Organic pyridine-pyrazole compounds and uses thereof

Abstract

The present invention relates to compounds of formula (IA), (IB), (IIA), and (IIB), or pharma- ceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof. The present invention also relates to processes for the preparation of the compounds, pharmaceutical compositions containing the compounds, and the use of the compounds in treating diseases or conditions associated with inflammatory bowel disease, particularly ulcerative colitis and Crohn's disease.

Description

[Technical field]

[0001] The present invention relates to compounds of formula (IA), (IB), (IIA), and (IIB), or pharma- ceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof. The present invention also relates to processes for the preparation of the compounds, pharmaceutical compositions containing the compounds, and the use of the compounds in treating diseases or conditions associated with inflammatory bowel disease, particularly ulcerative colitis and Crohn's disease. [Background technology]

[0002] Inflammatory bowel disease is characterized by chronic, uncontrolled inflammation affecting the digestive tract, leading to multiple symptoms such as weight loss, abdominal pain, recurrent diarrhea, and bleeding. The prevalence of IBD is approximately 1 in 1000 people in Europe, with higher prevalence and incidence found in westernized developed countries (Loftus EV, Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences, Gastroenterology. 126(6):1504-17200 (2004)). The peak age for onset is between 10 and 30 years old.

[0003] Ulcerative colitis (UC) and Crohn's disease (CD) are chronic immune-mediated diseases collectively known as inflammatory bowel diseases (IBD). Both CD and UC are characterized by dysregulation and abnormalities in the immune response of the intestinal mucosa. The goal of treatment for both CD and UC is to achieve symptom control or clinical remission and prevent disease progression by eliminating or controlling the inflammatory burden (Rubin, DT, Ananthakrishnan, et al., Clinical Guideline: Ulcerative Colitis in Adults. Am. J. Gastroenterol. 114, 384-413 (2019)).

[0004] UC and CD share many pathological mechanisms: antigen-presenting cells, Th1, Th2, regulatory T cells, and Th17 T cells are activated in both UC and CD, resulting in upregulated expression of multiple inflammatory cytokines and chemokines (Sartor, RB Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis. Nat Clin Pract Gastr. 3, 390-407 (2006)). There are many common pathways that play important roles in disease pathology and cytokines that are upregulated in both diseases, including IL-6 (Mudter, J. & Neurath, MF Il-6 signaling in inflammatory bowel disease: Pathophysiological role and clinical relevance. Inflamm Bowel Dis 13, 1016-1023 (2007)), IL-8 (Daig, R. et al. Increased interleukin 8 expression in the colon mucosa of patients with inflammatory bowel disease. Gut 38, 216 (1996)), and TNF-α (Friedrich, M., Pohin, M. & Powrie, F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity 50, 992-1006 (2019)), cytokines that the applicant measured in ex vivo colon biopsies of patients (Ramos, GP & Papadakis, KA Mechanisms of Disease: Inflammatory Bowel Diseases. Mayo Clin Proc 94, 155-165 (2019)).Given these common disease mechanisms for both UC and CD, it is well understood and strongly supported by theoretical justification that treatments effective for UC will also be effective for CD; for example, blockade of TNFα with neutralizing monoclonal antibodies has been clinically shown to treat both active CD and UC (Jarnerot, G. et al. Infliximab as Rescue Therapy in Severe to Moderately Severe Ulcerative Colitis: A Randomized, Placebo-Controlled Study. Gastroenterology 128, 1805-1811 (2005); Targan, SR et al. A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor α for Crohn's Disease. New Engl J Medicine 337, 1029-1036 (1997)).

[0005] Genetic studies have also shown that UC and CD share many genes involved in disease pathology, with only a few genes specific to each disease (Waterman, M. et al. Distinct and overlapping genetic loci in crohn's disease and ulcerative colitis: Correlations with pathogenesis. Inflamm Bowel Dis 17, 1936-1942 (2011)). A combined genome-wide analysis of CD and UC showed that 110 of 163 loci that met the genome-wide significance threshold were associated with both diseases, 50 of which had effect sizes that were indistinguishable between CD and UC, and most of the remaining had similar directions in the two diseases (Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124 (2012)). This degree of shared genetic risk suggests that nearly all biological mechanisms involved in one disease have a role in the other, and therefore effective treatments for UC may have therapeutic benefit for CD.

[0006] There is currently no cure for either UC or CD. Treatment strategies include lifestyle interventions and medical and surgical treatments. Pharmacological management includes corticosteroids, immunosuppressants, and anti-tumor necrosis factor (TNF)-α biologics (Baumgart et al., Inflammatory bowel disease: clinical aspects and established and evolving therapies, Lancet. 369(9573), 1641-57, (2007)).

[0007] Thus, there remains an urgent need for treatments for inflammatory bowel disease, particularly ulcerative colitis and Crohn's disease.

[0008] It is an object of the present invention to provide a therapy that can be used in a variety of inflammatory bowel disease conditions. It would be beneficial if such a therapy could be used to treat inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Summary of the Invention

