 406.7(M+H) + .

[0467] The following examples (92-94) were prepared using procedures similar to those of Example 91 using the appropriate starting materials.

[0468] 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

[0469] [ka]

[0470] Prepared using Example 90 as the starting reagent. 1 H-NMR: δ H (400 MHz, CDCl3) 7.33(1H, d, J 8.5), 6.45(1 H, 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 1.90 minutes, 100%, MS(ESI) 356.2(M+H) + .

[0471] 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

[0472] [ka]

[0473] Prepared using Example 87 as the starting reagent. 1 H-NMR: δ H(400 MHz, CDCl3, mixture of rotamers) 7.40 - 7.28(1 H, m), 6.54 - 6.38(1 H, 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 1.41 min, 99%, MS(ESI) 405.7(M+H) + .

[0474] 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

[0475] [ka]

[0476] Prepared using Example 88 as the starting reagent. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.39 - 7.27(1 H, m), 6.51 - 6.41(1 H, 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 2.67 minutes, 99%, MS(ESI) 355.2(M+H) + .

[0477] 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

[0478] [ka]

[0479] To a solution of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (125 mg, 0.65 mmol) and triethylamine (0.24 mL, 1.70 mmol) in dichloromethane (3 mL) was added 1-pyrrolidinecarbonyl chloride (0.09 mL, 0.79 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, suspended in methanol (1 mL), and diluted with water. The precipitate was collected by filtration, washed thoroughly with water, and dried to give (2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(pyrrolidin-1-yl)methanone (93 mg, 57%) as a pink solid. Under an argon atmosphere, RuPhos (31 mg, 0.07 mmol) and Pd(dba) (27 mg, 0.03 mmol) were suspended in 1,4-dioxane (1 mL) and heated at 80 °C for 5 min. 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 an argon atmosphere. The mixture was heated at 100 °C for 16 h. The mixture was filtered through Celite®, washed with acetonitrile, and concentrated in vacuo. The residue was purified by silica column chromatography (0%-100% ethyl acetate in n-heptane) to give 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, 24%) as a pale yellow solid. 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), purified by preparative reverse-phase chromatography (Waters XSelect® CSH C18 column, ammonium bicarbonate in water / acetonitrile), and lyophilized to afford (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(400 MHz, CDCl3) 7.33(1 H, d, J 8.5), 6.44(1 H, 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 1.70 min, 99%, MS(ESI) 328.2(M+H) + .

[0480] The following example (96) was prepared using a procedure similar to that of Example 95 using the appropriate starting materials. 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

[0481] [ka]

[0482] Prepared using diethylcarbamoyl chloride. 1 H-NMR: δ H (400 MHz, CDCl3) 7.32(1 H, d, J 8.5), 6.44(1 H, 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, 7.1H); UPLC (Method A): t R 1.91 min, 99%, MS(ESI) 330.2(M+H) + .

[0483] 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

[0484] [ka]

[0485] 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 at 45° C. for 16 hours, and the mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography (Waters XSelect® CSH C18 column, ammonium bicarbonate in water / acetonitrile, followed by Phenomenex LUNA C18 column, formic acid in water / acetonitrile) and lyophilized to give 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(400 MHz, CDCl3) 7.17(1 H, d, J 8.5), 6.42(1 H, d, J 8.5), 4.47(2H, s), 4.39(2H, s), 4.30(1 H, d, J 7.5), 3.90 - 3.78(1 H, 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(11 H, m), 1.54 - 1.45(2H, m); UPLC (Method B): t R 2.46 minutes, 99%, MS(ESI) 420.2(M+H) + .

[0486] The following example (106) was prepared using a procedure similar to that of Example 105 using the appropriate starting materials.

[0487] 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

[0488] [ka]

[0489] Prepared using Example 40 as the starting reagent. 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(1 H, 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(11 H, m), 1.40 -1.24(2H, m); UPLC (Method B): 2.73 min, 99%, MS(ESI) 419.4(M+H) + .

[0490] 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

[0491] [ka]

[0492] [ka]

[0493] To a stirred solution of 2-(4,4-difluorocyclohexyl)acetic acid (1.00 g, 5.61 mmol) in DCM (15 mL) at 0 °C, DIPEA (4.90 mL, 28.1 mmol) and n-propylphosphonic anhydride cyclic trimer (50% in ethyl acetate; 3.57 g, 5.61 mmol) were added. After 15 min, 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 h, 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. To a degassed mixture of 1-(2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one (1.10 g, 3.35 mmol) and tert-butyl piperazine-1-carboxylate (1.25 g, 6.69 mmol) in toluene (10 mL) was added sodium tert-butoxide (0.965 g, 10.0 mmol), XPhos (0.319 g, 0.669 mmol), and Pd(dba) (0.306 g, 0.335 mmol) under continuous bubbling of nitrogen. The mixture was stirred in a sealed vial at 100 °C for 16 h and then concentrated under reduced pressure. The residue was diluted with 10% MeOH in DCM (40 mL), filtered through Celite®, and washed with 10% MeOH in DCM (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 40% to 80% ethyl acetate in petroleum ether, and the product was washed with 20% ethyl acetate in petroleum ether and dried to give tert-butyl 4-(6-(2-(4,4-difluorocyclohexyl)acetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperazine-1-carboxylate (1.3 g, 81%) as a pale yellow solid. 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) at 0° C. was added HCl (4 M in 1,4 dioxane; 13.1 mL, 52.2 mmol). 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 (400 MHz, DMSO-d6, 80℃) 7.36(1 H, d, J 8.8), 6.67(1 H, 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).

