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 chain 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-chain form were recently disclosed in WO2016151300, WO2018060704, and WO2019193342. Recently, small molecule activators of the PDE4 long-chain form were evaluated in a cell-based model of autosomal dominant polycystic kidney disease (ADPKD) (Omar et al., PNAS 116: 13320-13329, 2019). Clinical development of small molecule activators of the PDE4 long-chain form has not yet been reported. Additional structurally distinct small molecule activators of the PDE4 long-chain form are still needed for potential development as therapeutic agents.

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

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

[0009] [ka]

[0010] One of X1 and X2 is N, the other is N or CR 3a One of Y1 and Y2 is N and the other is C, and one of Z1, Z2, and Z3 is N or CR 3b , and the others are CR 3b is; or One of X1 and X2 is N and the other is NR 3c or O, Y1 and Y2 are each C, and one of Z1, Z2 and Z3 is N or CR 3b and the other is CR 3b is; or One of X1 and X2 is S and the other is N or CR 3a wherein Y1 and Y2 are each C, one of Z1, Z2 and Z3 is N, and the others are each CR 3b is; 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; R 2 is one or more R 5 may be substituted with; Each R 3a are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R 3b are independently H, (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 3c are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R 4 is 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 5are independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy are optionally substituted with one or more halogens or OH;

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

[0012] [ka]

[0013] In the formula, one of X1 and X2 is N, and the other is N or CR 3a One of Y1 and Y2 is N and the other is C, and one of Z1, Z2, and Z3 is N or CR 3b and the others are each CR 3b is; or One of X1 and X2 is S and the other is N or CR 3a wherein Y1 and Y2 are each C, one of Z1, Z2 and Z3 is N, and the others are each CR 3b is; 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 selected from the group consisting of R 1a is not at the attachment point of R 1a is one or more R 4 may be substituted with; 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; R 2 is one or more R 5 may be substituted with; Each R 3a are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R 3b are independently H, (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 is 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, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein the (C1-6)alkyl and (C1-6)alkoxy may be substituted with one or more halogens or OH.

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

[0015] [ka]

[0016] In the formula, one of X1 and X2 is N, and the other is N or CR 3a One of Y1 and Y2 is N and the other is C, and one of Z1, Z2, and Z3 is N or CR 3b , and others are each CR 3b is; or One of X1 and X2 is S and the other is N or CR 3a wherein Y1 and Y2 are each C, one of Z1, Z2 and Z3 is N, and the others are each CR 3b is; 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; or (iv) a (C5-6)cycloalkyl group; R 2a is one or more R 5 may be substituted with; Each R 3a are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R 3b are independently -H, (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 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; one of X1 and X2 is S and the other is N, Y1 and Y2 are each C, one of Z1, Z2, and Z3 is N, and R 2a (iv) (C5-6)cycloalkyl; R 2a is at least two R 5 is replaced by .

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

[0018] [ka]

[0019] In the formula, one of X1 and X2 is N, and the other is N or CR 3a , one of Y1 and Y2 is N, the other is C, one of Z1, Z2, Z3 is N or CR 3b , and the others are CR 3b is; or One of X1 and X2 is S and the other is N or CR 3a wherein Y1 and Y2 are each C, one of Z1, Z2 and Z3 is N, and the others are each CR 3b is; R 1is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and R 1 is one or more R 4 optionally replaced by; 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; R 2 is one or more R 5 may be substituted with; Each R 3a are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R 3b are independently H, (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, and at least one R 3b is other than H; 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 by one or more halogen or OH.

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

[0023] Also provided are methods for treating or preventing a disease or disorder that can be ameliorated by activation of the long isoform of PDE4, comprising administering to a patient in need thereof an effective amount of a compound or pharmaceutical composition described herein.Also provided are methods for treating or preventing a disease or disorder mediated by excessive intracellular cAMP signaling, comprising administering to a patient in need thereof an effective amount of a compound or pharmaceutical composition described herein.

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

[0025] In certain embodiments of the aforementioned aspects, the compounds of the present invention are provided for the treatment or prevention of cancer. In certain embodiments of the aforementioned aspects, the compounds of the present invention are provided for the treatment or prevention of a disease or disorder selected from hyperthyroidism, Janssens metaphyseal chondrodysplasia, hyperparathyroidism, familial male-limited precocious puberty, pituitary adenoma, Cushing's disease, polycystic kidney disease, polycystic liver disease, McCune-Albright syndrome, cholera, pertussis, anthrax, tuberculosis, HIV, AIDS, common variable immunodeficiency (CVID), melanoma, pancreatic cancer, leukemia, prostate cancer, adrenocortical tumor, testicular cancer, primary pigmented nodular adrenocortical disease (PPNAD), Carney complex, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), maturity-onset diabetes of the young type 5 (MODY5), or cardiac hypertrophy. [Brief explanation of the drawings]

[0026] [Figure 1] FIG. 1 shows the concentration-dependent activation of the long form of PDE4, PDE4D5, according to Example 4 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 51 using the method described in Experiment 4.

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

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

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

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

[0031] In compounds of formula I, R 1 is a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom, and R 1 may contain one or more R 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, if unsubstituted, may be NH (where valence allows). It will also be understood that there are no additional ring heteroatoms other than "at least one ring N heteroatom" (i.e., one or more ring N heteroatoms) and any "ring O heteroatoms."

[0032] In embodiment (1) of Formula I, R 1 is R 1 (i.e., the ring N atom is not the point of attachment of R to the ring containing X, X, Y, and Y). 1 (The remainder of the moieties may be as defined in Formula I, or in any of embodiments (5)-(19) of Formula I described herein, mutatis mutandis.)

[0033] In embodiment (2) of Formula I, R 1 is a 4-10 membered monocyclic, bridged or bicyclic ring containing one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom; R 1 is one or more R 4 may be substituted with R 1 is R 1 may contain at least one ring N heteroatom other than at the point of attachment of Formula I. The remainder may be as defined mutatis mutandis in Formula I, or in any of embodiments (5)-(19) of Formula I described herein.

[0034] In embodiment (3) of Formula I, R 1is a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom (e.g., one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom); a 5-6 membered aromatic monocyclic ring containing one or two ring N heteroatoms; or a 7-8 membered saturated bridged ring containing one or two ring N heteroatoms; a 9 membered saturated bridged ring containing two ring N heteroatoms and a ring O heteroatom; or a 7-10 membered saturated, fused or spiro ring system containing one or two ring N heteroatoms and optionally two ring N heteroatoms; and R 1 is one or more R 4 and R 1 is one, two or three R 4 may be substituted with R 1 is R 1 may contain at least one ring N heteroatom other than at the point of attachment of: the remainder may be as defined in Formula I, or any of embodiments (5)-(19) of Formula I described herein, mutatis mutandis.

[0035] In formula I, or alternatively in embodiment (1), (2) or (3), R 1 R may be a 4- to 10-membered monocyclic, bridged, or bicyclic ring containing at least one ring N heteroatom (i.e., no ring O heteroatoms). 1 may be a 6-membered saturated or 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, and R 1 In some cases, R is 1 or more 4 It is replaced by R 1 may be a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms, at least one of which is R 1 is not at the attachment point of R 1 may contain one or more R 4 It is replaced by R 1may be a 6-membered saturated or aromatic monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms, at least one of which is R 1 is not at the attachment point of R 1 may be one R 4 is replaced by R 1 may be a 6-membered saturated or aromatic monocyclic ring containing two ring N heteroatoms; or may be a 7-8 membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one R 4 may be substituted with R 1 may be a 7-8 membered saturated bridged ring containing two ring N heteroatoms, and R 1 is one R 4 may be substituted with R 1 may be a 7-8 membered saturated bridged ring containing two ring N heteroatoms, for example, a bridged piperazine such as 3,8-diazabicyclo[3.2.1]octanyl, and R 1 In some cases, R 4 The remainder may be as defined in Formula I, or any of embodiments (5)-(19) of Formula I described herein, mutatis mutandis.

[0036] In formula I, or alternatively in embodiment (1), (2) or (3), R 1 is piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyridinyl, azetidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl or 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 4,7-diazaspiro[2. 5]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, octahydro-4H-pyrrolo[3,2-b]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, or hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, each of which may be one or more R4 and preferably 1 to 3 R 4 and preferably one R 4 Optionally substituted with R 1 can be a group of the structure:

[0037] [ka]

[0038] R 1 is one or more R 4 and R 1 1-3 R 4 may be substituted with R 1 may be piperidinyl, piperazinyl, 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 may be one or more R 4 and preferably 1 to 3 R 4 and preferably one R 4 may be substituted with R 1 is piperidinyl, piperazinyl, or pyridinyl, each of which is one or more R 4 and preferably 1-3 of R 4 and preferably one R 4 may be substituted with R 1 can be a radical of the following structure:

[0039] [ka]

[0040] wherein Z is CH or N, and R 4 ' is H or R 4 or optionally one R 4R is pyridyl (optionally 3-pyridyl) substituted with 1 may be a 7- to 8-membered saturated bridged ring containing two ring N heteroatoms, such as the bridged piperazine shown below:

[0041] [ka]

[0042] [ka]

[0043] The remainder may be as defined mutatis mutandis in Formula I or in any of embodiments (5)-(19) of Formula I described herein.

[0044] In embodiment (4) of 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 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 other than at the point of attachment. 1 R may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, or a 7-8 membered saturated bridged ring containing 1 or 2 ring N heteroatoms. 1 may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms or a 7-8-membered saturated bridged ring containing 1 or 2 ring N heteroatoms, and R 1 is one R 4 The remainder may be as defined in Formula I, or any of embodiments (5)-(19) of Formula I described herein, mutatis mutandis.

[0045] In Formula I or any of the 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 one R 4 may be substituted, preferably on the ring N atom. 1 In embodiments where R is an aromatic ring, 1 is 1, 2 or 3 R 4 may be substituted with R 1 In embodiments where R is a six-membered ring, 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.

[0046] In compounds of formula I, each R 4 are independently halogen, CN, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl, and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH, and (Ci_6)alkoxy. 4 may independently represent a substituent on a carbon atom or a substitutable N atom.

[0047] In embodiment (5) of Formula I, each R 4are 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, where (Ci_4)alkyl is optionally substituted with one or more substituents independently selected from halogen and OH. The remainder may be as defined in Formula I, or any of embodiments (1)-(4) or (8)-(19) of Formula I described herein, mutatis mutandis.

[0048] In embodiment (6) of Formula I, each R 4 are independently halogen, OH, (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl, or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_6)alkyl, (Ci_6)alkoxy, (C3_7)cycloalkyl, and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH, and (Ci_6)alkoxy. 4 may independently be halogen, OH, (Ci_4)alkyl, (Ci_3)alkoxy, (C3_6)cycloalkyl, or -(Ci_3)alkylene-(Ci_3)alkoxy, wherein the (Ci_3)alkyl, (Ci_3)alkoxy, (C3_6)cycloalkyl, and -(Ci_3)alkylene-(Ci_3)alkoxy can be substituted with one or more substituents independently selected from halogen, OH, and (Ci_3)alkoxy. 4may independently be F, Cl, OH, (Ci_4)alkyl, methoxy, ethoxy, cyclopropyl, or -(CH)-O-(CH)-O-CH, where the (Ci_4)alkyl is optionally substituted with one or more substituents independently selected from halogen and OH. The remainder may be as defined in Formula I, or any of embodiments (1)-(4) or (8)-(19) of Formula I described herein, mutatis mutandis.

[0049] In embodiment (7) of 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. 4 may independently be F, Cl, OH, (Ci_2)alkyl, methoxy, ethoxy, or -(CH2)2-O-(CH2)2-O-CH3, where the (Ci_2)alkyl is optionally substituted with one or more substituents independently selected from halogen and OH. The remainder may be as defined in Formula I, or any of embodiments (1)-(4) or (8)-(19) of Formula I described herein, mutatis mutandis.

[0050] In any of Formula I or embodiments (5)-(7), one of X1 and X2 is S and the other is N or CR 3a Then, Y1 and Y2 are each C, one of Z1, Z2, and Z3 is N, and the others are each CR 3b and R 1 is one R 4 is a 6-membered saturated monocyclic ring containing one or two ring N heteroatoms substituted with R 4is halogen, CN, OH, straight-chained or branched (Ci_6)alkyl, (Ci_6)alkoxy or -(Ci_6)alkylene-(Ci_6)alkoxy, wherein the (Ci_6)alkyl, (Ci_6)alkoxy and -(Ci_6)alkylene-(Ci_6)alkoxy are optionally substituted by one or more substituents independently selected from halogen, OH and (Ci_6)alkoxy.

[0051] In Formula I or alternative embodiments (5)-(7), when attached to a ring N atom, R 4 are independently excluding halogen, CN, OH, and -(C1-6)alkoxy, R 4 The options can be all the options defined for

[0052] In compounds of 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, cyclic, or a combination thereof; and R 2 is one or more R 5 may be substituted with.

[0053] In compounds of 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.

[0054] In embodiment (8) of Formula I, each R 5are 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 mutatis mutandis in Formula I, or in any of embodiments (1)-(7) or (9)-(19) of Formula I described herein.

[0055] In embodiment (9) of 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 one or more R 5 may be substituted with R 2 R may be 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 groups are optionally substituted with one or more fluoro, 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. 2 1-3 R 5 , preferably one R 5 The remainder may be as defined mutatis mutandis in Formula I, or in any of embodiments (1)-(8) or (15)-(19) of Formula I described herein. In any of the alternatives of embodiment (9), R 2 is optionally substituted with one halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy.

[0056] In embodiment (10) of Formula I, R 2 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. 2 is one or more R 5 may be substituted with R 2 R may be 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, wherein the 5-7 membered non-aromatic heterocycle 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, 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 in Formula I, or in any of embodiments (1)-(8) or (15)-(19) of Formula I described herein. In any of the alternatives of embodiment (10), R 2 is optionally substituted with one halogen, OH, CN, (Ci_4) alkyl or (Ci_4) alkoxy, and the remainder may be as defined for any aspect or embodiment of Formula I described herein, mutatis mutandis.

[0057] In embodiment (11) of 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 may contain one or more R 5 It is replaced by R5 Substitution by R 2 It will be understood that the -CH2- linker or Ar moiety of R 2 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, where the (C1-4) alkyl group is optionally substituted with OH. 2 1-3 R 5 , preferably one R 5 The remainder of the moieties may be as defined mutatis mutandis in Formula I, or in any of embodiments (1)-(8) or (15)-(19) of Formula I described herein. In any of the alternatives of embodiment (11), R 2 is optionally substituted with one halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy, said (C1-4) alkyl group being optionally substituted with OH.

[0058] In embodiment (12) of Formula I, R 2 is a (C3-8) 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 can be a (C4-8) alkyl group which can be linear, branched, or cyclic, or a combination thereof; R 2 is one or more R 5 R 2 R may be an optionally substituted branched or cyclic (C3-6) alkyl group. 2 R may be an optionally substituted (C4-6) alkyl group which may be branched or cyclic, and more preferably an optionally substituted (C5-6) cycloalkyl group. 2R 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 may contain 1-3 R 5 It may be cyclohexyl, cyclopentyl or cyclobutyl substituted with R 2 is two or more R 5 The remainder may be as defined mutatis mutandis in Formula I, or in any of embodiments (1)-(8) or (15)-(19) of 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 is optionally substituted with one OH. 2 is optionally substituted with 2 or 3 fluoro, preferably 2 fluoro, on the same carbon atom. In any of the alternatives of embodiment (12), R 2 R is optionally substituted on one or more ring carbons 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 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).

[0059] In embodiment (13) of Formula I, R 2 is as defined in embodiment (9), embodiment (10) or embodiment (12) of formula I. 2may 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 (C5-6)cycloalkyl; R 2 is one or more R 5 may be substituted with R 2 may also be a group of the formula:

[0060] [ka]

[0061] 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 ), and 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 mutatis mutandis in Formula I, or in any of embodiments (1)-(8) or (15)-(19) of Formula I described herein.

[0062] In embodiment (14) of Formula I, R 2 is as defined in embodiment (9), embodiment (10), or embodiment (11) of Formula I. The remainder can be as defined in Formula I or any of embodiments (1)-(8) or (15)-(19) of Formula I described herein.

[0063] In Formula I or any of the embodiments (9)-(14), 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 R2 There are two R 5 may be substituted with.

[0064] In compounds of formula I, each R 3a are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; and each R 3b are independently H, (C1-6) alkyl, (C1-6) alkoxyCN or halogen, wherein the (C1-6) alkyl and (C1-6) alkoxy are optionally substituted with one or more halogens; and each R 3c are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens.

[0065] In embodiment (15) of Formula I, each R 3a are independently H or (C1-3) alkyl, wherein the (C1-3) alkyl is optionally substituted with one or more halogens; and each R 3b are independently H, (C1-3)alkyl, (C1-3)alkoxy, CN or halogen, wherein the (C1-3)alkyl and (C1-3)alkoxy are optionally substituted with one or more halogens, and / or each R 3c are independently H or (C1-3) alkyl, wherein the (C1-3) alkyl is optionally substituted with one or more halogens. 3a may independently be -H or CH3. 3b may independently be -H, -CH, -OCH, halo, CN, or cyclopropyl. 3c may independently be —H or CH3, and the remainder may be as defined in Formula I, or any of embodiments (1)-(14) or (18)-(19) of Formula I described herein, mutatis mutandis.

[0066] In embodiment (16) of Formula I, R 3a , R 3b and R 3cWhen present, each is H or methyl. In some embodiments, 0 or 1 R 3a , R 3b and R 3c When present, each is methyl and when the other is present, each is H. Preferably, R 3a , R 3b and R 3c When present, each is H. The remainder are as defined in Formula I or any of embodiments (1)-(14) or (18)-(19) of Formula I described herein.

[0067] In embodiment (17) of Formula I, R 3a , R 3b and R 3c where one or two of R are groups other than H as defined for Formula I or embodiment (15) of Formula I herein, and the others, when present, are each H, preferably R 3a , R 3b and R 3c is a group other than H as defined with respect to Formula I or embodiment (15) of Formula I herein, and each other group present is H.

[0068] The compound may be of the following formula or a pharmaceutically acceptable salt or derivative thereof:

[0069] [ka]

[0070] In the formula, R 3b R' is (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; 3a , R 3b and R 3c When present, each is H. The remainder can be as defined in Formula I, or any of the described Formula I embodiments (1)-(14) or (18)-(19).

[0071] In the compound of formula I, one of X1 and X2 is N and the other is N or CR 3a one of Y1 and Y2 is N and the other is C; Z 1、 One of Z2 and Z3 is N or CR 3b and the others are CR 3b Or, one of X1 and X2 is N and the other is NR 3c or O, Y1 and Y2 are each C, and one of Z1, Z2 and Z3 is N or CR 3b and the other is CR 3b Or, one of X1 and X2 is S and the other is N or CR. 3a Y1 and Y2 are each C, and Z1, Z2 and Z 3 One of them is N and the other is CR 3b is.

[0072] In embodiment (18) of Formula I, the bicyclic heteroaromatic ring comprising X1, X2, Y1, Y2, Z1, Z2, and Z3 is selected from:

[0073] [ka]

[0074] [ka]

[0075] The bicyclic heteroaromatic ring comprising X1, X2, Y1, Y2, Z1, Z2 and Z3 may be selected from:

[0076] [ka]

[0077] The remainder may be as defined in Formula I or any of Formula I embodiments (1)-(17), mutatis mutandis.

[0078] In embodiment (19) of Formula I, the compound is selected from the following formulae:

[0079] [ka]

[0080] The remainder may be as defined in Formula I or any of the embodiments (1)-(17) of Formula I described herein, mutatis mutandis.

[0081] In Formula I, or alternative embodiments (18) or (19) of Formula I, one of X1 and X2 may be N, and the other may be N or CR 3a one of Y1 and Y2 may be N and the other may be C; one of Z1, Z2 and Z3 may be N or CR 3b and the others may be CR 3b may be.

[0082] In Formula I, or alternative embodiments (18) or (19) of Formula I, one of X1 and X2 may be S, and the other may be N or CR 3a wherein Y1 and Y2 each may be C, and one of Z1, Z2 and Z3 may be N, and the others each may be CR 3b may be.

[0083] In embodiment (20) of Formula I, R 1 is a 6-membered saturated monocyclic ring containing 1 or 2 (optionally 2) ring N heteroatoms, or a 7-8-membered saturated bridged ring containing 1 or 2 (optionally 2) ring N heteroatoms, with at least one ring N heteroatom being R 1 is not at the attachment point of R 1 is one R 4 is optionally replaced by

[0084] R 2teeth, (i) a (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; R 2 is one or more (possibly 1 or 2) R 5 may be substituted with; R 3a , R 3b and R 3c are each independently H or methyl, if present (optionally R 3a , R 3b and R 3c where 0 or 1 is methyl and the others are H); R 4 is, if present, (C1-6)alkyl optionally substituted with OH, and is (C1-2)alkyl optionally substituted with OH; R 5 If present, is OH or halo.

[0085] In embodiment (20) of Formula I, R 2 may also be a group of the formula:

[0086] [ka]

[0087] where A is O or CH2, p is 1, 2, or 3; 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.

[0088] Embodiments (1)-(7) and (15)-(19) of Formula I can be applied mutatis mutandis to any of the alternatives of embodiment (20) of Formula I.

[0089] In embodiment (21) of Formula I, when one of X1 and X2 is N and the other is O, then Y1 and Y2 are each C, and each of Z1, Z2, and Z3 is CR 3b and each R 3b is H. R 1 is 4-cyclopentylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, or 4-isopropylpiperazin-1-yl, and R 2 is unsubstituted, straight or branched chain (C3-6) alkyl, or unsubstituted (C3-8) cycloalkyl. The remainder may be as defined mutatis mutandis in Formula I, or in any of embodiments (1)-(19) of Formula I described herein.

[0090] Compounds of formula I include compounds of formulas II-IV. Embodiments (1)-(21) of formula I can be applied mutatis mutandis to each of formulas II-IV.

[0091] Also described herein are compounds of Formula II, or pharmaceutically acceptable salts or derivatives thereof:

[0092] [ka]

[0093] In the formula, 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 selected from the group consisting of R 1a is not at the attachment point of R 1a is one or more R 4 may be substituted with;

[0094] X1, X2, Y1, Y2, Z1, Z2, Z3, R2 , R 3a , R 3b , R 3c , R 4 and R 5 is as defined in Formula I or any of Formula I embodiments (5)-(19).

[0095] In the compound of formula II, R 1a is R 1a contains at least one ring N heteroatom that is not the point of attachment to R 1a must be located at a position that is not the point of attachment to the ring containing X1, X2, Y1, and Y2.

[0096] In embodiment (1) of Formula II, one of X1 and X2 is N and the other is O, Y1 and Y2 are each C, and each of Z1, Z2 and Z3 is CR 3b If R 3b is H and R 1a is 4-cyclopentylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, or 4-isopropylpiperazin-1-yl, and R 2 is not unsubstituted, straight or branched chain (C3-6) alkyl or unsubstituted (C3-8) cycloalkyl).

[0097] In embodiment (2) of 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 said (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; (ii)R 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 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; and R 2 is one or more R 5 may be substituted with.

[0098] In embodiment (3) of Formula II, R 1a is a 4- to 10-membered non-aromatic, monocyclic, bridged, or bicyclic ring containing one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom; R 1 is one or more R 4 may be substituted with R 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); a 7- to 8-membered saturated bridged ring containing one or two ring N heteroatoms; or a 9-membered saturated bridged ring containing two ring N heteroatoms and one ring O-heteroatom; or a 7- to 10-membered saturated, fused, or spirocyclic ring containing one or two ring N heteroatoms; 1a may contain one or more R 4 , possibly 1, 2 or 3 R 4 is replaced by

[0099] In embodiment (4) of Formula II, R 1a is a 5- to 6-membered saturated monocyclic ring containing at least one ring N heteroatom and optionally one ring O heteroatom (e.g., containing one ring N heteroatom, two ring N heteroatoms, or one ring N heteroatom and one ring O heteroatom); or a 7- to 8-membered saturated bridged ring containing one or two ring N heteroatoms, and R 1a is one or more R 4 , possibly 1, 2 or 3 R 4 may be substituted with R1a may be a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, optionally at least one ring N heteroatom being R 1a It is not at the connection point of R 1a may be a 6-membered saturated monocyclic ring containing 1 or 2 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 containing 1 or 2 ring N heteroatoms, R 1a is one or more R 4 , possibly 1, 2 or 3 R 4 may be substituted with R 1a may be a 7- to 8-membered saturated bridged ring containing two ring N heteroatoms, e.g., a bridged piperazine such as 3,8-diazabicyclo[3.2.1]octanyl, and R 1a may be one R 4 is replaced by .

[0100] In formula II, or alternatively in embodiment (3) or (4), R 1a is piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each of which may contain 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:

[0101] [ka]

[0102] In the formula, R 1a is an R of 1 or more 4 and R 1a 1-3 R 4and preferably one R 4 may be substituted with R 1a may be piperidinyl, piperazinyl, pyrrolidinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each of which may be one or more R 4 and preferably 1-3 of R 4 and preferably one R 4 may be substituted with R 1a is piperidinyl or piperazinyl, each of which is one or more R 4 and preferably 1-3 of R 4 and preferably one R 4 may be substituted with R 1a may also be a radical of the structure:

[0103] [ka]

[0104] where Z is H or N and R 4 ' is H or R 4 R 1a may be a 7-8 membered saturated bridged ring containing two ring N heteroatoms:

[0105] [ka]

[0106] For example, the following bridged piperazines:

[0107] [ka]

[0108] In Formula II, or alternative embodiments (3) or (4) of Formula II, R1a is one or more R 4 may 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 preferably one R on the ring N atom 4 may be substituted by

[0109] In Formula II, or alternative embodiments (3) or (4) of Formula II, R 1a R can be a 4-10 membered non-aromatic, monocyclic, bridged, or bicyclic ring with 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 containing 1 or 2 ring N heteroatoms, and R 1a may contain one or more R 4 is replaced by .

[0110] In embodiment (5) of Formula II, R 3a , R 3b and R 3c where one or two of R are groups other than H as defined for Formula I or embodiment (15) of Formula I herein, and the others, when present, are each H, preferably R 3a , R 3b and R 3c is a group other than H as defined with respect to Formula I or embodiment (15) of Formula I herein, and each other group present is H.