[0009] In a first aspect of the invention, there is provided a compound of formula (IA) or (IB) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein X is N and CR 4 Selected from; Y is N and CR 5 Selected from; CR 4 and CR 5 At least one of is present; Z is N and CR 6 Selected from; R 1 is H, C1-C6 alkyl and -SO2R 7 wherein said C1-C6 alkyl is optionally selected from the group consisting of halo, oxo, -NR a R b , -C(O)NR a R b , -C(O)OR c , -OR c substituted with one or more substituents independently selected from R 2 and R 3 is independently selected from the group consisting of H, halo, and C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more halo atoms; R 4 and R 5 H, -C(O)OR c , -C(O)N(R d )SO2R e, -C(O)N=S(O)R e 2. -N=S(O)R e 2, -N(R d )C(O)N=S(O)R e 2. -N(R d )C(O)NR e 2, -N(R d )SO2R e , -S(O)(=NR d )R e , [ka] independently selected from the group consisting of: R 6 is selected from H and C1-C6 alkyl, said C1-C6 alkyl optionally substituted with one or more halo atoms; R 7 is selected from H and C1-C6 alkyl, said C1-C6 alkyl optionally substituted with one or more halo atoms; R 8 is C1-C6 alkyl, -OH, and -NR a R b wherein said C1-C6 alkyl is optionally substituted with one or more halo atoms; R 9 is C1-C6 alkyl, -OH, oxo, and -NR a R b wherein said C1-C6 alkyl is optionally substituted with one or more halo atoms; R 10 is selected from H and C1-C6 alkyl, said C1-C6 alkyl optionally substituted with one or more halo atoms; R a , R b , R c , R d and R e are each independently selected from H and C1-C6 alkyl, said C1-C6 alkyl optionally substituted with one or more halo atoms; or R a and R bcan form a 5- or 6-membered heterocyclic ring together with the nitrogen atom to which they are attached; or two R attached to the same atom e groups, together with the atoms to which they are attached, can form a 5- or 6-membered heterocyclic ring; m is 0, 1, 2, 3 or 4; n is 1 or 2; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4; R 1 is H or optionally substituted C1-C6 alkyl, then R 4 and R 5 At least one of the following is present and is not H: Provided are compounds or pharma- ceutically acceptable salts, solvates, hydrates, tautomers, enantiomers, N-oxides, and / or prodrugs thereof.

[0010] In a second aspect of the present invention, there is provided a compound of formula (IIA) or (IIB) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein R 11 is H, C1-C6 alkyl and -SO2R 7 wherein said C1-C6 alkyl is optionally selected from the group consisting of halo, oxo, -NR a R b , -C(O)NR a R b , -C(O)OR c , -OR c substituted with one or more substituents independently selected from R 12 H, -C(O)OR c , -C(O)N(R d )SO2R e , -C(O)N=S(O)R e 2. -N=S(O)Re 2, -N(R d )C(O)N=S(O)R e 2, -N(R d )C(O)NR e 2. -N(R d )SO2R e , -S(O)(=NR d )R e , [ka] selected from the group consisting of; R 13 But, halo, -OR f and C1-C6 alkyl; R f is selected from the group consisting of H and C1-C6 alkyl; and r is 0, 1, 2, 3, or 4; and R 7 , R 8 , R 9 , R 10 , R a , R b , R c , R d , R e , m, n, p and q are as defined in the first aspect of the invention, including all preferred embodiments thereof; Provided are compounds or pharma- ceutically acceptable salts, solvates, hydrates, tautomers, enantiomers, N-oxides, and / or prodrugs thereof.

[0011] The compounds of formula (IA), (IB), (IIA) and (IIB) are "the compounds of the invention", or "the compounds".

[0012] A third aspect of the invention provides a pharmaceutical composition comprising a compound of the invention.

[0013] The compounds of the present invention may inhibit PDE10A at levels suitable for the prevention or treatment of IBD, particularly ulcerative colitis and / or Crohn's disease, for the reasons described below.

[0014] Selective inhibition of PDE10A by small molecule inhibitors has surprisingly been found to advantageously reduce proinflammatory cytokine levels in colonic samples from IBD patients, and thus represents an unexpected promising treatment for inflammatory bowel diseases, particularly ulcerative colitis and Crohn's disease.

[0015] Cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that catalyze the degradation of the cyclic nucleotide second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The intracellular levels of cAMP and cGMP are regulated both by the rate of their own synthesis (by adenylate cyclase and guanylate cyclase, respectively) and by their hydrolysis by phosphodiesterases. By regulating the duration and strength of cAMP and cGMP second messenger signals, PDEs play an important regulatory role in signal transduction.

[0016] There are 11 subtypes of PDEs (PDE1-PDE11), each encoding a PDE with unique substrate specificity, kinetics, allosteric regulators, tissue expression profile, and pharmacological sensitivity. PDE10A can hydrolyze both cAMP and cGMP. PDE10A has a K m It hydrolyzes cAMP at a K of 3 μM m PDE10A hydrolyzes cGMP. m is low, but the V max The ratio was 4.7, indicating high specific activity towards cGMP. Taken together, these findings suggest that PDE10A is a cAMP-inhibited cGMP phosphodiesterase.

[0017] In normal tissues, PDE10A has a restricted expression pattern. High PDE10A RNA levels are detected only in the striatum (caudate and tegmental nuclei) of the brain and in the testes (Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K. Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem. 274, 18438-18445 (1999)). To date, inhibitors of PDE10A have been primarily studied for neuropathologies, including schizophrenia and Parkinson's disease (Geerts H, Spiros A, Roberts P. Phosphodiesterase 10 inhibitors in clinical development for CNS disorders. Expert Rev Neurother. 17(6), 553-560 (2017)). PDE10A has not been studied much in inflammation. A literature search revealed one paper (Garcia AM et al. Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects. Molecules., 1472, 22(9), 2017) that described inhibition of LPS-induced nitrite release from the Raw264.7 macrophage cell line by PDE10A inhibitors, i.e., in a transformed mouse cell line but not in human primary cells. The authors attributed the effect to the cAMP hydrolysis activity of PDE10A rather than the cGMP activity.

[0018] The present inventors have surprisingly discovered that PDE10A inhibitors are able to reduce the levels of pro-inflammatory cytokines that are characteristic of IBD in colon biopsies taken from IBD patients, thus representing a new therapeutic opportunity for the treatment of these diseases.