[0494] 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

[0495] [ka]

[0496] 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 h, 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 pale yellow solid. 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) under continuous bubbling of nitrogen, (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) were added. After stirring at room temperature for 5 min, 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 h. 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 × 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 product-containing fractions were combined, concentrated under reduced pressure, basified with saturated NaHCO3 solution (20 mL), and extracted with 10% MeOH in DCM (2 x 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]pyrazin-2(1H)-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one (58 mg, 22%, Example 112) as a gummy solid. 1 H-NMR: δ H (400 MHz, DMSO-d6) 7.35(1 H, d, J 8.4), 6.73 - 6.69(1 H, m), 4.52 - 4.50(2H, m), 4.46 - 4.42(1 H, m), 4.31 - 4.33(1 H, 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).

[0497] The following example (113) was prepared using a procedure similar to that of Example 112 using the appropriate starting materials.

[0498] 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

[0499] [ka]

[0500] It was prepared using (S)-octahydropyrrolo[1,2-a]pyrazine instead of (R)-octahydropyrrolo[1,2-a]pyrazine. 1 H-NMR: δ H (400 MHz, DMSO-d6) 7.34(1 H, d, J 8.8), 6.72 - 6.69(1 H, m), 4.52 -4.50(2H, m), 4.42 - 4.44(1 H, 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).

[0501] Example 114: Synthesis of 2-cyclopentyl-1-(2-(piperidin-4-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one

[0502] [ka]

[0503] 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), CsCO (7.01 g, 21.5 mmol), and PdCl(dppf)-CHCl complex (0.586 g, 0.717 mmol) under continuous nitrogen sparging. 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, eluting with 0%-20% methanol in DCM, to give tert-butyl 4-(6-(2-cyclopentylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.5 g, 82%) as an off-white solid. 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) under nitrogen was added Pd / C (10%, dried; 300 mg). The mixture was stirred under H bladder pressure at room temperature for 16 hours, then filtered through Celite®, 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 carried on to the next step without further purification. 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) was added HCl in dioxane (4 M; 1.0 mL, 4.0 mmol) at 0° C. 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 (400 MHz, DMSO-d6) 7.52(1H, d, J 8.0), 7.10 -7.07(1 H, m), 4.60 - 4.70(2H, m), 3.78 - 3.75(2H, m), 2.99 - 2.91(2H, m), 2.90 - 2.80(1 H, m), 2.60 - 2.78(1 H, m), 2.56 - 2.51(2H, m), 2.50 - 2.41(3H, m), 2.19 - 2.16(1 H, 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).

[0504] 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

[0505] [ka]

[0506] 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 pale yellow gel. 1 H-NMR: δ H (400 MHz, DMSO-d6) 7.52(1 H, d, J 8.0), 7.13 - 7.09(1 H, m), 4.60 - 4.70(2H, m), 4.36(1 H, m), 3.78 - 3.75(2H, m), 3.53 - 3.48(2H, m), 2.97 - 2.91(2H, m), 2.89 - 2.79(1 H, m), 2.78(1 H, m), 2.57 - 2.52(1 H, m), 2.43 - 2.39(4H, m), 2.17(1 H, 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).

[0507] The following examples (119-124) were prepared using procedures similar to Example 39 using the appropriate starting materials. 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

[0508] [ka]

[0509] It is prepared using 2-(1-methylcyclopentyl)acetic acid as the acid component. 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(1 H, 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, UPLC (Method A): t R 1.45 minutes, 100%, MS(ESI) 369.2(M+H) + .

[0510] 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

[0511] [ka]

[0512] It is prepared using benzoic acid as the acid component. 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 1.05 minutes, 100%, MS(ESI) 349.2(M+H) + .

[0513] 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

[0514] [ka]

[0515] It is prepared using 2-methoxybenzoic acid as the acid component. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.40 - 7.26(2H, m), 7.26 - 7.23(1 H, m), 7.03 - 6.91(2H, m), 6.49 - 6.34(1 H, m), 4.87 - 4.72(1 H, m), 4.52 - 4.39(2H, m), 4.35 - 4.19(1 H, m), 3.94 - 3.73(3H, m), 3.61 - 3.44(1 H, 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 R1.09 min, 100%, MS(ESI) 379.2(M+H) + .

[0516] 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

[0517] [ka]

[0518] It is prepared using 2-methylbenzoic acid as the acid component. 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(1 H, 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 1.19 minutes, 100%, MS(ESI) 363.2(M+H) + .