[0111] The compound may be of the following formula, or a pharmaceutically acceptable salt or derivative thereof:

[0112] [ka]

[0113] R 3bR ' is (C1-6) alkyl, (C1-6) alkoxy, CN or halogen, (C1-6) alkyl and (C1-6) alkoxy optionally substituted by one or more halogens; 3a , R 3b and R 3c If present, all are H; R 1a can be as defined for Formula II or embodiment (3) or embodiment (4) of Formula II.

[0114] Embodiments (1) and (2) of Formula II can be applied mutatis mutandis to any of Embodiments (3)-(5) of Formula II.

[0115] In embodiment (6) of Formula II, 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 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 may be one R 4 is replaced by .

[0116] R 2 teeth, (i) a (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; R 2 is 1 or 2 R 5 may be substituted with; R 3a , R 3b and R 3c are each independently H or methyl, if present (optionally R 3a , R 3b and R 3c 0 or 1 of which is methyl, and the others are H); R 4is, if present, (C1-6) alkyl optionally substituted with OH, (C1-2) alkyl optionally substituted with OH; R 5 If there is R 5 is OH or halo.

[0117] In embodiment (6) of Formula II, R 2 may be a group of the formula:

[0118] [ka]

[0119] where A is O or CH2 and 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, such as CF2.) Ph may be absent.

[0120] Formula II embodiment (1) can be applied mutatis mutandis to Formula II embodiment (6).

[0121] In Formula II or an embodiment of Formula II, one of X1 and X2 is N and the other is N or CR 3a wherein one of Y1 and Y2 is N and the other is C; and one of Z1, Z2 and Z3 is N or CR 3b and the others may be CR 3b Alternatively, one of X1 and X2 may be S and the other may be N or CR. 3a Y1 and Y2 may each be C; one of Z1, Z2 and Z3 may be N and the others may each be CR 3b may be.

[0122] In Formula II or an embodiment of Formula II, the compound can be selected from the following formulae:

[0123] [ka]

[0124] Also described herein are compounds of Formula III, or pharmaceutically acceptable salts or derivatives thereof:

[0125] [ka]

[0126] 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 (C5-6)cycloalkyl group; R 2a is one or more R 5 may be substituted with; X1, X2, Y1, Y2, Z1, Z2, Z3, R 1 , R 3a , R 3b , R 3c , R 4 and R 5 is as defined in Formula I or any of embodiments (1)-(8) or (15)-(19) of Formula I.

[0127] R 2a is a (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms, where R 2a may contain one or more R 5 is replaced by R 2aR 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 is optionally substituted with one halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy.

[0128] In embodiment (2) of Formula III, R 2a is a 5-7 membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6 membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms, where R 2a is one or more R 5 may be substituted with R 2aR may be 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, (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 halogen, wherein the (Ci_4) alkyl and (Ci_4) alkoxy groups are optionally substituted with one or more fluoro. 2a 1-3 R 5 , preferably one R 5 In any of the alternatives of embodiment (2), R may be chroman or tetrahydropyran optionally substituted with 2a is optionally substituted with one halogen, OH, CN, (C1-4) alkyl or (C1-4) alkoxy.

[0129] According to embodiment (1) or (2) of formula III, R 2a may be a (C5-6)cycloalkyl fused to a phenyl ring, or a 5- to 6-membered heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring; R 2a is optionally substituted.

[0130] In embodiment (3) of Formula III, R 2a There are at least two R 5 R is a (C5-6)cycloalkyl group substituted with 2a For example, two R 5 It may be cyclohexyl or cyclopentyl substituted with R 2a is optionally substituted with two or more halogen, (C1-4)alkoxy, or OH. In any of the alternatives of embodiment (3), R 2ais optionally substituted on one or more ring carbons with two or more 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. 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 a single ring carbon atom).

[0131] In embodiment (4) of Formula III: R 1 is a 6-membered saturated monocyclic ring containing 1 or 2 (optionally 2) ring N heteroatoms, or a 7- to 8-membered saturated bridged ring 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 may be one R 4 is replaced by

[0132] 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 fused to a phenyl ring; or (iv) (C5-6) cycloalkyl group; R 2a is 1 or 2 R 5 and R 2a is (iv) a (C5-6) cycloalkyl group, two R 5 is replaced by; R 3a , R 3b and R 3c are each independently H or methyl, if present (optionally R 3a , R 3b and R3c where 0 or 1 is methyl and the others are H); R 4 is, if present, (C1-6) alkyl optionally substituted with OH, (C1-2) alkyl optionally substituted with OH; R 5 If there is R 5 is OH or halo.

[0133] According to embodiments (1)-(4) of Formula III, R 2a may be the following groups:

[0134] [ka]

[0135] where A is O or CH2, 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., 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.

[0136] In embodiment (5) of Formula III, R 3a , R 3b and R 3c where one or two of R are groups other than H as defined for Formula I or embodiment (15) of Formula I herein, and the others, when present, are each H; preferably, R 3a , R 3b and R 3c is a group other than H as defined with respect to Formula I or embodiment (15) of Formula I herein, and each other group present is H.

[0137] The compound can be of the following formula or a pharmaceutically acceptable salt or derivative thereof:

[0138] [ka]

[0139] R 3b R ′ is (C 1-6 )alkyl, (C 1-6 )alkoxy, CN or halogen, (C 1-6 )alkyl and (C 1-6 )alkoxy optionally substituted with one or more halogens; 3a , R 3b and R 3c If present, then all are H. 2a can be as defined in Formula III or any of embodiments (1)-(4) of Formula III.

[0140] In embodiment (6) of Formula III, R 2a is according to embodiment (2) or embodiment (3) of formula III.

[0141] In embodiment (7) of Formula III, R 1 is according to embodiment (4) of formula I, and R 2a is according to embodiment (3) of Formula III. The remainder may be as defined in Formula III or any of the embodiments of Formula III described herein, mutatis mutandis. R 1 may be a 7-8 membered saturated bridged ring containing 1 or 2 ring N heteroatoms, R 1 is one R 4 and R 2a R can be according to embodiment (3) of formula III. 1 may be a 7-8 membered saturated bridged ring 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 R may be a (C5-6)cycloalkyl substituted with 1may be a 7-8 membered saturated bridged ring containing 1 or 2 ring N heteroatoms, where R 1 is one R 4 may be substituted with R 2a is two or more R 5 In some cases, R 5 may be a halogen. n is 0 or 1.

[0142] In embodiment (8) of Formula III, when one of X1 and X2 is S and the other is N, Y1 and Y2 are each C, one of Z1, Z2, and Z3 is N, and R 2a is (iv) a (C5-6) cycloalkyl group, and R 2a is at least two R 5 The remainder may be as defined for Formula III or any embodiment of Formula III described herein, mutatis mutandis.

[0143] In Formula III or any of the embodiments of Formula III, one of X1 and X2 is N and the other is N or CR 3a wherein one of Y1 and Y2 is N and the other is C; and one of Z1, Z2 and Z3 is N or CR 3b and the others may be CR 3b Alternatively, one of X1 and X2 may be S and the other may be N or CR. 3a Y1 and Y2 may each be C; one of Z1, Z2 and Z3 may be N and the others may each be CR 3b may be.

[0144] In any of the Formula III or Formula III embodiments, the compound can be selected from the following formulae:

[0145] [ka]

[0146] Also described herein is a compound of Formula IV, or a pharmaceutically acceptable salt or derivative thereof:

[0147] [ka]

[0148] Each R 3a are independently H or (C1-6) alkyl, where (C1-6) alkyl may be substituted with one or more halogens.

[0149] Each R 3b are independently H, (Ci_6) alkyl, (Ci_6) alkoxy, CN or halogen, and the (Ci_6) alkyl and (Ci_6) alkoxy may be substituted with one or more halogens, and wherein at least one R 3b is other than H; Each R 3c is independently H or (C1-6) alkyl, wherein (C1-6) alkyl is optionally substituted with one or more halogens; and X1, X2, Y1, Y2, Z1, Z2, Z3, R 1 , R 2 , R 4 and R 5 is as defined in Formula I or any of embodiments (1)-(15) or (18)-(19) of Formula I above.

[0150] In embodiment (1) of Formula IV, R 3a , R 3b and R 3c where one or two of R are groups other than H as defined for Formula I or embodiment (15) of Formula I herein, and the others, when present, are each H. Preferably, one R 3b is a group other than H as defined for Formula I or embodiment (15) of Formula I described herein. Each other, when present, is H.

[0151] The compound may be of the following formula or a pharmaceutically acceptable salt or derivative thereof:

[0152] [ka]

[0153] R 3b R ' is (C1-6) alkyl, (C1-6) alkoxy, CN or halogen, (C1-6) alkyl and (C1-6) alkoxy optionally substituted by one or more halogens; 3a , R 3bお Yobi R 3c are all H, if present.

[0154] In Formula IV or any of the embodiments of Formula IV, one of X1 and X2 is N and the other is N or CR 3a wherein one of Y1 and Y2 is N and the other is C; and one of Z1, Z2 and Z3 is N or CR 3b and the others may be CR 3b Alternatively, one of X1 and X2 may be S and the other may be N or CR. 3a Y1 and Y2 may each be C; one of Z1, Z2 and Z3 may be N and the others may each be CR 3b may be.

[0155] In further embodiments of the compounds of Formulas I-IV or pharmaceutically acceptable salts thereof, including any of the above embodiments, one or more hydrogen atoms are 2 and is substituted with H. The remainder applies mutatis mutandis to any aspect or embodiment of Formulae I-IV described herein.

[0156] In one embodiment, the compound of formula I is selected from: (S)-N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)-N-(chroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)-N-(6-chlorochroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(6-chlorochroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)-2-(1-methylpiperidin-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(1-methylpiperidin-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)-N-(6-chlorochroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(6-chlorochroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide;

[0157] (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(pyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(piperazin-1-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-1-methyl-2-(piperazin-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;

[0158] (S)-N-(chroman-4-yl)-2-(2,6-dimethylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-morpholino-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(2,3-Dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(chroman-4-yl)-2-(4-hydroxypiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;

[0159] (S)-N-(chroman-4-yl)-2-morpholino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(chroman-4-yl)-2-(piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylimidazo[1,2-a]pyridine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(clonan-4-yl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-Cyclohexyl-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;

[0160] N-(4,4-difluorocyclohexyl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-Cyclopentyl-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-Cyclohexyl-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(2,3-dihydro-1H-inden-1-yl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxamide; N-Cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-Cyclopentyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-Cyclohexyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4-fluorobenzyl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide;

[0161] N-(4,4-difluorocyclohexyl)-2-(1-ethylpiperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)-N-(chroman-4-yl)-7-methyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-7-methyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-Cyclopentyl-2-(piperidin-4-yl)benzo[d]oxazole-5-carboxamide; N-Cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]oxazole-5-carboxamide; N-Cyclopentyl-2-(1-ethylpiperidin-4-yl)benzo[d]oxazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-Cyclopentyl-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-Cyclopentyl-2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide; (S)-N-(chroman-4-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-Cyclopentyl-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxamide; N-Cyclopentyl-2-(piperazin-1-yl)benzo[d]oxazole-6-carboxamide; (S)-N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxamide; N-Cyclopentyl-2-(piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide; N-Cyclopentyl-2-(1-methylpiperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide;

[0162] N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylthiazolo[5,4-b]pyridine-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thiazolo[5,4-b]pyridine-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thiazolo[4,5-b]pyridine-6-carboxamide; N-Cyclopentyl-2-(piperidin-4-yl)thiazolo[4,5-b]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylthiazolo[4,5-c]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thiazolo[4,5-c]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylthieno[3,2-b]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thieno[3,2-b]pyridine-6-carboxamide; and pharmaceutically acceptable salts or derivatives thereof.

[0163] In a further embodiment of the compound of formula I, R 1 may be as defined above in any of the compounds of formula I. In further embodiments of the compounds of formula I, R 2 may be as defined in any of the compounds of formula I above.

[0164] 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.

[0165] The term "carbocycle" refers to a ring system in which all ring atoms are carbon, which may be saturated, partially unsaturated, or aromatic. The term "heterocycle" refers to a ring system in which one or more ring atoms are a heteroatom, such as O, S, or N. A "non-aromatic carbocycle or heterocycle" may be saturated or partially unsaturated. Carbocycles and heterocycles may be bicyclic or polycyclic ring systems, such as bicyclic or polycyclic fused ring systems, or bicyclic or polycyclic spiro ring systems, or combinations thereof. Each ring within a fused ring system may independently be saturated, partially unsaturated, or aromatic. Examples of such fused bicyclic ring systems include indane and chroman. Non-aromatic carbocycles or heterocycles may include fused ring systems, for example, in which two rings share two adjacent atoms; bridged ring systems, for example, in which two rings share three or more adjacent atoms; or spiro ring systems, for example, in which two rings share one adjacent atom. Examples of fused ring systems include octahydropyrrolo[1,2-a]pyrazine and octahydro-2H-pyrido[1,2-a]pyrazine. Bridged rings may contain three or more rings. Examples of such bridged ring systems include 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, and 3,8-diazabicyclo[3.2.1]octane. Examples of spiro rings include spiro[4.3]octane and 2,6-diazaspiro[3.4]octane. In all of the above examples, the carbocyclic or heterocyclic ring may be optionally substituted as defined herein. When a ring is referred to herein as containing a particular ring heteroatom, it will be understood that there are no additional ring heteroatoms beyond the particular one.

[0166] "Monocyclic, bridged, or bicyclic ring" includes monocyclic, bridged, and bicyclic ring systems. "Monocyclic, bridged, or bicyclic rings" may be saturated, partially unsaturated, or aromatic, unless otherwise specified. They may be aromatic, heteroaromatic, carbocyclic, or heterocyclic, or combinations thereof. Bicyclic ring systems may include fused and spiro rings.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] The term "halogen" means F, Cl, Br or I. F and Cl are particularly preferred, with F being most preferred.

[0172] 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).

[0173] 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.

[0174] Without wishing to be bound by theory, the compounds described herein may act as PDE4 long-chain form activators. The compounds described herein are small molecules that are believed to directly bind to PDE4 long-chain forms and induce conformational changes that increase, stabilize, exert, and / or maintain the catalytic activity of these enzymes. Without being bound by theory, activation of PDE4 long-chain form by PDE4 long-chain form activators may be sensitive to the regulatory status of the enzyme, such as post-translational modifications (e.g., phosphorylation), specific physiological locations, or the introduction of protein-protein complexes associated with the context of cellular or biochemical assays. PDE4 long-chain form activators may exhibit enzyme activation in one or more states, but not necessarily in all states.

[0175] In the field of pharmacology, as used herein, a small molecule is defined as a low molecular weight organic compound capable of regulating biological processes. Preferred small molecule activators according to the present invention have a molecular weight of 700 daltons or less, which allows for rapid diffusion across cell membranes and allows them to reach the intracellular site of action (Veber, DF et al., J. Med. Chem. 45: 2615-2623, 2002). Particularly preferred small molecule activators according to the present invention have a molecular weight of 250 daltons or more and 500 daltons or less (Lipinski, CA Drug Discovery Today: Technologies 1: 337-341, 2004).

[0176] 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 [3 H] 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).

[0177] Using the assay procedures described above, as detailed in Experiment 1, preferred small molecule activators of the present invention produce an increase in background activity of one or more PDE4 long form(s) by 20% or more or 30% or more at test compound concentrations of 100 micromolar or less. Particularly preferred compounds according to the present invention produce an increase in background activity of one or more PDE4 long form(s) by 20% or more or 30% or more at concentrations of 10 micromolar or less, e.g., 3 micromolar.

[0178] 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).

[0179] Under the same assay conditions, as described in Experiment 1, compounds of the present invention produce less than a 30% or less than a 20% increase in background activity of the short or ultrashort forms of the PDE4A, PDE4B, PDE4C, or PDE4D enzymes at test compound concentrations of 100 micromolar or less. 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.

[0180] 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.

[0181] 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.

[0182] 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

[0183] [Table 1]

[0184] *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

[0185] Table B - Examples of known PDE4B isoforms

[0186] [Table 2]

[0187] Table C - Examples of known PDE4C isoforms

[0188] [Table 3]

[0189] Table D - Examples of known PDE4D isoforms

[0190] [Table 4]

[0191] 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).

[0192] In one aspect, the present invention provides a compound described herein (i.e., a small molecule activator of the PDE4 long chain form) for use in a method for treating or preventing a condition by reducing second messenger responses mediated by cyclic 3',5'-adenosine monophosphate (cAMP).

[0193] 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.

[0194] 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.

[0195] Diseases that are ameliorated by activation of the long isoform of PDE4 or that are characterized by elevated cAMP levels

[0196] 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).

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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).

[0204] 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.

[0205] 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.

[0206] 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).

[0207] Therefore, the PDE4 long form activators of the present invention are expected to be effective in treating, preventing or partially controlling polycystic kidney disease.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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:

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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).

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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).

[0224] 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).

[0225] 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.

[0226] 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).

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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).

[0233] 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).

[0234] 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).

[0235] 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).

[0236] 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).

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] Treatment method The compounds described herein can be used to treat or prevent diseases or disorders that can be improved by activating the long chain isoform of PDE4.The compounds described herein can be used to treat or prevent diseases or disorders that are mediated by excessive intracellular cyclic AMP signaling. The compounds described herein can be used to treat or prevent diseases or disorders mediated by excessive intracellular cyclic AMP signaling, which can be improved by activating the long-chain isoform of PDE4.In a further aspect, the present invention provides a small molecule activator of the PDE4 long-chain isoform 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 mediated by excessive intracellular cyclic AMP signaling, which comprises 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, which comprises 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.

[0246] 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.

[0247] The compounds described herein may be provided as solvates, for example, hydrates.

[0248] 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.

[0249] The term "pharmaceutically acceptable salts" includes salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and bases. Compounds of the present invention that contain a basic group, such as an amino group, can form pharmaceutically acceptable salts with acids. Examples of pharmaceutically acceptable acid addition salts of compounds of the present invention include acid addition salts made with organic carboxylic acids, such as acetic acid, lactic acid, tartaric acid, maleic acid, citric acid, pyruvic acid, oxalic acid, fumaric acid, oxaloacetic acid, isethionic acid, lactobionic acid, and succinic acid; organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid.

[0250] 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.

[0251] 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).

[0252] Prodrug The compounds of the present invention can be provided as prodrugs. Prodrugs are derivatives of the compounds described herein (which may themselves have little or no pharmacological activity) and are compounds that can be converted into the compounds described herein when applied in vivo.

[0253] Prodrugs can be produced, for example, by substituting a functional group in a compound described herein at a suitable site that is metabolized in vivo to form a compound described herein. The design of prodrugs is known in the art, as discussed in Bundgaard, Design of Prodrugs 1985 (Elsevier), The Practice of Medicinal Chemistry 2003, 2nd Ed., 561-585 and Leinweber, Drug Metab. Res. 1987, 18: 379.

[0254] In vivo metabolism of prodrugs of the compounds described herein includes, for example, hydrolysis, oxidative metabolism, or reductive metabolism of the prodrug. Examples of prodrugs of the compounds described herein are amides and esters of those compounds, which are hydrolyzed in vivo. For example, if a compound described herein contains a carboxylic acid group (—COOH), a hydrogen atom of the carboxylic acid group can be substituted to form an ester group (e.g., replacing the hydrogen atom with C 1-6 If the compound contains an alcohol group (-OH), the hydrogen atom of the alcoholic group can be substituted to form an ester (e.g., the hydrogen atom can be substituted with -C(O)C 1-6 (substituted with alkyl). Additionally, examples of prodrugs of the compounds described herein include pyridine N-oxides, which are reductively metabolized in vivo to form compounds described herein having a pyridine ring.

[0255] 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).

[0256] Isomers It will be appreciated that the compounds of the present invention may exist in various stereoisomeric forms. The compounds of the present invention include all stereoisomeric forms, including enantiomers and racemic mixtures. The present invention includes within its scope the use of any stereoisomer of the compounds described herein, or mixtures of stereoisomers, individual enantiomers, or wholly or partially racemic mixtures of such enantiomers, wherein appropriate isomers can be separated from such mixtures by the use or adaptation of known methods (e.g., chromatographic and recrystallization techniques). wherein appropriate isomers can be prepared by the use or adaptation of known methods (e.g., asymmetric synthesis). Furthermore, in some instances, the compounds of the present invention may exist in deuterated isomeric forms, and the compounds of the present invention herein encompass deuterated isomers and mixtures thereof.

[0257] isotope The present invention includes pharmaceutically acceptable isotopically labeled compounds of the compounds described herein 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.

[0258] 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 and 14 C is particularly useful for this purpose given the ease of detection and means of incorporation. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0259] 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)].

[0260] 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.

[0261] 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).

[0262] 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).

[0263] The pharmaceutical composition may further comprise an adjuvant and / or one or more additional therapeutically active agents.

[0264] The pharmaceutical composition may be provided in unit dosage form, generally in a hermetically sealed container, and may be provided as part of a kit. Such a kit will usually (but not necessarily) include instructions for use. It may include a plurality of said unit dosage forms.

[0265] 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.

[0266] For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions, and the like.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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).

[0271] Tablet formulations are discussed in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets 1980, vol. 1 (Marcel Dekker, New York).

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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)).

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] In one embodiment, the other therapeutic agent is: (i) a presynaptic α-2 adrenergic receptor agonist, optionally clonidine, dedexmedetomidine, or guanfacine; (ii) beta-1 adrenergic receptor antagonists ("beta-blockers"), optionally atenolol, metoprolol, bisoprolol; Acebutolol or Betaxolol.

[0293] example The invention will now be further described by the following non-limiting examples with reference to tables and figures. Table 1 shows the structures of Examples 1-122 of small molecule PDE4 long chain conformation activators according to the present invention. Table 2 shows the enzyme assay data for PDE4D5, the long form of PDE4. Table 3 shows enzyme assay data for PDE4B2, the truncated form of PDE4. Table 4 shows the inhibition of PGE2-stimulated cyst formation in 3D cultures of m-IMCD3 kidney cells treated with compounds of the invention.

[0294] FIG. 1 shows the concentration-dependent activation of the PDE4 long form PDE4D5 according to Example 4. FIG. 2 shows concentration-dependent inhibition of PGE2-stimulated cyst formation in 3D cultures of m-IMCD3 cells treated with Example 51.

[0295] Experiment details Preparation of Examples 1-122 The reaction was analyzed by thin layer chromatography (Merck Millipore TLC Silica Gel 60 F 254 ) were monitored. Flash column chromatography was performed on a Biotage Isolera® or Buchi Reveleris® X2 flash chromatography system using prepacked silica gel columns. NMR spectra were recorded on a Bruker 300 or 400 MHz spectrometer at 25°C using the residual signal of the deuterated solvent as an internal reference. In some cases, 1 The 1 H NMR spectrum did not distinguish exchangeable NH and OH residues.

[0296] A typical preparative HPLC method is as follows: Method A (preparative HPLC using formic acid as buffer): MS instrument type: ACQ-SQD2; HPLC instrument type: Waters modular preparative HPLC system. Column: Waters XSelect (C18, 100x30mm, 10µm); Flow rate: 55mL / min prep pump; Column temperature: room temperature. Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile; gradient: t = 0 min 2% B, t = 4 min 2% B, t = 13 min 30% B, t = 14.5 min 100% B, t = 17 min 100% B; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) mass range: 100-800; fraction collection based on MS and DAD.

[0297] Method B (preparative HPLC using ammonium bicarbonate as buffer): MS instrument type: Agilent Technologies G6130B Quadrupole HPLC; Instrument type: Agilent Technologies 1290 Preparative LC; Column: Waters XSelect CSH (C18, 150 x 19 mm, 10 μL); Flow rate: 25 mL / min. Column temperature: room temperature; Eluent A: 10 mM ammonium bicarbonate aqueous solution, pH = 9.5; Eluent B: 100% acetonitrile; Gradient: t = 0 min 10% B, t = 2.5 min 10% B, t = 11 min 50% B, t = 13 min 100% B, t = 17 min 100% B; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) mass range: 100-1000; Fractions were collected based on MS and DAD.

[0298] 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 (hour), HOBt (hydroxybenzotriazole), MW (microwave), rt (room temperature), SEM [2-(trimethylsilyl)ethoxymethyl], SFC (supercritical fluid chromatography), TBDPS (tert-butyldiphenylsilyl), THF (tetrahydrofuran). The following abbreviations are used for NMR signal assignments: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), app (approximate), br (broad), dd (double doublet), dt (double triplet), and td (triple doublet). In the following chemical formulas, "STEP" represents a step, "Example" represents an example, and "Scheme" represents a scheme.

[0299] General Procedure 1: Synthesis of Chiral Amines

[0300] [ka]

[0301] (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.

[0302] 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: (S)-N-(chroman-4-ylidene)-2-methylpropane-2-sulfinamide; (S)-N-(6-chlorochroman-4-ylidene)-2-methylpropane-2-sulfinamide.

[0303] Similarly, the corresponding (R)-configured sulfinamide can be made by substituting (R)-2-methylpropane-2-sulfinamide for (S)-2-methylpropane-2-sulfinamide.

[0304] 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. (S)-N-[(S)-6-chroman-4-yl]-2-methylpropane-2-sulfinamide; (S)-N-[(S)-6-chlorochroman-4-yl]-2-methylpropane-2-sulfinamide.

[0305] Similarly, the corresponding (R-configuration sulfinamide) can be prepared using the enantiomeric (R)-sulfinamide starting material.

[0306] 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: (S)-chroman-4-amine·HCl; (S)-6-Chlorochroman-4-amine·HCl.

[0307] Similarly, the corresponding R-configuration amine can be prepared using the enantiomer (the R-configuration 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 to remove the base, drying the separated organic phase (NaSO), and then recovering the free base amine by evaporation.

[0308] Example 1-4 Examples 1-4 can be prepared according to the route shown in Scheme 1.

[0309] [ka]

[0310] General procedure for step 1 (Scheme 1): To a solution of 3,4-diaminobenzoic acid (1.0 equiv.) and NaSO (1.3 equiv.) in DMF (12 vol.) was added the nicotinaldehyde derivative (1.0 equiv.). The reaction was stirred at 100° C. for 16 hours, then cooled to room temperature, quenched with ice water (15 vol.), and stirred for 15 minutes. The solid precipitate was filtered off and dried under vacuum to give the 2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid derivative as a brown solid.

