Compounds and their use as PDE4 activators - Patent application

Abstract

The present invention relates to compounds of formulas AD, I-IV and Z, their use as activators of the long form cyclic nucleotide phosphodiesterase-4 (PDE4) enzyme (isoforms), and for use in methods of treating or preventing diseases requiring a decrease 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 form were recently disclosed in WO2016151300, WO2018060704, and WO2019193342. Recently, small molecule activators of the PDE4 long 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 form has not yet been reported. Additional structurally distinct small molecule activators of the PDE4 long form are still needed for potential development as therapeutic agents.

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

[0008] Summary of the Invention In a first aspect of the invention, there is provided a compound of formula A, such as 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:

[0009] [ka]

[0010] One of X and Y is S and the other is N; 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; R 2 teeth, (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CHAr, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or (iv) a (C3-8) alkyl group which may be linear, branched, or cyclic, or a combination thereof, wherein the linear portion of said (C3-8) alkyl group may optionally be interrupted by one -O-; In the formula, R 2 is one or more R5 may be substituted with; Each R 3 is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted by one or more halogen, OH or (C1-4)alkoxy; 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 with one or more halogen or OH; R 6 is H or (C1-6) alkyl; n is 0, 1, 2, or 3.

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

[0012] [ka]

[0013] One of X and Y is S and the other is N; Q is C or S(O); R 1a is a 4- to 10-membered non-aromatic, monocyclic, bridged, or bicyclic ring 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 R1aの not at the point of attachment, where R 1a is one or more R 4 optionally substituted with; R 2 teeth (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CHAr, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or (iv) a (C3-8) alkyl group which may be linear, branched, or cyclic, or a combination thereof, wherein the linear portion of said (C3-8) alkyl group may optionally be interrupted by one -O-; In the formula, R 2 is one or more R 5 optionally replaced by; Each R 3 is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted by one or more halogen, OH or (C1-4)alkoxy; 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, (Ci_6)alkyl, (Ci_6)alkoxy, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein said (Ci_6)alkyl and (Ci_6)alkoxy are optionally substituted with one or more halogen or OH; R 6 is H or (C1-6) alkyl; n is 0, 1, 2, or 3. In the formula, R 1a is 4-cyclopentylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, or 4-isopropylpiperazin-1-yl, Q, if present, is C, n is 0, and R 2 is unsubstituted, uninterrupted, straight-chain or branched (C3-6) alkyl or unsubstituted (C3-8) cycloalkyl; The compound is not 2-(1-piperazinyl)-N-propyl-6-benzothiazolecarboxamide, N-(1-methylethyl)-2-(1-piperazinyl)-6-benzothiazolecarboxamide, or N-cyclopropyl-2-(1-piperazinyl)-6-benzothiazolecarboxamide. The uninterrupted (C3-6) alkyl is not interrupted by one -O-.

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

[0015] [ka]

[0016] One of X and Y is S and the other is N; 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; R 2a teeth (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iv) (4-6) cycloalkyl groups; In the formula, R 2a optionally, one or more R 5 is replaced by; Each R 3 is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted by one or more halogen, OH or (C1-4)alkoxy; 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 with one or more halogen or OH; R 6 is H or (C1-6) alkyl; and n is 0, 1, 2, or 3; and In the formula, R 2a is (iv) a (C4-6) cycloalkyl group, it is 5 is replaced by; wherein the compound is not 2-(4-morpholinyl)-N-(1,2,3,4-tetrahydronaphthalenyl)-6-benzothiazolecarboxamide or N-(2,3-dihydro-1H-inden-2-yl)-2-(1H-pyrrol-1-yl)-6-benzothiazolecarboxamide.

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

[0018] [ka]

[0019] One of X and Y is S and the other is N; 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; R 2 teeth (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CHAr, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or (iv) a (C3-8) alkyl group which may be linear, branched, or cyclic, or a combination thereof, wherein the linear portion of said (C3-8) alkyl group may optionally be interrupted by one -O-; In the formula, R 2 is one or more R 5 optionally replaced by; Each R 3is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted by one or more halogen, OH or (C1-4)alkoxy; 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 with one or more halogen or OH; R 6 is H or (C1-6) alkyl; m is 1, 2, or 3; wherein if Q is present and is S(O), then R 1 is not optionally substituted pyrazol-4-yl.

[0020] The compounds described herein are shown in the Examples to activate the PDE4 long chain enzyme.

[0021] 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.

[0022] 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 a disease or disorder that can be improved by activating the long-chain 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.

[0023] Also provided are methods for treating or preventing diseases or disorders 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 diseases or disorders 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.

[0024] 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 activation of 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.

[0025] In certain embodiments of the foregoing aspects, the compounds of the invention are provided for treating or preventing a disease 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 early age type 5 (MODY5), or cardiac hypertrophy. [Brief explanation of the drawings]

[0026] [Figure 1] FIG. 1 shows the dose-dependent activation of the long form of PDE4, PDE4D5, by Example 66 using the method described in Experiment 1. [Figure 2] FIG. 2 shows the inhibition of cyst formation in 3D cultures of m-IMCD3 mouse kidney cells treated with Example 191 using the method described in Experiment 4. [Figure 3] FIG. 3 shows the inhibition of PTH-induced cAMP elevation in the urine of anesthetized rats treated with Example 7 using the method described in Experiment 6.

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

[0028] The examples demonstrate that many compounds of Formula AD, Formula I-IV, and Formula Z can activate the long chain isoform of PDE4. The examples go on to demonstrate that certain test compounds of the present invention do not activate the short chain isoform of PDE4, thereby demonstrating selectivity for activating the long chain isoform of PDE4 over the short chain isoform of PDE4. The examples further demonstrate that compounds of the present invention reduce cAMP-driven cyst formation in an in vitro model of ADPKD. The examples also demonstrate that compounds of the present invention suppress the increase in urinary cAMP levels caused by parathyroid hormone (PTH) in an in vivo model of hyperparathyroidism.

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

[0030] Described herein are compounds of formula AD, I-IV and Z, or pharmaceutically acceptable salts or derivatives thereof. Formula AD, I-IV and Z are exemplified herein. Compounds of formula AD, I-IV and Z, 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 AD, I-IV and Z, 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.

[0031] In the compounds of formula A and formula I, R 1 is a 4-10 membered monocyclic, bridged or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and R 1 is any R greater than or equal to 1 4The 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, 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."

[0032] In embodiment (1) of Formula A or Formula I, R 1 is R 1 (i.e., a ring N atom must be present at a position other than where R is attached to the ring containing X and Y). The remainder may be as defined for Formula A or Formula I, or any of embodiments (5)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0033] In embodiment (2) of Formula A or Formula I, R 1 is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing one ring N heteroatom, two ring N heteroatoms, one ring N heteroatom and one ring O heteroatom, or two ring N heteroatoms and one ring O heteroatom, wherein R 1 is one or more R 4 may be substituted with R 1 can be 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, where R 1 optionally, one or more R 4 can be replaced by R 1 is R 1 and optionally, at least one ring N heteroatom that is not the point of attachment of Formula A. The remainder may be as defined for Formula A or Formula I, or any of embodiments (5)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0034] In embodiment (3) of Formula A or Formula I, R 1 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); a 5-6-membered aromatic monocyclic ring containing one or two ring N heteroatoms; a 7-8-membered saturated bridged ring system containing one or two ring N heteroatoms; or a 9-membered saturated bridged ring system containing two ring N heteroatoms and a ring O heteroatom; or a 7-10-membered saturated, fused, or spiro ring system containing one or two ring N heteroatoms, optionally two ring N heteroatoms; 1 is one or more R 4 and R 1 is optionally 1, 2 or 3 R 4 is replaced by R 1 can 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 5-6-membered aromatic monocyclic ring containing one or two ring N heteroatoms; a 7-8-membered saturated bridged ring system containing one or two ring N heteroatoms; 1 is one or more R 4 and R 1 is optionally 1, 2 or 3 R 4 is replaced by R 1 is R 1 and optionally, at least one ring N heteroatom that is not the point of attachment of Formula A. The remainder may be as defined for Formula A or Formula I, or any of embodiments (5)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0035] In Formula A or Formula I, or any of the options of embodiment (1), (2) or (3), R 1can be a 4-10 membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom (i.e., no ring O heteroatoms); a 6 membered saturated or aromatic monocyclic ring containing one or two ring N heteroatoms, or a 7-8 membered saturated bridged ring system containing one or two ring N heteroatoms; R 1 is any R greater than or equal to 1 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 system containing 1 or 2 ring N heteroatoms, where at least one ring N heteroatom is R 1 does not exist at the connection point of R 1 is one or more R 4 may be substituted with R 1 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 system 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 at the attachment point of R 1 is any one R 4 is replaced by

[0036] R 1 may be a 6-membered saturated or aromatic monocyclic ring containing two ring N heteroatoms, or a 7-8 membered saturated bridged ring system 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 system containing two ring N heteroatoms, and R 1 is any one R 4 and R 1a may be a 7- to 8-membered saturated bridged ring system containing up to two ring N heteroatoms. For example, a bridged piperazine (where R 1a is one R 4 (which may be substituted with).

[0037] In Formula A or Formula I, or any of the alternatives of embodiments (1), (2) or (3), R 1 are piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyridinyl, azetidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 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 is replaced by R 1 may be piperidinyl, piperazinyl, morpholinyl, 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 is optionally substituted with, preferably 1-3 R 4 and preferably one R 4 is optionally replaced by R 1 can be a group of structures:

[0038] [ka]

[0039] [ka]

[0040] R 1is one or more R 4 and R 1 1-3 R 4 may be substituted with R 1 can be a group of structures:

[0041] [ka]

[0042] In the formula, R 1 is one or more R 4 and optionally substituted with R 1 1-3 R 4 It is replaced by R 1 may 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 is optionally substituted with, preferably 1-3 R 4 and preferably one R 4 is optionally replaced by R 1 may be piperidinyl, piperazinyl, or pyridinyl, each of which may be one or more R 4 Optionally substituted with, preferably 1-3 R 4 and preferably one R 4 is optionally replaced by R 1 can be a group of the following structural formulas:

[0043] [ka]

[0044] (wherein Z is CH or N, and R 4 ' is H or R 4 or optionally one R4 R is pyridyl (optionally 3-pyridyl) substituted with 1 may be a 7- to 8-membered saturated bridged ring system containing two ring N heteroatoms, such as:

[0045] [ka]

[0046] For example, it can be the following bridged piperazine:

[0047] [ka]

[0048] The remainder may be as defined for Formula A or Formula I, or any of embodiments (5)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0049] In embodiment (4) of Formula A or Formula I, R 1 is a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; or a 7- to 8-membered saturated bridged ring system containing one or two ring N heteroatoms, and R 1 is one, two or three R 4 In any of the alternatives of embodiment (4), R 1 is R 1 R may contain at least one ring N heteroatom at a point other than the point of attachment of R 1 R may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms. 1 can be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, where R 1 is one R 4 may be substituted with R 1can be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, where R 1 is one or more R 4 may be substituted with R 1 can be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, where R 1 is one R 4 The remainder may be as defined for Formula A or Formula I, or any of embodiments (5)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0050] In Formula A or Formula I, or any of the options of embodiments (1)-(4), 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 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, for example, R 1 When is a bridged six-membered ring, R 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.

[0051] In the compounds of Formula A and Formula I, each R 4are 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.

[0052] In embodiment (5) of Formula A or Formula I, each R 4 are independently halogen, OH, CN, (C1-4)alkyl, (C1-3)alkoxy, (C3-6)cycloalkyl, or -(C1-3)alkylene-(C1-3)alkoxy, wherein the (C1-3)alkyl, (C1-3)alkoxy, (C3-6)cycloalkyl, and -(C1-3)alkylene-(C1-3)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH, and (C1-3)alkoxy. 4 may independently be F, Cl, OH, CN, (Ci_4)alkyl, methoxy, ethoxy, cyclopropyl, or -(CH)-O-(CH)-O-CH. 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 A or Formula I, or any of embodiments (1)-(4) or (8)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0053] In embodiment (6) of Formula A or Formula I, 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 A or Formula I, or any of embodiments (1)-(4) or (8)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0054] In embodiment (7) of Formula A or Formula I, each R 4 are independently halogen, CN, OH, (Ci_2)alkyl, (Ci_6)alkoxy, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_2)alkyl, (Ci_6)alkoxy, and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH, and (Ci_6)alkoxy. 4may independently be F, Cl, OH, (Ci_2)alkyl, methoxy, ethoxy, or -(CH2)2-O-(CH2)2-O-CH3, where the (Ci_2)alkyl is optionally substituted with one or more substituents independently selected from halogen and OH. The remainder may be as defined for Formula A or Formula I, or any of embodiments (1)-(4) or (8)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0055] In Formula A or Formula I, or any of the embodiments (5)-(7), 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 can be anything defined for

[0056] In the compounds of formula A and formula I, R 2 is a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; a 5-7 membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a (C3-8)alkyl group which may be linear, branched, or cyclic, or a combination thereof, wherein the linear portion of said (C3-8)alkyl group may optionally be interrupted by one -O-; 2 is one or more R 5 It will be understood that when an alkyl group is "interrupted" by a heteroatom such as O, the heteroatom is present in addition to the number of carbon atoms in the alkyl group. 2is a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; a 5-7 membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; CH2Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or a (C3-8)alkyl group which may be linear, branched, cyclic, or a combination thereof; 2 is one or more R 5 may be substituted with.

[0057] In the compounds of Formula A and Formula I, 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.

[0058] In embodiment (8) of Formula A or Formula I, each R 5 are independently halogen, OH, CN, (Ci_4)alkyl, or (Ci_4)alkoxy, wherein the (Ci_4)alkyl and (Ci_4)alkoxy groups are optionally substituted with one or more halogen or OH, preferably one or more fluoro or one OH. The remainder may be as defined for Formula A or Formula I, or any of embodiments (1)-(7) or (9)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0059] In embodiment (9) of Formula A or Formula I, R 2 is a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; R 2 is an arbitrary R greater than or equal to 1. 5 It is replaced by R 2R may be a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, where the (C5-7)cycloalkyl is optionally substituted with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl, and (C1-4)alkoxy, and the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN, and halogen, and the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluorines. 2 1-3 R 5 , preferably one R 5 The remainder may be as defined mutatis mutandis for Formula A or Formula I, or any of embodiments (1)-(8) or (17)-(20) of Formula A or Formula I described herein. In any of the alternatives of embodiment (9), R 2 may be optionally substituted with one of halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy.

[0060] In embodiment (10) of Formula A or Formula I, R 2 is 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; R 2 is one or more R 5 may be substituted with R 2R may be a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to 6 aromatic rings or heteroaromatic rings containing 0, 1, or 2 ring N atoms, wherein the 5- to 7-membered non-aromatic heterocyclic ring is optionally substituted on one or more ring carbon atoms with 1-3 substituents independently selected from OH, halogen, (C1-4) alkyl, and (C1-4) alkoxy, wherein the (C1-4) alkyl and (C1-4) alkoxy groups are optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4) alkyl, (C1-4) alkoxy, CN, and halogen, wherein the (C1-4) alkyl and (C1-4) alkoxy groups are optionally substituted with one or more fluoro. 2 1-3 R 5 , preferably one R 5 The remainder may be as defined mutatis mutandis for Formula A or Formula I, or any of embodiments (1)-(8) or (17)-(20) of Formula A or Formula I described herein. In any of the alternatives of embodiment (10), R 2 may be optionally substituted with one of halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy.

[0061] The remainder may be as defined with respect to any aspect or embodiment of Formula A or Formula I described herein, mutatis mutandis.

[0062] In embodiment (11) of Formula A or Formula I, R 2 is CHAr, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms, and R 2 is any R greater than or equal to 1 5 It is replaced by R 5 Substitution by R 2 It will be understood that the -CH2- linker or Ar moiety of R 2R may be CHAr, where Ar is optionally substituted with 1-3 substituents selected from halogen, CN, (C1-4) alkyl, (C1-4) alkoxy, and CH is optionally substituted with (C1-4) alkyl or -(C1-6) alkylene-(C1-6) alkoxy, and the (C1-4) alkyl group is optionally substituted with OH. 2 1-3 R 5 , preferably one R 5 The remainder may be as defined mutatis mutandis for Formula A or Formula I, or any of embodiments (1)-(8) or (17)-(20) of Formula A or Formula I described herein. In any of the alternatives of embodiment (11), R 2 is optionally substituted with one of halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy, wherein said (C1-4) alkyl group is optionally substituted with OH.

[0063] In embodiment (12) of Formula A or Formula I, R 2 is a (C3-8) alkyl group which may be linear, branched, or cyclic, or a combination thereof, and the linear portion of said (C3-8) alkyl group may optionally be interrupted by 1-O-; 2 is optionally one or more R 5 is replaced by R 2 may be a (C3-8) alkyl group, which may be linear, branched, or cyclic, or a combination thereof, where R 2 is one or more R 5 is optionally replaced by R 2 may be a (C4-8) alkyl group which may be linear, branched, or cyclic or a combination thereof; R 2 is one or more R 5 is optionally replaced by R 2 may be a (C4-8) alkyl group which may be linear, branched, or cyclic or a combination thereof, and the linear portion of said (C4-8) alkyl group may optionally be interrupted by one -O-, wherein R2 is one or more R 5 may be substituted with R 2 R may be a (C3-6) alkyl group which may be branched or cyclic and optionally substituted. 2 R may be a branched or cyclic, optionally substituted (C4-6) alkyl group. 2 R may be an optionally substituted (C4-6) cycloalkyl group, preferably an optionally substituted (C5-6) cycloalkyl group. 2 1-3 R 5 , preferably one R 5 R may be cyclohexyl, cyclopentyl, cyclobutyl, or isopropyl, optionally substituted with 2 is optionally 1-3 R 5 It may be cyclohexyl, cyclopentyl or cyclobutyl substituted with R 2 is two or more R 5 It may be a (C4-6)cycloalkyl substituted with

[0064] The remainder may be as defined mutatis mutandis for Formula A or Formula I, or any of embodiments (1)-(8) or (17)-(20) of Formula A or Formula I described herein. In any of the alternatives of embodiment (12), R 2 R may be substituted with one or more halogen, (C1-4)alkoxy, or OH. 2 R may be optionally substituted with one or two halogens or OH. 2 R may be optionally substituted with one OH. 2 is optionally substituted with two or three fluoros, preferably two fluoros, on the same carbon atom. In any of the alternatives of embodiment (12), R 2is optionally substituted on one or more ring carbon atoms with two or three substituents independently selected from OH, halogen, (C1-4) alkyl, (C1-4) alkoxy, and the (C1-4) alkyl and (C1-4) alkoxy groups are optionally substituted with one or more fluoro. 2 may be a (C5-6)cycloalkyl group substituted with two halogen substituents (optionally on one ring carbon atom).

[0065] In embodiment (13) of Formula A or Formula I, R 2 is as defined in embodiment (9), embodiment (10) or embodiment (12) of Formula A or Formula I. 2 may be a (C5-6)cycloalkyl fused to a phenyl ring; a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; or a (C4-6)cycloalkyl; 2 is one or more R 5 may be substituted with R 2 may also be a group of the formula:

[0066] [ka]

[0067] where A is O or CH2, p is 1 or 2; Ph is an optionally present fused phenyl ring, and R 2 is an R of 1 or more 5 (e.g., R of 1 or 2 5 ) optionally substituted with; optionally, when A is O, p is 2, or when A is CH2, p is 1 or 2. A is O or C(R 5 )2 (i.e., two R 5 Ph may be a substituted CH, e.g., CF). Ph may be absent. The remainder may be as defined for Formula A or Formula I, or any of embodiments (1)-(8) or (17)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0068] In embodiment (14) of Formula A or Formula I, R 2 is the base of the formula.

