Compounds and their use as PDE4 activators - Patent application

Abstract

The present invention relates to compounds of formulas I to V and Ia to Va, 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 molecules acting as activators of the PDE4 long-chain form were recently disclosed in WO2016 / 151300, WO2018 / 060704, and WO2019193342. Recently, small molecule activators of the PDE4 long-chain form were 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-chain form has not yet been reported. Additional structurally distinct small molecule activators of the PDE4 long-chain form are still needed for potential development as therapeutic agents. [Means for solving the problem]

[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.

[0008] Summary of the Invention In a first aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt or derivative thereof, for use in 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] In the formula, one of X1 and X2 is N, and the other is S, N, or CR 3b and X3 is N or C; 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 substituted with; 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; and 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 10-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 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 being 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]; a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2 or 3 ring N or O heteroatoms fused to 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; Each R 3a is independently (C1-6)alkyl or fluoro, wherein (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 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 is 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 by one or more halogen, OH, or (C1-6)alkoxy; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

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

[0012] [ka]

[0013] In the formula, one of X1 and X2 is N, and the other is S, N, or CR 3b and X3 is N or C; 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 , N.R. 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 10-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 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 being 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]; a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2 or 3 ring N or O heteroatoms fused to 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; 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 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 is 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 by one or more halogen, OH, or (C1-6)alkoxy; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

[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 X1 and X2 is N, and the other is S, N, or CR 3b and X3 is N or C; Q is C or S(O); R 1bis 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, wherein at least one ring N heteroatom is selected from the group consisting of R 1b where R 1b is one or more R 4 may be substituted with; A is R 2c , N.R. 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 2b together with the N atom to which they are attached form a 5- to 10-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 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, said (C3-10)alkyl group being 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]; a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2, or 3 ring N or O heteroatoms fused to 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; 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 an O heteroatom, optionally substituted with one or more halogens; Each R 3b are independently H or (C1-6)alkyl; each R4are 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 is 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 by one or more halogen, OH, or (C1-6)alkoxy; n is 0, 1, 2, 3, or 4; and a is 0 or 1; One of X1 and X2 is N, the other is S, X3 is C, and (a) A is R 2c or NR 2a R 2b If R 1b is not 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl, and (b) A is OR 2f If R 1b is not a monocyclic piperazine ring.

[0017] In a fourth aspect of the present invention, there is provided a compound of formula IV or a pharmaceutically acceptable salt or derivative thereof:

[0018] [ka]

[0019] In the formula, one of X1 and X2 is N, and the other is S, N, or CR 3b and X3 is N or C; Q is C or S(O); R 1is 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 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; and R 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, the C atoms of the linear or cyclic moieties of said (C3-10) alkyl groups being R 2e and R is optionally substituted 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]; 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; a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2, or 3 ring N or O heteroatoms fused to 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 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 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 5is 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 by one or more halogen, OH, or (C1-6)alkoxy; n is 0, 1, 2, 3, or 4; and a is 0 or 1; Optionally, the compound or pharmaceutically acceptable salt thereof is not selected from the group consisting of or a pharmaceutically acceptable salt thereof:

[0020] [ka]

[0021] In a fifth aspect of the present invention, there is provided a compound of formula V, or a pharmaceutically acceptable salt or derivative thereof:

[0022] [ka]

[0023] In the formula, one of X1 and X2 is N, and the other is S, N, or CR 3b and X3 is N or C; 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 substituted with; 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; 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 10-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 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 being 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]; a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2 or 3 ring N or O heteroatoms fused to 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- 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 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 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 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 is 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 by one or more halogen, OH, or (C1-6)alkoxy; m is 1, 2, 3, or 4; and a is 0 or 1.

[0024] The compounds described herein are shown in the Examples to activate the PDE4 long chain enzyme.

[0025] 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 the treatment or prevention of any disease or disorder described herein. The therapy can be the treatment or prevention of a disease or disorder that can be improved by activating the long isoform of PDE4. The therapy can be the 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.

[0026] 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.

[0027] 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.

[0028] 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. DETAILED DESCRIPTION OF THE INVENTION

[0029] 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. The examples demonstrate that many compounds of formula IV and Ia-Va 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.

[0030] 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.

[0031] 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.

[0032] Also described herein are compounds of formula Ia-Va, or pharmaceutically acceptable salts or derivatives thereof, as shown below. Formula Ia-Va is exemplified herein. Compounds of formula Ia-Va, 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 Ia-Va, or pharmaceutically acceptable salts or derivatives thereof, can be provided for use in the treatment or prevention of diseases or disorders that are mediated by excessive intracellular cAMP signaling.

[0033] Described herein are compounds of formula Ia, or a pharmaceutically acceptable salt or derivative thereof;

[0034] [ka]

[0035] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; 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 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, 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; 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 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 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.

[0036] Also described herein are compounds of formula IIa or pharmaceutically acceptable salts or derivatives thereof:

[0037] [ka]

[0038] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; 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 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.

[0039] Also described herein is a compound of formula IIIa, or a pharmaceutically acceptable salt or derivative thereof:

[0040] [ka]

[0041] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; 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 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, 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 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 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.

[0042] Also described herein is a compound of Formula IVa, or a pharmaceutically acceptable salt or derivative thereof:

[0043] [ka]

[0044] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; 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 2e and R is optionally substituted 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]; 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 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 optionally being 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.

[0045] Also described herein is a compound of formula Va, or a pharmaceutically acceptable salt or derivative thereof:

[0046] [ka]

[0047] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; 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- 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 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 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, 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; 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 3amay 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.

[0048] In compounds of formula I, R 1 is a 4-10 membered non-aromatic ring which may be monocyclic, bridged or bicyclic and contains at least one ring N heteroatom and optionally one ring O heteroatom; R 1 may optionally 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 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 "ring O heteroatoms."

[0049] In the compounds of formula Ia, 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 may contain one or more R 4 The monocyclic, bridged, or bicyclic ring may be saturated, partially saturated, aromatic, or in the case of a bicyclic ring, a combination thereof. It will be understood that the ring N atom in a saturated or partially saturated ring, if 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."

[0050] In embodiment (1) of formula I or Ia, R 1 is R 1 contains at least one ring N heteroatom other than the point of attachment of R to the ring containing X, X, and X 1 (The remainder of the formula I or Ia may be as defined for any of embodiments (6)-(34) of formula I or Ia described herein, mutatis mutandis.)

[0051] In embodiment (2) of formula I or Ia, R 1 is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom; R 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 the point of attachment of the ring N. The remainder may be as defined for Formula I or Ia, or any of embodiments (6)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0052] In embodiment (3) of Formula I, 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); 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 system containing one or two ring N heteroatoms and optionally two ring N heteroatoms; and R 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 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 embodiments (6)-(34) of Formula I described herein, mutatis mutandis.

[0053] In embodiment (3) of formula Ia, 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 a ring O-heteroatom; or a 7-10 membered saturated, fused or spiro ring system containing one or two ring N heteroatoms and optionally two ring N heteroatoms; and R 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 1and optionally includes at least one ring N heteroatom other than the point of attachment of Formula Ia. The remainder may be as defined for Formula Ia, or any of embodiments (6)-(34) of Formula Ia described herein, mutatis mutandis.

[0054] 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 It 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 where 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 may be a 7-8 membered saturated bridged ring containing two ring N heteroatoms, where 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, such as a bridged piperazine, e.g., 3,8-diazabicyclo[3.2.1]octanyl, where R 1 is one R 4 The remainder may be as defined for Formula I, or any of embodiments (6)-(34) of Formula I described herein, mutatis mutandis.

[0055] In formula Ia, 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 In some cases, R is 1 or more 4 It is replaced by R 1 can 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, where at least one ring N heteroatom is selected from the group consisting of R 1 is not present 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, where at least one ring N heteroatom is selected from the group consisting of R 1 is not present at the attachment point of R 1 may be one R 4 is replaced by R 1 is 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, where R 1 is one R 4 may be substituted with R 1may 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 7-8 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 1 is one R 4 The remainder may be as defined for Formula Ia, or any of embodiments (6)-(34) of Formula Ia described herein, mutatis mutandis.

[0056] In formula I, or any of the alternatives of embodiments (1), (2) or (3), R 1 are 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-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 may be one or more R 4 and preferably 1 to 3 R 4 may be substituted with R 4 is preferably one R 4 may be substituted with R 1 can be a group of the structure:

[0057] [ka]

[0058] [ka]

[0059] R 1 is one or more R 4 and R 1 1-3 R 4 may be substituted with R 1 may be piperidinyl, piperazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each optionally containing one or more R 4 and preferably 1-3 of R 4 and preferably one R 4 is replaced by R 1 can be piperidinyl or piperazinyl, each of which contains 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 following structure:

[0060] [ka]

[0061] where W is CH or N, and R 4 ' is H or R 4 R 1 may be a 7- to 8-membered saturated bridged ring containing two ring N heteroatoms, for example, the following bridged piperazine:

[0062] [ka]

[0063] [ka]

[0064] The remainder may be as defined for Formula I, or any of embodiments (6)-(34) of Formula I described herein, mutatis mutandis.

[0065] In formula Ia, 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 may be one or more R 4 and preferably 1 to 3 R 4 and preferably one R 4 may be 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 R1 can 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 to 3 R 4 and preferably one R 4 may be substituted with R 1 can be the following groups:

[0069] [ka]

[0070] where W is CH or N, and R 4 ' is H or R 4 or optionally 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, for example a bridged piperazine such as:

[0071] [ka]

[0072] The remainder may be as defined for Formula Ia or any of embodiments (6)-(34) of Formula Ia described herein, mutatis mutandis.

[0073] In embodiment (4) of formula I or Ia, R1 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 attachment point 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 Ia, or any of embodiments (6)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0074] In embodiment (5) of formula I or Ia, 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 1, 2 or 3 R 4 may be substituted with R 1 may 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 Ia, or any of embodiments (6)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0075] In any of the alternatives of Formula I or embodiments (1)-(5), R 1 is one or more R 4may 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 and preferably one R on the ring N atom 4 may be replaced by R 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 R 1 is one R 4 and preferably one R on the ring N atom 4 may be substituted by

[0076] In formula Ia or any of the alternative 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 and preferably one R on the ring N atom 4 may be replaced by R 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, 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.

[0077] In compounds of formula I and Ia, each R4 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.

[0078] In embodiment (6) of formula I or Ia, each R 4 are independently halogen, OH, CN, (Ci_4)alkyl, (Ci_3)alkoxy, (C3_6)cycloalkyl, or -(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 are independently selected from 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 Ia, or any of embodiments (1)-(5) or (9)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0079] In embodiment (7) of formula I or Ia, each R 4are 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 may 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, (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 Ia, or any of embodiments (1)-(5) or (9)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0080] In embodiment (8) of formula I or Ia, each R 4 are independently halogen, CN, OH, (Ci_3)alkyl, (Ci_6)alkoxy, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_3)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). 4can independently be 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. 4 may 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 Ia, or any of embodiments (1)-(5) or (9)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0081] In formula I or Ia, or any of embodiments (6)-(8), when attached to a ring N atom, R 4 are independently selected from the group consisting of halogen, CN, OH, and -(C1-6)alkoxy. 4 may be any of the options identified herein for

[0082] In the compounds of formula I, A is R 2c , N.R. 2a R 2b , or OR 2f where: 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 2ais one or more R 5 may be substituted with.

[0083] 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 10-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 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 being 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]; a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2 or 3 ring N or O heteroatoms fused to 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 2fis a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, and is 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.

[0084] In the compounds of formula Ia, 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.

[0085] 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 is replaced by;

[0086] 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.

[0087] In compounds of formula I, each R 5 are independently 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 are optionally substituted with one or more halogen, OH, or (Ci_6)alkoxy. It will be understood that the alkyl group may be linear, branched, cyclic, or a combination thereof.

[0088] In the compound of formula Ia, each R 5 are independently 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 are optionally substituted with one or more halogen or OH. It will be understood that the alkyl group may be linear, branched, cyclic, or a combination thereof.

[0089] In embodiment (9) of formula I or Ia, each R 5are independently halogen, OH, CN, (C1-4) alkyl, or (C1-4) alkoxy, and the (C1-4) alkyl and (C1-4) alkoxy groups may be substituted with one or more halogen or OH, preferably one or more fluoro, one OH, or one (C1-2) alkoxy. 5 may independently be halogen, OH, CN, (C1-4) alkyl, or (C1-4) alkoxy, and the (C1-4) alkyl and (C1-4) alkoxy groups may be 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 is independently halogen (preferably fluoro), CN, or CF. 5 may independently be halogen (preferably fluoro). The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(8) or (10)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0090] In embodiment (10) of formula I or Ia, 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. 2ais optionally substituted with halogen (preferably fluoro), CN, or CF. The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(9), (14), or (24)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0091] In embodiment (11) of formula I or Ia, R 2a is CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], where 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 2a is CH2-[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, wherein the (C1-4) alkyl group is optionally substituted with one or more halogens (preferably optionally substituted with 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 Ia, or any of embodiments (1)-(9), (14), or (24)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0092] In embodiment (12) of formula I or Ia, 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 R5 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 may 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 may 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, and R 2a is R 5 may be substituted with R 2c may be a (C5-8)cycloalkyl group or CH2-[(C5-6)cycloalkyl group]. R 2c is 1 or 2 R 5 and R 5 is preferably substituted with halogen (e.g., fluoro). 2c The cyclic part of the 5 (e.g., fluoro). The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(9), (14), or (24)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0093] In embodiment (13) of formula I or Ia, R 2a is 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 may be substituted with R 2amay be a 6-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 2a may be a 5- to 7-membered non-aromatic heterocycle containing one ring O heteroatom 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 2a is 0, 1 or 2 R 5 , preferably 0 or 1 R 5 and is preferably unsubstituted, and the remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(9), (14), or (24)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0094] In any of embodiments (10)-(13) of formula I or Ia, R 2a is one or more R 5 can be replaced by R 5 is preferably halogen (eg fluoro).