[0019] Inflammatory bowel disease can include ulcerative colitis and / or Crohn's disease.It is well understood that any treatment for ulcerative colitis is likely to be suitable for treating Crohn's disease, and vice versa.This is demonstrated by the compound of the present invention in the following examples.

[0020] The present invention provides a compound that may be a PDE10A inhibitor for use in the prevention and / or treatment of inflammatory bowel disease. Suitably, the inflammatory bowel disease is selected from ulcerative colitis and / or Crohn's disease. This is a fourth aspect of the present invention. [Brief description of the drawings]

[0021] [Figure 1] 1 includes plots showing RNA expression of PDE10A in normal tissues. The plots represent baseline gene expression of PDE10A and GUCY2C (guanylate cyclase 2C) in healthy samples based on GTEx data, with the x-axis representing tissue and the y-axis representing log2-transformed expression. [Diagram 2]FIG. 2 includes a volcano plot showing RNA differential expression analysis of PDE10A and GUCY2C. The volcano plot shows differential gene expression analysis for selected comparisons, where the x-axis represents log fold change (FC) and the y-axis represents log10-transformed adjusted p-value (FDR). The horizontal dotted line is the FDR=0.05 threshold, and values ​​above the dotted line are considered significant. Values ​​to the right of the central axis indicate increased expression, and values ​​to the left of the central axis indicate decreased expression. The OmicSoft differential expression datasets used for the analysis were as follows: colon mucosa - OmicSoft project names: GSE14580, GSE16879, GSE36807, GSE59071, GSE65114, GSE73661; colon - OmicSoft project names: GSE10191, GSE10616, GSE6731, GSE9686. [Diagram 3] FIG. 3 is a graph showing the effect of the PDE10A inhibitor PF-02545920 on isolated human neutrophil activation in response to IL-8. [Figure 4] Figure 4 includes graphs showing that PF-02545920 and TAK-063 inhibit the release of proinflammatory cytokines IL-6 and IL-8 in ex vivo cultures of colonic biopsy samples from UC patients (UC donor 1). (A) Effect of PDE10A inhibitors on IL-6 levels, (B) Effect of PDE10A inhibitors on IL-8 levels, (n=2; mean±SD), where Pred=prednisolone, Tofa=tofacitinib. [Diagram 5] 5 includes graphs showing that PF-02545920 and TAK-063 inhibit the release of proinflammatory cytokines IL-6 and IL-8 in ex vivo cultures of colonic biopsy samples from a UC patient (UC donor 2). (A) Effect of PDE10A inhibitors on IL-6 levels, (B) Effect of PDE10A inhibitors on IL-8 levels, (n=2; mean±SD), where Pred=prednisolone, Tofa=tofacitinib. [Figure 6-9]Figures 6 through 9 contain graphs showing the effect of the compounds of Example 4 (Figure 6A), Example 9 (Figure 6B), Example 10 (Figure 7A), Example 11 (Figure 7B), Example 17 (Figure 8A), Example 19 (Figure 8B), and Example 20 (Figure 9) on inflammatory cytokine release from ex vivo ulcerative colitis colon tissue (UC donor 3). [Figure 10] Figure 10 contains graphs showing that PF-02545920 (1 μM) inhibits the release of the proinflammatory cytokine TNFα in ex vivo cultures of inflamed colon tissue obtained from surgical resection of patients with treatment-resistant UC: (A) UC donor 4, (B) UC donor 5 (n=5; mean±SD; *p<0.05). [Figure 11] Figure 11 shows that PF-2545920 inhibits spontaneous release of the pro-inflammatory cytokines IL-6 and IL-8 in ex vivo cultures of inflamed CD colon tissue: Graph (A) CD donor 1, Graph (B) CD donor 2 (n=2; mean±SD). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Applicants have found that certain compounds can be used to prevent and / or treat diseases or conditions susceptible to PDE10A inhibition. In a first aspect of the invention, a compound of formula (IA) or (IB) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, X is N and CR 4 Selected from; Y is N and CR 5 Selected from; And CR 4 and CR 5 At least one of is present; Z is N and CR 6 Selected from; R 1 is H, C1-C6 alkyl and -SO2R 7wherein said C1-C6 alkyl is optionally selected from the group consisting of halo, oxo, -NR a R b , -C(O)NR a R b , -C(O)OR c , -OR c substituted with one or more substituents independently selected from R 2 and R 3 is independently selected from the group consisting of H, halo, and C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more halo atoms; R 4 and R 5 H, -C(O)OR c , -C(O)N(R d )SO2R e , -C(O)N=S(O)R e 2. -N=S(O)R e 2, -N(R d )C(O)N=S(O)R e 2. -N(R d )C(O)NR e 2, -N(R d )SO2R e , -S(O)(=NR d )R e , [ka] independently selected from the group consisting of: R 6 is selected from H and C1-C6 alkyl, said C1-C6 alkyl optionally substituted with one or more halo atoms; R 7 is selected from H and C1-C6 alkyl, said C1-C6 alkyl optionally substituted with one or more halo atoms; R 8 is C1-C6 alkyl, -OH, and -NR a R b wherein said C1-C6 alkyl is optionally substituted with one or more halo atoms; R 9 is C1-C6 alkyl, -OH, oxo, and -NR a R b wherein said C1-C6 alkyl is optionally substituted with one or more halo atoms; R 10 is selected from H and C1-C6 alkyl, said C1-C6 alkyl optionally substituted with one or more halo atoms; R a , R b , R c , R d and R e are each independently selected from H and C1-C6 alkyl, said C1-C6 alkyl optionally substituted with one or more halo atoms; or R a and R b can form a 5- or 6-membered heterocyclic ring together with the nitrogen atom to which they are attached; or two R attached to the same atom e groups, together with the atoms to which they are attached, can form a 5- or 6-membered heterocyclic ring; m is 0, 1, 2, 3 or 4; n is 1 or 2; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4; R 1 is H or optionally substituted C1-C6 alkyl, R 4 and R 5 At least one of the following is present and is not H: Provided are compounds or pharma- ceutically acceptable salts, solvates, hydrates, tautomers, enantiomers, N-oxides, and / or prodrugs thereof.