[0069] [ka]

[0070] where A is O or CH2, p is 1, 2, or 3; Ph is an optionally present fused phenyl ring, and R 2 is an R of 1 or more 5 (e.g., 1 or 2 R 5 ) and optionally, when A is O, p is 2, or when A is CH2, p is 1 or 2. A is O or C(R 5 )2 (e.g., CF2). When A is CH2, Ph is preferably present. The remainder may be as defined for Formula A or Formula I, or any of embodiments (1)-(8) or (17)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0071] In embodiment (15) of Formula A or Formula I, R 2 is as defined in embodiment (9), embodiment (10), or embodiment (11) of Formula A or Formula I. The remainder may be as defined mutatis mutandis for Formula A or Formula I, or any of embodiments (1)-(8) or (17)-(20) of Formula A or Formula I described herein.

[0072] In embodiment (16) of Formula A or Formula I, R 2 is as defined in embodiment (10), embodiment (11), or embodiment (12) of Formula A or Formula I. The remainder may be as defined mutatis mutandis for Formula A or Formula I, or for embodiments (1)-(8) or (17)-(20) of Formula A or Formula I described herein.

[0073] In Formula A or Formula I, or any of embodiments (9)-(16), R 2 is one or more R 5 , preferably 1, 2 or 3 R 5 may be substituted with R 2 is one R 5 may be substituted with R 2 There are two R 5 Each R 5 It will be understood that the substituents may be on the same atom or on different atoms as allowed by valence.

[0074] In the compounds of Formula A and Formula I, each R 3 are independently (C1-6)alkyl, (C1-6)alkoxy, CN, or halogen, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more of halogen, OH, or (C1-4)alkoxy; optionally, each R 3 are independently (C1-6) alkyl, (C1-6) alkoxy, CN or halogen, and the (C1-6) alkyl and (C1-6) alkoxy may be substituted with one or more halogens.

[0075] In embodiment (17) of Formula A or Formula I, each R 3 are independently (C1-4) alkyl, (C1-4) alkoxy, CN, or halogen, wherein the (C1-4) alkyl and (C1-4) alkoxy are optionally substituted by one or more halogen, OH, or (C1-4) alkoxy. 3 may independently be (C1-4) alkyl, (C1-4) alkoxy, CN, or halogen, and the (C1-4) alkyl and (C1-4) alkoxy may be substituted with one or more halogens. 3 may independently be —CH, —OCH, CN, halogen, cyclopropyl, or (C)alkyl substituted with OH. 3 may independently be -CH, -OCH, CN, or halogen. 3may independently be —CH or —OCH, and the remainder may be as defined for Formula A or Formula I, or any of embodiments (1)-(16) or (18)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0076] In the compounds of formula A and formula I, n is 0, 1, 2, or 3. In embodiment (18) of Formula A or Formula I, n is 0, 1, or 2. n can be 0 or 1. The remainder can be as defined for Formula A or Formula I, or any of embodiments (1)-(17) or (20) of Formula A or Formula I described herein, mutatis mutandis.

[0077] In embodiment (19) of Formula A or Formula I, n is 1, 2, or 3. n can also be 1. The remainder can be as defined for Formula A or Formula I, or any of embodiments (1)-(17) or (20) of Formula A or Formula I described herein, mutatis mutandis.

[0078] In the compounds of Formula A and Formula I, one of X and Y is S and the other is N. In embodiment (20) of Formula A or Formula I, X is S and Y is N. The remainder of the moieties may be as defined for Formula A or Formula I, or any of embodiments (1)-(19) of Formula A or Formula I described herein, mutatis mutandis.

[0079] In the compounds of formula A, Q is C or S(O). In the compound of formula A, R 6 is H or (C1-6)alkyl (e.g., (C1-3)alkyl such as methyl).

[0080] In embodiment (21) of Formula A or Formula I, X is S, Y is N; R 1is a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 (optionally 2) ring N heteroatoms; or a 7- to 8-membered saturated bridged ring system containing 1 or 2 (optionally 2) ring N heteroatoms, where at least one ring N heteroatom is R 1 is not at the attachment point of R 1 is any one R 4 and optionally R 1 is a 6-membered saturated or aromatic monocyclic ring containing one or two ring N heteroatoms, at least one of which is R 1 is not at the attachment point of R 1 is any one R 4 is replaced by; R 2 teeth, (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocycle containing one O heteroatom, optionally fused to a phenyl ring; In the formula, R 2 is 1 or 2 R 5 may be substituted with; R 3 If present, R 3 is methyl, CN or halogen, optionally methyl; R 4 is, if present, (C1-6) alkyl optionally substituted with OH, (C1-2) alkyl optionally substituted with OH; R, if present, 5 is OH or halo, optionally OH: n is 0 or 1.

[0081] In embodiment (21) of Formula A or Formula I, R 2 may also be a group of the formula:

[0082] [ka]

[0083] where A is O or CH; p is 1 or 2; Ph is an optionally present fused phenyl ring; and R 2 is 1 or 2 R 5 and optionally, when A is O, p is 2, or when A is CH, p is 1 or 2. A is O or C(R 5 )2 (i.e., two R 5 It may be a substituted CH2, e.g., CF2). Ph may be absent.

[0084] In embodiment (21) of Formula A or Formula I, R 2 may also be a group of the formula:

[0085] [ka]

[0086] where A is O or CH2, p is 1, 2, or 3 (optionally 1 or 2); Ph is an optionally present fused phenyl ring, and R 2 is 1 or 2 R 5 and optionally, when A is O, p is 2, or when A is CH, p is 1 or 2. A is O or C(R 5 )2 (i.e., two R 5 It may be a substituted CH2, such as CF2. When A is CH2, it is preferred that Ph is present.

[0087] Embodiments (1) through (4) of Formula A or Formula I can be applied mutatis mutandis to any of the alternatives of embodiment (21) of Formula A or Formula I.

[0088] In embodiment (22) of Formula A or Formula I, R 1 is according to embodiment (4) of Formula A or Formula I, and R 2is according to embodiment (13) of Formula A or Formula I. The remainder is as defined mutatis mutandis with respect to Formula A or Formula I, or any of embodiments (1)-(20) of Formula A or Formula I described herein. R 1 may be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, R 1 is one R 4 may be substituted with R 2 may be according to embodiment (13) of Formula A or Formula I. 1 may be a 7- to 8-membered saturated bridged ring system containing one or two ring N heteroatoms, and R may optionally be one R 4 and R 2 is one or more R 5 may be a (C4-6)cycloalkyl substituted with R 1 may be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, R 1 is one R 4 may be substituted with R 2 is two or more R 5 optionally, R 5 may be a halogen; n may be 0 or 1.

[0089] In embodiment (23) of Formula A or Formula I, R 1 is 4-cyclopentylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, or 4-isopropylpiperazin-1-yl, Q, if present, is C and n is 0; R 2 is not unsubstituted, uninterrupted, straight-chain or branched-chain (C3-6) alkyl or unsubstituted (C3-8) cycloalkyl. The remainder may be as defined for Formula A or Formula I, or any of embodiments (1)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0090] In embodiment (24) of Formula A or Formula I, R 1 is 1-piperazinyl, R 2is not a straight-chain, branched-chain, or cyclic (C3) alkyl group. The remainder may be as defined mutatis mutandis for Formula A or Formula I, or any of embodiments (1)-(20) of Formula A or Formula I described herein. In some embodiments, the compound is not 2-(1-piperazinyl)-N-propyl-6-benzothiazolecarboxamide, N-(1-methylethyl)-2-(1-piperazinyl)-6-benzothiazolecarboxamide, or N-cyclopropyl-2-(1-piperazinyl)-6-benzothiazolecarboxamide.

[0091] In embodiment (25) of Formula A or Formula I, R 1 is 4-morpholinyl, R 2 is not 1,2,3,4-tetrahydro-1-naphthalenyl. The remainder may be as defined mutatis mutandis for Formula A or Formula I, or any of embodiments (1)-(20) of Formula A or Formula I described herein. In some embodiments, the compound is not 2-(4-morpholinyl)-N-(1,2,3,4-tetrahydronaphthalenyl)-6-benzothiazolecarboxamide.

[0092] In embodiment (26) of Formula A or Formula I, when Q is present and is S(O), R 1 is not an optionally substituted pyrazol-4-yl, such as an optionally substituted group:

[0093] [ka]

[0094] The remainder may be as defined for Formula A or Formula I, or any of embodiments (1)-(20) of Formula A or Formula I described herein, mutatis mutandis.

[0095] In embodiment (27) of Formula A or Formula I, R 1is not pyrrol-1-yl. The remainder may be as defined mutatis mutandis for Formula A or Formula I, or any of embodiments (1)-(20) of Formula A or Formula I described herein. In some embodiments, the compound is not N-(2,3-dihydro-1H-inden-2-yl)-2-(1H-pyrrol-1-yl)-6-benzothiazolecarboxamide.

[0096] Q is C and R 6 It will be understood that compounds of formula A where is H correspond to compounds of formula I. Compounds of Formula A and Formula I include compounds of Formula BD and Formulas II-IV. Embodiments (1)-(27) of Formula A or Formula I can be applied mutatis mutandis to Formula BD and Formulas II-IV, respectively.

[0097] Described herein are compounds of Formula B or Formula II, or pharmaceutically acceptable salts or derivatives thereof:

[0098] [ka]

[0099] R 1a is a 4- to 10-membered non-aromatic, monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, wherein at least one ring N heteroatom is selected from the group consisting of R 1a is not at the attachment point of 1a is one or more R 4 may be substituted with;

[0100] X, Y, Q, R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined above for Formula A or Formula I, or any of embodiments (5)-(20) of Formula A or Formula I. In compounds of Formula B or Formula II, R 1a is R 1acontains 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 and Y. 1a must be located at a position that is not the attachment point of

[0101] In embodiment (1) of Formula B or Formula II, R 1a is 4-cyclopentylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, or 4-isopropylpiperazin-1-yl, Q, if present, is C, n is 0, and R 2 is not unsubstituted, straight or branched chain (C3_6) alkyl or unsubstituted (C3_8) cycloalkyl.

[0102] In embodiment (2) of Formula B or Formula II: (i) Each R 4 are independently halogen, CN, OH, (Ci_2)alkyl, (Ci_6)alkoxy, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_2)alkyl, (Ci_6)alkoxy and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; and / or (ii) n is 1, 2, or 3; and / or (iii) R 2 is a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 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; or CH2Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms. ;where R 2 is one or more R 5 may be substituted with.

[0103] In embodiment (3) of Formula B or Formula II, R 1ais 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 O heteroatom, or two ring N heteroatoms and one ring O heteroatom ring, and R 1a is one or more R 4 Optionally substituted with R 1a can be 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, where R 1a is optionally 1 or more R 4 It is replaced by R 1a 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 system containing one or two ring N heteroatoms; or a 9-membered saturated bridged ring system containing two ring N heteroatoms and a ring O-heteroatom; or a 7- to 10-membered saturated, fused, or spiro ring system containing one or two ring N heteroatoms, and R 1a is optionally one or more R 4 , optionally 1, 2 or 3 R 4 is replaced by

[0104] In embodiment (4) of Formula B or Formula II, R 1a 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 is a 7- to 8-membered saturated bridged ring system containing one or two ring N heteroatoms, and R 1a is one or more R 4 , optionally 1, 2 or 3 R 4 may be substituted with R 1a may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, optionally with at least one ring N heteroatom being R 1a It is not at the connection point of R1a may be a 6-membered saturated monocyclic ring containing one or two ring N heteroatoms, and R 1a is one R 4 may be substituted with R 1a may be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, R 1a is one or more R 4 , optionally 1, 2 or 3 R 4 may be substituted with R 1a may be a 7-8 membered saturated bridged ring system containing two ring N heteroatoms, for example, a bridged piperazine such as 3,8-diazabicyclo[3.2.1]octanyl, where R 1a is any one R 4 is replaced by .

[0105] In Formula B or Formula II, or any of the options of embodiment (3) or (4), R 1a 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 may be one or more R 4 and preferably 1 to 3 R 4 and preferably one R 4 may be substituted with R 1a can be a radical of the structure:

[0106] [ka]

[0107] In the formula, R 1a is an R of 1 or more 4 and R 1a 1-3 R 4 and preferably one R 4 may be substituted with R 1amay 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 1a may be piperidinyl or piperazinyl, each of which may be one or more R 4 and is optionally substituted with, preferably 1-3 R 4 and preferably one R 4 is optionally replaced by R 1a can be a radical of the structure:

[0108] [ka]

[0109] where Z is CH or N and R 4 ' is H or R 4 R 1a may be the following 7-8 membered saturated bridged ring system containing two ring N heteroatoms:

[0110] [ka]

[0111] For example, it may be a bridged piperazine such as:

[0112] [ka]

[0113] In Formula B or Formula II, or in either option (3) or (4) of Formula B or Formula II, R 1a is one or more R 4may be optionally substituted with R 1a When R contains a substitutable ring N atom, 1a R can be preferably substituted on a substitutable ring N atom. 1a is one R 4 , preferably on the ring N atom.

[0114] In Formula B or Formula II, or in either option (3) or (4) of Formula B or Formula II, R 1a R can be a 4-10 membered non-aromatic, monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom (i.e., no ring O heteroatoms). 1a may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms; or a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, and R 1a is optionally one or more R 4 is replaced by .

[0115] In embodiment (5) of Formula B or Formula II, the compound is of Formula B′ or B″, or a pharmaceutically acceptable salt or derivative thereof, or a compound of Formula IIa or IIb, or a pharmaceutically acceptable salt or derivative thereof:

[0116] [ka]

[0117] [ka]

[0118] R 1a may be as defined in embodiment (3) or embodiment (4) of Formula B or Formula II.

[0119] Embodiments (1) and (2) of Formula B or Formula II can be applied mutatis mutandis to any of Embodiments (3)-(5) of Formula B or Formula II.

[0120] In embodiment (6) of Formula B or Formula II, X is S, Y is N; R 1a is a 6-membered saturated monocyclic ring containing 1 or 2 (optionally 2) ring N heteroatoms, or a 7-8 membered saturated bridged ring system containing 1 or 2 (optionally 2) ring N heteroatoms, where at least one ring N heteroatom is R 1a is not at the attachment point of R 1a is any one R 4 and optionally R 1a is a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, where at least one ring N heteroatom is R 1a is not at the attachment point of R 1a is any one R 4 is replaced by

[0121] R 2 teeth (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocycle containing one O heteroatom, optionally fused to a phenyl ring; In the formula, R 2 is 1 or 2 R 5 may be substituted with. R 3 If present, R 3 is methyl, CN or halogen, optionally methyl. R 4 If present, R 4 is (C1-6)alkyl optionally substituted with OH, (C1-2)alkyl optionally substituted with OH; R 5 If present, R 5 is OH or halo, optionally OH; and n is 0 or 1.

[0122] In embodiment (6) of Formula B or Formula II, R 2 may be a group of the formula:

[0123] [ka]

[0124] where A is O or CH2, p is 1 or 2; Ph is an optionally present fused phenyl ring, and R 2 is 1 or 2 R 5 optionally substituted with; optionally, when A is O, p is 2, or when A is CH, p is 1 or 2. A is O or C(R 5 )2 (i.e., two R 5 It may be a substituted CH2, e.g., CF2). Ph may be absent.

[0125] Embodiment (1) of Formula B or Formula II can be applied mutatis mutandis to embodiment (6) of Formula B or Formula II.

[0126] In embodiment (7) of Formula B or Formula II, R 1a is according to embodiment (4) of Formula B or Formula II, and R 2 is according to embodiment (13) of Formula A or Formula I. The remainder is as defined mutatis mutandis with respect to Formula B or Formula II, or any of the embodiments of Formula B or Formula II described herein.

[0127] R 1a may be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, R 1a is one R 4 may be substituted with R 2 can be according to Formula A or Formula I, embodiment (13). 1a may be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, R 1a is any one R 4 and R 2 is one or more R 5 R may be a (C4-6)cycloalkyl substituted with 1amay be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, R 1a is one R 4 may be substituted with R 2 is two or more R 5 optionally, R 5 is a halogen; and n is 0 or 1.

[0128] In embodiment (8) of Formula B or Formula II, R 1a is 1-piperazinyl, R 2 is not a straight-chain, branched-chain, or cyclic (C3) alkyl group. The remainder may be as defined mutatis mutandis with respect to Formula B or Formula II, or the embodiments of Formula B or Formula II described herein. In some embodiments, the compound is not 2-(1-piperazinyl)-N-propyl-6-benzothiazolecarboxamide, N-(1-methylethyl)-2-(1-piperazinyl)-6-benzothiazolecarboxamide, or N-cyclopropyl-2-(1-piperazinyl)-6-benzothiazolecarboxamide.

[0129] Described herein is a compound of formula C or a compound of formula III or a pharmaceutically acceptable salt or derivative thereof:

[0130] [ka]

[0131] R 2a teeth (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; or (iv) a (C4-6)cycloalkyl group, optionally a (C5-6)cycloalkyl group; In the formula, R 2a is one or more R 5 may be substituted with; And X, Y, Q, R 1 , R 3 , R 4 , R 5 , R 6 and n is as defined for Formula A or Formula I, or any of embodiments (1)-(8) or (17)-(20) of Formula A or Formula I above; and In the formula, R 2a is (iv) a (C4-6) cycloalkyl group, it is 5 is replaced by .

[0132] In embodiment (1) of Formula C or Formula III, R 2a is a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; R 2a is any R greater than or equal to 1 5 is substituted with R 2a R may be a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, where the (C5-7)cycloalkyl is optionally substituted with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl, and (C1-4)alkoxy, and the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN, and halogen, and the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluorines. 2a 1-3 R 5 , preferably one R 5 In any of the alternatives of embodiment (1), R 2a may be optionally substituted with one of halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy.

[0133] In embodiment (2) of Formula C or Formula III, R 2a is 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; R 2a is one or more R 5 may be substituted with R 2a R can be a 5-7 membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6 membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms, wherein the 5-7 membered non-aromatic heterocyclic ring is optionally substituted on one or more ring carbon atoms with 1-3 substituents independently selected from OH, halogen, (C1-4) alkyl and (C1-4) alkoxy, wherein the (C1-4) alkyl and (C1-4) alkoxy groups are optionally substituted with one or more fluoro, and wherein the 6 membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4) alkyl, (C1-4) alkoxy, CN and halogen, wherein the (C1-4) alkyl and (C1-4) alkoxy are optionally substituted with one or more fluoro. 2a is optionally 1-3 R 5 , preferably one R 5 In any of the alternatives of embodiment (2), R may be a chroman or tetrahydropyran substituted with 2a may be optionally substituted with one of halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy.

[0134] According to embodiment (1) or (2) of Formula C or Formula III, R 2a may be a (C5-6)cycloalkyl fused to a phenyl ring; or may be a 5- to 6-membered heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring, wherein R 2a is optionally substituted.

[0135] In embodiment (3) of Formula C or Formula III, R 2aThere are at least two R 5 R is a (C4-6)cycloalkyl group substituted with 2a For example, two R 5 It may be cyclohexyl, cyclopentyl or cyclobutyl substituted with R 2a There are at least two R 5 R may be a (C5-6)cycloalkyl group substituted with 2a is optionally substituted with two or more halogen, (C1-4)alkoxy, or OH. In any of the alternatives of embodiment (3), R 2a is optionally substituted on one or more ring carbons with two or more independent substituents selected from OH, halogen, (C1-4) alkyl, (C1-4) alkoxy, and the (C1-4) alkyl and (C1-4) alkoxy groups are optionally substituted with one or more fluoro. 2a R may be optionally substituted with 2 or 3 halogens or OH. 2a R may be optionally substituted with two or three halogens, preferably two halogens, preferably on the same carbon atom. 2a may be a (C5-6)cycloalkyl group substituted with two halogen substituents (optionally on one ring carbon atom).