[0519] 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

[0520] [ka]

[0521] It is prepared using 4-fluorobenzoic acid as the acid component. 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 1.12 minutes, 99%, MS(ESI) 367.2(M+H) + .

[0522] 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

[0523] [ka]

[0524] It is prepared using (2R)-2-cyclopentyl-2-hydroxyacetic acid as the acid component. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.19(1 H, dd, J 16.5, 8.5), 6.44(1 H, t, J 7.6), 4.70 - 4.56(1 H, 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 1.15 minutes, 99%, MS(ESI) 371.2(M+H) + .

[0525] Example 125: Synthesis of cyclopentyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0526] [ka]

[0527] 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 (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) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0%-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 2.31 minutes, 94%, MS(ESI) 491.2(M+H) + . Under a 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 mmol) 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 filtered through Celite®, concentrated in vacuo, purified by preparative reverse-phase chromatography (Waters XSelect® CSH C18 column, ammonium bicarbonate in water / 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 (400 MHz, CDCl3) 7.17(1 H, d, J 8.6), 6.42(1 H, d, J 8.6), 5.19 - 5.12(1 H, 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 2.21 minutes, 99%, MS(ESI) 357.2(M+H) + .

[0528] The following Example 126 was prepared using a procedure similar to Example 125 using the appropriate starting materials.

[0529] Example 126: Synthesis of isopropyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0530] [ka]

[0531] Prepared using isopropyl chloroformate. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.17(1 H, d, J 8.6), 6.42(1 H, d, J 8.5), 4.97(1 H, 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 1.92 minutes, 95%, MS(ESI) 331.2(M+H) + .

[0532] Example 127: Synthesis of benzyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0533] [ka]

[0534] 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 4 M 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 R1.34 min, 89%, MS(ESI) 169.1(M+H) + .

[0535] To a solution of benzyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (417 mg, 1.17 mmol) and triethylamine (382 μL, 2.74 mmol) in 1,4-dioxane (5 mL), benzyl chloroformate (172 μL, 1.21 mmol) was added, and the mixture was stirred at room temperature for 3 days. The mixture was concentrated and partitioned between dichloromethane and saturated aqueous sodium bicarbonate, 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 benzyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (417 mg, quantitative) as a pale yellow gum. LCMS (Method B):t R 2.02 minutes, 84%, MS(ESI)303.1(M+H) + . Under a nitrogen atmosphere, a mixture of benzyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (208 mg, 583 μmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (186 mg, 874 μmol), cesium carbonate (342 mg, 1.05 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (15 mg, 32.0 μmol), and Pd(dba) (26 mg, 29 μmol) in 1,4-dioxane (5 mL) was heated at 90° C. for 16 hours. The mixture was filtered through Celite® and concentrated in vacuo. The residue was purified by silica column chromatography (0% to 50% ethyl acetate in n-heptane) and concentrated under reduced pressure to give benzyl 2-(3-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (138 mg, 48%) as a sticky clear solid. LCMS (Method B):t R2.29 minutes, 97%, MS(ESI)479.2(M+H) + . 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, purified by preparative reverse-phase chromatography (Waters XSelect® CSH C18 column, ammonium bicarbonate in water / 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 (400 MHz, CDCl3, 7.42 - 7.29(5H, m), 7.18(1 H, s), 6.42(1 H, d, J 8.5), 5.18(2H, s), 4.52(2H, s), 4.48 - 4.41(2H, m), 3.77(2H, t, UPLC (Method A): t R 1.97 minutes, 97%, MS(ESI) 379.2(M+H) +

[0536] The following examples (128-130) were prepared using procedures similar to Example 87 using the appropriate starting materials.

[0537] 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

[0538] [ka]

[0539] It is prepared using (S)-2,3-dimethylbutanoic acid as the acid component. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 7.41 - 7.29(1 H, m), 6.49 - 6.44(1 H, 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(1 H, m), 2.10 - 1.90(5H, m), 1.15(3H, d, J6.7), 1.00 - 0.91(6H, m); UPLC (Method C): t R 1.79 minutes, 100%, MS(ESI) 329.2(M+H) + .

[0540] 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

[0541] [ka]

[0542] It is prepared using 2-(1-methylcyclopentyl)acetic acid as the acid component. 1 H-NMR: δ H(400 MHz, CDCl3, mixture of rotamers) 7.54 - 7.38(1 H, m), 6.61 - 6.42(1 H, 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 2.09 minutes, 100%, MS(ESI) 355.2(M+H) + .

[0543] 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

[0544] [ka]

[0545] It is prepared using 2,2-difluoro-2-phenylacetic acid as the acid component. 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(1 H, 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), 2.13 - 1.89(4H, m); UPLC(Method A): t R 1.69 min, 98%, MS(ESI) 385.2(M+H) + .