[0311] General procedure for step 2 (Scheme 1): To a solution of 2-(pyridin-3-yl)-1H-benzo{d}imidazole-5-carboxylic acid derivative (1.0 equiv.) in DMF (12 vol.) was added DIPEA (3.0 equiv.), HOBt (2.0 equiv.), and EDC·HCl (2.0 equiv.), and the mixture was stirred at room temperature for 15 min. (S)-chroman-4-amine hydrochloride (1.1 equiv.) was then added. The reaction mixture was stirred at room temperature for 16 h, then quenched with ice water (15 vol.) and stirred for 10 min. The solid precipitate was filtered off and dried under vacuum to give the crude product, which was purified by flash chromatography using 5%-15% MeOH in DCM as eluent to give the required product as an off-white solid.

[0312] Example 1: (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 1 using 4-methylnicotinaldehyde as the nicotinaldehyde derivative in Step 1. 1 H NMR: δ H(400 MHz, DMSO-d6) 8.94 (1H, d, J 1.6), 8.86 (1H, d, J 8.0), 8.57 - 8.55 (1H, m), 8.37 (1H, s), 8.16 (1H, s), 7.91 (1H, dd, J 8.4, 1.6), 7.62 (1H, d, J 8.4), 7.47 - 7.45 (1H, m), 7.23 - 7.15 (2H, m), 6.89 (1H, t, J 7.2), 6.81 (1H, d, J 8.0), 5.38 - 5.31 (1H, m), 4.37 - 4.34 (1H, m), 4.28 - 4.24 (1H, m), 2.66 (3H, s), 2.14 - 2.08 (2H, m).

[0313] Example 2: (S)-N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 1 using 6-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 13.23 (1H, s), 9.24 (1H, s), 8.92 - 8.84 (1H, m), 8.41 (1H, d, J 8.0), 8.31 (1H, s), 7.89 - 7.82 (1H, m), 7.73 - 7.59 (1H, m), 7.48 (1H, d, J 8.0), 7.22 (1H, d, J 7.6), 7.17 (1H, t, J 8.4), 6.89 (1H, t, J 7.2), 6.82 (1H, d, J 8.0), 5.35 (1H, d, J 6.4), 4.37 - 4.33 (1H, m), 4.29 - 4.24 (1H, m), 2.57 (3H, s), 2.16 - 2.13 (2H, m).

[0314] Example 3: (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 1 using 2-methylnicotinaldehyde as the nicotinaldehyde derivative in Step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 13.03 (1H, s), 8.93 - 8.85 (1H, m), 8.61 - 8.59 (1H, m), 8.37 (1H, s), 8.16 (1H, d, J 8.0), 7.91 - 7.85 (1H, m), 7.76 (1H, d, J 8.4), 7.47 - 7.43 (1H, m), 7.22 (1H, d, J 7.6), 7.17 (1H, t, J 7.6), 6.89 (1H, t, J 7.6), 6.81 (1H, d, J 8.4), 5.38 - 5.31 (1H, m), 4.38 - 4.33 (1H, m), 4.29 - 4.24 (1H, m), 2.83 (3H, s), 2.14 - 2.08 (2H, m).

[0315] Example 4: (S)—N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 1 using 5-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR:δ H(400 MHz, DMSOd6) 13.28 (1H, s), 9.17 (1H, d, J 1.6), 8.85 (1H, dd, J 8.0, 2.4), 8.55 (1H, d, J 8.0), 8.35 (1H, dd, J 8.0, 2.4), 8.13 (1H, s), 7.88 (1H, dd, J 8.6, 1.2), 7.72 (1H, d, J 8.4), 7.21 (2H, d, J 7.6), 6.91 (2H, d, J 7.6), 5.35 (1H, q, J 6.8), 4.38 - 4.24 (2H, m), 2.49 (3H, s), 2.14 - 2.13 (2H, m).

[0316] Example 5-12 Examples 5-12 can be prepared according to the route shown in Scheme 2.

[0317] [ka]

[0318] Step 1 (Scheme 2): Synthesis of 2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid To a solution of 3,4-diaminobenzoic acid (1.5 g, 9.85 mmol) in DMF (20.0 mL) were added sodium thiosulfate (2.33 g, 14.8 mmol) and nicotinaldehyde (1.25 g, 11.8 mmol), and the mixture was stirred at 100 °C for 16 hours. The mixture was diluted with ice-cold water, and the resulting solid was filtered off and washed with water (30 mL). The filtrate was dried under vacuum to give 2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid (1.2 g, 51%) as a brown solid.

[0319] Step 2 (Scheme 2): Synthesis of Examples 5-12 To a solution of 2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid (1.0 equiv.) in DMF (12 vol.) was added DIPEA (3.0 equiv.), HOBt (2.0 equiv.), and EDC·HCl (2.0 equiv.), and the mixture was stirred at room temperature for 15 minutes. An amine (1.1 equiv.) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with ice water and stirred for 10 minutes. The solid precipitate was collected by filtration and purified by flash chromatography, eluting with 5%-15% methanol in DCM, to give Examples 5-12 as off-white solids.

[0320] Example 5: (R)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 2 using (1R)-1,2,3,4-tetrahydronaphthalen-1-amine as the amine in Step 2. 1 H NMR: δ H 400 MHz, DMSOd6) 13.34 (1H, s), 9.37 (1H, s), 8.81 (1H, s), 8.71 (1H, d, J 4.0), 8.52 (1H, d, J 8.0), 8.32 (1H, br s), 7.86 (1H, s), 7.63 - 7.60 (2H, m), 7.25 - 7.16 (4H, m), 5.30 (1H, t, J 8.0), 2.79 - 2.67 (2H, m), 1.88 - 1.79 (4H, m).

[0321] Example 6: (S)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 2 using (1S)-1,2,3,4-tetrahydronaphthalen-1-amine as the amine in Step 2. 1 H NMR:δ H(400 MHz, DMSO-d6) 13.34 (1H, s), 9.36 (1H, d, J 1.6), 8.80 (1H, d, J 8.8), 8.71 (1H, d, J 1.6), 8.53 - 8.50 (1H, m), 8.24 (1H, s), 7.86 (1H, d, J 8.4), 7.68 - 7.60 (2H, m), 7.24 - 7.23 (4H, m), 5.29 (1H, d, J 3.6), 2.79 - 2.51 (2H, m), 2.02 - 2.00 (2H, m), 1.88 - 1.79 (2H, m).

[0322] Example 7: (R)—N-(chroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 2 using (R)-chroman-4-amine as the amine in step 2. 1 H NMR: δ H (400 MHz, DMSOd6) 13.29 (1H, s), 9.36 (1H, s), 8.89 (1H, d, J 5.6), 8.71 (1H, t, J 1.2), 8.51 (1H, d, J 8.0), 8.34 (1H, br s), 7.86 (1H, d, J 7.2), 7.63 - 7.60 (2H, m), 7.22 - 7.14 (2H, m), 6.88 (1H, t, J 7.2), 6.81 (1H, d, J 8.4), 5.34 (1H, q, J 6.4), 4.36 - 4.32 (1H, m), 4.27 - 4.23 (1H, m), 2.13 - 2.09 (2H, m).

[0323] Example 8: (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 2 using (S)-chroman-4-amine as the amine in step 2. 1 H NMR: δH H (400 MHz, DMSO-d6) 13.34 (1H, s), 9.37 (1H, d, J 1.6), 8.90 (1H, d, J 8.4), 8.71 (1H, dd, J 4.8, 1.2), 8.52 (1H, d, J 8.0), 8.24 (1H, s), 7.87 (1H, d, J 8.0), 7.64 - 7.60 (2H, m), 7.23 - 7.15 (2H, m), 6.91 - 6.87 (2H, m), 5.34 (1H, q, J 6.8), 4.38 - 4.23 (2H, m), 2.14 - 2.10 (2H, m).

[0324] Example 9: (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 2 using (R)-1-aminoindan as the amine in Step 2. 1 H NMR: δ H (400 MHz, DMSO-d6) 13.33 (1H, s), 9.37 (1H, d, J 1.2), 8.80 (1H, s), 8.71 (1H, d, J 3.6), 8.52 (1H, d, J 8.0), 8.29 - 8.22 (1H, m), 7.87 (1H, d, J 8.0), 7.71 - 7.60 (2H, m), 7.30 - 7.18 (4H, m), 5.64 (1H, d, J 8.0), 3.05 - 2.99 (1H, m), 2.91 - 2.83 (1H, m), 2.33 - 2.30 (1H, m), 2.07 - 2.02 (1H, m).

[0325] Example 10: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 2 using (S)-1-aminoindan as the amine in Step 2. 1 H NMR: δ H (400 MHz, DMSO-d6) 13.33 (1H, s), 9.37 (1H, s), 8.80 (1H, d, J 5.6), 8.71 (1H, d, J 1.6), 8.52 (1H, dd, J 8.0, 1.6), 8.24 (1H, s), 7.86 (1H, d, J 8.0), 7.63 - 7.60 (2H, m), 7.27 - 7.18 (4H, m), 5.60 (1H, t, J 7.6), 3.33 - 3.32 (1H, m), 3.05 - 2.99 (1H, m), 2.91 - 2.85 (1H, m), 2.07 - 2.01 (1H, m).

[0326] Example 11: (R)—N-(6-chlorochroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 2 using (R)-6-chlorochroman-4-amine as the amine in Step 2. 1 H NMR: δ H (400 MHz, DMSO-d6) 13.32 (1H, s), 9.38 (1H, s), 8.93 (1H, d, J 7.1), 8.72 (1H, d, J 4.6), 8.53 (1H, d, J 6.5), 8.26 (1H, s), 7.87 (1H, d, J 8.1), 7.64 - 7.61 (2H, m), 7.22 (2H, d, J 6.4), 6.86 (1H, d, J 9.4), 5.34 (1H, d, J 6.9), 4.38 - 4.27 (2H, m), 2.15 - 2.14 (2H, m).

[0327] Example 12: (S)—N-(6-chlorochroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 2 using (S)-6-chlorochroman-4-amine as the amine in Step 2. 1 H NMR: δ H (400 MHz, DMSO-d6) 13.32 (1H, s), 9.38 (1H, s), 8.93 (1H, d, J 7.1), 8.72 (1H, d, J 4.6), 8.53 (1H, d, J 6.5), 8.26 (1H, s), 7.87 (1H, d, J 8.1), 7.64 - 7.61 (2H, m), 7.22 (2H, d, J 6.4), 6.86 (1H, d, J 9.4), 5.34 (1H, d, J 6.9), 4.38 - 4.27 (2H, m), 2.15 - 2.14 (2H, m).

[0328] Example 13-18 Examples 13-18 can be prepared according to the route shown in Scheme 3.

[0329] [ka]

[0330] Step 1 (Scheme 3): Synthesis of methyl 4-amino-3-(1-methylpiperidine-4-carboxamido)benzoate To a solution of 1-methylpiperidine-4-carboxylic acid (1.0 g, 8.54 mmol) in DMF (1.0 mL) were added DIPEA (1.47 mL, 25.6 mmol), HOBt (1.73 g, 12.8 mmol), and EDC·HCl (2.44 g, 12.8 mmol). The mixture was stirred at room temperature for 15 minutes. Methyl 3,4-diaminobenzoate (1.41 g, 8.54 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL), and the organic components were extracted with 10% MeOH in DCM (2 × 50 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 10% methanol in dichloromethane to give methyl 4-amino-3-(1-methylpiperidine-4-carboxamido)benzoate (0.9 g, 44%) as a brown solid.

[0331] Step 2 (Scheme 3): Synthesis of methyl 2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxylate A solution of methyl 4-amino-3-(1-methylpiperidine-4-carboxamido)benzoate (0.90 g, 3.43 mmol) in acetic acid (15 ml) was stirred for 16 hours at 110° C. The reaction mixture was concentrated under reduced pressure to give methyl 2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxylate (0.8 g, 95%) as a brown solid.

[0332] Step 3 (Scheme 3): Synthesis of 2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxylic acid To a solution of methyl 2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxylate (0.70 g, 2.56 mmol) in THF:HO (3:1; 15 mL) was added LiOH·HO (0.21 g, 5.12 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water, acidified to pH 2-3 with 1.5 N aqueous HCl, and concentrated under reduced pressure to give 2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxylic acid (0.6 g, 90%) as an off-white solid.

[0333] General procedure for Step 4 (Scheme 3): Amide coupling To a solution of 2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxylic acid (1 equivalent) in DMF (10 volumes) was added DIPEA (3 equivalents), HOBt (1.5 equivalents), and EDC·HCl (1.5 equivalents). The mixture was stirred at room temperature for 15 minutes. An amine (1 equivalent) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with ice water and stirred for 10 minutes. The solid precipitate was collected by filtration and purified by preparative HPLC to give Examples 13-18 as white solids.

[0334] Example 13: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 3 using (S)-1-aminoindan as the amine in step 4. 1 H NMR: δ H (400 MHz, DMSO-d6) 12.38 (1H, d, J 9.2), 8.73 - 8.65 (1H, m), 8.16 - 8.01 (1H, m), 7.78 - 7.72 (1H, m), 7.57 - 7.43 (1H, m), 7.28 - 7.17 (4H, m), 5.59 (1H, q, J 3.2), 3.04 - 2.97 (1H, m), 2.90 - 2.79 (4H, m), 2.20 (3H, s), 2.05 - 1.98 (6H, m), 1.88 - 1.82 (2H, m).

[0335] Example 14: (R)-2-(1-methylpiperidin-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 3 using (1R)-1,2,3,4-tetrahydronaphthalen-1-amine as the amine in Step 4. 1 H NMR: δ H (400 MHz, DMSO-d6) 12.38 (1H, d, J 7.6), 8.73 - 8.65 (1H, m), 8.16 (1H, s), 7.79 - 7.72 (1H, m), 7.57 - 7.43 (1H, m), 7.22 - 7.13 (4H, m), 5.27 (1H, s), 2.86 - 2.78 (5H, m), 2.21 (3H, s), 2.05 - 1.99 (6H, m), 1.86 - 1.79 (4H, m).

[0336] Example 15: (S)-2-(1-methylpiperidin-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 3 using (1S)-1,2,3,4-tetrahydronaphthalen-1-amine as the amine in Step 4. 1 H NMR: δ H (400 MHz, DMSO-d6) 12.38 (1H, d, J 8.0), 8.72 - 8.01 (1H, m), 8.00 (1H, s), 7.79 - 7.72 (1H, m), 7.57 - 7.43 (1H, m), 7.22 - 7.13 (4H, m), 5.27 (1H, s), 2.86 - 2.78 (5H, m), 2.20 (3H, s), 2.04 - 1.98 (6H, m), 1.88 - 1.82 (4H, m).

[0337] Example 16: (R)—N-(6-chlorochroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 3 using (R)-6-chlorochroman-4-amine as the amine in step 4. 1 H NMR: δ H (400 MHz, DMSO-d6) 12.43 (1H, s), 8.86 - 8.79 (1H, m), 8.17 - 8.01 (1H, m), 7.78 - 7.73 (1H, m), 7.59 - 7.55 (1H, m), 7.22 - 7.17 (2H, m), 6.85 (1H, d, J 8.8), 5.31 (1H, q, J 7.2), 4.36 - 4.24 (2H, m), 2.92 - 2.83 (3H, m), 2.26 (3H, s), 2.12 - 2.09 (4H, m), 2.08 - 2.00 (2H, m), 1.91 - 1.85 (2H, m).

[0338] Example 17: (S)—N-(6-chlorochroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 3 using (S)-6-chlorochroman-4-amine as the amine in Step 4. 1 H NMR: δ H (400 MHz, DMSO-d6) 12.42 (1H, d, J 4.8), 8.86 - 8.78 (1H, m), 8.18 - 8.01 (1H, m), 7.79 - 7.73 (1H, m), 7.59 - 7.45 (1H, m), 7.22 - 7.19 (2H, m), 7.17 (1H, d, J 2.0), 5.31 (1H, q, J 6.8), 4.37 - 4.24 (2H, m), 2.88 (3H, s), 2.24 (3H, s), 2.12 - 2.03 (6H, m), 2.00 - 1.84 (2H, m).

[0339] Example 18: (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 3 using (S)-chroman-4-amine as the amine in step 4. 1 H NMR: δ H(400 MHz, DMSO-d6) 12.39 (1H, d, J 6.0), 8.83 - 8.74 (1H, m), 8.16 - 8.01 (1H, m), 7.78 - 7.72 (1H, m), 7.57 - 7.43 (1H, m), 7.20 - 7.14 (2H, m), 6.87 (1H, t, J 7.2), 6.80 (1H, d, J 8.0), 5.32 (1H, q, J 6.8), 4.35 - 4.31 (1H, m), 4.27 - 4.22 (1H, m), 2.86 (3H, s), 2.20 (3H, s), 2.13 - 2.08 (2H, m), 2.04 -1.98 (4H, m), 1.88 - 1.82 (2H, m).

[0340] Example 19 (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1H-benzo[d]imidazole-5-carboxamide Example 19 can be prepared according to the route shown in Scheme 4.

[0341] [ka]

[0342] Step 1 (Scheme 4): Synthesis of methyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a solution of methyl 3,4-diaminobenzoate (25 g, 150 mmol, 1.0 equiv.) in THF (250 mL) was added CDI (36.6 g, 225 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 16 h, then quenched with ice-water, and the organic components were extracted twice with ethyl acetate. The combined organic layers were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 80% to 85% ethyl acetate in petroleum ether to give methyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (28 g, 97%) as a solid.

[0343] Step 2 (Scheme 4): Synthesis of methyl 2-chloro-1H-benzo[d]imidazole-5-carboxylate POCl3 (280 mL, 10 vol) and methyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (28 g, 192 mmol, 1.0 equiv) were added at 0 °C, and the reaction mixture was warmed to 120 °C, stirred for 16 h, and then concentrated under reduced pressure. The residue was basified with aqueous NaHCO3 (20 mL), and the resulting solid precipitate was filtered off and dried under vacuum to give methyl 2-chloro-1H-benzo[d]imidazole-5-carboxylate (13 g) as a brown solid.

[0344] Step 3 (Scheme 4): Synthesis of 2-chloro-1H-benzo[d]imidazole-5-carboxylic acid To a solution of methyl 2-chloro-1H-benzo[d]imidazole-5-carboxylate (6 g, 28.5 mmol, 1.0 equiv.) in THF:water (3:1, 66 mL) was added lithium hydroxide hydrate (0.81 g, 34.2 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to remove THF. The residue was acidified to approximately pH 4 with saturated aqueous citric acid. The resulting solid precipitate was filtered off, dried under vacuum, and then triturated with ethyl acetate to give crude 2-chloro-1H-benzo[d]imidazole-5-carboxylic acid (4.5 g), which was used in the next step without further purification.

[0345] Step 4 (Scheme 4): Synthesis of (S)-2-chloro-N-(chroman-4-yl)-1H-benzo[d]imidazole-5-carboxamide To a solution of 2-chloro-1H-benzo[d]imidazole-5-carboxylic acid (4.5 g, 22.9 mmol) in DMF (50 mL) was added DIPEA (11.8 g, 92 mmol, 4.0 equiv.) and (S)-chroman-4-amine hydrochloride (3.76 g, 25.2 mmol, 1.1 equiv.). The mixture was stirred for 10 min, followed by the addition of n-propylphosphonic anhydride cyclic trimer (14.57 g, 45.8 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 16 h, then quenched with ice water (100 mL) and stirred for 10 min. The resulting solid precipitate was filtered off, dried under vacuum, and purified by flash chromatography eluting with 80%-85% ethyl acetate in petroleum ether to give (S)-2-chloro-N-(chroman-4-yl)-1H-benzo[d]imidazole-5-carboxamide (0.25 g, 2.5%) as a light brown solid.

[0346] Step 5 leading to Example 19 (Scheme 4): (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1H-benzo[d]imidazole-5-carboxamide To a solution of (S)-2-chloro-N-(chroman-4-yl)-1H-benzo[d]imidazole-5-carboxamide (1 equivalent) and DIPEA (4 equivalents) in n-butanol (10 volumes) was added 1-ethylpiperazine (4 equivalents), and the mixture was stirred in a MW at 120° C. for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid. 1 H NMR: δ H(400 MHz, DMSO-d6) 11.59 (1H, d, J 3.2), 8.67 - 8.62 (1H, m), 7.82 (1H, s), 7.75 - 7.63 (1H, m), 7.20 - 7.13 (3H, m), 6.88 (1H, t, J 1.2), 6.86 (1H, d, J 6.4), 5.31 (1H, d, J 7.2), 4.36 - 4.31 (1H, m), 4.26 - 4.21 (1H, m), 3.53 (4H, t, J 4.8), 2.52 - 2.50 (4H, m), 2.41 - 2.35 (2H, m), 2.12 - 2.08 (2H, m), 1.04 (3H, t, J 7.2).

[0347] Example 20-24 Examples 20-24 can be prepared according to the route shown in Scheme 5.

[0348] [ka]

[0349] General procedure for Step 1 (Scheme 5): Preparation of benzimidazoles To a solution of methyl 3-amino-4-(methylamino)benzoate (1.0 equiv.) and NaSO (1.3 equiv.) in DMF (16 volumes) was added the nicotinaldehyde derivative (1.0 equiv.). The reaction was stirred at 100 °C for 16 h, then cooled to room temperature and quenched with ice-water. The organic components were extracted twice with ethyl acetate. The combined organic layers were separated, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was triturated with n-pentane and dried under reduced pressure to give the required benzimidazole ester as an off-white solid.

[0350] General procedure for Step 2 (Scheme 5): Ester hydrolysis To a solution of the benzimidazole ester (1 equiv) in THF:HO (3:1; 15 vol) was added LiOH·HO (2 equiv), and the mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure to remove the THF. The residue was diluted with water (5 vol) and acidified to approximately pH 4 with saturated aqueous citric acid. The resulting solid precipitate was filtered off, triturated with n-pentane, and dried under vacuum to give the required benzimidazole carboxylic acid as an off-white solid.

[0351] General procedure for Step 3 (Scheme 5): Amide coupling To a solution of benzimidazole carboxylic acid (1.0 equiv.) in DMF (10 volumes) was added DIPEA (3.0 equiv.), HOBt (2.0 equiv.), and EDC·HCl (2.0 equiv.). The mixture was stirred for 15 minutes. (S)-Chroman-4-amine hydrochloride (1.1 equiv.) was added, and the reaction mixture was stirred at room temperature for 16 hours. It was then quenched with ice-water, and the organic components were extracted twice with ethyl acetate. The combined organic layers were separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 5%-15% MeOH in DCM to give Examples 20-24 as off-white solids.

[0352] Example 20: (S)—N-(chroman-4-yl)-1-methyl-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 5 using 4-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H(400 MHz, DMSO-d6) 8.89 (1H, d, J 8.0), 8.67 (1H, s), 8.63 (1H, d, J 5.2), 8.35 (1H, d, J 1.2), 7.97 (1H, dd, J 8.4, 1.6), 7.73 (1H, d, J 8.4), 7.50 (1H, d, J 5.2), 7.20 (1H, d, J 8.0), 7.16 (1H, t, J 0.8), 6.89 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.35 (1H, q, J 6.8), 4.38 - 4.33 (1H, m), 4.29 - 4.24 (1H, m), 3.71 (3H, s), 2.34 (3H, s), 2.29 - 2.08 (2H, m).

[0353] Example 21: (S)—N-(chroman-4-yl)-1-methyl-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 5 using 6-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.94 (1H, d, J 2.0), 8.88 (1H, d, J 8.4), 8.33 (1H, d, J 1.2), 8.19 (1H, dd, J 8.0, 2.4), 7.95 (1H, dd, J 8.4, 1.6), 7.72 (1H, d, J 8.4), 7.49 (1H, d, J 8.0), 7.19 (1H, d, J 1.6), 7.16 (1H, t, J 7.2), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.35 (1H, d, J 7.2), 4.37 - 4.28 (1H, m), 4.27 - 4.25 (1H, m), 3.94 (3H, s), 2.68 (3H, s), 2.16 - 2.10 (2H, m).

[0354] Example 22: (S)—N-(chroman-4-yl)-1-methyl-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 5 using 2-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.89 (1H, d, J 8.4), 8.67 (1H, dd, J 4.8, 1.6), 8.34 (1H, d, J 0.8), 7.98 - 7.94 (2H, m), 7.72 (1H, d, J 8.4), 7.46 - 7.43 (1H, m), 7.22 (1H, d, J 7.6), 7.18 (1H, t, J 1.2), 6.90 (1H, t, J 1.2), 6.88 (1H, d, J 6.0), 5.35 (1H, q, J 7.2), 4.38 - 4.33 (1H, m), 4.29 - 4.24 (1H, m), 3.69 (3H, s), 2.43 (3H, s), 2.16 - 2.10 (2H, m).

[0355] Example 23: (S)—N-(chroman-4-yl)-1-methyl-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 5 using 5-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H(400 MHz, DMSO-d6) 8.87 (2H, d, J 2.4), 8.62 (1H, d, J 1.2), 8.34 (1H, d, J 1.2), 8.13 - 8.12 (1H, m), 7.96 (1H, dd, J 8.4, 1.6), 7.75 - 7.73 (1H, m), 7.23 - 7.15 (2H, m), 6.90 (1H, t, J 6.0), 6.87 (1H, d, J 1.2), 5.35 (1H, q, J 6.4), 4.38 - 4.24 (2H, m), 3.95 (3H, s), 2.44 (3H, s), 2.18 - 2.10 (2H, m).

[0356] Example 24: (S)—N-(chroman-4-yl)-1-methyl-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 5 using nicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.08 (1H, d, J 0.4), 8.89 (1H, d, J 8.0), 8.77 (1H, dd, J 4.8, 1.6), 8.35 - 8.30 (2H, m), 7.96 (1H, dd, J 8.8, 1.6), 7.74 (1H, d, J 8.4), 7.66 - 7.62 (1H, m), 7.23 (1H, d, J 7.6), 7.16 (1H, t, J 7.2), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.35 (1H, q, J 6.8), 4.38 - 4.33 (1H, m), 4.29 - 4.24 (1H, m), 3.96 (3H, s), 2.19 - 2.08 (2H, m).