[0095] In embodiment (14) of formula I or Ia, R 2b is H or (C1-3) alkyl, and the (C1-3) alkyl is one or more R 5 Optionally replaced by R 2b may be H, CH, or CHCH. The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(13) or (24)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0096] In embodiment (15) of formula I or Ia, R 2a and R 2btogether with the N atom to which they are attached form a 5- to 10-membered non-aromatic heterocycle, optionally further containing one heteroatom selected from O, and optionally one or more R 5 It will be understood that heterocyclic groups can be monocyclic or polycyclic (e.g., bicyclic) rings. Polycyclic (e.g., bicyclic) rings can include spiro and fused rings, preferably spiro rings. R 2a and R 2b may, 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 2a and R 2b together with the N atoms to which they are attached, form one or more R 5 R may form an optionally substituted 5- to 7-membered non-aromatic heterocycle. 2a and R 2b together with the N atoms to which they are attached, form one or more R 5 R may form an optionally substituted 5-membered non-aromatic heterocycle. 2a and R 2b The ring formed by these together is preferably formed by 0, 1 or 2 (preferably 0 or 1) R 5 The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(9) or (24)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0097] In embodiment (16) of formula I or Ia, A is R 2c Preferably, Q is also C. The remainder can be as defined for Formula I or Ia, or any of embodiments (1)-(9), (17)-(22), or (24)-(34) of Formula I or Ia described herein.

[0098] In embodiment (17) of formula I or Ia, R 2cis CH2-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], where 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 may 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 substituted with fluoro to form -CHF- or -CF2), 1 OH, or 1 (C1-4)alkoxy, and the aromatic or heteroaromatic ring is optionally substituted with 1, 2, or 3 (preferably 1 or 2, preferably 1) halogens, CN, (C1-4)alkyl, or (C1-4)alkoxy, and the (C1-4)alkyl group is optionally substituted with one or more halogens (preferably one or more fluoro). R 2c may 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 to form -CHF- or -CF2), and the aromatic or heteroaromatic ring is optionally substituted with 1, 2, or 3 (preferably 1 or 2, preferably 1) halogen, CN, or (C1-4) alkyl, where the (C1-4) alkyl group is substituted with one or more halogens (preferably optionally one or more fluoro). The aromatic or heteroaromatic ring may be optionally substituted with halogen (preferably fluoro), CN, or CF3. The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(9), (16), or (24)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0099] In embodiment (18) of formula I or Ia, R 2c is CH2-O-[6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], where R 2cis 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 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) halogen, CN, (C1-4)alkoxy or (C1-4)alkyl, wherein the (C1-4)alkyl group is substituted with one or more halogens (preferably optionally one or more fluoro). R 2c may be CH2-O-[6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], where CH2 is optionally substituted with 1 or 2 halogen (preferably fluoro), 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, and the (C1-4) alkyl group is substituted with one or more halogen (preferably optionally one or more fluoro). The aromatic or heteroaromatic ring may be optionally substituted with halogen (preferably fluoro), CN, or CF3. The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(9), (14), or (24)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0100] In embodiment (19) of formula I or Ia, R 2c is 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 R 2c R may be substituted with one -O- other than at the point of attachment of R, 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.2c is one or more R 5 It will be understood that cyclic moieties include polycyclic (e.g., bicyclic) moieties, such as fused, bridged, or spiro bicyclic rings. R 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 wherein the (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 R 2c may be a (C3-10) alkyl group containing a monocyclic moiety, wherein a C atom of the linear or cyclic moiety of said (C3-10) alkyl group is optionally selected from R 2c wherein the (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 R 2c may be a (C5-10) alkyl group containing a cyclic moiety; R 2c is one or more R 5 may be substituted with R 2c R may be a (C5-6)cycloalkyl group or a (C1-2)alkyl-[(C4-6)cycloalkyl group]. 2c is 1 or 2 R 5 and R 5 R may preferably be halogen (e.g., fluoro). 2c R may be substituted with one or more substituents selected from halogen, OH, and CN. 2c R may be substituted with 1, 2 or 3 halogens, 1 OH or 1 CN. 2c The cyclic part of the 5(e.g., fluoro). The remainder may be as defined for Formula I or Ia, or any of Formula I or Ia (1)-(9), (16), or (24)-(34) herein, mutatis mutandis.

[0101] In embodiment (20) of formula I or Ia, R 2c is a (C3-10) alkyl group which may be linear or branched, and the C atoms of said (C3-10) alkyl group are 2c The (C3-10) alkyl group may be optionally substituted with one -O- at a position other than the point of attachment of R. The (C3-10) alkyl group may be optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms, and R 2c is one or more R 5 may be substituted with R 2c may be a (C3-10) alkyl which may be linear or branched, and the C atoms of said (C3-10) alkyl group are 2c may be substituted with one -O- at a point other than the attachment point of R 2c is one or more R 5 may be substituted with R 2c may be a (C3-10) alkyl group, which may be straight or branched chain, where R 2c is one or more R 5 R 2c R may be substituted with one or more substituents selected from halogen, OH, and CN. 2c may be unsubstituted or substituted with one substituent, and the remainder may be as defined for Formula I or Ia, or any of (1)-(9), (16), or (24)-(34) of Formula I or Ia described herein, mutatis mutandis.

[0102] In any of embodiments (17)-(20) of formula I or Ia, R 2c is one or more R 5 can be replaced by R 5 may be halogen, for example fluoro.

[0103] In embodiment (21) of formula I or Ia, R 2c is a 6-membered aromatic or heteroaromatic ring containing one or two ring N atoms. 2c R may be phenyl or pyridyl. 2c is optionally substituted with 1, 2, or 3 (preferably 1 or 2, preferably 1) halogen, CN, (Ci_4)alkoxy, or (Ci_6)alkyl, wherein the (Ci_6)alkyl or (Ci_4)alkoxy is optionally substituted with one or more halogen (preferably one or more fluoro), and the (Ci_6)alkyl is optionally substituted with (Ci_4)alkoxy. It will be understood that the alkyl group may be linear, branched, cyclic, or combinations thereof. The remainder may be as defined for Formula I or Ia, or any of (1)-(9), (15), or (19)-(26) of Formula I or Ia described herein, mutatis mutandis.

[0104] In embodiment (22) of formula I or Ia, R 2c is a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocyclic ring containing 1, 2, or 3 ring N atoms or O heteroatoms fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms. 2c It will be understood that R may be attached to the remainder of the compound via a 5-6 membered aromatic or non-aromatic heterocyclic ring, or a 6 membered aromatic or heteroaromatic ring. 2cR can be a 9-membered bicyclic ring comprising a 5-membered aromatic heterocycle containing 1, 2, or 3 ring N atoms and / or 1 O heteroatom fused to a 6-membered aromatic or heteroaromatic ring containing 0 or 1 ring N atom; a 9-10-membered bicyclic ring comprising a 5-6-membered non-aromatic heterocycle containing 1 or 2 ring O heteroatoms fused to a 6-membered aromatic or heteroaromatic ring containing 0 or 1 ring N atom; or a 10-membered bicyclic ring comprising a 6-membered aromatic or non-aromatic heterocycle containing 1 or 2 ring N heteroatoms fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms. 2c can be benzofuranyl, 2,3-dihydro-1-benzofuranyl, 1,3-benzoxazolyl, 1,3,3a-triazaindenyl, 1,3-benzodioxolyl, indolyl, quinolyl, isoquinolyl, chromanyl, isochromanyl, or 2,3-dihydro-1,4-benzodioxinyl. The remainder can be as defined for Formula I or Ia, or any of (1)-(9), (15), or (19)-(26) of Formula I or Ia described herein, mutatis mutandis.

[0105] In embodiment (23) 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; and 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 may be CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms]; or a (C2-10) alkyl group which may be linear, branched, cyclic, or a combination thereof; and R 2f is one or more R 5The remainder may be as defined for Formula I, or any of embodiments (1)-(9) or (21)-(31) of Formula I described herein, mutatis mutandis.

[0106] In compounds of formula I and Ia, 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, wherein said ring is optionally substituted with one or more halogens; and each R 3b are independently H or (C1-6) alkyl.

[0107] In embodiment (24) of Formulas I and Ia, 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 are independently H or (C1-3) alkyl, and each R 3a may be -CH3 or F. Each R 3b may be —CH or H. The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(18) or (21)-(26) of Formula I or Ia described herein.

[0108] In embodiment (25) of formula I and Ia, 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 substituted with one or more halogens. Two R attached to the same carbon may 3amay be joined together with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl ring, or a 5- to 6-membered heterocycloalkyl ring containing an O heteroatom. Two R attached to the same or adjacent carbon atoms may 3a may be joined together with the atoms to which they are attached to form a 3- to 6-membered ring, wherein said ring is optionally substituted with one or more halogens. Two R attached to the same or adjacent carbon atoms may 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 Ia, or any of embodiments (1)-(18) or (21)-(26) of Formula I or Ia described herein, mutatis mutandis.

[0109] In embodiment (26) of formula I or Ia, each R 3b may independently be H or (C1-3) alkyl. 3b can be —CH or H. The remainder can be as defined in relation to Formula I or Ia, or any of embodiments (1)-(18) or (21)-(26) of Formula I or Ia described herein, mutatis mutandis.

[0110] In the compounds of formula I and Ia, n is 0, 1, 2, 3 or 4.

[0111] In embodiment (27) of Formula I and Ia, n is 0. The remainder of the moieties may be as defined for Formula I or Ia, or any of embodiments (1)-(18) or (21)-(26) of Formula I or Ia described herein, mutatis mutandis.

[0112] In embodiment (28) of Formula I and Ia, n is 0, 1, 2, or 3. Preferably, n is 0, 1, or 2. n may also be 1 or 2. When n is 2, both R 3a are preferably on the same ring carbon atom. The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(20) or (22)-(26) of Formula I or Ia described herein, mutatis mutandis.

[0113] In compounds of Formula I and Ia, Q is C or S(O).

[0114] In embodiment (29) of Formula I or Ia, Q is C. The remainder of the moieties may be as defined for Formula I or Ia, or any of embodiments (1)-(21) or (23)-(26) of Formula I or Ia described herein, mutatis mutandis.

[0115] In embodiment (30) of formula I or Ia, Q is S=O and A is R 2c R 2c may be 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 2c and R is optionally substituted 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]; or a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and R 2c may be according to embodiment (17), (19), or (20). The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(9), (19)-(21), or (23)-(26) of Formula I or Ia described herein, mutatis mutandis.

[0116] In the compounds of formula I or Ia, one of X1 and X2 is N and the other is N, S or CR 3b and X3 is N or C.

[0117] In embodiment (31), the compound of Formula I or Ia, or a pharmaceutically acceptable salt or derivative thereof, can be a compound of the following structure, or a pharmaceutically acceptable salt or derivative thereof:

[0118] [ka]

[0119] wherein one of X1 and X2 is N and the other is S. The compound of formula I or Ia can be a compound of the following structure or a pharmaceutically acceptable salt or derivative thereof:

[0120] [ka]

[0121] The remainder is as defined mutatis mutandis for Formula I or Ia, or any of embodiments (1)-(22) or (25)-(27) of Formula I or Ia described herein.

[0122] In embodiment (32), the compound of Formula I or Ia, or a pharmaceutically acceptable salt or derivative thereof, can be a compound of the following structure, or a pharmaceutically acceptable salt or derivative thereof:

[0123] [ka]

[0124] In the formula, one of X1 and X2 is N and the other is CR 3bor where both X1 and X2 are N, the compound of formula I or Ia, or a pharmaceutically acceptable salt or derivative thereof, may be a compound of the following structure, or a pharmaceutically acceptable salt or derivative thereof:

[0125] [ka]

[0126] The remainder is as defined mutatis mutandis for Formula I or Ia, or any of embodiments (1)-(22) or (25)-(27) of Formula I or Ia described herein.

[0127] In the compounds of formula I and Ia, a is 0 or 1.

[0128] In embodiment (33) of Formula I or Ia, a is 0. The compound of Formula I or Ia, or a pharmaceutically acceptable salt or derivative thereof, can be the following compound, or a pharmaceutically acceptable salt or derivative thereof:

[0129] [ka]

[0130] The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(24) or (27) of Formula I or Ia described herein, mutatis mutandis.