[0546] Examples 131 and 132: Synthesis of both 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)

[0547] [ka]

[0548] 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) and tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate (474 ​​mg, 1.44 mmol) in toluene (10 mL) under continuous nitrogen bubbling, sodium tert-butoxide (207 mg, 2.15 mmol) and XPhos (68 mg, 0.14 mmol) were added. After 5 min, Pd(dba) (65 mg, 0.072 mmol) was added, and the resulting mixture was heated at 100 °C for 16 h. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated to give a residue, which was diluted with water (15 mL) and extracted with 20% MeOH in DCM (20 mL × 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using EtOAc in petroleum ether (0 to 100%) as the eluent to give the desired product, tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(6-(2-cyclopentylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperazine-1-carboxylate (570 mg, 69%) as a yellow gum. To a 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) in DCM (10 mL) was added TFA (3.14 mL, 41.0 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by reverse-phase preparative HPLC. The fractions were concentrated, and the enantiomers were separated by chiral preparative SFC. Both fractions were collected and concentrated under lyophilization to give fraction-1 (30 mg, Example 131) and fraction-2 (36 mg, Example 132), respectively.

[0549] Fastest 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(1 ​​H, m), 7.47 - 7.44(1 H, m), 6.82 - 6.80(1 H, m), 5.45(1 H, br s), 4.55 - 4.41(2H, m), 4.28 - 4.21(2H, m), 3.74 - 3.72(2H, m), 3.69 - 3.61(1 H, m), 3.59 - 3.58(2H, m), 3.07 - 3.04(2H, m), 2.91 - 2.77(1 H, 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) + .

[0550] 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(1 ​​H, m), 7.47 - 7.44(1 H, m), 6.82 - 6.80(1 H, m), 5.45(1 H, br s), 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(1 H, m), 2.68 - 2.55(2H, m), 2.39 - 2.33(2H, m), 2.33 - 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) + .

[0551] 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

[0552] [ka]

[0553] To a stirred solution of 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (400 mg, 2.36 mmol) in DCM (7 mL) at 0 °C, n-propylphosphonic anhydride cyclic trimer (50% in EtOAc) (2.25 mL, 7.07 mmol) and DIPEA (1.92 mL, 11.8 mmol) were added. After 15 min, 2-phenylacetic acid (642 mg, 4.72 mmol) was added and stirred at room temperature for 16 h. Upon completion, the reaction mixture was diluted with water (15 mL) and extracted with 5% MeOH in DCM (15 mL x 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. 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 tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (2.66 g, 12.5 mmol) and DIPEA (3.07 mL, 18.8 mmol). The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was then 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 tert-butyl 8-(6-(2-phenylacetyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (2.5 g, 84%) as an off-white solid. To a stirred solution of tert-butyl 8-(6-(2-phenylacetyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (150 mg, 0.32 mmol) in DCM (3 mL) was added TFA (0.075 mL, 0.97 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was concentrated, diluted with water (15 mL), basified with saturated NH4HCO3 solution, 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 the crude material, which was purified by reverse-phase preparative HPLC using ammonium bicarbonate as a buffer. The pure fractions were lyophilized to give 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 (65.1 mg, 65%, Example 133) as an off-white solid. 1 H-NMR: δ H (400 MHz, DMSO-d6, 80℃) 8.13(1H, s), 7.35 - 7.20(5H, m), 4.60 - 4.50(4H, m), 3.81 - 3.75(4H, m), 2.86 - 2.83(2H, m), 2.68 - 2.53(4H, m),1.95 -1.75(4H, m); MS(ESI) 364.2(M+H) + .

[0554] The following examples (134-148) were prepared using procedures similar to those of Example 133 using the appropriate starting materials.

[0555] Example 134: Synthesis of 2-phenyl-1-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one

[0556] [ka]

[0557] Prepared as in example 133 using 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine and 2-phenylacetic acid in the first step and tert-butyl piperazine-1-carboxylate in the second step. 1 H-NMR: δ H (DMSO-d6, 400 MHz, mixture of rotamers) 8.19(0.6H, s), 8.12(0.4H, s), 7.33 - 7.20(5H, m), 4.57 - 4.48(2H, m), 3.81 - 3.73(4H, m), 3.62 - 3.58(4H, m), 2.70 - 2.68(4H, m), 2.65 - 2.62(2H, m); MS(ESI) 338.2(M+H) + .

[0558] Example 135: Synthesis of 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

[0559] [ka]

[0560] Prepared as in Example 133 using 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine and 2-phenylacetic acid in the first step and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate in the second step. 1 H-NMR: δ H(DMSO-d6, 400 MHz, mixture of rotamers) 8.17 - 8.10(1 H, m), 7.35 - 7.15(5H, m), 4.57 - 4.48(2H, m), 4.16 - 4.11(2H, m), 3.81 - 3.78(2H, m), 3.77 - 3.72(2H, m), 3.45 - 3.35(2H, m), 2.91 - 2.88(2H, m), 2.63 - 2.55(2H, m), 2.55 -2.30(1 H, br m), 1.70 - 1.45(4H, m); MS(ESI) 364.1(M+H) + .