[0357] Example 25-29 Examples 25-29 can be prepared according to the route shown in Scheme 5, using methyl 4-amino-3-(methylamino)benzoate in place of methyl 3-amino-4-(methylamino)benzoate in step 1.

[0358] Example 25: (S)—N-(chroman-4-yl)-1-methyl-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide Prepared according to Scheme 5 using methyl 4-amino-3-(methylamino)benzoate instead of methyl 3-amino-4-(methylamino)benzoate and 4-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.88 (1H, d, J 8.4), 8.66 (1H, s), 8.64 (1H, d, J 5.2), 8.31 (1H, s), 7.92 (1H, dd, J 8.4, 1.2), 7.76 (1H, d, J 8.4), 7.50 (1H, d, J 5.2), 7.23 - 7.16 (2H, m), 6.90 (1H, t, J 7.2), 6.83 (1H, d, J 8.0), 5.37 (1H, q, J 6.4), 4.37 - 4.26 (2H, m), 3.71 (3H, s), 2.34 (3H, s), 2.18 - 2.08 (2H, m).

[0359] Example 26: (S)—N-(chroman-4-yl)-1-methyl-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide Prepared according to Scheme 5 using methyl 4-amino-3-(methylamino)benzoate instead of methyl 3-amino-4-(methylamino)benzoate and 6-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H(400 MHz, DMSO-d6) 8.97 (1H, d, J 1.6), 8.89 (1H, d, J 8.0), 8.31 (1H, d, J 1.2), 8.24 (1H, dd, J 8.0, 2.0), 7.92 (1H, dd, J 8.6, 1.2), 7.76 (1H, d, J 8.4), 7.53 (1H, d, J 8.4), 7.24 - 7.16 (2H, m), 6.91 (1H, t, J 6.4), 6.88 (1H, d, J 1.2), 5.36 (1H, q, J 6.4), 4.38 - 4.26 (2H, m), 3.96 (3H, s), 2.68 (3H, s), 2.20 - 2.16 (2H, m).

[0360] Example 27: (S)—N-(chroman-4-yl)-1-methyl-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide Prepared according to Scheme 5 using methyl 4-amino-3-(methylamino)benzoate instead of methyl 3-amino-4-(methylamino)benzoate and 2-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.88 (1H, d, J 8.0), 8.68 - 8.66 (1H, m), 8.30 (1H, s), 7.96 - 7.90 (2H, m), 7.75 (1H, d, J 8.8), 7.46 - 7.43 (1H, m), 7.23 - 7.16 (2H, m), 6.90 (1H, t, J 6.4), 6.88 (1H, d, J 0.8), 5.37 (1H, q, J 6.8), 4.38 - 4.25 (2H, m), 3.71 (3H, s), 2.43 (3H, s), 2.20 - 2.07 (2H, m).

[0361] Example 28: (S)—N-(chroman-4-yl)-1-methyl-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide Prepared according to Scheme 5 using methyl 4-amino-3-(methylamino)benzoate instead of methyl 3-amino-4-(methylamino)benzoate and 5-methylnicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.89 - 8.86 (2H, m), 8.62 (1H, d, J 1.2), 8.30 (1H, d, J 0.8), 8.14 (1H, t, J 0.8), 7.91 (1H, dd, J 8.4, 1.6), 7.75 (1H, d, J 8.4), 7.19 (1H, t, J 6.4), 7.16 (1H, d, J 1.2), 6.91 (1H, t, J 6.4), 6.88 (1H, d, J 0.8), 5.37 (1H, q, J 6.4), 4.38 - 4.26 (2H, m), 3.96 (3H, s), 2.44 (3H, s), 2.19 - 2.09 (2H, m).

[0362] Example 29: (S)—N-(chroman-4-yl)-1-methyl-2-(pyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide Prepared according to Scheme 5 using methyl 4-amino-3-(methylamino)benzoate instead of methyl 3-amino-4-(methylamino)benzoate and using nicotinaldehyde as the nicotinaldehyde derivative in step 1. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.09 (1H, d, J 1.6), 8.89 (1H, d, J 8.0), 8.78 (1H, dd, J 4.8, 1.6), 8.34 - 8.31 (2H, m), 7.91 (1H, dd, J 8.4, 1.6), 7.77 (1H, d, J 8.4), 7.66 - 7.63 (1H, m), 7.24 - 7.16 (2H, m), 6.91 (1H, t, J 0.8), 6.89 (1H, d, J 6.4), 5.36 (1H, q, J 6.8), 4.37 - 4.26 (2H, m), 3.96 (3H, s), 2.18 - 2.09 (2H, m).

[0363] Example 30: (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide Prepared according to Scheme 4, using methyl 4-amino-3-(methylamino)benzoate in place of methyl 3,4-diaminobenzoate in step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.71 (1H, d, J 8.0), 8.01 (1H, s), 7.73 (1H, d, J 0.8), 7.40 (1H, d, J 8.4), 7.20 - 7.14 (2H, m), 6.86 (1H, t, J 6.8), 6.80 (1H, d, J 8.4), 5.31 (1H, q, J 6.4), 4.36 - 4.31 (1H, m), 4.27 - 4.22 (1H, m), 3.63 (3H, s), 3.34 (4H, s), 2.68 (4H, s), 2.41 (2H, q, J 7.2), 2.12 - 2.09 (2H, m), 1.05 (3H, t, J 7.2).

[0364] Example 31: (S)—N-(chroman-4-yl)-1-methyl-2-(piperazin-1-yl)-1H-benzo[d]imidazole-6-carboxamide Prepared according to Scheme 4, using methyl 4-amino-3-(methylamino)benzoate instead of methyl 3,4-diaminobenzoate in step 1 and piperazine instead of 1-ethylpiperazine in step 5. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.72 (1H, d, J 8.4), 8.01 (1H, d, J 1.2), 7.74 (1H, dd, J 8.4, 1.6), 7.39 (1H, d, J 8.4), 7.20 - 7.13 (2H, m), 6.88 (1H, t, J 6.4), 6.85 (1H, d, J 0.8), 5.31 (1H, q, J 5.31), 4.36 - 4.22 (2H, m), 3.63 (3H, s), 3.18 (4H, t, J 4.4), 2.88 (4H, t, J 4.8), 2.15 - 2.05 (2H, m). Note: NH proton of piperazine not observed.

[0365] Example 32: (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 4, using methyl 3-amino-4-(methylamino)benzoate in place of methyl 3,4-diaminobenzoate in step 1. 1 H NMR: δ H(400 MHz, DMSO-d6) 8.70 (1H, d, J 8.4), 8.02 (1H, d, J 1.2), 7.74 (1H, dd, J 8.4, 1.6), 7.40 (1H, d, J 8.4), 7.20 - 7.14 (2H, m), 6.89 - 6.79 (2H, m), 5.31 (1H, q, J 6.4), 4.32 - 4.31 (1H, m), 4.27 - 4.23 (1H, m), 3.63 (3H, s), 3.28 (4H, t, J 4.4), 2.68 (4H, s), 2.46 - 2.41 (2H, m), 2.12 - 2.07 (2H, m), 1.05 (3H, t, J 7.2).

[0366] Example 33: (S)—N-(chroman-4-yl)-1-methyl-2-(piperazin-1-yl)-1H-benzo[d]imidazole-5-carboxamide Prepared according to Scheme 4, using methyl 3-amino-4-(methylamino)benzoate instead of methyl 3,4-diaminobenzoate in step 1 and piperazine instead of 1-ethylpiperazine in step 5. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.70 (1H, d, J 8.4), 8.01 (1H, d, J 0.8), 7.74 (1H, dd, J 8.2, 1.2), 7.39 (1H, d, J 8.4), 7.20 - 7.13 (2H, m), 6.88 (1H, t, J 6.4), 6.85 (1H, d, J 1.2), 5.34 - 5.31 (1H, m), 4.36 - 4.23 (2H, m), 3.63 (3H, s), 3.17 (4H, t, J 4.4), 2.88 (4H, t, J 4.8), 2.13 - 2.08 (2H, m). Note: The NH proton of piperazine was not observed.

[0367] Example 34-39 Examples 34-39 can be prepared according to the route shown in Scheme 6.

[0368] [ka]

[0369] Step 1 (Scheme 6): Synthesis of methyl 6-(3-(ethoxycarbonyl)thioureido)nicotinate To a solution of methyl 6-aminonicotinate (10 g, 65.7 mmol) in 1,4 dioxane (100 mL) was added ethoxycarbonyl isothiocyanate (11.7 mL, 98.6 mmol). The reaction was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 6-(3-(ethoxycarbonyl)thioureido)nicotinate (14 g, 77%) as a pale yellow solid.

[0370] Step 2 (Scheme 6): Synthesis of methyl 2-amino-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate To a stirred solution of methyl 6-(3-(ethoxycarbonyl)thioureido)nicotinate (15 g, 52.9 mmol, 1 equiv.) and DIPEA (34.0 mL, 198 mmol, 4 equiv.) in EtOH (150 mL) was added hydroxylamine·HCl (11.1 g, 158 mmol, 3.2 equiv.). The reaction mixture was stirred at 60 °C for 16 h and then concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-amino-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (8.0 g, 79%) as an off-white solid.

[0371] Step 3 (Scheme 6): Synthesis of methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate To a solution of CuBr (11.1 g, 50 mmol) and BuONO (8.58 mL, 94.4 mmol) in acetonitrile (80 mL) was added methyl 2-amino-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (8.0 g, 41.7 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and then filtered through Celite®. The filtrate was diluted with water, and the organic components were extracted with 5% MeOH in DCM (2 × 100 mL). The combined organic layers were washed with 1N aqueous HCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (7.0 g, 65%).

[0372] Step 4 (Scheme 6): Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid To a solution of methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (2.0 g, 7.81 mmol) in THF:HO (3:1; 15 mL) was added LiOH·HO (0.98 g, 23.4 mmol). The mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure to remove THF. The residue was diluted with water (5 mL) and acidified to approximately pH 4 with saturated aqueous citric acid. The resulting solid precipitate was filtered off, triturated with n-pentane, and dried under vacuum to give 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (1.6 g, 84%) as an off-white solid.

[0373] Step 5 (Scheme 6): Synthesis of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide To a solution of 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (1 equivalent) in DMF (5 volumes) was added (S)-chroman-4-amine (1.2 equivalents) and DIPEA (4.0 equivalents). The mixture was stirred for 15 minutes. T3P (1.5 equivalents) was added, and the reaction mixture was stirred at room temperature for 16 hours, then quenched with ice water (10 volumes) and stirred for 10 minutes. The precipitate was filtered off and dried under reduced pressure to give (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide as an off-white solid.

[0374] General procedure for Step 6 (Scheme 6): Suzuki coupling reaction A solution of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (1 equivalent) in THF:HO (9:1; 10 volumes) was purged with nitrogen gas for 15 minutes, followed by the addition of (pyridin-3-yl)boronic acid derivative (1.2 equivalents), NaCO (3 equivalents), and PdCl(dppf)DCM (0.1 equivalents). The reaction mixture was stirred under nitrogen at 70°C for 16 hours. The reaction mixture was cooled and filtered through Celite®. The filtrate was diluted with water and extracted twice with dichloromethane. The combined organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Examples 34-39.

[0375] Example 34: (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 6 using (pyridin-3-yl)boronic acid as the (pyridin-3-yl)boronic acid derivative in step 6. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.58 (1H, s), 9.37 (1H, s), 9.15 (1H, d, J 8.8), 8.74 (1H, d, J 6.0), 8.53 (1H, d, J 10.4), 8.19 (1H, d, J 12.0), 7.98 (1H, d, J 12.0), 7.63 - 7.59 (1H, m), 7.28 - 7.17 (2H, m), 6.93 - 6.82 (2H, m), 5.31 (1H, d, J 7.6), 4.30 (2H, s), 2.17 (2H, s).

[0376] Example 35: (S)—N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 6 using (6-methylpyridin-3-yl)boronic acid as the (pyridin-3-yl)boronic acid derivative in step 6. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.55 (1H, s), 9.24 (1H, d, J 2.4), 9.14 (1H, d, J 10.4), 8.40 (1H, dd, J 10.6, 3.2), 8.17 (1H, d, J 12.4), 7.94 (1H, d, J 12.4), 7.46 (1H, d, J 10.4), 7.27 - 7.17 (2H, m), 6.93 - 6.82 (2H, m), 5.30 (1H, q, J 8.0), 4.32 - 4.25 (2H, m), 2.63 (2H, s), 2.13 (3H, s).

[0377] Example 36: (S)—N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 6 using (5-methylpyridin-3-yl)boronic acid as the (pyridin-3-yl)boronic acid derivative in step 6. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.56 (1H, s), 9.16 (2H, d, J 8.0), 8.58 (1H, s), 8.35 (1H, s), 8.19 (1H, d, J 8.4), 7.96 (1H, d, J 9.2), 7.27 - 7.18 (2H, m), 6.91 (1H, t, J 7.6), 6.84 (1H, d, J 8.4), 5.31 (1H, d, J 6.8), 4.30 (2H, d, J 2.8), 2.33 (3H, s), 2.10 - 2.09 (2H, m).

[0378] Example 37: (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 6 using (4-methylpyridin-3-yl)boronic acid as the (pyridin-3-yl)boronic acid derivative in step 6. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.62 (1H, s), 9.20 (1H, s), 9.17 (1H, d, J 8.0), 8.55 (1H, d, J 5.2), 8.19 (1H, dd, J 9.2, 1.6), 7.99 (1H, d, J 9.2), 7.44 (1H, d, J 5.2), 7.26 (1H, d, J 7.6), 7.21 (1H, t, J 1.2), 6.89 (1H, t, J 6.4), 6.84 (1H, d, J 8.4), 5.30 (1H, q, J 6.0), 4.35 - 4.26 (2H, m), 2.72 (3H, s), 2.21 - 2.14 (1H, m), 2.10 - 2.06 (1H, m).

[0379] Example 38: (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 6 using (2-methylpyridin-3-yl)boronic acid as the (pyridin-3-yl)boronic acid derivative in step 6. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.61 (1H, d, J 0.4), 9.16 (1H, d, J 7.6), 8.59 (1H, dd, J 4.8, 2.0), 8.45 (1H, dd, J 8.0, 1.6), 8.18 (1H, dd, J 9.2, 1.6), 7.99 - 7.97 (1H, m), 7.45 - 7.42 (1H, m), 7.22 (1H, d, J 1.6), 7.19 (1H, t, J 7.2), 6.92 (1H, t, J 0.8), 6.90 (1H, d, J 6.4), 5.30 (1H, q, J 6.0), 4.35 - 4.26 (2H, m), 2.90 (3H, s), 2.21 - 2.14 (1H, m), 2.12 - 2.05 (1H, m).

[0380] Example 39: (S)—N-(chroman-4-yl)-2-(2,6-dimethylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 6 using (2,6-dimethylpyridin-3-yl)boronic acid as the (pyridin-3-yl)boronic acid derivative in Step 6. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.59 (1H, s), 9.15 (1H, d, J 8.0), 8.34 (1H, d, J 8.0), 8.17 (1H, dd, J 9.4, 2.0), 7.95 (1H, d, J 9.6), 7.29 - 7.18 (3H, m), 6.92 - 6.85 (2H, m), 5.30 (1H, q, J 6.0), 4.32 - 4.28 (2H, m), 3.51 (3H, s), 2.86 (3H, s), 2.21 - 2.14 (1H, m), 2.12 - 2.09 (1H, m).

[0381] Example 40-46 Examples 40-46 can be prepared according to the route shown in Scheme 7.

[0382] [ka]

[0383] Step 1 (Scheme 7): S leading to Examples 40-46 N Ar reaction To a solution of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (1 equivalent) and DIPEA (4 equivalents) in n-butanol (10 volumes) was added the amine derivative (4 equivalents). The mixture was stirred at 120° C. for 16-32 hours while being monitored by TLC. Upon completion, the reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Examples 40-46 as white solids.

[0384] Example 40: (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 7 using piperazine as the amine derivative. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.20 (1H, d, J 0.8), 8.95 (1H, d, J 8.0), 7.99 (1H, dd, J 9.2, 1.6), 7.50 (1H, d, J 9.2), 7.23 - 7.16 (2H, m), 6.89 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.27 (1H, q, J 6.0), 4.33 - 4.23 (2H, m), 3.46 (4H, t, J 4.8), 2.82 (4H, t, J 4.8), 2.18 - 2.03 (2H, m). NOTE: The NH protons of piperazine are not observed.

[0385] Example 41: (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 7 using 1-methylpiperazine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.20 (1H, d, J 0.8), 8.95 (1H, d, J 8.0), 7.99 (1H, dd, J 9.2, 2.0), 7.50 (1H, dd, J 9.2, 0.4), 7.23 - 7.16 (2H, m), 6.89 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.27 (1H, q, J 6.0), 4.30 - 4.26 (2H, m), 3.52 (4H, t, J 4.4), 2.34 (4H, t, J 1.6 ), 2.23 (3H, s), 2.15 - 2.03 (2H, m).

[0386] Example 42: (S)—N-(chroman-4-yl)-2-morpholino-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 7 using morpholine as the amine derivative. 1H NMR: δ H (400 MHz, DMSO-d6) 9.22 (1H, d, J 1.2), 8.96 (1H, d, J 8.0), 8.01 (1H, dd, J 9.2, 1.6), 7.53 (1H, dd, J 9.2, 0.4), 7.23 - 7.16 (2H, m), 6.89 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.27 (1H, q, J 6.0), 4.32 - 4.24 (2H, m), 3.71 (4H, t, J 4.4), 3.48 (4H, t, J 4.8), 2.16 - 2.02 (2H, m).

[0387] Example 43: (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 7 using 1-tert-butylpiperazine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.20 (1H, d, J 0.8), 8.94 (1H, d, J 8.0), 7.98 (1H, dd, J 9.2, 2.0), 7.49 (1H, dd, J 9.2, 0.8), 7.23 - 7.16 (2H, m), 6.89 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.26 (1H, t, J 6.8), 4.33 - 4.23 (2H, m), 3.48 (4H, t, J 4.8), 2.57 (4H, t, J 5.2), 2.10 (2H, s), 1.04 (9H, s).

[0388] Example 44: (S)—N-(chroman-4-yl)-2-(piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 7 using piperidine as the amine derivative. 1H NMR: δ H (400 MHz, DMSO-d6) 9.19 - 9.18 (1H, m), 8.93 (1H, d, J 8.0), 7.97 (1H, dd, J 9.2, 1.6), 7.47 (1H, dd, J 9.2, 0.4), 7.23 - 7.16 (2H, m), 6.89 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.27 (1H, q, J 6.0), 4.32 - 4.24 (2H, m), 3.52 (4H, d, J 5.6), 2.17 - 2.11 (1H, m), 2.08 - 2.01 (1H, m), 1.59 (6H, s).

[0389] Example 45: (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 7 using 1-ethylpiperazine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.20 (1H, t, J 0.8), 8.95 (1H, d, J 8.0), 7.99 (1H, dd, J 9.2, 1.6), 7.50 (1H, dd, J 9.2, 0.8), 7.23 - 7.16 (2H, m), 6.91 - 6.81 (2H, m), 5.26 (1H, t, J 7.2),

[0390] Example 46: (S)—N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 7 using 1-(propan-2-yl)piperazine as the amine derivative. 1 H NMR:δ H(400 MHz, DMSO-d6) 9.19 (1H, d, J 0.8), 9.03 (1H, d, J 1.2), 8.01 (1H, dd, J 9.2, 2.0), 7.45 (1H, dd, J 9.4, 0.4), 7.26 (1H, d, J 7.6), 7.20 - 7.16 (1H, m), 6.92 (1H, t, J 6.4), 6.90 (1H, d, J 1.2), 5.27 (1H, d, J 7.2), 4.30 - 4.25 (2H, m), 3.49 (4H, t, J 4.8), 2.82 (1H, s), 2.70 (4H, t, J 6.4), 2.02 - 2.00 (2H, m), 0.99 (6H, d, J 6.8).

[0391] Example 47: (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 7 using (R)-2-bromo-N-(2,3-dihydro-1H-inden-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide [prepared according to Scheme 6 using (R)-1-aminoindan instead of (S)-chroman-4-amine in Step 5] instead of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide and piperazine as the amine derivative. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.18 (1H, d, J 0.8), 8.85 (1H, d, J 8.0), 7.99 (1H, dd, J 9.2, 2.0), 7.49 (1H, dd, J 9.2, 0.4), 7.30 - 7.18 (4H, m), 5.56 (1H, d, J 8.0), 3.44 (4H, t, J 4.8), 3.02 - 3.00 (1H, m), 2.99 - 2.91 (1H, m), 2.87 (4H, t, J 8.0), 2.56 - 2.50 (1H, m), 2.01 - 1.96 (1H, m).

[0392] Example 48: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Prepared according to Scheme 7, using (S)-2-bromo-N-(2,3-dihydro-1H-inden-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide [prepared according to Scheme 6 using (S)-1-aminoindan instead of (S)-chroman-4-amine in step 5] instead of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide, and piperazine as the amine derivative. The title compound was isolated as the trifluoroacetate salt. 1 H NMR:δ H (400 MHz, DMSO-d6) 9.32 (2H, s), 9.25 (1H, s), 8.94 (1H, d, J 8.0), 8.05 (1H, d, J 9.2), 7.57 (1H, d, J 9.2), 7.28 - 7.18 (4H, m), 5.56 (1H, q, J 8.0), 3.76 (4H, t, J 4.4), 3.22 (4H, s), 3.05 - 3.01 (1H, m), 2.99 - 2.85 (1H, m), 2.51 - 2.51 (1H, m), 2.04 - 1.98 (1H, m)

[0393] Example 49: (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Example 49 can be prepared according to the route shown in Scheme 8.

[0394] [ka]

[0395] Scheme 8 Step 1 (Scheme 8): Synthesis of tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate To a degassed solution of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (1.0 g, 2.6 mmol, 1 equiv.) in dioxane (27 mL) and HO (3 mL) under argon, tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.24 g, 4.01 mmol, 1.5 eq.), KCO (1.10 g, 8.01 mol, 3 equiv.), and Pd(PPh) (0.3 g, 0.26 mol, 0.1 equiv.) were added. The mixture was heated to reflux under argon for 16 hours, then cooled to room temperature, filtered through Celite®, and washed with 5% MeOH in DCM. The filtrate was concentrated under reduced pressure. The residue was dissolved in 5% MeOH in DCM and washed with water, followed by brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 70% EtOAc in hexane to give tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 86%) as a light brown solid.

[0396] Step 2 (Scheme 8): Synthesis of tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)piperidine-1-carboxylate To a degassed solution of tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g, 2.5 mmol, 1 equiv.) in ethanol (12 mL) under argon was added Pd / C (10%, dried; 120 mg). The mixture was stirred at ambient temperature under H bladder pressure for 16 h. The reaction mixture was filtered through Celite®, washed with MeOH, and the filtrate was concentrated under reduced pressure. The solid residue was triturated with hexane and dried under reduced pressure to give tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)piperidine-1-carboxylate (1.1 g, 92%) as a brown solid.

[0397] Step 3 leading to Example 49 (Scheme 8): Synthesis of (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide To a solution of tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)piperidine-1-carboxylate (0.13 g, 0.27 mmol) in DCM (0.2 M in substrate) was added HCl in 1,4-dioxane (4 M, 8.0 equiv. of HCl) at 0° C. The reaction was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide hydrochloride (0.05 g, 45%) as an off-white solid. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.46 (1H, d, J 0.4), 9.11 (1H, d, J 8.0), 8.98 (1H, s), 8.81 (1H, d, J 7.6), 8.12 (1H, dd, J 9.2, 1.6), 7.84 (1H, d, J 9.2), 7.24 - 7.17 (2H, m), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.29 (1H, d, J 7.2), 4.31 - 4.27 (2H, m), 3.34 - 3.25 (3H, m), 3.12 - 3.06 (2H, m), 2.22 - 2.15 (3H, m), 2.09 - 2.06 (3H, m).

[0398] Example 50: (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Example 50 can be prepared according to the route shown in Scheme 9.

[0399] [ka]

[0400] To a solution of (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide hydrochloride (0.15 g, 0.39 mmol) and acetic acid (0.1 mL) in methanol (5.0 mL) was added formaldehyde (37% in HO; 0.053 g, 0.59 mmol). The mixture was stirred at room temperature for 5 hours, then NaCNBH (0.049 g, 0.79 mmol) was added and stirring was continued at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the organic components were extracted with EtOAc (2 × 10 mL). The combined organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by preparative HPLC using NH4HCO3 as a buffer to give (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (0.05 g, 33%) as an off-white solid. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.42 (1H, d, J 0.4), 9.07 (1H, d, J 8.0), 8.08 (1H, dd, J 9.2, 1.6), 7.80 (1H, dd, J 9.2, 0.8), 7.25 - 7.17 (2H, m), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.28 (1H, q, J 6.0), 4.33 - 4.26 (2H, m), 2.83 - 2.80 (3H, m), 2.19 - 2.12 (4H, m), 2.10 - 2.00 (5H, m), 1.99 - 1.84 (2H, m).

[0401] Example 51: (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide Example 51 can be prepared according to the route shown in Scheme 10.

[0402] [ka]

[0403] To a solution of (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide hydrochloride (0.15 g, 0.39 mmol) and acetic acid (0.1 mL) in methanol (5.0 mL) was added acetaldehyde (20-30% in HO; 0.078 g, 0.59 mmol). The mixture was stirred at room temperature for 5 hours, then NaCNBH (0.049 g, 0.79 mmol) was added and stirring was continued at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the organic components were extracted with EtOAc (2 × 10 mL). The combined organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by preparative HPLC using NH4HCO3 as a buffer to give (S)-N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-[1,2,4]triazolo[1.5-a]pyridine-6-carboxamide (0.05 g, 31%) as an off-white solid. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.42 (1H, s), 9.06 (1H, d, J 8.0), 8.08 (1H, dd, J 9.4, 1.2), 7.80 (1H, d, J 9.2), 7.25 - 7.17 (2H, m), 6.89 (1H, t, J 7.2), 6.83 (1H, d, J 8.0), 5.28 (1H, q, J 6.0), 4.33 - 4.25 (2H, m), 2.93 - 2.83 (3H, m), 2.37 - 2.32 (2H, m), 2.19 - 2.13 (1H, m), 2.10 - 2.01 (5H, m), 1.85 - 1.76 (2H, m), 1.02 (3H, t, J 7.2).

