5-ARYL-TH I AZOL-2-YL-AM I N E COMPOUNDS AND THEIR THERAPEUTIC USE

RELATED APPLICATION This application is related to US provisional patent application number 61/868,649 filed 22 August 2013, the contents of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain 5-aryl-thiazol-2-yl-amine compounds (for convenience, collectively referred to herein as "5AT2A compounds"), which, inter alia, inhibit LIM kinase (LIMK) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit LIMK activity, and in the treatment of diseases and conditions that are mediated by LIMK, that are ameliorated by the inhibition of LIMK activity, etc., including proliferative conditions such as cancer (e.g., breast cancer, prostate cancer, melanoma, glioma, etc.), as well as vasodilation (including, e.g., hypertension, angina, cerebral vasospasm, and ischemia following subarachnoid hemorrhage), neurodegenerative disorders, atherosclerosis, fibrosis, and inflammatory diseases (including, e.g., Crohn's disease and chronic obstructive pulmonary disease (COPD)), and glaucoma (also known as ocular hypertension). BACKGROUND

A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.

This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

LIMK

The LIM kinase (LIMK) family of serine/threonine protein kinases sit at the centre of multiple signalling pathways downstream of the Rho family of GTPases. There are two members of the family, LIMK1 and LIMK2, both of which are directly involved in regulating multiple cellular processes via their ability to reorganise the actin-cytoskeleton network (see, e.g., Scott et al., 2007). Overall, the LIMKs share 50% homology (see, e.g., Mizuno et al., 1994; Nunoue et al., 1995). They are composed of two N-terminal LIM domains, each of which contains a double zinc-finger motif. The LIM domains play an important role in regulating kinase activity (see, e.g., Nagata et al., 1999; Tomiyoshi et al., 2004) and may also contribute to LIMK function by mediating protein-to-protein and protein-to- DNA interactions (see, e.g., Hiraoka et al., 1996; Nishiya et al., 1998). Next lies a PDZ domain which also influences protein-protein interactions but additionally contains two nuclear export signals (see, e.g., Yang et al., 1998; Yang et al., 1999) which together with nuclear localisation signals (see, e.g., Goyal et al., 2006) most likely regulate

nuclear/cytoplasmic shuttling. A proline/serine rich region then follows with the kinase domain of the protein being located at the extreme C-terminus. The kinase domains of LIMK1 and LIMK2 are 70% identical and phosphorylation within the activation loop enhances their activity.

LIMK is activated via a number of signalling networks downstream of growth factors, integrins and cytokines (for a comprehensive review see, e.g., Scott et al., 2007).

Specifically, the Rho effector, Rho kinase (ROCK) has been shown to phosphorylate LIMK on conserved threonine residues (Thr-508 on LIMK1 or Thr-505 LIMK2), modifications that are essential for kinase activation (see, e.g., Amano et al., 2001 ; Ohashi et al., 2000; Sumi et al., 2001a), Pak1 (see, e.g., Edwards et al., 1999), Pak4 (see, e.g., Dan et al., 2001), and the myotonic dystrophy kinase- related Cdc42-binding kinase (MRCKa) have also been shown to phosphorylate LIMK1 with MRCKa also phosphorylating LIMK2 (see, e.g., Sumi et al., 2001 b). Transphosphorylation of LIMK1 , following association with HSP90, has been shown to increase the half life of the protein and increases its specific activity (see, e.g., Li et al., 2006). Autophosphorylation of LIMK also occurs, although the site of phosphorylation and functional consequence remains uncertain (see, e.g., Kobayashi et al., 2006; Proschel et al., 1995). Conversely, LIMK is subject to deactivation by the direct action of phosphatases. Slingshotl (SSH1) binds directly to the kinase domain and dephosphorylates LIMK1 on Thr-508 and additional autophosphorylated serine residues resulting in decreased activity (see, e.g., Soosairajah et al., 2005).

Downstream of LIMK there are relatively few substrates known. The best characterised are the cofilin family of proteins, cofilinl (non-muscle cofilin), cofilin2 (muscle cofilin) and destrin (also known as actin depolymerizing factor, ADF). Unphosphorylated active cofilin binds to actin filaments in vivo, depolymerises filamentous actin (F-actin), and produces free barbed ends that serve to nucleate new actin filaments (see, e.g., Ghosh et al., 2004; Lorenz et al., 2004). Ultimately it is a balance between phosphorylated and

dephosphorylated cofilin that determines a cell's ability to reorganise the cytoskeleton, controlling cell shape and influencing its ability to move, invade or metastasise. LIMK reorganises actin-cytoskeleton dynamics through direct phosphorylation of cofilin on serine-3 resulting in its inactivation and subsequent inhibition of its actin-severing activity (see, e.g., Maekawa et al., 1999; Sumi et al., 1999). Through this modulation of the actin- cytoskeleton, LIMK is implicated to play pivotal a role in several human diseases with inhibition via small molecule kinase inhibitors having potential utility.

LIMK and Cancer Enhanced LIMK activity has been associated with tumour types. LIMK1 has been found unregulated via chromosomal translocation in malignant melanoma cells (see, e.g., Okamoto et al., 2005), breast cancer tumours (see, e.g., Bagheri-Yarmand et al., 2006) and breast cancer cell lines (see, e.g., Yoshioka et al., 2003), in prostate tumours (see, e.g., Davila et al., 2003) and prostate cancer cell lines (see, e.g., Bagheri-Yarmand et al., 2006; Yoshioka et al., 2003). In line with increased LIMK activity, co-ordinately increased phosphorylated cofilin has also been found in several studies (see, e.g., Davila et al., 2003; Wang et al., 2004; Wang et al., 2005).

LIMK expression levels have been linked to tumour cell growth. For example, reduction in LIMK1 caused a decrease in prostate cancer cell proliferation, arresting cells in G2/M (see, e.g., Davila et al., 2003). Similarly, lowering expression of LIMK2 in human fibrosarcoma cells limited their ability to form colonies in a long term growth assay (see, e.g., Suyama et al., 2004). LIMK has been reported to modify the p53 pathway (see, e.g., Freidman et al., 2002). p53 is a potent tumour suppressor protein which is stabilised in response to cellular stress signals to induce cell-cycle arrest or apoptosis depending on signal strength and duration (see, e.g., Vousden et al., 2009). The exact mechanism by which LIMK regulates p53 signalling however remains unclear.

Consistent with LIMKs ability to reorganise the actin-cytoskeleton network, the most convincing role for LIMK in cancer is to modulate tumour cell invasion and metastasis. Metastasis occurs through a series of complex biological events which together allow tumour cells to detach and extravasate from their site of origin and repopulate at a distal site within the body (see, e.g., Klein, 2009).

Currently there are no therapeutic strategies to control metastasis although it is estimated to account for over 90% of all human deaths from cancer (see, e.g., Sporn, 1996).

Overexpression of LIMK has been shown to increase the motility and invasive capacity of tumour cells in several different systems. Overexpression of LIMK1 increased motility, invasiveness and metastatic ability of human breast cancer cells (see, e.g., Bagheri- Yarmand et al., 2006; Yoshioka et al., 2003) as well as increasing the invasive phenotype of benign prostate cells (see, e.g., Davila et al., 2003).

Importantly, it has been demonstrated in several studies that interfering with LIMK function reduces tumour cell invasion. Silencing of LIMK expression with anti-sense oligonuceotides in metastatic prostate cells resulted in decreased cell invasion (see, e.g., Davila et al., 2003), and ribozyme-mediated knockdown of LIMK2 inhibited the motility of metastatic fibrosarcoma cells (see, e.g., Suyama et al., 2004). Furthermore, expression of dominant-negative LIMK1 resulted in decreased invasion of metastatic breast cancer cells in vitro and in an in vivo model of breast cancer metastasis caused a decrease in the number osteolytic lesions formed after tumour cells were injected into nude mice (see, e.g., Yoshioka et al., 2003). Collectively these studies suggest that targeting LIMK may be a viable therapeutic strategy for preventing or controlling metastatic disease.

LIMK and Glaucoma Glaucoma is one of the leading causes of irreversible blindness in the world. It is characterized by degeneration of the optic nerve and progressive visual field loss and is often associated with elevated intraocular pressure (IOP) (see, e.g., Ferrer, 2006). The actin cytoskeleton network is thought to be an important modulator of IOP and

subsequently LIMK has been proposed to play a role in regulating IOP. Downregulation of LIMK1 with short-interfering RNA in cultured corneal fibroblasts was shown to reduce actin polymerization, focal adhesion formation and delay cell migration. In an in vivo mouse model, deletion or downregulation of LIMK1 significantly reduced ocular inflammation (see, e.g., Gorovoy et al., 2008). Accordingly, LIMK inhibitors have been proposed for the treatment of glaucoma (see, e.g., Hizaki et al., 2004; Harrison et al., 2009; Burgoon et al., 2009).

SUMMARY OF THE INVENTION

One aspect of the invention pertains to certain 5-aryl-thiazol-2-yl-amine compounds (for convenience, collectively referred to herein as "5AT2A compounds"), as described herein.

Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a 5AT2A compound, as described herein, and a

pharmaceutically acceptable carrier or diluent.

Another aspect of the invention pertains to method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of admixing a 5AT2A compound, as described herein, and a pharmaceutically acceptable carrier or diluent. Another aspect of the present invention pertains to a method of inhibiting LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a 5AT2A compound, as described herein. Another aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a 5AT2A compound, as described herein. Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a 5AT2A compound, as described herein, preferably in the form of a pharmaceutical composition. Another aspect of the present invention pertains to a 5AT2A compound as described herein for use in a method of treatment of the human or animal body by therapy.

Another aspect of the present invention pertains to use of a 5AT2A compound, as described herein, in the manufacture of a medicament for use in treatment.

In one embodiment, the treatment is treatment of a disease or condition that is mediated by LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2).

In one embodiment, the treatment is treatment of a disease or condition that is

ameliorated by the inhibition of LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity). ln one embodiment, the treatment is treatment of a proliferative condition. In one embodiment, the treatment is treatment of cancer.

In one embodiment, the treatment is treatment of cancer characterised by, or further characterised by, cancer cells which overexpress LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2). In one embodiment, the treatment is treatment of solid tumour cancer.

In one embodiment, the treatment is treatment of breast cancer, prostate cancer, melanoma, or glioma. In one embodiment, the treatment is treatment of vasodilation.

In one embodiment, the treatment is treatment of hypertension, angina, cerebral vasospasm, or ischemia following subarachnoid hemorrhage. In one embodiment, the treatment is treatment of a neurodegenerative disorder.

In one embodiment, the treatment is treatment of atherosclerosis.

In one embodiment, the treatment is treatment of fibrosis.

In one embodiment, the treatment is treatment of an inflammatory disease.

In one embodiment, the treatment is treatment of Crohn's disease or chronic obstructive pulmonary disease (COPD).

In one embodiment, the treatment is treatment of glaucoma (also known as ocular hypertension).

Another aspect of the present invention pertains to a kit comprising (a) a

5AT2A compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and

(b) instructions for use, for example, written instructions on how to administer the compound. Another aspect of the present invention pertains to a 5AT2A compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. Another aspect of the present invention pertains to a 5AT2A compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.

Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein. As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds One aspect of the present invention relates to certain compounds which are structurally related to the following compounds:

The compounds are also characterized by (a) the lack of a substituent at the 4-position of the thiazol-2-yl group, (b) the presence of an aromatic substituent positioned ortho to the thiazol-2-yl group, and (c) the presence of a nitrogen group (i.e., an amine, an amide, a carbamate, a urea, or a sulphonamide) at the 2-position of the thiazol-2-yl, for example, as shown below:

Thus, one aspect of the present invention pertains to compounds selected from compounds of the following formula, and salts, hydrates, and solvates thereof

(e.g., pharmaceutically acceptable salts, hydrates, and solvates thereof), wherein -J, -Q-, =W-, -X=, =Y-, and -Z= are as defined herein (for convenience, collectively referred to herein as "5-aryl-thiazol-2-yl-amine T2A compounds"):

Some embodiments of the invention include the following: (1 ) A compound is selected from compounds having the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

wherein:

=W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =N-; and -Z= is =CR ^V4 - ("pyridine"); or

=W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =N(0)-; and ^{■ ■} Z= is =CR ^V4 - ("pyridine"); or

=W- is =CR ^V1 -; -x= is =CR ^V2 -; =Y- is =CR ^V3 -; and -Z= is =N- ("pyridine"); or

=W- is =CR ^V1 -; -x= is =N-; =Y- is =CR ^V3 -; and -Z= is =CR ^V4 - ("pyridine"); or

=W- is =N-; -X= = is = CR 2.; =γ. is =N-; and -Z= is = _: Q _R V4. ("pyrimidine"); or

=W- is =CR ^V1 -; -X= is =N-; =Y- is =CR ^V3 -; and -Z= is =N- ("pyrimidine"); or

=W- is =N-; -X= = is = N-; =Y- is =CR ^V3 -; and -Z= is = _: Q _R V4. ("pyridazine"); or

=W- is =CR ^V1 -; -X= is =N-; =Y- is =N-; and -Z= is = _: Q _R V4. ("pyridazine"); or

=W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =N-; and -Z= is =N- ("pyridazine"); or

=W- is =CR ^V1 -; -x= is =CR ^V2 -; =Y- is =CR ^V3 -; and -Z= is =CR ^V4 - ("benzene"); wherein: each -R ^V s independently -H or -R ^T

each -R ^V2 s independently -H or -R ^T

each -R ^V3 s independently -H or -R ^T and

each -R ^V4 s independently -H or -R ^T and additionally, -R ^V2 and -R ^V3 may together form -CH=CH-CH=CH-; wherein: each -R ^T is independently: -F, -CI, -Br, -I, -R ^TT , -CF ₃ , -CHF ₂ , -OH, -OR ^TT , -OCF ₃ ,

-NH2, -NHR ^TT , -NR ^TT 2, pyrrolidino, piperidino, piperizino, N-(Ci-4alkyl)piperizino, morpholino, -C(=0)R^ -C(=0)OH, -C(=0)OR ^TT , -OC(=0)R ^TT , -CN, or -N0 ₂ ;

wherein each -R ^TT is independently saturated aliphatic or saturated C3-ecycloalkyl; and wherein:

-Q is independently -Q ^CA or -Q ^HA ; wherein:

-Q ^CA is independently phenyl,

and is optionally substituted with one or more groups -R ^pp ;

-Q ^HA is independently Cs-6heteroaryl,

and is optionally substituted with one or more groups -R ^pp ; wherein: each -R ^pp is independently:

-F, -CI, -Br, -I,

-R ^R , -R ^RA ,

-OH, -L ^R -OH, -0-L ^R -OH, -NH-L ^R -OH, -NR ^K -L ^R -OH,

-OR ^R , -L ^R -OR ^R , -0-L ^R -OR ^R , -NH-L ^R -OR ^R , -NR ^K -L ^R -OR ^R ,

-NH ₂ , -NHR ^R , -NR ^R 2, -M ^R ,

-L ^R -NH ₂ , -L ^R -NHR ^R , -L ^R -NR ^R ₂ , -L ^R -M ^R ,

-0-L ^R -NH ₂ , -0-L ^R -NHR ^R , -0-L ^R -NR ^R ₂ , -0-L ^R -M ^R ,

-NH-L ^R -NH ₂ , -NH-L ^R -NHR ^R , -NH-L ^R -NR ^R ₂ , -NH-L ^R -M ^R ,

-NR ^K -L ^R -NH ₂ , -NR ^K -L ^R -NHR ^R , -NR ^K -L ^R -NR ^R ₂ , -NR ^K -L ^R -M ^R ,

-NHC(=0)R ^R , -NR ^K C(=0)R ^R ,

-NHC(=0)OR ^R , -NR ^K C(=0)OR ^R ,

-NHC(=0)NH ₂ , -NHC(=0)NHR ^R , -NHC(=0)NR ^R ₂ , -NHC(=0)M ^R ,

-NR ^K C(=0)NH ₂ , -NR ^K C(=0)NHR ^R , -NR ^K C(=0)NR ^R ₂ , -NR ^K C(=0)M ^R ,

-C(=0)NH ₂ , -C(=0)NHR ^R , -C(=0)NR ^R ₂ , -C(=0)M ^R ,

-C(=0)OH, -C(=0)OR ^R ,

-NHS(=0) ₂ R ^R , -NR ^K S(=0) ₂ R ^R , -S(=0) ₂ NH ₂ , -S(=0) ₂ NHR ^R , -S(=0) ₂ NR ^R ₂ , -S(=0) ₂ M ^R ,

-SH, -SR ^R ,

-CN, or -N0 ₂ ;

and additionally, two adjacent groups -R ^pp , if present, may form -0-CH ₂ -0-, -0-CH ₂ CH ₂ -0-, -CH ₂ -0-CH ₂ -, or -0-CH ₂ CH ₂ -; wherein: each -R ^R is independently saturated aliphatic Ci-ealkyl, saturated C3-6cycloalkyl, phenyl, or -CH ₂ -phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR ^RR , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R ^RR , -CF3, -OH, -OR ^RR , or -OCF3, wherein each -R ^RR is independently saturated aliphatic Ci-4alkyl;

each -R is independently aliphatic C ₂ -6alkenyl;

each -M ^R is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, or azepino, each optionally substituted, for example, with one or more groups selected from saturated aliphatic

each -L ^R - is independently saturated aliphatic C ₂ -4alkylene; and

each -R ^K is independently saturated aliphatic and wherein:

-J is independently:

-NH ₂ , -NHR ^J , -NR ^J ₂ , -M ^J ,

-NHC(=0)R ^J , -N(R ^N )C(=0)R ^J ,

-NHC(=0)OR ^J , -N(R ^N )C(=0)OR ^J ,

-NHC(=0)NH ₂ , -N(R ^N )C(=0)NH ₂ ,

-NHC(=0)NHR ^J , -N(R ^N )C(=0)NHR ^J ,

-NHC(=0)NR ^J ₂ , -N(R ^N )C(=0)NR ^J ₂ ,

-NHC(=0)M ^J , -N(R ^N )C(=0)M ^J ,

-NHS(=0) ₂ R ^J , or -N(R ^N )S(=0) ₂ R ^J ; wherein: each -R ^N is independently saturated aliphatic each -M ^J is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, or azepino, each optionally substituted, for example, with one or more groups selected from saturated aliphatic Ci^alkyl; each -R ^J is independently:

-R ^J1 , -R ^J2 ,

-R ^J3 , -L ^J -R ^J3 ,

-R ^J4 , -L ^J -R ^J4 ,

-R ^J5 , -L ^J -R ^J5 ,

-R ^J6 , or -L ^J -R ^J6 ; wherein: each -R ^J is independently saturated aliphatic Ci-ealkyl;

each -R ^J2 is independently saturated aliphatic Ci-ealkyl, and is substituted with one or more groups -R ^J2X ;

each -R ^J3 is independently saturated C3- ₇ cycloalkyl, and is optionally substituted, for example, with one or more groups -R ^JJ ;

each -R ^J4 is independently non-aromatic C3-6heterocyclyl, and is optionally substituted, for example, with one or more groups -R ^JJ ;

each -R ^J5 is independently phenyl, and is optionally substituted, for example, with one or more groups -R ^JJ ;

each -R ^J6 is independently Cs-6heteroaryl, and is optionally substituted, for example, with one or more groups -R ^JJ ;

each -L ^J - is independently saturated aliphatic Ci-4alkylene; wherein: each -R ^J2X is independently -OH , -OR ^J2XX , -N H ₂ , -N H R ^J2XX , -N R ^J2XX ₂ , pyrrolidino, piperidino, piperizino, N-(Ci-4alkyl)piperizino, or morpholino;

wherein each -R ^J2XX is independently saturated aliphatic each -R ^JJ is independently:

-F, -CI, -Br, -I ,

-R ^JJJ ,

-OH , -OR ^JJJ ,

-L ^JJJ -OH , -L ^JJJ -OR ^JJJ , -0-L ^JJJ -OH , -0-L ^JJJ -OR ^JJJ ,

-CF ₃ , -CH F ₂ , -OCFs,

-N H ₂ , -N H R ^JJJ , -N R ^JJJ ₂ ,

pyrrolidino, piperidino, piperizino, N-(Ci-4alkyl)piperizino, morpholino,

-L ^JJJ -N H ₂ , -L ^JJJ -N H R ^JJJ , -L ^JJJ -N R ^JJJ ₂ ,

-L ^JJJ -pyrrolidino, -L ^JJJ -piperidino, -L ^JJJ -piperizino,

-L ^JJJ -N-(Ci-4alkyl)piperizino, -L ^JJJ -morpholino, -0-L ^JJJ -NH ₂ , -0-L ^JJJ -NHR ^JJJ , -0-L ^JJJ -NR ^JJJ ₂ ,

-0-L ^JJJ -pyrrolidino, -0-L ^JJJ -piperidino, -0-L ^JJJ -piperizino,

-0-L ^JJJ -N-(Ci-4alkyl)piperizino, -0-L ^JJJ -morpholino,

-NHC(=0)R ^JJJ , -NR ^JJJ C(=0)R ^JJJ ,

-C(=0)R ^JJJ , -C(=0)OH, -C(=0)OR ^JJJ ,

-CN, or -N0 ₂ ;

wherein:

each -R ^JJJ is independently saturated aliphatic Ci-4alkyl or saturated C3-6cycloalkyl; and

each -L ^JJJ - is independently saturated aliphatic C^alkylene.

The Groups W. X. Y. and Z

(2) A compound according to (1), wherein:

=W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =N-; and -Z= is =CR ^V4 - ("pyridine"); or =W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =N(0)-; and -Z= is =CR ^V4 - ("pyridine"); or =W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =CR ^V3 -; and -Z= is =N- ("pyridine"); or =W- is =CR ^V1 -; -X= is =N-; =Y- is =CR ^V3 -; and -Z= is =CR ^V4 - ("pyridine").