[0561] Example 136: Synthesis of 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

[0562] [ka]

[0563] Prepared as in Example 133 using 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine and 2-(4-cyanophenyl)acetic acid in the first step and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate in the second step. 1 H-NMR: δ H (DMSO-d6, 400 MHz, mixture of rotamers) 8.19 & 8.13(1 H,2x s, rotamers), 7.79 - 7.75(2H, m), 7.47 - 7.42(2H, m), 4.59 - 4.49(4H, m), 3.95 - 3.93(2H, m), 3.81 - 3.74(2H, m), 2.81 - 2.78(2H, m), 2.71 - 2.63(2H, m), 2.61 - 2.53(2H, m),1.95 -1 .75(4H, m); MS(ESI) 389.2(M+H)+ .

[0564] Example 137: Synthesis of 4-(2-oxo-2-(2-(piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethyl)benzonitrile

[0565] [ka]

[0566] Prepared as in Example 133 using 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine and 2-(4-cyanophenyl)acetic acid in the first step and tert-butyl piperazine-1-carboxylate in the second step. 1 H NMR: δ H (400 MHz, DMSO-d6, mixture of rotamers) 8.20 - 8.14(1 H, m), 7.79 - 7.74(2H, m), 7.46 - 7.42(2H, m), 4.59 - 4.49(2H, m), 3.95 - 3.93(2H, m),...

Claims

1. 1. A compound of formula I below, or a pharmaceutically acceptable salt or derivative thereof, for use in the treatment or prevention of a disease or disorder that can be ameliorated by activation of the long isoform of PDE4, or a disease or disorder mediated by excessive intracellular cyclic AMP signaling: 【Chemical 1】 In the formula, Y １ , Y ２ , and Y ３ One or two of these are N and the rest are CR ３ｂ is; Q is C or S(O); R １ is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally a ring O heteroatom; R １ is one or more R ４ optionally substituted with; A is R ２ｃ , N.R. ２ａ R ２ｂ or OR ２ｆ and R ２ａ is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH ２ -[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ａ is one or more R ５ optionally substituted with; R ２ｂ is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R ５ or R ２ａ and R ２ｂ together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R ５ may be substituted with; R ２ｃ is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic part of said (C3-10) alkyl group is optionally selected from R ２ｃ may be substituted with one —O— at a position other than the point of attachment of The (C3-10) alkyl group is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ -[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH ２ -O-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R ２ｃ is one or more R ５ optionally substituted with; R ２ｆ is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH ２ -[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ｆ is one or more R ５ optionally substituted with; Each R ３ａ is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two Rs bonded to the same or adjacent carbon atoms ３ａ may be joined together with the atoms to which they are attached to form a 3- to 6-membered carbocyclic or heterocyclic ring containing an O heteroatom; The ring may be optionally substituted with one or more halogens; Each R ３ｂ is independently H or (C1-6) alkyl; Each R ４ is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (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; Each R ５ are independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (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, and when b is 2, a is 0.

2. 2. The compound for use according to claim 1, which is a compound of the following formula or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 2】

3. 3. A compound for use according to claim 1 or 2, or a pharmaceutically acceptable salt or derivative thereof, R １ is a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; a 7-9 membered saturated bridged ring containing one or two N heteroatoms; a 9 membered saturated bridged ring containing two ring N heteroatoms and a ring O-heteroatom; or a 7-10 membered saturated, fused or spirocyclic ring containing one or two ring N heteroatoms, and R １ optionally 1, 2 or 3 R ４ is replaced by

4. A compound for use according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or derivative thereof, R １ is a 4-10 membered non-aromatic ring which may be monocyclic, bridged, or bicyclic containing at least one ring N heteroatom and optionally a ring O heteroatom; R １ is one R ４ may be substituted with.

5. A compound for use according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or derivative thereof, R １ is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, optionally a 7-8 membered saturated bridged ring containing two ring N heteroatoms (e.g., a bridged piperazine, e.g., 3,8-diazabicyclo[3.2.1]octanyl), and R １ is any one R ４ is replaced by

6. A compound for use according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or derivative thereof, When substituted on an aliphatic group, each R ５ 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 by one or more halogen or OH, and when substituted on an aromatic group, each R ５ is independently halogen, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (C1-6)alkyl and (C1-6)alkoxy are optionally substituted by one or more halogen or OH.

7. A compound for use according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or derivative thereof, a) R ２ａ is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH ２ -[a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10) alkyl group (optionally a (C3-10) alkyl group) which may be linear, branched, or cyclic, or a combination thereof; R ２ａ is one or more R ５ and R ２ｂ is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R ５ or R ２ａ and R ２ｂ together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R ５ may be substituted with; or b) R ２ｃ is CH ２ -[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH ２ -O-[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 of the linear or cyclic portion of said (C3-10) alkyl group are selected from the group consisting of R ２ｃ and the (C3-10) alkyl group is optionally substituted with one —O— at a position other than the point of attachment of R ２ｃ is one or more R ５ or c) R ２ｆ is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH ２ -[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, cyclic, or a combination thereof; R ２ｆ is one or more R ５ may be substituted with.

8. A compound for use according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or derivative thereof, a) R ２ａ is a (C5-10) alkyl group containing a cyclic moiety, and R ２ａ is one or more R ５ may be substituted with R ２ｂ is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R ５ or b) R ２ａ is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH ２ -[a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10) alkyl group (optionally a (C3-10) alkyl group) which may be linear or branched; and R ２ａ is one or more R ５ (optionally substituted with R ５ is halogen); R ２ｂ is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R ５ may be substituted with.