[0404] Examples 52 and 53 Examples 52 and 53 can be prepared according to the route shown in Scheme 11.

[0405] [ka]

[0406] Step 1 (Scheme 11): Synthesis of methyl 2-(3-(ethoxycarbonyl)thioureido)isonicotinate To a solution of methyl 2-aminoisonicotinate (10 g, 65.7 mmol) in 1,4-dioxane (100 mL) was added ethoxycarbonyl isothiocyanate (11.7 mL, 98.6 mmol). The reaction was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-(3-(ethoxycarbonyl)thioureido)isonicotinate (14 g, 77%) as a pale yellow solid.

[0407] Step 2 (Scheme 11): Synthesis of methyl 2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate To a solution of methyl 2-(3-(ethoxycarbonyl)thioureido)isonicotinate (14 g, 49.4 mmol, 1 equiv.) and DIPEA (34.0 mL, 198 mmol, 4 equiv.) in EtOH (150 mL) was added hydroxylamine·HCl (11.1 g, 158 mmol, 3.2 equiv.). The reaction mixture was stirred at 60 °C for 16 h and then concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (8.0 g, 84%) as an off-white solid.

[0408] Step 3 (Scheme 11): Synthesis of methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate To a stirred solution of CuBr (11.1 g, 50 mmol) and BuONO (8.58 mL, 94.4 mmol) in acetonitrile (80 mL) at 0 °C was added methyl 2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (8.0 g, 41.7 mmol). The reaction mixture was stirred at room temperature for 2 hours and then filtered through Celite®. The filtrate was diluted with water, and the organic components were extracted with 5% MeOH in DCM (2 × 100 mL). The combined organic layers were washed with 1N aqueous HCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (5.5 g, 51%) as an off-white solid.

[0409] Step 4 (Scheme 11): Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid To a solution of methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (2.0 g, 7.81 mmol) in THF:HO (3:1; 15 mL) was added LiOH·HO (0.98 g, 23.4 mmol). The mixture was stirred at room temperature for 16 h, concentrated under reduced pressure to remove THF, and the residue was diluted with water (5 mL) and acidified to approximately pH 4 with saturated aqueous citric acid. The resulting solid precipitate was filtered off, triturated with n-pentane, and dried under vacuum to give 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (1.6 g, 84%) as an off-white solid.

[0410] Step 5 (Scheme 11): Synthesis of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide To a solution of 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (1.6 g, 6.61 mmol) in DMF (6.0 mL) was added (S)-chroman-4-amine hydrochloride (1.46 g, 7.93 mmol) and DIPEA (4.5 mL, 26.4 mmol). The mixture was stirred for 15 minutes. T3P (6.30 g, 9.91 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. It was then quenched with ice water (20 mL) and stirred for 10 minutes. The precipitate was filtered off and dried under reduced pressure to give (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (1.7 g, 69%) as an off-white solid.

[0411] General procedure for Step 6 (Scheme 11): Suzuki coupling reaction A solution of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (1 equivalent) in THF:HO (9:1; 10 volumes) was purged with nitrogen gas for 15 minutes, followed by the addition of (pyridin-3-yl)boronic acid derivative (1.2 equivalents), NaCO (3 equivalents), and PdCl(dppf).DCM (0.1 equivalents). The reaction mixture was stirred under nitrogen at 70 °C for 16 hours. The reaction mixture was cooled and filtered through Celite®. The filtrate was diluted with water and extracted twice with dichloromethane. The combined organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Examples 52 and 53.

[0412] Example 52: (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Prepared according to Scheme 11 using (2-methylpyridin-3-yl)boronic acid as the (pyridin-3-yl)boronic acid derivative in step 6. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.27 (1H, d, J 8.0), 9.13 (1H, dd, J 7.2, 0.8), 8.59 (1H, dd, J 4.6, 2.0), 8.46 - 8.41 (2H, m), 7.69 (1H, dd, J 7.2, 1.6), 7.44 - 7.41 (1H, m), 7.26 - 7.17 (1H, m), 6.92 (1H, t, J 1.2), 6.90 (1H, d, J 6.0), 5.32 (1H, q, J 6.4), 4.36 - 4.26 (2H, m), 2.90 (3H, s), 2.21 - 2.08 (2H, m). Note: Amide NH proton was not observed. Note: Amide NH protons were not observed.

[0413] Example 53: (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Prepared according to Scheme 11 using (4-methylpyridin-3-yl)boronic acid as the (pyridin-3-yl)boronic acid derivative in step 6. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.26 (1H, d, J 8.0), 9.18 (1H, s), 9.13 (1H, d, J 7.2), 8.55 (1H, d, J 5.2), 8.47 (1H, s), 7.70 (1H, dd, J 7.2, 2.0), 7.44 (1H, d, J 5.2), 7.25 (1H, d, J 7.2), 7.20 (1H, t, J 8.8), 6.91 (1H, t, J 7.6), 6.84 (1H, d, J 8.0), 5.32 (1H, q, J 6.8), 4.36 - 4.26 (2H, m), 2.72 (3H, s), 2.20 - 2.10 (2H, m).

[0414] Example 54: (S)—N-(chroman-4-yl)-2-(4-hydroxypiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Example 51 can be prepared according to the route shown in Scheme 12.

[0415] [ka]

[0416] To a degassed solution of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (0.1 g, 0.26 mmol) in toluene (10 mL) under nitrogen, 4-hydroxypiperidine (0.032 g, 0.32 mmol), CsCO (0.17 g, 0.32 mmol), BINAP (0.031 g, 0.052 mmol), and Pd(OAc) (0.006 g, 0.026 mmol) were added. The reaction was stirred at 110 °C for 16 h. The mixture was cooled to room temperature, filtered through Celite®, washed with 10% MeOH / DCM, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by preparative HPLC using NHHCO as a buffer to give (S)—N-(chroman-4-yl)-2-(4-hydroxypiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (0.03 g, 30%). 1 H NMR: δ H(400 MHz, DMSO-d6) 9.12 (1H, d, J 8.0), 8.72 (1H, d, J 7.2), 7.96 (1H, s), 7.40 (1H, dd, J 7.2, 1.6), 7.21 - 7.16 (2H, m), 6.89 (1H, t, J 7.2), 6.82 (1H, d, J 8.0), 5.28 (1H, d, J 6.8), 5.10 - 4.51 (1H, m), 4.31 - 4.25 (2H, m), 3.95 - 3.90 (2H, m), 3.72 - 3.67 (1H, m), 3.20 - 3.13 (2H, m), 2.15 - 2.06 (2H, m), 1.83 - 1.79 (2H, m), 1.45 - 1.37 (2H, m).

[0417] Example 55-61 Examples 55-61 can be prepared according to the route shown in Scheme 13.

[0418] [ka]

[0419] Step 1 (Scheme 13): S leading to Examples 55-61 N Ar reaction To a solution of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (1 equivalent) and DIPEA (4 equivalents) in n-butanol (10 volumes) was added the amine derivative (4 equivalents). The mixture was stirred at 120° C. for 16-32 hours while being monitored by TLC. Upon completion, the reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Examples 55-61 as white solids.

[0420] Example 55: (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Prepared according to Scheme 13 using piperazine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.11 (1H, d, J 8.0), 8.73 (1H, d, J 7.2), 7.97 (1H, d, J 1.2), 7.40 (1H, dd, J 7.0, 2.0), 7.21 - 7.16 (2H, m), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 0.8), 5.29 (1H, d, J 7.2), 4.31 - 4.26 (2H, m), 3.43 (4H, t, J 4.4), 2.79 (4H, t, J 5.2), 2.14 - 2.07 (m, 2H). Note: The NH protons of piperazine were not observed.

[0421] Example 56: (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Prepared according to Scheme 13 using 1-methylpiperazine as the amine derivative. 1 H NMR: δ H (400 MHz, methanol-d4) 8.58 (1H, dd, J 6.8, 0.8), 7.91 - 7.90 (1H, m), 7.43 (1H, dd, J 7.0, 1.6), 7.26 (1H, d, J 7.6), 7.21 - 7.16 (1H, m), 6.93 (1H, t, J 6.4), 6.90 (1H, d, J 1.2), 5.37 (1H, t, J 6.0), 4.32 - 4.29 (2H, m), 3.68 (4H, t, J 4.4), 2.72 (4H, t, J 4.8), 2.46 (3H, s), 2.30 - 2.20 (2H, m). Note: Amide NH protons were not observed.

[0422] Example 57: (S)-N-(chroman-4-yl)-2-morpholino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Prepared according to Scheme 13 using morpholine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d69.14 (1H, d, J 8.0), 8.76 (1H, dd, J 6.8, 0.8), 8.01 - 8.01 (1H, m), 7.44 (1H, dd, J 6.8, 2.0), 7.21 - 7.16 (2H, m), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.29 (1H, q, J 6.8), 4.33 - 4.24 (2H, m), 3.72 (4H, t, J 4.8), 3.48 (4H, t, J 4.8), 2.16 - 2.07 (2H, m).

[0423] Example 58: (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Prepared according to Scheme 13 using 1-tert-butylpiperazine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.12 (1H, d, J 8.0), 8.74 (1H, d, J 6.8), 7.98 (1H, s), 7.41 (1H, d, J 5.6), 7.21 - 7.16 (2H, m), 6.91 - 6.81 (2H, m), 5.29 (1H, q, J 6.4), 4.34 - 4.23 (2H, m), 3.48 (4H, s), 2.68 (4H, s), 2.18 - 2.05 (2H, m), 1.04 (9H, s).

[0424] Example 59: (S)—N-(chroman-4-yl)-2-(piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Prepared according to Scheme 13 using piperidine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.11 (1H, d, J 8.4), 8.72 (1H, dd, J 6.8, 0.8), 7.96 - 7.96 (1H, m), 7.40 - 7.38 (1H, m), 7.21 - 7.16 (2H, m), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.29 (1H, q, J 6.8), 4.33 - 4.24 (2H, m), 3.52 (4H, d, J 5.2), 2.19 - 2.02 (2H, m), 1.59 (6H, s).

[0425] Example 60: (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Prepared according to Scheme 13 using 1-ethylpiperazine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.18 (1H, d, J 8.0), 8.81 (1H, d, J 7.2), 8.06 (1H, s), 7.49 (1H, d, J 6.4), 7.21 - 7.17 (2H, m), 6.89 (1H, t, J 7.2), 6.82 (1H, d, J 8.0), 5.30 (1H, t, J 5.6), 4.33 - 4.22 (4H, m), 3.56 (2H, d, J 11.6), 3.45 - 3.42 (2H, m), 3.16 - 3.07 (4H, m), 2.14 - 2.08 (2H, m), 1.27 (3H, t, J 7.2).

[0426] Example 61: (S)—N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide Prepared according to Scheme 13 using 1-(propan-2-yl)piperazine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.13 (1H, d, J 8.0), 8.73 (1H, dd, J 7.0, 0.8), 7.98 - 7.98 (1H, m), 7.42 - 7.40 (1H, m), 7.21 - 7.16 (2H, m), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 5.29 (1H, q, J 6.8), 4.34 - 4.23 (2H, m), 3.49 (4H, t, J 4.4), 2.71 - 2.67 (1H, m), 2.55 - 2.53 (4H, m), 2.15 - 2.06 (2H, m), 1.00 (6H, d, J 6.4).

[0427] Example 62: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (S)-2-Bromo-N-(2,3-dihydro-1H-inden-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide [prepared according to Scheme 11 using (S)-chroman-4-amine (S)-1-aminoindan in step 5] was used in place of (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide and prepared according to Scheme 13 using piperazine as the amine derivative. 1 H NMR:δ H(400 MHz, DMSO-d6) 9.05 (1H, d, J 8.0), 8.75 (1H, d, J 7.2), 7.99 (1H, s), 7.44 - 7.42 (1H, m), 7.30 - 7.18 (4H, m), 5.57 (1H, q, J 7.6), 3.51 (4H, brs), 3.05 - 3.03 (1H, m), 3.03 - 2.99 (5H, m), 2.91 - 2.83 (1H, m), 2.51 - 2.51 (1H, m), 2.04 - 1.98 (1H, m).

[0428] Example 63: (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (R)-2-Bromo-N-(2,3-dihydro-1H-inden-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide [prepared according to Scheme 11 using (R)-1-aminoindan instead of (S)-chroman-4-amine in step 5] was prepared according to Scheme 13 using (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide and piperazine as the amine derivative. 1 H NMR:δ H (400 MHz, DMSO-d6) 9.02 (1H, d, J 8.4), 8.73 (1H, d, J 6.8), 7.97 (1H, s), 7.41 (1H, dd, J 7.0, 2.0), 7.30 - 7.18 (4H, m), 5.57 (1H, q, J 7.6), 3.44 (4H, t, J 4.8), 3.05 - 3.01 (1H, m), 2.99 - 2.91 (1H, m), 2.85 (4H, t, J 8.0), 2.68 - 2.67 (1H, m), 2.51 - 2.50 (1H, m), 2.03 - 1.98 (1H, m).

[0429] Example 64: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (S)-2-Bromo-N-(2,3-dihydro-1H-inden-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide [prepared according to Scheme 11 using (S)-1-aminoindan instead of (S)-chroman-4-amine in step 5] was prepared according to Scheme 13 using (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide and 1-methylpiperazine as the amine derivative. 1 H NMR:δ H (400 MHz, DMSO-d6) 9.04 (1H, d, J 8.0), 8.74 (1H, d, J 7.2), 7.98 (1H, s), 7.42 (1H, d, J 7.2), 7.30 - 7.18 (4H, m), 5.57 (1H, q, J 8.0), 3.51 (4H, t, J 4.4), 3.05 - 3.01 (1H, m), 2.99 - 2.83 (1H, m), 2.51 - 2.51 (1H, m), 2.46 (4H, t, J 9.6), 2.34 (3H, s), 2.06 - 2.00 (1H, m).

[0430] Example 65: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (S)-2-Bromo-N-(2,3-dihydro-1H-inden-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide [prepared according to Scheme 11 using (S)-1-aminoindan instead of (S)-chroman-4-amine in step 5] was prepared according to Scheme 13 using (S)-2-bromo-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide and 1-ethylpiperazine as the amine derivative. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.03 (1H, d, J 8.4), 8.74 (1H, d, J 6.8), 7.98 (1H, d, J 1.2), 7.43 - 7.41 (1H, m), 7.30 - 7.18 (4H, m), 5.57 (1H, q, J 8.0), 3.51 (4H, t, J 4.8), 3.05 - 3.01 (1H, m), 2.99 - 2.83 (1H, m), 2.48 - 2.45 (7H, m), 2.16 - 2.00 (1H, m), 1.04 (3H, t, J 7.2).

[0431] Example 66: 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide Example 66 can be prepared according to the route shown in Scheme 14.

[0432] [ka]

[0433] Step 1 (Scheme 14): Synthesis of N-(2,4-dimethoxybenzyl)-4,4-difluorocyclohexan-1-amine To a solution of 2,4-dimethoxybenzaldehyde (502 mg, 3.02 mmol) in dichloromethane (15 mL) was added N,N-diisopropylethylamine (560 μL, 3.21 mmol) and 4,4-difluorocyclohexylamine hydrochloride (525 mg, 3.06 mmol). The reaction mixture was stirred under nitrogen at room temperature for 2 hours, after which sodium triacetoxyborohydride (1.2 g, 5.66 mmol) was added and stirring continued overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and dichloromethane, the layers were separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated to give N-(2,4-dimethoxybenzyl)-4,4-difluorocyclohexan-1-amine (905 mg, quantitative) as a cloudy gel.

[0434] Step 2 (Scheme 14): Synthesis of 2-bromoimidazo[1,2-a]pyridine-6-carboxylic acid To a suspension of methyl 2-bromoimidazo[1,2-a]pyridine-6-carboxylate (440 mg, 1.73 mmol) in tetrahydrofuran (10 mL) was added 0.5 N aqueous lithium hydroxide (8 mL, 4.00 mmol), and the reaction was stirred at room temperature for 2 hours. The mixture was partitioned between water and dichloromethane. The layers were separated, and the basic aqueous layer was neutralized to pH 5-6 with 2 N aqueous HCl. The resulting milky suspension was extracted six times with dichloromethane, and the combined milky organic layers were concentrated to give crude 2-bromoimidazo[1,2-a]pyridine-6-carboxylic acid as a yellow solid, which was used directly without further purification.

[0435] Step 3 (Scheme 14): Synthesis of 2-bromo-N-(4,4-difluorocyclohexyl)-N-(2,4-dimethoxybenzyl)imidazo[1,2-a]pyridine-6-carboxamide To a solution of crude 2-bromoimidazo[1,2-a]pyridine-6-carboxylic acid (303 mg, 1.26 mmol) and N-(2,4-dimethoxybenzyl)-4,4-difluorocyclohexane-1-amine (247 mg, 0.87 mmol) in N,N-dimethylformamide (10 mL) was added EDCI·HCl (180 mg, 0.94 mmol) and Oxyma Pure (19 mg, 0.13 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0% to 75% ethyl acetate in heptane to give 2-bromo-N-(4,4-difluorocyclohexyl)-N-(2,4-dimethoxybenzyl)imidazo[1.2-a]pyridine-6-carboxamide (301 mg, 68% over two steps) as a white solid.

[0436] Step 4 (Scheme 14): Synthesis of tert-butyl 8-(6-((4,4-difluorocyclohexyl)(2,4-dimethoxybenzyl)carbamoyl)imidazo[1,2-a]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate A suspension of 2-bromo-N-(4,4-difluorocyclohexyl)-N-(2,4-dimethoxybenzyl)imidazo[1,2-a]pyridine-6-carboxamide (153 mg, 0.30 mmol), 3-Boc-3,8-diazabicyclo[3.2.1]octane (135 mg, 0.64 mmol), (t-Bu)PhCPhos (21 mg, 0.052 mmol), and NaOtBu (75 mg, 0.78 mmol) in 1,4-dioxane (5 mL) was flushed with argon for 5 min, after which Pd2dba3 (41 mg, 0.045 mmol) was added, and the reaction was heated at 100 °C in a sealed vial for 4 h. The reaction mixture was cooled to room temperature, diluted with water (25 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography eluting with 30% to 100% ethyl acetate in heptane to give tert-butyl 8-(6-((4,4-difluorocyclohexyl)(2,4-dimethoxybenzyl)carbamoyl)imidazo[1.2-a]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (103 mg, 54%) as a brown solid.

[0437] Step 5 leading to Example 66 (Scheme 14) To a solution of tert-butyl 8-(6-((4,4-difluorocyclohexyl)(2,4-dimethoxybenzyl)carbamoyl)imidazo[1,2-a]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (101 mg, 0.16 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (350 μL, 4.57 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was transferred to an SCX cartridge, eluted with 1 N NH in MeOH, and concentrated. The resulting material was purified twice by preparative HPLC, and the product was lyophilized from acetonitrile / water to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide (12 mg, 20%) as a pale yellow solid. 1 H NMR δ H (400 MHz, CDCl3) 8.63 (1H, t, J 1.3), 7.35 (1H, d, J 9.2), 7.23 (1H, dd, J 9.3, 1.8), 6.82 (1H, s), 5.90 (1H, d, J 7.8), 4.11 (1H, d, J 10.4), 3.65 (2H, s), 3.55 (2H, dd, J 11.3, 2.5), 3.03 (2H, d, J 11.1), 2.13 (4H, d, J 12.6), 1.99 - 1.83 (6H, m), 1.68 - 1.57 (3H, m).

[0438] Example 67: 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylimidazo[1,2-a]pyridine-6-carboxamide Prepared according to Scheme 14, using cyclopentylamine instead of 4,4-difluorocyclohexylamine in step 1. 1 H NMR δ H (400 MHz, DMSO-d6) 8.81 (1H, d, J 1.7), 8.25 (1H, d, J 7.2), 7.51 (1H, dd, J 9.1, 1.8), 7.34 - 7.24 (2H, m), 4.28 - 4.15 (1H, m), 4.02 (2H, dd, J 4.3, 2.3), 2.95 (2H, dd, J 12.2, 1.7), 1.96 - 1.81 (4H, m), 1.81 - 1.74 (2H, m), 1.74 - 1.64 (2H, m, J 4.9, 4.4), 1.61 - 1.46 (4H, m). Note: One signal (2H) coincides with the DMSO signal. NOTE: One signal (2H) coincides with the DMSO signal.

[0439] Example 68: (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 68 can be prepared according to the route shown in Scheme 15.

[0440] [ka]

[0441] Step 1 (Scheme 15): Synthesis of ethyl 2-bromopyrazolo[1,5-a]pyrimidine-6-carboxylate To a suspension of 3-bromo-1H-pyrazol-5-amine (3.0 g, 18.5 mmol) in EtOH (45 mL) was added ethyl 2-formyl-3-oxopropanoate (2.66 g, 18.5 mmol), and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and triturated with n-pentane to give ethyl 2-bromopyrazolo[1,5-a]pyrimidine-6-carboxylate (4.8 g, 95%) as a pale yellow solid.

[0442] Step 2 (Scheme 15): Synthesis of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate To a degassed solution of ethyl 2-bromopyrazolo[1,5-a]pyrimidine-6-carboxylate (3 g, 11.1 mmol), tert-butyl piperazine-1-carboxylate (4.63 g, 22.2 mmol), CsCO (7.22 g, 22.2 mmol), and BINAP (1.38 g, 2.22 mmol) in toluene (40 mL) under nitrogen was added Pd(OAc) (0.24 g, 1.11 mmol), and the reaction was stirred at 110° C. for 16 h. The reaction mixture was cooled and filtered through Celite®, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by flash chromatography eluting with 5% methanol in dichloromethane to give ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.9 g, 21%) as a pale yellow solid.

[0443] Step 3 (Scheme 15): Synthesis of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid To a solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.8 g, 2.4 mmol) in THF:HO (3:1; 15 mL) was added LiOH·HO (0.15 g, 3.6 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water and acidified with citric acid. The resulting solid precipitate was filtered off, dried under reduced pressure, and then triturated with n-pentane to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.64 g, 86%) as a pale yellow solid.

[0444] Step 4 (Scheme 15): Synthesis of tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)piperazine-1-carboxylate To a solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.63 g, 2.21 mmol) in DMF (6 mL) was added (S)-chroman-4-amine hydrochloride (0.61 g, 3.32 mmol) and DIPEA (1.14 mL, 6.63 mmol). The mixture was stirred for 15 min, followed by the addition of n-propylphosphonic anhydride cyclic trimer (2.8 g, 4.42 mmol). The reaction mixture was stirred at room temperature for 16 h, then quenched with ice water (20 mL) and stirred for 10 min. The resulting solid precipitate was filtered off and dried under reduced pressure to give tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)piperazine-1-carboxylate (0.64 g, 74%) as a pale yellow solid.

[0445] Step 5 leading to Example 68 (Scheme 15): Synthesis of (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide To a stirred solution of tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)piperazine-1-carboxylate (0.12 g, 0.25 mmol) in dichloromethane (5.0 mL) was added a solution of HCl in 1,4-dioxane (4 M; 2.0 mL). The mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was basified with aqueous NaHCO (8 mL), and the organic components were extracted with dichloromethane (2 × 10 mL). The combined organic layers were separated, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by preparative HPLC using NHHCO as buffer to give the title compound (0.05 g, 53%) as an off-white solid. 1 H NMR:δ H(400 MHz, DMSO-d6) 9.26 (1H, d, J 1.6), 8.88 (1H, d, J 7.6), 8.75 (1H, d, J 2.0), 7.21 (1H, d, J 10.0), 7.18 (1H, t, J 7.2), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 6.22 (1H, s), 5.26 (1H, d, J 6.8), 4.30 - 4.26 (2H, m), 3.30 - 3.27 (5H, m), 2.80 (4H, t, J 4.8), 2.14 - 2.04 (2H, m).

[0446] Example 69: (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 69 can be prepared by reductive alkylation of Example 68 using formaldehyde according to the method in Scheme 9. 1 H NMR:δ H (400 MHz, DMSO-d6) 9.26 (1H, d, J 1.6), 8.88 (1H, d, J 8.0), 8.76 (1H, d, J 2.4), 7.20 (1H, d, J 1.2), 7.17 (1H, t, J 6.8), 6.90 (1H, t, J 0.8), 6.87 (1H, d, J 1.2), 6.25 (1H, s), 5.26 (1H, q, J 6.0), 4.30 - 4.26 (2H, m), 3.34 (4H, s), 2.42 (4H, t, J 4.8), 2.22 (3H, s), 2.17 - 2.13 (2H, m).

[0447] Example 70: (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 70 can be prepared by reductive alkylation of Example 68 using acetaldehyde according to the method of Scheme 10. 1 H NMR:δ H (400 MHz, DMSO-d6) 9.27 (1H, d, J 1.6), 8.87 (1H, d, J 8.0), 8.76 (1H, d, J 2.4), 7.25 - 7.16 (2H, m), 6.90 (1H, t, J 6.4), 6.87 (1H, d, J 1.2), 6.25 (1H, s), 5.26 (1H, d, J 7.2), 4.30 - 4.26 (2H, m), 3.35 (4H, s), 2.55 (4H, s), 2.48 - 2.33 (2H, m), 2.22 - 2.03 (2H, m), 1.04 (3H, t, J 7.2).

[0448] Example 71: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 71 can be prepared according to Scheme 15, using (S)-1-aminoindan hydrochloride in place of (S)-chroman-4-amine hydrochloride in step 4. 1 H NMR:δ H (400 MHz, DMSO-d6) 9.25 (1H, d, J 1.6), 8.76 (2H, d, J 2.4), 7.32 - 7.26 (2H, m), 7.24 - 7.20 (2H, m), 6.22 (1H, s), 5.55 (1H, q, J 8.0), 3.32 - 3.29 (4H, m), 3.04 - 3.00 (2H, m), 2.99 - 2.81 (5H, m), 2.53 - 2.53 (1H, m), 2.00 - 1.94 (1H, m).