[0136] In embodiment (4) of Formula C or Formula III: X is S, Y is N; R 1 is a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 (optionally 2) ring N heteroatoms, or a 7- to 8-membered saturated bridged ring system containing 1 or 2 (optionally 2) ring N heteroatoms, where at least one ring N heteroatom is selected from the group consisting of R 1 is not at the attachment point of R 1 is any one R 4 and optionally R 1 is a 6-membered saturated or aromatic monocyclic ring containing one or two ring N heteroatoms, at least one of which is R 1 is not at the attachment point of R 1 is any one R 4 is replaced by . R 2a teeth (i) a (C5-6)cycloalkyl fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; or (iv) (C4-6) cycloalkyl groups; In the formula, R 2a is one or two R 5 and R 2a is (iv) a (C4-6) cycloalkyl group, two R 5 is replaced by; R 4 when present, is (C1-6)alkyl optionally substituted with OH, preferably (C1-2)alkyl optionally substituted with OH; R 5 If present, R 5 is OH or halo, optionally OH; and n is 0 or 1.

[0137] According to any of embodiments (1)-(4) of Formula C or Formula III, R 2a may be a group of the formula:

[0138] [ka]

[0139] where A is O or CH; p is 1 or 2; Ph is an optionally present fused phenyl ring; and R 2a is 1 or 2 R 5 and when A is CH2, Ph is present or A is C(R 5 )2 (i.e., CH2, two R 5 optionally, when A is O, p is 2, or when A is CH, p is 1 or 2. Ph may be absent.

[0140] According to any of embodiments (1)-(4) of Formula C or Formula III, R 2a may be a group of the formula:

[0141] [ka]

[0142] where A is O or CH; p is 1, 2, or 3; Ph is an optionally present fused phenyl ring; and R 2a is 1 or 2 R 5 and when A is CH2, Ph is present or A is C(R 5 )2 (e.g., CF2); optionally, when A is O, p is 2, or when A is CH2, p is 1 or 2.

[0143] In embodiment (5) of Formula C or Formula III, the compound is a compound of Formula C' or C'' or a pharmaceutically acceptable salt or derivative thereof, or a compound of Formula IIIa or IIIb or a pharmaceutically acceptable salt or derivative thereof:

[0144] [ka]

[0145] R 2a can be as defined with respect to any of embodiments (1)-(4) of Formula C or Formula III.

[0146] In embodiment (6) of Formula C or Formula III, R 2a is according to embodiment (2) or embodiment (3) of Formula C or Formula III.

[0147] In embodiment (7) of Formula C or Formula III, R 1 is according to embodiment (4) of Formula A or Formula I, and R 2ais according to embodiment (3) of Formula C or Formula III. The remainder may be as defined for Formula C or Formula III, or any of the embodiments of Formula C or Formula III described herein, mutatis mutandis. R 1 may be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, R 1 is one R 4 may be substituted with R 2a R can be according to Formula C or Formula III embodiment (3). 1 may be a 7- to 8-membered saturated bridged ring system containing one or two ring N heteroatoms, where R 1 is any one R 4 Replaced by ;R 2a is two or more R 5 may be (C4-6)cycloalkyl substituted with; R 1 may be a 7-8 membered saturated bridged ring system containing 1 or 2 ring N heteroatoms, R 1 is one R 4 may be substituted with R 2a is two or more R 5 optionally, R 5 may be halogen; n may be 0 or 1.

[0148] In embodiment (8) of Formula C or Formula III, R 1 is 4-morpholinyl, R 2a is not 1,2,3,4-tetrahydro-1-naphthalenyl. The remainder may be as defined mutatis mutandis with respect to Formula C or Formula III, or any embodiment of Formula C or Formula III described herein. In some embodiments, the compound is not 2-(4-morpholinyl)-N-(1,2,3,4-tetrahydronaphthalenyl)-6-benzothiazolecarboxamide.

[0149] In embodiment (9) of Formula C or Formula III, when Q is present and is S(O), R 1is not an optionally substituted pyrazol-4-yl, such as the substituted:

[0150] [ka]

[0151] The remainder may be as defined for Formula C or Formula III, or any of the embodiments of Formula C or Formula III described herein, mutatis mutandis.

[0152] In embodiment (10) of Formula C or Formula III, R 1 is not pyrrol-1-yl. The remainder may be as defined mutatis mutandis with respect to Formula C or Formula III, or the embodiments of Formula C or Formula III described herein. In some embodiments, the compound is not N-(2,3-dihydro-1H-inden-2-yl)-2-(1H-pyrrol-1-yl)-6-benzothiazolecarboxamide.

[0153] In embodiment (11) of Formula C or Formula III, R 1 is pyridine or pyrimidine, R 2a is not tetrahydro-2-furanyl. 1 is pyridine or pyrimidine, R 2a R does not have to be tetrahydrofuran. 2a may not be tetrahydrofuran.

[0154] Described herein are compounds of Formula D or Formula IV, or pharmaceutically acceptable salts or derivatives thereof:

[0155] [ka]

[0156] where m is 1, 2, or 3; and X, Y, Q, R 1 , R 2 , R3 , R 4 , R 5 and R 6 is as defined for Formula A or Formula I, or any of embodiments (1)-(17) or (20) of Formula A or Formula I above.

[0157] In embodiment (1) of Formula D or Formula IV, m is 1 or 2. m can also be 1.

[0158] In some embodiments, when Q is S(O), R 1 is not an optionally substituted pyrazol-4-yl, for example, is not an optionally substituted:

[0159] [ka]

[0160] In embodiment 1(2) of formula D or formula IV, R 1 is not optionally substituted pyrazol-4-yl.

[0161] In embodiment (3) of Formula D or Formula IV, the compound is a compound of Formula D′ or D″, or a pharmaceutically acceptable salt or derivative thereof, or a compound of Formula IVa or IVb, or a pharmaceutically acceptable salt or derivative thereof:

[0162] [ka]

[0163] In embodiment (4) of Formula D or Formula IV, the compound is a compound of Formula D''' or Formula IVc, or a pharmaceutically acceptable salt or derivative thereof:

[0164] [ka]

[0165] Also disclosed herein is a compound of formula Z, or a pharmaceutically acceptable salt or derivative thereof:

[0166] [ka]

[0167] R 2’ and R 6’ together with the N atom to which they are attached form a 4- to 7-membered saturated heterocycle optionally containing one further heteroatom selected from O, wherein the 4- to 7-membered saturated heterocycle is 5 The remaining parts X, Y, Q, and R may be substituted with 1 , R 3 , R 4 , R 5 and n are as defined mutatis mutandis with respect to any of Formula A, B, D, I, II or IV, or to embodiments (1)-(8) or (17)-(20) of Formula A or I described herein, or to any embodiment of Formula B, II, D or IV described herein. 2’ and R 6’ together with the N atom to which they are attached form a 5- to 6-membered saturated heterocycle. In compounds of formula Z, Q is preferably C.

[0168] In further embodiments of the compound of Formula AD, Formula I-IV or Formula Z, or a pharmaceutically acceptable salt thereof (including any of the above embodiments), one or more hydrogen atoms are 2 The remainder applies mutatis mutandis as defined with respect to any aspect or embodiment of Formula AD, Formulas I-IV, or Formula Z described herein.

[0169] In one embodiment, the compound of Formula A or Formula I is selected from: N-(4-chlorobenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-Methoxybenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-fluorobenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(2-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(pyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-benzyl-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-Methoxybenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-chlorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide;

[0170] N-(3-fluorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-Methoxybenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(6-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2,6-dimethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-cyclopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-isopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide;

[0171] (S)-N-(chroman-4-yl)-2-(6-ethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-benzyl-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-Methoxybenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-chlorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-fluorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-Methoxybenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide;

[0172] N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(5-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; 2-(5-methylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-cyclopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-isopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2,4-dimethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(5-chloropyridin-3-yl)-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(pyridin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(3-methylpyridin-4-yl)benzo[d]thiazole-6-carboxamide;

[0173] (S)-N-(chroman-4-yl)-2-(2-methylpyridin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1,4-dimethyl-1H-pyrazol-5-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1,5-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-(difluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-(difluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)benzo[d]thiazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(pyridin-3-yl)benzo[d]thiazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(4-hydroxypiperidin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-morpholinobenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methoxypiperidin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0174] (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperidin-1-yl)benzo[d]thiazole-6-carboxamide; 2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-N-(4-fluorobenzyl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-N-isopropylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(8-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0175] (R)-N-(8-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(7-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(5-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(7-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-cyanochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; S)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0176] (S)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-Methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0177] (S)-N-(6-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(6-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclohexyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-Methoxybenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide;

[0178] N-(4-cyanobenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Isopropyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclohexyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(3,3-difluorocyclobutyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide;

[0179] (S)-N-(2-methoxy-1-phenylethyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2-methoxy-1-phenylethyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2-hydroxy-1-phenylethyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-benzyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-Methoxybenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-cyanobenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-methylbenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-methylpiperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclohexyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide;

[0180] N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Isopropyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(3,3-difluorocyclobutyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2-methoxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2-methoxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2-hydroxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2-hydroxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide;

[0181] (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-(2-hydroxyethyl)piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclohexyl-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-(2-(2-methoxyethoxy)ethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-((S)-piperidin-3-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-((R)-piperidin-3-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-(pyrrolidin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide;

[0182] N-Cyclopentyl-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-Methyl-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)-5-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-5-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-7-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide;

[0183] (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-7-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 5-Methoxy-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-methyl-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; 4-Methyl-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide;

[0184] (S)-N-(chroman-4-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-5-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-5-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-7-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-7-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-4-methoxybenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0185] N-Cyclopentyl-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-5-methoxybenzo[d]thiazole-6-carboxamide; 5-Methoxy-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-5-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4,7-dimethyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-Cyclopropyl-N-isopropyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-cyclopropyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclobutyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclopentyl-2-(4-(3-hydroxypropyl)piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-7-methoxybenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-bromo-N-cyclopentylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-cyano-N-isopropylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide;

[0186] 2-(3-cyclopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamide; 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-(3-fluoropropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4-(1-hydroxypropan-2-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4-(2-hydroxyethyl)benzo[d]thiazole-6-carboxamide; 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide;

[0187] N-Cyclopentyl-2-(4,7-diazaspiro[2.5]octan-7-yl)benzo[d]thiazole-6-carboxamide; N-Cyclohexyl-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2,6-diazaspiro[3.4]octan-6-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2,7-diazaspiro[3.5]nonan-7-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(octahydro-4H-pyrrolo[3,2-b]pyridin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)benzo[d]thiazole-6-carboxamide; N-Cyclohexyl-2-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-methyloctahydro-4H-pyrrolo[3,2-b]pyridin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)benzo[d]thiazole-6-carboxamide;

[0188] (S)-N-(chroman-4-yl)-N-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-N-methyl-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-N-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(pyridin-4-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(pyridin-3-ylmethyl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxycyclopentyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(pyridin-4-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(pyridin-3-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(pyridazin-4-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(2-isopropoxyethyl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(2-(cyclopentyloxy)ethyl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1,2-dimethyl-1H-imidazol-5-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylazetidin-3-yl)benzo[d]thiazole-6-carboxamide; rac-N-cyclopentyl-2-((3S,4R)-3-hydroxy-1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(piperidin-4-yl)benzo[d]thiazole-5-carboxamide;

[0189] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylbenzo[d]thiazole-5-carboxamide; N-Cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-5-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-sulfonamide; N-cyclopentyl-2-(piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-sulfonamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; and pharmaceutically acceptable salts thereof.

[0190] In further embodiments of the compounds of Formula A or Formula I, R 1 can be as defined above in any of the compounds of Formula A or Formula I. In further embodiments of the compounds of Formula A or Formula I, R 2 can be as defined in either the compounds of formula A or formula I above.

[0191] In one embodiment, the compound of Formula B or Formula II is selected from: (S)-N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-N-(4-fluorobenzyl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-N-isopropylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(8-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(8-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0192] (R)-N-(7-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(5-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(7-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-cyanochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0193] (R)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-Methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0194] (R)-N-(6-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclohexyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide;

[0195] N-(4-Methoxybenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-cyanobenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Isopropyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclohexyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(3,3-difluorocyclobutyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide;

[0196] (S)-N-(2-methoxy-1-phenylethyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2-methoxy-1-phenylethyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2-hydroxy-1-phenylethyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-benzyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-Methoxybenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-cyanobenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-methylbenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-methylpiperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide;

[0197] N-cyclohexyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Isopropyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(3,3-difluorocyclobutyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2-methoxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2-methoxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2-hydroxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2-hydroxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide;

[0198] 2-(1-ethylpiperidin-4-yl)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-(2-hydroxyethyl)piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclohexyl-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-(2-(2-methoxyethoxy)ethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-((S)-piperidin-3-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-((R)-piperidin-3-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-(pyrrolidin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide;

[0199] (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-Methyl-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)-5-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-5-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-7-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide;

[0200] (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-7-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 5-Methoxy-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-methyl-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0201] 4-Methyl-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-5-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-5-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-7-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-7-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-4-methoxybenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0202] (S)-N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-5-methoxybenzo[d]thiazole-6-carboxamide; 5-Methoxy-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-5-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4,7-dimethyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-Cyclopropyl-N-isopropyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-cyclopropyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclobutyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclopentyl-2-(4-(3-hydroxypropyl)piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-7-methoxybenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-bromo-N-cyclopentylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-cyano-N-isopropylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide;

[0203] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; 2-(3-cyclopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamide; 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-(3-fluoropropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4-(1-hydroxypropan-2-yl)benzo[d]thiazole-6-carboxamide;

[0204] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4-(2-hydroxyethyl)benzo[d]thiazole-6-carboxamide; 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4,7-diazaspiro[2.5]octan-7-yl)benzo[d]thiazole-6-carboxamide; N-Cyclohexyl-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2,6-diazaspiro[3.4]octan-6-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2,7-diazaspiro[3.5]nonan-7-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(octahydro-4H-pyrrolo[3,2-b]pyridin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)benzo[d]thiazole-6-carboxamide; N-Cyclohexyl-2-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)benzo[d]thiazole-6-carboxamide;

[0205] N-Cyclopentyl-2-(1-methyloctahydro-4H-pyrrolo[3,2-b]pyridin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-N-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-N-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(pyridin-4-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(pyridin-3-ylmethyl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxycyclopentyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(pyridin-4-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(pyridin-3-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(pyridazin-4-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(2-isopropoxyethyl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(2-(cyclopentyloxy)ethyl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylazetidin-3-yl)benzo[d]thiazole-6-carboxamide; rac-N-cyclopentyl-2-((3S,4R)-3-hydroxy-1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(piperidin-4-yl)benzo[d]thiazole-5-carboxamide;

[0206] 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylbenzo[d]thiazole-5-carboxamide; N-Cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-5-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-sulfonamide; N-cyclopentyl-2-(piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-sulfonamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; and pharmaceutically acceptable salts thereof.

[0207] In one embodiment, the compound of Formula C or Formula III is selected from: (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(2-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(6-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2,6-dimethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-cyclopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-isopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-ethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide;

[0208] (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(5-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; 2-(5-methylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-cyclopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-isopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide;

[0209] (S)-N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2,4-dimethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(5-chloropyridin-3-yl)-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(pyridin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(3-methylpyridin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2-methylpyridin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1,4-dimethyl-1H-pyrazol-5-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1,5-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-(difluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-(difluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)benzo[d]thiazole-5-carboxamide;

[0210] (S)-N-(chroman-4-yl)-2-(pyridin-3-yl)benzo[d]thiazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(4-hydroxypiperidin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-morpholinobenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methoxypiperidin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperidin-1-yl)benzo[d]thiazole-6-carboxamide; 2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0211] (R)-N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(8-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(8-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(7-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(5-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(7-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-cyanochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0212] (R)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(7-Methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0213] (R)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(6-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(6-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide;

[0214] N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(3,3-difluorocyclobutyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-methylpiperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(3,3-difluorocyclobutyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide;

[0215] 2-(1-ethylpiperidin-4-yl)-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-(2-hydroxyethyl)piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-(2-(2-methoxyethoxy)ethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-((S)-piperidin-3-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-((R)-piperidin-3-yl)benzo[d]thiazole-6-carboxamide;

[0216] N-((S)-chroman-4-yl)-2-(pyrrolidin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; 4-Methyl-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-5-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-7-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide;

[0217] 5-Methoxy-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; 4-Methyl-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-5-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0218] 5-Methoxy-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-5-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4,7-dimethyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; 2-(3-cyclopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide;

[0219] N-(4,4-difluorocyclohexyl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-(3-fluoropropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide;

[0220] (S)-N-(chroman-4-yl)-N-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-N-methyl-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; and pharmaceutically acceptable salts thereof.

[0221] In one embodiment, the compound of formula D or formula IV is selected from: (S)—N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-Methyl-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide;

[0222] (S)-N-(chroman-4-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)-5-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-5-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-7-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-7-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide;

[0223] 5-Methoxy-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-methyl-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methyl-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; 4-Methyl-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-5-methylbenzo[d]thiazole-6-carboxamide;

[0224] (S)-N-(chroman-4-yl)-5-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-5-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-7-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-7-methylbenzo[d]thiazole-6-carboxamide; N-Cyclopentyl-4-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-4-methoxybenzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-4-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)-5-methoxybenzo[d]thiazole-6-carboxamide; 5-Methoxy-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-5-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)-N-(chroman-4-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide;

[0225] (S)-N-(chroman-4-yl)-4,7-dimethyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-Cyclopropyl-N-isopropyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-cyclopropyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclobutyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclopentyl-2-(4-(3-hydroxypropyl)piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-7-methoxybenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-bromo-N-cyclopentylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-cyano-N-isopropylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4-(1-hydroxypropan-2-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4-(2-hydroxyethyl)benzo[d]thiazole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0226] The compound of formula Z described herein is (2-(piperazin-1-yl)benzo[d]thiazol-6-yl)(pyrrolidin-1-yl)methanone; (2-(piperidin-4-yl)benzo[d]thiazol-6-yl)(pyrrolidin-1-yl)methanone; Morpholino(2-(piperidin-4-yl)benzo[d]thiazol-6-yl)methanone; and pharmaceutically acceptable salts thereof.

[0227] Further aspects and embodiments are described in the following numbered clauses. Paragraph 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 chain isoform of PDE4:

[0228] [ka]

[0229] One of X and Y is S and the other is N. 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; R 2 teeth (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CHAr, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or (iv) a (C3-8) alkyl group which may be linear, branched, or cyclic, or a combination thereof; In the formula, R 2 is one or more R 5 may be substituted with; Each R 3 is independently (C1-6) alkyl, (C1-6) alkoxy, CN or halogen, wherein the (C1-6) alkyl and (C1-6) alkoxy may be substituted with one or more halogens; 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, (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; and n is 0, 1, 2, or 3.

[0230] Item 2: A compound according to item 1, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; or is a 7- to 8-membered saturated bridged ring containing one or two ring N heteroatoms; 1 is one, two or three R 4 may be substituted with.