[0023] Compounds of formula (IA) and (IB) are R on the pyrazole 1The compounds of both formulas are capable of inhibiting PDE10A, but the compounds of formula (IA) are preferred because of the additional advantages they bring. Thus, a feature of the first aspect of the present invention is that the compound is of formula (IA).

[0024] In the broadest sense of the invention, X is N and CR 4 and Y is selected from N and CR 5 However, compounds in which both X and Y and N are not within the scope of this specification. 4 and CR 5 This means that at least one of the following is present: CR 4 and CR 5 may both be present in the compound. Thus, compounds of formula (IA) and (IB) may contain the following groups: [ka]

[0025] X is CR 4 And Y is CR 5 Particularly preferred are compounds in which

[0026] Certain substituents on compounds of formula (IA) and (IB) are preferred. In one aspect, R 4 and R 5 At least one of -C(O)OR is present; c , -C(O)N(R d )SO2R e , -C(O)N=S(O)R e 2. -N=S(O)R e 2. -N(R d )C(O)N=S(O)R e 2, -N(R d )C(O)NR e 2, -N(R d )SO2R e , -S(O)(=NR d )R e , [ka] is selected from the group consisting of:

[0027] For the following groups: [ka] It is preferably a 4- to 6-membered ring. Examples of such rings include: [ka] These include, but are not limited to:

[0028] With respect to the following groups: [ka] and [ka] Preferably, n is 2, so that each of these groups is: [ka] and [ka] It is.

[0029] With this in mind, a preferred feature of the first aspect of the invention is 4 and R 5 At least one of -C(O)OR c , -C(O)N(R d )SO2R e , -C(O)N=S(O)R e 2. -N=S(O)R e 2. -N(R d )C(O)N=S(O)R e 2, -N(R d )C(O)NR e 2, -N(Rd )SO2R e , -S(O)(=NR d )R e , [ka] is selected from the group consisting of:

[0030] More specifically for the group X, it is N and CR 4 Selected from R 4 H, -C(O)OR c , -C(O)N(R d )SO2R e ;-C(O)N=S(O)R e 2. [ka] It is preferably selected from:

[0031] X is N and CR 4 Selected from R 4 H, -C(O)OR c , -C(O)N(R d )SO2R e ;-C(O)N=S(O)R e 2. [ka] It is more preferred to select from:

[0032] X is N and CR 4 Selected from R 4 is H, -C(O)OH, -C(O)NHSO2Me, -C(O)NMeSO2Me, -C(O)N=S(O)Me2, [ka] It is most preferred that the aryl group is selected from the following:

[0033] More specifically for the group Y, it is N and CR 5 Selected from R 5is H, -C(O)OH, -C(O)N(Me)SO2Me, -C(O)N=S(O)Me2, -N=S(O)Me2, -NHC(O)N=S(O)Me2, -NHC(O)NHMe, -NHSO2Me, -S(O)(=NH)Me, [ka] It is preferably selected from:

[0034] R 4 Groups and R 5 Either or both of the groups are substituents R d If it contains, R d is preferably selected from H and Me. 4 Groups and R 5 Either or both of the groups may contain one or more substituents R e If it contains, each R e can be independently Me, cyclopropyl, or two R e Preferably, the groups, together with the atoms to which they are attached, can form a 5- or 6-membered heterocyclic ring. In these cases, R d is selected from H and Me, and each R e are independently Me, cyclopropyl, or two R e Preferably, the groups, together with the atoms to which they are attached, are capable of forming a 5- or 6-membered heterocyclic ring.

[0035] Two R's bonded to the same atom e When groups, together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring, they can form groups such as, but not limited to, the following: [ka]

[0036] R 2 and R 3is independently selected from the group consisting of H, halo, and C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more halo atoms. 2 and R 3 is preferably selected from H, F, and Me. More specifically, in particularly useful compounds, R 2 can be selected from H and F, R 3 may be selected from H, F and Me. In one feature of the first aspect of the invention, R 2 is H, R 3 is H or R 2 and R 3 Both are H.

[0037] R 1 With respect to R, it is preferred that it is selected from the group consisting of H, C1-C3 alkyl and -SO2Me, where C1-C3 alkyl is optionally substituted with one or more substituents independently selected from halo and -C(O)OH. More preferably, R 1 may be selected from the group consisting of H, Me, Et, -CH2CF3, -CH2C(O)OH, cyclopropyl, and -SO2Me. These compounds may be particularly advantageous.