[0131] In embodiment (34) of Formula I or Ia, a is 1. The compound of Formula I or Ia, or a pharmaceutically acceptable salt or derivative thereof, can be the following compound, or a pharmaceutically acceptable salt or derivative thereof:

[0132] [ka]

[0133] The remainder may be as defined for Formula I or Ia, or any of embodiments (1)-(24) or (27) of Formula I or Ia described herein, mutatis mutandis.

[0134] In embodiment (35) of formula I or Ia: 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 at any point 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, and R 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. The remainder may be as defined mutatis mutandis for Formula I or Ia, or any of embodiments (1)-(34) of Formula I or Ia described herein. For example, preferably, X3 is C, one of X1 and X2 is S, and the other is N (preferably, X1 is N and X2 is S). n may be 0. R 2c may be as defined in embodiment (19) or (20) of formula I or Ia.

[0135] Compounds of formula I include compounds of formulae II-V. Compounds of formula Ia include compounds of formulae IIa-Va. Embodiments (1)-(35) of formula I or Ia may be applied mutatis mutandis to formulae II-V or formulae IIa-Va, respectively.

[0136] Described herein are compounds of Formula II or pharmaceutically acceptable salts or derivatives thereof:

[0137] [ka]

[0138] 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 may be substituted with. X1, X2, X3, 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 Formula I embodiments (6)-(34).

[0139] Also described herein is a compound of formula IIa, or a pharmaceutically acceptable salt or derivative thereof:

[0140] [ka]

[0141] 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 may be substituted with; X1, X2, X3, R 2a , R 2b, R 2c , R 3a , R 3b , A, Q, R 4 , R 5 , a and n are as defined for Formula Ia or any of embodiments (6)-(34) of Formula Ia above.

[0142] In embodiment (1) of formula II or IIa, 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 may be 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, where R 1a is one R 4 may be substituted with R 1a may also be a bridged piperazine such as:

[0143] [ka]

[0144] In any of Formula II or IIa, or embodiments of Formula II or IIa, R 1a is one or more R 4 may be optionally substituted with R 1a When R contains a substitutable ring N atom, 1a is preferably unsubstituted or may be substituted on a substitutable ring N atom. 1a may be unsubstituted or may contain one R 4 and preferably one R on the ring N atom 4 may be substituted by; In any of Formula II or IIa, or embodiments of Formula II or IIa, A is R 2c or NR 2a R 2b It could be.

[0145] In embodiment (2) of Formula II or IIa: Q is C; 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 may 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; 2c is one or more R 5 optionally replaced by; 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.

[0146] In embodiment (2) of Formula II or IIa, preferably, X3 is C, one of X1 and X2 is S and the other is N (preferably, X1 is N and X2 is S), n may be 0, and R 2c may be as defined in embodiment (19) or (20) of formula I or Ia.

[0147] Also described herein are compounds of Formula III, or pharmaceutically acceptable salts or derivatives thereof:

[0148] [ka]

[0149] 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; And X1, X2, X3, 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)-(34) of Formula I above.

[0150] Also described herein is a compound of formula IIIa, or a pharmaceutically acceptable salt or derivative thereof:

[0151] [ka]

[0152] In the formula, R 1b 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, 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; X1, X2, X3, R 2a , R 2b , R 2c , R 3a , R 3b , A, Q, R 4 , R 5, a and n are as defined for Formula Ia or any of Formula Ia embodiments (6)-(34) above.

[0153] In the compounds of formula III or IIIa, 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 X, X, and X. 1b must be located at a position that is not a joining point with

[0154] In embodiment (1) of formula III or IIIa, R 1b is a 4- to 10-membered non-aromatic, monocyclic, bridged, or bicyclic ring containing one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom; R 1 is one or more R 4 may be substituted with 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; 1b may contain one or more R 4 , possibly 1, 2 or 3 R 4 is replaced by

[0155] In embodiment (2) of formula III or IIIa, R 1b is 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, 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 6-membered saturated monocyclic ring containing one or two ring N heteroatoms, and optionally at least one ring N heteroatom is R 1b R 1b may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, where R 1b is optionally one R 4 is replaced by R 1b may be a 7-8 membered saturated bridged ring containing 1 or 2 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 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 .

[0156] In any of Formula III or IIIa, or embodiments of Formula III or IIIa, R 1b may be piperidinyl, piperazinyl, morpholinyl, 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 to 3 R 4 and preferably one R 4 may be substituted with R 1b can be a radical of the structure:

[0157] [ka]

[0158] In the formula, R 1b is an R of 1 or more 4and 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 one or more R 4 and preferably 1-3 of R 4 and preferably one R 4 may be substituted with R 1b may be piperidinyl or piperazinyl, 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 1b can be a radical of the following structure:

[0159] [ka]

[0160] where W is CH or N, and R 4 ' is H or R 4 R 1b may be a 7-8 membered saturated bridged ring containing two ring N heteroatoms such as:

[0161] [ka]

[0162] For example, it may be a bridged piperazine such as:

[0163] [ka]

[0164] In any of Formula III or IIIa, or embodiments of Formula III or IIIa, R 1b is one or more R 4 may be optionally substituted with R 1b When R contains a substitutable ring N atom, 1b R can be preferably substituted on a substitutable ring N atom. 1b is one R 4 and preferably one R on the ring N atom 4 may be substituted by

[0165] In any of Formula III or IIIa, or embodiments of Formula III or IIIa, R 1b R may be a 4- to 10-membered non-aromatic, monocyclic, bridged, or bicyclic ring 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 .

[0166] In Formula III or IIIa, or any of the embodiments of Formula III or IIIa, A is R 2c or NR 2a R 2b It could be.

[0167] In any of Formula III or IIIa, or the embodiments of Formula III or IIIa, optionally one of X1 and X2 is N and the other is S, X3 is C, and A is R 2c If R 1b is not 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl.

[0168] In any of Formula III or IIIa, or embodiments of Formula III or IIIa, optionally, one of X1 and X2 is N and the other is S, X3 is C, and A is OR 2f If R 1b is not a (substituted or unsubstituted) monocyclic piperazine ring.

[0169] In Formula III or IIIa, or any of the embodiments of Formula III or IIIa, optionally when one of X1 and X2 is N and the other is S, and X3 is C, R 1b is not a (substituted or unsubstituted) monocyclic piperazine ring.

[0170] In embodiment (3) of Formula III or IIIa: Q is C; R 1b is a 7-9 membered saturated bridged ring containing two ring N heteroatoms, 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 at any point 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, and R 2c is one or more R 5 optionally 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.

[0171] In embodiment (3) of formula III or IIIa, preferably, X3 is C, one of X1 and X2 is S and the other is N (preferably, X1 is N and X2 is S), n may be 0, and R 2c may be as defined in embodiment (19) or (20) of formula I or Ia.

[0172] Also described herein is a compound of Formula IV, or a pharmaceutically acceptable salt or derivative thereof:

[0173] [ka]

[0174] 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 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; and R 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 2eand R is optionally substituted 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]; 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, said (C3-10)alkyl group being optionally substituted with 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 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2 or 3 ring N or O heteroatoms fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; and 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 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. And X1, X2, X3, R 1 , R 3a , R 3b , Q, R 4 , R 5 , a, and n are as defined for Formula I or any of the embodiments (1)-(9) and (24)-(34) of Formula I above.

[0175] Also described herein is a compound of formula IVa, or a pharmaceutically acceptable salt or derivative 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 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; and R 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— 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, said (C3-10) alkyl group being optionally substituted with a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms, and 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 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. X1, X2, X3, R 1 , R 3a , R 3b , Q, R 4 , R 5 , a, and n are as defined for Formula Ia or any of embodiments (1)-(9) and (24)-(34) of Formula Ia above.

[0178] In embodiment (1) of formula IV or IVa, R 2d is a 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 2d is one or two R 5 , preferably one R 5 may be substituted with R 2dis 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.

[0179] In embodiment (2) of formula IV or IVa, 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 2d is CH2-[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 may be substituted with one or more halogens (preferably optionally substituted with one or more halogens). The aromatic or heteroaromatic ring may be optionally substituted with halogens (preferably fluoro), CN or CF3.

[0180] In embodiment (3) of formula IV or IVa, 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 may be a (C3-10) alkyl group, which may be linear, branched, or cyclic, or a combination thereof, where R 2d is R5 It is replaced by R 2d may be a (C4-10) alkyl group, which may be linear, branched, or cyclic, or a combination thereof, where R 2d is R 5 It is replaced by R 2d is a (C5-10) alkyl group which may be linear, branched, or cyclic or a combination thereof, where R 2d is R 5 It is replaced by R 2d may be a (C5-10) alkyl group containing a cyclic moiety, where R 2d is R 5 The remainder may be as defined for Formula Ia, or any of embodiments (1)-(9), (13), or (19)-(26) of Formula Ia described herein, mutatis mutandis.

[0181] In embodiment (4) of formula IV or IVa, R 2d is a (C5-10) alkyl group containing a cyclic moiety, and R 2d is one or more R 5 and optionally substituted with R 2d may be a (C5-8)cycloalkyl group or CH2-[(C5-6)cycloalkyl group]. R 2d is 1 or 2 R 5 and R 5 R may preferably be halogen (e.g., fluoro). 2d The cyclic part of the 5 (e.g., fluoro).

[0182] In embodiment (5) of formula IV or IVa, 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.

[0183] In embodiment (6) of formula IV or IVa, Z is R 2e Preferably, Q is also C.

[0184] In embodiment (7) of formula IV or IVa, 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 2e R may 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), 1 OH, or 1 (C1-4)alkoxy. The aromatic or heteroaromatic ring may be substituted with 1, 2, or 3 (preferably 1 or 2, preferably 1) halogen, CN, (C1-4)alkoxy, or (C1-4)alkyl, with the (C1-4)alkyl optionally substituted with one or more halogens (preferably one or more fluoro). R 2e may be CH2-[a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms], where CH2 may be substituted with 1 or 2 halogens (preferably fluoro, which may form -CHF- or -CF2-). The aromatic or heteroaromatic ring may be substituted with 1, 2, or 3 (preferably 1 or 2, preferably 1) halogens, CN, or (C1-4) alkyl, and the (C1-4) alkyl group may be substituted with one or more halogens (preferably optionally one or more fluoro). The aromatic or heteroaromatic ring may be optionally substituted with halogens (preferably fluoro), CN, or CF3.

[0185] In embodiment (8) of formula IV or IVa, R 2e is CH2-O-[6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms], and R 2eis 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], 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) halogen, CN, (C1-4)alkoxy or (C1-4)alkyl, and the (C1-4)alkyl group is optionally substituted with one or more halogens (preferably optionally one or more fluoro). R 2e may be CH2-O-[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 may be substituted with one or more halogens (preferably one or more fluoro). The aromatic or heteroaromatic ring may optionally be substituted with halogens (preferably fluoro), CN or CF3.

[0186] In embodiment (9) of formula IV or IVa, R 2e is a (C3-10) alkyl group which may be linear, branched, or cyclic, or a combination thereof, wherein said (C3-10) alkyl group is selected from R 2e with one -O- other than at the point of attachment of R, 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; R 2e is one or more R 5 It will be understood that cyclic moieties include polycyclic (e.g., bicyclic) moieties, such as fused, bridged, or spiro bicyclic rings. R2e 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 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; wherein R 2e is one or more R 5 It is replaced by R 2e may be a (C3-10) alkyl group containing a monocyclic moiety, and a C atom of the linear or cyclic moiety of said (C3-10) alkyl group may optionally be 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; 2e is one or more R 5 It is replaced by R 2e R may be substituted with one or more substituents selected from halogen, OH, and CN. 2e is optionally substituted with 1, 2 or 3 halogens, 1 OH or 1 CN.

[0187] In embodiment (10) of formula IV or IVa, R 2e is a (C5-10) alkyl group containing a cyclic moiety, and R 2e is one or more R 5 It will be understood that cyclic moieties include polycyclic (e.g., bicyclic) moieties, such as fused, bridged, or spiro bicyclic rings. R 2e may be a (C5-10) alkyl group containing a monocyclic moiety, and R 2e is one or more R 5 is optionally replaced by R 2e R may be a (C5-6)cycloalkyl group or a (C1-2)alkyl-[(C4-6)cycloalkyl group]. 2e is 1 or 2 R 5 and R 5 R may preferably be halogen (e.g., fluoro).2e The cyclic part of the 5 (e.g., fluoro).

[0188] In embodiment (11) of formula IV or IVa, R 2e is a 6-membered aromatic or heteroaromatic ring containing one or two ring N atoms. 2e R may be phenyl or pyridyl. 2e is optionally substituted with 1, 2 or 3 (preferably 1 or 2, preferably 1) halogen, CN, (C1-6) alkyl or (C1-4) alkoxy, wherein the (C1-6) alkyl or (C1-4) alkoxy is optionally substituted with one or more halogen (preferably optionally substituted with one or more fluoro), and the (C1-6) alkyl group is optionally substituted with (C1-4) alkoxy. It will be understood that the alkyl group may be linear, branched, cyclic, or a combination thereof.