[0449] Example 72-75 Examples 72-75 can be prepared according to the route shown in Scheme 16.

[0450] [ka]

[0451] Step 1 (Scheme 16): Synthesis of ethyl 2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate To a stirred solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (700 mg, 1.87 mmol) in DCM (15 mL) at 0° C. was added TFA (425 mg, 3.73 mmol). After 15 min, the reaction mixture was allowed to warm to ambient temperature and maintained at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water, and washed with saturated NaHCO 3水 The pH was adjusted to approximately 7 using a solution of 1,2-dimethyl-2,4-dimethyl-1,3-dimethyl-2,4-dimethyl-1,4 ...

[0452] Step 2 (Scheme 16): Synthesis of ethyl 2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate To a stirred solution of ethyl 2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (700 mg, 2.54 mmol) in acetone (5 mL) was added ethyl iodide (476 mg, 3.05 mmol) and K2CO3 (1050 mg, 7.63 mmol) at 0 °C. After 15 min, the reaction mixture was heated at 55 °C for 16 h and then concentrated under reduced pressure. The residue was diluted with water (20 mL), and the organic components were extracted with 10% methanol in dichloromethane (2 × 25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product (800 mg) was triturated with 10% ethyl acetate in hexane to give ethyl 2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (700 mg, 89%) as a light brown solid.

[0453] Step 3 (Scheme 16): Synthesis of 2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid To a solution of ethyl 2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (650 mg, 2.14 mmol) in THF:HO (3:1; 5 mL) was added LiOH HO (180 mg, 4.29 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness, and the product was used in the next step as the lithium salt without further purification.

[0454] General procedure for Step 4 (Scheme 16): Amide coupling leading to Examples 72-75 A solution of 2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid lithium salt (1 equiv.), amine (1.2 equiv.), and DIPEA (3 equiv.) in DCM (10 vol.) was stirred for 15 min, followed by the addition of n-propylphosphonic anhydride cyclic trimer (50% in ethyl acetate; 2 equiv.). The reaction mixture was stirred at room temperature for 16 h and then quenched with ice-water. The organic components were extracted twice with 10% MeOH in DCM. The combined organic layers were separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude products were purified by preparative HPLC to give Examples 72–75 as off-white solids.

[0455] Example 72: N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 16 using cyclopentylamine as the amine in step 4. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.23 (1H, d, J 7.6), 8.70 (1H, d, J 2.0), 8.27 (1H, d, J 7.2), 6.23 (1H, d, J 0.4), 4.23 (1H, d, J 6.4), 3.37 (4H, t, J 4.8), 2.48 - 2.41 (4H, m), 2.39 - 2.34 (2H, m), 1.92 - 1.89 (2H, m), 1.72 - 1.71 (2H, m), 1.57 - 1.51 (4H, m), 1.04 (3H, t, J 7.2).

[0456] Example 73: N-cyclohexyl-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 16 using cyclohexylamine as the amine in step 4. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.22 (1H, t, J 1.2), 8.70 (1H, d, J 2.4), 8.21 (1H, d, J 7.6), 6.23 (1H, s), 3.77 - 3.75 (1H, m), 3.37 (4H, t, J 4.4), 2.56 - 2.50 (4H, m), 2.48 - 2.47 (2H, m), 1.86 - 1.85 (2H, m), 1.84 - 1.74 (2H, m), 1.63 - 1.60 (1H, m), 1.30 - 1.17 (4H, m), 1.16 - 1.11 (1H, m), 1.04 (3H, t, J 7.2).

[0457] Example 74: N-(4,4-difluorocyclohexyl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 16 using 4,4-difluorocyclohexylamine as the amine in Step 4. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.25 (1H, d, J 2.0), 8.70 (1H, d, J 2.0), 8.30 - 8.25 (1H, m), 6.25 (1H, s), 4.06 - 3.94 (1H, m), 3.43 - 3.33 (4H, m), 2.62 - 2.50 (4H, m), 2.44 - 2.32 (2H, m), 2.14 - 1.92 (6H, m), 1.68 - 1.62 (2H, m), 1.05 (3H, t, J 6.4).

[0458] Example 75: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 16 using (S)-1-aminoindan as the amine in Step 4. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.25 (1H, s), 8.77 (2H, d, J 2.0), 7.31 - 7.20 (4H, m), 6.25 (1H, s), 5.55 (1H, d, J 7.2), 3.37 (4H, s), 3.04 - 2.98 (1H, m), 2.91 - 2.85 (1H, m), 2.51 (4H, s), 2.40 - 2.33 (3H, m), 2.01 - 1.92 (1H, m), 1.04 (3H, t, J 7.2).

[0459] Examples 76-79 Examples 76-79 can be prepared according to the route shown in Scheme 17.

[0460] [ka]

[0461] Step 1 (Scheme 17): Synthesis of ethyl 2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate To a stirred solution of ethyl 2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (130 mg, 0.47 mmol, 1 equiv.) in acetone (30 mL) was added K2CO3 (98 mg, 0.71 mmol, 1.5 equiv.) and methyl iodide (53.6 mg, 0.38 mmol, 0.8 equiv.). The reaction mixture was stirred at room temperature for 2 hours, then quenched with ice-cold water and concentrated under reduced pressure. The residue was diluted with brine (10 mL), and the organic components were extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 0% to 10% methanol in dichloromethane to give ethyl 2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (55 mg, 97%) as a light brown solid.

[0462] General Procedure for Step 2 (Scheme 17): Amide Coupling Leading to Examples 76-79 To a stirred solution of ethyl 2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1 equivalent) in toluene (10 volumes) was added the amine (2 equivalents), DIPEA (3 equivalents), and triethylenediaminebis(trimethylaluminum) (2 equivalents). The mixture was heated at 110° C. for 16 hours, then cooled to room temperature, quenched with ice-cold water, and concentrated under reduced pressure. The residue was diluted with water (5 volumes), and the organic components were extracted with 5% MeOH in DCM (2×10 volumes). The combined organic extracts were washed with brine (5 volumes), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude products were purified by preparative HPLC, and the purified fractions were lyophilized to give Examples 76–79 as off-white solids.

[0463] Example 76: N-Cyclopentyl-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 17 using cyclopentylamine as the amine in Step 2. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.23 (1H, d, J 1.6), 8.70 (1H, d, J 2.4), 8.29 (1H, d, J 7.2), 6.23 (1H, s), 4.25 - 4.20 (1H, m), 3.37 (4H, t, J 4.8), 2.43 (4H, t, J 4.8), 2.23 (3H, s), 1.91 - 1.87 (2H, m), 1.71 - 1.68 (2H, m), 1.57 - 1.54 (m, 4H).

[0464] Example 77: N-cyclohexyl-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 17 using cyclohexylamine as the amine in Step 2. 1H NMR: δ H (400 MHz, DMSO-d6) 9.22 (1H, d, J 1.6), 8.70 (1H, d, J 2.0), 8.22 (1H, d, J 7.6), 6.23 (1H, s), 3.77 - 3.75 (1H, m), 3.37 (4H, t, J 4.8), 2.43 (4H, t, J 4.8), 2.23 (3H, s), 1.86 - 1.84 (2H, m), 1.76 - 1.74 (2H, m), 1.63 - 1.60 (1H, m), 1.30 - 1.24 (4H, m), 1.16 - 1.13 (1H, m).

[0465] Example 78: N-(4,4-difluorocyclohexyl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 17 using 4,4-difluorocyclohexylamine as the amine in Step 2. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.24 (1H, d, J 1.6), 8.69 (1H, d, J 2.0), 8.29 (1H, d, J 7.6), 6.25 (1H, d, J 0.4), 4.00 (1H, d, J 6.4), 3.37 (4H, t, J 4.8), 2.43 (4H, t, J 4.8), 2.23 (3H, s), 2.08 - 1.89 (6H, m), 1.65 - 1.62 (2H, m).

[0466] Example 79: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 17 using (S)-1-aminoindan as the amine in Step 2. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.25 (1H, t, J 1.6), 8.81 - 8.77 (2H, m), 7.31 - 7.24 (2H, m), 7.23 - 7.19 (2H, m), 6.25 (1H, s), 5.5 (1H, d, J 8.0), 3.39 - 3.37 (4H, m), 3.05 - 2.98 (1H, m), 2.91 - 2.83 (1H, m), 2.52 - 2.50 (1H, m), 2.50 - 2.45 (4H, m), 2.25 (3H, s), 1.99 - 1.92 (1H, m).

[0467] Example 80: 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxamide Example 80 can be prepared by the method of Scheme 15 using tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate instead of tert-butyl piperazine-1-carboxylate in Step 2 and cyclopentylamine instead of (S)-chroman-4-amine hydrochloride in Step 4. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.23 (1H, d, J 1.6), 8.67 (1H, d, J 2.4), 8.22 - 8.28 (1H, m), 6.17 (1H, s), 4.25 - 4.21 (1H, m), 4.15 - 4.10 (2H, m), 2.97 - 2.94 (2H, m), 1.93 - 1.84 (6H, m), 1.68 - 1.70 (2H, m), 1.56 - 1.50 (4H, m). Note: One signal (2H) coincides with the DMSO signal. NOTE: One signal (2H) coincides with the DMSO signal.

[0468] Example 81: N-cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 81 can be prepared by reductive alkylation of Example 80 using formaldehyde according to the method of Scheme 9. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.23 (1H, s), 8.68 (1H, d J 2.0), 8.22 - 8.28 (1H, m), 6.21 (1H, s), 4.25 - 4.22 (3H, m), 2.68 - 2.51 (2H, m), 2.33 - 2.28 (2H, m), 2.10 - 2.08 (3H, m), 1.88 - 1.82 (6H, m), 1.84 - 1.71 (2H, m), 1.51 - 1.54 (4H, m).

[0469] Example 82: (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 82 can be prepared according to the route shown in Scheme 18.

[0470] [ka]

[0471] Step 1 (Scheme 18): Synthesis of tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate (200 mg, 0.79 mmol) in ethanol (5 mL) was added N2H4·H2O (0.078 mL, 1.59 mmol) at room temperature. The reaction mixture was heated under reflux with stirring for 16 h and then concentrated under reduced pressure. The residue was diluted with water (5 mL) and extracted with 5% MeOH / DCM (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product (180 mg, 84%), which was used in the next step without further purification.

[0472] Step 2 (Scheme 18): Synthesis of ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate To a stirred solution of tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate (200 mg, 0.75 mmol) in ethanol (5 mL) was added ethyl 2-formyl-3-oxopropanoate (108 mg, 0.751 mmol) at room temperature. The reaction mixture was heated under reflux with stirring for 16 hours and then concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with 5% MeOH in DCM (2 × 50 mL). The combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 20%-40% EtOAc in hexane to give the desired product (170 mg, 63%) as an off-white solid.

[0473] Step 3 (Scheme 18): Synthesis of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid To a mixture of ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (150 mg, 0.40 mmol) in THF:HO (3:1; 5 mL) was added LiOH·HO (19.2 mg, 0.80 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (10 mL), and the pH was adjusted to approximately 4 using citric acid, followed by extraction with 5% MeOH / DCM (2 × 25 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated with 10% ethyl acetate in hexane to give the desired product (120 mg, 85%) as a pale yellow solid.

[0474] General procedure for Step 4 (Scheme 18): Amide coupling To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1 eq) in DCM (10 vol) was added at 0° C. n-Propylphosphonic anhydride cyclic trimer (50% in ethyl acetate; 2 eq) and DIPEA (4 eq) were added. The mixture was stirred for 15 min, followed by the addition of (S)-chroman-4-amine (1.3 eq). The reaction mixture was allowed to warm to room temperature and stirred for 16 h, then diluted with water (20 vol) and extracted with 5% MeOH in DCM (2×15 vol). The combined organic extracts were washed with brine (10 vol), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate as an off-white solid.

[0475] General procedure for step 5 (Scheme 18) leading to Example 82: Boc deprotection To a stirred solution of tert-butyl (S)-4-(6-(chroman-4-ylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate (1 equivalent) in DCM (10 volumes) at 0° C. was added HCl in dioxane (4 M; 3 volumes). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours, then concentrated under reduced pressure. The residue was washed with acetonitrile and dried under reduced pressure to give (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide (Example 82, isolated as its hydrochloride salt) as an off-white solid. 1 H NMR:δ H (400 MHz, DMSO-d6) 9.54 (1H, d, J 1.6), 9.08 (1H, d, J 8.0), 8.94 (1H, d, J 2.0), 8.85 (1H, s), 8.63 (1H, d, J 10.8), 7.26 (1H, d, J 7.6), 7.19 (1H, t, J 8.4), 6.90 (1H, t, J 7.2), 6.83 (1H, d, J 8.4), 6.74 (1H, s), 5.28 (1H, q, J 6.0), 4.33 - 4.28 (2H, m), 3.35 - 3.17 (1H, m), 3.11 - 3.02 (2H, m), 2.21 - 2.17 (3H, m), 2.15 - 2.05 (1H, m), 1.98 - 1.91 (2H, m). NOTE: One signal (2H) coincides with the DMSO signal.

[0476] Example 83: (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to the method of Scheme 18, using (S)-1-aminoindan instead of (S)-chroman-4-amine in step 4. The title compound was isolated as the free base. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.49 (1H, d, J 1.6), 8.95 (1H, d, J 8.0), 8.92 (1H, d, J 2.4), 7.34 - 7.25 (2H, m), 7.23 - 7.19 (2H, m), 6.68 (1H, s), 5.57 (1H, q, J 8.0), 3.07 - 2.86 (6H, m), 2.73 - 2.67 (2H, m), 2.01 - 1.95 (4H, m), 1.69 - 1.65 (2H, m).

[0477] Example 84: (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 84 can be prepared according to the method in Scheme 19.

[0478] [ka]

[0479] Step 1 (Scheme 19): Synthesis of ethyl 2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate To a stirred solution of ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1.8 g, 4.81 mmol, 1 equiv) in DCM (5 mL) at 0° C. was added TFA (1.11 mL, 14.4 mmol, 3 equiv). The reaction mixture was warmed to room temperature, stirred for 16 hours, and then concentrated under reduced pressure. The residue was diluted with 10% MeOH in DCM (15 mL) and washed with aqueous sodium bicarbonate (5 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (500 mg, 36%) as an off-white solid.

[0480] Step 2 (Scheme 19): Synthesis of ethyl 2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate A solution of ethyl 2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (100 mg, 0.37 mmol, 1 equiv.) in acetone (10 mL) was added under nitrogen with K2CO3 (101 mg, 0.73 mmol, 2 equiv.) and ethyl iodide (68.2 mg, 0.44 mmol, 1.2 equiv.). The reaction mixture was heated to reflux under nitrogen for 16 hours and then concentrated under reduced pressure. The residue was dissolved in 10% MeOH in DCM (10 mL) and washed with brine (25 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude ethyl 2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (80 mg, 57%), which was used in the next step without further purification.

[0481] Step 3 (Scheme 19): Synthesis of 2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid lithium salt To a mixture of ethyl 2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (120 mg, 0.40 mmol, 1 equiv.) in THF:water (9:1; 10 mL) was added lithium hydroxide (14.3 mg, 0.60 mmol, 1.5 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to give crude 2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid lithium salt, which was used in the next step without further purification.

[0482] Step 4 leading to Example 84 (Scheme 19) To a stirred solution of 2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (190 mg, 0.69 mmol) in DCM (5 mL) at 0 °C was added n-propylphosphonic anhydride cyclic trimer (0.63 mL, 1.39 mmol) and DIPEA (358 mg, 2.77 mmol). The mixture was stirred for 15 min, followed by the addition of (S)-chroman-4-amine (134 mg, 0.90 mmol). The mixture was warmed to room temperature and stirred for 16 h, then diluted with water (10 mL) and extracted with 5% MeOH in DCM (2 × 25 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide (20 mg, 99%) as an off-white solid. 1 H NMR:δ H (400 MHz, DMSO-d6) 9.51 (1H, d, J 1.2), 9.06 - 9.02 (1H, m), 8.93 (1H, d, J 2.4), 7.27 - 7.17 (2H, m), 6.91 (1H, t, J 1.2), 6.88 (1H, d, J 1.2), 6.73 (1H, s), 5.28 (1H, q, J 6.8), 4.31 - 4.27 (2H, m), 3.17 - 3.07 (2H, m), 2.19 - 2.01 (5H, m), 1.87 - 1.84 (2H, m), 1.24 - 1.13 (3H, m). NOTE: One signal (4H) coincides with the DMSO signal.

[0483] Example 85-87 Examples 85-87 can be prepared according to the methods in Scheme 20.

[0484] [ka]

[0485] Step 1 (Scheme 20): Synthesis of ethyl 2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate To a stirred solution of ethyl 2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1.13 g, 4.12 mmol, 1.0 equiv.) in THF (50 mL) was added iodomethane (0.283 mL, 4.53 mmol, 1.1 equiv.) followed by NaH (60% in mineral oil; 0.247 g, 6.18 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at room temperature for 2 h, then quenched with ice-cold water, and the organic components were extracted with 10% MeOH / DCM (2 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0% to 10% MeOH in DCM to give ethyl 2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (320 mg, 25%) as a yellow solid.

[0486] General procedure for Step 2 (Scheme 20): Amide coupling To a stirred solution of ethyl 2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1 equivalent) in toluene (10 volumes) was added the required amine (2 equivalents), DIPEA (3 equivalents), and triethylenediamine bis(trimethylaluminum) (2 equivalents). The reaction mixture was stirred at 110° C. for 16 hours, then cooled to room temperature, quenched with ice-cold water, and concentrated under reduced pressure. The residue was diluted with water (5 volumes), and the organic components were extracted with 5% MeOH in DCM (2×10 volumes). The combined organic extracts were washed with brine (5 volumes), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude products were purified by preparative HPLC to give Examples 85-87 as off-white solids.

[0487] Example 85: N-Cyclopentyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 20 using cyclopentylamine as the amine in Step 2. 1 H NMR: δ H (400 MHz, DMSO-d6): 9.46 (1H, s), 8.85 (1H, d, J 1.6), 8.45 (1H, d, J 6.8), 6.69 (1H, s), 4.27 - 4.24 (1H, m), 2.86 - 2.77 (3H, m), 2.20 (3H, s), 2.09 - 1.91 (5H, m), 1.77 - 1.64 (5H, m), 1.56 - 1.36 (4H, m).

[0488] Example 86: N-cyclohexyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 20 using cyclohexylamine as the amine in step 2. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.46 - 9.45 (1H, m), 8.84 (1H, d, J 2.0), 8.38 (1H, d, J 7.6), 6.69 (1H, s), 3.89 - 3.70 (1H, m), 2.83 - 2.73 (2H, m), 2.71 - 2.65 (2H, m), 2.20 (3H, s), 2.04 - 1.95 (3H, m), 1.87 - 1.86 (2H, m), 1.77 - 1.74 (4H, m), 1.63 - 1.60 (1H, m), 1.36 - 1.34 (4H, m), 1.32 - 1.29 (1H, m).

[0489] Example 87: N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 20 using 4,4-difluorocyclohexylamine as the amine in Step 2. 1H NMR:δ H (400 MHz, DMSO-d6) 9.48 (1H, d, J 1.6), 8.84 (1H, d, J 2.0), 8.44 (1H, d, J 7.6), 6.69 (1H, s), 3.94 - 3.92 (1H, m), 2.83 - 2.78 (3H, m), 2.46 (3H, s), 2.34 - 2.33 (4H, m), 2.08 - 2.00 (6H, m), 1.96 - 1.89 (2H, m), 1.78 - 1.75 (2H, m).

[0490] Example 88: (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to Scheme 19 using ethyl 2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate instead of ethyl 2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate in step 3. 1 H NMR:δ H (400 MHz, DMSO-d6): 9.51 (1H, dd, J 2.2 and 0.8), 9.05 (1H, br. d, J 7.8), 8.90 (1H, d, J 2.2), 7.27 - 7.23 (1H, m), 7.20 - 7.16 (1H, m), 6.89 (1H, td, J 7.5 and 1.2), 6.82 (1H, dd, J 8.2 and 1.0), 6.69 (1H, app. s), 5.29 - 5.24 (1H, m), 4.33 - 4.22 (2H, m), 2.86 - 2.80 (2H, m), 2.75 (1H, tt, J 11.5 and 3.8), 2.18 (3H, s), 2.18 - 2.11 (1H, m), 2.09 - 1.91 (5H, m), 1.80 - 1.69 (2H, m).

[0491] Example 89: N-(4-fluorobenzyl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 89 is prepared according to Scheme 18 using 4-(fluorophenyl)methanamine in place of (S)-chroman-4-amine in step 4. 1 H NMR: δ H (400 MHz, DMSO-d6): 9.47 (1H, d, J 1.6), 9.23 - 9.20 (1H, m), 8.88 (1H, d, J 2.4), 7.43 - 7.40 (2H, m), 7.19 - 7.15 (2H, m), 6.67 (1H, s), 4.50 (2H, d, J 6.0), 3.03 - 2.86 (2H, m), 2.68 - 2.58 (1H, m), 2.61 - 2.53 (2H, m), 1.90 (2H, d, J 12.8), 1.66 - 1.57 (2H, m).

[0492] Example 90: (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 90 can be prepared according to the method in Scheme 21.

[0493] [ka]

[0494] Step 1 (Scheme 21): Synthesis of ethyl 2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate To a stirred suspension of 3-(pyridin-3-yl)-1H-pyrazol-5-amine (500 mg, 3.12 mmol) in IPA (5 mL) was added ethyl 2-formyl-3-oxopropanoate (495 mg, 3.43 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure, diluted with DCM (20 mL), and washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was triturated with n-pentane to give ethyl 2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (400 mg, 48%) as a pale yellow solid.

[0495] Step 2 (Scheme 21): Synthesis of 2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid To a stirred solution of ethyl 2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.4 g, 1.49 mmol) in THF:HO (3:1; 10 mL) was added LiOH·HO (0.125 g, 3.0 mmol). The mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure to remove THF. The residue was diluted with water (3.5 mL) and acidified to approximately pH 4 with saturated aqueous citric acid. The resulting solid precipitate was filtered off and triturated with n-pentane to give 2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.25 g, 70%) as an off-white solid.

[0496] Step 3 leading to Example 90 (Scheme 21) To a solution of 2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (200 mg, 0.83 mmol, 1 equiv.) and (S)-chroman-4-amine hydrochloride (185 mg, 0.1 mmol, 1.2 equiv.) in DMF (10 vol.) was added DIPEA (430 mg, 3.33 mmol, 3 equiv.). The mixture was stirred for 15 minutes, after which T3P (50% in ethyl acetate; 1.06 g, 1.66 mmol, 2 equiv.) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, ice water was added to the reaction mixture, and the organic components were extracted with DCM (2 × 20 mL). The combined organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide (11 mg) as an off-white solid. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.66 (1H, d, J 1.6), 9.28 (1H, d, J 1.6), 9.14 (1H, d, J 7.6), 9.00 (1H, d, J 2.4), 8.67 - 8.65 (1H, m), 8.44 - 8.41 (1H, m), 7.58 - 7.55 (1H, m), 7.50 (1H, s), 7.28 (1H, d, J 8.0), 7.21 (1H, t, J 1.6), 6.92 (1H, t, J 0.8), 6.90 (1H, d, J 6.4), 5.30 (1H, q, J 6.0), 4.32 - 4.29 (2H, m), 2.21 - 2.15 (1H, m), 2.11 - 2.05 (1H, m).

[0497] Examples 91 and 92 Examples 91 and 92 can be prepared according to the method in Scheme 22.

[0498] [ka]

[0499] Step 1 (Scheme 22): Synthesis of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate To a stirred solution of ethyl 3-oxobutanoate (10 g, 77 mmol) in ethanol (50 mL) was added DMF·DMA (11.3 mL, 85 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure to give crude ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (12.3 g, 59%) as a yellow liquid, which was carried on to the next step without further purification.

[0500] Step 2 (Scheme 22): Synthesis of ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate To a stirred solution of tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate (5.1 g, 19.2 mmol) in ethanol (50 mL) was added ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (10.6 g, 57.4 mmol). The resulting mixture was stirred at 80° C. for 16 hours and then concentrated under reduced pressure. The residue was diluted with water and extracted twice with 5% MeOH in DCM. The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0% to 15% ethyl acetate in petroleum ether to give ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (6.7 g, 88%).

[0501] Step 3 (Scheme 22): Synthesis of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid To a stirred solution of ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (1.0 g, 2.57 mmol) in THF:HO (7:3; 20 mL) at 0 °C was added lithium hydroxide (0.123 g, 5.15 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h, then concentrated under reduced pressure, diluted with ice water, and acidified to approximately pH 4 with saturated citric acid solution. The solid precipitate was filtered off, washed with water (2 × 10 mL), and dried under vacuum to give 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.89 g, 92%) as an off-white solid.

[0502] General procedure for Step 4 (Scheme 22): Amide coupling To a stirred solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1 equiv.) in DCM (10 vol.) was added n-propylphosphonic anhydride cyclic trimer (50% in ethyl acetate; 2 equiv.) and DIPEA (5 equiv.) were added at 0°C. The mixture was stirred for 15 min, followed by the addition of the amine (2 equiv.). The reaction mixture was warmed to room temperature and stirred for 16 h, then diluted with water (20 vol.) and extracted with 5% MeOH in DCM (2 x 15 vol.). The combined organic extracts were washed with brine (10 vol.), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC using ammonium bicarbonate as a buffer to afford the required Boc-protected amide as an off-white solid.

[0503] General procedure for Step 5 (Scheme 22) leading to Examples 91 and 92: Boc Deprotection To a stirred solution of Boc-protected amide (1 equiv) in DCM (10 vol) at 0° C. was added HCl in dioxane (4 M; 3 vol). The reaction mixture was warmed to room temperature, stirred for 2 h, and then concentrated under reduced pressure. The residue was washed with 5% ethyl acetate in petroleum ether and dried under vacuum to give Examples 91 and 92 as off-white solids.