[0038] Z is N and CR 6 Selected from R 6 is selected from H and C1-C6 alkyl, where C1-C6 alkyl is optionally substituted with one or more halo atoms. Thus, compounds of formula (IA) and (IB) include the following groups: [ka]

[0039] Z is N and CR 6 wherein R 6 is preferably selected from H, F, Cl and Me. Z is CR 6 In particular, Z is R 6 is selected from H, F, Cl and Me 6 It is more preferable that:

[0040] In view of the above, compounds of formulae (IA) and (IB) may therefore include the following groups: [ka]

[0041] In a particularly preferred feature of the first aspect of the invention, X is selected from the group consisting of N and CR 4 Selected from R 4 H, -C(O)OR c , -C(O)N(R d )SO2R e ;-C(O)N=S(O)R e 2. [ka] Selected from; Y is N and CR 5 Selected from R 5 is H, -C(O)OH, -C(O)N(Me)SO2Me, -C(O)N=S(O)Me2, -N=S(O)Me2, -NHC(O)N=S(O)Me2, -NHC(O)NHMe, -NHSO2Me, -S(O)(=NH)Me, [ka] Selected from; And CR 4 and CR 5 At least one of is present; Z is N and CR 6 Selected from R 6 is selected from H, F, Cl and Me; R 1 is selected from the group consisting of H, C1-C3 alkyl, and -SO2Me, wherein C1-C3 alkyl is optionally substituted with one or more substituents independently selected from halo and -C(O)OH; R 2 is selected from H and F; R 3 is selected from H, F and Me; R 8 is C1-C6 alkyl, -OH, and -NR a R b wherein C1-C6 alkyl is optionally substituted with one or more halo atoms; R 9 is C1-C6 alkyl, -OH, oxo, and -NR a R b wherein C1-C6 alkyl is optionally substituted with one or more halo atoms; R 10 is selected from H and C1-C6 alkyl, C1-C6 alkyl optionally substituted with one or more halo atoms; R a , R b , R c are each independently selected from H and C1-C6 alkyl, C1-C6 alkyl optionally substituted with one or more halo atoms; or R a and R b can form a 5- or 6-membered heterocyclic ring together with the nitrogen atom to which they are attached; Each R e is Me and R d is selected from H and Me, or two R e Groups, together with the atoms to which they are attached, can form a 5- or 6-membered heterocyclic ring; m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and R 1 is H or optionally substituted C1-C6 alkyl, R 4 and R 5 At least one of is present and is not H.

[0042] In a more preferred aspect of the first aspect of the invention, X is selected from the group consisting of N and CR 4 and R 4 is H, -C(O)OH, -C(O)NHSO2Me, -C(O)NMeSO2Me, -C(O)N=S(O)Me2, [ka] Selected from; Y is N and CR 5 and R 5 is H, -C(O)OH, -C(O)N(Me)SO2Me, -C(O)N=S(O)Me2, -N=S(O)Me2, -NHC(O)N=S(O)Me2, -NHC(O)NHMe, -NHSO2Me, -S(O)(=NH)Me, [ka] Selected from; And CR 4 and CR 5 At least one of is present; Z is N and CR 6 wherein R 6 is selected from H, F, Cl and Me; R 1 is selected from the group consisting of H, Me, Et, -CHCF, CHC(O)OH, cyclopropyl, and -SOMe; R 2 is selected from H and F; R 3 is selected from H, F and Me; and R 1 is H or optionally substituted C1-C6 alkyl, R 4 and R 5 At least one of is present and is not H.

[0043] Notwithstanding the above, preferred compounds according to the first aspect of the invention are 2-[[4-[2-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylic acid 2-[[4-[2-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid Ammonium 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylate 2-[4-(4-pyridyl)-3-[4-(2-quinolylmethoxy)phenyl]pyrazol-1-yl]acetic acid 2-[[4-[1-Methylsulfonyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline N-[Dimethyl(oxo)-λ6-sulfanylidene]-5-methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[4-(4-pyridyl)-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-methylsulfonyl-quinoline-3-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-(1-oxothiolan-1-ylidene)quinoline-3-carboxamide N-(cyclopropyl-methyl-oxo-lambda6-sulfanylidene)-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide N-Methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-methylsulfonyl-quinoline-3-carboxamide N-Methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-methylsulfonyl-quinoline-4-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazoline-4-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-3-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoxaline-2-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-1,5-naphthyridine-3-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-7-fluoro-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-6-fluoro-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-5-fluoro-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-6-methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-6-fluoro-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide 5-Chloro-N-[dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[1-ethyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide 2-[[4-[1-cyclopropyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-[dimethyl(oxo)-λ6-sulfanylidene]quinoline-4-carboxamide 2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid 2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylic acid N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide Dimethyl-oxo-[[2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]imino]-lambda 6-sulfane Imino-methyl-oxo-[2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]-lambda 6-sulfane N-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]methanesulfonamide 1-Methyl-3-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]urea 1-[Dimethyl(oxo)-λ6-sulfanylidene]-3-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]urea 4-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]-1,4-thiazinane-1,1-dioxide 4-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]piperazin-2-one 1-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]azetidin-3-amine 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-piperazin-1-yl-quinazoline 1-[3-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoxalin-2-yl]azetidin-3-amine 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-3-piperazin-1-yl-quinoxaline or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

[0044] In a second aspect of the present invention, there is provided a compound of formula (IIA) or (IIB) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein R 11 is H, C1-C6 alkyl and -SO2R 7 wherein C1-C6 alkyl is optionally selected from the group consisting of halo, oxo, -NR a R b , -C(O)NR a Rb , -C(O)OR c , -OR c and substituted with one or more substituents independently selected from (preferably R 11 is selected from the group consisting of H and C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more halo, preferably one or more halo being one or more F; R 12 H, -C(O)OR c , -C(O)N(R d )SO2R e , -C(O)N=S(O)R e 2. -N=S(O)R e 2, -N(R d )C(O)N=S(O)R e 2, -N(R d )C(O)NR e 2. -N(R d )SO2R e , -S(O)(=NR d )R e , [ka] selected from the group consisting of; R 13 But, halo, -OR f and C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more halo, preferably F; R f is selected from the group consisting of H and C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more halo, preferably F; r is 0, 1, 2, 3, or 4; and R 7 , R 8 , R 9 , R 10 , R a , R b , R c , R d , R e, m, n, p, and q are as defined in the first aspect of the invention, including all preferred embodiments thereof. Provided is a compound or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

[0045] Compounds of formula (IIA) and (IIB) are R 11 The compounds of both formulas are capable of inhibiting PDE10A, but the compounds of formula (IIA) are preferred because of the additional benefits they provide. Thus, a feature of the second aspect of the present invention is that the compound is of formula (IIA).