[0189] In embodiment (12) of formula IV or IVa, R 2e is a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocyclic ring containing 1, 2, or 3 ring N or O atoms fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms. 2e It will be understood that R may be attached to the remainder of the compound via a 5-6 membered aromatic or non-aromatic heterocyclic ring, or a 6 membered aromatic or heteroaromatic ring. 2e can be a 9-membered bicyclic ring comprising a 5-membered aromatic heterocycle containing 1, 2, or 3 ring N heteroatoms and / or 1 O heteroatom fused to a 6-membered aromatic or heteroaromatic ring containing 0 or 1 ring N atom; a 9- or 10-membered bicyclic ring comprising a 5- to 6-membered non-aromatic heterocycle containing 1 or 2 ring O heteroatoms fused to a 6-membered aromatic or heteroaromatic ring containing 0 or 1 ring N atom; or a 10-membered bicyclic ring comprising a 6-membered aromatic or non-aromatic heterocycle containing 1 or 2 ring N heteroatoms fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms.

[0190] In Formula IV or IVa, or any embodiment of Formula IV or IVa, optionally the compound is not selected from the group consisting of compounds or pharmaceutically acceptable salts thereof:

[0191] [ka]

[0192] Also described herein is a compound of formula V, or a pharmaceutically acceptable salt or derivative thereof:

[0193] [ka]

[0194] m is 1, 2, 3, or 4; And X1, X2, X3, R 1 , R 2a , R 2b , R 2c , R 2f , R 3a , R 3b , A, Q, R 4 , R 5 and a are as defined for Formula I or the description of embodiments (1)-(26) and (29)-(34) of Formula I above.

[0195] Also described herein is a compound of formula Va, or a pharmaceutically acceptable salt or derivative thereof:

[0196] [ka]

[0197] m is 1, 2, 3, or 4; And X1, X2, X3, R 1、 R 2a , R 2b , R 2c , R 3a , R 3b , A, Q, R4 , R 5 and a are as defined for Formula Ia or any of embodiments (1)-(26) and (29)-(34) of Formula Ia above.

[0198] In embodiment (1) of formula V or Va, m is 1 or 2. When m is 2, both R 3a are preferably on the same ring carbon atom.

[0199] In Formula V or Va, or any of the embodiments of Formula V or Va, A is R 2c or NR 2a R 2b It could be.

[0200] In further embodiments of the compound of Formula IV or Ia-Va or a pharmaceutically acceptable salt thereof (including any of the embodiments thereof described above), one or more hydrogen atoms is 2 is substituted with H. The remainder may be as defined for any aspect or embodiment of Formula Ia-Va described herein.

[0201] Compounds of formula IV (including any embodiment thereof) may be preferred.

[0202] In one embodiment, the compound of formula I or Ia is selected from: 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-isopropoxyetan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-phenylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-phenoxyethan-1-one; 4-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-oxopropyl)benzonitrile; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-phenylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3-dimethylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclobutylethan-1-one;

[0203] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(bicyclo[1.1.1]pentan-1-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclohexylethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4,4-difluorocyclohexyl)methanone; (2S)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylbutan-1-one; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3-dimethylbutan-1-one; (2S)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3-dimethylbutan-1-one; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3-dimethylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenoxy)ethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(cyclopentyl)methanone;

[0204] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-phenoxypropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2,2-difluoroethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3,3-trifluoropropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(1-methylcyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-hydroxy-3-methylbutan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3,3-difluorocyclopentyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methyl-2-phenoxypropan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-phenoxycyclopropyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3,3 -trifluoro-2,2-dimethylpropan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-phenylcyclopropyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-fluoroethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4,4-difluorocyclohexyl)-2-fluoroethan-1-one;

[0205] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-difluoro-2-phenylethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,2-dimethylcyclopentyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3,3-dimethylcyclopentyl)methanone; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-isopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclohexyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cycloheptyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(cyclohexylmethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-fluorobenzyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-(trifluoromethyl)benzyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-phenyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(pyrrolidin-1-yl)methanone;

[0206] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-methyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-dimethylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamide; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-(4-fluorophenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-((2-fluoropyridin-4-yl)oxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-((6-fluoropyridin-3-yl)oxy)ethan-1-one; 2-Cyclopentyl-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one;

[0207] N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; N-Cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-((2-fluoropyridin-4-yl)oxy)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-((6-fluoropyridin-3-yl)oxy)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide; N-Cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide; 2-Cyclopentyl-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)ethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)ethan-1-one; N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamide; 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(7,7-dimethyl-2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one;

[0208] 2-Cyclopentyl-1-(7,7-dimethyl-2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-Cyclopentyl-1-(7,7-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(7,7-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(7,7-dimethyl-2-(4-methylpiperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-((cyclopentylmethyl)sulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-sulfonamide; 2-Cyclopentyl-1-(2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4-fluorophenoxy)-1-(2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; (S)-2-Cyclopentyl-1-(2-(3-(hydroxymethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; (R)-2-Cyclopentyl-1-(2-(3-(hydroxymethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-Cyclopentyl-1-(2-(piperidin-4-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(3,3-dimethylcyclobutyl)ethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,2-dimethylpyrrolidin-1-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3,3-dimethylpyrrolidin-1-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-azaspiro[4.4]nonane)-2-yl)methanone;

[0209] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-azaspiro[3.4]octan)-6-yl)methanone; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1-methylcyclobutyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1-methylcyclopentyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2,2-difluoro-2-phenylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-(1-methylcyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(2-methoxyethoxy)phenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(1-methylcyclobutyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenyl)-2-methoxyethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenyl)-2-hydroxyethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(tetrahydrofuran-2-yl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(1-methoxycyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(1-(methoxymethyl)cyclopentyl)ethan-1-one;

[0210] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(pyrazin-2-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(3,3-difluorocyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-methoxyphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-methoxyphenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluoro-2-methoxyphenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-fluoropyridin-4-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-(6-fluoropyridin-3-yl)propan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluoro-2-methoxyphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2,4-difluorophenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluoro-2-methylphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-methylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-(4-fluoro-2-methoxyphenyl)propan-1-one;

[0211] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2,4-difluorophenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(cyclopentyloxy)ethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-methylcyclopentyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-fluorocyclopentyl)methanone; 3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-3-oxopropanenitrile; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2,6-dimethylpyridin-4-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-dimethylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-oxaspiro[3.5]nonan-7-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluoro-2-methylphenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-methoxyethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3,3-trimethylbutan-1-one (enantiomer-1); 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3,3-trimethylbutan-1-one (enantiomer-2); 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(bicyclo[2.2.1]heptan-1-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2,3-trimethylbutan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(spiro[2.4]heptan-1-yl)methanone;

[0212] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-isopropoxyphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(trifluoromethoxy)phenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(6-fluoropyridin-3-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-difluoro-2-(6-fluoropyridin-3-yl)ethan-1-one; 2-(2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-oxoethoxy)benzonitrile; 2-(2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-oxoethoxy)-3-methoxybenzonitrile; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(cyclopentyloxy)propan-1-one; (2S)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxyethan-1-one; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxyethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2,6-dimethoxyphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(difluoromethyl)phenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3-dimethylpentan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-4,4-difluoro-3,3-dimethylbutan-1-one;

[0213] (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-hydroxy-3,3-dimethylbutan-1-one; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclohexyl-2-hydroxyethan-1-one; 4-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-dimethyl-4-oxobutanenitrile; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzofuran-2)-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(chroman-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(chroman-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(isochroman-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzofuran-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(benzofuran-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(isoquinolin-1-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(benzofuran-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1H-indol-2-yl)methanone;

[0214] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-methyl-1H-indol)-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(benzo[d]oxazol-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(isoquinolin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(o-tolyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(m-tolyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(p-tolyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-methoxyphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-fluorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3-(difluoromethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-fluoropyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(pyridin-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(5-fluoropyridin-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(difluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(difluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3-(trifluoromethoxy)phenyl)methanone;

[0215] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3-(difluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(trifluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(trifluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-fluorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-chlorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-isopropoxyphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,4-difluorophenyl)methanone; 2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-5-carbonyl)benzonitrile; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(methoxymethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-isopropylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-fluoro-2-methylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(chroman-8-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(difluoromethyl)phenyl)methanone;

[0216] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-methoxy-4-methylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-cyclopropylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-chloropyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-fluoro-2-methoxyphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(1,1-difluoroethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-chloropyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,4-dimethylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-chlorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(trifluoromethyl)phenyl)methanone;

[0217] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-cyclopropylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(difluoromethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzofuran-7-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(2,2-difluoroethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(2,2,2-trifluoroethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,2-difluorobenzo[d][1,3]dioxol-4-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(benzo[d][1,3]dioxol-4-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3-fluorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzofuran-4-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(quinolin-8-yl)methanone; 2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-5-carbonyl)-5-methylbenzonitrile; 4-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-5-carbonyl)benzonitrile; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-fluoro-2-methoxypyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone;

[0218] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-fluoro-4-methylpyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-(difluoromethyl)pyridin-3-yl)methanone; Cyclopentyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate; Isopropyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate; Benzyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate; Phenyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-hydroxy-2-(1-methylcyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methoxy-2-(1-methylcyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(2-hydroxyethoxy)phenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-difluoro-2-(2-fluoropyridin-4-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(difluoromethoxy)phenoxy)ethan-1-one; 2-(2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-oxoethoxy)-5-fluoro-3-methoxybenzonitrile; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxypropan-1-one (enantiomer-1); 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxypropan-1-one (enantiomer-2);

[0219] (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(cyclopentyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-hydroxy-3-methylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-oxaspiro[3.5]nonan-7-yl)ethan-1-one; 3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-3-oxopropanenitrile; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxyethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-fluoropyridin-3-yl)methanone; 1-(2'-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4'H-spiro[cyclopropane-1,7'-thiazolo[5,4-c]pyridin]-5'(6'H)-yl)-2-cyclopentylethan-1-one; 1-(2'-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2,3,5,6-tetrahydro-4'H-spiro[pyran-4,7'-thiazolo[5,4-c]pyridin]-5'(6'H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one;

[0220] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylpropan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(phenyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; (S)-2-Cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; (R)-2-Cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 3,3-dimethyl-1-(2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)butan-1-one; (R)-2-Cyclopentyl-1-(2-(2-(hydroxymethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one;

[0221] 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-3,3-dimethylbutan-1-one; 2-Cyclopentyl-1-(2-(7-hydroxy-3,9-diazabicyclo[3.3.1]nonan-9-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; (S)-2-Cyclopentyl-1-(2-(2-(hydroxymethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-((4-fluorobenzyl)sulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-((4-fluorobenzyl)sulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 5-((4-fluorobenzyl)sulfonyl)-2-(piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 5-(benzylsulfonyl)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 5-(benzylsulfonyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 2-Cyclopentyl-1-(2-(3-isopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-Cyclopentyl-1-(2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-Cyclopentyl-1-(2-(3-propyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-((S)-chroman-4-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; N-((S)-chroman-4-yl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; N-((R)-chroman-4-yl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide;

[0222] (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(4-fluorophenoxy)-1-(2-(3-isopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(4-ethylpiperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3-dimethylbutan-1-one; 2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-fluorobenzyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(4-fluorophenoxy)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenoxy)ethan-1-one; 2-(4-fluorophenoxy)-1-(2-(3-propyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4-ethylpiperazin-1-yl)-5-((4-fluorobenzyl)sulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 2-Cyclopentyl-1-(2-(6-methylpyridin-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-Cyclopentyl-1-(2-(5-methylpyridin-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; and pharmaceutically acceptable salts thereof.

[0223] In a further embodiment of the compound of Formula I or Ia, R 1 can be as defined above in any of the compounds of formula I or Ia. In a further embodiment of the compounds of formula I or Ia, A can be as defined above in any of the compounds of formula I or Ia.

[0224] Further aspects and embodiments are described in the following numbered paragraphs. Section 1. A compound of formula Ia 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:

[0225] [ka]

[0226] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; 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 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 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 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.

[0227] Section 2. The compound or pharmaceutically acceptable salt or derivative thereof for use in section 1 is a compound of the following formula or a pharmaceutically acceptable salt or derivative thereof:

[0228] [ka]

[0229] 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.

[0230] Paragraph 4. A compound or a pharmaceutically acceptable salt or derivative thereof for use according to any one of paragraphs 1 to 3, 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.

[0231] Paragraph 5. A compound or a pharmaceutically acceptable salt or derivative thereof for use according to any one of paragraphs 1 to 3, R 1 is 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.

[0232] Paragraph 6: A compound for use according to any of the preceding paragraphs, 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; 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 2cmay 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; 2c is one or more R 5 may be substituted with.

[0233] 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; and 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.

[0234] 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) (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 2cand R is optionally substituted 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; 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 2c and R is optionally substituted 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).

[0235] Item 9. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 7, having the following formula: or a pharmaceutically acceptable salt or derivative thereof:

[0236] [ka]

[0237] 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 to form a cyclopropyl ring.

[0238] 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.

[0239] Item 12. The compound for use according to any of the preceding items, wherein the compound is of formula Ia, one of X1 and X2 is N, the other is S, and X3 is C, or a pharmaceutically acceptable salt or derivative thereof.

[0240] Section 13 Q is C and / or A is R 2c 4. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0241] 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 other than the point of attachment of -, optionally substituted with one -O-, wherein the (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 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, if present, is OH or halo; and n is 0, 1, or 2.