For the avoidance of doubt, the group =N(0)- denotes an N-oxide, as in, for example:

(3) A compound according to (1), wherein:

=W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =N-; and -Z= is =CR ^V4 - ("pyridine"); or =W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =CR ^V3 -; and -Z= is =N- ("pyridine"); or =W- is =CR ^V1 -; -X= is =N-; =Y- is =CR ^V3 -; and -Z= is =CR ^V4 - ("pyridine").

(4) A compound according to (1), wherein:

=W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =N-; and -Z= is =CR ^V3 - ("pyridine");

for example, as in:

(5) A compound according to (1), wherein:

=W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =CR ^V3 -; and -Z= is =N- ("pyridine"); for example, as in:

(6) A compound according to (1), wherein:

=W- is =CR ^V1 -; -X= is =N-; =Y- is =CR ^V3 -; and -Z= is =CR ^V4 - ("pyridine"); for example, as in:

(7) A compound according to (1), wherein:

=W- is =N-; -X= is =CR ^V1 -; =Y- is =N-; and -Z= is =CR ^V4 - ("pyrimidine"); =W- is =CR ^V1 -; -X= is =N-; =Y- is =CR ^V3 -; and -Z= is =N- ("pyrimidine").

(8) A compound according to (1), wherein:

=W- is =N-; -X= is =CR ^V2 -; =Y- is =N-; and -Z= is =CR ^V4 - ("pyrimidine"); for example, as in:

(9) A compound according to (1), wherein:

=W- is =CR ^V1 -; -X= is =N-; =Y- is =CR ^V3 -; and -Z= is =N- ("pyrimidine"); for example, as in:

(10) A compound according to (1), wherein:

=W- is =N-; -X= is =N-; =Y- is =CR ^V3 -; and -Z= is =CR ^V4 - ("pyridazine"); or =W- is =CR ^V1 -; -X= is =N-; =Y- is =N-; and -Z= is =CR ^V4 - ("pyridazine"); or =W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =N-; and -Z= is =N- ("pyridazine").

(11) A compound according to (1), wherein:

=W- is =N-; -X= is =N-; =Y- is =CR ^V3 -; and -Z= is =CR ^V4 - ("pyridazine"); for example, as in:

(12) A compound according to (1), wherein:

=W- is =CR ^V1 -; -X= is =N-; =Y- is =N-; and -Z= is =CR ^V4 - ("pyridazine"); for example, as in:

(13) A compound according to (1), wherein:

=W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =N-; and -Z= is =N- ("pyridazine"); for example, as in:

(14) A compound according to (1), wherein:

=W- is =CR ^V1 -; -X= is =CR ^V2 -; =Y- is =CR ^V3 -; and -Z= is =CR ^V4 - ("benzene"); for example, as in:

The Groups -R ^V . -R ^V2 . -R ^V3 . and -R ^V4

(15) A compound according to any one of (1) to (14), wherein:

each -R ^V , if present, is independently -H or -R ^T ;

each -R ^V2 , if present, is independently -H or -R ^T ;

each -R ^V3 , if present, is independently -H or -R ^T ; and

each -R ^V4 , if present, is independently -H or -R ^T .

The Group -R V1

(16) A compound according to any one of (1) to (15), wherein each -R ^V , if present, is independently -H or -R ^T . (1 ) A compound according to any one of (1) to (15), wherein each -R ^V , if present, is independently -H.

(18) A compound according to any one of (1) to (15), wherein each -R ^V , if present, is independently -R ^T .

The Group -R ^V2

(19) A compound according to any one of (1) to (18), wherein each -R ^V2 , if present, is independently -H or -R ^T .

(20) A compound according to any one of (1) to (18), wherein each -R ^V2 , if present, is independently -H.

(21) A compound according to any one of (1) to (18), wherein each -R ^V2 , if present, is independently -R ^T .

The Group -R V3

(22) A compound according to any one of (1) to (21), wherein each -R ^V3 , if present, is independently -H or -R ^T .

(23) A compound according to any one of (1) to (21), wherein each -R ^V3 , if present, is independently -H. (24) A compound according to any one of (1) to (21), wherein each -R ^V3 , if present, is independently -R ^T . The Group -R ^'

(25) A compound according to any one of (1) to (24), wherein each -R ^V4 , if present, is independently -H or -R ^T .

(26) A compound according to any one of (1) to (24), wherein each -R ^V4 , if present, is independently -H. (27) A compound according to any one of (1) to (24), wherein each -R ^V4 , if present, is independently -R ^T .

The Groups -R ^V . -R ^V2 . -R ^V3 . and -R ^V4 : Some Preferred Combinations (28) A compound according to any one of (1) to (14), wherein:

each -R ^V , if present, is independently -H;

each -R ^V2 , if present, is independently -H;

each -R ^V3 , if present, is independently -H; and

each -R ^V4 , if present, is independently -H.

The Groups W. X. Y. Z. -R ^V . -R ^V2 . -R ^V3 . and -R ^V4 : Some Preferred Combinations

(29) A compound according to (1), wherein:

=W- is =CH-; -X= is =CR ^V2 -; =Y- is =N-; -Z= is =CH-; and

-R ^V2 is independently -H or -R ^T ;

for example, as in:

(30) A compound according to (1), wherein:

=W- is =CH-; -X= is =CH-; =Y- is =N-; -Z= is =CH-;

for example, as in:

(31) A compound according to (1), wherein:

=W- is =CH-; -X= is =CH-; =Y- is =CR ^'

each -R ^V3 is independently -H or -R ^T ;

for example, as in:

(32) A compound according to (1), wherein:

=W- is =CH-; -X= is =CH-; =Y- is =CH-; -Z= is =N-;

for example, as in:

(33) A compound according to (1), wherein:

=W- is =CH-; -X= is =CR ^V2 -; =Y- is =CR ^V3 -; -Z

-R ^V2 and -R ^V3 together form -CH=CH-CH=CH

for example, as in:

The Group -R ^T

(34) A compound according to any one of (1) to (33), wherein each -R ^T , if present, is independently:

-F, -CI, -Br, -I, -R ^TT , -CF ₃ , -CHF ₂ , -OH, -OR ^TT , -OCF ₃ , -NH ₂ , -NHR ^TT , -NR ^TT ₂ , pyrrolidino, piperidino, piperizino, N-(Ci-4alkyl)piperizino, morpholino, -C(=0)R ^TT , -C(=0)OH, -C(=0)OR ^TT , or -OC(=0)R ^TT ;

wherein each -R ^TT is independently saturated aliphatic or saturated C3-6cycloalkyl. (35) A compound according to any one of (1) to (33), wherein each -R ^T , if present, is independently:

-F, -CI, -Br, -I, -R ^TT , -CF ₃ , -CHF ₂ , -OH, -OR ^TT , -OCF ₃ , -NH ₂ , -NHR ^TT , -NR ^TT ₂ , pyrrolidino, piperidino, piperizino, N-(Ci-4alkyl)piperizino, or morpholino.

(36) A compound according to any one of (1) to (33), wherein each -R ^T , if present, is independently:

-F, -CI, -Br, -I, -R ^TT , -CF ₃ , -CHF ₂ , -OH, -OR ^TT , -OCF ₃ , -NH ₂ , -NHR ^TT , or -NR^. (37) A compound according to any one of (1) to (33), wherein each -R ^T , if present, is independently:

-F, -CI, -Br, -I, -R ^TT , -OH, -OR^ -NH ₂ , -NHR ^TT , or -NR ^TT ₂ .

(38) A compound according to any one of (1) to (33), wherein each -R ^T , if present, is independently:

-F, -CI, -R ^TT , -OH, -OR^ -NH ₂ , -NHR^ or -NR ^TT ₂ .

(39) A compound according to any one of (1) to (38), wherein each -R ^TT , if present, is independently saturated aliphatic

(40) A compound according to any one of (1) to (38), wherein each -R ^TT , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.

(41) A compound according to any one of (1) to (38), wherein each -R ^TT , if present, is independently -Me or -Et.

(42) A compound according to any one of (1) to (33), wherein each -R ^T , if present, is independently: -F, -CI, -Me, -Et, -OH, -OMe, -OEt, -NH ₂ , -NHMe, or -NMe ₂ . The Group -Q

(43) A compound according to any one of (1) to (42), wherein -Q is independently -Q ^CA .

(44) A compound according to any one of (1) to (42), wherein -Q is independently -Q ^HA .

The Group -Q ^HA

(45) A compound according to any one of (1) to (44), wherein -Q ^HA , if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, and is optionally substituted with one or more groups -R ^pp . (46) A compound according to any one of (1) to (44), wherein -Q ^HA , if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, and is optionally substituted with one or more groups -R ^pp .

(47) A compound according to any one of (1) to (44), wherein -Q ^HA , if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, or pyrimidinyl, and is optionally substituted with one or more groups -R ^pp .

(48) A compound according to any one of (1) to (44), wherein -Q ^HA , if present, is independently thienyl, pyrazolyl, pyridyl, or pyrimidinyl, and is optionally substituted with one or more groups -R ^pp . The Group -R ^pp

(49) A compound according to any one of (1) to (48), wherein each -R ^pp , if present, is independently:

-F, -CI, -Br, -I,

-R ^R , -R ^RA ,

-OH, -L ^R -OH, -0-L ^R -OH, -NH-L ^R -OH, -NR ^K -L ^R -OH,

-OR ^R , -L ^R -OR ^R , -0-L ^R -OR ^R , -NH-L ^R -OR ^R , -NR ^K -L ^R -OR ^R ,

-NH ₂ , -NHR ^R , -NR ^R 2, -M ^R ,

-L ^R -NH ₂ , -L ^R -NHR ^R , -L ^R -NR ^R ₂ , -L ^R -M ^R ,

-0-L ^R -NH ₂ , -0-L ^R -NHR ^R , -0-L ^R -NR ^R ₂ , -0-L ^R -M ^R ,

-NH-L ^R -NH ₂ , -NH-L ^R -NHR ^R , -NH-L ^R -NR ^R ₂ , -NH-L ^R -M ^R ,

-NR ^K -L ^R -NH ₂ , -NR ^K -L ^R -NHR ^R , -NR ^K -L ^R -NR ^R ₂ , -NR ^K -L ^R -M ^R ,

-NHC(=0)R ^R , -NR ^K C(=0)R ^R ,

-NHC(=0)OR ^R , -NR ^K C(=0)OR ^R ,

-NHC(=0)NH ₂ , -NHC(=0)NHR ^R , -NHC(=0)NR ^R ₂ , -NHC(=0)M ^R ,

-NR ^K C(=0)NH ₂ , -NR ^K C(=0)NHR ^R , -NR ^K C(=0)NR ^R ₂ , -NR ^K C(=0)M ^R ,

-C(=0)NH ₂ , -C(=0)NHR ^R , -C(=0)NR ^R ₂ , -C(=0)M ^R ,

-C(=0)OH, -C(=0)OR ^R ,

-NHS(=0) ₂ R ^R , -NR ^K S(=0) ₂ R ^R ,

-S(=0) ₂ NH ₂ , -S(=0) ₂ NHR ^R , -S(=0) ₂ NR ^R ₂ , -S(=0) ₂ M ^R ,

-SH, or -SR ^R ;

and additionally, two adjacent groups -R ^pp , if present, may form -0-CH ₂ -0-, -0-CH ₂ CH ₂ -0-, -CH ₂ -0-CH ₂ -, or -0-CH ₂ CH ₂ -. (50) A compound according to any one of (1) to (48), wherein each -R ^pp , if present, is independently:

-F, -CI, -Br, -I,

-R ^R , -R ^RA ,

-CF ₃ , -CHF ₂ , -OCFs,

-OH, -L ^R -OH, -0-L ^R -OH, -NH-L ^R -OH, -NR ^K -L ^R -OH,

-OR ^R , -L ^R -OR ^R , -0-L ^R -OR ^R , -NH-L ^R -OR ^R , -NR ^K -L ^R -OR ^R ,

-NH ₂ , -NHR ^R , -NR ^R 2, -M ^R ,

-L ^R -NH ₂ , -L ^R -NHR ^R , -L ^R -NR ^R ₂ , -L ^R -M ^R ,

-0-L ^R -NH ₂ , -0-L ^R -NHR ^R , -0-L ^R -NR ^R ₂ , -0-L ^R -M ^R ,

-NH-L ^R -NH ₂ , -NH-L ^R -NHR ^R , -NH-L ^R -NR ^R ₂ , -NH-L ^R -M ^R ,

-NR ^K -L ^R -NH ₂ , -NR ^K -L ^R -NHR ^R , -NR ^K -L ^R -NR ^R ₂ , -NR ^K -L ^R -M ^R ,

-NHC(=0)R ^R , -NR ^K C(=0)R ^R ,

-C(=0)NH ₂ , -C(=0)NHR ^R , -C(=0)NR ^R ₂ , -C(=0)M ^R ,

-C(=0)OH, or -C(=0)OR ^R ;

and additionally, two adjacent groups -R ^pp , if present, may form -0-CH ₂ -0-, -0-CH ₂ CH ₂ -0-, -CH ₂ -0-CH ₂ -, or -0-CH ₂ CH ₂ -.

(51) A compound according to any one of (1) to (48), wherein each -R ^pp , if present, is independently:

-F, -CI, -Br, -I,

-R ^R , -R ^RA ,

-CF ₃ , -OCFs,

-OH,

-OR ^R ,

-NH ₂ , -NHR ^R , -NR ^R 2, -M ^R ,

-NHC(=0)R ^R , -NR ^K C(=0)R ^R ,

-C(=0)NH ₂ , -C(=0)NHR ^R , -C(=0)NR ^R ₂ , -C(=0)M ^R ,

-C(=0)OH, or -C(=0)OR ^R ;

and additionally, two adjacent groups -R ^pp , if present, may form -0-CH ₂ -0- or

-0-CH ₂ CH ₂ -0-.

(52) A compound according to any one of (1) to (48), wherein each -R ^pp , if present, is independently: -F, -CI, -Br, -I, -R ^R , -R ^RA , -CF ₃ , -OCF ₃ , -OH, or -OR ^R .

The Group -R ^R

(53) A compound according to any one of (1) to (52) wherein each -R ^R , if present, is independently saturated aliphatic Ci-ealkyl, saturated C3-6cycloalkyl, phenyl, or -CH ₂ -phenyl. (54) A compound according to any one of (1) to (52), wherein each -R ^R , if present, is independently saturated aliphatic Ci-ealkyl, phenyl, or -Ch -phenyl.

(55) A compound according to any one of (1) to (52), wherein each -R ^R , if present, is independently saturated aliphatic Ci-ealkyl.

(56) A compound according to any one of (1) to (52), wherein each -R ^R , if present, is independently saturated aliphatic (57) A compound according to any one of (1) to (52), wherein each -R ^R , if present, is independently -Me, -Et, -nPr, -iPr, -cPr, -nBu, -iBu, -tBu, -Ph, or -CH ₂ Ph.

(58) A compound according to any one of (1) to (52), wherein each -R ^R , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.

(59) A compound according to any one of (1) to (52), wherein each -R ^R , if present, is independently -Me, -Et, -nPr, or -iPr.

The Group -R ^RA

(60) A compound according to any one of (1) to (59), wherein each -R ^RA , if present, is independently aliphatic C^alkenyl.

(61) A compound according to any one of (1) to (59), wherein each -R ^RA , if present, is independently -CH=CH ₂ .

The Group -Q as -Q ^CA

(62) A compound according to any one of (1) to (61), wherein -Q ^CA , if present, is independently:

wherein each of -R ^P2 , -R ^P3 , -R ^P4 , -R ^P5 , and -R ^P6 is independently -H or -R' PP- as in, for example:

as in, for example:

(63) A compound according to (62), wherein:

-R ^P2 is independently -R ^pp ; and

each of -R ^P3 , -R ^P4 , -R ^P5 , and -R ^P6 is independently -H or -R ^pp . (64) A compound according to (62), wherein:

each of -R ^P2 and -R ^P4 is independently -R ^pp ; and

each of -R ^P3 , -R ^P5 , and -R ^P6 is independently -H or -R ^pp . (65) A compound according to any one of (1) to (61), wherein -Q ^CA , if present, is independently:

wherein each of -R ^P2 , -R ^P3 , -R ^P4 , -R ^P5 , and -R ^P6 is independently -R ^pp .

(66) A compound according to any one of (1) to (61), wherein -Q ^CA , if present, is independently:

wherein each of -R ^P2 and -R ^P4 is independently -R ^pp .

(67) A compound according to any one of (1) to (61), wherein -Q ^CA , if present, is independently:

wherein each of -R ^P2 and -R ^P4 is independently -R PP-

as

as

as

(68) A compound according to any one of (1) to (61), wherein -Q ^CA , if present, is independently:

wherein -R ^P2 is independently -R' as in, for example:

as in,

as in,

as in,

The Group -R ^P2 (69) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -F, -CI, -Br, -I, -R ^P2R , -R ^P2RA , -CF ₃ , -CHF ₂ , -OH, -OR ^P2R , or -OCF ₃ , wherein each -R ^P2R is independently saturated aliphatic saturated C3- ₆ cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR ^AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R ^AK , -CF ₃ , -OH, -OR ^AK , or -OCF ₃ , wherein each -R ^AK is independently saturated aliphatic and wherein -R ^P2RA is

independently aliphatic C^alkenyl.

(70) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -F, -CI, -Br, -I, -R ^P2R , -R ^P2RA , -CF ₃ , -CHF ₂ -OH, -OR ^P2R , or -OCF ₃ , wherein each -R ^P2R is independently saturated aliphatic saturated C3-6cycloalkyl, phenyl, or -CH2-phenyl; and wherein -R ^P2RA is independently aliphatic C^alkenyl.

(71) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -F, -CI, -Br, -I, -R ^P2R , -R ^P2RA , -CF ₃ , -CHF ₂ -OH, -OR ^P2R , or -OCF ₃ , wherein each -R ^P2R is independently saturated aliphatic and wherein -R ^P2RA is independently aliphatic C^alkenyl.

(72) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -F, -CI, -Br, -I, -R ^P2R , -CF ₃ , -CHF ₂ -OH, -OR ^P2R , or -OCF ₃ , wherein each -R ^P2R is independently saturated aliphatic Ci-4alkyl.

(73) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -nPr, -iPr, -cPr, -CH=CH ₂ , -Ph, -CH ₂ Ph, -CH ₂ OH, -CF ₃ , -OH, -OMe, -OEt, -O(nPr), -O(iPr), -OCF ₃ , -OPh, or -OCH ₂ Ph.

(74) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -nPr, -iPr, -CH=CH ₂ , -CH ₂ OH, -CF ₃ , -OH, -OMe, -OEt, -O(nPr), -O(iPr), or -OCF ₃ .

(75) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -CI, -Me, or -CF ₃ .

(76) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -CI.

(77) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -Me. (78) A compound according to any one of (62) to (68), wherein -R ^P2 , if present, is independently -CF ₃ .

The Group -R ^P3 (79) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Br, -I, -R ^P3R , -R ^P3RA , -CF ₃ , -CHF ₂ , -OH, -OR ^P3R , or -OCF ₃ , wherein each -R ^P3R is independently saturated aliphatic saturated C3- ₆ cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR ^AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I , -R ^AK , -CF ₃ , -OH, -OR ^AK , or -OCF ₃ , wherein each -R ^AK is independently saturated aliphatic and wherein -R ^P3RA is

independently aliphatic C^alkenyl.

(80) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Br, -I, -R ^P3R , -CF ₃ , -CHF ₂ , -OH, -OR ^P3R , or -OCF ₃ , wherein each -R ^P3R is independently saturated aliphatic Ci-4alkyl, saturated C ₃ -6cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR ^AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I , -R ^AK , -CF ₃ , -OH, -OR ^AK , or -OCF ₃ , wherein each -R ^AK is independently saturated aliphatic

(81) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Br, -I, -R ^P3R , -R ^P3RA , -CF ₃ , -CHF ₂ , -OH, -OR ^P3R , or -OCF ₃ , wherein each -R ^P3R is independently saturated aliphatic saturated C ₃ -6cycloalkyl, phenyl, or -CH2-phenyl; and wherein -R ^P3RA is independently aliphatic C^alkenyl.

(82) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Br, -I, -R ^P3R , -CF ₃ , -CHF ₂ , -OH, -OR ^P3R , or -OCF ₃ , wherein each -R ^P3R is independently saturated aliphatic Ci-4alkyl, saturated C ₃ -6cycloalkyl, phenyl, or -CH ₂ -phenyl.

(83) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Br, -I, -R ^P3R , -R ^P3RA , -CF ₃ , -OH, -OR ^P3R , or -OCF ₃ , wherein each -R ^P3R is independently saturated aliphatic Ci-4alkyl; and wherein -R ^P3RA is independently aliphatic C^alkenyl.

(84) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Br, -I, -R ^P3R , -CF ₃ , -OH, -OR ^P3R , or -OCF ₃ , wherein each -R ^P3R is independently saturated aliphatic (85) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -nPr, -iPr, -CH=CH ₂ , -cPr, -CF ₃ , -OH, -OMe, -OEt, -O(nPr), -O(iPr), or -OCF ₃ .

(86) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Br, -I , -Me, -Et, -nPr, -iPr, -cPr, -CF ₃ , -OH, -OMe, -OEt, -O(nPr), -O(iPr), or -OCF ₃ . (87) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -CF ₃ , -OH, -OMe, -OEt, or -OCF ₃ . (88) A compound according to any one of (62) to (78), wherein -R ^P3 , if present, is independently -F, -CI, -Me, -OH, or -OMe.

(89) A compound according to any one of (62) to (85), wherein -R ^P3 , if present, is independently -CI, -Me, or -OMe.

The Group -R ^P4

(90) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Br, -I, -R ^P4R , -R ^P4RA , -CF ₃ , -CHF ₂ , -OH, -OR ^P4R , or -OCF ₃ , wherein each -R ^P4R is independently saturated aliphatic saturated C ₃ -6cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from:-OH or -OR ^AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R ^AK , -CF ₃ , -OH, -OR ^AK , or -OCF ₃ , wherein each -R ^AK is independently saturated aliphatic and wherein -R ^P4RA is

independently aliphatic C^alkenyl.