[0046] R 11 is preferably C1-C6 alkyl, more preferably C1-C3 alkyl, even more preferably Me.

[0047] R 12 is -C(O)OR c , -C(O)N(R d )SO2R e , -C(O)N=S(O)R e 2. -N=S(O)R e 2, -N(R d )C(O)N=S(O)R e 2. -N(R d )C(O)NR e 2, -N(R d )SO2R e , -S(O)(=NR d )R e , [ka] It is preferred that the compound is selected from the group consisting of:

[0048] Although not wishing to be bound by theory, R 12This is believed to be due to the presence of a substituent other than hydrogen in the R 12 position may lead to).

[0049] R 12 is -C(O)OR c , -C(O)N(R d )SO2R e , -C(O)N=S(O)R e 2. -N=S(O)R e 2, -N(R d )C(O)N=S(O)R e 2. -N(R d )C(O)NR e 2, -N(R d )SO2R e , -S(O)(=NR d )R e , and more preferably -C(O)N=S(O)R e More preferably, R is 2. 12 Regarding R e is preferably Me, cyclopropyl, or two R e The groups, together with the atoms to which they are attached, can form a 5- or 6-membered heterocyclic ring, and most preferably each R e is Me. Therefore, R 12 The most preferred groups are -C(O)N=S(O)Me2 It is.

[0050] As stated above, r can be 0, 1, 2, 3, or 4, however, it is preferred that r is 0.

[0051] In a feature of the second aspect of the present invention, R 11 is Me; R 12 is -C(O)OR c , -C(O)N(R d )SO2Re , -C(O)N=S(O)R e 2. -N=S(O)R e 2, -N(R d )C(O)N=S(O)R e 2, -N(R d )C(O)NR e 2. -N(R d )SO2R e , -S(O)(=NR d )R e and more preferably -C(O)N=S(O)R e 2; Each R e is Me; and r is 0.

[0052] Notwithstanding the above, N-[dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]imidazo[1,2-a]pyridine-3-carboxamide, or a pharma-ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, is a preferred example of the second aspect of the invention.

[0053] Where only certain variables are defined in the features of the first and second aspects of the invention described herein, it is intended that the remaining variables are as defined in other features herein. Thus, the invention provides any combination of closed or optional definitions of the variables.

[0054] As used herein, "optionally substituted" means that the group being referred to can be unsubstituted or substituted at one or more positions, i.e., 1, 2, 3, 4, 5, 6 or more positions, with any one or any combination of substituents such as those listed thereafter.

[0055] As used herein, the term "halo" refers to fluoro, chloro, bromo, and iodo. Preferably, halo is fluoro or chloro, which may be designated as F and Cl, respectively. Most preferably, halo is F.

[0056] As used herein, the term "(C1-C6) alkyl" refers to a fully saturated branched, unbranched or cyclic hydrocarbon moiety having 1, 2, 3, 4, 5 or 6 carbon atoms. In any instance herein, (C1-C6) alkyl is preferably (C1-C3) alkyl. It is a fully saturated branched, unbranched or cyclic hydrocarbon moiety having 1, 2 or 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl.

[0057] The term "oxo" means =O. It will be understood that the oxo group is divalent and thus, when used as a substituent, replaces two hydrogen atoms on one carbon atom.

[0058] Throughout this specification and in the claims which follow, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising" should 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.

[0059] The compound of the present invention can exist as its pharmaceutically acceptable salt.The term "pharmaceutically acceptable salt" is intended to mean a free acid or base salt of the compound represented by one of the above formulas, which is non-toxic, biologically acceptable, or biologically suitable for administration to a subject in general.Such pharmaceutically acceptable salts are known to those skilled in the art.

[0060] Examples of suitable pharma- ceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject without undue toxicity, irritation, or allergic response. The compounds of the present invention possess sufficiently acidic groups, sufficiently basic groups, or both, and accordingly can react with a number of inorganic or organic bases, and inorganic and organic acids, to form pharma- ceutically acceptable salts.

[0061] Pharmaceutically acceptable acid addition salts include those of inorganic and organic acids, such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorphonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, etc. The salts may be formed as salts of the following acids: maleate, malonate, mandelate, mesylate, methyl sulfate, naphthate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, trifluoroacetate, and trifluoromethylsulfonate.

[0062] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0063] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoromethylsulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0064] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table, in particular embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly preferred salts being derived from ammonium, potassium, sodium, calcium, and magnesium salts.

[0065] Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Particular organic amines include isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0066] Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, subberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-diate, hexyne-2,3-di ... Particular mention may be made of oates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0067] Furthermore, any formula shown herein is intended to mean hydrates and solvates of the compounds of the present invention and mixtures thereof, even if the form is not explicitly described. The compounds of the present invention or pharma- ceutically acceptable salts of the compounds of the present invention may be obtained as solvates. Solvates include those formed from the interaction or complexation of the compounds of the present invention with one or more solvents, either in solution or as solid or crystalline form. The solvent may be water, in which case the solvate is a hydrate. Furthermore, certain crystalline forms of the compounds of the present invention or pharma- ceutically acceptable salts of the compounds of the present invention may be obtained as co-crystals. The compounds of the present invention or pharma- ceutically acceptable salts of the compounds of the present invention may be obtained in crystalline form.

[0068] The compounds of the invention may be obtained in one of several polymorphic forms, as a mixture of crystalline forms, as polymorphic forms, or as amorphous forms. The compounds of the invention may convert between one or more crystalline and / or polymorphic forms in solution.