[0504] Example 91: N-(4,4-difluorocyclohexyl)-7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to the method of Scheme 22 using 4,4-difluorocyclohexylamine as the amine in Step 4. The title compound was isolated as the hydrochloride salt. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.12 - 9.09 (1H, m), 8.84 - 8.82 (1H, m), 8.59 (1H, d, J 7.60), 8.52 (1H, s), 6.70 (1H, s), 4.02 - 4.00 (1H, m), 3.34 (2H, d, J 12.8), 3.22 - 3.18 (1H, m), 3.10 - 3.04 (2H, m), 2.83 (3H, s), 2.19 (2H, d, J 11.6), 1.98 - 1.92 (8H, m), 1.67 - 1.62 (2H, m).

[0505] Example 92: (S)—N-(chroman-4-yl)-7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Prepared according to the method of Scheme 22 using (S)-chroman-4-amine as the amine in Step 4. The title compound was isolated as the hydrochloride salt. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.21 - 9.19 (1H, m), 9.11 (1H, d, J 8.0), 8.92 - 8.90 (1H, m), 8.56 (1H, s), 3.83 (1H, m), 7.18 (1H, t, J 1.6), 6.92 (1H, t, J 0.8), 6.81 (1H, d, J 8.0), 6.70 (1H, s), 5.28 - 5.23 (1H, m), 4.27 - 4.23 (2H, m), 3.35 - 3.32 (2H, m), 3.22 - 3.18 (1H, m), 3.10 - 3.04 (2H, m), 2.87 (3H, s), 2.19 (3H, s), 2.07 - 1.95 (3H, m).

[0506] Example 93: (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide Example 93 can be prepared according to the method of Scheme 19, using ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate in place of ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate in Step 1. 1 H NMR: δ H(400 MHz, DMSO-d6) 9.04 (1H, d, J 8.0), 8.53 (1H, s), 7.32 (1H, d, J 7.6), 7.18 (1H, m), 6.93 (1H, td, J 7.5 and 1.2), 6.81 (1H, dd, J 8.2 and 1.2), 6.67 (1H, s), 5.27 - 5.25 (1H, m), 4.30 - 4.20 (2H, m), 3.00 - 2.90 (2H, m), 2.86 - 2.78 (4H, m), 2.37 - 2.33 (2H, m), 2.19 - 2.18 (1H, m), 2.07 - 1.94 (5H, m), 1.79 - 1.73 (2H, m), 1.03 (3H, t, J 7.2).

[0507] Example 94: N-(4,4-difluorocyclohexyl)-2-(1-ethylpiperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide Example 94 can be prepared according to the method of Scheme 19 by using ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate instead of ethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate in Step 1 and 4,4-difluorocyclohexylamine instead of (S)-chroman-4-amine in Step 4. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.53 - 8.48 (2H, m), 6.68 (1H, s), 4.05 - 3.95 (1H, m), 3.00 - 2.90 (2H, m), 2.82 - 2.78 (4H, m), 2.38 - 2.33 (2H, m), 2.02 - 1.94 (10H, m), 1.79 - 1.73 (2H, m), 1.63 - 1.61 (2H, m), 1.04 - 1.01 (3H, m).

[0508] Example 95: N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-methyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 95 can be prepared according to the method of Scheme 20 using ethyl 7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate instead of ethyl 2-(piperidin-4)-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate in Step 1 and (S)-chroman-4-amine as the amine in Step 2. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.06 (1H, d, J 8.0), 8.53 (1H, s), 7.32 (1H, d, J 7.2), 7.20 - 7.16 (1H, m), 6.94 - 6.90 (1H, m), 6.82 - 6.80 (1H, m), 6.67 (1H, s), 5.24 (1H, m), 4.28 - 4.24 (2H, m), 2.88 - 2.67 (5H, m), 2.34 - 2.20 (1H, m), 2.19-2.10 (3H, m), 2.09 - 2.07 (1H, m), 2.06 - 2.04 (3H, m), 1.99 - 1.83 (2H, m), 1.80 - 1.77 (2H, m).

[0509] Example 96: N-(4,4-difluorocyclohexyl)-7-methyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 96 can be prepared according to the method of Scheme 20 using ethyl 7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate instead of ethyl 2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate in Step 1 and 4,4-difluorocyclohexylamine as the amine in Step 2. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.53 - 8.48 (2H, m), 6.67 (1H, s), 4.05 - 3.95 (1H, m), 2.87 - 2.75 (6H, m), 2.21 (3H, s), 2.08 - 1.91 (10H, m), 1.82 - 1.70 (2H, m), 1.70 - 1.55 (2H, m).

[0510] Example 97: N-Cyclopentyl-2-(piperidin-4-yl)-benzo[d]oxazole-5-carboxamide Example 97 can be prepared according to the method in Scheme 23.

[0511] [ka]

[0512] Step 1 (Scheme 23): Synthesis of methyl 2-aminobenzo[d]oxazole-5-carboxylate To a stirred solution of methyl 3-amino-4-hydroxybenzoate (10 g, 59.8 mmol) in methanol (10 mL) was added cyanogen bromide (7.60 g, 71.8 mmol) at 0° C. The reaction mixture was warmed to room temperature, stirred for 16 hours, and then concentrated under reduced pressure. Saturated sodium bicarbonate solution (50 mL) was added, and the resulting solid was filtered off and dried. The crude product was purified by flash chromatography eluting with 80-100% ethyl acetate in petroleum ether to give methyl 2-aminobenzo[d]oxazole-5-carboxylate (7.8 g, 58%) as an off-white solid.

[0513] Step 2 (Scheme 23): Synthesis of methyl 2-bromobenzo[d]oxazole-5-carboxylate To a stirred solution of copper(II) bromide (12.4 g, 55.4 mmol) in acetonitrile (40 mL) at 0° C. was added tert-butyl nitrite (5.71 g, 55.4 mmol) dropwise. The mixture was stirred at 0° C. for 20 minutes, and then methyl 2-aminobenzo[d]oxazole-5-carboxylate (5.6 g, 29.1 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 16 hours, then diluted with EtOAc (50 mL), filtered through Celite®, washed with ethyl acetate (10 mL), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0%-15% ethyl acetate in petroleum ether to give methyl 2-bromobenzo[d]oxazole-5-carboxylate (4.0 g, 54%) as an off-white solid.

[0514] Step 3 (Scheme 23): Synthesis of methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole-5-carboxylate To a mixture of methyl 2-bromobenzo[d]oxazole-5-carboxylate (300 mg, 1.17 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (435 mg, 1.41 mmol) in toluene (2.0 mL), anhydrous potassium phosphate (612 mg, 3.51 mmol), ethanol (1 mL), and Pd(PhP) (135 mg, 0.117 mmol) were added under continuous bubbling of nitrogen. The reaction mixture was stirred at 100 °C for 1 h and then concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 20% to 40% ethyl acetate in petroleum ether, to give methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole-5-carboxylate (85 mg, 20%) as an off-white solid.

[0515] Step 4 (Scheme 23): Synthesis of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzo[d]oxazole-5-carboxylate To a stirred solution of methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole-5-carboxylate (0.28 g, 0.78 mmol) in ethanol (40 mL) was added Pd / C (10%, dry; 0.056 g). The reaction mixture was stirred under H bladder pressure at room temperature for 6 hours, then filtered through Celite®, washed with ethanol (10 mL), and concentrated under reduced pressure to give crude methyl 2-(1-(tert-butoxycarbonyl)piperidin-4)-yl)benzo[d]oxazole-5-carboxylate (250 mg), which was carried on to the next step without further purification.

[0516] Step 5 (Scheme 23): Synthesis of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzo[d]oxazole-5-carboxylic acid To a stirred solution of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzo[d]oxazole-5-carboxylate (250 mg, 0.694 mmol) in THF:water (7:3; 10 mL) was added LiOH·HO (49.8 mg, 2.08 mmol) at 0 °C. The reaction mixture was warmed to room temperature, stirred for 5 h, and then concentrated under reduced pressure. The residue was dissolved in water (2 mL), acidified to approximately pH 4 with saturated citric acid solution, and extracted with 10% MeOH in DCM (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzo[d]oxazole-5-carboxylic acid (180 mg, 75%) as a solid.

[0517] Step 6 (Scheme 23): Synthesis of tert-butyl 4-(5-(cyclopentylcarbamoyl)benzo[d]oxazol-2-yl)piperidine-1-carboxylate To a stirred solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzo[d]oxazole-5-carboxylic acid (180 mg, 0.52 mmol) in DCM (10 mL) at 0 °C was added DIPEA (201 mg, 1.56 mmol) and n-propylphosphonic anhydride cyclic trimer (50% in ethyl acetate; 661 mg, 1.04 mmol). The mixture was stirred at 0 °C for 15 min, after which cyclopentanamine (53.1 mg, 0.624 mmol) was added. The mixture was warmed to room temperature and stirred for 16 h, then concentrated under reduced pressure, diluted with water (10 mL), and extracted with 10% MeOH in DCM (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 20% to 40% ethyl acetate in petroleum ether to give tert-butyl 4-(5-(cyclopentylcarbamoyl)benzo[d]oxazol-2-yl)piperidine-1-carboxylate (70 mg, 32%) as an off-white solid.

[0518] Step 7 leading to Example 97 (Scheme 23): Synthesis of N-cyclopentyl-2-(piperidin-4-yl)benzo[d]oxazole-5-carboxamide To a stirred solution of tert-butyl 4-(5-(cyclopentylcarbamoyl)benzo[d]oxazol-2-yl)piperidine-1-carboxylate (110 mg, 0.266 mmol) in DCM (10 mL) at 0° C. was added HCl in 1,4-dioxane (4 M; 0.067 mL, 0.266 mmol). The reaction was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was diluted with brine (10 mL), basified with saturated sodium bicarbonate solution (5 mL), and extracted with 10% MeOH in DCM (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford N-cyclopentyl-2-(piperidin-4-yl)benzo[d]oxazole-5-carboxamide (15.0 mg, 18%) as an off-white solid. 1 H NMR: δH (400 MHz, DMSO-d6) 8.36 (1H, d, J 7.2), 8.22 (1H, d, J 1.2), 7.91 (1H, dd, J 1.6, 8.4), 7.76 (1H, d, J 8.4), 4.28 - 4.24 (1H, m), 3.33 - 3.03 (3H, m), 3.06 - 3.03 (2H, m), 2.34 - 2.22 (2H, m), 1.96 - 1.90 (4H, m), 1.90 - 1.71 (2H, m), 1.71 - 1.60 (4H, m).

[0519] Example 98: N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]oxazole-5-carboxamide Example 98 can be prepared by reductive alkylation with formaldehyde according to the route shown in Scheme 9, using N-cyclopentyl-2-(piperidin-4yl)benzo[d]oxazole-5-carboxamide in place of (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide hydrochloride. 1 H NMR:δ H (400 MHz, DMSO-d6) 8.30 - 8.36 (1H, m), 8.19 (1H, s), 7.87 (1H, dd, J 8.4, 2.0), 7.73 (1H, d, J 8.4), 4.24 - 4.21 (1H, m), 2.99 - 2.96 (1H, m), 2.81 - 2.78 (2H, m), 2.18 (3H, s), 2.08 - 2.03 (4H, m), 1.90 - 1.87 (4H, m), 1.82 - 1.70 (2H, m), 1.57 - 1.54 (4H, m).

[0520] Example 99: N-cyclopentyl-2-(1-ethylpiperidin-4-yl)benzo[d]oxazole-5-carboxamide Example 99 can be prepared by reductive alkylation with acetaldehyde according to the route shown in Scheme 10, using N-cyclopentyl-2-piperidin-4yl)benzo[d]oxazole-5-carboxamide in place of (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide hydrochloride. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.30 - 8.36 (1H, m), 8.20 (1H, d, J 1.6), 7.88 (1H, dd, J 8.4, 2.0), 7.73 (1H, d, J 8.4), 4.25 - 4.24 (1H, m), 3.00 - 2.89 (3H, m), 2.37 - 2.33 (2H, m), 2.11 - 2.05 (4H, m), 1.89 - 1.81 (4H, m), 1.71 - 1.69 (2H, m), 1.60 - 1.55 (4H, m), 1.02 (3H, t, J 7.2).

[0521] Example 100: (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide Example 100 can be prepared according to the method of Scheme 24.

[0522] [ka]

[0523] Step 1 (Scheme 24): Synthesis of methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]oxazole-5-carboxylate To a stirred solution of methyl 2-bromobenzo[d]oxazole-5-carboxylate (500 mg, 1.95 mmol) in acetonitrile (30 mL) at room temperature was added tert-butyl piperazine-1-carboxylate (436 mg, 2.34 mmol) and KCO (540 mg, 3.91 mmol). The reaction was heated at 80 °C for 2 h, diluted with water (10 mL), and extracted with 10% MeOH in DCM (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 50% to 60% ethyl acetate in petroleum ether to give methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]oxazole-5-carboxylate (690 mg, 97%) as an off-white solid.

[0524] Step 2 (Scheme 24): Synthesis of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]oxazole-5-carboxylic acid To a stirred solution of methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]oxazole-5-carboxylate (620 mg, 1.72 mmol) in THF:water (7:3; 10 mL) was added LiOH·HO (82 mg, 3.43 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 16 h, then concentrated under reduced pressure, diluted with water (10 mL), and acidified to approximately pH 4 with saturated aqueous citric acid. The solid precipitate was filtered off and dried under vacuum to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]oxazole-5-carboxylic acid (600 mg) as an off-white solid.

[0525] Step 3 (Scheme 24): Synthesis of tert-butyl (S)-4-(5-(chroman-4-ylcarbamoyl)benzo[d]oxazol-2-yl)piperazine-1-carboxylate To a stirred solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]oxazole-5-carboxylic acid (500 mg, 1.41 mmol) in DCM (10 mL) at 0 °C, DIPEA (730 mg, 5.64 mmol) and n-propylphosphonic anhydride cyclic trimer (50% in ethyl acetate; 1.8 g, 2.82 mmol) were added. The mixture was stirred for 15 min, after which (S)-chroman-4-amine hydrochloride (314 mg, 1.69 mmol) was added, and the mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH in DCM (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 50% to 80% ethyl acetate in petroleum ether to give tert-butyl (S)-4-(5-(chroman-4-ylcarbamoyl)benzo[d]oxazol-2-yl)piperazine-1-carboxylate (400 mg, 59%) as an off-white solid.

[0526] Step 4 leading to Example 100 (Scheme 24): Synthesis of (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide To a stirred solution of tert-butyl (S)-4-(5-(chroman-4-ylcarbamoyl)benzo[d]oxazol-2-yl)piperazine-1-carboxylate (0.4 g, 0.84 mmol) in DCM (10 mL) was added HCl in dioxane (4 M; 0.21 mL, 0.84 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 h, then concentrated under reduced pressure, washed with acetonitrile (10 mL), and lyophilized to dryness to afford the title compound as the hydrochloride salt (40 mg, 12%). 1 H NMR: δ H(400 MHz, DMSO-d6) 9.20 (2H, br s), 8.84 (1H, d, J 8.4), 7.89 (1H, d, J 1.6), 7.71 (1H, dd, J 1.6, 8.4), 7.52 (1H, d, J 8.4), 7.19 - 7.15 (2H, m), 6.89 - 6.80 (2H, m), 5.32 - 5.27 (1H, m), 4.26 - 4.22 (2H, m), 3.87 - 3.58 (4H, m), 3.21 - 3.27 (4H, m), 2.09 - 2.04 (2H, m).

[0527] Example 101: N-cyclopentyl-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide Example 101 can be prepared according to the method of Scheme 24, using cyclopentylamine instead of (S)-chroman-4-amine hydrochloride in Step 3. The title compound was isolated as the hydrochloride salt. 1 H NMR: δ H (400 MHz, DMSO-d6) 9.26 (2H, s), 8.24 (1H, d, J 7.2), 7.83 (1H, d, J 1.2), 7.62 (1H, dd, J 2.0, 8.4), 7.50 (1H, d, J 8.4), 4.23 - 4.22 (1H, m), 3.87 - 3.85 (4H, m), 3.27 (4H, m), 1.90 - 1.87 (2H, m), 1.70 - 1.67 (2H, m), 1.59 - 1.51 (4H, m).

[0528] Example 102: (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide Example 102 can be prepared according to the method of Scheme 25.

[0529] [ka]

[0530] Step 1 (Scheme 25): Synthesis of methyl 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxylate To a stirred solution of methyl 2-bromobenzo[d]oxazole-5-carboxylate (300 mg, 1.17 mmol) in acetonitrile (20 mL) was added KCO (324 mg, 2.34 mmol) and 1-ethylpiperazine (161 mg, 1.41 mmol). The mixture was warmed to 80 °C, stirred for 2 h, and then concentrated under reduced pressure. The residue was diluted with water (5 mL) and extracted with 10% MeOH in DCM (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxylate as a solid (350 mg) product.

[0531] Step 2 (Scheme 25): Synthesis of 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxylic acid To a stirred solution of methyl 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxylate (350 mg, 1.21 mmol) in THF (7 mL) and water (3 mL) was added lithium hydroxide (57.9 mg, 2.42 mmol). The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was washed with acetone and 5% ethyl acetate in petroleum ether to give the lithium salt of the title compound (320 mg) as a yellow solid.

[0532] Step 3 leading to Example 102 (Scheme 25): Synthesis of (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide To a stirred solution of 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxylic acid, lithium salt (200 mg, 0.71 mmol) in DCM (10 mL) at 0 °C, DIPEA (0.523 mL, 2.83 mmol) and n-propylphosphonic anhydride cyclic trimer (50% in ethyl acetate; 0.902 mL, 1.42 mmol) were added. The mixture was warmed to room temperature and stirred for 15 min, followed by the addition of (S)-chroman-4-amine hydrochloride (158 mg, 0.85 mmol). The mixture was stirred at room temperature for 16 h, then diluted with water (5 mL) and extracted with 10% MeOH in DCM (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide (70 mg, 24%) as an off-white solid. 1 H NMR:δ H (400 MHz, DMSO-d6) 8.79 (1H, d, J 8.4), 7.84 (1H, d, J 1.6), 7.65 (1H, dd, J 1.6, 8.2), 7.46 (1H, d, J 8.4), 7.19 - 7.14 (2H, m), 6.89 - 6.76 (2H, m), 5.32 - 5.27 (1H, m), 4.30 - 4.21 (2H, m), 3.63 - 3.61 (4H, m), 2.42 - 2.37 (2H, m), 2.10 - 2.05 (2H, m), 1.06 - 1.04 (3H, m). Note: One signal (4H) coincides with the DMSO signal.

[0533] Example 103: N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide Example 103 can be prepared according to the method of Scheme 25, using cyclopentylamine in place of (S)-chroman-4-amine hydrochloride in Step 3. 1 H NMR:δH (400 MHz, DMSO-d6) 8.20 (1H, d, J 7.2), 7.77 (1H, s), 7.56 (1H, dd, J 1.6), 7.44 (1H, d, J 8.4), 4.27 - 4.18 (1H, m), 3.64 - 3.60 (4H, m), 2.50 - 2.42 (4H, m), 2.42 - 2.37 (2H, m), 1.92 - 1.86 (2H, m), 1.89 - 1.86 (2H ,m), 1.58 - 1.51 (4H, m), 1.04 (3H, t, J 7.2).

[0534] Example 104: (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide Example 104 can be prepared following the method of Scheme 25, substituting 1-methylpiperazine for 1-ethylpiperazine in Step 1. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.79 (1H, d, J 8.0), 7.84 (1H, d, J 1.2), 7.65 (1H, dd, J 1.6, 8.4), 7.46 (1H, d, J 8.4), 7.18 - 7.14 (2H, m), 6.89 - 6.86 (1H, m), 6.81 - 6.79 (1H, m), 5.30 - 5.29 (1H, m), 4.32 - 4.30 (1H, m), 4.27-4.24 (1H, m), 3.63 - 3.61 (4H, m), 2.42 - 2.33 (4H, m), 2.24 (3H, s), 2.13 - 2.10 (2H, m).

[0535] Example 105: N-cyclopentyl-2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide Example 105 can be prepared according to the method of Scheme 25, substituting 1-methylpiperazine for 1-ethylpiperazine in Step 1 and cyclopentylamine for (S)-chroman-4-amine hydrochloride in Step 3. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.22 - 8.18 (1H, m), 7.78 - 7.77 (1H, m), 7.57 (1H, dd, J 2.0, 8.4), 7.44 (1H, d, J 8.4), 4.25 - 4.20 (1H, m), 3.63 - 3.61 (4H, m), 2.45 - 2.42 (4H, m), 2.24 (3H, s), 1.92 - 1.86 (2H, m), 1.70 - 1.67 (2H, m), 1.58 - 1.51 (4H, m).

[0536] Example 106: (S)—N-(chroman-4-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]oxazole-5-carboxamide Example 106 can be prepared according to the methods in Scheme 26.

[0537] [ka]

[0538] To a stirred solution of (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide (100 mg, 0.264 mmol) in acetonitrile (10 mL) under nitrogen, potassium carbonate (110 mg, 0.793 mmol) and 2-bromoethan-1-ol (100 mg, 0.793 mmol) were added. The reaction mixture was stirred at 80° C. for 16 hours and then concentrated under reduced pressure. The residue was diluted with ice-cold water (15 mL) and extracted with 5% MeOH in DCM (3×20 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC using NH4HCO3 as a buffer to give the title compound (96 mg, 86%) as an off-white solid. 1 H NMR:δ H (400 MHz, DMSO-d6) 8.79 (1H, d, J 8.4), 7.84 (1H, d, J 1.6), 7.65 (1H, dd, J 2.0, 8.4), 7.46 (1H, d, J 8.4), 7.19 - 7.14 (2H, m), 6.88 - 6.86 (1H, m), 6.81 - 6.79 (1H, m), 5.32 - 5.27 (1H, m), 4.25 - 4.21 (3H, m), 3.63 - 3.60 (4H, m), 3.55 - 3.52 (2H, m), 2.55 - 2.51 (4H, m), 2.51 - 2.50 (2H, m), 2.11 - 2.08 (2H, m).

[0539] Example 107: N-cyclopentyl-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]oxazole-5-carboxamide Example 107 can be prepared according to the method of Scheme 26, using N-cyclopentyl-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide instead of (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide. 1 H NMR: δ H (400 MHz, DMSO-d6) 8.21 (1H, d, J 7.2), 7.77 (1H, d, J 1.6), 7.56 (1H, dd, J 1.6, 8.2), 7.44 (1H, d, J 8.4), 4.49 - 4.25 (1H, m), 4.23 - 4.19 (1H, m), 3.70 - 3.56 (4H, m), 3.54 - 3.53 (2H, m), 2.54 - 2.51 (4H, m), 2.47 - 2.44 (2H, m), 1.89 - 1.86 (2H, m), 1.70 - 1.67 (2H, m), 1.67 - 1.56 (4H, m).

[0540] Example 108: N-Cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxamide Example 108 can be prepared according to the method of Scheme 27:

[0541] [ka]

[0542] Step 1 (Scheme 27): Synthesis of methyl 2-aminobenzo[d]oxazole-6-carboxylate To a stirred solution of methyl 4-amino-3-hydroxybenzoate (10 g, 29.9 mmol) in methanol (100 mL) was added cyanogen bromide (7.60 g, 35.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was diluted with water (10 mL) and basified with saturated sodium bicarbonate solution. The solid precipitate was filtered off, washed with water, and dried under vacuum to give crude methyl 2-aminobenzo[d]oxazole-6-carboxylate (9.50 g, 81%) as a gray solid, which was carried on to the next step without further purification.

[0543] Step 2 (Scheme 27): Synthesis of methyl 2-bromobenzo[d]oxazole-6-carboxylate To a stirred solution of copper(II) bromide (11.0 g, 49.4 mmol) in acetonitrile (40 mL) at 0° C. was added tert-butyl nitrite (5.10 g, 49.4 mmol) dropwise. The mixture was stirred at 0° C. for 40 minutes, and then methyl 2-aminobenzo[d]oxazole-6-carboxylate (5.0 g, 26.0 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 16 hours, then diluted with EtOAc (50 mL), filtered through Celite®, washed with ethyl acetate (10 mL), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0%-20% ethyl acetate in petroleum ether to give methyl 2-bromobenzo[d]oxazole-6-carboxylate (1.7 g, 26%) as an off-white solid.

[0544] Step 3 (Scheme 27): Synthesis of methyl 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxylate To a stirred solution of methyl 2-bromobenzo[d]oxazole-6-carboxylate (0.35 g, 1.37 mmol) in acetonitrile (10 mL) at room temperature was added potassium carbonate (0.38 g, 2.73 mmol) and 1-ethylpiperazine (0.187 g, 1.64 mmol). The reaction mixture was stirred at 80 °C for 2 hours and then concentrated under reduced pressure. The residue was diluted with water (25 mL) and extracted with 10% MeOH in DCM (3 × 25 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxylate (0.34 g) as a yellow solid.

[0545] Step 4 (Scheme 27): Synthesis of 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxylic acid To a stirred solution of methyl 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxylate (0.33 g, 1.14 mmol) in THF (2 mL) and water (1 mL) was added lithium hydroxide (0.144 g, 3.42 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was triturated with pentane and dried in vacuo to give 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxylic acid, lithium salt (0.4 g) as a white solid.

[0546] Step 5 leading to Example 108 (Scheme 27): Synthesis of N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxamide To a stirred solution of 2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxylic acid, lithium salt (0.30 g, 1.09 mmol) in DCM (8 mL) at 0 °C, n-propylphosphonic anhydride cyclic trimer (1.39 g, 2.18 mmol) and DIPEA (0.563 g, 4.36 mmol) were added. The mixture was stirred at 0 °C for 15 min, followed by the addition of cyclopentanamine (50% in ethyl acetate; 0.111 g, 1.31 mmol). The mixture was stirred at room temperature for 16 h, then diluted with water (30 mL) and extracted with 15% MeOH in DCM (3 × 20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxamide (0.08 g, 21%) as an off-white solid. 1 H NMR: δ H(400 MHz, DMSO-d6) 8.15 (1H, d, J 7.2), 7.89 - 7.88 (1H, m), 7.75 (1H, dd, J 1.6), 7.29 (1H, d, J 8.4), 4.25 - 4.20 (1H, m), 3.65-3.64 (4H, m), 2.68 - 2.67 (4H, m), 2.56 - 2.52 (2H, m), 2.51 - 2.50 (2H, m), 2.48 (2H, m), 2.42 - 2.37 (4H, m), 2.34 - 2.33 (3H, m).