(91) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Br, -I, -R ^P4R , -R ^P4RA , -CF ₃ , -OH, -OR ^P4R , or -OCF ₃ , wherein each -R ^P4R is independently saturated aliphatic Ci-4alkyl, saturated C ₃ - ₆ cycloalkyl, phenyl, or -CH2-phenyl; and wherein -R ^P4RA is independently aliphatic C2- ₄ alkenyl.

(92) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Br, -I, -R ^P4R , -R ^P4R A, _ _C F ₃ , -OH, -OR ^P4R , or -OCF ₃ , wherein each -R ^P4R is independently saturated aliphatic Ci- ₄ alkyl; and wherein -R ^P4RA is independently aliphatic C2- ₄ alkenyl.

(93) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Br, -I, -R ^P4R , -CF ₃ , -OH, -OR ^P4R , or -OCF ₃ , wherein each -R ^P4R is independently saturated aliphatic Ci- ₄ alkyl.

(94) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -nPr, -iPr, -cPr, -CF ₃ , -OH, -OMe, -OEt, -O(nPr), -O(iPr), or -OCF ₃ . (95) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -iPr, -CF ₃ , -OH, -OMe, -OEt, -O(iPr), or -OCF ₃ . (96) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Me, -Et, -iPr, -CF ₃ , -OH, -OMe, -OEt, -O(iPr), or -OCF ₃ . (97) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Me, -CF ₃ , -OH, -OMe, -OEt, or -O(iPr).

(98) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Me, -OH, or -OMe.

(99) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F, -CI, -Me, or -OMe.

(100) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -Me or -OMe.

(101) A compound according to any one of (62) to (89), wherein -R ^P4 , if present, is independently -F or -CI. The Group -R ^P5

(102) A compound according to any one of (62) to (101), wherein -R ^P5 , if present, is independently -F, -CI, -Br, -I, -R ^P5R , _ _CF3] _CHF ₂ , -OH, -OR ^P5R , or -OCF ₃ , wherein each -R ^P5R is independently saturated aliphatic saturated C ₃ - ₆ cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR ^AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R ^AK , -CF ₃ , -OH, -OR ^AK , or -OCF ₃ , wherein each -R ^AK is independently saturated aliphatic and wherein -R ^P5RA is

independently aliphatic C^alkenyl.

(103) A compound according to any one of (62) to (101), wherein -R ^P5 , if present, is independently -F, -CI, -Br, -I, -R ^P5R , _ _C F ₃ , -OH, -OR ^P5R , or -OCF ₃ , wherein each -R ^P5R is independently saturated aliphatic Ci-4alkyl, saturated C ₃ -6cycloalkyl, phenyl, or -CH ₂ -phenyl; and wherein -R ^P5RA is independently aliphatic C2-4alkenyl.

(104) A compound according to any one of (62) to (101), wherein -R ^P5 , if present, is independently -F, -CI, -Br, -I, -R ^P5R , _ _CF3] _ ₀ H, -OR ^P5R , or -OCF ₃ , wherein each -R ^P5R is independently saturated aliphatic Ci-4alkyl; and wherein -R ^P5RA is independently aliphatic C^alkenyl. - sa il 05) A compound according to any one of (62) to (101), wherein -R ^P5 , if present, is independently -F, -CI, -Br, -I, -R ^P5R , -CF ₃ , -OH, -OR ^P5R , or -OCF ₃ , wherein each -R ^P5R is independently saturated aliphatic (106) A compound according to any one of (62) to (101), wherein -R ^P5 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -nPr, -iPr, -cPr, -CF ₃ , -OH, -OMe, -OEt, -O(nPr), -O(iPr), or -OCFs.

(107) A compound according to any one of (62) to (101), wherein -R ^P5 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -CF ₃ , -OH, -OMe, -OEt, or -OCF ₃ .

(108) A compound according to any one of (62) to (101), wherein -R ^P5 , if present, is independently -F, -CI, -Me, -CF ₃ , -OH, -OMe, or -OCF ₃ . (109) A compound according to any one of (62) to (101), wherein -R ^P5 , if present, is independently -F, -CI, -Me, -OH, -OMe, or -OCF ₃ .

The Group -R ^P6 (1 10) A compound according to any one of (62) to (109), wherein -R ^P6 , if present, is independently -F, -CI, -Br, -I, -R ^P6R , -R ^p 6RA, -CF ₃ , -CHF ₂ , -OH, -OR ^P6R , or -OCF ₃ , wherein each -R ^P6R is independently saturated aliphatic saturated C ₃ -6cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR ^AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R ^AK , -CF ₃ , -OH, -OR ^AK , or -OCF ₃ , wherein each -R ^AK is independently saturated aliphatic and wherein -R ^P6RA is

independently aliphatic C^alkenyl.

(1 11) A compound according to any one of (62) to (109), wherein -R ^P6 , if present, is independently -F, -CI, -Br, -I, -R ^P6R , -R ^reRA , -CF ₃ , -OH, -OR ^P6R , or -OCF ₃ , wherein each

-R ^P6R is independently saturated aliphatic Ci-4alkyl, saturated C ₃ -6cycloalkyl, phenyl, or -CH ₂ -phenyl; and wherein -R ^P6RA is independently aliphatic C ₂ - ₄ alkenyl.

(1 12) A compound according to any one of (62) to (109), wherein -R ^P6 , if present, is independently -F, -CI, -Br, -I, -R ^P6R , -R ^p 6RA, -CF ₃ , -OH, -OR ^P6R , or -OCF ₃ , wherein each

-R ^P6R is independently saturated aliphatic Ci- ₄ alkyl; and wherein -R ^P6RA is independently aliphatic C^alkenyl.

(1 13) A compound according to any one of (62) to (109), wherein -R ^P6 , if present, is independently -F, -CI, -Br, -I, -R ^P6R , -CF ₃ , -OH, -OR ^P6R , or -OCF ₃ , wherein each -R ^P6R is independently saturated aliphatic Ci^alkyl. (1 14) A compound according to any one of (62) to (109), wherein -R ^P6 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -nPr, -iPr, -cPr, -CF ₃ , -OH, -OMe, -OEt, -O(nPr), -O(iPr), or -OCFs.

(1 15) A compound according to any one of (62) to (109), wherein -R ^P6 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -CF ₃ , -OH, -OMe, -OEt, or -OCF ₃ .

(1 16) A compound according to any one of (62) to (109), wherein -R ^P6 , if present, is independently -Me or -Et.

(1 17) A compound according to any one of (62) to (109), wherein -R ^P6 , if present, is independently -Me. The Group -J

(1 18) A compound according to any one of (1) to (117), wherein -J is independently:

-NHC(=0)R ^J ,

-NHC(=0)OR ^J ,

-NHC(=0)NH ₂ , -NHC(=0)NHR ^J , -NHC(=0)NR ^J ₂ , -NHC(=0)M ^J , or

-NHS(=0) ₂ R ^J .

(1 19) A compound according to any one of (1) to (117), wherein -J is independently:

-NH ₂ , -NHR ^J ,

-NHC(=0)R ^J ,

-NHC(=0)OR ^J ,

-NHC(=0)NH ₂ , -NHC(=0)NHR ^J , -NHC(=0)NR ^J ₂ , or

-NHS(=0) ₂ R ^J .

(120) A compound according to any one of (1) to (117), wherein -J is independently:

-NHR ^J ,

-NHC(=0)R ^J ,

-NHC(=0)OR ^J ,

-NHC(=0)NH ₂ , -NHC(=0)NHR ^J , or

-NHS(=0) ₂ R ^J .

(121) A compound according to any one of (1) to (117), wherein -J is independently:

-NHR ^J ,

-NHC(=0)R ^J ,

-NHC(=0)OR ^J , -NHC(=0)NHR ^J , or

-NHS(=0) ₂ R ^J .

(122) A compound according to any one of (1) to (117), wherein -J is independently: -NHR ^J or -NHC(=0)R ^J .

(123) A compound according to any one of (1) to (117), wherein -J is independently -NHR ^J . (124) A compound according to any one of (1) to (117), wherein -J is independently -NHC(=0)R ^J .

(125) A compound according to any one of (1) to (117), wherein -J is independently -NH ₂ . (126) A compound according to any one of (1) to (117), wherein -J is independently -NHC(=0)OR ^J .

(127) A compound according to any one of (1) to (117), wherein -J is independently -NHC(=0)NH ₂ , -NHC(=0)NHR ^J , -NHC(=0)NR ^J ₂ , or -NHC(=0)M ^J .

(128) A compound according to any one of (1) to (117), wherein -J is independently -NHC(=0)NH ₂ or -NHC(=0)NHR ^J .

(129) A compound according to any one of (1) to (117), wherein -J is independently -NHC(=0)NHR ^J .

(130) A compound according to any one of (1) to (117), wherein -J is independently -NHS(=0) ₂ R ^J . The Group -M ^J

(131 ) A compound according to any one of (1) to (130), wherein each -M ^J , if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, each optionally substituted, for example, with one or more groups selected from saturated aliphatic Ci- ₄ alkyl.

The Group -R ^N

(132) A compound according to any one of (1) to (131), wherein each -R ^N , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu. (133) A compound according to any one of (1) to (131), wherein each -R ^N , if present, is independently -Me or -Et.

(134) A compound according to any one of (1) to (131), wherein each -R ^N , if present, is independently -Me.

The Group -R ^J

(135) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently:

-R ^J1 , -R ^J2 ,

-R ^J3 , -L ^J -R ^J3 ,

-R ^J4 ,

-R ^J5 , -L ^J -R ^J5 , or

-R ^J6 .

(136) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently:

-R ^J1 , -R ^J2 ,

-R ^J3 , -L ^J -R ^J3 ,

-R ^J5 , -L ^J -R ^J5 , or

-R ^J6 .

(137) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently:

-R ^J1 ,

-R ^J3 , -L ^J -R ^J3 ,

-R ^J5 , -L ^J -R ^J5 , or

-R ^J6 .

(138) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently:

-R ^J1 ,

-R ^J3 , -L ^J -R ^J3 ,

-R ^J5 , or -L ^J -R ^J5 .

(139) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -R ^J or -R ^J2 . (140) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -R ^J . (141) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -R ^J2 . (142) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -R ^J3 or -L ^J -R ^J3 .

(143) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -R ^J3 .

(144) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -L ^J -R ^J3 .

(145) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -R ^J5 or -L ^J -R ^J5 .

(146) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -R ^J5 . (147) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -L ^J -R ^J5 .

(148) A compound according to any one of (1) to (134), wherein each -R ^J , if present, is independently -R ^J6 .

The Group -L ^J -

(149) A compound according to any one of (1) to (148), wherein each -L ^J -, if present, is independently saturated aliphatic Ci-3alkylene

(150) A compound according to any one of (1) to (148), wherein each -L ^J -, if present, is independently -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH(Me)-, -C(Me) ₂ -, -CH(Me)CH ₂ -, -C(Me) ₂ CH ₂ -, -CH ₂ CH(Me)-, or -CH ₂ CH(Me) ₂ -. (151) A compound according to any one of (1) to (148), wherein each -L ^J -, if present, is independently -CH ₂ - or -CH(Me)-.

(152) A compound according to any one of (1) to (148), wherein each -L ^J -, if present, is independently -CH ₂ CH ₂ -, -CH(Me)CH ₂ -, or -CH ₂ CH(Me)-. (153) A compound according to any one of (1) to (148), wherein each -L ^J -, if present, is independently -CH2- or -CH2CH2-.

The Group -R ^J

(154) A compound according to any one of (1) to (153), wherein each -R ^J , if present, is independently saturated aliphatic

(155) A compound according to any one of (1) to (153), wherein each -R ^J , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.

(156) A compound according to any one of (1) to (153), wherein each -R ^J , if present, is independently -Me, -Et, -nPr, -iPr, or -iBu. (157) A compound according to any one of (1) to (153), wherein each -R ^J , if present, is independently -nPr, -iPr, or -iBu.

(158) A compound according to any one of (1) to (153), wherein each -R ^J , if present, is independently -nPr.

(159) A compound according to any one of (1) to (153), wherein each -R ^J , if present, is independently -iPr.

(160) A compound according to any one of (1) to (153), wherein each -R ^J , if present, is independently -iBu.

The Group -R ^J2

(161) A compound according to any one of (1) to (160), wherein each -R ^J2 , if present, is independently saturated aliphatic and is substituted with one or more groups

(162) A compound according to any one of (1) to (160), wherein each -R ^J2 , if present, is independently -Me or -Et, and is substituted with one or more groups -R ^J2X .

The Group -R ^J2X

(163) A compound according to any one of (1) to (162), wherein each -R ^J2X , if present, is independently -OH or -OR ^J2XX . (164) A compound according to any one of (1) to (162), wherein each -R ^J2X , if present, is independently -OR ^J2XX .

(165) A compound according to any one of (1) to (162), wherein each -R ^J2X , if present, is independently -NH ₂ , -NHR ^J2XX , -NR ^J2XX ₂ , pyrrolidino, piperidino, piperizino,

N-(Ci-4alkyl)piperizino, or morpholino.

(166) A compound according to any one of (1) to (162), wherein each -R ^J2X , if present, is independently -NH ₂ , -NHR ^J2XX , or -NR ^J2XX ₂ .

(167) A compound according to any one of (1) to (161), wherein each -R ^J2X , if present, is independently -NHR ^J2XX or -NR ^J2XX ₂ .

(168) A compound according to any one of (1) to (162), wherein each -R ^J2XX , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.

(169) A compound according to any one of (1) to (162), wherein each -R ^J2XX , if present, is independently -Me or -Et. (170) A compound according to any one of (1) to (162), wherein each -R ^J2XX , if present, is independently -Me.

The Group -R ^J3 (171) A compound according to any one of (1) to (170), wherein each -R ^J3 , if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more groups -R ^JJ .

(172) A compound according to any one of (1) to (170), wherein each -R ^J3 , if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The Group -R ^J4

(173) A compound according to any one of (1) to (172), wherein each -R ^J4 , if present, is independently azetidinyl, oxitanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,

tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1 , 1 -dioxide, azepanyl, diazepanyl, or oxazepanyl, and is optionally substituted with one or more groups -R ^JJ . (174) A compound according to any one of (1) to (172), wherein each -R ^J4 , if present, is independently, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl piperizinyl, or morpholinyl, and is optionally substituted with one or more groups -R ^JJ . (175) A compound according to any one of (1) to (172), wherein each -R ^J4 , if present, is independently tetrahydropyranyl, and is optionally substituted with one or more groups -R ^JJ .

(176) A compound according to any one of (1) to (172), wherein each -R ^J4 , if present, is independently tetrahydropyranyl.

The Group -R ^J5

(177) A compound according to any one of (1) to (176), wherein each -R ^J5 , if present, is independently phenyl.

The Group -R ^J6

(178) A compound according to any one of (1) to (177), wherein each -R ^J6 , if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, and is optionally substituted, for example, with one or more groups -R ^JJ .

(179) A compound according to any one of (1) to (177), wherein each -R ^J6 , if present, is independently furanyl, thienyl, pyrrolyl, pyridyl, or pyrimidinyl, and is optionally

substituted, for example, with one or more groups -R ^JJ .

(180) A compound according to any one of (1) to (177), wherein each -R ^J6 , if present, is independently pyridyl or pyrimidinyl, and is optionally substituted, for example, with one or more groups -R ^JJ .

(181) A compound according to any one of (1) to (177), wherein each -R ^J6 , if present, is independently pyridyl, and is optionally substituted, for example, with one or more groups -R ^JJ .

(182) A compound according to any one of (1) to (177), wherein each -R ^J6 , if present, is independently pyridyl. The Group -R ^JJ

(183) A compound according to any one of (1) to (182), wherein each -R ^JJ , if present, is independently:

-F, -CI, -Br, -I,

-R ^JJJ ,

-OH, -OR ^JJJ ,

-L ^JJJ -OH, -L ^JJJ -OR ^JJJ , -0-L ^JJJ -OH, -0-L ^JJJ -OR ^JJJ ,

-CF ₃ , -OCFs,

-NH ₂ , -NHR ^JJJ , -NR ^JJJ 2,

pyrrolidino, piperidino, piperizino, N-(Ci-4alkyl)piperizino, morpholino,

-L ^JJJ -NH ₂ , -L ^JJJ -NHR ^JJJ , -L ^JJJ -NR ^JJJ ₂ ,

-L ^JJJ -pyrrolidino, -L ^JJJ -piperidino, -L ^JJJ -piperizino,

-L ^JJJ -N-(Ci-4alkyl)piperizino, -L ^JJJ -morpholino,

-0-L ^JJJ -NH ₂ , -0-L ^JJJ -NHR ^JJJ , -0-L ^JJJ -NR ^JJJ ₂ ,

-0-L ^JJJ -pyrrolidino, -0-L ^JJJ -piperidino, -0-L ^JJJ -piperizino,

-0-L ^JJJ -N-(Ci-4alkyl)piperizino, -0-L ^JJJ -morpholino,

-NHC(=0)R ^JJJ , -NR ^JJJ C(=0)R ^JJJ ,

-C(=0)R ^JJJ , -C(=0)OH, or -C(=0)OR ^JJJ .

(184) A compound according to any one of (1) to (182), wherein each -R ^JJ , if present, is independently:

-F, -CI, -Br, -I,

-R ^JJJ ,

-OH, -OR ^JJJ ,

.L ^JJJ -OH, -L ^JJJ -OR ^JJJ , -0-L ^JJJ -OH, -0-L ^JJJ -OR ^JJJ ,

-NH ₂ , -NHR ^JJJ , -NR ^JJJ ₂ ,

pyrrolidino, piperidino, piperizino, N-(Ci- ₄ alkyl)piperizino, morpholino,

-0-L ^JJJ -NH ₂ , -0-L ^JJJ -NHR ^JJJ , -0-L ^JJJ -NR ^JJJ ₂ ,

-0-L ^JJJ -pyrrolidino, -0-L ^JJJ -piperidino, -0-L ^JJJ -piperizino,

-0-L ^JJJ -N-(Ci-4alkyl)piperizino, -0-L ^JJJ -morpholino,

-NHC(=0)R ^JJJ , or -NR ^JJJ C(=0)R ^JJJ .

The Group -L ^JJJ -

(185) A compound according to any one of (1) to (184), wherein each -L ^JJJ -, if present, is independently -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -.

(186) A compound according to any one of (1) to (184), wherein each -L ^JJJ -, if present, is independently -CH ₂ CH ₂ -. Molecular Weight

(187) A compound according to any one of (1) to (186), wherein the compound has a molecular weight of from 250 to 1200.

(188) A compound according to (187), wherein the bottom of range is 275, 300, 325, 350, 375, 400, or 500.

(189) A compound according to (187) or (188), wherein the top of range is 1100, 1000, 900, 800, 700, or 600.

(190) A compound according to any one of (1) to (186), wherein the compound has a molecular weight of range from 300 to 800.

Specific Compounds

(191) A compound according to (1), selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:

(192) A compound according to (1), selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:

(193) A compound according to (1), selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Combinations

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., -J, =W-, -X=, =Y-, -Z=, -Q, -R ^V , -R ^V2 , -R ^V3 , -R ^V4 , -R ^T , -R ^TT , -Q ^CA , -Q ^HA , -R ^pp , -R ^R , -R ^RA , -L ^R -, -M ^R , -R ^K , -R ^RR , -R ^J , -M ^J , -R ^N , -R ^J , -R ^J2 , -R ^J3 , -R ^J4 , -R ^J5 , -R ^J6 , -L ^J -, -R ^J2X , -R ^J2XX , -R ^JJ , -R ^JJJ , -L ^JJJ -, -R ^P2 , -R ^P3 , -R ^P4 , -R ^P5 , -R ^P6 , -R ^P2R , -R ^P2RA , -R ^P3R , -R ^P3RA , -R ^P4R , -R ^P4RA , -R ^P5R , -R ^P5RA , -R ^P6R , -R ^P6RA , -R ^AK , etc.) are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterised, and tested for biological activity). In addition, all

sub-combinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.

Substantially Purified Forms

One aspect of the present invention pertains to 5AT2A compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.

In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.

Unless specified, the substantially purified form refers to the compound in any

stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one

stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer. ln one embodiment, the contaminants represent no more than 50% by weight, e.g. , no more than 40% by weight, e.g. , no more than 30% by weight, e.g. , no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g. , no more than 3% by weight, e.g., no more than 2% by weight, e.g. , no more than 1 % by weight.

Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.

In one embodiment, the substantially purified form is at least 60% optically pure (i.e. , 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g. , at least 70% optically pure, e.g., at least 80% optically pure, e.g. , at least 90% optically pure, e.g. , at least 95% optically pure, e.g. , at least 97% optically pure, e.g. , at least 98% optically pure, e.g., at least 99% optically pure.

Isomers Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

A reference to a class of structures may well include structurally isomeric forms falling within that class (e.g. , Ci- ₇ alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). However, reference to a specifc group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space. For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a

hydroxymethyl group, -CH ₂ OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.

The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,

thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

keto enol enolate Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including H, ² H (D), and ³ H (T); C may be in any isotopic form, including ² C, ³ C, and ⁴ C; O may be in any isotopic form, including ⁶ 0 and ⁸ 0; and the like. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.

Salts

It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of

pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci.. Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO ^" ), then a salt may be formed with a suitable cation.

Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na ⁺ and K ⁺ , alkaline earth cations such as Ca ²⁺ and Mg ²⁺ , and other cations such as Α ³ . Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH ₄ ⁺ ) and substituted ammonium ions (e.g., NH ₃ R ⁺ , NH ₂ R ₂ ⁺ , NHR ₃ ⁺ , NR ₄ ⁺ ). Examples of some suitable substituted ammonium ions are those derived from:

ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH.3) ₄ ⁺ .