[0069] Compounds of the present invention that contain groups capable of acting as hydrogen bond donors and / or acceptors may have the ability to form co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of the present invention by known co-crystal formation procedures. Such procedures include contacting a solution compound of the present invention with a co-crystal former under grinding, heating, co-sublimation, eutectic, or crystallization conditions, and isolating the co-crystal formed thereby. Thus, the present invention further provides co-crystals that include compounds of the present invention.

[0070] Any formula shown herein is intended to represent a compound having the structure depicted by the structural formula, as well as certain variations or forms. In particular, any compound of any formula shown herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of a compound of a general formula, as well as mixtures thereof, are considered within the scope of the formula. Thus, any formula shown herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, a particular structure may exist as a geometric isomer (i.e., cis and trans isomers), as a tautomer, or as an atropisomer.

[0071] Included within the scope of the claimed compounds of the invention are all stereoisomeric, geometric isomeric and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof, as well as acid or base addition salts in which the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., DL-tartrate or DL-arginine.

[0072] Where the compounds of the invention contain, for example, a keto or guanidine group or an aromatic moiety, tautomeric isomerism ("tautomerism") can occur. As a result, a compound can exhibit more than one type of isomer. Examples of potential types of tautomerism exhibited by compounds of the invention include: amide <=> hydroxylimine and keto <=> enol tautomerism. [ka]

[0073] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0074] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable, optically pure precursors, or separation of the racemate (or the racemate of a salt or other derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0075] The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on a resin comprising an asymmetric stationary phase and a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50%, typically 2-20% ethanol. Concentration of the eluate gives the enriched mixture.

[0076] Mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art.

[0077] As used herein, the term "isomer" refers to compounds that have the same molecular formula but differ in the arrangement and configuration of atoms. Also as used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the invention, including geometric isomers. It is understood that a substituent may be attached to a chiral center of a carbon atom. Thus, the invention includes enantiomers, diastereomers, or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to refer to racemic mixtures where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is determined according to the Cahn-Ingold-Prelog ranking rules. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be designated as either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers or axes and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-. The present invention is intended to encompass all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound contains a double bond, the substituent can be in the E or Z configuration. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent can have a cis or trans configuration.

[0078] Also intended to include all tautomeric forms. A tautomer is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. Examples of tautomers include, but are not limited to, the compounds defined in the claims. Any asymmetric atom (e.g., carbon or the like) of the compounds of the invention can be present in racemic or enantiomerically enriched, e.g., (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms containing unsaturated bonds may be present in either cis- (Z)- or trans- (E)-form, where such is possible.

[0079] Thus, as used herein, the compounds of the invention may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, such as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0080] Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, on the basis of the physicochemical differences of the components, for example, by chromatography and / or fractional crystallization.

[0081] Any racemic final products or intermediates obtained can be resolved into their optical antipodes by known methods, for example by separation of the resulting diastereomeric salts with optically active acids or bases and liberating the optically active acidic or basic compounds. In particular, basic moieties can thus be used to resolve the compounds of the invention into their optical antipodes by fractional crystallization of salts formed with optically active acids, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, such as high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0082] Because the compounds of the invention are intended for use in pharmaceutical compositions, it will be readily understood that each of those compounds is preferably provided in substantially pure form, e.g., at least 60% pure, more preferably at least 75% pure, preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used to prepare more pure forms for use in pharmaceutical compositions; impure preparations of the compounds should contain at least 1%, more preferably at least 5%, preferably 10-59% of a compound of the invention.

[0083] When both basic and acidic groups are present in the same molecule, the compounds of the invention may also form internal salts, e.g., zwitterionic molecules.

[0084] The present invention also relates to pharma- ceutically acceptable prodrugs of the compounds of the present invention and methods of treatment using such pharma- ceutically acceptable prodrugs.

[0085] The term "prodrug" refers to a precursor of the specified compound that yields the compound in vivo via a chemical or physiological process, such as solvolysis or enzymatic cleavage, or under physiological conditions after administration to a subject (e.g., a prodrug subjected to physiological pH is converted to a compound of formula (IA), (IB), (IIA) or (IIB)).

[0086] A "pharmacologically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and typically biologically suitable for administration to a subject.

[0087] A prodrug is an active or inactive compound that is converted to a compound of the present invention after administration of the prodrug to a subject through physiological actions in vivo, such as hydrolysis, metabolism, and the like. The compounds of the present invention may be active themselves and / or act as prodrugs that are converted to active compounds in vivo. The suitability and techniques involved in making and using prodrugs are well known to those skilled in the art. Prodrugs can be conceptually divided into two non-exclusive categories: bioprecursor prodrugs and carrier prodrugs. In general, bioprecursor prodrugs are compounds that are inactive or less active compared to the corresponding active drug compound, contain one or more protecting groups, and are converted to an active form by metabolism or solvent dissolution. Both the active drug form and any released metabolites should have acceptably low toxicity. Carrier prodrugs are drug compounds that contain a transport moiety that, for example, enhances uptake and / or localized delivery to the site(s) of action.

[0088] Desirably for such carrier prodrugs, the bond between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any release transport moiety is deemed non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize moieties that provide sustained release, such as certain polymers or other moieties such as cyclodextrins. Carrier prodrugs can be used, for example, to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effect, increased site specificity, reduced toxicity and adverse reactions, and / or improved drug formulation (e.g., stability, water solubility, suppression of undesirable organoleptic or physiochemical properties). For example, lipophilicity can be increased by (a) esterification of the hydroxyl group with a lipophilic carboxylic acid (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) esterification of the carboxylic acid group with a lipophilic alcohol (e.g., an alcohol having at least one lipophilic moiety, such as an aliphatic alcohol).