[0242] Item 15. A compound of formula IIa or a pharmaceutically acceptable salt or derivative thereof:

[0243] [ka]

[0244] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; 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; R2c 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 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 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.

[0245] 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.

[0246] Item 17. The compound of item 15 or 16, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound is a compound of the following formula:

[0247] [ka]

[0248] Item 18. The compound of any of items 15-17, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound is of formula IIa, one of X1 and X2 is N, the other is S, and X3 is C.

[0249] Item 19. A compound of formula IIIa or a pharmaceutically acceptable salt or derivative thereof:

[0250] [ka]

[0251] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; Q is C or S(O); R 1bis 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, 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 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 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.

[0252] Item 20: A compound according to item 19, or a pharmaceutically acceptable salt or derivative thereof, R1b 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 one ring O-heteroatom; or a 7- to 10-membered saturated, fused, or spirocyclic ring containing one or two ring N heteroatoms; and R 1b is one, two or three R 4 may be substituted with.

[0253] Item 21. A compound according to item 19 or 20, 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; R 1a may be one R 4 and optionally 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); R 1b is one R 4 may be substituted with.

[0254] 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 R2b 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 5 may be substituted with.

[0255] Item 23: A compound according to any one of items 15-22, or a pharmaceutically acceptable salt or derivative thereof, R 2c but, 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 2c may 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; 2c is one or more R 5 may be substituted with; b) 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 (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 2cmay 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; 2c is one or more R 5 (possibly substituted with R 5 is a halogen).

[0256] 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:

[0257] [ka]

[0258] Section 25 Q is C and / or A is R 2c 25. The compound according to any one of paragraphs 15-24, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0259] 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 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 R5 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.

[0260] Item 27. A compound of formula IVa or a pharmaceutically acceptable salt or derivative thereof:

[0261] [ka]

[0262] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; 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; 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 and R is optionally substituted 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]; 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; and 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; R3b 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.

[0263] Section 28 Z is R 2e 28. The compound of claim 27, wherein:

[0264] 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.

[0265] Section 30 R 1is 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 29. The compound according to any one of paragraphs 27-29, or a pharmaceutically acceptable salt or derivative thereof, optionally substituted with:

[0266] Section 31 R 1 is a 7-9 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 31. The compound according to any one of items 27-30, or a pharmaceutically acceptable salt or derivative thereof, optionally substituted with:

[0267] Section 32 Each R 3a is -CH3 or two R attached to the same carbon 3a A compound according to any one of paragraphs 15-31, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0268] 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.

[0269] Item 34. A compound of formula Va or a pharmaceutically acceptable salt or derivative thereof:

[0270] [ka]

[0271] In the formula, one of X1 and X2 is N, and the other is N, S, or CR 3b and X3 is N or C; Q is C or S(O); R 1is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and 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 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 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 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.

[0272] 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.

[0273] 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.

[0274] "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.

[0275] 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.

[0276] 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. 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.

[0277] 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.

[0278] As used herein, the term "can be" is to be construed as optional. When a feature is expressed as "can be 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.

[0279] The term "halogen" means F, Cl, Br or I. F and Cl are particularly preferred, with F being most preferred.

[0280] Activation of long-chain PDE4 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).

[0281] 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.

[0282] 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).

[0283] 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).

[0284] 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.

[0285] 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).

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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

[0291] [Table 1]

[0292] *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

[0293] Table B - Examples of known PDE4B isoforms

[0294] [Table 2]

[0295] Table C - Examples of known PDE4C isoforms

[0296] [Table 3]

[0297] Table D - Examples of known PDE4D isoforms

[0298] [Table 4]

[0299] 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).

[0300] In one aspect, the present invention provides small molecule activators of the PDE4 long chain forms described herein, which are useful in methods for treating or preventing disease by reducing second messenger responses mediated by cyclic 3',5'-adenosine monophosphate (cAMP).

[0301] For example, gain-of-function genetic mutations in proteins involved in driving cAMP signaling upstream of adenylyl cyclases (e.g., 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.

[0302] 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.

[0303] Diseases that are ameliorated by activation of the long isoform of PDE4 or that are characterized by elevated cAMP levels

[0304] 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).

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] 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).

[0312] 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.

[0313] 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.

[0314] 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).

[0315] Therefore, the PDE4 long form activators of the present invention are expected to be effective in treating, preventing or partially controlling polycystic kidney disease.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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:

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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).

[0326] 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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).

[0332] 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).

[0333] 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.

[0334] 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).

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] 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.

[0340] 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).

[0341] 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).

[0342] 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).

[0343] 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).

[0344] 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).

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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 that are 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 diseases or disorders that can be improved by activating the long chain isoform of PDE4 are diseases or disorders that are 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 diseases or disorders in patients in need of treatment.The present invention also provides a method for treating or preventing diseases or disorders in patients in need of treatment, comprising administering an effective amount of a compound described herein to the patient in need thereof. The present invention provides a method for treating or preventing a disease or disorder that can be ameliorated by activation of the long isoform of PDE4, comprising administering a therapeutically effective amount of any compound described herein or a pharmaceutically acceptable salt or derivative thereof to a 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 a therapeutically effective amount of any compound described herein or a pharmaceutically acceptable salt or derivative thereof to a patient in need thereof.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.

[0354] 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. Compounds of Formula Ia encompass pharmaceutically acceptable salts thereof. Furthermore, these terms encompass sub-embodiments of the disclosed compounds, including Formulas IV, Ia-Va, and embodiments thereof.

[0355] The compounds described herein may be provided as solvates, for example, hydrates.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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).

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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).

[0364] 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 a compound of Formula I, 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.

[0365] 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.

[0366] 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, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0367] The hydrogen atom bonded to carbon is deuterium [ 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)].

[0368] 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.

[0369] 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).

[0370] 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).

[0371] The pharmaceutical composition may further comprise an adjuvant and / or one or more additional therapeutically active agents.

[0372] 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, which will usually (but not necessarily) include instructions for use, and which may include a plurality of said unit dosage forms.

[0373] 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.

[0374] For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions, and the like.

[0375] 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.

[0376] 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.

[0377] 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.

[0378] 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).

[0379] Tablet formulations are discussed in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets 1980, vol. 1 (Marcel Dekker, New York).

[0380] 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.

[0381] 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.

[0382] 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.

[0383] 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)).

[0384] 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.

[0385] 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.

[0386] 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.

[0387] 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.

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] 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.

[0393] 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.

[0394] 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.

[0395] 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.

[0396] 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.

[0397] 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.

[0398] 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.

[0399] 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.

[0400] 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.

[0401] Example The invention is further illustrated by the following non-limiting examples with reference to 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.

[0402] General Experimental Details The reaction was analyzed by thin layer chromatography (Merck Millipore TLC silica gel 60 F 254 ) was monitored. Flash column chromatography was performed on a Biotage Isolera® or Buchi Reveleris® X2 flash chromatography system using prepacked silica gel columns. Unless otherwise stated, NMR spectra were recorded on a Bruker 300 or 400 MHz spectrometer at 25 °C using the residual signal of the deuterated solvent as the internal standard. Exchangeable NH and OH residues were occasionally 1 The H-NMR spectrum did not allow identification.

[0403] 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, Postrun: 0.5 min.

[0404] 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) in water. 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, Postrun: 0.5 min.

[0405] 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, Postrun: 2.5 min.

[0406] 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, Postrun: 2.5 min.

[0407] 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% Formic acid in acetonitrile, gradient: t = 0 min 5% B, t = 1.6 min 98% B, t = 3 min 98% B, post run: 1.3 min.

[0408] Method B: Instrument: Agilent 1260 Infinity, 1260G312B 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. Post-run: 1.4 min.

[0409] Method C: 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 (50x2.1 mm 3.5 μm), Flow Rate: 0.8 mL / min, Column Temperature: 60°C, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% Formic acid in acetonitrile, gradient: t = 0 min 5% B, t = 4 min 98% B, t = 6 min 98% B, post run: 2 min.

[0410] HPLC method Method A: (Preparative HPLC using formic acid as buffer): MS Instrument Type: ACQ-SQD2; HPLC Instrument Type: Waters Modular Preparative HPLC System; Column: Waters XSelect (C18, 100x30 mm, 10 μm); Flow Rate: 55 mL / min Prep Pump; Column Temperature: Room Temperature; Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile; Gradient: t = 0 min 2% B, t = 4 min 2% B, t = 13 min 30% B, t = 14.5 min 100% B, t = 17 min 100% B. Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) Mass Range: 100-800; Fraction Collection Based on MS and DAD

[0411] Method B: (Preparative HPLC using ammonium bicarbonate as buffer): MS instrument type: Agilent Technologies G6130B quadrupole; HPLC instrument type: Agilent Technologies 1290 preparative LC; Column: Waters XSelect CSH (C18, 150x19 mm, 10 μm); Flow rate: 25 mL / min; Column temperature: room temperature; Eluent A: 10 mM aqueous ammonium bicarbonate (pH = 9.5); Eluent B: 100% acetonitrile; gradient: t = 0 min 0% B, t = 2.5 min 10% B, t = 11 min 50% B, t = 13 min 100% B, t = 17 min 100% B; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) mass range: 100-1000; fraction collection based on MS and DAD. The abbreviations used herein are as follows:

[0412] [Table 5]

[0413] Abbreviation: The following abbreviations may also be used in experimental details: CDI (1,1'-carbonyldiimidazole), DCM (dichloromethane), DIPEA (N,N-diisopropylethylamine), DMF (N,N-dimethylformamide), EDC (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide), h (hour), HOBt (hydroxybenzotriazole), MW (microwave), rt (room temperature), SEM [2-(trimethylsilyl)ethoxymethyl], TBDPS (tert-butyldiphenylsilyl), THF (tetrahydrofuran). The following abbreviations are used for NMR signal assignments: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), app. (approximate), br. (broad), dd (double doublet), dt (double triplet), and td (triple doublet). In the chemical formula, "intermediate" means "intermediate", "Example" means "Example", "1,4-dioxane" means "1,4-dioxane", and "RT" means "room temperature". In the chemical formula, "Example" means "Example" and "Intermediate" means "Intermediate."

[0414] Synthetic procedures for key intermediates: Intermediate 1: Synthesis of benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0415] [ka]

[0416] 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).

[0417] Intermediate 2: Synthesis of benzyl 8-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0418] [ka]

[0419] Under an argon atmosphere, tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (500 mg, 1.57 mmol, 4), benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (424 mg, 1.72 mmol, Intermediate 1), and cesium carbonate (1.53 g, 4.70 mmol) were dissolved in 1,4-dioxane (20 mL). Argon gas was bubbled through for 5 minutes. Next, Pd(PhP) (91 mg, 0.08 mmol) and Xantphos (91 mg, 0.16 mmol) were added, and the mixture was stirred at 100 °C for 20 hours. The mixture was cooled to room temperature, poured into water, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a yellow oil. The oil was purified by silica column chromatography (0%-100% 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)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (503 mg, 61%) as a yellow gum. To a solution of tert-butyl 2-(3-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (500 mg, 1.03 mmol) in 1,4-dioxane (10 mL) was added 4 M hydrochloric acid in 1,4-dioxane (5 mL, 20.0 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, redissolved in methanol, and purified by SCX (ion exchange) chromatography (washing with methanol and eluting with 3.5 M ammonia in methanol) to give benzyl 8-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (360 mg, 86%, Intermediate 2) as a pale yellow gum. 1 H-NMR: δ H(400 MHz, CDCl3) 7.40 - 7.29 (5H, m), 5.14 (2H, s), 4.27 - 4.15 (2H, m), 3.92 - 3.86 (3H, m), 3.79 (1H, d, J 12.8), 3.45 - 3.29 (2H, m), 3.24 - 3.14 (3H, m), 2.69 - 2.60 (2H, m), 2.08 - 1.99 (2H, m), 1.80 - 1.72 (2H, m).

[0420] Intermediate 3 Synthesis of benzyl 8-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0421] [ka]

[0422] A solution of di-tert-butyl dicarbonate (0.30 mL, 1.28 mmol) in acetonitrile (2 mL) was added dropwise to a solution of 2-bromo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole hydrobromide (244 mg, 0.85 mmol) and 4-dimethylaminopyridine (136 mg, 1.11 mmol) in acetonitrile (2 mL). The mixture was stirred at room temperature for 1 hour. The mixture was poured into water (30 mL), and the suspension was stirred for 30 minutes. The precipitate was filtered off, washed with water, and air-dried. The solid was redissolved in dichloromethane, dried over sodium sulfate, and concentrated in vacuo to give tert-butyl 2-bromo-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate (216 mg, 82%) as a gray solid. Under an argon atmosphere, RuPhos (57.8 mg, 0.12 mmol) and Pd(dba) (50.4 mg, 0.06 mmol) were suspended in 1,4-dioxane (0.5 mL) and heated to 80 °C for 5 min. The mixture was cooled to room temperature and added to a stirred solution of tert-butyl 2-bromo-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate (210 mg, 0.69 mmol), benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (288 mg, 1.17 mmol, Intermediate 1), and cesium carbonate (673 mg, 2.06 mmol) in 1,4-dioxane (4 mL) under an argon atmosphere. The mixture was heated to 100 °C, stirred for 20 h, and concentrated in vacuo. The residue was partitioned between ethyl acetate (15 mL) and water (10 mL) and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a brown oil. The crude oil was purified by silica column chromatography (0%-70% 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)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate (177 mg, 54%) as a white foam. To a solution of tert-butyl 2-(3-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate (162 mg, 0.34 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.53 mL, 6.89 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was poured into saturated aqueous sodium carbonate (pH > 10) and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give benzyl 8-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (138 mg, 95%, Intermediate 3). LCMS (Method B):t R1.69 min, 95%, MS(ESI) 371.1(M+H) + .