[0231] Item 3: A compound according to item 1 or 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 is a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, and at least one ring N heteroatom is R 1 is not at the attachment point of R 1 is any one R 4 is replaced by

[0232] Section 4: R 2 A compound according to any preceding claim, or a pharmaceutically acceptable salt or derivative thereof, wherein: (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, wherein the (C5-7)cycloalkyl is optionally substituted with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl, and (C1-4)alkoxy, wherein the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluoro, and wherein the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN, and halogen, and wherein the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluorines; (ii) a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, wherein the 5- to 7-membered non-aromatic heterocyclic ring is optionally substituted on one or more ring carbon atoms with one or more 1-3 substituents independently selected from OH, halogen, (Ci_4) alkyl, and (Ci_4) alkoxy, wherein the (Ci_4) alkyl and (Ci_4) alkoxy groups are optionally substituted with one or more fluoro, and wherein the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (Ci_4) alkyl, (Ci_4) alkoxy, CN, and (Ci_4) alkoxy, CN, and wherein the (Ci_4) alkyl and (Ci_4) alkoxy groups are optionally substituted with one or more fluoro; (iii) CH2Ar, where Ar is optionally substituted with 1-3 substituents selected from halogen, CN, (C1-4)alkyl, (C1-4)alkoxy, and CH2 is optionally substituted with (C1-4)alkyl, wherein the (C1-4)alkyl group is optionally substituted with OH or (C1-4)alkyloxy; or (iv) A (C3-8) alkyl group which may be linear, branched or cyclic, or a combination thereof, and which is optionally substituted with one or more halogen, (C1-4) alkoxy, or OH.

[0233] Section 5: R 2 A compound according to any preceding claim, or a pharmaceutically acceptable salt or derivative thereof, wherein: (i) (C5-6)cycloalkyl fused to a phenyl ring; (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; or (iii) (C4-6)cycloalkyl; In the formula, R 2 is one or more R 5 may be substituted with.

[0234] Section 6: R 2 A compound according to any preceding claim, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0235] [ka]

[0236] where A is O or CH2 and p is 1, 2 or 3. Ph is an optionally present fused phenyl ring and R 2 is optionally substituted with one substituent, and optionally, when A is O, p is 2, or when A is CH2, p is 1 or 2.

[0237] Section 7: Each R 3 are independently -CH3 or -OCH3, or a pharmaceutically acceptable salt or derivative thereof.

[0238] Item 8: A compound according to any of the preceding items, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0, 1 or 2, preferably 0 or 1.

[0239] Paragraph 9: A compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt or derivative thereof, wherein said compound is:

[0240] [ka]

[0241] Item 10: A compound according to any preceding item, or a pharmaceutically acceptable salt or derivative thereof, wherein X is S and Y is N.

[0242] Item 11: A compound according to any preceding item, or a pharmaceutically acceptable salt or derivative thereof, X is S, Y is N; R 1 is a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, at least one of which is R 1 is not at the attachment point of R 1 is one R 4 optionally replaced by; R 2 teeth (i) (C5-6)cycloalkyl optionally fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; In the formula, R 2 is one R 5 may be substituted with; R 3 If there is R 3 is methyl; R 4 is, if present, (C1-6) alkyl optionally substituted with OH; R 5 If there is R 5 is OH; and n is 0 or 1.

[0243] Item 12: A compound of formula II or a pharmaceutically acceptable salt or derivative thereof;

[0244] [ka]

[0245] One of X and Y is S and the other is N; R 1a is a 4- to 10-membered non-aromatic, monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom, wherein at least one ring N heteroatom is selected from the group consisting of R 1a is not at the attachment point of 1a is one or more R 4 may be substituted with; R 2 teeth (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CHAr, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or (iv) a (C3-8) alkyl group which may be linear, branched, cyclic, or a combination thereof; In the formula, R 2 is one or more R 5 may be substituted with; Each R 3 are independently (C1-6) alkyl, (C1-6) alkoxy, CN or halogen, wherein the (C1-6) alkyl and (C1-6) alkoxy are optionally substituted with one or more halogens; 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, (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; and n is 0, 1, 2, or 3; In the formula, R 1a is 4-cyclopentylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, or 4-isopropylpiperazin-1-yl, and n is 0, then R 2 is not unsubstituted straight or branched chain (C3_6) alkyl or unsubstituted (C3_8) cycloalkyl.

[0246] Item 13: A compound according to item 12, or a pharmaceutically acceptable salt or derivative thereof: a) Each R 4 are independently halogen, CN, OH, (Ci_2)alkyl, (Ci_6)alkoxy, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_2)alkyl, (Ci_6)alkoxy and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy; and / or b) n is 1, 2, or 3; and / or c) R 2 is (C5-7)cycloalkyl, fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 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; or CH2Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; 2 is one or more R 5 may be substituted with.

[0247] Item 14: A compound according to item 12 or 13, or a pharmaceutically acceptable salt or derivative thereof; R 1a is a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; or is a 7- to 8-membered saturated bridged ring containing one or two ring N heteroatoms; where R 1a is 1, 2 or 3 R 4 is optionally replaced by

[0248] Item 15: A compound according to any one of items 12 to 14, or a pharmaceutically acceptable salt or derivative thereof; wherein R 1a is a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, and R 1a is any one R 4 is replaced by .

[0249] Section 16: R 2 A compound according to any one of items 12 to 15, or a pharmaceutically acceptable salt or derivative thereof, wherein: (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, wherein the (C5-7)cycloalkyl is optionally substituted with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl, and (C1-4)alkoxy, wherein the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluoro, and wherein the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN, and halogen, wherein the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluorines; (ii) a 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, wherein the 5- to 7-membered heterocyclic ring is optionally substituted on one or more ring carbon atoms with 1-3 substituents independently selected from OH, halogen, (Ci_4) alkyl, (Ci_4) alkoxy, wherein the (Ci_4) alkyl and (Ci_4) alkoxy groups are optionally substituted with one or more fluoro, and wherein the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (Ci_4) alkyl(Ci_4) alkoxy, CN, and halogen, wherein the (Ci_4) alkyl and (Ci_4) alkoxy groups are optionally substituted with one or more fluoro; (iii) CH2Ar, where Ar is optionally substituted with 1-3 substituents selected from halogen, CN, (C1-4)alkyl, (C1-4)alkoxy, and CH2 is optionally substituted with (C1-4)alkyl, where the (C1-4)alkyl group is optionally substituted with OH or (C1-4)alkyloxy; or (iv) (C3-8) alkyl groups which may be linear, branched or cyclic, or combinations thereof, optionally substituted with one or more halogen, OH, or (C1-4) alkoxy.

[0250] Section 17: R 2 17. The compound of any one of items 12 to 16, or a pharmaceutically acceptable salt or derivative thereof, wherein: (i) (C5-6)cycloalkyl fused to a phenyl ring; (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; or (iii) (C4-6)cycloalkyl; In the formula, R 2 is one or more R 5 may be substituted with.

[0251] Section 18: R 218. The compound according to any one of paragraphs 12-17, or a pharmaceutically acceptable salt or derivative thereof, wherein:

[0252] [ka]

[0253] where A is O or CH, p is 1, 2, or 3; Ph is an optionally present fused phenyl ring, and R 2 is optionally substituted with one substituent, and optionally, when A is O, p is 2, or when A is CH2, p is 1 or 2.

[0254] Item 19: A compound according to any one of items 12 to 18, or a pharmaceutically acceptable salt or derivative thereof; X is S and Y is N. R 1a is a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, at least one of which is R 1a is not at the attachment point of R 1a is one R 4 may be substituted with R 2 teeth (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; In the formula, R 2 is one R 5 may be substituted with; R 3 If there is R 3 is methyl; R 4 is, if present, (C1-6) alkyl optionally substituted with OH; R 5 If present, R 5 is OH; and n is 0 or 1.

[0255] Item 20: A compound of formula III or a pharmaceutically acceptable salt or derivative thereof;

[0256] [ka]

[0257] One of X and Y is S and the other is N; 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; R 2a teeth (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; In the formula, R 2a is one or more R 5 may be substituted with; Each R 3 is independently (C1-6) alkyl, (C1-6) alkoxy, CN or halogen, wherein the (C1-6) alkyl and (C1-6) alkoxy may be substituted with one or more halogens; 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, (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; and n is 0, 1, 2, or 3.

[0258] Item 21: A compound according to any one of items 12 to 20, or a pharmaceutically acceptable salt or derivative thereof, wherein n is 0, 1 or 2, optionally wherein n is 0 or 1.

[0259] Item 22: A compound of formula IV or a pharmaceutically acceptable salt or derivative thereof;

[0260] [ka]

[0261] One of X and Y is S and the other is N; 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; R 2 teeth (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CHAr, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or (iv) a (C3-8) alkyl group which may be linear, branched, or cyclic, or a combination thereof; In the formula, R 2 is one or more R5 may be substituted with; Each R 3 are independently (C1-6) alkyl, (C1-6) alkoxy, CN or halogen, wherein the (C1-6) alkyl and (C1-6) alkoxy are optionally substituted with one or more halogens; 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; and 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; and n is 1, 2, or 3.

[0262] Item 23: The compound according to item 22, or a pharmaceutically acceptable salt or derivative thereof, wherein the compound is a compound derivative of formula IVa or IVb;

[0263] [ka]

[0264] Section 24: Each R 3 is independently -CH3 or -OCH3, or a pharmaceutically acceptable salt or derivative thereof.

[0265] Section 25: R 2 or R 2aA compound according to any one of paragraphs 12-24, or a pharmaceutically acceptable salt or derivative thereof, wherein: (i) a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, wherein the (C5-7)cycloalkyl is optionally substituted with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl, (C1-4)alkoxy, and wherein the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluoro, and wherein the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN, and halogen, and wherein the (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluorines; (ii) A 5- to 7-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, wherein the 5- to 7-membered non-aromatic heterocyclic ring is optionally substituted on one or more ring carbon atoms with 1-3 substituents independently selected from OH, halogen, (C1-4) alkyl, and (C1-4) alkoxy, wherein the (C1-4) alkyl and (C1-4) alkoxy groups are optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4) alkyl, (C1-4) alkoxy, CN, and halogen, wherein the (C1-4) alkyl and (C1-4) alkoxy groups are optionally substituted with one or more fluoro.

[0266] Section 26: R 2 or R 2a A compound according to any one of items 12-25, or a pharmaceutically acceptable salt or derivative thereof, wherein: (i) a (C5-6)cycloalkyl fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocyclic ring containing one ring O heteroatom, optionally fused to a phenyl ring; In the formula, R 2 or R 2a is optionally substituted.

[0267] Section 27: R 2 or R 2a is the following formula: or a pharmaceutically acceptable salt or derivative thereof;

[0268] [ka]

[0269] where A is O or CH, p is 1, 2, or 3; Ph is an optionally present fused phenyl ring, and R 2 or R 2a is optionally substituted with one substituent, and when A is CH, Ph is present; optionally, when A is O, p is 2, or when A is CH, p is 1 or 2.

[0270] Item 28: A compound according to item 20, or a pharmaceutically acceptable salt or derivative thereof; X is S, Y is N; R 1 is a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, at least one of which is R 1 is not at the attachment point of R 1 is one R 4 optionally replaced by; R 2a teeth (i) a (C5-6)cycloalkyl fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring; In the formula, R 2a is one R 5 may be substituted with; R 4 is, if present, (C1-6) alkyl optionally substituted with OH; R5 If present, R 5 is OH; and n is 0.

[0271] Item 29: A compound according to any one of items 20-28, or a pharmaceutically acceptable salt or derivative thereof; R 1 is a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; a 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; R 1 is one, two or three R 4 is optionally replaced by

[0272] Item 30: A compound according to any one of items 20-29, or a pharmaceutically acceptable salt or derivative thereof; R 1 is a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, and at least one ring N heteroatom is R 1 is not at the attachment point of R 1 is any one R 4 is replaced by

[0273] Item 31: The compound according to any one of items 12-30, or a pharmaceutically acceptable salt or derivative thereof, wherein X is S and Y is N.

[0274] Section 32: A pharmaceutical composition comprising a compound as defined in any of Articles 1 to 31 or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable excipient.

[0275] Item 33: A compound, pharmaceutically acceptable salt or derivative of any of items 12-31 for use in therapy.

[0276] Item 34: A compound or a pharmaceutically acceptable salt or derivative of any of items 12-31, or a pharmaceutical composition according to item 32, for use in the treatment or prevention of a disease or disorder that can be ameliorated by activation of the long chain isoform of PDE4.

[0277] Item 35: A compound or a pharmaceutically acceptable salt or derivative of any of items 1 to 11, or a pharmaceutical composition of item 34, for use in the treatment or prevention of a disease or disorder mediated by excessive intracellular cyclic AMP signaling.

[0278] Clause 36: Use of a compound, pharmaceutically acceptable salt, derivative, or pharmaceutical composition according to clause 35, wherein excessive intracellular cyclic AMP signaling is caused by: Excessive hormone levels produced by the adenoma; bGain-of-function genetic mutations in G protein-coupled receptors (GPCRs); an activating mutation in the GNAS1 gene, which encodes the α subunit of the cG protein Gs; or D. Bacterial toxins.

[0279] Item 37: Use of a compound, pharmaceutically acceptable salt, derivative, or pharmaceutical composition according to any one of items 1-11 or 34-36, wherein the disease is cancer.

[0280] Item 38: Use of a compound, pharmaceutically acceptable salt, derivative, or pharmaceutical composition for use according to item 37, wherein the cancer is prostate cancer.

[0281] Paragraph 39: Use of a compound, pharmaceutically acceptable salt, derivative, or pharmaceutical composition according to any of paragraphs 1-11 or 34-36, in the treatment of a disease comprising: 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, adrenal cortical tumor, testicular cancer, primary pigmented nodular adrenocortical disease (PPNAD) or Cannibalism 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.

[0282] Paragraph 40: Use of a compound, pharmaceutically acceptable salt, derivative, or pharmaceutical composition for use according to paragraph 39, wherein the disease is: a. Autosomal dominant polycystic kidney disease (ADPKD); or b. Autosomal recessive polycystic kidney disease (ARPKD).

[0283] Article 41: Use of a compound, pharmaceutically acceptable salt, derivative, or pharmaceutical composition according to Article 39, wherein the disease is hyperparathyroidism.

[0284] 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.

[0285] 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 carbocyclic or heterocyclic rings 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 ring systems 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. For example, a bridged ring system may exist where two rings share two adjacent atoms, e.g., two rings share three or more adjacent atoms, or a spiro ring system may exist where 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. The bridged ring 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 spirocyclic ring systems 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.

[0286] "Monocyclic, bridged, or bicyclic ring" includes monocyclic rings, bridged ring systems, 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] The term "halogen" means F, Cl, Br or I. F and Cl are particularly preferred, with F being most preferred.

[0292] 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).

[0293] 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.

[0294] 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 wishing to be 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), the introduction of protein-protein complexes associated with a particular physiological location, or the context of a cellular or biochemical assay. 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. This allows rapid diffusion across the cell membrane and allows it to reach the site of action within the cell (Veber, DF et al., J. Med. Chem. 45: 2615-2623, 2002). Particularly preferred small molecule activators according to the present invention have a molecular weight of 250 daltons or more and 500 daltons or less (Lipinski, CA Drug Discovery Today: Technologies 1: 337-341, 2004).

[0295] 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).

[0296] 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) of 30% or greater 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) of 30% or greater at concentrations of 10 micromolar or less, e.g., 3 micromolar.

[0297] 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).

[0298] Under the same assay conditions, as described in Experiment 1, compounds of the present invention produce less than a 30% increase in background activity of short or ultrashort forms of the PDE4A, PDE4B, PDE4C or PDE4D enzymes at test compound concentrations of 100 micromolar or less.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] The following examples illustrate the analysis of compound activity of human PDE4D5 and PDE4C3 long isoforms and the lack of activity of human PDE4B2 short isoforms. 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

[0303] [Table 1]

[0304] *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

[0305] Table B - Examples of known PDE4B isoforms

[0306] [Table 2]

[0307] Table C - Examples of known PDE4C isoforms

[0308] [Table 3]

[0309] Table D - Examples of known PDE4D isoforms

[0310] [Table 4]

[0311] 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).

[0312] 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).

[0313] 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.

[0314] 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.

[0315] Diseases that are ameliorated by activation of the long isoform of PDE4 or that are characterized by elevated cAMP levels

[0316] 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).

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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).

[0324] 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.

[0325] 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.

[0326] 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).

[0327] Therefore, the PDE4 long form activators of the present invention are expected to be effective in treating, preventing or partially controlling polycystic kidney disease.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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:

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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).

[0338] 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.

[0339] 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.

[0340] 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.

[0341] 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.

[0342] 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.

[0343] 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).

[0344] 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).

[0345] 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.

[0346] 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).

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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).

[0353] 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).

[0354] 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).

[0355] 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).

[0356] 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).

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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.

[0364] 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.

[0365] Treatment method The compounds described herein can be used to treat or prevent diseases or disorders that can be improved by activating the long-chain isoform of PDE4.The compounds described herein can be used to treat or prevent diseases or disorders mediated by excessive intracellular cyclic AMP signaling.In a further aspect, the present invention provides a small molecule activator of the long-chain isoform of PDE4 described herein for use in a method for treating or preventing a disease or disorder in a patient in need of treatment.The present invention also provides a method for treating or preventing a disease or disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound described herein.The present invention provides a method for treating or preventing a disease or disorder that can be improved by activating the long-chain isoform of PDE4, comprising administering to the patient in need thereof a therapeutically effective amount of any compound described herein or a pharmaceutically acceptable salt or derivative.The present invention provides a method for treating or preventing a disease or disorder mediated by excessive intracellular cyclic AMP signaling, comprising administering to the patient in need thereof a therapeutically effective amount of any compound described herein or a pharmaceutically acceptable salt or derivative.The diseases or disorders include diseases associated with increased cAMP production and signaling (e.g., hyperthyroidism, Janssen's metaphyseal chondrodysplasia, hyperparathyroidism, familial male-limited precocious puberty, pituitary adenoma, Cushing's disease, polycystic kidney disease, polycystic liver disease, MODY5, cardiac hypertrophy); diseases known to be associated with increased cAMP-mediated signaling, including diseases associated with activating mutations in the α subunit of G protein (GNAS1), such as McCune-Albright syndrome; ameliorating toxin-induced increases in adenylyl cyclase activity in infectious diseases (e.g., cholera, pertussis, anthrax, tuberculosis); treating diseases known to depend on PKA activation by cAMP elevation (e.g., HIV infection, AIDS, common variable immunodeficiency (CVID)); treating diseases known to depend on activation of Epac1 and / or Epac2 by cAMP elevation (e.g., melanoma and pancreatic cancer); and treating diseases dependent on the regulation of cAMP-gated ion channels by cAMP elevation. Treatment of diseases known to be associated with increased activity of cAMP response element binding proteins (e.g., leukemia and prostate cancer); treatment of diseases known to be associated with decreased activity of cAMP-hydrolyzing PDE enzymes (e.g., adrenocortical tumors, testicular cancer, primary pigmented nodular adrenocortical disease (PPNAD) and Carney complex); mimicking or enhancing the effects of drugs known to produce their therapeutic effect through a reduction in intracellular cAMP levels.

[0366] As used herein, the terms "compounds of the invention," "disclosed compounds," "compounds described herein," "compounds of Formula I," and the like, encompass pharmaceutically acceptable salts, derivatives, polymorphs, isomers (e.g., stereoisomers and tautomers), and isotopically labeled variations thereof. For example, compounds of Formula I encompass pharmaceutically acceptable salts thereof. Furthermore, these terms encompass sub-embodiments of the disclosed compounds, including Formulas AD, I-IV, and Z, and embodiments thereof.

[0367] The compounds described herein may be provided as solvates, for example, hydrates.

[0368] 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.

[0369] 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 sulfuric 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.

[0370] 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.

[0371] 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).

[0372] Prodrug The compounds of the present invention can be provided as prodrugs. Prodrugs are derivatives of the compounds of formula I (which may themselves have little or no pharmacological activity) and are compounds that can be converted into compounds of formula I when applied in vivo.

[0373] Prodrugs can be produced, for example, by substituting a functional group in a compound of Formula I at a suitable site that is metabolized in vivo to form a compound of Formula I. 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.