If the compound is cationic, or has a functional group which upon protonation may become cationic (e.g., -NH.2 may become -NH.3 ⁺ ), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.

Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

Solvates and Hydrates

It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof.

Chemically Protected Forms It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).

A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (-OR) or an ester

(-OC(=0)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=0)CH ₃ , -OAc).

For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=0) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated, for example, by hydrolysis using water in the presence of acid.

For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH ₂ C ₆ H ₅ , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH ₃ ) ₃ , -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC CHs^CeFUCeHs, -NH-Bpoc), as a

9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2-(phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>Ν-0·).

For example, a carboxylic acid group may be protected as an ester for example, as: an Ci- ₇ alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci- ₇ haloalkyl ester (e.g., a

Ci- ₇ trihaloalkyl ester); a triCi- ₇ alkylsilyl-Ci- ₇ alkyl ester; or a C5-2oaryl-Ci- ₇ alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.

For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=0)CH3). Prodrugs

It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.

For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=0)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=0)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), lipid directed enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Chemical Synthesis Several methods for the chemical synthesis of 5AT2A compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention. Compositions

One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising a 5AT2A compound, as described herein, and a

pharmaceutically acceptable carrier, diluent, or excipient.

Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a 5AT2A compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. Uses

The compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity), such as, for example, proliferative conditions, cancer, etc.

Use in Methods of Inhibiting LIM Kinase (LIMK) One aspect of the present invention pertains to a method of inhibiting LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity), in vitro or in vivo, comprising contacting LIMK (e.g., LIMK1 and/or LIMK2) with an effective amount of a

5AT2A compound, as described herein. One aspect of the present invention pertains to a method of inhibiting LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a 5AT2A compound, as described herein.

Suitable assays for determining LIMK activity inhibition are described herein and/or are known in the art.

Use in Methods of Inhibiting Cell Proliferation, Etc.

The 5AT2A compounds described herein, e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these.

One aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a 5AT2A compound, as described herein.

In one embodiment, the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting a cell with an effective amount of a 5AT2A compound, as described herein.

In one embodiment, the method is performed in vitro.

In one embodiment, the method is performed in vivo. In one embodiment, the 5AT2A compound is provided in the form of a pharmaceutically acceptable composition. Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described herein.

For example, a sample of cells (e.g., from a tumour) may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.

Use in Methods of Therapy Another aspect of the present invention pertains to a 5AT2A compound, as described herein, for use in a method of treatment of the human or animal body by therapy.

Use in the Manufacture of Medicaments Another aspect of the present invention pertains to use of a 5AT2A compound, as described herein, in the manufacture of a medicament for use in treatment.

In one embodiment, the medicament comprises the 5AT2A compound. Methods of Treatment

Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a 5AT2A compound, as described herein, preferably in the form of a pharmaceutical composition.

Conditions Treated - Conditions Mediated by LIM Kinase (LIMK)

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disease or condition that is mediated by LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2). Conditions Treated - Conditions Ameliorated by the Inhibition of LIMK Activity

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disease or condition that is ameliorated by the inhibition of LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity).

Conditions Treated - Proliferative Conditions

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a proliferative condition. The term "proliferative condition," as used herein, pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth.

In one embodiment, the treatment is treatment of: a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.

Conditions Treated - Cancer

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of cancer.

In one embodiment, the treatment is treatment of cancer characterised by, or further characterised by, cancer cells which overexpress LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2). In one embodiment, the treatment is treatment of lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer (e.g., head cancer, neck cancer), skin cancer, squamous cancer, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.

In one embodiment, the treatment is treatment of:

a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma); a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma;

a hematopoietic tumor of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplasia syndrome, or promyelocytic leukemia;

a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma;

melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma

pigmentoum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

In one embodiment, the treatment is treatment of solid tumour cancer.

In one embodiment, the treatment is treatment of breast cancer, prostate cancer, melanoma, or glioma.

In one embodiment, the treatment is treatment of cancer metastasis.

In one embodiment, the cancer is characterised by, or further characterised by, cancer stem cells.

The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of cell migration (the spread of cance cells to other parts of the body), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis

(programmed cell death). The compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein. Conditions Treated - Additional Conditions

In one embodiment, the treatment is treatment of vasodilation. In one embodiment, the treatment is treatment of hypertension, angina, cerebral vasospasm, or ischemia following subarachnoid hemorrhage.

In one embodiment, the treatment is treatment of a neurodegenerative disorder. In one embodiment, the treatment is treatment of atherosclerosis.

In one embodiment, the treatment is treatment of fibrosis.

In one embodiment, the treatment is treatment of an inflammatory disease.

In one embodiment, the treatment is treatment of Crohn's disease or chronic obstructive pulmonary disease (COPD).

In one embodiment, the treatment is treatment of glaucoma (also known as ocular hypertension).

Treatment

The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment."

For example, treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.

The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen. Combination Therapies

The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, cytotoxic agents, anticancer agents, etc. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.

For example, it may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1 , 2, 3, 4) agents or therapies that regulates cell growth or survival or differentiation via a different mechanism, thus treating several characteristic features of cancer development.

One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.

The particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner. The agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).

The agents (i.e., the compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use. Other Uses

The 5AT2A compounds described herein may also be used as cell culture additives to inhibit (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity), e.g., to inhibit cell proliferation, etc.

The 5AT2A compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.

The 5AT2A compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other LIMK activity inhibitors, other anti-proliferative agents, other anti-cancer agents, etc.

Kits

One aspect of the invention pertains to a kit comprising (a) a 5AT2A compound as described herein, or a composition comprising a 5AT2A compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.

The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.

Routes of Administration

The 5AT2A compound or pharmaceutical composition comprising the 5AT2A compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal,

intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. The Subject/Patient

The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject/patient may be any of its forms of development, for example, a foetus. In one preferred embodiment, the subject/patient is a human. Formulations

While it is possible for the 5AT2A compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one 5AT2A compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one 5AT2A compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.

The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.

The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.

The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.

Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non- aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.

The compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.

Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses. Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier.

Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g. , aqueous, non-aqueous), emulsions (e.g. , oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g. , aqueous, non-aqueous), suspensions (e.g. , aqueous, non-aqueous), emulsions (e.g. , oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs. Tablets may be made by conventional means, e.g. , compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. , povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. , lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. , magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g. , sodium lauryl sulfate); preservatives (e.g. , methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach. Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base. Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.

Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound. Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other micro particulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.

Typically, the concentration of the compound in the liquid is from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 μg/ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Dosage

It will be appreciated by one of skill in the art that appropriate dosages of the

5AT2A compounds, and compositions comprising the 5AT2A compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular 5AT2A compound, the route of administration, the time of administration, the rate of excretion of the 5AT2A compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of 5AT2A compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.

Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

In general, a suitable dose of the 5AT2A compound is in the range of about 10 μg to about 250 mg (more typically about 100 μg to about 25 mg) per kilogram body weight of the subject per day. Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.

EXAMPLES

The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

Chemical Synthesis LCMS Methods Analytical 1

Analytical method employed Waters 2545 pumps, a Waters System fluidics organiser and a Waters 2998 diode array detector. The detection was performed between 210nm and 650nm. The mass spectrometer used was a Waters 3100 and a Waters Sunfire, 5μηι pore size, C18 column of dimensions 50 x 4.6mm was used. The injection volume was 5μΙ_.

The flow rate was 1.5 mL/min and the mobile phases of water and methanol contained 0.1 % formic acid. The elution was started at 85% water: 15% methanol ramping up to 5% water:95% methanol over 4.5minutes. These conditions were held for 1 minute. The eluent level was returned to the starting conditions of 85% water: 15% methanol over 0.1 minutes. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 minutes in total. Analytical 2

Analytical method employed Waters 2545 pumps, a Waters System fluidics organiser and a Waters 2998 diode array detector. The detection was performed between 210nm and 650nm. The mass spectrometer used was a Waters 3100 and a Waters Sunfire, 5μηι pore size, C18 column of dimensions 50 x 4.6mm was used. The injection volume was 5μΙ_.

The flow rate was 1.5 mL/min and the mobile phases of water and acetonitrile contained 0.1 % formic acid. The elution was started at 95% water:5% acetonitrile ramping up to 5% water:95% acetonitrile over 5.5minutes. The eluent level was returned to the starting conditions of 95% water:5% acetonitrile over 0.1 minutes. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 minutes in total. Prep Method 1

Samples purified by Mass Spectrometry directed High Performance Liquid

Chromatography employed Waters 2545 and 515 pumps, a Waters System fluidics organiser and a Waters 2998 diode array detector. The detection was performed between 210nm and 650nm. The mass spectrometer used was a Waters 3100 and Waters Sunfire, 5μηι pore size, C18 column of dimensions 50 x 19mm was used. The injection volume was up to 500 μΙ_ of solution at a maximum concentration of 50mg/ml_. The flow rate was 25 mL/min and the mobile phases of water and methanol contained 0.1 % formic acid. The elution was started at 85% water: 15% methanol ramping up to 5% water:95% methanol over 4.5 minutes. These conditions were held for 1 minute. The eluent level was returned to the starting conditions of 85% water: 15% methanol over 30 seconds. There are 2 purification columns so the second one was equilibrated at 85% water: 15% methanol during the previous run so the next injection could be performed straight away.

Prep Method 2 Samples purified by Mass Spectrometry directed High Performance Liquid

Chromatography employed Waters 2545 and 515 pumps, a Waters System fluidics organiser and a Waters 2998 diode array detector. The detection was performed between 210nm and 650nm. The mass spectrometer used was a Waters 3100 and Waters Sunfire, 5μηι pore size, C18 column of dimensions 50 x 19mm was used. The injection volume was up to 500 of solution at a maximum concentration of 50mg/mL.

The flow rate was 25 mL/min and the mobile phases of water and acetonitrile contained 0.1 % formic acid. The elution was started at 95% water:5% acetonitrile ramping up to 5% water:95% acetonitrile over 5 minutes. The eluent level was returned to the starting conditions of 95% water:5% acetonitrile over 30 seconds. There are 2 purification columns so the second one was equilibrated at 5% acetonitrile 95% water during the previous run so the next injection could be performed straight away.

NMR Proton NMR spectra were recorded using a Bruker AMX-300 NMR machine at 300 MHz or a Bruker AVANCE 500 at 500 MHz. Shifts were reported in ppm values relative to an internal standard of trimethylsilane (TMS) or residual protic solvent. The following abbreviations were used to describe the shifting patterns:s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double-doublet), dt (double-triplet), br (broad). Microwave Reactor

The microwave reactor used was a Biotage 30-lnitiator 60.

Scheme 1 : General Method 1

R1

HN NH,

Y S

boronic acid or ester

Synthesis 1

1-[1-Dimethylamin -meth-(E)-ylidene]-3-propyl-thiourea

N-Propylthiourea (45 mmol, 5.32 g) was dissolved in ethanol (200 mL) and treated with dimethylformamide dimethylacetal (49.5 mmol, 6.6 g) and heated at reflux for 90 minutes The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residual oil was stirred vigorously in cyclohexane (60 mL) for 2 hours. The resultant white suspension was stirred, with cooling for 30 minutes and then filtered. The white precipitate was washed with cyclohexane and dried to give a white solid.

LCMS, analytical method 1 , T _R =2.10 mins, 100%, Ml+H=174. H NMR (500 MHz, DMSO- d6) δ: 8.62 (2 H, m), 3.41 (2H, m), 3.11 (3 H, d, J 17.2), 2.99 (3 H, m), 1.49 (2 H, m), 0.82 (3 H, m).

The following intermediates were made in an analogous manner: Synthesis 1-A

1-[1-Dimethylamin -meth-(E)-ylidene]-3-pyridin-2-yl-thiourea

Synthesised from 2-pyridyl thiourea using a method similar to that described in Synthesis 1. LCMS, analytical method 1 , T _R =0.65 mins, 100%, Ml+H= no ionisation. H NMR (300 MHz, DMSO-d6) δ: 10.20 (1 H, s), 8.74 (1 H, s), 8.32 (1 H, d, J 4.7), 7.75 (1 H, m), 7.08 (1 H, m), 3.21 (3 H, s), 3.06 (3 H, s). Yield: 1g, 96%.

Synthesis 1-B

1-[1-Dimethylam -phenyl-thiourea

Synthesised from phenyl thiourea using using a method similar to that described in Synthesis 1. LCMS, analytical method 1 , T _R =3.29 mins, 100%, Ml+H=207. Yield: 6 g, 72%.

Synthesis 1-C

1-[1-Dimethylamino-meth-(E)-ylidene]-3-(4-fluoro-phenyl)-thi ourea

Synthesised from 4-fluoro phenyl thiourea using a method similar to that described in

Synthesis 1. LCMS, analytical method 1 , T _R =2.10 mins, 100%, Ml+H=226. Yield: 0.23 g, 100%.

Synthesis 1-D

1-[1-Dimethylamino-meth- E - lidene -3- 3-fluoro-phenyl)-thiourea

Synthesised from 3-fluoro phenyl thiourea using a method similar to that described in Synthesis 1. LCMS, analytical method 1 , T _R =3.77 mins, 100%, Ml+H=226. Yield: 0.23 g, 100% Svnthesis 1-E

[1-Dimethylamino-meth- E - lidene]-thiourea Synthesised from thiourea using a method similar to that described in Synthesis 1.

LCMS, analytical method 1 , T _R =0.59 mins, 100%, Ml+H= no ionisition. Yield:13.10 g, 100%. H NMR (300 MHz, DMSO-d6) δ: 8.61 (1 H, s), 8.20 (1 H, s), 7.93 (1 H, s), 3.12 (3 H, s), 2.97 (3 H, s). Synthesis 1-F

1-[1-Dimethylamino-meth-(E)-ylidene]-3-(4-hydroxy-phenyl)-th iourea

Synthesised from 4-hydroxy phenyl thiourea using a method similar to that described in Synthesis 1. LCMS, analytical method 1 , T _R =2.26 mins, 71 %, Ml+H=224. Yield: 1g, 89%.

Synthesis 2

(3-Bromo methanol

A solution of 3-bromo-pyridine-4-carbaldehyde (5 mmol, 0.93 g) in methanol (10 mL) was cooled to 0 °C under nitrogen. This was treated with sodium borohydride (5.5 mmol,

0.200 g) portionwise, and allowed to stir at 0 °C for 1 hour, then slowly allowed to return to room temperature overnight. The reaction was quenched by the addition of saturated ammonium chloride (5 mL), then evaporated under reduced pressure. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was then separated and dried with MgSCU, filtered and evaporated to yield the title compound as a white solid.

Yield: 0.94 g, 100%. LCMS, analytical method 1 , T _R = 2.18 mins, 100%, Ml+H=188/190. H NMR (300 MHz, DMSO-d6) δ: 8.62 (1 H, m), 8.53 (1 H, d, J 4.9), 7.53 (1 H, dd, J 0.6, 4.9), 5.69 (1 H, t, J 5.6), 4.51 (2 H, dd, J 0.8, 5.6). Synthesis 3

3-Bromo-4 yl-pyridine

A solution of (3-bromo-pyridin-4-yl)-methanol (3.5 mmol, 0.66 g) in anhydrous DCM (50 mL) and DMF (0.02 mL) was treated with thionyl chloride (7 mmol, 0.507 mL). The reaction mixture was refluxed for 4 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure and carefully treated with saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted into ethyl acetate (2x20 mL), dried with MgSC¼, filtered and evaporated to a dark red oil. This was purified by flash column chromatography eluting with 1 : 1 ethyl acetate: cyclohexane to yield the title compound as a dark red oil.

Yield: 0.550 g, 77%. LCMS, analytical method 1 , T _R = 4.03 mins, 100%, MI+H=205/207.

Synthesis 4

[5-(3-Bromo-pyrid -4-yl)-thiazol-2-yl]-propyl-amine

3-Bromo-4-chloromethyl-pyridine (2.6 mmol, 0.54 g) and [l-dimethylamino-meth-(E)- ylidene]-thiourea (2.6 mmol, 0.45 g) were dissolved in acetonitrile (20 mL) and treated with triethylamine (5.2 mmol, 0.69 mL). The reaction mixture was heated at reflux for 2 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in DCM (20 mL) and washed with water (20 mL). The organics were passed through a phase separation cartridge and evaporated to a dark brown solid. The solid was purified by flash column chromatography eluting with 0-80% ethyl acetate in cyclohexane to yield the title compound as a dark orange solid. LCMS, analytical method 1 , T _R =4.37 mins, 46%, MI+H=298/300. The compound was used crude in the next step. Synthesis 5

[5-(3-Bromo-pyridin-4-yl)-thiazol-2- l - ro l-carbamic acid tert-butyl ester

5-(3-Bromo-pyridin-4-yl)-thiazol-2-yl]-propyl-amine (2.4 mmol, 0.72 g) was dissolved in DCM (10 mL) with DMAP (0.50 mmol, 0.056 g) then di-tert-butyl dicarbonate (2.8 mmol, 0.62 g) was added, this was left to stir overnight. The reaction mixture was diluted with DCM (20 mL) washed with saturated sodium bicarbonate solution (50 mL), passed through a phase separator and the DCM layer was evaporated under reduced pressure. This was then purified by flash column chromatography, eluting with 0-40% ethyl acetate in cyclohexane. The fractions containing the product were evaporated to yield the title compound as a yellow gum.

Yield: 0.41 g, 44%. LCMS, analytical method 1 , T _R =5.83 mins, 85%, MI+H=398/400. H

NMR (300 MHz, DMSO) δ: 8.81 (1 H, s), 8.52 (1 H, d, J 5.1), 8.09 (1 H, s), 7.71 (1 H, d, J 5.1), 4.02 (2 H, m), 1.67 (2 H, m), 1.53 (9 H, s), 0.88 (3 H, t, J 7.4).

Synthesis 6

Propyl-{5-[3-(2-trifluoromet in-4-yl]-thiazol-2-yl}-

To a microwave tube were added [5-(3-Bromo-pyridin-4-yl)-thiazol-2-yl]-propyl-carbamic acid tert-butyl ester (0.13 mmol, 0.05 g), 2-trifluoromethylphenylboronic acid (0.15 mmol, 0.028 g), potassium carbonate (0.4 mmol, 0.055 g) and bis(triphenylphosphine) palladium(ll)dichloride (0.01 mmol, 0.007 g), 1 ,4-dioxane (1.5 mL) and water (0.5 mL). This was heated to 120 °C in a microwave reactor for 15 minutes. The reaction mixture was evaporated under reduced pressure then diluted with DCM (10 mL) and washed with water (10 mL). The organics were evaporated under reduced pressure re-dissolved in DCM (1 mL) and treated with TFA (1 mL) and left to stir for 15 hours at room temperature. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL). The aqueous was extracted into DCM (5 mL), passed through a phase separating cartridge and evaporated under reduced pressure. The residue was taken up in DMSO and purified by mass directed HPLC using prep method 1. The fractions were evaporated to yield the title compound as a white solid.

LCMS, analytical method 1 , T _R =3.72 mins, 100%, Ml+H=364. H NMR (300 MHz, DMSO- d6) δ: 8.50 (1 H, d, J 5.7), 8.33 (1 H, s), 8.07 (1 H, s), 7.92 (1 H, m), 7.77 (3 H, t, J 3.8), 7.43 (2 H, m), 3.07 (2 H, dd, J6.9, 12.4), 1.43 (2 H, dt, J 7.3, 14.4), 0.81 (3 H, t, J 7.4).

Synthesis 7

{5-[3-(2-Chloro-phenyl)-1-oxy- ol-2-yl}-propyl-amine (AA-028)

{5-[3-(2-Chloro-phenyl)-pyridin-4-yl]-thiazol-2-yl}-propyl-a mine (0.6 mmol, 0.20 g) was dissolved in acetone (10 mL) and treated with m-CPBA (2.4 mmol, 0.40 g). The reaction mixture was allowed to stir at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was dissolved in DCM (10 mL). The organics were washed with a saturated solution of sodium bicarbonate (10 mL) and the organics were separated and evaporated under reduced pressure. The residue was dissolved in DMSO and purified by mass directed LCMS using prep method 1. The fractions were evaporated to yield the title compound as an orange solid.

LCMS analytical method 1 , T _R =3.92 mins, 85%, Ml+H=346.

The following compounds were made by the same general procedure starting from the appropriate thiourea and coupling with the appropriate boronic acid.

Code MW Method T _R /mins Ml+H

AA-001 343.8745 Anal 1 3.8 344

AA-003 359.8738 Anal 1 3.54 360

AA-004 364.2926 Anal 1 4.41 364

AA-005 393.4271 Anal 1 3.82 394

AA-007 397.8458 Anal 1 4.72 398 Code MW Method TR/mins Ml+H

AA-008 364.2926 Anal 1 4.25 364

AA-009 329.8479 Anal 1 3.46 330

AA-012 347.8383 Anal 1 3.82 348

AA-014 345.8473 Anal 1 3.16 346

AA-015 359.8738 Anal 1 3.63 360

AA-016 343.8745 Anal 1 3.76 344

AA-018 364.2926 Anal 1 4.18 364

AA-019 363.4011 Anal 1 3.72 364

AA-021 309.4297 Anal 1 3.24 310

AA-024 325.4291 Anal 1 2.53 326

AA-025 323.4563 Anal 1 3.47 324

AA-026 323.4563 Anal 1 3.57 324

AA-027 413.8452 Anal 1 4.61 414

AA-028 345.8473 Anal 1 3.92 346

AA-029 329.8479 Anal 1 3.96 330

AA-031 329.8479 Anal 1 3.99 330

AA-032 295.4031 Anal 1 3.16 296

AA-036 337.4828 Anal 1 3.9 338

AA-039 364.8522 Anal 1 4.09 365

AA-043 363.8641 Anal 1 4.56 364

AA-047 378.8788 Anal 1 4.38 379

Scheme 2: General Method 1 b

Where R gives the

boronic acid or ester The starting material 3-bromo-4-chloromethyl-pyridine and [1-dimethylamino-meth- ylidene]-thiourea were synthesised by the method outlined in General Method 1.