[0423] Intermediate 5: Synthesis of benzyl 8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0424] [ka]

[0425] Under an argon atmosphere, RuPhos (265 mg, 0.57 mmol) and Pd(dba) (236 mg, 0.26 mmol) were suspended in 1,4-dioxane (2 mL) and heated to 80 °C for 5 min. The mixture was cooled to room temperature and transferred to a stirred solution of tert-butyl 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (779 mg, 2.58 mmol), benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (889 mg, 3.61 mmol, Intermediate 1), and cesium carbonate (2.52 g, 7.73 mmol) in 1,4-dioxane (7 mL) under an argon atmosphere, and the mixture was heated at 110 °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 2-(3-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (494 mg, 41%) as an orange solid. To a solution of tert-butyl 2-(3-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (494 mg, 1.06 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.63 mL, 21.1 mmol), and the mixture was stirred at room temperature for 45 minutes. The mixture was concentrated in vacuo, redissolved in dichloromethane (10 mL), and basified with aqueous potassium carbonate. The biphasic mixture was extracted three times with dichloromethane. The combined organic layers were washed with brine, concentrated in vacuo, and co-evaporated with n-heptane to give benzyl 8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (354 mg, 89%, Intermediate 5) as an orange solid. LCMS (Method B): R 1.77 min, 97%, MS(ESI)368.2(M+H) + .

[0426] Intermediate 6: Synthesis of tert-butyl 8-carbamothioyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0427] [ka]

[0428] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (450 mg, 2.12 mmol) in tetrahydrofuran (7 mL) was added 1,1'-thiocarbonyldiimidazole (529 mg, 2.97 mmol). The mixture was stirred at room temperature for 6 hours. Next, a 7N solution of ammonia in methanol (9 mL, 63 mmol) was added, and the mixture was stirred in a sealed vial at 100 °C for 16 hours. The mixture was concentrated in vacuo, and the residue was partitioned between 10% aqueous citric acid and ethyl acetate. The organic layer was washed with 10% aqueous citric acid, followed by water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give tert-butyl 8-carbamothioyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (488 mg, 84%, Intermediate 6) as an orange foam. LCMS (Method B):t R 1.73 min, 98%, MS(ESI)272.1(M+H) + .

[0429] Intermediate 7: Synthesis of 5-bromo-3,3-dimethyl-1-(2,2,2-trifluoroacetyl)piperidin-4-one

[0430] [ka]

[0431] To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (750 mg, 3.30 mmol) in chloroform (15 mL) was added a 33% solution of hydrogen bromide in acetic acid (0.57 mL, 3.30 mmol), and the mixture was stirred at room temperature for 5 minutes. Next, a solution of bromine (0.17 mL, 3.30 mmol) in chloroform (3 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was suspended in a mixture of triethylamine (1.80 mL, 12.9 mmol) and dichloromethane (15 mL) and carried on to the next step without further purification. To the above solution, trifluoroacetic anhydride (0.70 mL, 5.03 mmol) was slowly added, and the mixture was stirred at room temperature for 45 minutes. The mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 5-bromo-3,3-dimethyl-1-(2,2,2-trifluoroacetyl)piperidin-4-one (1.32 g, 80%, over two steps, Intermediate 7) as a pale orange solid. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 4.93 - 4.84 (0.5H, m), 4.83 - 4.68 (1H, m), 4.58 - 4.48 (0.5H, m), 4.40 - 4.31 (0.5H, m), 3.86 - 3.68 (1H, m), 3.63 - 3.48 (1H, m), 3.19 - 3.10 (0.5H, m), 1.27 (3H, s), 1.25 - 1.21 (3H, m).

[0432] Intermediate 8: Synthesis of tert-butyl 8-(7,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0433] [ka]

[0434] A mixture of tert-butyl 8-carbamothioyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (386 mg, 1.42 mmol, Intermediate 6), 5-bromo-3,3-dimethyl-1-(2,2,2-trifluoroacetyl)piperidin-4-one (602 mg, 1.99 mmol, Intermediate 7) and N,N-diisopropylethylamine (2.5 mL, 14.3 mmol) in ethanol (3 mL) was heated at 100° C. for 4 hours. The mixture was concentrated in vacuo, purified by silica column chromatography (0% to 100% ethyl acetate in n-heptane), and concentrated in vacuo to give 8-(7,7-dimethyl-5-(2,2,2-trifluoroacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (758 mg, 97%) as a yellow oil. To a solution of tert-butyl 8-(7,7-dimethyl-5-(2,2,2-trifluoroacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (750 mg, 1.58 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was added a solution of lithium hydroxide monohydrate (66.3 mg, 1.58 mmol) in water (1.5 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and partitioned between water and dichloromethane, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, concentrated in vacuo, and co-evaporated with n-heptane to give tert-butyl 8-(7,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (507 mg, 84%, Intermediate 8) as a yellow solid. LCMS (Method B): R 2.04 minutes, 99%, MS(ESI)379.2(M+H) + .

[0435] Intermediate 9: Synthesis of tert-butyl 8-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0436] [ka]

[0437] A mixture of tert-butyl 8-carbamothioyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.50 g, 20.3 mmol, Intermediate 6), 3-bromo-1-(2,2,2-trifluoroacetyl)piperidin-4-one (6.11 g, 22.3 mmol), and N,N-diisopropylethylamine (4.25 mL, 24.3 mmol) in 2-propanol (60 mL) was heated to 70 °C with stirring for 16 h. The mixture was concentrated in vacuo and partitioned between 10% aqueous citric acid and ethyl acetate. The layers were separated, and the organic layer was subsequently washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and coated onto silica. The coated product was purified by silica column chromatography (0%-100% ethyl acetate in n-heptane) and concentrated in vacuo to give tert-butyl 8-(5-(2,2,2-trifluoroacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (6.06 g, 66%) as a white solid. To a solution of tert-butyl 8-(5-(2,2,2-trifluoroacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (6.06 g, 13.6 mmol) in methanol (40 mL) was added potassium carbonate (2.06 g, 14.9 mmol), and the mixture was stirred at room temperature for 2 days. The mixture was concentrated in vacuo, partitioned between water and diethyl ether, and acidified with 1 M potassium hydrogen sulfate. The aqueous layer was washed twice with diethyl ether, basified to pH > 10 with aqueous potassium carbonate, and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give butyl 8-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (4.22 g, 88%, Intermediate 9) as a pale yellow solid. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 4.28 - 4.11 (2H, m), 3.93 - 3.61 (4H, m), 3.41 - 3.19 (2H, m), 3.19 - 3.08 (2H, m), 2.67 - 2.55 (2H, m), 2.10 - 1.93 (2H, m), 1.93 - 1.72 (2H, m), 1.45 (9H, s); LCMS (Method ): t R 1.83 min, 98%, MS (ESI) 351.2 (M+H) + .

[0438] Intermediate 10: Synthesis of tert-butyl 4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate

[0439] [ka]

[0440] To a stirred solution of tert-butyl piperazine-1-carboxylate (10.0 g, 53.7 mmol) in DCM (50 mL) was added benzoyl isothiocyanate (8.76 g, 53.7 mmol). The mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. To the crude residue was added hydrazine hydrate (13.4 g, 268 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane to give tert-butyl 4-carbamothioylpiperazine-1-carboxylate (13.0 g, 98%) as an off-white solid. To a stirred solution of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (25.0 g, 90.0 mmol) in DCM (50 mL) was added HCl (4 M in dioxane; 45 mL, 180 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to give 3-bromopiperidin-4-one hydrochloride (19.0 g, 99%) as an off-white solid. To a stirred solution of 3-bromopiperidin-4-one hydrochloride (19.5 g, 91.0 mmol) in DCM (200 mL) was added 2,2,2-trifluoroacetic anhydride (63.2 mL, 455 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was diluted with water, neutralized with saturated sodium bicarbonate solution, and the organic components were extracted with DCM (2 × 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material, which was triturated with hexane to give 3-bromo-1-(2,2,2-trifluoroacetyl)piperidin-4-one (20 g, 79%) as a brown solid. To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (7.50 g, 30.6 mmol) in EtOH (30 mL) was added 3-bromo-1-(2,2,2-trifluoroacetyl)piperidin-4-one (8.38 g, 30.6 mmol). The mixture was heated at 60° C. for 30 minutes and then concentrated under reduced pressure. The residue was triturated with 20% EtOAc in petroleum ether (50 mL), then washed with petroleum ether (50 mL) and dried under vacuum to give tert-butyl 4-(5-(2,2,2-trifluoroacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate (5.50 g, 43%) as an off-white solid. To a stirred solution of tert-butyl 4-(5-(2,2,2-trifluoroacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate (11.0 g, 26.2 mmol) in MeOH (100 mL) and water (50 mL) was added potassium carbonate (7.23 g, 52.3 mmol). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, diluted with water (50 mL), and extracted with 10% MeOH in DCM (2×50 mL). The combined organic layers were then washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with 10% MeOH in EtOAc to give tert-butyl 4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate (6.70 g, 79%, Intermediate 10) as a pale yellow solid.

[0441] Intermediate 11: Synthesis of 1-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one

[0442] [ka]

[0443] To a stirred solution of thiourea (0.958 g, 12.6 mmol) in EtOH (30 mL) was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (5.0 g, 18.0 mmol). The mixture was heated at 60° C. for 40 minutes and then concentrated under reduced pressure. The residue was triturated with 20% ethyl acetate in petroleum ether, and the solid was filtered off, washed with petroleum ether, and dried under vacuum to give tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (4.50 g, 90%). To a stirred solution of copper(II) bromide (4.55 g, 20.4 mmol) in acetonitrile (25 mL) at 0 °C under nitrogen, tert-butyl nitrite (2.10 g, 20.4 mmol) was added dropwise. After 20 min, tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (4.00 g, 15.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate (100 mL), washed with 1.5 N aqueous HCl (2 × 10 mL), then with water (20 mL) and brine (20 mL), dried over NaSO, and concentrated under reduced pressure to give tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (3.80 g, 40%). To a stirred solution of tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (5.0 g, 15.7 mmol) in DCM (25 mL) was added HCl in 1,4-dioxane (4 M; 7.83 mL, 31.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride (2.70 g, 24%). To a stirred solution of 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride (2.80 g, 11.0 mmol) in DCM (25 mL) was added 2-cyclopentylacetic acid (2.11 g, 16.4 mmol), n-propylphosphonic anhydride, cyclic trimer (50% in ethyl acetate; 3.19 mL, 11.0 mmol), and N,N-diisopropylethylamine (7.08 g, 54.8 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 3 hours, then diluted with DCM (25 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 70% ethyl acetate in petroleum ether to give 1-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one (1.30 g, 29%, Intermediate 11). The following intermediates (Intermediates 12-13) were prepared using a similar procedure to Intermediate 8 using the appropriate starting materials.

[0444] Intermediate 12: Synthesis of tert-butyl 8-(5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thiazolo[5,4-c]pyridin]-2'-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0445] [ka]

[0446] Prepared using tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate and Intermediate 6. LCMS (Method B): R 2.06 minutes, 100%, MS(ESI)377.2(M+H) + .

[0447] Intermediate 13: Synthesis of tert-butyl 8-(2,3,5,5',6,6'-hexahydro-4'H-spiro[pyran-4,7'-thiazolo[5,4-c]pyridin]-2'-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0448] [ka]

[0449] Prepared using 9-oxa-2-azaspiro[5.5]undecan-5-one hydrochloride and intermediate 6. 1 H-NMR: δ H (400 MHz,CDCl3,mixture of rotamers) 4.20 (2H, s), 4.13 - 3.99 (2H, m), 3.90 - 3.77 (3H, m), 3.75 - 3.61 (3H, m), 3.33 (1H, d, J 12.8), 3.24 (1H, LCMS (Method A): t R 1.51 min, 100%, MS (ESI) 421.2 (M+H) + .