[0374] In vivo metabolism of prodrugs of compounds of Formula I includes, for example, hydrolysis, oxidative metabolism, or reductive metabolism of the prodrug. Examples of prodrugs of compounds of Formula I are amides and esters of those compounds that are hydrolyzed in vivo. For example, if a compound of Formula I contains a carboxylic acid group (—COOH), a hydrogen atom of the carboxylic acid group can be substituted to form an ester group (e.g., by substituting a 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). Further examples of prodrugs of compounds of formula I include pyridine N-oxides, which are reductively metabolized in vivo to form compounds of formula I having a pyridine ring.

[0375] 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).

[0376] 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.

[0377] 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.

[0378] 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. 35 For example, isotopically labeled compounds, e.g., those incorporating radioisotopes, are useful for drug and / or substrate biodistribution studies. 3 H and14 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.

[0379] 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)].

[0380] 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.

[0381] 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).

[0382] 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).

[0383] The pharmaceutical composition may further comprise an adjuvant and / or one or more additional therapeutically active agents.

[0384] 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.

[0385] 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.

[0386] For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions, and the like.

[0387] 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.

[0388] 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.

[0389] 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.

[0390] 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).

[0391] Tablet formulations are discussed in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets 1980, vol. 1 (Marcel Dekker, New York).

[0392] 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.

[0393] 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.

[0394] 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.

[0395] 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)).

[0396] 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.

[0397] 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.

[0398] 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.

[0399] 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.

[0400] 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.

[0401] 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.

[0402] 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.

[0403] 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.

[0404] 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.

[0405] 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.

[0406] 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.

[0407] 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.

[0408] 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.

[0409] 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.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] Example The invention is further described by the following non-limiting examples, and tables and figures: Table 1 shows the structures of small molecule PDE4 long chain conformation activators according to the present invention, Examples 1-292. Table 2 shows the enzyme assay data for PDE4D5, the long form of PDE4. Table 3 shows enzyme assay data for another long chain form of PDE4, PDE4C3. Table 4 shows the enzyme assay data for PDE4B2, the truncated form of PDE4. Table 5 shows the inhibition of PGE2-stimulated cyst formation in 3D cultures of m-IMCD3 kidney cells treated with compounds of the invention. Table 6 shows the inhibition of PGE2-stimulated cyst formation in 3D cultures of MDCK kidney cells treated with compounds of the invention. Table 7 shows the reduction in cAMP levels in m-IMCD3 kidney cell cultures treated with compounds of the invention.

[0414] FIG. 1 shows the concentration-dependent activation of the PDE4 long form PDE4D5 by Example 66. FIG. 2 shows concentration-dependent inhibition of PGE2-stimulated cyst formation in 3D cultures of m-IMCD3 cells treated with Example 191. FIG. 3 shows the inhibition of PTH-induced cAMP elevation in rat urine by Example 7.

[0415] Experiment details Preparation of Examples 1-292 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® using prepacked silica gel columns. NMR spectra were recorded at 25°C using a Bruke® 300 or 400 MHz spectrometer, using the residual signal of the deuterated solvent as an internal reference. Exchangeable NH and OH residues were occasionally 1 The H NMR spectrum was indistinguishable. The following abbreviations are used in the experimental details: CDI (1,1'-carbonyldiimidazole), DCM (dichloromethane), DIPEA (N,N-diisopropylethylamine), DMF (dimethylformamide), EDC (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide), h (hours), HOBt (hydroxybenzotriazole), rt (room temperature), SEM [2-(trimethylsilyl)ethoxymethyl], SFC (supercritical fluid chromatography), TBDPS (tert-butyldiphenylsilyl), THF (tetrahydrofuran). The following abbreviations are used for the assignment of NMR signals: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), app. (approximate), br. (broad), dd (double doublet), dt (double triplet), td (triple doublet).

[0416] General Procedure 1: Synthesis of Chiral Amines

[0417] [ka]

[0418] (In the above schemes, when utilized to synthesize compounds of formula I, it will be understood that Z can be C or N, A can be C or a heteroatom (e.g., O), p is 1 or 2, and R' is absent or represents one or more substituents suitable to provide compounds of formula I.)

[0419] Step 1: To a stirred solution of the ketone (1.0 equiv.) and (S)-2-methylpropane-2-sulfinamide (3.0 equiv.) in dry THF (0.25 M in substrate) was added titanium(IV) ethoxide (5 equiv.). The resulting mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled to ambient temperature and then diluted with brine and EtOAc. The resulting suspension was filtered through Celite® and the filter cake was washed with EtOAc. The organic layer was separated from the filtrate, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give the desired product:

[0420] (S)-N-(chroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(8-fluorochroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(7-fluorochroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(6-fluorochroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(5-fluorochroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(7-methoxychroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(6-methoxychroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(6-chlorochroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(7-cyanochroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(7-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(6-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(5-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(4-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(7-methoxy-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(5-methoxy-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(4-methoxy-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(6-cyano-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(5-cyano-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(4-cyano-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide; (S)—N-(6,7-dihydro-5H-cyclopenta[b]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide.

[0421] Similarly, the corresponding (R)-configured sulfinamide can be made by substituting (R)-2-methylpropane-2-sulfinamide for (S)-2-methylpropane-2-sulfinamide.

[0422] Step 2: N-Sulfinyl imine (1.0 equiv.) was dissolved in wet THF (2-3% water, 0.31 M in substrate) and cooled to 0 °C. Sodium borohydride (3.0 equiv.) was added in one portion. The mixture was then stirred at 0 °C for 30 minutes, after which the bath temperature was gradually raised to ambient temperature. The reaction mixture was stirred at ambient temperature for 16 hours (monitored by TLC). The mixture was then concentrated under reduced pressure to remove THF and diluted with DCM. The mixture was washed with water, followed by brine, dried (NaSO), and concentrated under reduced pressure. The crude product was subjected to flash column chromatography and / or SFC to separate the mixture of diastereoisomers and to obtain the desired major diastereoisomer in good purity.

[0423] (S)-N-[(S)-6-chroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-8-fluorochroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-7-fluorochroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-6-fluorochroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-5-fluorochroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-7-methoxychroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-6-methoxychroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-6-chlorochroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-7-cyanochroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-7-fluoro-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-6-fluoro-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-5-fluoro-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-4-fluoro-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-7-methoxy-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-6-methoxy-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-4-methoxy-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-6-cyano-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-5-cyano-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-4-cyano-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]-2-methylpropane-2-sulfinamide;

[0424] Similarly, the corresponding (R,R)-configured sulfinamides can be prepared using the enantiomeric (R)-sulfinamide starting material.

[0425] Step 3: To an ice-cold solution of sulfinamide (1 eq) in DCM (0.33 M in substrate) was added 4N HCl in 1,4-dioxane (10 eq HCl). The resulting mixture was stirred at ambient temperature for 16 hours (monitored by TLC). The mixture was then concentrated under reduced pressure to give a residue which was triturated with hexane and dried to give the amine hydrochloride salt as a solid:

[0426] (S)-Chromin-4-amine·HCl; (S)-8-Fluorochroman-4-amine·HCl; (S)-7-Fluorochroman-4-amine·HCl; (S)-6-Fluorochroman-4-amine·HCl; (S)-5-Fluorochroman-4-amine·HCl; (S)-7-Methoxychroman-4-amine·HCl; (S)-6-Methoxychroman-4-amine·HCl; (S)-6-chlorochroman-4-amine·HCl; (S)-7-Cyanochroman-4-amine·HCl; (S)-7-Fluoro-2,3-dihydro-1H-inden-1-amine·HCl; (S)-6-Fluoro-2,3-dihydro-1H-inden-1-amine·HCl; (S)-5-Fluoro-2,3-dihydro-1H-inden-1-amine·HCl; (S)-4-Fluoro-2,3-dihydro-1H-inden-1-amine·HCl; (S)-7-Methoxy-2,3-dihydro-1H-inden-1-amine·HCl; (S)-6-Methoxy-2,3-dihydro-1H-inden-1-amine·HCl; (S)-5-Methoxy-2,3-dihydro-1H-inden-1-amine·HCl; (S)-4-Methoxy-2,3-dihydro-1H-inden-1-amine·HCl; (S)-6-Cyano-2,3-dihydro-1H-inden-1-amine·HCl; (S)-5-cyano-2,3-dihydro-1H-inden-1-amine·HCl; (S)-4-Cyano-2,3-dihydro-1H-inden-1-amine·HCl; (S)-6,7-Dihydro-5H-cyclopenta[b]pyridin-5-amine·HCl;

[0427] Similarly, the corresponding (R)-configured amine can be prepared using the enantiomeric (R,R)-configured sulfinamide starting material. The amine hydrochloride salt can be used in salt form without further purification for the preparation of compounds of the invention, or it can be desalted by partitioning between DCM and aqueous base, drying the separated organic phase (NaSO), and then recovering the free base amine by distillation.

[0428] Example 1-7 Examples 1-7 can be prepared according to the route shown in Scheme 1.

[0429] [ka]

[0430] Step 1 (Scheme 1): Synthesis of ethyl 2-bromobenzo[d]thiazole-6-carboxylate To an ice-cooled, stirred suspension of copper(II) bromide (1.9 equiv.) in acetonitrile (volume selected to obtain a 0.22 M solution of the benzothiazole substrate) was added tert-butyl nitrite (1.9 equiv.). The mixture was allowed to reach ambient temperature and stirred for 30 min, after which ethyl 2-aminobenzo[d]thiazole-6-carboxylate substrate (1.0 equiv.) was added and stirred at ambient temperature for an additional 16 h. The mixture was then concentrated in vacuo to give a residue that was partitioned between EtOAc and 1.5 M hydrochloric acid. The organic phase was washed with brine, dried (Na2SO4), and evaporated. The resulting residue was triturated with hexane to give ethyl 2-bromobenzo[d]thiazole-6-carboxylate as a brown solid (69% yield). 1 H NMR (400 MHz, DMSO-d6): δ 8.81 (1H, app. s), 8.11 - 8.06 (2H, m), 4.37(2H, q, J 6.8 Hz), 1.36 (3H, t, J 6.8 Hz).

[0431] Step 2 (Scheme 1): Synthesis of ethyl 2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxylate To a stirred, argon-purged mixture of ethyl 2-bromobenzo[d]thiazole-6-carboxylate (1.0 equiv.) in 91% v / v 1,4-dioxane / HO (0.34 M in substrate) was added (3-methylpyridin-4-yl)boronic acid (1.1 equiv.), KCO (3.0 equiv.), and Pd(PPh) (10 mol %). The reaction mixture was heated to reflux under argon for 16 h, then cooled, filtered through Celite®, and washed with EtOAc. The filtrate was washed with water, followed by brine, dried (NaSO), and concentrated under reduced pressure. The crude product was subjected to flash column chromatography (30-40% EtOAc / hexanes). Fractions containing the target material were combined and evaporated to afford ethyl 2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxylate as a pale yellow solid (74% yield).

[0432] Step 3 (Scheme 1): Synthesis of 2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxylic acid To a mixture of ethyl 2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxylate (1.0 equiv.) in 2.3:1 v / v THF / HO (0.33 M in substrate), LiOH·HO (2.0 equiv.) was added and stirred at ambient temperature for 16 h (monitored by TLC). The reaction mixture was concentrated under reduced pressure to give a residue that was diluted with ice-cold water and acidified with 1.5 N hydrochloric acid. The resulting precipitate was collected by filtration and dried to give 2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxylic acid as a pale yellow solid (95% yield).

[0433] Step 4 (Scheme 1) leading to Examples 1-7: General Amide Coupling Procedure To a solution of 2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxylic acid (1.0 equiv.) in DMF (0.1 M in substrate) at 0 °C was added EDC·HCl (2.0 equiv.), HOBt (1.5 equiv.), DIPEA (1.0 equiv.) and an amine (R 2 NH2; 2.0 equiv.) was added and stirred at ambient temperature for 16 hours. The reaction mixture was diluted with DCM and washed with water followed by brine. The separated organic layer was then dried (Na2SO4) and concentrated under reduced pressure. The crude material was subjected to flash chromatography (5-10% MeOH in DCM eluent). Fractions containing the target material were combined and evaporated to dryness. The resulting solid was triturated with diethyl ether and dried to give Examples 1-7 as off-white solids.

[0434] Example 1: N-(4-chlorobenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide It was prepared according to Scheme 1 using 4-chlorobenzylamine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.26 (1H, br. t, J 5.9), 8.73 (1H, app. d, J 1.7), 8.64 (1H, dd, J 4.8 and 1.6), 8.25 (1H, dd, J 7.9 and 1.6), 8.20 (1H, tented d, J 8.6), 8.08 (1H, tented dd, J 8.6 and 1.7), 7.47(1H, dd, J 7.8 and 4.8), 7.42 - 7.37(4H, AA?BB? m), 4.52 (2H, d, J 5.9), 2.85 (3H, s).

[0435] Example 2: N-(4-fluorobenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using 4-fluorobenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.24 (1H, br. t, J 5.9), 8.73 (1H, app. d, J 1.7), 8.64 (1H, dd, J 4.8 and 1.6), 8.25 (1H, dd, J 7.9 and 1.6), 8.19 (1H, tented d, J 8.6), 8.08 (1H, tented dd, J 8.6 and 1.7), 7.47(1H, dd, J 7.8 and 4.8), 7.43 - 7.38 (2H, m), 7.20 - 7.14 (2H, m), 4.51 (2H, d, J 5.9), 2.85 (3H, s).

[0436] Example 3: N-(4-Methoxybenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide It was prepared according to Scheme 1 using 4-methoxybenzylamine as the amine component. 1H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.16 (1H, br. t, J 5.9), 8.71 (1H, app. d, J 1.7), 8.64 (1H, dd, J 4.8 and 1.6), 8.25 (1H, dd, J 7.9 and 1.6), 8.19 (1H, tented d. J 5.9), 3.73 (3H, s), 2.85 (3H, s).

[0437] Example 4: N-(3-fluorobenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide It was prepared according to Scheme 1 using 3-fluorobenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.25 (1H, br. t, J 5.9), 8.74 (1H, app. d, J 1.7), 8.64 (1H, dd, J 4.8 and 1.6), 8.25 (1H, dd, J 7.9 and 1.6), 8.20 (1H, tented d, J 8.6), 8.09 (1H, tented dd, J 8.6 and 1.7), 7.47(1H, dd, J 7.9 and 4.8), 7.42 - 7.36 (1H, m), 7.23 - 7.15 (2H, m), 7.11 - 7.06 (1H, m), 4.55 (2H, d, J 5.9), 2.85 (3H, s).

[0438] Example 5: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (S)-1-aminoindan as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 8.96 (1H, br. d, J 8.2), 8.75 (1H, app. d, J 1.7), 8.65 (1H, dd, J 4.8 and 1.6), 8.25 (1H, dd, J 7.9, 1.6), 8.19 (1H, tented d, J 8.6), 8.12 (1H, tented dd, J 8.6 and 1.7), 7.47(1H, dd, J 7.8 and 4.8), 7.30 - 7.18 (4H, m), 5.64 - 5.58 (1H, m), 3.06 - 2.99 (1H, m), 2.92 - 2.84 (4H, m), 2.53 - 2.45 (1H, m), 2.07- 1.98 (1H, m).

[0439] Example 6: (S)-2-(2-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (S)-1-amino-1,2,3,4-tetrahydronaphthalene as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 8.95 (1H, d, J 8.5), 8.75 (1H, app. d, J 1.7), 8.64 (1H, dd, J 4.8, 1.5), 8.25 (1H, dd, J 7.8 and 1.5), 8.18 (1H, tented d, J 8.6), 8.12 (1H, tented dd, J 8.6 and 1.7), 7.47(1H, dd, J 7.8 and 4.8), 7.25 - 7.22 (1H, m), 7.20 - 7.12 (3H, m), 5.32 - 5.26 (1H, m), 2.85 (3H, s), 2.84 - 2.72 (2H, m), 2.07- 1.95 (2H, m), 1.91 - 1.73 (2H, m).

[0440] Example 7: (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.06 (1H, br. d, J 8.1), 8.75 (1H, app. d, J 1.7), 8.64 (1H, dd, J 4.7and 1.3), 8.25 (1H, dd, J 7.8 and 1.3), 8.18 (1H, tented d, J 8.6), 8.12 (1H, tented dd, J 8.6 and 1.7), 7.47(1H, dd, J 7.8 and 4.8), 7.23 (1H, d, J 7.5), 7.18 (1H, apps. 7.7), 6.83 (1H, d, J 8.2), 5.35 - 5.30 (1H, m), 4.37- 4.23 (2H, m), 2.85 (3H, s), 2.20 - 2.04 (2H, m).

[0441] Example 8: (S)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using pyridin-3-ylboronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-1-amino-1,2,3,4-tetrahydronaphthalene as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.30 (1H, dd, J 2.2 and 0.6), 8.94 (1H, br. d, J 8.5), 8.78 (1H, dd, J 4.8 and 1.6), 8.75 (1H, app. d, J 1.7), 8.49 (1H, ddd, J 8.0, 2.2 and 1.6), 8.17(1H, tented d, J 8.6), 8.11 (1H, tented dd, J 8.6 and 1.7), 7.64 (1H, ddd, J 8.0, 4.8 and 0.6), 7.26 -7.11 (4H, m), 5.31 - 5.26 (1H, m), 2.88 - 2.72 (2H, m), 2.07- 1.95 (2H, m), 1.92 - 1.73 (2H, m).

[0442] Example 9: (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using pyridin-3-ylboronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.30 (1H, dd, J 2.2 and 0.6), 9.04 (1H, br. d, J 8.1), 8.78 (1H, dd, J 4.8 and 1.6), 8.75 (1H, app. d, J 1.7), 8.49 (1H, ddd. 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.4 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.20 - 2.05 (2H, m).

[0443] Example 10: N-benzyl-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and benzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.21 (1H, br. t, J 5.8), 9.17(1H, d, J 2.2), 8.71 (1H, app. d, J 1.7), 8.37(1H, dd, J 8.1 and 2.2), 8.16 (1H, tented d, J 8.6), 8.07(1H, tented dd, J 8.6 and 1.7), 7.49 (1H, d, J 8.1), 7.39 - 7.30 (4H, m), 7.30 - 7.22 (1H, m), 4.53 (2H, d, J 5.8), 2.58 (3H, s).

[0444] Example 11: N-(4-chlorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 4-chlorobenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.25 (1H, br. t, J 6.0), 9.17(1H, d, J 2.3), 8.70 (1H, app. d, J 1.7), 8.37(1H, dd, J 8.1 and 2.3), 8.16 (1H, tented d, J 8.6), 8.06 (1H, tented dd, J 8.6 and 1.7), 7.50 (1H, d, J 8.1), 7.42 - 7.36 (4H, AA?BB? m), 4.51 (2H, d, J 6.0), 2.58 (3H, s).

[0445] Example 12: N-(4-fluorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 4-fluorobenzylamine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.22 (1H, br. t, J 5.9), 9.17(1H, d, J 2.3), 8.69 (1H, app. d, J 1.7), 8.37(1H, dd, J 8.1 and 2.3), 8.16 (1H, tented d, J 8.6), 8.06 (1H, tented dd, J 8.6 and 1.7), 7.50 (1H, d, J 8.1), 7.43 - 7.37(2H, m), 7.20 - 7.14 (2H, m), 4.51 (2H, d, J 5.9), 2.58 (3H, s).

[0446] Example 13: N-(4-Methoxybenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 4-methoxybenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.17(1H, d, J 2.3), 9.22 (1H, br. t, J 5.9), 8.69 (1H, app. d, J 1.7), 8.37(1H, dd, J 8.1 and 2.3), 8.15 (1H, tented d, J 8.6), 8.06 (1H, tented dd, J 8.6 and 1.7), 7.49 (1H, d, J 8.1), 7.30 - 7.26 (2H, AA?BB? m), 6.92 - 7.88 (2H, AA?BB? m), 4.45 (2H, d, J 5.9), 3.73 (3H, s), 2.58 (3H, s).