9. A compound for use according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or derivative thereof, R ２ｃ but: a) (C3-10) alkyl groups containing cyclic moieties, the C atoms of the linear or cyclic moieties of said (C3-10) alkyl groups being R ２ｃ and the (C3-10) alkyl group is optionally substituted with one —O— at any point other than the point of attachment of R ２ｃ is one or more R ５ optionally substituted with; b) CH ２ -[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH ２ -O-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a (C3-10) alkyl group which may be linear or branched, wherein the C atom of the linear part of said (C3-10) alkyl group is selected from the group consisting of R ２ｃ and the (C3-10) alkyl group is optionally substituted with one —O— at a position other than the point of attachment of R ２ｃ is one or more R ５ (optionally substituted with R ５ is a halogen).

10. 10. The compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any of claims 1 to 9, which is a compound of the following formula: 【Chemistry 3】

11. Each R ３ａ But -CH ３ or F, or two R attached to the same carbon ３ａ is joined together with the atoms to which they are attached to form a cyclopropyl ring, or a pharmaceutically acceptable salt or derivative thereof, for use according to any of claims 1-10.

12. 12. The compound for use according to any one of claims 1-11, wherein n is 0, 1, or 2, or a pharmaceutically acceptable salt or derivative thereof.

13. 13. The compound for use according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0.

14. Q is C and / or A is R ２ｃ 14. The compound for use according to any one of claims 1 to 13, which is: or a pharmaceutically acceptable salt or derivative thereof.

15. A compound for use according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or derivative thereof, Q is C; R １ is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R １ is one R ４ optionally substituted with; A is R ２ｃ and R ２ｃ is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and the C atoms of the linear or cyclic part of said (C3-10) alkyl group are each independently selected from R ２ｃ at a position other than the point of attachment of R to R, and said (C3-10) alkyl group is optionally substituted with one —O—, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ｃ is one or more R ５ optionally substituted with; R ３ａ is, if present, methyl; R ４ when present, is (C1-6)alkyl optionally substituted with OH, and can be (C1-2)alkyl optionally substituted with OH; R ５ is, if present, OH or halo; and n is 0, 1, or 2.

16. Y １ , Y ２ and Y ３ One of them is N and the others are CR ３ｂ 16. The compound for use according to any one of claims 1 to 15, which is: or a pharmaceutically acceptable salt or derivative thereof.

17. 17. The compound for use according to any one of claims 1-16, wherein a is 1 and b is 1, or a pharmaceutically acceptable salt or derivative thereof.

18. 18. The compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any of claims 1 to 17, which is a compound of the following formula: 【Chemistry 4】 R １ is a 6-membered saturated monocyclic ring containing two ring N heteroatoms, or a 7-9 membered saturated bridged ring containing two ring N heteroatoms, optionally containing one or more R ４ and / or is substituted with R ２ｃ is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and the C atoms of the linear or cyclic part of said (C3-10) alkyl group are each independently selected from R ２ｃ at a position other than the point of attachment of R to R, and said (C3-10) alkyl group is optionally substituted with one —O—, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ｃ is one or more R ５ may be substituted with.

19. A compound of formula II or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 5】 In the formula, Y １ , Y ２ and Y ３ One or two of these are N, and the rest are CR ３ｂ is; Q is C or S(O); R １ａ is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R １ａ is one or more R ４ optionally substituted with; A is R ２ｃ , N.R. ２ａ R ２ｂ or OR ２ｆ and R ２ａ is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH ２ -[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl 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 heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ａ is one or more R ５ optionally substituted with; R ２ｂ is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R ５ or R ２ａ and R ２ｂ together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R ５ may be substituted with; R ２ｃ is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic part of said (C3-10) alkyl group is optionally selected from R ２ｃ at any point other than the point of attachment of said (C3-10) alkyl group, which may be substituted with one -O-, and said (C3-10) alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ -[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH ２ -O-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R ２ｃ is one or more R ５ optionally substituted with; R ２ｆ is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH ２ -[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ｆ is one or more R ５ optionally substituted with; Each R ３ａ is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two Rs attached to the same or adjacent carbon atoms ３ａ may be joined together to form a 3- to 6-membered carbocyclic or heterocyclic ring containing an O heteroatom, optionally substituted with one or more halogens; Each R ３ｂ is independently H or (C1-6) alkyl; Each R ４ is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (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; Each R ５ are independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (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, and when b is 2, a is 0.