Synthesis 8

5-(3-Brom -2-ylami

3-Bromo-4-chloromethyl-pyridine (31.8 mmol, 6.55 g) was added to a solution of [1- dimethylamino-meth-(E)-ylidene]-thiourea (31.8 mmol, 4.17 g) in acetonitrile (300 mL) with triethylamine (31.8 mmol, 4.2 mL). The reaction mixture was heated at reflux for 15 hours. The solvent was evaporated under pressure and the reaction mixture was dissolved in DCM (200 mL) and then washed with saturated sodium bicarbonate solution (200 mL) then brine (200 mL). The organics were evaporated under reduced pressure to yield the title compound as a dark brown solid which was used crude in the next step.

LCMS, analytical method 1 , T _R = 2.36 mins, 66%, MI+H=256/258.

Synthesis 9

5-(3-Bromo-pyridin- -yl)-thiazol-2 -yl]-dicarbamic acid tert-butyl ester

A solution of 5-(3-bromo-pyridin-4-yl)-thiazol-2-ylamine (20 mmol, 5.12 g) was dissolved in THF (150 mL) with DMAP (0.002 g) and di-tert-butyl dicarbonate (70 mmol, 15.26 g) was added. The reaction mixture was heated at reflux for 6 hours, then allowed to cool to room temperature. The reaction mixture was diluted with DCM (100 mL), then washed with saturated sodium bicarbonate solution (100 mL). The organics were separated and evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 0-20% EtOAc: cyclohexane to yield the title compound as a yellow solid.

Yield: 1.6 g, 18%. LCMS, analytical method 1 , T _R =5.43 mins, 74%, MI+H=456/458. H NMR (300 MHz, DMSO-d6) δ: 8.85 (1 H, s), 8.57 (1 H, d, J 5.1), 8.12 (1 H, s), 7.75 (1 H, d, J 5.1), 1.52 (18 H, s). Synthesis 10

{5-[3-(2-Chloro-phenyl)-pyridi -4-yl]-thiazol-2-yl}-carbamic acid tert-butyl ester

To a microwave tube were added [5-(3-bromo-pyridin-4-yl)-thiazol-2 -yl]-dicarbamic acid tert-butyl ester (1 mmol, 0.46 g), 2-chlorophenylboronic acid (1.5 mmol, 0.23 g), potassium carbonate (2 mmol, 0.27 g) and bis(triphenylphosphine) palladium(ll)dichloride (0.1 mmol, 0.070 g) then 1 ,4-dioxane (8 mL) and water (2 mL). The reaction mixture was heated to 150 °C in a microwave reactor for 30 minutes. The reaction mixture was diluted with DCM (100 mL) and washed with water (100 mL) and brine (100 mL). The organics were evaporated under reduced pressure and then purified by flash column

chromatography eluting with 30-100% ethyl acetate: cyclohexane to yield the title compound as a cream solid.

Yield: 0.48 g, 18% yield. LCMS, analytical method 1 , T _R =4.79 mins, 100%, Ml+H=388. H NMR (300 MHz, DMSO-d6) δ: 11.55 (1 H, s), 8.59 (1 H, d, J 5.3), 8.39 (1 H, s), 7.52 (5 H, m), 7.32 (1 H, s), 1.43 (9 H, s). The deBOC protected product was also isolated as a brown gum. LCMS, analytical method 1 , T _R =2.37 mins, 100%, Ml+H=288. H NMR (300 MHz, DMSO-d6) δ: 8.47 (1 H, d, J 5.4), 8.24 (1 H, s), 7.50 (7 H, m), 7.27 (3 H, d, J 4.9).

Synthesis 11

5-[3-(2-Chloro-phenyl)-pyri (S)-1-phenyl-ethyl)-

To a solution of {5-[3-(2-chloro-phenyl)-pyridin-4-yl]-thiazol-2-yl}-carbamic acid tert-butyl ester (0.15 mmol, 0.060 g) in THF (2 mL) cooled to 0 °C, triphenyl phosphine (0.15 mmol, 0.039 g) and ((R)-(+)-phenylethanol (0.2 mmol, 0.024 g) were added followed by the slow addition of DIAD (0.15 mmol, 0.030 g). The reaction was left to warm to room

temperature overnight. The reaction mixture was diluted with DCM (5 mL) then washed with water (5 mL), passed through a phase separating cartridge and evaporated under reduced pressure. The residue was then dissolved in DCM (1 mL) and treated with TFA (1 mL) and left to stir for 15 hours at room temperature. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL). The aqueous was extracted into DCM (5 mL), passed through a phase separating cartridge and evaporated under reduced pressure. The residue was taken up in DMSO and purified by mass directed HPLC using prep method 1. The fractions were evaporated to yield the title compound as a white solid.

LCMS, analytical method 1 , T _R =4.08 mins 100%, Ml+H=392. H NMR (300 MHz, DMSO- d6) δ: 8.44 (2 H, t, J 6.0), 8.23 (1 H, s), 7.40 (11 H, m), 4.66 (1 H, d, J 4.6), 1.36 (3 H, d, J 6.9).

The following compounds were made by the same general procedure using the appropriate alcohol and boronic acid.

Code MW Method TR/mins Ml+H

AA-041 405.9438 Anal 1 4.32 406

AA-042 405.9438 Anal 1 4.24 406

AA-044 419.9704 Anal 1 4.59 420

AA-045 391.9172 Anal 1 4.08 392

AA-046 405.9438 Anal 1 4.48 406

AA-050 391.9172 Anal 1 4.14 392

AA-052 405.9438 Anal 1 4.33 406

AA-053 377.8907 Anal 1 4.03 378

AA-054 391.9172 Anal 1 4.13 392

Scheme 3: General Method 1c

The starting material 5-(3-bromo-pyridin-4-yl)-thiazol-2-ylamine was synthesised by an analogous method outlined in General Method 1 and 1 b starting from thiourea.

Synthesis 12

[5-(3-Bromo-pyridi -4-yl)-thiazol-2-yl]-carbamic acid tert-butyl ester

5-(3-Bromo-pyridin-4-yl)-thiazol-2-ylamine (10 mmol, 2.56 g) was dissolved in DCM (100 mL) with DMAP (2 mmol, 0.224 g) and di-tert-butyl dicarbonate (24 mmol, 2.06 g) was added and the reaction was left to stir overnight at room temperature. The reaction mixture was diluted with DCM (100 mL) then washed with saturated sodium bicarbonate solution. The organics were evaporated under reduced pressure and purified by flash column chromatography, eluting with 0-50% EtOAc: cyclohexane to yield the title compound.

Yield: 1.1 g, 24%. LCMS, analytical method 1 , T _R =5.00 mins, 100%, Ml+H=357. H NMR (500 MHz, DMSO) δ: 1 1.78 (1 H, s), 8.80 (1 H, s), 8.50 (1 H, d, J 5.2), 8.03 (1 H, s), 7.70 (1 H, d, J 5.1), 1.49 (9 H, s). Synthesis 13

[5-(3-Bromo-pyridin-4-yl)-thi carbamic acid tert-butyl ester

To a solution of [5-(3-bromo-pyridin-4-yl)-thiazol-2-yl]-carbamic acid tert-butyl ester (0.2 mmol, 0.070 g) in THF (2 mL) cooled to 0 °C, triphenyl phosphine (0.3 mmol, 0.078 g) and isobutanol (0.3 mmol, 0.022 g) were added followed by the slow addition of DIAD (0.3 mmol, 0.060 g). This was left to warm to room temperature overnight. The reaction mixture was passed down an SCX cartridge, washing first with methanol then eluting with 2 M triethylamine in methanol. The solvent was evaporated under reduced pressure to yield the crude title compound.

LCMS, analytical method 1 , T _R =5.97 mins, 90%, Ml+H=412/414.

Synthesis 14

{5-[3-(2-Chloro-phenyl)-py l}-isobutyl-amine (AA-002)

To a microwave tube were added [5-(3-bromo-pyridin-4-yl)-thiazol-2-yl]-isobutyl-carbamic acid tert-butyl ester (0.2 mmol, 0.082 g), 2-chlorophenylboronic acid (0.2 mmol, 0.031 g), potassium carbonate (0.4 mmol, 0.055 g) and bis(triphenylphosphine)

palladium(ll)dichloride (0.02 mmol, 0.014 g), 1 ,4-dioxane (1 mL) and water (0.5 mL). This was heated to 150 °C in a microwave reactor for 15 minutes. The reaction mixture was then passed down an SCX column, washing with methanol first then eluting with 2 M triethylamine in methanol. The solvent was evaporated under reduced pressure then dissolved in DMSO and purified by mass directed HPLC using prep method 1. The fractions were evaporated to yield the title compound. LCMS, analytical method 1 , T _R =3.94 mins, 91 %, Ml+H=344. H NMR (300 MHz, DMSO- d6) δ: 8.47 (1 H, d, J 5.4), 8.25 (1 H, s), 7.93 (1 H, t, J 5.6), 7.50 (5 H, m), 7.24 (1 H, s), 2.95 (2 H, m), 1.76 (1 H, dt, J 6.7, 13.4), 0.82 (6 H, d, J6.7). The following compounds were made by the same general procedure using the relevant boronic acid and alcohol.

Scheme 4: General Method 2

General Method 3

In cases where R2 is not equal to hydrogen the final products were purified by mass directed LCMS after the thiazole formation.

(3-Bromo-pyridin-4-yl)-methanol was synthesised by the method outlined in General Method 1. Synthesis 15

3-(4-Methoxy-2-trifluoromethyl-phenyl)-pyridin-4-yl]-methano l

(3-Bromo-pyridin-4-yl)-methanol (0.5 mmol, 0.090 g), 4-methoxy-2-(trifluoromethyl) phenylboronic acid (0.5 mmol, 0.109 g), potassium carbonate (1 mmol, 0.138 g) and bis(triphenylphosphine)palladium(ll)dichloride (0.05 mmol, 0.035 g) were weighed into a microwave vial and treated with water (0.5 ml_) and dioxane (1.5 ml_). The vial was capped and heated to 150°C in a microwave reactor for 15 minutes. The reaction mixture was diluted with DCM (10 ml_), washed with water (10 ml_) and passed through a phase separating cartridge. The organics were evaporated under reduced pressure to yield the title compound which was used crude in the next step.

LCMS, analytical method 1 , T _R =2.98 mins, 84%, Ml+H=284. H NMR (300 MHz, DMSO- d6) δ: 8.58 (1 H, d, J 5.0), 8.21 (1 H, s), 7.58 (2 H, m), 7.30 (2 H, m), 5.40 (1 H, t, J 5.4), 4.18 (2 H, m), 3.88 (3 H, s).

Synthesis 16

5-[3-(4-Methoxy-2-trifluo in-4-yl]-thiazol-2-ylamine:

To a solution of [1-dimethylamino-meth-(E)-ylidene]-thiourea (0.5 mmol, 0.07 g) in acetonitrile (5 ml_) and triethylamine (0.5 mmol, 0.066 ml_), 4-chloromethyl-3-(4-methoxy- 2-trifluoromethyl-phenyl)-pyridine (0.5 mmol, 0.15 g) was added, this was heated to reflux for one hour. The acetonitirile was then removed under reduced pressure, and the residue was taken up in DCM (10 ml_) washed with water (10 ml_) and brine (10 ml_), dried MgSCU filtered and evaporated under reduced pressure to yield the crude title compound.

Yield: 0.12 g, 66%. LCMS, analytical method 1 , T _R =2.83 mins, 72%, Ml+H=352. Synthesis 17

N-{5-[3-(4-Methoxy-2-trifluor -4-yl]-thiazol-2-yl}-acetamid

Acetyl chloride (0.2 mmol, 0.016 g) was added to a suspension of 5-[3-(4-methoxy-2- trifluoromethyl-phenyl)-pyridin-4-yl]-thiazol-2-ylamine (0.16 mmol 0.060 g) in THF (1 mL) and triethylamine (0.2 mmol, 0.02 mL). This was left to stir for 30 minutes at room temperature then the reaction was quenched with saturated sodium bicarbonate solution (~3 mL). The reaction mixture was washed with DCM (3 mL), passed through a phase separator then evaporated under reduced pressure. The residue was then taken up in DMSO (1 mL) and purified by mass directed HPLC using prep method 1. The fractions were evaporated under reduced pressure to yield the title compound.

LCMS, analytical method 1 , T _R =4.10 mins, 93%, Ml+H=394. H NMR (300 MHz, DMSO- d6) δ: 12.12 (1 H, s), 8.57 (1 H, d, J 5.3), 8.35 (1 H, s), 7.76 (1 H, d, J 5.3), 7.57 (1 H, s), 7.34 (3 H, dd, J 6.5, 9.0), 3.90 (3 H, s), 2.07 (3 H, s).

Code MW TR/mins Ml+H Method

AA-038 393.890045 3.64 394 Anal 1

AA-040 377.890656 4.76 378 Anal 1

AA-048 395.881134 5.11 396 Anal 1

AA-049 395.881134 4.87 396 Anal 1

AA-056 371.884552 4.65 372 Anal 1

AA-057 421.437164 4.58 422 Anal 1

AA-059 393.384003 4.1 394 Anal 1

AA-060 407.410583 4.35 408 Anal 1 Scheme 5: General Method 4

[5-(3-bromo-pyridin-4-yl)-thiazol-2 -yl]-dicarbamic acid tert-butyl ester was synthesised as outlined in General Method 1 and 1 b.

The amide and carbamate examples were synthesised in an analogous fashion to the method described in general method 3 from 5-[3-(2-chloro-phenyl)-pyridin-4-yl]-thiazol-2- ylamine and the appropriate acid chloride or chloroformate.

Synthesis 18

5-[3-(2-Chloro-phenyl)-pyridin-4-yl]-thiazol-2-ylamine

To a solution of [5-(3-bromo-pyridin-4-yl)-thiazol-2 -yl]-dicarbamic acid tert-butyl ester (1.1 mmol, 0.52 g) in 1 ,4-dioxane (8 mL), 2-chlorophenylboronic acid (1.4 mmol, 0.21 g), potassium carbonate (2.33 mmol, 0.32 g), bis(triphenylphosphine) palladium(ll)dichloride (0.1 17 mmol, 0.081 g), and water (2 mL) were added. This was heated to 80 °C in a microwave reactor for 15 minutes. The reaction mixture was then diluted with DCM (100 mL), washed with water (100 mL) and brine (100 mL). The organics were separated, dried with MgS0 ₄ , filtered and evaporated under reduced pressure. The residue was then purified by flash column chromatography eluting with 0-50% ethyl acetate:cyclohexane, both mono and diboc material were combined and evaporated. The residue was dissolved in DCM (15 mL), TFA (5 mL) was added and this was left to stir for 15 hours at room temperature. The TFA was quenched by the slow addition of saturated sodium bicarbonate solution (100 mL), then left to stir for an hour then extracted into DCM (100 mL) which was then evaporated under reduced pressure to yield the title compound as a yellow solid. Yield: 0.31 g, 94%. LCMS, analytical method 1 , T _R =2.29 mins, 100%, Ml+H=288. H NMR (300 MHz, DMSO d-6) δ: 8.47 (1 H, d, J 5.4), 8.24 (1 H, s), 7.50 (7 H, m), 7.27 (3 H, d, J 4.9) contains 10% triphenylphosphine oxide.

Synthesis 19

N-{5-[3-(2-Chloro-phenyl)-pyridin-4-yl]-thiazol-2-yl}- :

To a solution of 5-[3-(2-chloro-phenyl)-pyridin-4-yl]-thiazol-2-ylamine (0.1 mmol, 0.030 g) in pyridine (2 ml_), methanesulfonyl chloride (0.12 mmol, 0.014 g) was added and the reaction mixture was heated to reflux for 4 hours. The reaction mixture was then diluted with DCM (5 ml_) and washed with water (5 ml_) and passed through a phase separator. The DCM was evaporated then the residue was taken up in DMSO and purified by mass directed HPLC using prep method 1. The fractions were evaporated under reduced pressure to yield the title compound.

LCMS, analytical method 1 , T _R =3.37 mins, 100%, Ml+H=366. H NMR (300 MHz, DMSO d-6) δ: 8.62 (1 H, d, J 5.3), 8.42 (1 H, s), 7.70 (1 H, d, J 5.3), 7.52 (5 H, m), 2.82 (3 H, s).

Synthesis 20

1-Butyl-3-{5-[3-(2-chlo -phenyl)-pyridin-4-yl]-thiazol-2-yl}-urea

To a solution of 5-[3-(2-chloro-phenyl)-pyridin-4-yl]-thiazol-2-ylamine (0.15 mmol, 40 mg) in toluene (3 ml_) butylisocyanate (0.15 mmol, 15 mg) was added. The reaction mixture was heated to reflux for 2 hours then allowed to cool to room temperature. To the solution was added 2 M ammonia in methanol (1 mL) and left to stir for 1 hour at room

temperature. The reaction mixture was then diluted with DCM (5 mL) and washed with water (5 mL) and passed through a phase separator. The DCM was then evaporated under reduced pressure and the residue was dissolved in DMSO (1 mL) and purified by mass directed HPLC using prep method 1. The fractions were evaporated under reduced pressure to yield the title compound.

LCMS, analytical method 1 , T _R =4.55 mins, 86%, Ml+H=387. H NMR (300 MHz, DMSO d-6) 10.41 (1 H, s), 8.57 (1 H, d, J 5.3), 8.35 (1 H, s), 7.67 (1 H, d, J 5.3), 7.49 (4 H, ddd, J 6.8, 18.0, 20.7), 7.35 (1 H, s), 3.06 (2 H, d, J 6.3), 1.30 (4 H, m), 0.86 (3 H, t, J 7.2).

The following compounds were synthesised using an analogous procedure using the appropriate acid chloride, chloroformate, sulphonyl chloride or isocyanate.

Code MW TR/mins Ml+H Method

AA-055 287.768127 2.35 288 Anal 1

AA-058 357.857971 4.35 358 Anal 1

AA-061 343.83139 4.08 344 Anal 1

AA-062 371.884552 4.7 372 Anal 1

AA-063 369.868652 4.59 370 Anal 1

AA-064 355.842072 4.25 356 Anal 1

AA-065 329.80481 3.69 330 Anal 1

AA-066 359.83078 3.86 360 Anal 1

AA-067 397.921814 5 398 Anal 1

AA-068 411.948395 5.31 412 Anal 1

AA-069 448.925537 4.4 449 Anal 1

AA-070 391.874176 4.79 392 Anal 1

AA-071 392.862274 4.16 393 Anal 1

AA-072 399.894653 4.05 400 Anal 1

AA-073 358.846069 3.75 359 Anal 1

AA-074 372.87265 4.13 373 Anal 1

AA-075 406.888855 4.8 407 Anal 1

AA-076 420.915436 4.56 421 Anal 1

AA-077 359.83078 4.41 360 Anal 1

AA-078 345.804199 3.88 346 Anal 1

AA-079 373.857361 4.64 374 Anal 1

AA-080 387.883942 4.93 388 Anal 1

AA-081 407.873566 4.75 408 Anal 1

AA-082 421.900146 4.94 422 Anal 1

AA-083 365.859497 3.37 366 Anal 1 Code MW TR/mins Ml+H Method

AA-084 427.928894 4.1 428 Anal 1

Scheme 6: General Method 5

Synthesis 21

5-Bromo-4-methy -1-oxy-pyridin-2-ylamine hydrochloride

5-Bromo-4-methyl-pyridin-2-ylamine (22 mmol, 4.1 1 g) was dissolved in acetone (40 mL) and cooled to 0 °C and then treated with m-CPBA (44 mmol, 7.59 g). The reaction mixture was allowed to stir at room temperature for 2 hours and then evaporated under reduced pressure to an orange solid. This was dissolved in chloroform cooled to 0 °C and treated portion-wise with 2 M ethereal hydrogen chloride (40 mL). The cooling bath was removed and the suspension was stirred at room temperature for 3 hours. The solid precipitate was filtered off and washed with ether (1x10 mL). The solid was dried under reduced pressure to provide the title compound as beige solid.

Yield: 5.27 g, 100%. LCMS, analytical method 1 , T _R =2.43 mins, 100%, MI+H=203/205. H NMR (300 MHz, DMSO-d6) δ: 8.64 (1 H, s), 8.30 (2 H, m), 7.05 (1 H, s), 2.32 (3 H, s).

Synthesis 22

N-(5-Bromo-4-c -2-yl)-acetamide

5-Bromo-4-methyl-1-oxy-pyridin-2-ylamine hydrochloride (22 mmol, 5.27 g) was suspended in dioxane (80 mL) and then treated with acetic anhydride (44 mmol, 4.49 g). The reaction mixture was then heated at reflux for 2 hours to give a dark solution. The solvent was removed under reduced pressure to provide a dark oil. This was taken up in DCM (250 mL) and washed twice with saturated sodium bicarbonate solution (250 mL) then dried over MgSCU, filtered and evaporated under reduced pressure to a provide a dark oil. The mixture was purified by flash column chromatography 3:2 cyclohexane:ethyl acetate to provide the title compound as a pale yellow solid.

Yield: 2.30 g, 40%. LCMS, analytical method 1 , T _R =4.19 mins, 89%, MI+H=263/265. H NMR (300 MHz, CDC ) δ: 10.74 (1 H, s), 8.48 (1 H, s), 8.35 (1 H, s), 4.78 (2 H, s), 2.09 (3 H, s).