[0447] Example 14: N-(3-chlorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 3-chlorobenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.25 (1H, br. t, J 5.9), 9.17(1H, d, J 2.3), 8.71 (1H, app. d, J 1.7), 8.37(1H, dd, J 8.1 and 2.3), 8.16 (1H, tented d, J 8.6), 8.06 (1H, tented dd, J 8.6 and 1.7), 7.49 (1H, d, J 8.1), 7.42 - 7.31 (4H, m), 4.53 (2H, d, J 5.9), 2.58 (3H, s).

[0448] Example 15: N-(3-fluorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 3-fluorobenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.26 (1H, br. t, J 5.3), 9.17(1H, app. s), 8.71 (1H, app. s), 8.37(1H, app. d, J 8.1), 8.16 (1H, d, J 8.6), 8.07(1H, d, J 8.6), 7.49 (1H, d, J 8.1), 7.42 - 7.35 (1H, m), 7.23 - 7.14 (2H, m), 7.12 - 7.05 (1H, m), 4.54 (2H, d, J 5.3), 2.58 (3H, s).

[0449] Example 16: N-(3-Methoxybenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 3-methoxybenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.19 (1H, br. t, J 5.9), 9.17(1H, d, J 2.3), 8.71 (1H, app. d, J 1.7), 8.37(1H, dd, J 8.1 and 2.3), 8.16 (1H, tented d, J 8.6), 8.06 (1H, tented dd, J 8.6 and 1.7), 7.49 (1H, d, J 8.1), 7.25 (1H, t, J 8.1), 6.95 - 6.91 (2H, m), 6.84 - 6.80 (1H, m), 4.50 (2H, d, J 5.9), 3.74 (3H, s), 2.58 (3H, s).

[0450] Example 17: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-1-aminoindan as the amine component. 1 H NMR (free base form): δ H(400 MHz, CD3OD) 9.15 (1H, d, J 2.3), 8.57(1H, dd, J 1.7and 0.5), 8.41 (1H, dd, J 8.1 and 2.3), 8.11 (1H, tented dd, J 8.6 and 0.5), 8.05 (1H, tented dd, J 8.6 and 1.7), 7.51 (1H, d, J 8.1), 7.36 - 7.18 (4H, m), 5.69 (1H, apps. 2.59 (1H, m), 2.64 (3H, s), 2.11 - 2.01 (1H, m). [Amide NH lost to deuterium exchange.] Amide NH lost to deuterium exchange. Lost.

[0451] Example 18: (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (R)-1-aminoindan as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.17(1H, d, J 2.3), 8.93 (1H, br. d, J 8.3), 8.72 (1H, app. d, J 1.7), 8.37(1H, dd, J 8.1 and 2.3), 8.14 (1H, tented d, J 8.6), 8.09 (1H, tented dd, J 8.6 and 1.7), 7.49 (1H, d, J 8.1), 7.32 - 7.17(4H, m), 5.64 - 5.57(1H, m), 3.06 - 2.99 (1H, m), 2.91 - 2.83 (1H, m), 2.58 (3H, s), 2.54 - 2.45 (1H, m), 2.07- 1.97(1H, m).

[0452] Example 19: N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (1S,2R)-1-amino-2-indanol as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.18 (1H, d, J 2.3), 8.82 (1H, app. s), 8.49 (1H, br. d, J 8.4), 8.38 (1H, dd, J 8.1 and 2.3), 8.15 (2H, app. s), 7.49 (1H, d, J 8.1), 7.31 - 7.18 (4H, m), 5.49 (1H, dd, J 8.4 and 5.3), 5.17(1H, br. d, J 4.6), 4.58 - 4.53 (1H, m), 3.12 (1H, dd, J 16.1 and 5.0), 2.91 (1H, app. d, J 16.1), 2.58 (3H, s).

[0453] Example 20: N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (1R,2S)-1-amino-2-indanol as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.18 (1H, d, J 2.3), 8.82 (1H, app. s), 8.48 (1H, br. d, J 8.4), 8.38 (1H, dd, J 8.1 and 2.3), 8.15 (2H, app. s), 7.49 (1H, d, J 8.1), 7.31 - 7.18 (4H, m), 5.49 (1H, dd, J 8.4 and 5.3), 5.16 (1H, br. d, J 4.6), 4.58 - 4.53 (1H, m), 3.12 (1H, dd, J 16.1 and 5.0), 2.91 (1H, app. d, J 16.1), 2.58 (3H, s).

[0454] Example 21: N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (1R,2R)-1-amino-2-indanol as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.18 (1H, d, J 2.3), 8.92 (1H, br. d, J 8.4), 8.74 (1H, app. d, J 1.7), 8.38 (1H, dd, J 8.1 and 2.3), 8.17(1H, tented d, J 8.6), 8.12 (1H, tented dd, J 8.6 and 1.7), 7.50 (1H, d, J 8.1), 7.25 - 7.14 (4H, m), 5.39 (1H, d, J 5.7), 5.34 (1H, app. t, J 7.6), 4.50 - 4.43 (1H, m), 3.20 (1H, dd, J 15.4 and 7.2), 2.77(1H, dd, J 15.4 and 7.7), 2.58 (3H, s).

[0455] Example 22: N-cyclopentyl-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and cyclopentylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.17(1H, d, J 2.3), 8.65 (1H, app. d, J 1.7), 8.47(1H, br. d, J 7.2), 8.37(1H, dd, J 8.1 and 2.3), 8.13 (1H, tented d, J 8.6), 8.02 (1H, tented dd, J 8.6 and 1.7), 7.49 (1H, d, J 8.1), 4.31 - 4.22 (1H, m), 2.58 (3H, s), 1.97- 1.86 (2H, m), 1.77- 1.66 (2H, m), 1.63 - 1.50 (4H, m).

[0456] Example 23: (S)-2-(6-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-1-amino-1,2,3,4-tetrahydronaphthalene as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.17(1H, d, J 2.3), 8.92 (1H, br. d, J 8.5), 8.73 (1H, app. d, J 1.7), 8.36 (1H, dd, J 8.1 and 2.3), 8.14 (1H, tented d, J 8.6), 8.09 (1H, tented dd, J 8.6 and 1.7), 7.49 (1H, d, J 8.1), 7.26 - 7.21 (1H, m), 7.20 - 7.11 (3H, m), 5.31 - 5.26 (1H, m), 2.88 - 2.72 (2H, m), 2.58 (3H, s), 2.07- 1.94 (2H, m), 1.92 - 1.73 (2H, m).

[0457] Example 24: (S)—N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.17(1H, d, J 2.3), 9.03 (1H, br. d, J 8.1), 8.74 (1H, app. d, J 1.7), 8.36 (1H, dd, J 8.1 and 2.3), 8.14 (11H, tented d, J 8.6), 8.09 (1H, tented dd, J 8.6 and 1.7), 7.49 (1H, d, J 8.1), 7.23 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.4 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.23 (2H, m), 2.58 (3H, s), 2.20 - 2.04 (2H, m).

[0458] Example 25: (S)—N-(chroman-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-(trifluoromethyl)pyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.48 (1H, d, J 2.0), 9.07(1H, d, J 8.1), 8.80 (1H, app. d, J 1.7), 9.77(1H, dd, J 8.1 and 2.0), 8.23 ​​(1H, tented d, J 8.6), 8.15 - 8.11 (2H, m), 7.23 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.4 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.21 - 2.04 (2H, m).

[0459] Example 26: (S)—N-(chroman-4-yl)-2-(2,6-dimethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (2,6-dimethylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.04 (1H, br. d, J 8.1), 8.74 (1H, app. d, J 1.7), 8.17- 8.09 (3H, m), 7.32 (1H, d, J 8.1), 7.22 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.4 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.82 (3H, s), 2.53 (3H, s), 2.20 - 2.04 (2H, m).

[0460] Example 27: (S)—N-(chroman-4-yl)-2-(6-cyclopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-cyclopropylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.11 (1H, d, J 2.3), 9.03 (1H, br. d, J 8.1), 8.71 (1H, app. d, J 1.7), 8.32 (1H, dd, J 8.2 and 2.3), 8.13 (1H, tented d, J 8.6), 8.08 (1H, tented dd, J 8.6 and 1.7), 7.53 (1H, d, J 8.2), 7.22 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.4 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.34 - 5.29 (1H, m), 4.36 - 4.23 (2H, m), 2.27- 2.21 (1H, m), 2.20 - 2.04 (2H, m), 1.10 - 1.01 (4H, m).

[0461] Example 28: (S)—N-(chroman-4-yl)-2-(6-isopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-isopropylpyridin-3yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.21 (1H, d, J 2.3), 9.02 (1H, br. d, J 8.0), 8.73 (1H, app. d, J 1.7), 8.40 (1H, dd, J 8.1 and 2.3), 8.15 (1H, tented d, J 8.6), 8.09 (1H, tented dd, J 8.6 and 1.7), 7.52 (1H, d, J 8.1), 7.23 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.4 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.23 (2H, m), 3.14 (1H, septet, J 6.9), 2.20 - 2.04 (2H, m), 1.29 (6H, d, J 6.9).

[0462] Example 29: (S)—N-(chroman-4-yl)-2-(6-ethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (6-ethylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.20 (1H, d, J 2.3), 9.03 (1H, br. d, J 8.1), 8.73 (1H, app. d, J 1.7), 8.39 (1H, dd, J 8.2 and 2.3), 8.15 (1H, tented d, J 8.6), 8.09 (1H, tented dd, J 8.6 and 1.7), 7.50 (1H, d, J 8.2), 7.23 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.4 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.23 (2H, m), 2.86 (2H, q, J 7.6), 2.20 - 2.04 (2H, m), 1.28 (3H, t, J 7.6).

[0463] Example 30: N-benzyl-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid in place of (2-methylpyridin-3-yl)boronic acid in step 2 and benzylamine as the amine component. 1 H NMR (free base form): δ H (300 MHz, DMSO-d6) 9.23 (1H, br. t, J 5.9), 9.10 (1H, d, J 2.0), 8.71 (1H, app. d, J 1.7), 8.62 (1H, app. d, J 2.0), 8.33 (1H, tq, J 2.0 and 0.7), 8.17(1H, tented d, J 8.6), 8.07(1H, tented dd, J 8.6 and 1.7), 7.41 - 7.21 (5H, m), 4.53 (2H, d, J 5.9), 2.44 (3H, app. s).

[0464] Example 31: N-(4-chlorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 4-chlorobenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.23 (1H, br. t, J 5.9), 9.10 (1H, d, J 2.0), 8.72 (1H, app. d, J 1.7), 8.62 (1H, app. d, J 2.0), 8.32 (1H, tq, J 2.0 and 0.7), 8.17(1H, tented d, J 8.6), 8.07(1H, tented dd, J 8.6 and 1.7), 7.42 - 7.36 (4H, AA?BB? m), 4.51 (2H, d, J 5.9), 2.44 (3H, app. s).

[0465] Example 32: N-(4-fluorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 4-fluorobenzylamine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.22 (1H, br. t, J 5.9), 9.11 (1H, d, J 2.0), 8.72 (1H, app. d, J 1.7), 8.63 (1H, app. d, J 2.0), 8.32 (1H, tq, J 2.0 and 0.7), 8.17(1H, tented d, J 8.6), 8.07(1H, tented dd, J 8.6 and 1.7), 7.43 - 7.37(2H, m), 7.20 - 7.14 (2H, m), 4.51 (2H, d, J 5.9), 2.44 (3H, app.s).

[0466] Example 33: N-(4-Methoxybenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 4-methoxybenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.15 (1H, br. t, J 5.9), 9.10 (1H, d, J 2.0), 8.71 (1H, app. d, J 1.7), 8.63 (1H, app. d, J 2.0), 8.32 (1H, tq, J 2.0 and 0.7), 8.16 (1H, tented d, J 8.6), 8.06 (1H, tented dd, J 8.6 and 1.7), 7.31 - 7.27(2H, AA?BB? m), 6.92 - 6.88 (2H, AA?BB? m), 4.45 (2H, d, J 5.9), 3.73 (3H, s), 2.44 (3H, app. s).

[0467] Example 34: N-[(3-chlorophenyl)methyl]-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 3-chlorobenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.26 (1H, br. t, J 5.9), 9.11 (1H, d, J 2.0), 8.73 (1H, app. d, J 1.7), 8.63 (1H, app. d, J 1.8), 8.33 (1H, tq, J 2.0 and 0.7), 8.18 (1H, tented d, J 8.6), 8.07(1H, tented dd, J 8.6 and 1.7), 7.43 - 7.28 (4H, m), 4.53 (2H, d, J 5.9), 2.44 (3H, app. s).

[0468] Example 35: N-(3-fluorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 3-fluorobenzylamine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.25 (1H, br. t, J 5.9), 9.11 (1H, d, J 2.0), 8.73 (1H, app. d, J 1.7), 8.63 (1H, app. d, J 2.0), 8.32 (1H, tq, J 2.0 and 0.7), 8.18 (1H, tented d, J 8.6), 8.08 (1H, tented dd, J 8.6 and 1.7), 7.42 - 7.36 (1H, m), 7.22 - 7.15 (2H, m), 7.11 - 7.06 (1H, m), 4.54 (2H, d, J 5.9), 2.44 (3H, app. s).

[0469] Example 36: N-(3-Methoxybenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 3-methoxybenzylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.19 (1H, br. t, J 5.9), 9.11 (1H, d, J 2.0), 8.72 (1H, app. d, J 1.7), 8.63 (1H, app. d, J 2.0), 8.32 (1H, tq, J 2.0 and 0.7), 8.17(1H, tented d, J 8.6), 8.07(1H, tented dd, J 8.6 and 1.7), 7.26 (1H, t, J 8.1), 6.96 - 6.91 (2H, m), 6.85 - 6.81 (1H, m), 4.50 (2H, d, J 5.9), 3.74 (3H, s), 2.44 (3H, app. s).

[0470] Example 37: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-1-aminoindan as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.11 (1H, d, J 2.0), 8.94 (1H, br. d, J 8.2), 8.74 (1H, app. d, J 1.7), 8.62 (1H, app. d, J 2.0), 8.32 (1H, tq, J 2.0 and 0.7), 8.16 (1H, tented d, J 8.6), 8.10 (1H, tented dd, J 8.6 and 1.7), 7.31 - 7.17(4H, m), 5.64 - 5.57(1H, m), 3.03 (1H, tented ddd, J 15.9, 8.9 and 3.2), 2.88 (1H, tented dt, J 15.9 and 8.4), 2.53 - 2.44 (1H, m), 2.44 (3H, app. s), 2.03 (1H, dq, J 12.5 and 8.4).

[0471] Example 38: (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (R)-1-aminoindan as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.11 (1H, d, J 2.0), 8.95 (1H, br. d, J 8.3), 8.74 (1H, app. d, J 1.7), 8.62 (1H, app. d, J 2.0), 8.32 (1H, tq, J 2.0 and 0.7), 8.16 (1H, tented d, J 8.6), 8.10 (1H, tented dd, J 8.6 and 1.7), 7.31 - 7.17(4H, m), 5.64 - 5.57(1H, m), 3.02 (1H, tented ddd, J 15.9, 8.9 and 3.2), 2.87(1H, tented dt, J 15.9 and 8.4), 2.53 - 2.44 (1H, m), 2.44 (3H, app. s), 2.02 (1H, dq, J 12.5 and 8.4).

[0472] Example 39: N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (1R,2S)-1-amino-2-indanol as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.11 (1H, d, J 2.0), 8.84 - 8.83 (1H, m), 8.63 (1H, app. d, J 2.0), 8.48 (1H, br. d, J 8.6), 8.33 (1H, tq, J 2.0 and 0.7), 8.18 - 8.13 (2H, m), 7.31 - 7.18 (4H, m), 5.50 (1H, dd, J 8.6 and 5.2), 5.15 (1H, br. d, J 4.5), 4.58 - 4.54 (1H, m), 3.13 (1H, dd, J 16.2 and 5.1), 2.91 (1H, dd, J 16.2 and 1.7), 2.44 (3H, app. s).

[0473] Example 40: N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (1S,2R)-1-amino-2-indanol as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.11 (1H, d, J 2.0), 8.84 - 8.83 (1H, m), 8.63 (1H, app. d, J 2.0), 8.48 (1H, br. d, J 8.6), 8.33 (1H, tq, J 2.0 and 0.7), 8.18 - 8.13 (2H, m), 7.31 - 7.18 (4H, m), 5.50 (1H, dd, J 8.6 and 5.2), 5.15 (1H, br. d, J 4.1), 4.58 - 4.54 (1H, m), 3.13 (1H, dd, J 16.2 and 5.1), 2.91 (1H, dd, J 16.2 and 1.7), 2.44 (3H, app. s).

[0474] Example 41: N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (1S,2S)-1-amino-2-indanol as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.11 (1H, d, J 2.0), 8.94 (1H, br. d, J 8.4), 8.76 (1H, dd, J 1.7and 0.5), 8.63 (1H, dq, J 2.0 and 0.7), 8.33 (1H, tq, J 2.0 and 0.7), 8.18 (1H, tented dd, J 8.6 and 0.5), 8.13 (1H, tented dd, J 8.6 and 1.7), 7.25 - 7.14 (4H, m), 5.41 (1H, br. d, J 5.6), 5.36 - 5.32 (1H, m), 4.50 - 4.43 (1H, m), 3.20 (1H, dd, J 15.5 and 7.2), 2.77(1H, dd, J 15.5 and 7.7), 2.44 (3H, app. s).

[0475] Example 42: N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (1R,2R)-1-amino-2-indanol as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.11 (1H, d, J 2.0), 8.93 (1H, br. d, J 8.4), 8.76 (1H, dd, J 1.7and 0.5), 8.63 (1H, dq, J 2.0 and 0.7), 8.33 (1H, tq, J 2.0 and 0.7), 8.18 (1H, tented dd, J 8.6 and 0.5), 8.13 (1H, tented dd, J 8.6 and 1.7), 7.25 - 7.14 (4H, m), 5.40 (1H, br. d, J 5.7), 5.36 - 5.32 (1H, m), 4.50 - 4.43 (1H, m), 3.20 (1H, dd, J 15.5 and 7.2), 2.77(1H, dd, J 15.5 and 7.7), 2.44 (3H, app. s)

[0476] Example 43: N-cyclopentyl-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1, using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in Step 2 and cyclopentylamine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.10 (1H, d, J 2.0), 8.66 (1H, dd, J 1.7and 0.4), 8.62 (1H, app. d, J 2.0), 8.47(1H, br. d, J 7.2), 8.31 (1H, tq, J 2.0 and 0.7), 8.14 (1H, tented dd, J 8.6 and 0.4), 8.02 (1H, tented dd, J 8.6 and 1.7), 4.31 - 4.22 (1H, m), 2.44 (3H, app. s), 1.97- 1.85 (2H, m), 1.78 - 1.66 (2H, m), 1.62 - 1.50 (4H, m).

[0477] Example 44: (S)-2-(5-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-1-amino-1,2,3,4-tetrahydronaphthalene as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.10 (1H, d, J 2.0), 8.94 (1H, br. d, J 8.8), 8.74 (1H, app. d, J 1.7), 8.62 (1H, app. d, J 2.0), 8.32 (1H, tq, J 2.0 and 0.7), 8.15 (1H, tented d, J 8.6), 8.10 (1H, tented dd, J 8.6 and 1.7), 7.27- 7.11 (4H, m), 5.32 - 5.25 (1H, m), 2.88 - 2.72 (2H, m), 2.44 (3H, s), 2.07- 1.95 (2H, m), 1.92 - 1.73 (2H, m).

[0478] Example 45: (S)—N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.10 (1H, d, J 2.0), 9.04 (1H, d, J 8.1), 8.75 (1H, app. d, J 1.7), 8.62 (1H, app. d, J 2.0), 8.31 (1H, tq, J 2.0 and 0.7), 8.16 (1H, tented d, J 8.6), 8.10 (1H, tented dd, J 8.6 and 1.7), 7.23 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.44 (3H, s), 2.21 - 2.04 (2H, m).