20. 20. A compound according to claim 19, or a pharmaceutically acceptable salt or derivative thereof, R １ａ is a 7-8 membered saturated bridged ring containing two ring N heteroatoms (e.g., a bridged piperazine, e.g., 3,8-diazabicyclo[3.2.1]octanyl), and R １ In some cases, one R ４ is replaced by

21. 21. The compound of claim 19 or 20, which is a compound of the following formula, or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 6】

22. Y １ , Y ２ and Y ３ One of them is N and the others are CR ３ｂ 22. The compound of any one of claims 19 to 21, or a pharmaceutically acceptable salt or derivative thereof, wherein:

23. A compound of formula III, or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 7】 In the formula, Y １ , Y ２ , and Y ３ One of them is N and the others are CR ３ｂ is; Q is C or S(O); R １ｂ is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally a ring O heteroatom, wherein at least one ring N heteroatom is R １ｂ is not at the attachment point of R １ｂ is one or more R ４ optionally substituted with; A is R ２ｃ , or NR ２ａ R ２ｂ and R ２ａ is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH ２ -[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, cyclic, or a combination thereof; a (C5-7) cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 5-7-membered non-aromatic heterocycle containing one ring O heteroatom optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ａ is one or more R ５ optionally substituted with; R ２ｂ is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R ５ or R ２ａ and R ２ｂ together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R ５ may be substituted with; R ２ｃ is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic part of said (C3-10) alkyl group is optionally selected from R ２ｃ at any point other than the point of attachment of said (C3-10) alkyl group, which may be substituted with one -O-, and said (C3-10) alkyl group may be substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ -[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH ２ -O-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and R ２ｃ is one or more R ５ optionally substituted with; Each R ３ａ is independently (C1-6)alkyl or fluoro, wherein the (C1-6)alkyl is optionally substituted with one or more halogens; or Two Rs attached to the same or adjacent carbon atoms ３ａ may be joined together to form a 3-6 membered carbocyclic or heterocyclic ring containing an O heteroatom, optionally substituted with one or more halogens; Each R ３ｂ is independently H or (C1-6) alkyl; Each R ４ is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (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; Each R ５ are independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (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. 24. A compound according to claim 23, or a pharmaceutically acceptable salt or derivative thereof, R １ｂ is a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; or a 7-9 membered saturated bridged ring containing one or two ring N heteroatoms; a 9 membered saturated bridged ring containing two ring N heteroatoms and a ring O-heteroatom; or a 7-10 membered saturated fused or spirocyclic ring containing one or two ring N heteroatoms; １ｂ is one, two or three R ４ may be substituted with.

25. 25. A compound according to claim 23 or 24, or a pharmaceutically acceptable salt or derivative thereof, R １ｂ is a 6-membered saturated monocyclic ring containing two ring N heteroatoms or a 7-9-membered saturated bridged ring containing two ring N heteroatoms; and R １ａ In some cases, one R ４ and optionally substituted with R １ａ is a 7-8 membered saturated bridged ring containing two ring N heteroatoms (e.g., a bridged piperazine, e.g., 3,8-diazabicyclo[3.2.1]octanyl), and R １ｂ is one R ４ may be substituted with.

26. 26. The compound of any one of claims 19-25, or a pharmaceutically acceptable salt or derivative thereof, wherein a is 1 and, if present, b is 1.

27. 27. The compound of any one of claims 19-26, which is a compound of the following formula or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 8】 The compound is of formula III, wherein: R １ｂ is a 6-membered saturated monocyclic ring containing two ring N heteroatoms or a 7-9-membered saturated bridged ring containing two ring N heteroatoms, optionally with one or more R ４ and / or R ２ｃ is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic part of said (C3-10) alkyl group is optionally selected from R ２ｃ at a position other than the point of attachment of R to R, and said (C3-10) alkyl group is optionally substituted with one —O—, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ｃ is one or more R ５ may be substituted with.

28. 27. A compound according to any one of claims 19 to 26, or a pharmaceutically acceptable salt or derivative thereof, a) R ２ａ is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; CH ２ -[a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10)alkyl group (optionally a (C3-10)alkyl group) which may be linear, branched, or cyclic, or a combination thereof; and R ２ａ is one or more R ５ and R ２ｂ is H or (C1-6) alkyl, and the (C1-6) alkyl is one or more R ５ or R ２ａ and R ２ｂ together with the N atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R ５ may be substituted with; or b) R ２ｃ is CH ２ -[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH ２ -O-[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 a C atom of the linear or cyclic portion of said (C3-10) alkyl group is selected from the group consisting of R ２ｃ and the (C3-10) alkyl group is optionally substituted with one —O— at any point other than the point of attachment of R ２ｃ is one or more R ５ may be substituted with.

29. 29. A compound according to any one of claims 19 to 28, or a pharmaceutically acceptable salt or derivative thereof, R ２ｃ is one of the following: a) a (C3-10) alkyl group containing a cyclic moiety, wherein the C atoms of the linear or cyclic moiety of said (C3-10) alkyl group are R ２ｃ and the (C3-10) alkyl group is optionally substituted with one —O— at a position other than the point of attachment of R ２ｃ is one or more R ５ optionally substituted with; b) CH ２ -[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; CH ２ -O-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; 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 a C atom of the linear or cyclic part of said (C3-10) alkyl group is selected from the group consisting of R ２ｃ and wherein said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; and wherein R ２ｃ is one or more R ５ (optionally substituted with R ５ is a halogen).