[0450] Intermediate 14: Synthesis of 2-bromo-6,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[0451] [ka]

[0452] A solution of tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (1.30 g, 5.72 mmol) and p-toluenesulfonic acid monohydrate (0.05 g, 0.26 mmol) in a mixture of pyrrolidine (1.5 mL, 18.14 mmol) and toluene (10 mL) was refluxed in a Dean-Stark apparatus for 16 h. The mixture was concentrated in vacuo and redissolved in methanol (10 mL). Next, sulfur (0.24 g, 7.43 mmol) and cyanamide (433 mg, 10.29 mmol) were added, and the mixture was stirred at room temperature for 4 h. The mixture was coated onto silica and purified by silica column chromatography (0% to 100% ethyl acetate in n-heptane) and concentrated in vacuo to give tert-butyl 2-amino-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (749 mg, 36%) as an orange liquid. LCMS (Method B):t R 1.89 min, 99%, MS(ESI)284.2(M+H) + A solution of tert-butyl 2-amino-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (695 mg, 2.45 mmol), copper(I) bromide (457 mg, 3.19 mmol), and lithium bromide (319 mg, 3.68 mmol) in acetonitrile (10 mL) was cooled to 0 °C. tert-Butyl nitrite (0.42 mL, 3.19 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution, and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate, brine (50 mL), and concentrated in vacuo. The residue was dissolved in dichloromethane, purified by silica column chromatography (0% to 100% ethyl acetate in n-heptane), and concentrated in vacuo to give tert-butyl 2-bromo-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (106 mg, 10%) as a colorless oil. 1 H-NMR: δ H(400 MHz, CDCl3, mixture of rotamers) 4.59 (2H, d, J 1.6), 2.84 (2H, d, J 1.7), 1.50 (6H, s), 1.47 (9H, s); LCMS (Method B): t R 2.24 minutes, 91%, MS (ESI) 349.0 (M+H) + .

[0453] tert-Butyl 2-bromo-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (106 mg, 0.31 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.35 mL, 4.58 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the mixture was concentrated in vacuo. The residue was partitioned between aqueous potassium carbonate and dichloromethane. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were filtered, concentrated in vacuo, and co-evaporated with heptane to give 2-bromo-6,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (57 mg, 70%, Intermediate 14) as a colorless oil. LCMS (Method B): t R 1.63 min, 95%, MS(ESI)249.0(M+H + .

[0454] The following intermediate (Intermediate 15) was prepared using a similar procedure to Intermediate 14 using the appropriate starting materials. Intermediate 15: Synthesis of tert-butyl 2-bromo-7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

[0455] [ka]

[0456] Prepared using tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate. 1 H-NMR: δ H(400 MHz, CDCl3) 4.70 (2H, s), 4.06 (2H, t, J 10.5), 1.49 (9H, s); LCMS (Method B): t R 2.09 minutes, 99%, MS (ESI) 355.0 (M+H) + .

[0457] Synthesis procedure for the final compound: Example 1: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one

[0458] [ka]

[0459] A solution of benzyl 8-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (150 mg, 0.39 mmol, Intermediate 2), 2-cyclopentylacetic acid (55.0 mg, 0.43 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (90 mg, 0.47 mmol), and 1-hydroxy-7-azabenzotriazole (26.6 mg, 0.20 mmol) in N,N-dimethylacetamide (3 mL) was stirred at room temperature for 16 hours. The crude mixture was purified by preparative reverse-phase chromatography (Phenomenex LUNA C18 column, formic acid in water / acetonitrile) and lyophilized to give benzyl 8-(5-(2-cyclopentylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (95 mg, 47%) as a white solid. A solution of benzyl 8-(5-(2-cyclopentylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (95 mg, 0.18 mmol) in 33% hydrogen bromide in acetic acid (5 mL, 87 mmol) was stirred at room temperature for 2 hours. The mixture was slowly poured into diethyl ether, and the resulting suspension was filtered and quickly rinsed with diethyl ether. The residue was dissolved in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate 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 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one (15 mg, 20%, Example 1) as a white solid. 1 H-NMR: δ H (400 MHz, CDCl3, mixture of rotamers) 6.10 (1H, s), 4.57 - 4.43 (2H, m), 4.19 - 3.92 (2H, m), 3.77 - 3.67 (2H, m), 3.07 - 2.89 (2H, m), 2.62 - 2.52 UPLC (Method A): t R 1.50 min, 100%, MS (ESI) 361.2 (M+H) + .

[0460] The following examples (2-29) were prepared using procedures similar to those in Example 1 using the appropriate starting materials. Example 2: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one

[0461] [ka]

[0462] It is prepared using 2-(4,4-difluorocyclohexyl)acetic acid as the acid component. 1 H-NMR: δ H (400 MHz, CDCl 3, mixture of rotamers) 4.66 - 4.45 (2H, m), 4.17 - 4.08 (2H, m), 3.93 - 3.70 (2H, m), 3.22 (2H, d, J 12.2), 2.76 - 2.64 (4H, m), 2.38 - 2.28 (2H, m), 2.12 - 1.65 (12H, m), 1.40 - 1.22 (2H, m); UPLC (Method C): t R 4.06 min, 98%, MS (ESI) 411.2 (M+H) + .

[0463] Example 3: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one

[0464] [ka]

[0465] It is prepared using 2-(tetrahydro-2H-pyran-4-yl)acetic acid as the acid component. UPLC (Method B):t R 0.90 min, 97%, MS(ESI)377.2(M+H) +.

[0466] Example 4: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-isopropoxyetan-1-one

[0467] [ka]

[0468] It is prepared using 2-isopropoxyacetic acid as the acid component. 1 H-NMR: δ H (400 MHz, DMSO-d6, mixture of rotamers) 4.57 - 3.92 (6H, m), 3.78 - 3.65 (2H, m), 3.65 - 3.54 (1H, m), 2.92 (3H, d, J 12.1), 2.71 - 2.57 (2H, m), 2.54 - 2.51 (2H, m), 1.97 - 1.78 (4H, m), 1.15 - 1.01 (6H, m); UPLC (Method B): t R 0.95 min, 93%, MS (ESI) 351.2 (M+H) + .

[0469] Example 5: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-phenylpropan-1-one

[0470] [ka]

[0471] It is prepared using 3-phenylpropanoic acid as the acid component. 1 H-NMR: δ H(400 MHz, DMSO-d6, mixture of rotamers) 7.32 - 7.10 (6H, m), 4.81 - 4.46 (2H, m), 4.14 - 3.94 (2H, m), 3.79 - 3.66 (2H, m), 3.01 - 2.64 (8H, m), 1.94 - 1.80 (4H, m); UPLC (Method B): t R 1.19 min, 100%, MS (ESI) 383.2 (M+H) + .

[0472] Example 6: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-phenoxyethan-1-one

[0473] [ka]

[0474] It is prepared using 2-phenoxyacetic acid as the acid component. UPLC (Method B):t R 1.3 min, 97%, MS(ESI)385.1(M+H) + .

[0475] Example 7: Synthesis of 4-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-oxopropyl)benzonitrile

[0476] [ka]

[0477] It is prepared using 3-(4-cyanophenyl)propanoic acid as the acid component. 1 H-NMR: δ H(400 MHz, DMSO-d6, mixture of rotamers) 7.82 - 7.63 (2H, m), 7.55 - 7.35 (2H, m), 4.79 - 4.70 (1H, m), 4.55 - 4.45 (1H, m), 3.98 (1H, s), 3.83 - 3.65 (2H, m), 2.98 - 2.88 (3H, m), 2.88 - 2.71 (3H, m), 2.61 - 2.51 (4H, m), 1.94 - 1.80 (2H, m); UPLC (Method B): t R 1.12 minutes, 99%, MS (ESI) 408.1 (M+H) + .

[0478] Example 8: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-phenylethan-1-one

[0479] [ka]

[0480] It is prepared using 2-phenylacetic acid as the acid component. 1 H-NMR: δ H (400 MHz, DMSO-d6, mixture of rotamers) 7.37 - 7.13 (5H, m), 4.85 - 4.43 (2H, m), 4.00 - 3.70 (5H, m), 2.96 - 2.68 (2H, m), 2.50 - 2.38 (6H, m), 1.92 - 1.80 (4H, m); UPLC (Method B): t R 1.11 min, 95%, MS (ESI) 369.1 (M+H) + .

[0481] Example 9: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methylbutan-1-one

[0482] [ka]

[0483] It is prepared using 3-methylbutanoic acid as the acid component. 1 H-NMR: δ H (400 MHz, DMSO-d6, mixture of rotamers) 4.60 - 4.44 (2H, m), 4.16 - 3.94 (2H, m), 3.85 - 3.64 (2H, m), 3.02 - 2.84 (2H, m), 2.70 - 2.55 (4H, m), 2.35 - 2.20 (2H, m), 2.10 - 1.64 (2H, m), 1.05 - 0.81 (6H, m); UPLC (Method B): t R 0.69 min, 96%, MS (ESI) 335.1 (M+H) + .

[0484] Example 10: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3-dimethylbutan-1-one

[0485] [ka]

[0486] It is prepared using 3,3-dimethylbutanoic acid as the acid component. 1 H-NMR: δ H(400 MHz, DMSO-d6, mixture of rotamers) 4.88 - 4.44 (2H, m), 3.98 (2H, s), 3.88 - 3.69 (2H, m), 2.96 - 2.72 (2H, m), 2.62 - 2.51 (4H, m), 2.36 - 2.25 (3H, m), 1.94 - 1.79 (3H, m), 1.04 - 0.90 (9H, m); UPLC (Method B): t R 1.14 min, 95%, MS (ESI) 349.2 (M+H) + .

[0487] Example 11: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclobutylethan-1-one

[0488] [ka]

[0489] It is prepared using 2-cyclobutylacetic acid as the acid component. 1 H-NMR: δ H (400 MHz, DMSO-d6, mixture of rotamers) 4.55 - 4.41 (2H, m), 4.17 - 3.94 (2H, m), 3.81 - 3.64 (2H, m), 3.07 - 2.87 (2H, m), 2.67 - 2.52 (5H, m), 2.05 (3H, m), 1.94 - 1.73 (6H, m), 1.72 - 1.57 (3H, m); UPLC (Method B): t R 0.73min, 93%, MS (ESI) 347.1 (M+H) + .

[0490] Example 12: Synthesis of 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(bicyclo[1.1.1]pentan-1-yl)ethan-1-one

[0491] [ka]

[0492] It is prepared using 2-(bicyclo[1.1.1]pentan-1-yl)acetic acid ...

Claims

1. 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 or a disease or disorder mediated by excessive intracellular cyclic AMP signaling: [Chemical 1] In the formula, X １ and X ２ One of the groups is N and the other is S, N or CR ３ｂ and X ３ is N or C; 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 10-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 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 the (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]; a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2, or 3 ring N or O heteroatoms fused to 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 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, said ring being 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 is 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 by one or more halogen, OH, or (C1-6)alkoxy; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

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, or a pharmaceutically acceptable salt or derivative thereof, for use according to claim 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 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.

4. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 3, 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, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 3, 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 one R ４ may be substituted with.

6. A is R ２ｃ or NR ２ａ R ２ｂ 6. The compound for use according to any one of claims 1 to 5, which is: or a pharmaceutically acceptable salt or derivative thereof.

7. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 6, 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 5-10 membered (optionally 5-7 membered) non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R ５ is replaced by; 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 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; 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 -[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; and R ２ｆ is one or more R ５ may be substituted with.

8. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 7, 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, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 7, 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]; 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 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; or a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2 or 3 ring N or O heteroatoms fused to a 6-membered aromatic or heteroaromatic ring containing 0 or 1 N atom; ２ｃ is one or more R ５ (optionally substituted with R ５ is a halogen).

10. 10. A compound or a pharmaceutically acceptable salt or derivative thereof for use according to any one of claims 1 to 9, having the formula: 【Chemistry 3】

11. A compound or a pharmaceutically acceptable salt or derivative thereof for use according to any one of claims 1 to 10, Each R ３ａ Ga-CH ３ or F, or two R attached to the same carbon ３ａ are joined together with the atoms to which they are attached to form a 3-6 membered cycloalkyl ring, or a 5-6 membered heterocycloalkyl ring containing an O heteroatom (optionally a cyclopropyl ring).

12. n is 0, 1 or 2, optionally n is 2, and both R ３ａ 12. The compound or a pharmaceutically acceptable salt or derivative thereof for use according to any one of claims 1 to 11, wherein the substituents are on the same ring carbon atom.

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

14. X １ and X ２ One of the groups is N and the other is S, and X ３ 14. The compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any of claims 1-13, wherein

15. Q is C and / or A is R ２ｃ 15. The compound for use according to any one of claims 1 to 14, which is: or a pharmaceutically acceptable salt or derivative thereof.

16. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 14, 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 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.

17. A compound of formula II or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 4】 In the formula, X １ and X ２ One of the groups is N and the other is S, N or CR ３ｂ and X ３ is N or C; 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 5-7-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 10-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 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 the (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]; a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2, or 3 ring N or O heteroatoms fused to 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 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 is 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 by one or more halogen, OH, or (C1-6)alkoxy; n is 0, 1, 2, 3, or 4; and a is 0 or 1.

18. 18. The compound of claim 17, 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 is one R ４ may be substituted with.

19. 19. The compound of claim 17 or 18, or a pharmaceutically acceptable salt or derivative thereof, which is a compound of the following formula: 【Chemistry 5】

20. X １ and X ２ One of the groups is N and the other is S, and X ３ 20. The compound of any one of claims 17-19, or a pharmaceutically acceptable salt or derivative thereof, wherein

21. A compound having the following formula: or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 6】 In the formula, X １ and X ２ One of the groups is N and the other is S, N or CR ３ｂ and X ３ is N or C; 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 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 10-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 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]; a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2, or 3 ring N or O heteroatoms fused to 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 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 Ｒ４ 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 is 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 by one or more halogen, OH, or (C1-6)alkoxy; n is 0, 1, 2, 3, or 4; and a is 0 or 1; X １ and X ２ One of the groups is N and the other is S, and X ３ is C, and (a) A is R ２ｃ or NR ２ａ R ２ｂ If R １ｂ is not 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl, and (b) A is OR ２ｆ If R １ｂ is not a monocyclic piperazine ring.