[0479] Example 46: 2-(5-methylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and 4-aminotetrahydropyran as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.10 (1H, d, J 2.0), 8.67(1H, app. d, J 1.7), 8.62 (1H, app. d, J 2.0), 8.48 (1H, br. d, J 7.6), 8.31 (1H, tq, J 2.0 and 0.7), 8.15 (1H, tented d, J 8.6), 8.03 (1H, tented dd, J 8.6 and 1.7), 4.09 - 4.00 (1H, m), 3.93 - 3.87(2H, m), 3.41 (2H, td, J 11.6 and 2.1), 2.44 (3H, app. s), 1.84 - 1.77(2H, m), 1.67- 1.56 (2H, m).

[0480] Example 47: (S)—N-(chroman-4-yl)-2-(5-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-(trifluoromethyl)pyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.58 (1H, d, J 2.0), 9.21 (1H, dq, J 2.0 and 0.9), 9.07(1H, br. d, J 8.1), 8.80 - 8.87(2H, m), 8.22 (1H, tented d, J 8.6), 8.13 (1H, tented dd, J 8.6 and 1.7), 7.23 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.21 - 2.04 (2H, m).

[0481] Example 48: (S)—N-(chroman-4-yl)-2-(5-cyclopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-cyclopropylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.06 (1H, d, J 2.1), 9.05 (1H, br. d, J 7.8), 8.74 (1H, app. d, J 1.7), 8.59 (1H, d, J 2.1), 8.17(1H, tented d, J 8.6), 8.10 (1H, tented dd, J 8.6 and 1.7), 8.07(1H, t, J 2.1), 7.23 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.23 (2H, m), 2.21 - 2.04 (3H, m), 1.12 - 1.07(2H, m), 0.93 - 0.89 (2H, m).

[0482] Example 49: (S)—N-(chroman-4-yl)-2-(5-isopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-isopropylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.12 (1H, d, J 2.1), 9.05 (1H, d, J 8.1), 8.75 (1H, app. d, J 1.7), 8.71 (1H, d, J 2.1), 8.32 (1H, t, J 2.1), 8.18 (1H, tented d, J 8.6), 8.10 (1H, tented dd, J 8.6 and 1.7), 7.23 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.23 (2H, m), 3.11 (1H, septet, J 7.0), 2.21 - 2.04 (2H, m), 1.33 (6H, d, J 7.0 Hz).

[0483] Example 50: (S)-2-(4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (4-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-1-amino-1,2,3,4-tetrahydronaphthalene as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.00 (1H, s), 8.96 (1H, d, J 8.5), 8.75 (1H, app. d, J 1.5), 8.60 (1H, d, J 5.0), 8.18 (1H, tented d, J 8.6), 8.12 (1H, tented dd, J 8.6 and 1.5), 7.50 (1H, d, J 5.0), 7.27- 7.11 (4H, m), 5.32 - 5.26 (1H, m), 2.89 - 2.69 (2H, m), 2.68 (3H, s), 2.08 - 1.94 (2H, m), 1.93 - 1.73 (2H, m).

[0484] Example 51: (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (4-methylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.04 (1H, br. d, J 8.1), 9.00 (1H, s), 8.76 (1H, app. d, J 1.7), 8.60 (1H, d, J 5.0), 8.19 (1H, tented d, J 8.6), 8.12 (1H, tented dd, J 8.6 and 1.7), 7.50 (1H, d, J 5.0), 7.23 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.23 (2H, m), 2.68 (3H, s), 2.21 - 2.04 (2H, m).

[0485] Example 52: (S)—N-(chroman-4-yl)-2-(2,4-dimethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (2,4-dimethylpyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6 / D2O) 8.70 (1H, app. d, J 1.7), 8.45 (1H, d, J 5.1), 8.17(1H, tented d, J 8.6), 8.08 (1H, tented dd, J 8.6 and 1.7), 7.30 (1H, d, J 5.1), 7.22 - 7.13 (2H, m), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.30 (1H, app. t, J 6.1), 4.34 - 4.20 (2H, m), 2.30 (3H, s), 2.20 - 2.03 (5H, m). [Amide NH lost to deuterium exchange.] Amide NH lost due to deuterium exchange.

[0486] Example 53: (S)-2-(5-chloropyridin-3-yl)-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (5-chloropyridin-3-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.25 (1H, d, J 1.9), 9.06 (1H, br. d, J 8.1), 8.85 (1H, d, J 2.3), 8.78 (1H, app. d, J 1.7), 8.60 (1H, app. t, J 2.1), 8.19 (1H, tented d, J 8.6), 8.12 (1H, tented dd, J 8.6 and 1.7), 7.23 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.21 - 2.04 (2H, m).

[0487] Example 54: (S)—N-(chroman-4-yl)-2-(pyridin-4-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (pyridin-4-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.06 (1H, br. d, J 8.1), 8.82 - 8.80 (2H, m), 8.78 (1H, app. d, J 1.7), 8.21 (1H, tented d, J 8.6), 8.12 (1H, tented dd, J 8.6 and 1.7), 8.07- 8.06 (2H, m), 7.23 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.21 - 2.04 (2H, m).

[0488] Example 55: (S)—N-(chroman-4-yl)-2-(3-methylpyridin-4-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (3-methylpyridin-4-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.07(1H, br. d, J 8.1), 8.78 (1H, app. d, J 1.7), 8.70 (1H, s), 8.63 (1H, d, J 5.1), 8.22 (1H, tented d, J 8.6), 8.13 (1H, tented dd, J 8.6 and 1.7), 7.87(1H, d, J 5.1), 7.23 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.67(3H, s), 2.21 - 2.04 (2H, m).

[0489] Example 56: (S)—N-(chroman-4-yl)-2-(2-methylpyridin-4-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (2-methylpyridin-4-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.06 (1H, br. d, J 8.1), 8.77(1H, app. d, J 1.7), 8.67(1H, d, J 5.2), 8.19 (1H, tented d, J 8.6), 8.12 (1H, tented dd, J 8.6 and 1.7), 7.95 - 7.93 (1H, m), 7.86 (1H, dd, J 5.2 and 1.6), 7.23 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.61 (3H, s), 2.21 - 2.04 (2H, m).

[0490] Example 57: (S)—N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (1-methyl-1H-pyrazol-4-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 8.96 (1H, br. d, J 8.1), 8.62 (1H, app. d, J 1.6), 8.56 (s, 1H), 8.10 (s, 1H), 8.03 (1H, tented dd, J 8.6 and 1.7), 7.97(1H, tented d, J 8.6), 7.21 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.88 (1H, td, J 7.5 and 1.1), 6.81 (1H, dd, J 8.2 and 1.1), 5.34 - 5.27(1H, m), 4.35 - 4.23 (2H, m), 3.93 (3H, s), 2.20 - 2.03 (2H, m).

[0491] Example 58: (S)—N-(chroman-4-yl)-2-(1,4-dimethyl-1H-pyrazol-5-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (1,4-dimethyl-1H-pyrazol-5-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.04 (1H, br. d, J 8.1), 8.76 (1H, app. d, J 1.7), 8.17(1H, tented d, J 8.6), 8.11 (1H, tented dd, J 8.6 and 1.7), 7.51 (1H, s), 7.22 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.24 (2H, m), 2.24 (3H, s), 2.35 (3H, s), 2.20 - 2.04 (2H, m).

[0492] Example 59: (S)—N-(chroman-4-yl)-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (1,3,5-trimethyl-1H-pyrazol-4-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 8.97(1H, br. d, J 8.1), 8.64 (1H, app. dd, J 1.7and 0.5), 8.04 (1H, tented dd, J 8.6 and 1.7), 8.00 (1H, tented dd, J 8.6 and 0.5), 7.21 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.88 (1H, td, J 7.5 and 1.1), 6.81 (1H, dd, J 8.2 and 1.1), 5.34 - 5.29 (1H, m), 4.36 - 4.23 (2H, m), 3.77(3H, s), 2.66 (3H, s), 2.47(3H, s), 2.20 - 2.03 (2H, m).

[0493] Example 60: (S)—N-(chroman-4-yl)-2-(1,5-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 8.97(1H, br. d, J 8.1), 8.62 (1H, app. d, J 1.7), 8.48 (1H, s), 8.03 (1H, tented dd, J 8.6 and 1.7), 7.97(1H, tented d, J 8.6), 7.21 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.88 (1H, td, J 7.5 and 1.1), 6.81 (1H, dd, J 8.2 and 1.1), 5.34 - 5.29 (1H, m), 4.35 - 4.23 (2H, m), 3.85 (3H, s), 2.52 (3H, s), 2.20 - 2.03 (2H, m).

[0494] Example 61: (S)—N-(chroman-4-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide Prepared according to Scheme 1 using (1,3-dimethyl-1H-pyrazol-4-yl)boronic acid instead of (2-methylpyridin-3-yl)boronic acid in step 2 and (S)-chroman-4-amine as the amine component. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 8.97(1H, d, J 8.1), 8.62 (1H, app. d, J 1.7), 8.03 (1H, tented dd, J 8.6 and 1.7), 8.01 (1H, s), 7.98 (1H, tented d, J 8.6), 7.21 (1H, app. d, J 7.6), 7.17(1H, app. td, J 7.7and 1.5), 6.88 (1H, td, J 7.5 and 1.1), 6.81 (1H, dd, J 8.2 and 1.1), 5.34 - 5.29 (1H, m), 4.35 - 4.23 (2H, m), 3.84 (3H, s), 2.70 (3H, s), 2.20 - 2.03 (2H, m).

[0495] Example 62: (S)—N-(chroman-4-yl)-2-(5-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide

[0496] [ka]

[0497] Step 1 (Scheme 2): Ester hydrolysis To a stirred mixture of ethyl 2-bromobenzo[d]thiazole-6-carboxylate (prepared as in Scheme 1, Step 1) (1 equiv.) in 2.3:1 v / v THF / HO (0.35 M in substrate) was added LiOH·HO (1.5 equiv.). The reaction mixture was stirred at ambient temperature for 16 h, then concentrated under reduced pressure, diluted with ice-cold water, and acidified with 1.5 N hydrochloric acid (to pH 3-4). The precipitated solid was collected by filtration, washed with diethyl ether and n-pentane, and dried to afford 2-bromobenzo[d]thiazole-6-carboxylic acid as an off-white solid (95% yield).

[0498] Step 2 (Scheme 2): Amide coupling To a stirred solution of 2-bromobenzo[d]thiazole-6-carboxylic acid (1.0 equiv.) in DMF (0.39 M in substrate) at 0 °C was added n-propylphosphonic anhydride cyclic trimer (50% in EtOAc; 2.0 equiv.), DIPEA (4.0 equiv.), and (S)-chroman-4-amine (2.0 equiv.). The reaction mixture was stirred at ambient temperature for 16 h, then concentrated under reduced pressure, diluted with ice-cold water, and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give the crude product. The latter was subjected to flash column chromatography (80-100% EtOAc / petroleum ether). Fractions containing the target material were combined and evaporated to give (S)-2-bromo-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide as an off-white solid (65% yield).

[0499] Step 3 (Scheme 2): Suzuki Coupling To a stirred, degassed mixture of (S)-2-bromo-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide (1.0 equiv.) in 4:1 v / v 1,4-dioxane / HO (0.51 M in substrate) under Ar was added 5-formylpyridin-3-yl)boronic acid (1.5 equiv.), NaCO (2.0 equiv.), and PdCl(dppf) DCM complex (10 mol%). The reaction mixture was heated to reflux under Ar for 16 h, then cooled, filtered through Celite®, and washed with EtOAc. The filtrate was washed with water, followed by brine, then dried (NaSO) and evaporated. The crude product was purified by flash column chromatography (40-60% EtOAc / hexanes), and the fractions containing the target material were combined and evaporated to give (S)-N-(chroman-4-yl)-2-(5-formylpyridin-3-yl)benzo[d]thiazole-6-carboxamide as an off-white solid (45% yield).

[0500] Step 4 to Example 62 (Scheme 2): Reduction of the aldehyde To (S)-N-(chroman-4-yl)-2-(5-formylpyridin-3-yl)benzo[d]thiazole-6-carboxamide (1.0 equiv.) in THF (0.51 M in substrate) at 0 °C was added sodium borohydride (1.5 equiv.) in one portion. The mixture was stirred at 0 °C for 30 min, then warmed to ambient temperature and stirred for an additional 1 h (monitored by TLC). The mixture was concentrated under reduced pressure, diluted with EtOAc, and the EtOAc mixture was washed with water followed by brine. The organic phase was dried (Na2SO4) and evaporated to give the crude product, which was subjected to preparative HPLC to give (S)-N-(chroman-4-yl)-2-(5-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide as an off-white solid (33% yield). 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.18 (1H, d, J 2.1), 9.05 (1H, br. d, J 8.1), 8.76 (1H, app. d, J 1.7), 8.71 (1H, d, J 1.9), 8.42 - 8.41 (1H, m), 8.17(1H, tented d, J 8.6), 8.11 (1H, tented dd, J 8.6 and 1.7), 7.23 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.55 (1H, t, J 5.7), 5.35 - 5.30 (1H, m), 4.68 (2H, d, J 5.7), 4.36 - 4.23 (2H, m), 2.20 - 2.03 (2H, m).

[0501] Example 63: (S)—N-(chroman-4-yl)-2-(5-(difluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide Step 1: Preparation of boronic ester 3-Bromo-5-(difluoromethyl)pyridine (1.0 equiv.), bispinacolatodiboron (3.0 equiv.), and KOAc (3.0 equiv.) in 1,4-dioxane (0.1 M in substrate) were purged with N2 gas for 15 min. Pd(dppf)Cl2·DCM (10 mol%) was added, and the reaction mixture was stirred at 90 °C for 16 h (monitored by TLC). After completion of the reaction, the mixture was cooled, filtered through Celite®, and the filtrate was evaporated to give crude (5-(difluoromethyl)pyridin-3-yl)boronic acid ester as a brown gummy solid, which was used directly in the next step.

[0502] Step 2: Suzuki Coupling To a degassed solution of (S)-2-bromo-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide (1.0 equiv.; prepared as described in Scheme 2) in 9:1 v / v 1,4-dioxane / HO (0.1 M in substrate) under N2, (5-(difluoromethyl)pyridin-3-yl)boronic acid ester (1.5 equiv.), Na2CO3 (3.0 equiv.), and Pd(dppf)Cl2·DCM (10 mol%) were added. The reaction mixture was stirred at 100 °C for 16 h (monitored by TLC). After completion of the reaction, the mixture was cooled and filtered through Celite®. The filtrate was diluted with water and extracted with DCM. The extract was dried (Na2SO4) and evaporated to give the crude product, which was subjected to preparative HPLC to give (S)-N-(chroman-4-yl)-2-(5-(difluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide as an off-white solid. 1 H NMR (free base form): δ H(400 MHz, DMSO-d6) 9.47- 9.45 (1H, m), 9.07(1H, br. d, J 8.1), 9.01 - 9.00 (1H, m), 8.78 (1H, dd, J 1.7and 0.4), 8.68 - 8.66 (1H, m), 8.21 (1H, tented dd, J 8.6 and 0.4), 8.12 (1H, tented dd, J 8.6 and 1.7), 7.31 (1H, t, 2 J HF 55.0), 7.23 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.23 (2H, m), 2.21 - 2.04 (2H, m).

[0503] Example 64: (S)—N-(chroman-4-yl)-2-(6-(difluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide Prepared as described in Example 63 using 3-bromo-6-(difluoromethyl)pyridine instead of 3-bromo-5-(difluoromethyl)pyridine. 1 H NMR (free base form): δ H (400 MHz, DMSO-d6) 9.41 (1H, app. d, J 2.2), 9.07(1H, br. d, J 8.1), 8.78 (1H, dd, J 1.7and 0.5), 8.69 (1H, dd, J 8.1 and 2.2), 8.21 (1H, dd, J 8.6 and 0.5), 8.12 (1H, dd, J 8.6 and 1.7), 7.92 (1H, d, J 8.1), 7.23 (1H, app. d, J 7.6), 7.18 (1H, app. td, J 7.7and 1.5), 7.10 (1H, t, 2JHF 54.7), 6.89 (1H, td, J 7.5 and 1.1), 6.82 (1H, dd, J 8.2 and 1.1), 5.35 - 5.30 (1H, m), 4.36 - 4.23 (2H, m), 2.20 - 2.04 (2H, m).

[0504] Example 65-67 Examples 65-67 can be prepared according to the route shown in Scheme 3. Scheme 3

[0505] [ka]

[0506] Step 1 (Scheme 3): Synthesis of ethyl 4-fluoro-3-(nicotinamido)benzoate intermediate To a stirred solution of the nicotinic acid derivative (1.2 equiv.) in DMF (0.1 M in substrate) at 0 °C was added HATU (1.5 equiv.), DIPEA (2.0 equiv.), and ethyl 3-amino-4-fluorobenzoate (1.0 equiv.). The reaction mixture was stirred at ambient temperature for 16 h and then concentrated in vacuo. The residue was diluted with DCM, and the resulting solution was washed with water followed by brine. The organic layer was dried (Na2SO4) and evaporated to give the nicotinamide derivative, which was used in the next step without further purification.

[0507] Step 2 (Scheme 3): Synthesis of ethyl 2-(pyridin-3-yl)benzo[...

Claims

1. 2. A compound of formula A, or a pharma- ceutically acceptable salt 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: 【Chemistry 1】 During the ceremony, One of X and Y is S and the other is N; 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; R １ is one or more R ４ optionally substituted with; R ２ is one of the following: (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or (iv) (C3-8) alkyl, which may be linear, branched, or cyclic, or combinations thereof, wherein the linear portion of said (C3-8) alkyl may optionally be interrupted by one -O-; In the formula, R ２ is one or more R ５ Optionally substituted with; Each R ３ is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, said (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by one or more halogen, OH or (C1-4)alkoxy; Each R ４ are independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; Each R ５ is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogen or OH; R ６ is H or (C1-6)alkyl; n is 0, 1, 2, or 3.

2. 2. A compound or a pharma- ceutically acceptable salt thereof for use according to claim 1 : 【Chemistry 2】 During the ceremony, R ２ is one of the following: (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or (iv) (C3-8) alkyl, which may be linear, branched, or cyclic, or combinations thereof; In the formula, R ２ is one or more R ５ is optionally substituted with; and Each R ３ is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted by one or more halogens.

3. When Q is S(O), R １ is not optionally substituted pyrazol-4-yl, or a pharma- ceutically acceptable salt thereof.

4. X is S and Y is N; R １ is a 6-membered saturated or aromatic monocyclic ring containing two ring N heteroatoms, or a 7-8-membered saturated bridged ring system containing two ring N heteroatoms; R １ is one R ４ optionally substituted with; R ２ is one of the following: (i) a (C5-6)cycloalkyl optionally fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; In the formula, R ２ is one or two R ５ optionally substituted with; R ３ is, if present, methyl, CN or halogen; R ４ when present, is (C1-6)alkyl optionally substituted with OH, and can be (C1-2)alkyl optionally substituted with OH; R ５ is, if present, OH or halo; and n is 0 or 1; 4. A compound for use according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. A compound of formula B, or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】 One of X and Y is S and the other is N; Q is C or S(O); R １ａ is a 4- to 10-membered non-aromatic ring that may be monocyclic, bridged, or bicyclic, containing at least one ring N heteroatom and optionally a ring O heteroatom, wherein at least one ring N heteroatom is R １ａ is not at the connection point of R １ａ is one or more R ４ optionally substituted with; R ２ is one of the following: (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or (iv) (C3-8)alkyl, which may be linear, branched or cyclic, or a combination thereof, wherein the linear portion of said (C3-8)alkyl may optionally be interrupted by one -O-, and (C4-8)alkyl, which may be linear, branched or cyclic, or a combination thereof, wherein the linear portion of said (C4-8)alkyl may optionally be interrupted by one -O-; In the formula, R ２ is one or more R ５ optionally substituted with; Each R ３ is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, said (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by one or more halogen, OH or (C1-4)alkoxy; Each R ４ are independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; Each R ５ is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogen or OH; R ６ is H or (C1-6)alkyl; and n is 0, 1, 2, or 3; In the formula, R １ａ is 4-cyclopentylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl or 4-isopropylpiperazin-1-yl, Q is C, n is 0, and R ２ is unsubstituted, uninterrupted, straight chain or branched (C3-6) alkyl or unsubstituted (C3-8) cycloalkyl; The compound is not 2-(1-piperazinyl)-N-propyl-6-benzothiazolecarboxamide, N-(1-methylethyl)-2-(1-piperazinyl)-6-benzothiazolecarboxamide, or N-cyclopropyl-2-(1-piperazinyl)-6-benzothiazolecarboxamide.