30. 30. The compound of any one of claims 19-29, which is a compound of the following formula or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 9】

31. Q is C and / or A is R ２ｃ 31. The compound of any one of claims 19 to 30, or a pharmaceutically acceptable salt or derivative thereof, wherein:

32. 31. A compound according to any one of claims 19 to 30, or a pharmaceutically acceptable salt or derivative thereof, Q is C; R １ａ or R １ｂ is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, and R １ａ and R １ｂ is one R ４ optionally substituted with; A is R ２ｃ and R ２ｃ is a (C3-10) alkyl group which may be linear, branched or cyclic, or a combination thereof, and a C atom of the linear or cyclic part of said (C3-10) alkyl group is optionally selected from R ２ｃ at a position other than the point of attachment of R to R, and said (C3-10) alkyl group is optionally substituted with one —O—, and said (C3-10) alkyl group is optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; ２ｃ is one or more R ５ optionally substituted with; R ３ａ is, if present, methyl; R ４ is, if present, (C1-6)alkyl optionally substituted with OH, and is (C1-2)alkyl optionally substituted with OH; R ５ is, if present, OH or halo; and n is 0, 1, or 2.

33. Each R ３ａ Ga-CH ３ or two R attached to the same carbon ３ａ 33. The compound of any one of claims 19-32, or a pharmaceutically acceptable salt or derivative thereof, wherein: together with the atoms to which they are attached, form a cyclopropyl ring.

34. 34. The compound of any one of claims 19-33, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0, 1, or 2.

35. 35. The compound of any one of claims 19-34, 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; Cyclopentyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; Isopropyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; 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]octan-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]nonan-9-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,9-diazabicyclo[3.3.1]nonan-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]heptan-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]heptan-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]nonan-9-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-((4-fluorobenzyl)sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-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]octan-8-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 6-(benzylsulfonyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-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; and pharmaceutically acceptable salts or derivatives thereof.

37. 37. A pharmaceutical composition comprising a compound of any one of claims 1-36 or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable excipient.

38. 37. A compound according to any one of claims 19 to 36, or a pharmaceutically acceptable salt or derivative thereof, for use in therapy.

39. A compound or a pharmaceutically acceptable salt or derivative according to any one of claims 19 to 36, or a pharmaceutical composition according to claim 37, for use in the treatment or prevention of a disease or disorder that can be ameliorated by activation of the long isoform of PDE4, or a disorder mediated by excessive intracellular cyclic AMP signaling.

40. A compound or a pharmaceutically acceptable salt or derivative for use according to any of claims 1-18, or a pharmaceutical composition for use according to claim 39, in the treatment or prevention of a disease or disorder mediated by excessive intracellular cyclic AMP signaling.

41. A method for treating or preventing a disease or disorder that can be ameliorated by activation of the long isoform of PDE4 or a disease or disorder mediated by excessive intracellular cyclic AMP signaling, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any of claims 1-36, or a pharmaceutically acceptable salt or derivative thereof.

42. 37. Use of a compound or a pharmaceutically acceptable salt or derivative according to any one of claims 1 to 36 in the manufacture of a medicament for the treatment or prevention of a disease or disorder that can be ameliorated by activation of PDE4 or the long isoform of PDE4, or a disease or disorder mediated by excessive intracellular cyclic AMP signaling.

43. 43. The method of claim 41 or the use of claim 42, wherein the disease or disorder that can be ameliorated by activation of the long isoform of PDE4 is a disease or disorder mediated by excessive intracellular cyclic AMP signaling.

44. 44. The compound of any of claims 40, or a pharmaceutically acceptable salt or derivative thereof, or the method or use of any of claims 41-43, wherein excessive intracellular cyclic AMP signaling is caused by: a. Excessive hormone levels produced by the adenoma; b. Gain-of-function genetic mutations in G protein-coupled receptors (GPCRs); c. an activating mutation in the GNAS1 gene, which encodes the α subunit of the G protein Gs; or D. Bacterial toxins.

45. A compound or a pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to any one of claims 1 to 18, 39, 40 or 44, or a method or use according to any one of claims 41 to 44, wherein the disease is cancer, optionally wherein the cancer is prostate cancer.

46. A compound or a pharmaceutically acceptable salt or derivative or a pharmaceutical composition for use according to any one of claims 1 to 18, 39, 40 or 44, or a method or use according to any one of claims 41 to 44, wherein the disease is: a. Pituitary adenoma, Cushing's disease, polycystic kidney disease or polycystic liver disease; b. hyperthyroidism, Janssen metaphyseal chondrodysplasia, hyperparathyroidism or familial male-restricted precocious puberty; c. McCune-Albright syndrome; d. cholera, whooping cough, anthrax, or tuberculosis; e. HIV, AIDS or common variable immunodeficiency (CVID); f. melanoma, pancreatic cancer, leukemia, prostate cancer, tumors of the adrenal cortex, 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); h. Maturity-onset diabetes of the young type 5 (MODY5); or i. Cardiac hypertrophy.

47. 47. The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition of claim 46, wherein the disease is: a. Autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), or b. Hyperparathyroidism.

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