[0547] Example 109: N-Cyclopentyl-2-(piperazin-1-yl)benzo[d]oxazole-6-carboxamide The title compound can be prepared according to the method of Scheme 24, using methyl 2-bromobenzo[d]oxazole-6-carboxylate instead of methyl 2-bromobenzo[d]oxazole-5-carboxylate in Step 1 and cyclopentylamine instead of (S)-chroman-4-amine hydrochloride in Step 3. 1 H NMR:δ H (400 MHz, DMSO-d6) 8.15 (1H, d, J 7.2), 7.88 (1H, d, J 1.2), 7.73 (1H, dd, J 1.2, 8.2), 7.28 (1H, d, J 8.0), 4.25 - 4.20 (1H, m), 3.57 - 3.54 (4H, m), 2.82 - 2.80 (4H, m), 1.92 - 1.87 (2H, m), 1.70 (2H, m), 1.56 - 1.54 (4H, m).

[0548] Example 110: (S)—N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxamide The title compound can be prepared according to the method in Scheme 28.

[0549] [ka]

[0550] Step 1 (Scheme 28): Synthesis of methyl 2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxylate A degassed solution of methyl 2-bromobenzo[d]oxazole-5-carboxylate (0.30 g, 1.17 mmol) in toluene (9 mL) and ethanol (3 mL) was mixed under nitrogen with (1-methyl-1H-pyrazol-4-yl)boronic acid (0.177 g, 1.41 mmol), KCO (0.486 g, 3.51 mmol), and Pd(PhP) (0.135 g, 0.117 mmol) under continuous nitrogen bubbling. The mixture was stirred at 100 °C for 1 h, then cooled to room temperature and filtered through Celite®, washing with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0% to 30% ethyl acetate in petroleum ether to give methyl 2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxylate (0.20 g, 53%) as an off-white solid.

[0551] Step 2 (Scheme 28): Synthesis of 2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxylic acid To a stirred solution of methyl 2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxylate (0.20 g, 0.78 mmol) in THF (7 mL) and water (3 mL) was added lithium hydroxide (0.056 g, 2.33 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was diluted with water (10 mL) and washed with diethyl ether (20 mL). The aqueous layer was separated, acidified to approximately pH 4 with saturated citric acid solution, and then extracted with 10% MeOH in DCM (3 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxylic acid (0.10 g) as an off-white solid.

[0552] Step 3 to Example 110 (Scheme 28): Synthesis of (S)—N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxamide To a stirred solution of 2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxylic acid (0.05 g, 0.21 mmol) in DCM (5 mL) at 0 °C, n-propylphosphonic anhydride cyclic trimer (0.13 g, 0.41 mmol) and DIPEA (0.11 g, 0.82 mmol) were added. The mixture was stirred at 0 °C for 15 min, followed by the addition of (S)-chroman-4-amine (0.046 g, 0.31 mmol). The mixture was stirred at room temperature for 16 h, then diluted with water (15 mL) and extracted with 10% MeOH in DCM (3 × 20 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (S)—N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxamide (35 mg, 44%) as an off-white solid. 1 H NMR:δ H(400 MHz, DMSO-d6) 8.96 (1H, d, J 8.4), 8.62 (1H, s), 8.25 (1H, d, J 1.2), 8.16 (1H, m), 7.99 (1H, dd, J 1.6, 8.0), 7.75 (1H, d, J 8.4), 7.22 - 7.15 (2H, m), 6.91 - 6.87 (1H, m), 6.83 - 6.81 (1H, m), 5.35 - 5.30 (1H, m), 4.27 - 4.24 (2H, m), 3.97 (3H, s), 2.11 - 2.07 (2H, m).

[0553] Examples 111 and 112 Examples 111 and 112 can be prepared according to the method in Scheme 29.

[0554] [ka]

[0555] Step 1 (Scheme 29): Synthesis of tert-butyl (5-chlorothiazolo[5,4-b]pyridin-2-yl)carbamate To a stirred solution of 5-chlorothiazolo[5,4-b]pyridin-2-amine (500 mg, 2.69 mmol) in DCM (10 mL) was added DMAP (65.8 mg, 0.539 mmol) and Boc anhydride (0.938 mL, 4.04 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours, then diluted with water (10 mL) and extracted with DCM (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with 10% EtOAc in petroleum ether to give tert-butyl (5-chlorothiazolo[5,4-b]pyridin-2-yl)carbamate (400 mg, 47%).

[0556] Step 2 (Scheme 29): Synthesis of methyl 2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridine-5-carboxylate To a stirred, degassed solution of tert-butyl (5-chlorothiazolo[5,4-b]pyridin-2-yl)carbamate (3.50 g, 12.3 mmol) in methanol (5 mL) and DMF (2.5 mL) in a Tinyclave steel pressure reactor under nitrogen, potassium carbonate (2.88 g, 20.8 mmol) and palladium(II) acetate (0.357 g, 1.59 mmol) were added, followed by 1,3-bis(diphenylphosphino)propane (0.657 g, 1.59 mmol). The reaction mixture was placed under CO pressure (48 psi) at 85° C. for 16 hours. The resulting mixture was filtered through Celite® and washed with ethyl acetate (50 mL). The filtrate was washed with water (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridine-5-carboxylate (2.20 g, 57%) as an off-white solid.

[0557] Step 3 (Scheme 29): Synthesis of methyl 2-aminothiazolo[5,4-b]pyridine-5-carboxylate To a stirred solution of methyl 2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridine-5-carboxylate (2.20 g, 7.11 mmol) in DCM (25 mL) was added TFA (52.1 mL, 676 mmol) at 0° C. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was dissolved in 10% MeOH in DCM, basified with triethylamine to approximately pH 9, filtered through Celite®, washed with 10% MeOH in DCM, and concentrated under reduced pressure to give methyl 2-aminothiazolo[5,4-b]pyridine-5-carboxylate (1.10 g, 66%).

[0558] Step 4 (Scheme 29): Synthesis of methyl 2-bromothiazolo[5,4-b]pyridine-5-carboxylate To a stirred solution of copper(II) bromide (801 mg, 3.58 mmol) in acetonitrile (30 mL) under nitrogen at 0 °C was added dropwise tert-butyl nitrite (798 mg, 7.74 mmol). After 20 min, methyl 2-aminothiazolo[5,4-b]pyridine-5-carboxylate (300 mg, 1.43 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, then diluted with DCM (50 mL) and washed with aqueous HCl (1.5 N; 10 mL). The organic layer was separated, washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-bromothiazolo[5,4-b]pyridine-5-carboxylate (200 mg, 77%) as a yellow solid.

[0559] Step 5 (Scheme 29): Synthesis of methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)thiazolo[5,4-b]pyridine-5-carboxylate To a stirred solution of methyl 2-bromothiazolo[5,4-b]pyridine-5-carboxylate (1.05 g, 3.84 mmol) in dioxane (90 mL) and water (10 mL) at room temperature under continuous nitrogen bubbling, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.43 g, 4.61 mmol) was added, followed by potassium carbonate (1.06 g, 7.69 mmol). The mixture was stirred for 10 minutes, then tetrakis(triphenylphosphine)palladium(0) (0.222 g, 0.192 mmol) was added, and nitrogen bubbling was continued for an additional 5 minutes. The reaction mixture was heated with stirring at 100 °C for 3 hours and then concentrated under reduced pressure. The residue was dissolved in DCM (100 mL), washed with water (2 × 50 mL) and brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 50% to 55% ethyl acetate in petroleum ether to give methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)thiazolo[5,4-b]pyridine-5-carboxylate (0.80 g, 55%) as a brown solid.

[0560] Step 6 (Scheme 29): Synthesis of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxylate To a degassed solution of methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)thiazolo[5,4-b]pyridine-5-carboxylate (750 mg, 2.00 mmol) in ethanol (10 mL) under nitrogen, platinum(IV) oxide (454 mg, 2.00 mmol) was added over 15 minutes. The reaction mixture was stirred under hydrogen bladder pressure at room temperature for 16 hours and then filtered through Celite®, rinsing with methanol (10 mL). The filtrate was concentrated under reduced pressure to give methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxylate (0.73 g, 69%) as a brown solid.

[0561] Step 7 (Scheme 29): Synthesis of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxylic acid To a stirred solution of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxylate (700 mg, 1.86 mmol) in THF (10 mL), methanol (3 mL), and water (3 mL) was added lithium hydroxide monohydrate (78 mg, 1.86 mmol) at 0° C. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure, diluted with water (10 mL), acidified to approximately pH 4 with saturated aqueous citric acid, and extracted with 10% methanol in DCM (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxylic acid (550 mg, 37%).

[0562] General proce...

Claims

1. 1. A compound of formula I or a pharmaceutically acceptable salt or derivative thereof for use in the treatment or prevention of a disease or disorder that can be ameliorated by activation of the long isoform of PDE4 or a disease or disorder mediated by excessive intracellular cyclic AMP signaling: 【Chemical 1】 In the formula, X １ and X ２ One of them is N, the other is N or CR ３ａ and Y １ and Y ２ One of them is N and the other is C, and Z １ , Z ２ , Z ３ One of the is N or CR ３ｂ , and the others are CR ３ｂ is; or X １ and X ２ One of them is N and the other is NR ３ｃ or O, and Y １ and Y ２ are C and Z １ , Z ２ and Z ３ One of the is N or CR ３ｂ and the other is CR ３ｂ is; or X １ and X ２ One of them is S and the other is N or CR ３ａ and Y １ and Y ２ are C and Z １ , Z ２ and Z ３ One of them is N and the other is CR ３ｂ is. 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; R １ is one or more R ４ optionally substituted with; R ２ teeth, (v) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (vi) 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; (vii) CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or (viii) a (C3-8) alkyl group which may be linear, branched, or cyclic, or a combination thereof; R ２ is one or more R ５ optionally substituted with; Each R ３ａ are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R ３b are independently H, (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 ３ｃ are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R ４ is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and 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 may be substituted with one or more halogens or OH.

2. 2. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to claim 1, 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 containing one or two ring N heteroatoms; a 9-membered saturated bridged ring containing two ring N heteroatoms and a ring O-heteroatom; or a 7-10-membered saturated, fused, or spirocyclic ring containing one or two ring N heteroatoms; １ is one, two or three R ４ and optionally R １ is a 7-8 membered saturated bridged ring containing 1 or 2 ring N heteroatoms.

3. 3. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to claim 1 or 2, R １ is a 7-8 membered saturated bridged 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 In some cases, one R ４ is replaced by

4. 4. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 3, R ２ is: (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, 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 fluoro; (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 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 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), said (C1-4) alkyl group being 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.

5. 5. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 4, R ２ is: (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, optionally fused to a phenyl ring; R ２ is one or more R ５ may be substituted with.

6. 6. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 5, R ２ is a group of the formula: 【Chemistry 2】 In the formula, A is O or CH ２ where 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, CF ２ )

7. 7. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 6, a) Each R ３ａ are independently —H or CH ３ and b) Each R ３ｂ are independently —H, —CH ３ , -OCH ３ , halo, CN, or cyclopropyl; and / or c) Each R ３ｃ are independently —H or CH ３ is.

8. 8. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 7, R ３ａ , R ３ｂ and R ３ｃ One or two (preferably one) of are as defined in either claim 1 or 7, and the others, if present, are each -H.

9. 9. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 8, X １ , X ２ , Y １ , Y ２ , Z １ , Z ２ and Z ３ is selected from: 【Chemistry 3】

10. 10. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 9, X １ and X ２ One of them is N and the other is N or CR ３ａ and Y １ and Y ２ One of the groups is N and the other is C, and Z １ , Z ２ and Z ３ One of them is N or CR ３ｂ and the others are CR ３ｂ is.

11. 10. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 9: X １ and X ２ One of them is S and the other is N or CR ３ａ and Y １ and Y ２ are C and Z １ , Z ２ and Z ３ One of them is N and the others are CR ３ｂ is.

12. 12. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 1 to 11, R １ is a 6-membered saturated monocyclic ring containing one or two ring N heteroatoms, wherein at least one ring N heteroatom is R １ or a 7-8 membered saturated bridged ring containing two ring N heteroatoms, and R １ In some cases, one R ４ is replaced by; R ２ teeth, (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, optionally fused to a phenyl ring; R ２ is one or more R ５ optionally substituted with; R ３ａ , R ３ｂ and R ３ｃ are each independently H or methyl, if present (optionally R ３ａ , R ３ｂ and R ３ｃ wherein 0 or 1 is methyl, and the others are H; R ４ is, if present, (C1-6) alkyl optionally substituted with OH, and R ５ When present, is OH.

13. A compound of formula II or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 4】 In the formula, X １ and X ２ One of them is N, the other is N or CR ３ａ And Y １ and Y ２ One of them is N and the other is C, and Z １ , Z ２ , Z ３ One of the is N or CR ３ｂ The rest are each CR ３ｂ or X １ and X ２ One of them is S and the other is N or CR ３ａ and Y １ and Y ２ are C and Z １ , Z ２ and Z ３ One of them is N and the other is CR ３ｂ is; 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 not R １ａ is not at the attachment point of R １ａ is one or more R ４ optionally substituted with; R ２ teeth, (v) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (vi) 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; (vii) CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or (viii) a (C3-8) alkyl group which may be linear, branched, cyclic, or a combination thereof; R ２ is one or more R ５ optionally substituted with; Each R ３ａ are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R ３ｂ are independently H, (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 is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and 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.

14. 14. A compound of claim 13, or a pharmaceutically acceptable salt or derivative thereof, comprising: a) Each R ４ are 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 by one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and / or b) 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; R ２ is one or more R ５ is optionally replaced by

15. 15. A compound according to claim 13 or 14, or a pharmaceutically acceptable salt or derivative thereof, wherein R １ａ is a 5-6 membered saturated monocyclic ring containing at least one ring N heteroatom and optionally a ring O heteroatom; or a 7-8 membered saturated bridged ring containing one or two ring N heteroatoms; a 9 membered saturated bridged ring containing two ring N heteroatoms and a ring O-heteroatom; or a 7-10 membered saturated, fused or spirocyclic ring containing one or two ring N heteroatoms; １ａ is one, two or three R ４ is optionally replaced by

16. 16. A compound according to any one of claims 13 to 15, 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, or a 7-8 membered saturated, bridged ring containing two ring N heteroatoms, and R １ａ is one R ４ and optionally substituted with R １ａ is a 7-8 membered saturated bridged ring containing two ring N heteroatoms, and R １ａ In some cases, one R ４ is replaced by .

17. 17. A compound according to any one of claims 13 to 16, or a pharmaceutically acceptable salt or derivative thereof, 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, 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 fluoro; (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, (C1-4)alkyl, (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 fluoro; (iii) CH ２ Ar, where Ar is optionally substituted with 1-3 substituents selected from halogen, CN, (C1-4) alkyl, (C1-4) alkoxy; CH ２ is optionally substituted with (C1-4) alkyl, said (C1-4) alkyl group being 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, OH, or (C1-4) alkoxy.

18. 18. A compound according to any one of claims 13 to 17, or a pharmaceutically acceptable salt or derivative thereof, 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, optionally fused to a phenyl ring; R ２ is one or more R ５ is optionally replaced by

19. 19. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 13 to 18, R ２ is a group of the formula: 【Chemistry 5】 In the formula, A is O or CH ２ where 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, CF ２ )

20. 20. A compound according to any one of claims 13 to 19, or a pharmaceutically acceptable salt or derivative thereof, R １ａ is a 6-membered saturated monocyclic ring containing one or two ring N heteroatoms, at least one of which is R １ａ is not at the connection point of, or R is a 7-8 membered saturated bridged ring containing two ring N heteroatoms. １ａ may contain one R ４ is replaced by; 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, optionally fused to a phenyl ring; R ２ is one R ５ optionally substituted with; R ３ａ and R ３ｂ are each independently H or methyl, if present (optionally with 0 or 1 R ３ａ and R ３ｂ is methyl, and the others are H); R ４ is, if present, (C1-6) alkyl optionally substituted with OH; and R ５ When present, is OH.

21. A compound of formula III or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 6】 In the formula, X １ and X ２ One of them is N, the other is N or CR ３ａ and Y １ and Y ２ One of them is N and the other is C, and Z １ , Z ２ , Z ３ One of the is N or CR ３ｂ , and the others are CR ３ｂ or X １ and X ２ One of them is S and the other is N or CR ３ａ and Y １ and Y ２ are C and Z １ , Z ２ and Z ３ One of them is N and the other is CR ３ｂ is; 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; R １ is one or more R ４ optionally substituted with; R ２ａ teeth, (iii) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (iv) 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 (v) a (C5-6)cycloalkyl group; R ２ａ is one or more R ５ optionally substituted with; Each R ３ａ are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R ３ｂ are independently —H, (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 is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and -(C1-6)alkylene-(C1-6)alkoxy are optionally substituted with one or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and 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 may be substituted with one or more halogen or OH; X １ and X ２ One of the groups is S and the other is N, and Y １ and Y ２ are C and Z １ , Z ２ and Z ３ One of the is N and R ２ａ (iv) when (C5-6)cycloalkyl; R ２ａ is at least two R ５ is replaced by .

22. 22. A compound according to any one of claims 13 to 21, or a pharmaceutically acceptable salt or derivative thereof, R ３ａ and R ３ｂ One or two (preferably one) of the following is not H, and the others, if present, are each H.

23. A compound of formula IV or a pharmaceutically acceptable salt or derivative thereof: 【Chemistry 7】 In the formula, X １ and X ２ One of them is N, the other is N or CR ３ａ , Y １ and Y ２ One is N, the other is C, Z １ , Z ２ , Z ３ One of the is N or CR ３ｂ , and the others are CR ３ｂ or X １ and X ２ One of them is S and the other is N or CR ３ａ and Y １ and Y ２ are C and Z １ , Z ２ and Z ３ One of them is N and the other is CR ３ｂ is; 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; R １ is one or more R ４ optionally substituted with; R ２ teeth, (v) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring containing 0, 1, or 2 ring N atoms; (vi) 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; (vii) CH ２ Ar, where Ar is a 6-membered aromatic or heteroaromatic ring containing 0, 1 or 2 ring N atoms; or (viii) a (C3-8) alkyl group which may be linear, branched, or cyclic, or a combination thereof; R ２ is one or more R ５ optionally substituted with; Each R ３ａ are independently H or (C1-6) alkyl, wherein the (C1-6) alkyl is optionally substituted with one or more halogens; Each R ３ｂ are independently H, (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, and at least one R ３ｂ is other than H; 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; and Each R ５ are independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy, or -(C1-6)alkylene-(C1-6)alkoxy, wherein said (C1-6)alkyl and (C1-6)alkoxy are optionally substituted by one or more halogen or OH.

24. 24. A compound according to any one of claims 13 to 23, or a pharmaceutically acceptable salt or derivative thereof, Each R ３ａ are independently —H or CH ３ and / or Each R ３ｂ are independently —H, —CH ３ , OCH ３ , halo, CN, or cyclopropyl.

25. 25. A compound according to any one of claims 13 to 24, or a pharmaceutically acceptable salt or derivative thereof, R ２ or 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; said (C5-7)cycloalkyl optionally substituted with 1-3 substituents independently selected from OH, halogen, (C1-4)alkyl, and (C1-4)alkoxy, wherein said (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluoro, and said 6-membered aromatic or heteroaromatic ring optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN, and halogen, wherein said (C1-4)alkyl and (C1-4)alkoxy groups are optionally substituted with one or more fluoro; (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, (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 fluoro; (iv) a (C5-6)cycloalkyl group 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 groups are optionally substituted with one or more fluoro, and optionally the (C5-6)cycloalkyl group is substituted with two halogen substituents (optionally on one ring carbon atom).

26. 26. A compound according to any one of claims 13 to 25, or a pharmaceutically acceptable salt or derivative thereof, R ２ or R ２ａ is one of the following: (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring; (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring; R ２ or R ２ａ is optionally substituted, and R ２ａ is a (C5-6)cycloalkyl group that is not fused to a phenyl ring, at least two R ５ is replaced by .

27. 27. A compound, or a pharmaceutically acceptable salt or derivative thereof, for use according to any one of claims 13 to 26, R ２ or R ２ａ is a group of the formula: 【Chemistry 8】 In the formula, A is O or CH ２ where p is 1, 2, or 3; Ph is an optionally present fused phenyl ring; R ２ or R ２ａ is 1 or more R ５ and A is optionally substituted with CH ２ When Ph exists or A is C(R ５ ) ２ (For example, CF ２ )

28. 22. The compound of claim 21, or a pharmaceutically acceptable salt or derivative thereof, R １ is a 6-membered saturated monocyclic ring containing one or two ring N heteroatoms, at least one of which is R １ a 7-8 membered saturated bridged ring containing no or two ring N heteroatoms at the attachment point of R １ may contain one R ４ is replaced by; R ２ａ 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, optionally fused to a phenyl ring; R ２ａ is 1 or 2 R ５ optionally substituted with; R ２ａ is (C5-6)cycloalkyl, it is not fused to a phenyl ring, and two R ５ is replaced by; R ４ is, if present, (C1-6) alkyl optionally substituted with OH; R ５ When present, is OH.

29. 29. A compound according to any one of claims 21 to 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; or a 7-8 membered saturated bridged ring containing one or two ring N heteroatoms; a 9 membered saturated bridged ring containing two ring N heteroatoms and a ring O-heteroatom; or a 7-10 membered saturated, fused or spiro ring containing one or two ring N heteroatoms; １ is one, two or three R ４ may be substituted with.

30. 30. A compound according to any one of claims 21 to 29, or a pharmaceutically acceptable salt or derivative thereof, R １ is a 6-membered saturated monocyclic ring containing one or two ring N heteroatoms, at least one of which is R １ or a 7-8 membered saturated bridged ring containing two ring N heteroatoms, and R １ is one R ４ and optionally R １ is a 7-8 membered saturated bridged ring containing two ring N heteroatoms; and at least one ring N heteroatom is R １ is not at the attachment point of R １ is one R ４ is optionally replaced by

31. A compound according to any one of claims 13 to 30, or a pharmaceutically acceptable salt or derivative thereof, comprising X １ , X ２ , Y １ , Y ２ , Z １ , Z ２ and Z ３ is selected from: 【Chemistry 9】

32. A compound selected from: (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)—N-(chroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)—N-(6-chlorochroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(6-chlorochroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)-2-(1-methylpiperidin-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(1-methylpiperidin-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (R)—N-(6-chlorochroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(6-chlorochroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(pyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(piperazin-1-yl)-1H-benzo[d]imidazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-1-methyl-2-(piperazin-1-yl)-1H-benzo[d]imidazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(2,6-dimethylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-morpholino-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(chroman-4-yl)-2-(4-hydroxypiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(chroman-4-yl)-2-morpholino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(chroman-4-yl)-2-(piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylimidazo[1,2-a]pyridine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(clonan-4-yl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-cyclohexyl-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-cyclopentyl-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-cyclohexyl-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxamide; N-cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-cyclopentyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-cyclohexyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4-fluorobenzyl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(chroman-4-yl)-7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-ethylpiperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide; (S)—N-(chroman-4-yl)-7-methyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-(4,4-difluorocyclohexyl)-7-methyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide; N-cyclopentyl-2-(piperidin-4-yl)benzo[d]oxazole-5-carboxamide; N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]oxazole-5-carboxamide; N-cyclopentyl-2-(1-ethylpiperidin-4-yl)benzo[d]oxazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-cyclopentyl-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-cyclopentyl-2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide; (S)—N-(chroman-4-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-cyclopentyl-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]oxazole-5-carboxamide; N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxamide; N-cyclopentyl-2-(piperazin-1-yl)benzo[d]oxazole-6-carboxamide; (S)—N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxamide; N-cyclopentyl-2-(piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide; N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide; N-cyclopentyl-2-(1-methylpiperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylthiazolo[5,4-b]pyridine-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thiazolo[5,4-b]pyridine-5-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thiazolo[4,5-b]pyridine-6-carboxamide; N-cyclopentyl-2-(piperidin-4-yl)thiazolo[4,5-b]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylthiazolo[4,5-c]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thiazolo[4,5-c]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylthieno[3,2-b]pyridine-6-carboxamide; 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thieno[3,2-b]pyridine-6-carboxamide; and pharmaceutically acceptable salts or derivatives thereof.

33. 33. A pharmaceutical composition comprising a compound according to any one of claims 1-32 or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable excipient.

34. 33. A compound according to any one of claims 13 to 32, or a pharmaceutically acceptable salt or derivative thereof, for use in therapy.

35. A compound or a pharmaceutically acceptable salt or derivative according to any one of claims 13 to 32, or a pharmaceutical composition according to claim 33, for use in the treatment or prevention of a disease or disorder that can be ameliorated by activation of the long isoform of PDE4, or a disorder mediated by excessive intracellular cyclic AMP signaling.

36. A compound or a pharmaceutically acceptable salt or derivative for use according to any of claims 1-12, or a pharmaceutical composition for use according to claim 35, in the treatment or prevention of a disease or disorder mediated by excessive intracellular cyclic AMP signaling.

37. 37. The compound or pharmaceutically acceptable salt or derivative for use according to claim 36, wherein 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 toxin.

38. 38. The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to any one of claims 1 to 12 or 34 to 37, wherein the disease is cancer.

39. 39. The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to claim 38, wherein the disease is prostate cancer.

40. The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use according to any one of claims 1 to 12 or 34 to 37, wherein the disease is: a. Pituitary adenoma, Cushing's disease, polycystic kidney disease or polycystic liver disease; b. hyperthyroidism, Janssen metaphyseal chondrodysplasia, hyperparathyroidism or familial male-restricted precocious puberty; c. McCune-Albright syndrome; d. cholera, whooping cough, anthrax, or tuberculosis; e. HIV, AIDS or common variable immunodeficiency (CVID); f. melanoma, pancreatic cancer, leukemia, prostate cancer, tumors of the adrenal cortex, testicular cancer, primary pigmented nodular adrenocortical disease (PPNAD) or Carney complex; g. Autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD); h. Maturity-onset diabetes of the young type 5 (MODY5); or i. Cardiac hypertrophy.

41. 41. The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition of claim 40, wherein the disease is: a. Autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), or b. Hyperparathyroidism.

Images