6. 6. The compound of claim 5, wherein the compound is a compound of formula II, or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】 R ２ is one of the following: (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or (iv) (C3-8) alkyl, which may be linear, branched, or cyclic, or combinations thereof, and optionally (C4-8) alkyl, which may be linear, branched, or cyclic, or combinations thereof; In the formula, R ２ is one or more R ５ optionally substituted with; Each R ３ is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogens; R １ａ is 4-cyclopentylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl or 4-isopropylpiperazin-1-yl, and n is 0, then R ２ is unsubstituted, straight chain or branched (C3-6) alkyl or unsubstituted (C3-8) cycloalkyl.

7. 7. A compound according to claim 5 or 6, or a pharma- ceutically acceptable salt thereof, a) Each R ４ is independently halogen, CN, OH, (C1-2)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-2)alkyl, (C1-6)alkoxy and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and / or b) n is 1, 2, or 3; and / or c) R ２ is a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; a 5-7 membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; or CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; ２ is 1 or more R ５ and / or d) R １ａ is a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; a 7-8 membered saturated bridged ring system containing one or two ring N heteroatoms; a 9 membered saturated bridged ring system containing two ring N heteroatoms and a ring O heteroatom; or a 7-10 membered saturated, fused or spiro ring system containing one or two ring N heteroatoms; １ａ is one, two or three R ４ Optionally replaced by; R １ａ is a 6-membered saturated monocyclic ring containing two ring N heteroatoms or a 7-8-membered saturated bridged ring containing two ring N heteroatoms; R １ａ is any one R ４ and optionally substituted with R １ａ is a 7-8 membered saturated bridged ring system containing two ring N heteroatoms (e.g., a bridged piperazine, such as 3,8-diazabicyclo[3.2.1]octanyl), where R １ａ is one R ４ is optionally replaced by

8. R ２ A compound for use according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, or a compound according to any one of claims 5 to 7, or a pharma- ceutically acceptable salt thereof, wherein (i) a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms, wherein the (C5-7)cycloalkyl is optionally substituted with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl and (C1-4)alkoxy, wherein the (C1-4)alkyl and (C1-4)alkoxy are optionally substituted with one or more fluoro, and wherein the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, and wherein the (C1-4)alkyl and (C1-4)alkoxy are optionally substituted with one or more fluoro; (ii) 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, said 5- to 7-membered non-aromatic heterocycle optionally substituted on one or more ring carbon atoms with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl and (C1-4)alkoxy, said (C1-4)alkyl and (C1-4)alkoxy being optionally substituted with one or more fluoro, said 6-membered aromatic or heteroaromatic ring being optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, said (C1-4)alkyl and (C1-4)alkoxy being optionally substituted with one or more fluoro; (iii) CH ２ Ar, where Ar is optionally substituted with 1-3 substituents selected from halogen, CN, (C1-4) alkyl, (C1-4) alkoxy; ２ is optionally substituted with (C1-4)alkyl, said (C1-4)alkyl being optionally substituted with OH or (C1-4)alkyloxy; (iv) (C3-8) alkyl, which may be linear, branched or cyclic, or a combination thereof, optionally substituted with one or more halogen, OH, or (C1-4) alkoxy; (C4-8) alkyl, which may be linear, branched or cyclic, or a combination thereof, optionally substituted with one or more halogen, OH, or (C1-4) alkoxy; Optionally, R ２ teeth; (i) a (C5-6)cycloalkyl fused to a phenyl ring; (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; or (iii) (C4-6)cycloalkyl; In the formula, R ２ optionally, one or more R ５ is replaced by.

9. R ２ A compound for use according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, or a compound according to any one of claims 5 to 8, or a pharma- ceutically acceptable salt thereof, wherein is a group of the formula: 【Chemistry 5】 In the formula, A is O or CH ２ p is 1, 2 or 3; Ph is an optionally present fused phenyl ring; R ２ is 1 or more R ５ and optionally A is O or C(R ５ ) ２ (For example, C.F. ２ ).

10. A compound according to any one of claims 5 to 9, or a pharma- ceutically acceptable salt thereof, X is S and Y is N; R １ａ is a 6-membered saturated monocyclic ring containing two ring N heteroatoms or a 7-8-membered saturated bridged ring system containing two ring N heteroatoms; R １ａ is one R ４ optionally substituted with; R ２ teeth (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring; In the formula, R ２ is one or two R ５ optionally substituted with; R ３ is, if present, methyl, CN or halogen; R ４ when present, is (C1-6)alkyl optionally substituted with OH, and can be (C1-2)alkyl optionally substituted with OH; R ５ is, if present, OH or halo; and n is 0 or 1.

11. A compound of formula C or a pharma- ceutically acceptable salt thereof: 【Chemistry 6】 One of X and Y is S and the other is N; 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 a ring O heteroatom; (optionally a 4- to 10-membered monocyclic, bridged or bicyclic ring containing at least one ring N heteroatom); R １ is one or more R ４ optionally substituted with; R ２ａ is one of the following: (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; or (iv) (C5-6)cycloalkyl; In the formula, R ２ａ optionally one or more R ５ is replaced by; Each R ３ is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, said (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by one or more halogen, OH or (C1-4)alkoxy; Each R ４ are independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; Each R ５ is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogen or OH; R ６ is H or (C1-6)alkyl; and n is 0, 1, 2, or 3; and In the formula, R ２ａ is (iv) (C5-6) cycloalkyl, it is selected from at least two R ５ is replaced by; wherein the compound is not 2-(4-morpholinyl)-N-(1,2,3,4-tetrahydronaphthalenyl)-6-benzothiazolecarboxamide or N-(2,3-dihydro-1H-inden-2-yl)-2-(1H-pyrrol-1-yl)-6-benzothiazolecarboxamide.

12. 12. The compound of claim 11, wherein the compound is a compound of formula III, or a pharma- ceutically acceptable salt thereof: 【Chemistry 7】 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; R １ is one or more R ４ optionally substituted with; Each R ３ is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted by one or more halogens.

13. A compound of formula D or a pharma- ceutically acceptable salt thereof: 【Chemistry 8】 One of X and Y is S and the other is N; 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; R １ is one or more R ４ optionally substituted with; R ２ is one of the following: (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or (iv) (C3-8) alkyl, which may be linear, branched, or cyclic, or combinations thereof, wherein the linear portion of said (C3-8) alkyl may optionally be interrupted by one -O-; In the formula, R ２ is one or more R ５ optionally substituted with; Each R ３ is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, said (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by one or more halogen, OH or (C1-4)alkoxy; Each R ４ are independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; Each R ５ is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogen or OH; R ６ is H or (C1-6)alkyl; m is 1, 2 or 3; In the formula, when Q is S(O), R １ is not optionally substituted pyrazol-4-yl.

14. 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof: a) the compound is of formula IV or a pharma- ceutically acceptable salt thereof; 【Chemistry 9】 R ２ is one of the following: (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (ii) 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; (iii) CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or (iv) (C3-8) alkyl, which may be linear, branched, or cyclic, or combinations thereof; In the formula, R ２ is one or more R ５ optionally substituted with; Each R ３ is independently (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogens; Optionally, the compound is of formula IVa or IVb, or a pharma- ceutically acceptable salt thereof: 【Chemistry 10】 b) Or the compound is of formula D' or D'', or a pharma- ceutically acceptable salt thereof: 【Chemistry 11】 Optionally the compound is a compound of formula D'.

15. Each R ３ are independently -CH ３ , -OCH ３ , halo, CN or cyclopropyl, or a pharma- ceutically acceptable salt thereof; or a compound according to any one of claims 5-14, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 1-4, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,

16. R ２ Or R ２ａ A compound for use according to any one of claims 1-4, or a pharma- ceutically acceptable salt thereof, or a compound according to any one of claims 5-15, or a pharma- ceutically acceptable salt thereof, wherein (i) a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms, wherein the (C5-7)cycloalkyl is optionally substituted with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl and (C1-4)alkoxy, wherein the (C1-4)alkyl and (C1-4)alkoxy are optionally substituted with one or more fluoro, and wherein the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, and wherein the (C1-4)alkyl and (C1-4)alkoxy are optionally substituted with one or more fluoro; (ii) 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, said 5- to 7-membered non-aromatic heterocycle being optionally substituted on one or more ring carbon atoms with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl and (C1-4)alkoxy, said (C1-4)alkyl and (C1-4)alkoxy being optionally substituted with one or more fluoro, said 6-membered aromatic or heteroaromatic ring being optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, said (C1-4)alkyl and (C1-4)alkoxy being optionally substituted with one or more fluoro; or (iv) (C5-6)cycloalkyl substituted on one or more ring carbon atoms with two or three substituents independently selected from OH, halogen, (C1-4)alkyl, (C1-4)alkoxy, wherein the (C1-4)alkyl and (C1-4)alkoxy are optionally substituted with one or more fluoro, and the (C5-6)cycloalkyl is optionally substituted (optionally on one ring carbon) with two halogen substituents; Optionally, R ２ Or R ２ａ is: (i) a (C5-6)cycloalkyl fused to a phenyl ring; (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; or (iv) (C5-6)cycloalkyl; In the formula, R ２ Or R ２ａ is optionally substituted, R ２ａ is (iv) (C5-6) cycloalkyl, it is selected from at least two R ５ has been replaced with.

17. R ２ Or R ２ａ A compound for use according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, or a compound according to any one of claims 5 to 16, or a pharma- ceutically acceptable salt thereof, wherein is a group of the formula: 【Chemistry 12】 where A is O or CH ２ p is 1, 2 or 3; Ph is an optionally present fused phenyl ring; R ２ Or R ２ａ is one or more R ５ wherein A is optionally substituted with CH ２ If Ph is present or A is C(R ５ ) ２（ For example, CF ２ ).

18. 13. A compound according to claim 11 or 12, or a pharma- ceutically acceptable salt thereof, X is S and Y is N; R １ is a 6-membered saturated or aromatic monocyclic ring containing two ring N heteroatoms, or a 7-8-membered saturated bridged ring system containing two ring N heteroatoms; R １ is any one R ４ is replaced by; R ２ａ teeth, (i) a (C5-6)cycloalkyl fused to a phenyl ring; or (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom and optionally fused to a phenyl ring; or (iv) (C5-6)cycloalkyl; In the formula, R ２ａ is one or two R ５ and R ２ａ (iv) when (C5-6)cycloalkyl, two R ５ is replaced by; R ４ when present, is (C1-6)alkyl optionally substituted with OH and can be (C1-2)alkyl optionally substituted with OH; R ５ is, if present, OH or halo; and n is 0 or 1.

19. A compound for use according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, or a compound according to any one of claims 12 to 18, or a pharma- ceutically acceptable salt 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 5-6-membered aromatic monocyclic ring containing one or two ring N heteroatoms; a 7-8-membered saturated bridged ring system containing one or two ring N heteroatoms; a 9-membered saturated bridged ring system containing two ring N heteroatoms and a ring O heteroatom; or a 7-10-membered saturated, fused or spiro ring system containing one or two ring N heteroatoms; １ optionally 1, 2 or 3 R ４ is replaced by; Optionally, R １ is a 6-membered saturated or aromatic monocyclic ring containing two ring N heteroatoms; or a 7-8 membered saturated bridged ring system containing two ring N heteroatoms; １ is one R ４ optionally substituted with; Optionally, R １ is a 7-8 membered saturated bridged ring system containing two ring N heteroatoms (e.g., a bridged piperazine, e.g., 3,8-diazabicyclo[3.2.1]octanyl), where R １ is one R ４ is optionally replaced by

20. 20. A compound for use according to any one of claims 1-4, or a pharma- ceutically acceptable salt thereof, wherein X is S and Y is N; or a compound according to any one of claims 5-19, or a pharma- ceutically acceptable salt thereof.

21. A compound selected from the following: N-(4-chlorobenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-methoxybenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-fluorobenzyl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(2-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-benzyl-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-methoxybenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-chlorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-fluorobenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-methoxybenzyl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(6-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(2,6-dimethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(6-cyclopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(6-isopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(6-ethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-benzyl-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(4-methoxybenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-chlorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-fluorobenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-(3-methoxybenzyl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(5-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; 2-(5-methylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(5-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(5-cyclopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(5-isopropylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(2,4-dimethylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(5-chloropyridin-3-yl)-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(pyridin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(3-methylpyridin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(2-methylpyridin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1,4-dimethyl-1H-pyrazol-5-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1,5-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(5-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(5-(difluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(6-(difluoromethyl)pyridin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)benzo[d]thiazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)benzo[d]thiazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)benzo[d]thiazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(4-hydroxypiperidin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-morpholinobenzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methoxypiperidin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(piperidin-1-yl)benzo[d]thiazole-6-carboxamide; 2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-N-(4-fluorobenzyl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-N-isopropylbenzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(8-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(8-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(7-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(7-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(6-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(5-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(5-fluorochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(7-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(7-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(6-methoxychroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(7-cyanochroman-4-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(6-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(6-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclohexyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-((S)-chroman-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-methoxybenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-cyanobenzyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-isopropyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclohexyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(3,3-difluorocyclobutyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2-methoxy-1-phenylethyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(2-methoxy-1-phenylethyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(2-hydroxy-1-phenylethyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-benzyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-chlorobenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-fluorobenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-methoxybenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-cyanobenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4-methylbenzyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-methylpiperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclohexyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-isopropyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(3,3-difluorocyclobutyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2-methoxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)—N-(2-methoxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2-hydroxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (R)-N-(2-hydroxy-1-phenylethyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1-ethylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-(2-hydroxyethyl)piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclohexyl-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-(2-(2-methoxyethoxy)ethyl)piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-((S)-piperidin-3-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-((R)-piperidin-3-yl)benzo[d]thiazole-6-carboxamide; N-((S)-chroman-4-yl)-2-(pyrrolidin-3-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-cyclopentyl-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-cyclopentyl-4-methyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-Methyl-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-4-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-cyclopentyl-5-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1-ethylpiperidin-4-yl)-5-methylbenzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-5-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-5-methylbenzo[d]thiazole-6-carboxamide; N-cyclopentyl-7-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-7-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-ethylpiperidin-4-yl)-7-methylbenzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-7-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 5-Methoxy-2-(piperidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-5-methoxy-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-methyl-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-cyclopentyl-4-methyl-2-(4-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxamide; 4-methyl-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-4-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-4-methylbenzo[d]thiazole-6-carboxamide; N-cyclopentyl-5-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)-5-methylbenzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-5-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-5-methylbenzo[d]thiazole-6-carboxamide; N-cyclopentyl-7-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)-7-methylbenzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-7-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-7-methylbenzo[d]thiazole-6-carboxamide; N-cyclopentyl-4-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)-4-methoxybenzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-4-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)-5-methoxybenzo[d]thiazole-6-carboxamide; 5-Methoxy-2-(piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; 2-(4-ethylpiperazin-1-yl)-5-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-5-methoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-4,7-dimethyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-Cyclopropyl-N-isopropyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclobutyl-4-cyclopropyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclobutyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 4-chloro-N-cyclopentyl-2-(4-(3-hydroxypropyl)piperazin-1-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-7-methoxybenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-bromo-N-cyclopentylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4-cyano-N-isopropylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; 2-(3-cyclopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(3-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamide; 2-(3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(8-(3-fluoropropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4-(1-hydroxypropan-2-yl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentyl-4-(2-hydroxyethyl)benzo[d]thiazole-6-carboxamide; 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(4,7-diazaspiro[2.5]octan-7-yl)benzo[d]thiazole-6-carboxamide; N-cyclohexyl-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(2,6-diazaspiro[3.4]octan-6-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(2,7-diazaspiro[3.5]non-7-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(octahydro-4H-pyrrolo[3,2-b)]pyridin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)benzo[d]thiazole-6-carboxamide; N-cyclohexyl-2-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-1-2(1H)-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(2-methyl-2,7-diazaspiro[3.5]non-7-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1-methyloctahydro-4H-pyrrolo[3,2-b)]pyridin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-N-methyl-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide; (S)—N-(chroman-4-yl)-N-methyl-2-(2-methylpyridin-3-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-N-methyl-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(pyridin-4-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(piperidin-4-yl)-N-(pyridin-3-ylmethyl)benzo[d]thiazole-6-carboxamide; N-((1R,2R)-2-hydroxycyclopentyl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(pyridin-4-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(pyridin-3-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(1-ethylpiperidin-4-yl)-N-(pyridazin-4-ylmethyl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(2-isopropoxyethyl)benzo[d]thiazole-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(2-(cyclopentyloxy)ethyl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1,2-dimethyl-1H-imidazol-5-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(1-ethylazetidin-3-yl)benzo[d]thiazole-6-carboxamide; rac-N-cyclopentyl-2-((3S,4R)-3-hydroxy-1-methylpiperidin-4-yl)benzo[d]thiazole-6-carboxamide; N-cyclopentyl-2-(piperidin-4-yl)benzo[d]thiazole-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylbenzo[d]thiazole-5-carboxamide; N-cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-5-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]thiazole-6-sulfonamide; N-cyclopentyl-2-(piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]thiazole-6-sulfonamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(3-ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; N-(4,4-difluorocyclohexyl)-2-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]thiazole-6-sulfonamide; or a pharma- ceutically acceptable salt thereof.

22. 22. A pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt according to any one of claims 1-21, and a pharma- ceutically acceptable excipient.

23. 22. A compound, or a pharma- ceutically acceptable salt, according to any one of claims 5 to 21 for use in therapy.

24. A compound or a pharma- ceutical acceptable salt according to any one of claims 5-21, or a pharmaceutical composition according to claim 22, for use in the treatment or prevention of a disease or disorder that can be ameliorated by activation of the long isoform of PDE4.

25. A compound according to any one of claims 1-4, or a pharma- ceutically acceptable salt, or a pharmaceutical composition according to claim 24, for use in the treatment of the following diseases or disorders: i) the disease or disorder is a disease or disorder caused by excessive intracellular cyclic AMP signaling, optionally where the 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, and / or ii) The disease is selected from: a. the disease is cancer, optionally the cancer is prostate cancer; b. Pituitary adenoma, Cushing's disease, polycystic kidney disease or polycystic liver disease; c. hyperthyroidism, Janssen metaphyseal chondrodysplasia, hyperparathyroidism or familial male-restricted precocious puberty; D. McCune-Albright syndrome; e. cholera, whooping cough, anthrax or tuberculosis; f. HIV, AIDS or common variable immunodeficiency (CVID); g. melanoma, pancreatic cancer, leukemia, prostate cancer, tumors of the adrenal cortex, testicular cancer, primary pigmented nodular adrenal disease (PPNAD) or Carney complex; h. Autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD); i. Maturity-onset diabetes of the young type 5 (MODY5); or j. Cardiac hypertrophy, or k. Hyperparathyroidism.

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