22. 22. A compound according to claim 21, 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.

23. 23. A compound according to claim 21 or 22, or a pharmaceutically acceptable salt or derivative thereof, R １ｂ is 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.

24. 24. A compound according to any one of claims 17 to 23, 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 5-10 membered (optionally 5-7 membered) non-aromatic heterocycle, optionally containing one additional heteroatom selected from O, and optionally one or more R ５ is replaced by; 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 part 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 or c) 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; and R ２ｆ is one or more R ５ may be substituted with.

25. 25. A compound according to any one of claims 17 to 24, or a pharmaceutically acceptable salt or derivative thereof, R ２ｃ 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 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; 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]; 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; or a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2, or 3 ring N or O heteroatoms fused to 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 ５ is a halogen).

26. 27. The compound of any one of claims 17-26, which is a compound having the following formula, or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 7】

27. Q is C and / or A is R ２ｃ 27. The compound of any one of claims 17 to 26, or a pharmaceutically acceptable salt or derivative thereof, wherein:

28. 27. A compound according to any one of claims 17 to 26, 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, when present, (C1-6)alkyl optionally substituted with OH, and optionally (C1-2)alkyl optionally substituted with OH; R ５ is, if present, OH or halo; and n is 0, 1, or 2.

29. A compound according to any one of claims 17 to 28, or a pharmaceutically acceptable salt or derivative thereof, Each R ３ａ Ha-CH ３ or two R attached to the same carbon ３ａ together with the atoms to which they are attached form a cyclopropyl ring.

30. 30. The compound of any one of claims 17-29, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0, 1 or 2.

31. 31. The compound of any one of claims 17-30, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0.

32. A compound having formula V, or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 8】 In the formula, X １ and X ２ One of the groups is N and the other is S, N or CR ３ｂ and X ３ is N or C; 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 10-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 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 the (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]; a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a 9- or 10-membered bicyclic ring containing a 5-6-membered aromatic or non-aromatic heterocycle containing 1, 2, or 3 ring N or O heteroatoms fused to 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 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- 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; 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, said ring being optionally substituted with one or more halogens; Each R ３ｂ are 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 is 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 by one or more halogen, OH, or (C1-6)alkoxy; m is 1, 2, 3, or 4; and a is 0 or 1.

33. A is R ２ｃ or NR ２ａ R ２ｂ 33. The compound of any one of claims 17 to 32, or a pharmaceutically acceptable salt or derivative thereof, wherein:

34. A compound selected from the following or a pharmaceutically acceptable salt or derivative thereof: 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-isopropoxyetan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-phenylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-phenoxyethan-1-one; 4-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-oxopropyl)benzonitrile; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-phenylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3-dimethylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclobutylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(bicyclo[1.1.1]pentan-1-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclohexylethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4,4-difluorocyclohexyl)methanone; (2S)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylbutan-1-one; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3-dimethylbutan-1-one; (2S)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3-dimethylbutan-1-one; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3-dimethylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenoxy)ethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(cyclopentyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-phenoxypropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2,2-difluoroethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3,3-trifluoropropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(1-methylcyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-hydroxy-3-methylbutan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3,3-difluorocyclopentyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methyl-2-phenoxypropan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-phenoxycyclopropyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3,3-trifluoro-2,2-dimethylpropan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-phenylcyclopropyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-fluoroethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4,4-difluorocyclohexyl)-2-fluoroethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-difluoro-2-phenylethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,2-dimethylcyclopentyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3,3-dimethylcyclopentyl)methanone; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-isopropyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclohexyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cycloheptyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(cyclohexylmethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-fluorobenzyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-(trifluoromethyl)benzyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-phenyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(pyrrolidin-1-yl)methanone; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-N-methyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-dimethylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamide; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-(4-fluorophenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-((2-fluoropyridin-4-yl)oxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-((6-fluoropyridin-3-yl)oxy)ethan-1-one; 2-cyclopentyl-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; N-cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-((2-fluoropyridin-4-yl)oxy)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-((6-fluoropyridin-3-yl)oxy)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide; N-cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide; 2-cyclopentyl-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)ethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)ethan-1-one; N-(4,4-difluorocyclohexyl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamide; 2-(4,4-difluorocyclohexyl)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4,4-difluorocyclohexyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(7,7-dimethyl-2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-cyclopentyl-1-(7,7-dimethyl-2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-cyclopentyl-1-(7,7-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(7,7-dimethyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4,4-difluorocyclohexyl)-1-(7,7-dimethyl-2-(4-methylpiperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-((cyclopentylmethyl)sulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-sulfonamide; 2-cyclopentyl-1-(2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4-fluorophenoxy)-1-(2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; (S)-2-cyclopentyl-1-(2-(3-(hydroxymethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; (R)-2-cyclopentyl-1-(2-(3-(hydroxymethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-cyclopentyl-1-(2-(piperidin-4-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(3,3-dimethylcyclobutyl)ethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,2-dimethylpyrrolidin-1-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3,3-dimethylpyrrolidin-1-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-azaspiro[4.4]nonane)-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-azaspiro[3.4]octan)-6-yl)methanone; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1-methylcyclobutyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1-methylcyclopentyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2,2-difluoro-2-phenylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-2-(1-methylcyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(2-methoxyethoxy)phenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(1-methylcyclobutyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenyl)-2-methoxyethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenyl)-2-hydroxyethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(tetrahydrofuran-2-yl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(1-methoxycyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(1-(methoxymethyl)cyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(pyrazin-2-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(3,3-difluorocyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-methoxyphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-methoxyphenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluoro-2-methoxyphenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-fluoropyridin-4-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-(6-fluoropyridin-3-yl)propan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluoro-2-methoxyphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2,4-difluorophenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluoro-2-methylphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-methylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-(4-fluoro-2-methoxyphenyl)propan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2,4-difluorophenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(cyclopentyloxy)ethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-methylcyclopentyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-fluorocyclopentyl)methanone; 3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-3-oxopropanenitrile; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2,6-dimethylpyridin-4-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-dimethylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-oxaspiro[3.5]nonan-7-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluoro-2-methylphenyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-methoxyethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3,3-trimethylbutan-1-one (enantiomer-1); 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,3,3-trimethylbutan-1-one (enantiomer-2); 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(bicyclo[2.2.1]heptan-1-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2,3-trimethylbutan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(spiro[2.4]heptan-1-yl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-isopropoxyphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(trifluoromethoxy)phenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(6-fluoropyridin-3-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-difluoro-2-(6-fluoropyridin-3-yl)ethan-1-one; 2-(2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-oxoethoxy)benzonitrile; 2-(2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-oxoethoxy)-3-methoxybenzonitrile; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(cyclopentyloxy)propan-1-one; (2S)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxyethan-1-one; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxyethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2,6-dimethoxyphenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(difluoromethyl)phenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3-dimethylpentan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-4,4-difluoro-3,3-dimethylbutan-1-one; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-hydroxy-3,3-dimethylbutan-1-one; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclohexyl-2-hydroxyethan-1-one; 4-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-dimethyl-4-oxobutanenitrile; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzofuran-2)-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(chroman-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(chroman-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(isochroman-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzofuran-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(benzofuran-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(isoquinolin-1-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(benzofuran-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1H-indol-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(1-methyl-1H-indol)-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(benzo[d]oxazol-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(isoquinolin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(o-tolyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(m-tolyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(p-tolyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-methoxyphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-fluorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3-(difluoromethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-fluoropyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(pyridin-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(5-fluoropyridin-2-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(difluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(difluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3-(trifluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3-(difluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(trifluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(trifluoromethoxy)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-fluorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-chlorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-isopropoxyphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,4-difluorophenyl)methanone; 2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-5-carbonyl)benzonitrile; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(methoxymethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-isopropylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-fluoro-2-methylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(chroman-8-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(difluoromethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-methoxy-4-methylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-cyclopropylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-chloropyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-fluoro-2-methoxyphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-(1,1-difluoroethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2-chloropyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,4-dimethylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-chlorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(trifluoromethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-cyclopropylphenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(difluoromethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzofuran-7-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(2,2-difluoroethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(4-(2,2,2-trifluoroethyl)phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,2-difluorobenzo[d][1,3]dioxol-4-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(benzo[d][1,3]dioxol-4-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(3-fluorophenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(2,3-dihydrobenzofuran-4-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(quinolin-8-yl)methanone; 2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-5-carbonyl)-5-methylbenzonitrile; 4-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-5-carbonyl)benzonitrile; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-fluoro-2-methoxypyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-fluoro-4-methylpyridin-3-yl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-(difluoromethyl)pyridin-3-yl)methanone; Cyclopentyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate; Isopropyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate; benzyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate; Phenyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-hydroxy-2-(1-methylcyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methoxy-2-(1-methylcyclopentyl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(2-hydroxyethoxy)phenoxy)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2,2-difluoro-2-(2-fluoropyridin-4-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-(difluoromethoxy)phenoxy)ethan-1-one; 2-(2-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-oxoethoxy)-5-fluoro-3-methoxybenzonitrile; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxypropan-1-one (Enantiomer-1); 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxypropan-1-one (Enantiomer-2); (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(cyclopentyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylpropan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-hydroxy-3-methylbutan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(2-oxaspiro[3.5]nonan-7-yl)ethan-1-one; 3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-3-oxopropanenitrile; (2R)-1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentyl-2-hydroxyethan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(phenyl)methanone; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(6-fluoropyridin-3-yl)methanone; 1-(2'-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4'H-spiro[cyclopropane-1,7'-thiazolo[5,4-c]pyridine]-5'(6'H)-yl)-2-cyclopentylethan-1-one; 1-(2'-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2,3,5,6-tetrahydro-4'H-spiro[pyran-4,7'-thiazolo[5,4-c]pyridin]-5'(6'H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-methylpropan-1-one; (2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,6-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)(phenyl)methanone; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; (S)-2-cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; (R)-2-cyclopentyl-1-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 3,3-dimethyl-1-(2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)butan-1-one; (R)-2-cyclopentyl-1-(2-(2-(hydroxymethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-2-cyclopentylethan-1-one; 1-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-3,3-dimethylbutan-1-one; 2-cyclopentyl-1-(2-(7-hydroxy-3,9-diazabicyclo[3.3.1]nonan-9-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; (S)-2-cyclopentyl-1-(2-(2-(hydroxymethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-((4-fluorobenzyl)sulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-((4-fluorobenzyl)sulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 5-((4-fluorobenzyl)sulfonyl)-2-(piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 5-(benzylsulfonyl)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 5-(benzylsulfonyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine; 2-cyclopentyl-1-(2-(3-isopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-cyclopentyl-1-(2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-cyclopentyl-1-(2-(3-propyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-((S)-chroman-4-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; N-((S)-chroman-4-yl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; N-((R)-chroman-4-yl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(4-fluorophenoxy)-1-(2-(3-isopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(4-ethylpiperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,3-dimethylbutan-1-one; 2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-fluorobenzyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxamide; 2-(4-fluorophenoxy)-1-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 1-(2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-(4-fluorophenoxy)ethan-1-one; 2-(4-fluorophenoxy)-1-(2-(3-propyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one; 2-(4-ethylpiperazin-1-yl)-5-((4-fluorobenzyl)sulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine.

35. 35. A pharmaceutical composition comprising a compound of any one of claims 1-34 or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable excipient.

36. 35. A compound according to any one of claims 17 to 34, or a pharmaceutically acceptable salt or derivative thereof, for use in therapy.

37. A compound or a pharmaceutically acceptable salt or derivative according to any of claims 17-34, or a pharmaceutical composition according to claim 36, 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.

38. A compound or a pharmaceutically acceptable salt or derivative thereof for use according to any of claims 1-16, or a compound or a pharmaceutically acceptable salt or derivative thereof according to claim 37, for use in the treatment or prevention of a disease or disorder mediated by excessive intracellular cyclic AMP signalling.

39. 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 1-34, or a pharmaceutically acceptable salt or derivative thereof.

40. 35. Use of a compound or a pharmaceutically acceptable salt or derivative according to any one of claims 1 to 34 in the manufacture of a medicament for 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 signalling.

41. 41. The method of claim 39 or the use of claim 40, 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.

42. 42. The compound of claim 38, or a pharmaceutically acceptable salt or derivative thereof, or the method or use of any of claims 39-41, 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.

43. A compound or a pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to any one of claims 1 to 16 or 36, 37, 38 or 42, or a method or use according to any one of claims 40 to 43, wherein the disease is cancer, optionally wherein the cancer is prostate cancer.

44. A compound or a pharmaceutically acceptable salt or derivative or a pharmaceutical composition for use according to any one of claims 1 to 16 or 36, 37, 38 or 42, or a method or use according to any one of claims 39 to 42, 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.

45. 45. The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition, or method or use according to claim 44, wherein the disease is: a. Autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), or b. Hyperparathyroidism.

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