Synthesis 23

N-[5-Bromo-4-(2-pro ridin-2-yl]-acetamide

N-(5-Bromo-4-chloromethyl-pyridin-2-yl)-acetamide (6.8 mmol, 1.79 g) was dissolved in acetonitrile (70 mL) and triethylamine (13.6 mmol, 1.9 mL) and treated with 1-[1- dimethylamino-meth-(E)-ylidene]-3-propyl-thiourea (6.8 mmol, 1.17 g). The reaction mixture was heated at reflux for 3 hours and allowed to cool to room temperature. The reaction mixture was allowed to cool to room temperature and then evaporated under reduced pressure to a pale brown solid. Purified by flash column chromatography 1 :4 cyclohexane:ethyl acetate to yield the title compound as a yellow solid. Yield: 1.50 g, 62%. LCMS, analytical method 1 , T _R =4.44 mins, 100%, MI+H=355/357. H NMR (300 MHz, DMSO-d6) (300 MHz, DMSO) δ: 8.66 (1 H, d, J 7.7), 8.43 (1 H, s), 8.37 (1 H, s), 8.20 (1 H t), 7.76 (1 H, s), 4.01 (1 H, q, J 7.1), 3.22 (2 H, m), 2.08 (3 H, s), 1.59 (2 H, dt, J 7.3, 14.3), 0.91 (3 H, t, J 7.4). Synthesis 24

Acetyl-{5-bromo-4-[2-(tert-butoxycarbonyl-propyl-amino)-thia zol-5-l]-pyridin-2-yl}-carbamic

N-[5-Bromo-4-(2-propylamino-thiazol-5-yl)-pyridin-2-yl]-acet amide (3 mmol, 1.07 g), ditert butyl dicarbonate (6.3 mmol, 1.37 g) and dimethylaminopyridine (0.01 g) were weighed into a round bottom flask and dissolved in triethylamine (6.3 mmol, 0.88 mL) and DCM (45 mL). The resultant solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (2x50 mL). The organics were passed through a phase separation cartridge and evaporated under reduced pressure to a light brown oil which was purified by passing through a small column of silica 1 :4 ethyl acetate:cyclohexane to provide the title compound as a pale yellow gum.

Yield: 0.56 g, 78%. LCMS, analytical method 1 , T _R =5.82 mins, 89%, Ml+H=555 and 455 - (t-BuCOO). Svnthesis 25

5-(2-Chloro-phenyl)-4-( -propylamino-thiazol-5-yl)-pyridin-2-ylarnine

Acetyl-{5-bromo-4-[2-(tert-butoxycarbonyl-propyl-amino)-thia zol-5-yl]-pyridin-2-yl}- carbamic acid tert-butyl ester (1 mmol, 0.56 g), 2-chlorophenyl boronic acid (1 mmol, 0.156 g), potassium carbonate (2 mmol, 0.276 g) and bis(triphenylphosphine)

palladium(ll)dichloride (0.005 mmol, 0.035 g) were weighed into a microwave vial and treated with dioxane (3 mL) and water (1 mL). The vial was sealed and heated in a microwave reactor at 150 °C for 15 minutes. The solvent was removed under reduced pressure, redissolved in DCM (50 mL) and washed with water (50 mL). The organics were washed with brine (10 mL) and separated using a phase separation cartridge. The organics were evaporated under reduced pressure to an orange solid. This solid was suspended in 3M hydrochloric acid (50 mL) and heated at reflux for 1 hour. The reaction mixture was carefully neutralised with 2M sodium hydroxide solution and extracted with DCM (2x50 mL). The organics were evaporated under reduced pressure, the residue was dissolved in DMSO and purified by mass directed LCMS using prep method 1. The fractions were evaporated to yield the title compound as a yellow solid.

Yield: 0.13 g, 38%. LCMS, analytical method 1 , T _R =2.85 mins, 100%, Ml+H=344. H NMR

(500 MHz, DMSO-d6) δ: 7.74 (1 H, t, J 5.4), 7.62 (1 H, s), 7.50 (1 H, m), 7.39 (2 H, m), 7.31 (1 H, m), 6.59 (1 H, s), 6.51 (1 H, s), 6.01 (2 H, s), 3.07 (2 H, dd, J 7.0, 12.5), 1.47 (2 H, m), 0.85 (3 H, dt, J 7.4, 14.8).

Synthesis 26

{5-[2-Chloro-5-(2-chloro-p thiazol-2-yl}-propyl-

5-(2-Chloro-phenyl)-4-(2-propylamino-thiazol-5-yl)-pyridin-2 -ylamine (0.15 mmol, 0.05 g) was dissolved in 37% hydrochloric acid (2 mL) and cooled to 0 °C. The solution was treated with sodium nitrite (2.25 mmol, 0.15 g) and left to stir at 0 °C for 1 hour and then room temperature for 15 hours. The reaction mixture was added to NH ₄ OH solution (20 mL) and extracted with DCM (2x10 mL). The organics were passed through a phase separation cartridge and evaporated under reduced pressure to yield the title compound as a yellow oil.

Yield: 0.01 g, 20%. LCMS, analytical method 1 , T _R =5.15 mins, 53%, MI=364/366.

Synthesis 27

-[5-(2-Chloro-phenyl)-2-methoxy-pyridin-4-yl]-thiazol-2-yl}- propyl-

{5-[2-Chloro-5-(2-chloro-phenyl)-pyridin-4-yl]-thiazol-2-yl} -propyl-amine (0.10 mmol, 0.04 g) was weighed into a microwave tube and dissolved in methanol (1 mL). The solution was treated with sodium methoxide (1.5 mmol, 0.081 g) and the reaction mixture was heated at 160 °C for 45 minutes in a microwave reactor. The mixture was diluted with water (20 mL) and extracted with DCM (2x15 mL). The organics were evaporated under reduced pressure and purified by mass directed LCMS using prep method 1. The fractions were evaporated to yield the title compound as a yellow solid.

Yield: 0.02, 50%. LCMS, analytical method 1 , T _R =5.16 mins, 100%, Ml+H=360. H NMR (300 MHz, DMSO-d6) δ: 7.86 (2 H, m), 7.47 (4 H, m), 7.11 (1 H, s), 6.97 (1 H, s), 3.89 (3 H, s), 3.07 (2 H, dd, J 6.6, 12.6), 1.46 (2 H, m), 0.82 (3 H, t, J 7.4).

Synthesis 28

[5-(2-Chloro-phenyl)-4-(2-pro -pyridin-2-yl]-dimethyl-amine

{5-[2-Chloro-5-(2-chloro-phenyl)-pyridin-4-yl]-thiazol-2- yl}-propyl-amine (0.1 mmol, 0.040 g) was weighed into a microwave tube and dissolved in DMA (1 mL). The solution was treated with dimethylamine 2 M in THF (5 mL). The reaction mixture was heated at 180 °C for 1 hour in a microwave reactor. LCMS analysis showed an approximate 50:50 mixture between product and starting material. The mixture was diluted with water (20 mL) and extracted with DCM (2x15 mL). The organics were evaporated under reduced pressure and purified by mass directed LCMS using prep method 1. The fractions were evaporated to yield the title compound as an orange solid.

Yield: 0.01 g, 25%. LCMS, analytical method 1 , T _R =3.18 mins, 100%, Ml+H=373. H NMR (300 MHz, DMSO-d6) δ: 7.80 (1 H, s), 7.73 (1 H, t, J 5.4), 7.51 (1 H, m), 7.40 (2 H, m ), 7.31 (1 H, m), 6.99 (1 H, s), 6.64 (1 H, s), 3.06 (8 H, m), 1.46 (2 H, m), 0.83 (3 H, t, J 7.4).

Synthesis 29

{5-[5-(2-Chloro-phenyl)-2-fluoro-pyridin-4-yl]-thiazol-2-yl} -propyl-amine

5-(2-Chloro-phenyl)-4-(2-propylamino-thiazol-5-yl)-pyridin-2 -ylamine (0.19 mmol, 0.17 g) was suspended in 48% fluoroboric acid (3 mL) and cooled to 0 °C. Sodium nitrite (2.85 mmol, 0.19 g) was added portionwise to the stirred mixture resulting in the evolution of a brown gas. The reaction mixture was stirred at 0 °C for 1 hour and then 2 hours at room temperature. The reaction mixture was added to ammonium hydroxide (20 mL) and extracted with DCM (3x15 mL). The solvent was evaporated under reduced pressure and the residue was dissolved in DMSO and purified by mass directed LCMS using prep method 1. The fractions were evaporated to yield the title compound as a yellow solid.

Yield: 0.010, 14%. LCMS, analytical method 1 , T _R =5.04 mins, 100%, Ml=348. The following compounds were synthesised by an analogous method to that described above using the appropriate boronic acid or thiourea starting material.

Compound AA-013 was synthesised from {5-[2-chloro-5-(2-chloro-phenyl)-pyridin-4-yl]- thiazol-2-yl}-propyl-amine using methylamine solution in THF in place of dimethylamine.

Compound AA-035 was synthesised from {5-[2-chloro-5-(2-chloro-phenyl)-pyridin-4-yl]- thiazol-2-yl}-propyl-amine using sodium ethoxide and ethanol in place of sodium methoxide and methanol. Code MW TR/mins Ml+H Method

AA-013 358.88913 2.93 359 Anal 1

AA-017 344.862549 2.89 345 Anal 1

AA-020 378.415741 2.98 379 Anal 1

AA-022 347.838318 5.04 348 Anal 1

AA-030 397.845825 5.17 398 Anal 1

AA-033 372.91571 3.18 373 Anal 1

AA-034 359.87384 5.16 360 Anal 1

AA-035 373.900421 5.37 374 Anal 1

AA-051 378.878754 3.3 379 Anal 1

Scheme 7: General Method 6

5-[3-(2-Chloro-phenyl)-pyridin-4-yl]-thiazol-2-ylamine was synthesised using the method outlined in General Method 4

Synthesis 30

3-(2-Chloro-phen azol-5-yl)-pyridine

A solution of 5-[3-(2-Chloro-phenyl)-pyridin-4-yl]-thiazol-2-ylamine (0.2 mmol, 0.060 g) in 37% hydrochloric acid (2 mL) was cooled to 0 °C and treated with sodium nitrite (3 mmol, 0.20 g) and left to stir at 0 °C for 1 hour and then room temperature for 15 hours. The reaction mixture was added to NH4OH (20 mL) and extracted with DCM (2x10 mL). The organics were passed through a phase separation cartridge and evaporated under reduced pressure to yield the title compound.

Yield: 0.060 g, 100%. LCMS, analytical method 1 , T _R =4.76 mins, 68%, MI+H=307/309. H NMR (300 MHz, DMSO d-6) δ: 8.75 (1 H, d, J 5.4), 8.56 (1 H, s), 8.13 (1 H, s), 7.96 (1 H, d, J 5.4), 7.56 (4 H, m). Svnthesis 31

{5-[3-(2-Chloro-phenyl)-pyridin-4-yl]-thiazol-2-yl}-methyl-p ropyl-amine (AA-037)

N-Methyl propylamine (1 mmol, 0.072 g) was added to a solution of 3-(2-chloro-phenyl)-4- (2-chloro-thiazol-5-yl)-pyridine (0.2 mmol, 0.060 g) in methanol (2 ml_) and heated to 150 °C in a microwave reactor for 15 minutes. The reaction mixture was then diluted with DCM (5 ml_) and washed with water (5 ml_) and passed through a phase separator. The solvent was then evaporated under reduced pressure, dissolved in DMSO and purified by mass directed HPLC using prep method 1. The fractions were evaporated under reduced pressure to yield the title compound.

LCMS, analytical method 1 , T _R =3.88 mins, 100%, Ml+H=344. H NMR (300 MHz, DMSO d-6) δ: 8.49 (1 H, s), 8.28 (1 H, s), 7.50 (5 H, m), 7.20 (1 H, s), 3.27 (2 H, s), 2.91 (3 H, s), 1.50 (2 H, s), 0.79 (3 H, s).

Scheme 8: General Method 7

RNH ₂ , NaO ^t Bu,

Method 9 Pd ₂ (dba) ₃ , Xantphos,

dioxane, DMA,

MW 120°C

Svnthesis 32

2-Chlor -3-thiazol-5-yl-pyridine

To a degassed suspension of 5-bromothiazole (3 mmol, 0.5 g) and 2-chloro-3-(4, 4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyridine (3 mmol, 0.73 g) in 1 ,4-dioxane (14 mL) water (6 mL) was added potassium carbonate (9 mmol, 1.25 g) and

bis(triphenylphenylphospine) palladium (II) dichloride (0.15 mmol, 0.10 g). The mixture was heated in a microwave reactor at 120 °C for 15 minutes. The mixture was purified by flash chromatography using a gradient elution of 0-100% ethyl acetate/cyclohexane. The solvent was removed by evaporation under reduced pressure to yield the title compound as a low-melting point colourless solid.

Yield: 0.42 g, 72%. LCMS, analytical method 1 , T _R = 3.37 mins, 95%, M+H=197. H NMR

(300 MHz, CDCIs) δ: 8.92 (1 H, s), 8.42 (1 H, d), 8.15 (1 H, s), 7.85 (1 H, d), 7.35 (1 H, m).

Synthesis 33

3-Thiazol-5-yl- -(2-trifluoromethyl-phenyl)-pyridine

To a degassed suspension of 2-chloro-3-thiazol-5-yl-pyridine (5.9 mmol, 1.16 g;) and 2- (trifluoromethyl)phenylboronic (5.9 mmol, 1.12 g,) in 1 ,4-dioxane (14 mL) and water (6 mL) was added potassium carbonate (18 mmol, 2.44 g) and bis(triphenylphenylphospine) palladium (II) dichloride (0.29 mmol, 0.20 g). The mixture was heated in a microwave reactor at 130 °C for 15 minutes. The mixture was purified by flash chromatography using a gradient elution of cyclohexane/ethyl acetate to yield the title compound as a light brown oil.

Yield: 1.3g, 72%. LCMS, analytical method 1 , T _R =4.03 mins, 90%, Ml+H=307. H NMR (300 MHz, DMSO) δ: 8.96 (1 H, s), 8.64 (1 H, dd, J 1.5, 4.7), 8.20 (1 H, m), 7.84 (2 H, m), 7.69 (2 H, dd, J4.6, 9.4), 7.57 (1 H, dd, J 4.8, 8.0), 7.38 (1 H, m). Svnthesis 34

3-(2-Bromo-thiazol- -yl)-2-(2-trifluoromethyl-phenyl)-pyridine

To a stirred solution of 3-thiazol-5-yl-2-(2-trifluoromethyl-phenyl)-pyridine (1.63 mmol, 0.5 g) in dry THF (40 ml_), under a nitrogen atmosphere at -70 °C, was added n-butyl lithium (1.63 mmol, 0.65 ml_) whilst maintaining the temperature below -70 °C. After the addition the resultant brown mixture was left to stir at -70 °C for 30 mins. A solution of carbon tetrabromide (1.63 mmol, 0.54 g,) in dry THF (5 ml_) was then added to the stirred mixture, under a nitrogen atmosphere, whilst maintaining the temperature below -70 °C. The brown mixture was left to stir at -70 °C for 1 hour and left to warm to room

temperature. After 4 hours the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was collected and evaporated under reduced pressure. The resultant gum was purified by flash chromatography using 0-100% ethyl acetate:cyclohexane as eluent to give the title compound as a brown gum. Yield: 0.52 g, 82%.

LCMS, analytical method 1 , T _R =4.72 mins, 93%, MI+H=385/387. H NMR (500 MHz, DMSO) δ: 8.66 (1 H, dd, J 1.5, 4.7), 8.23 (1 H, dd, J 1.6, 8.0), 7.88 (1 H, m), 7.75 (3 H, m), 7.58 (1 H, dd, J 4.8, 8.0), 7.43 (1 H, m).

General Method 8

Synthesis 35

5-[2-(2-Trifluorome l]-thiazol-2-ylamine

To a solution of 3-(2-bromo-thiazol-5-yl)-2-(2-trifluoromethyl-phenyl)-pyridi ne (1.3 mmol, 0.5 g) in 7 M ammonia in methanol (20 ml_) was added copper (I) oxide (0.13 mmol, 0.018 g) and the mixture was heated in a microwave reactor at 1 10 °C for 1 hour. The solvent was removed by evaporation under reduced pressure and the resultant gum purified by flash chromatography using a gradient elution of 0-100% ethyl

acetate: cyclohexane to yield the title compound as a brown gum.

Yield: 0.23 g, 54%. LCMS, analytical method 1 , T _R =2.75 mins, 94%, Ml+H=322. Svnthesis 36

N-{5-[2-(2-Trifluoromet ol-2-yl}-isobutyramide

To a stirred solution of 5-[2-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-thiazol-2-ylam ine (0.12 mmol, 0.040 g) and triethylamine (0.128 mmol, 0.013 g) in dry THF at room temperature was added isobutyryl chloride (0.122 mmol, 0.013 g). After the addition the mixture was left to stir at room temperature for three hours. The solvent was removed by evaporation under reduced pressure and the solid was dissolved in DCM washed with water and separated. The organic phase was evaporated under reduced pressure to yield the title compound.

Yield: 0.042 g, 80%. LCMS, analytical method 1 , T _R =4.49 mins, 93%, Ml+H=392. Compounds BB-052 and BB-051 were synthesised by an analogous method.

Synthesis 37

N-{5-[2-(2-Trifluorome hiazol-2-yl}-acetamide

A homogenous solution of 5-[2-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-thiazol-2-ylam ine (0.12 mmol, 0.040 g) in a 50/50 mixture of acetic acid/acetic anhydride (10 ml_) was heated at 100 °C for three hours. The solvent mixture was removed by evaporation under reduced pressure and the crude product was washed with saturated sodium bicarbonate and then extracted with dichloromethane. The organic phase was collected, dried over MgSCU, filtered and evaporated under reduced pressure to yield the product.

Yield: 0.040 g, 100%. LCMS, analytical method 1 , T _R =4.02 mins, 95%, Ml+H=364. H NMR (300 MHz, CDC ) δ: 11.8 (1 H, s), 8.65 (1 H, d), 7.9 (1 H, d), 7.7 (1 H, d), 7.52 (2H, m), 7.35 (2H, m), 6.8 (1 H, s), 2.1 (3H, s). General Method 9

Synthesis 38

Phenyl-{5-[2-(2-trifluorome in-3-yl]-thiazol-2-yl}-

3-(2-Bromo-thiazol-5-yl)-2-(2-trifluoromethyl-phenyl)-pyr idine (0.2 mmol, 0.08 g), aniline (0.24 mmol, 0.022 g), sodium tert-butoxide (0.22 mmol, 0.021 g), Pd ₂ (dba) ₃ (0.01 mmol, 0.009 g), and Xantphos (0.02 mmol, 0.01 g) were weighed into a microwave tube. 1 ,4- dioxane and DMA were added and the mixture was heated to 120 °C in a microwave reactor for 15 minutes. The reaction mixture was then diluted with DCM (5 ml_) and washed with saturated sodium bicarbonate solution (10 ml_), passed through a phase separator and evaporated under reduced pressure. The residue was then taken up in DMSO and purified by mass directed HPLC using prep method 1. The product was purified by SCX eluting first with methanol, then 1 M ammonia in methanol, this was evaporated to yield the title compound as a yellow solid.

LCMS, analytical method 1 , T _R = 4.90 mins, 100%, Ml+H=398. H (300 MHz DMSO-d6) δ: 10.15 (1 H, s), 8.53 (1 H, dd, J 1.5, 4.7), 8.13 (1 H, dd, J 1.6, 8.0), 7.87 (1 H, m), 7.73 (2 H, m), 7.47 (4 H, ddd, J 6.5, 10.4, 24.7), 7.24 (3 H, dd, J 5.4, 10.5), 6.91 (1 H, t, J 7.3). The following compounds were synthesised in an analogous manner using the appropriate acid chloride or anhydride in general method 9 and the appropriate amine in general method 9. [3-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-{5-[2-(2-trifluorometh yl-phenyl)- pyridin-3-yl]-thiazol-2-yl}-amine was synthesised from 3-(2-Pyrrolidin-1-yl-ethoxy)-phenyl which was derived by methods known in the literature starting from 3-amino-phenol and 1-(2-chloroethyl)pyrrolidine.HCI.

Scheme 9: General Method 10

boronic acid/ester

where R= boronic acid or boronate ester

2-biphenyl

boronic acid

Synthesis 39

(5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester

To a stirred slurry of 2-amino-5-bromothiazole monohydrobromide (18.5 mmol, 4.81 g) in pyridine (50 ml) at room temperature was added, portionwise, di-tert-butyl dicarbonate (20.3 mmol, 4.43 g). The mixture was left to stir at room temperature for 16 hours. The solvent was removed by evaporation under reduced pressure. Water (150 ml_) was added to the slurry and the crude product was extracted with ethyl acetate (2x100 ml_). The organic phase was collected, washed with 1 M hydrochloric acid, then washed with saturated sodium bicarbonate solution. The organic phase was dried over MgSCU, filtered and evaporated under reduced pressure to yield the title compound as a brown/pink powder. Yield: 3.5 g, 67%. LCMS, analytical method 1 , T _R =4.82 mins, 100%, MI=222/224 (-tert- Bu). H NMR (300 MHz, CDCI ₃ ) δ: 7.23 (1 H, s), 1.58 (9H, s).

Synthesis 40

(5-Bromo-thiazol-2- -propyl-carbamic acid tert-butyl ester

To a solution of 5-bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (5.7 mmol, 1.6 g), propanol (8.6 mmol, 0.52 g), and triphenylphosphine (8.6 mmol, 2.26 g) in dry THF (50 mL) at room temperature was added, dropwise over a 5 minute period, diethyl azodicarboxylate (8.6 mmol, 1.5 g). After the addition, the rose coloured solution was left to stir at room temperature for 15 hours. The solvent was removed by evaporation under reduced pressure and the crude gum was adsorbed onto silica and purified by flash chromatography using 4:1 cyclohexane:ethyl acetate as eluent. Fractions were pooled together and evaporated to give the title compound as a brown oil.

Yield: 1.6 g, 86%. LCMS, analytical method 1 , T _R =6.00 mins, 100%, MI+H=265/267 (-tert- Bu). H NMR (300 MHz, CDC ) δ: 7.32 (1 H, s), 3.98 (2H, q), 1.72 (2H, m), 1.55 (9H, s), 0.92 (3H, t).

Synthesis 41

[5-(2-Chloro- propyl-

To a degassed suspension of (5-bromo-thiazol-2-yl)-propyl-carbamic acid tert-butyl ester (2 mmol, 0.64 g) and 2-chloro-3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyridine (2 mmol, 0.5 g) in 1 ,4-dioxane (10 mL) and water (5 mL) was added potassium carbonate (6 mmol, 0.83 g) and bis(triphenylphenylphospine) palladium (II) dichloride (0.01 mmol, 0.070 g). The mixture was heated in a microwave reactor at 150 °C for 15 mins. The solvent was removed by evaporation under reduced pressure. Water was added and the mixture was extracted with dichloromethane. The organic phase was collected, dried over MgS0 ₄ , filtered and evaporated under reduced pressure to give a gum which was purified by flash chromatography using 2: 1 cyclohexane:ethyl acetate as eluent. Fractions were pooled and evaporated under reduced pressure to give the title compound as a colourless oil which solidified on standing. Yield: 0.3 g, 58%. LCMS, analytical method 2, T _R =2.75 mins, 100%, Ml+H=254. H NMR (300 MHz, DMSO-d6): 8.26 (1 H, dd); 8.0 (2H, m); 7.56 (1 H, s); 7.4 (1 H, m); 3.21 (2H, q); 1.56 (2H, m); 0.92 (3H, t).

Synthesis 42

{5-[2-(2-Chloro-ph -2-yl}-propyl-amine

To a degassed suspension of [5-(2-chloro-pyridin-3-yl)-thiazol-2-yl]-propyl-amine (0.20 mmol, 0.05 g), and 2-chlorophenylboronic acid (0.20 mmol, 0.031 g) in 1 ,4-dioxane (2 mL) and water (0.5 mL) was added potassium carbonate (0.4 mmol, 0.082 g) and bis(triphenylphenylphospine) palladium (II) dichloride (0.1 mmol, 0.007 g). The mixture was heated in a microwave reactor at 130 °C for 15 minutes. The resultant mixture was filtered through MgS0 ₄ and the solvent was removed by evaporation under reduced pressure to give a brown gum. The residue was dissolved dimethyl sulfoxide (1 mL) and then purified by mass directed LCMS using prep method 2. The fractions were evaporated to yield the title compound.

Yield: 0.010 g, 20%. LCMS, analytical method 2, T _R =3.02 mins, 100%, Ml+H=330. H NMR (300 MHz, DMSO-d6) δ: 8.47 (1 H, dd, J 1.5, 4.7), 7.99 (1 H, dd, J 1.6, 8.0), 7.66 (1 H, t, J 5.4), 7.45 (5 H, m), 6.95 (1 H, s), 3.06 (2 H, dd, J 7.0, 12.5), 1.45 (2 H, dt, J 7.2, 14.3), 0.83 (3 H, t, J 7.4).

The following compounds were synthesised in by an analogous method using the appropriate boronic acid and alcohol.

(Compound CC-005 was synthesised in an analogous fashion from (5-bromo-thiazol-2- yl)-propyl-carbamic acid tert-butyl ester using 2-biphenyl boronic acid as the coupling partner to yield (5-biphenyl-2-yl-thiazol-2-yl)-propyl-amine.)

Code MW TR/mins Ml+H Method

BB-001 363.40106 3.92 364 Anal 1

BB-003 363.401062 3.34 364 Anal 2

BB-004 325.429077 2.72 326 Anal 1

BB-005 397.845825 4.69 398 Anal 1

BB-006 323.456268 4.38 324 Anal 2 Code MW TR/mins Ml+H Method

BB-007 329.84787 3.62 330 Anal 1

BB-008 309.429688 2.63 310 Anal 2

BB-009 323.456268 3.8 324 Anal 1

BB-010 381.391541 4.38 382 Anal 1

BB-011 309.429688 3.4 310 Anal 1

BB-012 343.874451 4.86 344 Anal 2

BB-013 321.440369 3.72 322 Anal 1

BB-015 349.374481 3.61 350 Anal 1

BB-016 327.420135 4.06 328 Anal 1

BB-017 323.456268 3.88 324 Anal 1

BB-018 323.456268 3.82 324 Anal 1

BB-019 329.84787 3.02 330 Anal 2

BB-020 367.50882 4.03 368 Anal 1

BB-021 309.429688 2.68 310 Anal 2

BB-022 325.429077 2.34 326 Anal 2

BB-023 295.403107 3.05 296 Anal 2

BB-024 325.429077 2.43 326 Anal 2

BB-025 327.420135 3.92 328 Anal 1

BB-026 335.3479 3.25 336 Anal 1

BB-027 313.393555 2.82 314 Anal 2

BB-028 364.292633 4.4 364 Anal 1

BB-029 315.821289 3.35 316 Anal 1

BB-030 281.376526 2.69 282 Anal 1

BB-031 329.84787 3.32 330 Anal 2

BB-032 329.84787 3.21 330 Anal 2

BB-033 339.412598 2.41 340 Anal 2

BB-034 325.429077 3.39 326 Anal 2

BB-035 415.551605 4.58 416 Anal 1

BB-036 301.794708 2.89 302 Anal 2

BB-038 341.428467 2.07 342 Anal 2

BB-039 295.403107 2.54 296 Anal 2

BB-040 353.482239 2.71 354 Anal 2

BB-041 392.442322 2.14 393 Anal 1

BB-042 401.525055 3.07 402 Anal 2

BB-043 387.49846 3.31 388 Anal 2

BB-044 311.402496 2.11 312 Anal 2

BB-047 357.472473 4.76 358 Anal 2

BB-048 411.443878 4.46 412 Anal 1 Code MW TR/mins Ml+H Method

BB-053 379.906555 3.98 380 Anal 2

BB-054 330.835968 3.33 331 Anal 1

BB-055 327.448334 1.97 328 Anal 2

BB-056 297.379303 2.17 298 Anal 2

BB-057 313.421753 1.85 314 Anal 2

BB-058 301.431824 2.41 302 Anal 2

BB-059 310.417786 1.91 31 1 Anal 2

CC-005 294.41500 3.92 295 Anal 2

Scheme 10: General Method 1 1

Synthesis 43

1-Chloro-2- yl-benzene

(Following a procedure described in Synthesis, 2006, 11, 1781-1786 for the synthesis of 3-dimethoxymethylphenyl pivalate.) To a solution of 2-chlorobenzaldehyde (40.0 mmol, 4.5 ml) and para-toluenesulfonic acid (14.0 mmol, 2.66 g) in methanol (100 ml_) was added trimethyl orthoformate (41.1 mmol, 4.5 ml), dropwise and the solution was stirred at room temperature for 16 hours. The mixture was treated with sodium hydrogen carbonate (2.5 g), stirred and evaporated under reduced pressure. The solid residue was stirred in ethyl acetate for 15 minutes and filtered through phase separation paper, washing with ethyl acetate. The filtrate was evaporated under reduced pressure and the oily residue was filtered through a cotton wool plug to remove remaining precipitate, washed with DCM and evaporated under reduced pressure to give the title compound as a colourless liquid.

Yield: 7.47 g, 100%. LCMS, analytical method 1 , T _R =5.12 mins, ES+MI-OMe = 155.02,

ES-MI = 185 (-H).

Synthesis 44

[(2-Chloro-phenyl)-metho -methyl]-phosphonic acid diethyl ester

(Following a procedure described in Synthesis, 2006, 11, 1781-1786 for the synthesis of 3-[(diethoxyphosphoryl)(methoxy)methyl]phenyl pivalate.) To a solution of 1-chloro-2- dimethoxymethyl-benzene (40.0 mmol, 7.47 g) in DCM (300 ml_) was added triethyl phosphite (40.4 mmol, 7.0 ml_) and stirred under nitrogen at room temperature for 16 hours. The solution was cooled in a chloroform / dry ice slush bath (-60 °C) and treated with boron trifluoride (41.0 mmol, 5.2 ml_), dropwise over 45 minutes. The mixture was stirred for 3 hours at -60 °C, followed by 3 hours at 5 °C and then at room temperature for 16 hours. The solution was poured into water (300 ml_) and stirred for 10 minutes. The layers were separated and the aqueous was extracted into DCM (2x200 ml_). The combined extracts were dried and evaporated under reduced pressure to provide a colourless liquid. The crude product was purified by flash column chromatography eluting with 10 to 20% ethyl acetate / cyclohexane, followed by 60% ethyl acetate / cyclohexane. Fractions were pooled and evaporated under reduced pressure to give the title compound as a colourless liquid as well as the mixed phosphonate.

Combined yield: 9.35 g, 80%. LCMS; title compound T _R =5.07 mins, Ml+H=293.13; mixed OMe/OEt phosphonate T _R = 4.74 mins, Ml+H= 279.15. Svnthesis 45

2-Bromo-5-[2-(2-chl thoxy-vinyl]-thiazole

To a solution of [(2-chloro-phenyl)-methoxy-methyl]-phosphonic acid diethyl ester (2.5 mmol, 0.73 g) in THF (5 mL) was slowly added a 2.5 M solution of n-butyl lithium in hexanes (2.5 mmol, 1.0 mL) at -78 °C, under nitrogen. The mixture was stirred for 20 minutes and then treated with a solution of 2-bromo-thiazole-5-carbaldehyde (2.3 mmol, 0.44 g) in THF (5 mL). The mixture was stirred for 1 hour at below -60 °C before slowly warming to -10 °C (over 30 minutes). The reaction was stirred for a further 1.5 hours, warmed to room temperature and quenched with saturated aqueous ammonium chloride (50 mL). The mixture was extracted into ethyl acetate (100 mL), washed with brine (50 mL), dried and evaporated under reduced pressure. The crude product was purified by flash column chromatography eluting with 0 to 20% ethyl acetate / cyclohexane.

Fractions were pooled and evaporated under reduced pressure to give the title compound (mixture of E and Z isomers) as a yellow liquid.

Yield: 0.33 g, 60%. LCMS, analytical method 1 , mixture of E and Z isomers T _R = 5.05 mins and 5.40 mins, ES positive ion Ml+H = 330.00/332.00.

Synthesis 46

5-[2-(2-Chloro-phen yl]-thiazol-2-ylamine

To a solution of 2-bromo-5-[2-(2-chloro-phenyl)-2-methoxy-vinyl]-thiazole (1.36 mmol, 0.45 g,) in 7 M methanolic ammonia (4.5 mL) was added copper(l)oxide (0.70 mmol, 0.10 g). The mixture was heated to 120 °C for 30 minutes in a microwave reactor. The suspension was diluted with ethyl acetate, washed twice with brine dried with MgSCU, filtered and evaporated under reduced pressure. The crude product was purified by flash column chromatography eluting with 20 to 80% ethyl acetate / cyclohexane. Fractions were pooled and evaporated to give the title compound (mixture of E and Z isomers) as a brown oil. Yield: 0.200 g, 56%. LCMS, analytical method 1 , mixture of E and Z isomers T _R = 2.53 mins and 2.75 mins, Ml+H=267.12.

Synthesis 47

N-{5-[2-(2-Chloro-phen zol-2-yl}-isobutyramide

To a suspension of 5-[2-(2-chloro-phenyl)-2-methoxy-vinyl]-thiazol-2-ylamine (0.75 mmol, 0.20 g) in water (10 ml_) was slowly added concentrated sulfuric acid (2 ml_). The solution was warmed to 80 °C and stirred for 4 hours and then cooled to room

temperature. The solution was added to ice cold NaHCC>3 solution, extracted twice with dried with MgSCU, filtered and evaporated. The crude intermediate was suspended in THF, treated with triethylamine (0.9 mmol, 0.13 ml_) and isobutyryl chloride (0.77 mmol, 0.08 ml_) and stirred at room temperature for 30 minutes. The reaction mixture was treated with saturated NaHCC>3 and extracted into ethyl acetate, which was washed with brine, dried and evaporated under reduced pressure. The crude product was

chromatographed on silica, eluting with 40-70% ethyl acetate / cyclohexane. Appropriate fractions were pooled and evaporated under reduced pressure to give the title compound as a red oil.

Yield: 0.17 g, 17%. LCMS, analytical method 1 , T _R = 4.51 mins, Ml+H=323.14.

Synthesis 48

N-{5-[4-(2-Chloro-phenyl)-2 -thiazol-2-yl}-isobutyramide

To a solution of N-{5-[2-(2-chloro-phenyl)-2-oxo-ethyl]-thiazol-2-yl}-isobuty ramide (0.5 mmol, 0.161 g) in ethanol (20 ml_) was added dimethylformamide dimethylacetal (3.6 mmol, 0.48 ml_) and heated to reflux for 16 hours and then cooled to room temperature. The solution was treated with acetamidine hydrochloride (1.5 mmol, 0.142 g) and a solution of sodium hydroxide (2.0 mmol, 0.080 g,) in ethanol (6 ml_) and heated to reflux for 90 minutes. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated NaHCC solution and brine, dried with MgSCU filtered and evaporated under reduced pressure. The crude product was purified by mass directed prep HPLC using prep method 1. Fractions were pooled and evaporated under reduced pressure to give the title compound as an orange solid (0.060 g, 32%).

LCMS, analytical method 1 , T _R =4.55 mins, 100%, Ml+H=373. H NMR (300 MHz, DMSO- d6) δ: 12.10 (1 H, s), 9.03 (1 H, s), 7.54-7.44 (5H, m), 2.68-2.65 (1 H, m), 2.67 (3H, s), 1.05 (6H, d).

Compound CC-003 was synthesised by an analogous procedure using formamidine hydrochloride in place of acetamidine hydrochloride.

Scheme 1 1 : General Method 12

Synthesis 49

1-Chlo -3-o-tolyl-propan-2-one:

A solution of o-Tolyl-acetic acid ethyl ester (5.6 mmol, 1 g) in THF (150 ml_) under nitrogen was cooled to minus 78 °C and treated with chloroiodomethane (26.88 mmol, 4.74 g) and left to stir for 5 minutes. To the solution was added 1.5 M LDA THF complex in cyclohexane (26.88 mmol, 17.92 mL) was added slowly and left to stir for 3 hours at minus 78 °C. Acetic acid (12 mL) dissolved in THF (12 mL) was then added dropwise and the reaction mixture was allowed to slowly return to room temperature. The reaction mixture was then diluted with ethyl acetate (100 mL) and washed with sat NaHCC (2x100 mL), then brine (100 mL). The ethyl acetate was then evaporated under reduced pressure and the resulting brown solid was used crude in the next step.

Synthesis 50

1-(2-Pro thanone:

[1-Dimethylamino-meth-(E)-ylidene]-thiourea (5.6 mmol, 0.96 g) was added to a solution of 2-chloro-1-(1-o-tolyl-piperidin-4-yl)-ethanone (5.6 mmol, 1.02 g) in acetonitrile (20 mL) and triethylamine (5.6 mmol, 0.744 mL). The reaction mixture was heated to relfux for 15 hours, evaporated under reduced pressure and purified by flash column chromatography eluting with 0-100% ethyl acetate:cyclohexane. The fractions containing the product were combined and evaporated to yield the title compound as an orange solid.

Yield: 0.61 g, 59%. LCMS, analytical method 1 , T _R =4.70 mins, 84%, Ml+H=274. H NMR (300 MHz, DMSO d-6) δ: 8.70 (1 H, s), 8.18 (1 H, s), 7.13 (4 H, m), 4.12 (2 H, s), 3.22 (2 H, dd, J 6.7, 12.7), 2.20 (3 H, s), 1.56 (2 H, m), 0.89 (3 H, t, J 7.4).

Synthesis 51

Propyl-[5-(5-o-tolyl-p 2-yl]-amine (CC-004)

A solution of 1-(2-propylamino-thiazol-5-yl)-2-o-tolyl-ethanone (0.5 mmol, 0.14 g) in ethanol (7 mL) was treated with dimethylformamide dimethylacetal (1 mmol, 0.13 mL). The dark reaction mixture was heated to 80 °C for 4 hours. The solution was cooled in an ice bath and treated with formamidine acetate (0.8 mmol, 0.083 g) and sodium ethoxide (1 mmol, 0.068 g). The reaction mixture was then heated in a microwave reactor at 150 °C for 15 minutes. The solution was then diluted with DCM (10 mL) and washed with saturated sodium bicarbonate (10 mL). The organics were combined and evaporated under reduced pressure. Starting material was still present by LCMS analysis and it was not possible to separate from the title compound. The residue was then taken up in methanol cooled to 0 °C and treated with of sodium borohydride (0.036 g) and then left to stir for 15 hours. The reaction mixture was quenched by slow addition of water. The reaction mixture was then evaporated under reduced pressure taken up in DCM (5 ml_) washed with water and evaporated under reduced pressure. The residue was then taken up in DMSO and purified by mass directed HPLC using prep method 1. Fractions were evaporated to yield the title compound.

LCMS, analytical method 1 , T _R =4.83 mins, 100%, Ml+H=311. H NMR (300 MHz, DMSO- d6) δ: 8.97 (1 H, s), 8.39 (1 H, s), 8.29 (1 H, t, J 5.5), 7.41 (3 H, m), 7.23 (1 H, d, J 7.3), 6.38 (1 H, s), 3.12 (2 H, dd, J 6.8, 12.7), 2.00 (3 H, s), 1.49 (2 H, dd, J 7.2, 14.4), 0.84 (3 H, t, J 7.4).

Scheme 12: General Method 13

(5-Bromo-thiazol-2-yl)-propyl-carbamic acid tert-butyl ester was obtained using the protocol outlined in General Method 10.

Synthesis 52

Propyl-[5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxoborolan-2-yl)-thiazol-2-yl]-carbamic acid tert-

(5-Bromo-thiazol-2-yl)-propyl-carbamic acid tert-butyl ester (20 mmol, 6.42 g) was weighed into a 3 neck round bottom flask . The flask was placed under a nitrogen atmosphere and THF (60 mL) was added. The reaction mixture was cooled to -78 °C and treated dropwise with n-butyl lithium 2.5 M in hexanes (22 mmol, 8.8 mL) keeping the temperature below -60 °C. The reaction mixture was allowed to stir at -70 °C for 1 hour and then treated with 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (22 mmol, 4.09 mL) dropwise. The reaction mixture was then allowed to warm to room temperature and stirred for 15 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (10 mL) and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (100 mL). The organics were separated dried with MgSCU filtered and evaporated under reduced pressure. The brown solid was purified by flash column chromatography eluting with 2:3 ethyl acetate:cyclohexane. The solvent was removed to yield the title compound as a yellow solid. Yield: 4.60g, 62%. LCMS, analytical method 1 , T _R =4.98 mins, 91 %, Ml= no ionisation. H NMR (300 MHz, DMSO-d6) δ: 7.78 (1 H, s) 4.0 (2H, t) 1.63 (2H, m) 1.52 (9H, s) 1.26 (12H, s) 0.87 (3H, t).

Synthesis 53

[5-(2-Chloro-5-methyl-pyridi -3-yl)-thiazol-2-yl]-propyl-carbamic acid tert-butyl ester

3-tert-Butyl-1-propyl-1-[5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-thiazol-2-yl]-urea (1 mmol, 0.37 g) 2-chloro-3-bromo-5-methylpyridine (1 mmol, 0.20 g), potassium carbonate (2 mmol, 0.27 g) and bis(triphenylphosphine) palladium(ll)dichloride (0.050 mmol, 0.035 g) were weighed into a microwave vial and treated with dioxane (1.5 mL) and water (0.5 mL). The reaction mixture was heated at 130 °C for 15 minutes in a microwave reactor. The reaction mixture was diluted with water (40 mL), extracted with DCM (2x30 mL) and passed through a phase separation cartridge. The organics were evaporated to a brown oil. This was purified by flash column chromatography 1 :9 ethyl acetate cyclohexane to yield the title compound as a pale yellow oil.

LCMS, analytical method 2, T _R =6.22 mins, 70%, Ml+H=368.

Synthesis 54

{5-[2-(2-Chloro-phenyl)-5- -yl}-propyl-amine (BB-002)

[5-(2-Chloro-5-methyl-pyridin-3-yl)-thiazol-2-yl]-propyl-car bamic acid tert-butyl ester (0.2 mmol, 0.070 g), 2-chlorophenyl boronic acid 0.2 mmol, 0.047g), potassium carbonate and bis(triphenylphosphine) palladium(ll)dichloride (0.01 mmol, 0.007 g) were weighed into a microwave vial and dioxane (1 mL) and water (0.3 mL) were added. The reaction mixture was heated at 150°C for 15 minutes in a microwave reactor. The reaction mixture was allowed to cool, evaporated and diluted with DCM (10 mL) and water (10 mL). The organics were separated and evaporated to a brown oil that was dissolved in DCM (0.5 mL) and TFA (0.5 mL) and allowed to stir at room temperature for 4 hours. Saturated sodium bicarbonate solution (5 mL) was cautiously added and the mixture was left to stir for 2 hours at room temperature. To the solution was added DCM (5 mL) and the layers were separated. The organics were evaporated and then dissolved in DMSO 1 mL and purified by mass directed LCMS using prep method 2. The fractions were evaporated to yield the title compound.

LCMS analytical method 2, T _R =3.18 mins, 100%, Ml+H=344.

H NMR (300 MHz, DMSO-d6) δ: 8.30 (1 H, s), 7.80 (1 H, s), 7.64 (1 H, s), 7.44 (3 H, m), 7.33 (1 H, d, J 7.3), 6.92 (1 H, s), 3.06 (2 H, dd, J 7.0, 12.5), 2.36 (3 H, s), 1.46 (2 H, dd, J 7.2, 14.3), 0.83 (3 H, t, J 7.4).

Compound BB-014 was synthesised using the same procedure outlined above starting from 5-bromo-6-chloro-2-methylpyridine. Code MW TR/mins Ml+H Method

BB-002 343.8744351 3.18 344 Anal 2

BB-014 343.8744351 3.69 344 Anal 1

Scheme 13: General Method 14

3-tert-Butyl-1-propyl-1-[5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-thiazol-2-yl]-urea was obtained by the procedures outlined in general methods 10 and 12.

Synthesis 55

[5-(4-Chloro-pyridin-3-yl) amic acid tert-butyl ester

3-tert-Butyl-1-propyl-1-[5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-thiazol-2-yl]-urea (1 mmol, 0.37 g), 3-bromo-4-chloropyridine (1 mmol, 0.19 g), potassium carbonate (2 mmol, 0.55 g), bis(triphenylphosphine) palladium(ll)dichloride (0.05 mmol, 0.035 g) were weighed into a microwave vial. 1 ,4 dioxane (3 mL) and water (1 mL) were added and the reaction mixture was heated at 120 °C for 15 minutes in a microwave reactor. The solvent was removed under reduced pressure and the residue was dissolved in DCM (50 mL) and washed with water (50 mL). The layers were separated and the solvent was removed under reduced pressure to a dark brown oil. This was purified by flash column chromatography using a gradient elution 0-100% ethyl acetate:cyclohexane. The solvent was removed under reduced pressure to yield the title compound as a yellow gum.

LCMS analytical method 2, T _R = 6.05 mins, 70%, MI+H(-tBu)=298. H NMR (300 MHz, DMSO-d6) δ: 8.83 (1 H, s), 8.49 (1 H, d, J 5.4), 7.91 (1 H, s), 7.67 (1 H, d, J 5.3), 4.07 - 3.94 (2 H, m), 1.68 (2 H, dd, J 7.3, 14.7), 1.53 (9 H, s), 0.89 (3 H, t, J 7.4).

Synthesis 56

{5-[4-(2-Chloro-phenyl)-p l}-propyl-amine (CC-001)

[5-(4-Chloro-pyridin-3-yl)-thiazol-2-yl]-propyl-carbamic acid tert-butyl ester (0.16 mmol, 0.06 g), 2-chloro phenyl boronic acid (0.16 mmol, 0.025 g), potassium carbonate (0.32 mmol, 0.044 g) and bis(triphenylphosphine) palladium(ll)dichloride (0.008 mmol, 0.005 g) were weighed into a microwave vial. 1 ,4-dioxane (1 ml_) and water (0.3 ml_) were added and the reaction mixture was heated at 150 °C for 15 minutes in a microwave reactor.

The solvent was removed under reduced pressure, the residue was dissolved in DCM (10 ml_) and washed with water (10 ml_). The layers were separated and the organics were evaporated under reduced pressure to a dark brown oil. This was treated with DCM (1 ml_) and trifluoroacetic acid (0.5 ml_). The reaction mixture was allowed to stir at room temperature for 4 hours and then carefully treated with saturated sodium bicarbonate solution (10 ml_). The mixture was diluted with DCM (10 ml_) and the organics were separated using a phase separation cartridge, the solvent was evaporated under reduced pressure. The residue was then passed through a small silica plug eluting with ethyl acetate. After evaporation the residue was purified by mass directed LCMS using prep method 2. Evaporation of the fractions yielded the title compound as a yellow solid.

Yield: 0.015 g, 20%. LCMS analytical method 2, T _R =4.80 mins, 100%, Ml+H=330. H NMR (300 MHz, DMSO-d6) δ: 8.80 (1 H, s), 8.46 (1 H, d, J 5.0), 7.56 (4H, m), 7.33 (1 H, dd, J 1.9, 7.3), 7.21 (1 H, d, J 5.0), 7.05 (1 H, s), 3.06 (2 H, dd, J 6.9, 12.5), 1.46 (2 H, dd, J 7.2, 14.4), 0.83 (3 H, t, J 7.4). Method 15

Synthesis 57

(5-{2-[2-Methyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin -3-yl}-thiazol-2-yl)-propyl- -037)

3-Methyl-4-[3-(2-propylamino-thiazol-5-yl)-pyridin-2-yl]-phe nol (0.13 mmol, 0.040 g) was dissolved in DMF (1 mL) then 1-(2-chloroethyl)pyrrolidine.HCI (0.15 mmol, 0.026 g) and sodium hydroxide (0.26 mmol, 0.010 g) were added. The mixture was then heated to 60 degrees for 6 hours. The reaction mixture was diluted with DCM (5 mL) and washed with water (5 mL) and passed through a phase separator. The DCM was evaporated under reduced pressure then the residue was taken up in DMSO and purified by mass directed HPLC using prep method 1. LCMS analytical method 1 , T _R =1.77 mins, 100%, Ml+H=423 Biological Methods

Assay 1 - LIMK1 (Kinase Domain) Enzyme Activity Assay

Reagents:

Kinase Assay 2.5X Reaction Buffer: 50 mM HEPES at pH 6.8, 25 mM MgCI ₂ , 0.625 mM EGTA, 0.025% v/v Triton X-100 and 2.5 mM DTT (add DTT immediately prior to use).

Detection buffer: 50 mM HEPES pH 7, 20 mM EDTA, 0.8 M KF and 0.2% BSA.

Kinase Enzyme: LIM Kinase 1 , active recombinant protein expressed in Sf21 cells (N-terminal 6His-tagged, amino acids 285-638) purchased from Upstate (Product code 14-656MG) (Lot # 30899U; Stock concentration = 229 ng/μί. with specific activity of 1132 U/mg). Aliquots stored at -80°C. A 0.125 ng/μί. LIMK1 working solution was prepared in 2.5 X assay buffer to give 0.5 ng/well of LIMK1 [final] by diluting 1 : 1832 in Reaction Buffer.

Substrates:

Cofilin: Protein made in-house. Store at -80°C. Concentration of cofilin to be used in assay optimised for each new batch by titration to give equivalent signal window.

ATP: Supplied by Sigma (product code A-7699). A 10 mM stock in 20 mM NaOH was prepared and stored as aliquots at -20°C.

A 50 μΜ ATP/cofilin working solution was prepared to give 20 μΜ ATP/cofilin [final] (cofilin concentration used varied according to batch to give equivalent signal window) by diluting the 10 mM ATP stock 1 :200 in milliQ water and adding the required volume of Cofilin protein as found by batch titration and vortexed prior to use.

ADP-HTRF ^® Transcreener Reagents:

HTRF ^® Transcreener ADP assay kit (Product code 64ADPPEB) was obtained from Cisbio. HTRF ^® Transcreener ADP enzymatic buffer 5 X (HEPES 250 mM pH 7.0, NaN ₃ 0.1 % and BSA 0.05%) and HTRF ^® Transcreener ADP detection buffer were stored at +4°C but were not used in the assay. Both detection reagents (ADP-d2 and anti-ADP cryptate) were supplied lyophilised and therefore each vial was reconstituted with 5 mL of distilled water and mixed gently prior to aliquoting and storing at -20°C. The ADP-d2 and anti-ADP cryptate were diluted 1 in 20 in detection buffer (50 mM HEPES pH 7, 20 mM EDTA, 0.8 M KF and 0.2% BSA) and vortexed before addition to wells. Method:

Dry spot 2 μΙ_ of compound in 20% DMSO to test wells, or 20% DMSO to blanks and controls into a white polystyrene non-binding surface 384-well low volume microplate (Matrix, product code 4365) using a BioMek Nx. 4 μΙ_ of LIMK1 working solution was added to test and control samples, and 4 μΙ_ of 2.5 X assay buffer to blanks and cryptate control wells using a MATRIX 125 μΙ_ 16 multi-channel pipette. 4 μΙ_ of the ATP/cofilin working solution was added to all wells using a MATRIX 125 μΙ_ 16 multi-channel pipette except the cryptate control wells where 4 μΙ_ of miliQ water was added instead. The reaction mixture was then incubated at room temperature 60 minutes. The incubation period was followed by the addition of 2.5 μΙ_ of ADP-d2 using a MATRIX 30 μΙ_ 16 multi-channel pipette to all wells except the cryptate control wells (where detection buffer was added instead) and 2.5 μΙ_ of anti-ADP cryptate to all wells. The reaction mixture was further incubated at room temperature for 60 minutes then read on a Tecan Ultra plate reader where two sequential measurements were measured: one at 620 nm for the cryptate emission, and the other at 665 nm for the specific signal emitted by the acceptor (XL665). A ratio of the two fluorescence intensities (acceptor/donor) then allowed the calculation of Delta F (%), i.e., the relative energy transfer rate for each data point.

Tecan settings: Measurement 1: Excitation Filter 320 nm, Emission Filter 620 nm, Mirror Dichroic2

(e.g., Fl 96), Lag time 150 με, Integration time 500 με, Number of flashes 10, Gain 130, Z- position 12320.

Measurement 2: Excitation Filter 320 nm, Emission Filter 665 nm, Mirror Dichroic2 (e.g., Fl 96), Lag time 150 με, Integration time 500 με, Number of flashes 10, Gain 135, Z- position 12320.

Percentage inhibition was calculated based on activity of the test sample minus the average values in the blank wells relative to the average values measured in control wells minus the average values in the blank wells.

IC50 values were calculated from 10 point dose sigmoid "dose-response" curves using Xlfit software (IDBS Inc, USA). Data were fitted to a 4 parameter logistic model / sigmoidal dose response:

where:

A = fit minimum (locked to 0);

B = fit maximum (locked to 100);

C = fit midpoint (pre-fit to 1);

D = slope at linear portion of curve, hillslope (pre-fit to 0.1).

The value for C represents the IC5 ₀ of the test compound. Assay 2 - LIMK1 (Kinase Domain) Enzyme Binding Assay

Reagents: 1X Kinase Buffer A: 50 mM HEPES at pH 7.5, 10 mM MgCI ₂ , 1 mM EGTA, 0.01 % Brij-35.

Kinase Enzyme: LIM Kinase 1 , active recombinant protein expressed in Sf21 cells (N-terminal 6His-tagged, amino acids 285-638) purchased from Upstate (Product code 14-656MG) (Lot # 30899U; Stock concentration = 229 ng/μί. with specific activity of 1132U/mg). Aliquots stored at -80°C.

LanthaScreen™ Eu Kinase Binding Assay Reagents: Kinase tracer 236 (Product code PV5592) and Eu-anti His antibody (Product code PV5596) were obtained from Invitrogen. Both reagents were stored at -20°C. Prior to IC50 determinations, a Tracer Kd experiment was run to optimise the concentration of each new batch of Tracer 236 to use to ensure that the concentration of Tracer selected was near or slightly below Kd to ensure sensitive detection of inhibitors. Method:

Dry spot 5 μΙ_ of compound in 3% DMSO to test wells, or 3% DMSO to blanks and controls into a white polystyrene non-binding surface 384-well low volume microplate (Matrix, product code 4365) using a BioMek Nx. A 15 nM kinase and 6 nM antibody kinase/antibody solution (3 X the desired final assay concentration) was prepared in 1 X Kinase Buffer A. The antibody tube was centrifuged at approximately 10,000 x g for 10 minutes and the desired volume aspirated from the top of the solution to eliminate spurious data points that can arise on occasion due to any particulates in the product. A working solution of tracer 236 was prepared at 3x the final desired concentration in 1 X Buffer A. 5 μΙ_ of kinase/antibody solution was added to all test compound wells and positive control wells. An antibody solution containing no LIMK1 kinase was added to the final two columns to give negative control wells. 5 μΙ_ of Tracer 236 was added to all wells of the plate and then incubated at room temperature for 60 minutes. Following the incubation period the plate was read on a Tecan Ultra plate reader where two sequential measurements were measured: one at 620 nm for the antibody/donor emission, and the other at 665 nm for the acceptor/tracer emission. The emission ratio is calculated by the ratio of the two fluorescence intensities (acceptor/donor). Tecan settings:

Measurement 1: Excitation Filter 337 nm, Emission Filter 620 nm, Mirror Dichroic2 (e.g., Fl 96), Lag time 100 με, Integration time 200 με, optimal Gain, optimal Z-position.

Measurement 2: Excitation Filter 337 nm, Emission Filter 665 nm, Mirror Dichroic2 (e.g., Fl 96), Lag time 100 με, Integration time 200 με, optimal Gain, optimal Z-position.

Assay 3 - LIMK2 (Full Length) Enzyme Binding Assay

Reagents:

1X Kinase Buffer A: 50 mM HEPES at pH 7.5, 10 mM MgCI ₂ , 1 mM EGTA, 0.01 % Brij-35.

Kinase Enzyme: LIM Kinase 2, full length human N-terminal GST-fusion protein (99 kDa) with human His-tagged ROCK2 using baculovirus expression system purchased from Carna Biosciences (Product code 09-106) (Lot # 08CBS-0416 C); Stock concentration = 279 μg/mL. Aliquots stored at -80°C.

LanthaScreen™ Eu Kinase Binding Assay Reagents: Kinase tracer 178 (Product code PV5593) and Eu-anti GST antibody (Product code PV5594) were obtained from

Invitrogen. Both reagents were stored at -20°C. Prior to IC50 determinations, a Tracer Kd experiment was run to optimise the concentration of each new batch of Tracer 178 to use to ensure that the concentration of Tracer selected was near or slightly below Kd to ensure sensitive detection of inhibitors.

Method: Dry spot 5 μί of compound in 3% DMSO to test wells, or 3% DMSO to blanks and controls into a white polystyrene non-binding surface 384-well low volume microplate (Matrix, product code 4365) using a BioMek Nx. A 15 nM kinase and 6 nM antibody kinase/antibody solution (3 X the desired final assay concentration) was prepared in 1 X Kinase Buffer A. The antibody tube was centrifuged at approximately 10,000 x g for 10 minutes and the desired volume aspirated from the top of the solution to eliminate spurious data points that can arise on occasion due to any particulates in the product. A working solution of tracer 178 was prepared at 3x the final desired concentration in 1 X Buffer A. 5 μί of kinase/antibody solution was added to all test compound wells and positive control wells. An antibody solution containing no LIMK2 kinase was added to the final two columns to give negative control wells. 5 μί of Tracer 178 was added to all wells of the plate and then incubated at room temperature for 60 minutes. Following the incubation period the plate was read on a Tecan Ultra plate reader where two sequential measurements were measured: one at 620 nm for the antibody/donor emission, and the other at 665 nm for the acceptor/tracer emission. The emission ratio is calculated by the ratio of the two fluorescence intensities (acceptor/donor).

Tecan settings:

Measurement 1: Excitation Filter 337 nm, Emission Filter 620 nm, Mirror Dichroic2 (e.g., Fl 96), Lag time 100 με, Integration time 200 με, optimal Gain, optimal Z-position.

Measurement 2: Excitation Filter 337 nm, Emission Filter 665 nm, Mirror Dichroic2 (e.g., Fl 96), Lag time 100 με, Integration time 200 με, optimal Gain, optimal Z-position.

Biological Data - Assay 1 - LIMK1 (Kinase Domain) Enzyme Activity Assay

The following compounds were examined using Assay 1 : AA-001 through AA-084, BB-001 through BB-059, and CC-001 through CC-005.

All of these compounds were found to have an IC50 of less than 10 μΜ.

The following compounds were found to have an IC50 of less than 5 μΜ:

AA- 001 , AA- 002, AA- -003, AA-004, AA-005, AA- 006, AA- -007, AA- -008, AA- -009, AA- -010,

AA- 011 , AA- 012, AA- -013, AA-014, AA-015, AA- 016, AA- -017, AA- -018, AA- -019, AA- -020,

AA- 021 , AA- 022, AA- -023, AA-024, AA-025, AA- 026, AA- -027, AA- -028, AA- -029, AA- -030,

AA- 031 , AA- 032, AA- -033, AA-034, AA-035, AA- 036, AA- -037, AA- -038, AA- -039, AA- -040,

AA- 041 , AA- 042, AA- -043, AA-044, AA-045, AA- 046, AA- -047, AA- -048, AA- -049, AA- -050,

AA- 051 , AA- 052, AA- -053, AA-054, AA-055, AA- 056, AA- -057, AA- -058, AA- -059, AA- -060,

AA- 061 , AA- 062, AA- -063, AA-064, AA-065, AA- 066, AA- -067, AA- -068, AA- -069, AA- -070,

AA- 071 , AA- 072, AA- -073, AA-074, AA-075, AA- 076, AA- -077, AA- -078, AA- -079, AA- -080,

AA- 081 , AA- 082, AA- -083, AA-084, BB-001 , BB- 002, BB- -003, BB- -004, BB- -005, BB- -006,

BB- 007, BB- 008, BB- -009, BB-010, BB-011 , BB- 012, BB- -013, BB- -014, BB- -015, BB- -016,

BB- 017, BB- 018, BB- -019, BB-020, BB-021 , BB- 022, BB- -023, BB- -024, BB- -025, BB- -026,

BB- 027, BB- 028, BB- -029, BB-030, BB-031 , BB- 032, BB- -033, BB- -034, BB- -035, BB- -036,

BB- 045, BB- 046, BB- -047, BB-048, BB-049, BB- 050, BB- -051 , BB- -052, BB- -053, BB- -054,

BB- 055, CC-001 CC-002 CC-003, CC-004. The following compounds were found to have an IC50 of less than 0.5 μΜ:

AA-001 , AA-002 AA-003, AA- 004, AA- 005, AA- 006, AA- 007, AA- 008, AA- 009, AA-010, AA-011 , AA-012 AA-013, AA- 014, AA- 015, AA- 016, AA- 017, AA- 018, AA- 019, AA-020, AA-021 , AA-022 AA-023, AA- 024, AA- 025, AA- 026, AA- 027, AA- 028, AA- 038, AA-039, AA-040, AA-041 AA-042, AA- 043, AA- 044, AA- 045, AA- 046, AA- 047, AA- 048, AA-049, AA-050, AA-051 AA-052, AA- 053, AA- 054, AA- 055, AA- 056, AA- 057, AA- 058, AA-059, AA-060, AA-061 AA-062, AA- 063, AA- 064, AA- 065, AA- 066, AA- 067, AA- 068, AA-069, AA-070, AA-071 AA-072, AA- 073, AA- 074, AA- 075, AA- 076, AA- 077, AA- 078, AA-079, AA-080, AA-081 AA-082, AA- 083, BB- 001 , BB- 002, BB- 003, BB- 004, BB- 005, BB-006, BB-007, BB-045 BB-046, BB- 049, BB- 050, BB- 051 , BB- 052, BB- 053.

The following compounds were found to have an IC50 of less than 0.05 μΜ: AA-001 , AA-002, AA-003, AA-004, AA-005, AA-006, AA-007, AA-008, AA-009, AA-010, AA-011 , AA-012, AA-013, AA-014, AA-015, AA-016, AA-017, AA-018, AA-019, AA-020, AA-038, AA-039, AA-040, AA-041 , AA-042, AA-043, AA-044, AA-045, AA-046, AA-047, AA-048, AA-049, AA-050, AA-051 , AA-052, AA-053, AA-054, AA-056, AA-057, AA-058, AA-059, AA-060, AA-061 , AA-062, AA-063, AA-064, AA-065, AA-066, AA-069, AA-070, AA-073, AA-077, BB-045, BB-046.

Biological Data - Assay 2 - LIMK1 (Kinase Domain) Enzyme Binding Assay The following compounds were examined using Assay 2:

AA-001 , AA-002, AA-003, AA-009, AA-011 , AA-017, AA-020, AA-031 , AA-041 , AA-043, AA-045, AA-052, AA-054, AA-057, AA-058, AA-059, AA-060, BB-001 , BB-002, BB-003, BB-019, BB-049, BB-050, CC-001 , CC-005. All of these compounds were found to have an IC5 ₀ of less than 0.5 μΜ.

The following compounds were found to have an IC50 of less than 0.05 μΜ:

AA-001 , AA-002, AA-003, AA-009, AA-011 , AA-017, AA-020, AA-041 , AA-043, AA-045, AA-052, AA-054, AA-057, AA-058, AA-059, AA-060, BB-001 , BB-003, BB-049, BB-050, CC-001. Biological Data - Assay 3 - LIMK2 (Full Length) Enzyme Binding Assay

The following compounds were examined using Assay 3: AA-001 , AA-002, AA-003, AA-004, AA-008, AA-009, AA-011 , AA-013, AA-017, AA-019, AA-020, AA-022, AA-023, AA-038, AA-039, AA-040, AA-041 , AA-042, AA-043, AA-044, AA-045, AA-047, AA-048, AA-049, AA-051 , AA-052, AA-054, AA-056, AA-057, AA-058, AA-059, AA-060, AA-061 , AA-062, AA-065, AA-069, AA-070, AA-072, AA-073, AA-083, AA-084, BB-001 , BB-002, BB-003, BB-019, BB-037, BB-045, BB-046, BB-049, BB-050, CC-001 , CC-005.

All of these compounds were found to have an IC50 of less than 3 μΜ.

The following compounds were found to have an IC50 of less than 0.5 μΜ:

AA-001 , AA-002, AA-003, AA-004, AA-008, AA-009, AA-011 , AA-013, AA-017, AA-019, AA-020, AA-022, AA-023, AA-038, AA-039, AA-040, AA-041 , AA-042, AA-043, AA-044, AA-045, AA-047, AA-048, AA-049, AA-051 , AA-052, AA-054, AA-056, AA-057, AA-058, AA-059, AA-060, AA-061 , AA-062, AA-065, AA-069, AA-070, AA-072, AA-073, BB-001 , BB-002, BB-003, BB-019, BB-037, BB-045, BB-046, BB-049, BB-050, CC-001.

The following compounds were found to have an IC50 of less than 0.05 μΜ:

AA-001 , AA-002, AA-003, AA-009, AA-011 , AA-017, AA-019, AA-020, AA-038, AA-039, AA-040, AA-041 , AA-042, AA-043, AA-044, AA-045, AA-056, AA-057, AA-058, AA-059, AA-060, AA-061 , AA-062, AA-065, AA-069, AA-070, AA-073, BB-045, BB-050.

Biological Data - Selected Compounds

Data for some of the compounds is shown in the following table.

* * * The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.

REFERENCES

A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is

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