[0089] Exemplary prodrugs are, for example, esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, where acyl has the meaning defined herein.Suitable prodrugs are often pharma-ceutically acceptable ester derivatives that can be converted to the parent carboxylic acid by solvent decomposition under physiological conditions, such as lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, ω(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, α-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as pivaloyloxymethyl esters and the like, which are conventionally used in the art.In addition, amines are masked as arylcarbonyloxymethyl-substituted derivatives, which are cleaved by esterases in vivo to release free drug and formaldehyde. Additionally, drugs containing an acidic NH group, such as imidazole, imide, indole, and the like, have been masked with N-acyloxymethyl groups. Hydroxy groups have been masked as esters and ethers.

[0090] The compounds of the present invention may also be N-oxides. It will be understood that an N-oxide, or "amine oxide", is a compound that contains an NO coordinate covalent bond. Examples of N-oxide groups include the following functional groups: [ka]

[0091] Any formula provided herein is intended to represent both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas provided herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, respectively. 2 H, 3 H,11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 0, 18 0, 18 Such isotope-labeled compounds are useful for metabolic studies (preferably 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques including drug or substrate tissue distribution assays, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or radiation treatment of a subject. 11 C and 18 F, 15 O. 13 Substitution with positron emitting isotopes, such as N, can be useful in PET studies for examining substrate receptor occupancy. In particular, 18 F or 11 C-labeled compounds may be particularly preferred for PET studies. In addition, deuterium (i.e. 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages due to increased metabolic stability, for example increased half-life in vivo or reduced dosage requirements. Certain isotopically labeled compounds incorporating radioisotopes of the present invention are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C is particularly useful for this purpose given its ease of incorporation and ready availability of detection means.

[0092] Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by following the procedures disclosed in the Schemes or Examples and Preparations below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0093] In addition, the heavier isotopes, especially deuterium (i.e. 2Substitution with H or D) may provide certain therapeutic advantages due to increased metabolic stability, for example increased half-life in vivo or reduced dosage requirements, or improved therapeutic index. It is understood that deuterium in this context is considered a substituent of the compounds of the present invention. The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated as deuterium, the isotopic enrichment factor of such compounds is at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom.

[0094] Pharmaceutically acceptable solvates in accordance with the present invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0095] In the event of a discrepancy between a chemical structure and an associated chemical name, the chemical structure will control unless the opposite is readily understood to be true.

[0096] The compound of the present invention may be used for the prevention and / or treatment of diseases or conditions that are susceptible to PDE10A inhibition, so in the third aspect of the present invention, a pharmaceutical composition comprising the compound of the present invention is provided.As is well known, a pharmaceutical composition may comprise one or more excipients in addition to other optional components.Preferably, the excipient is a pharmaceutically acceptable excipient.

[0097] The compounds of the present invention can be used alone or in combination with one or more additional active ingredients to formulate pharmaceutical compositions. The pharmaceutical compositions of the present invention can include (a) an effective amount of at least one compound of the present invention; and (b) a pharma- ceutical acceptable excipient.

[0098] By "pharmaceutical acceptable excipient" is meant a substance that is non-toxic, biologically acceptable, and usually biologically suitable for administration to a subject, e.g., a substance that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug, and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0099] As used herein, the term "pharmaceutically acceptable carrier" includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and the like, and combinations thereof, that would be known to one of ordinary skill in the art. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0100] The pharmaceutical compositions according to the present invention can be formulated in a conventional manner using readily available ingredients. Thus, the active ingredient can be incorporated, optionally with other active substances, one or more conventional carriers, diluents and / or excipients, to produce conventional galenic preparations such as tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid media), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.

[0101] The pharmaceutical composition of the present invention can be formulated according to a specific route of administration, such as oral administration, parenteral administration, and rectal administration.Furthermore, the pharmaceutical composition of the present invention can be configured in a solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in a liquid form (including but not limited to solutions, suspensions, or emulsions).The pharmaceutical composition can be subjected to conventional pharmaceutical operations such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0102] When the pharmaceutical composition is a tablet or gelatin capsule, it may contain the following active ingredients (compounds of the present invention) together: a) diluents, such as lactose, polylactones, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in tablets also c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; optionally d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) Absorbents, colouring agents, flavouring agents and sweeteners.

[0103] Tablets may be film coated or enteric coated according to methods known in the art.

[0104] Compositions suitable for oral administration contain an effective amount of the compounds of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, in order to provide pharma-ceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with pharma-ceutically acceptable non-toxic excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binding agents such as starch, gelatin or acacia; lubricants such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the digestive tract, thereby providing a sustained action over a longer period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0105] Certain injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain auxiliary substances such as preservatives, stabilizing agents, wetting agents or emulsifying agents, solution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or about 1-50%, of the active ingredient.

[0106] The compounds of the present invention can be administered topically. Compositions suitable for topical application to the skin or mucous membranes (e.g., skin and eye), dermally or transdermally, include aqueous solutions, suspensions, ointments, creams, gels, hydrogels, microemulsions, dusting powders, dressings, foams, films, skin patches, wafers, implants, fibers, bandages or spray formulations for delivery, e.g., by aerosol or the like. Such topical delivery systems will be particularly suitable for dermal applications, e.g., for the treatment of atopic dermatitis. Thus, they are particularly suitable for use in topical formulations, including cosmetics, as are well known in the art. Such may include solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated.

[0107] Compositions suitable for transdermal application include an effective amount of the compound of the present invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to aid in passage through the host's skin. For example, a transdermal device is in the form of a dressing and consists of a backing member, a reservoir containing the compound, optionally with a carrier, a rate-controlling barrier that delivers the compound of the skin of the host at a controlled, predetermined rate, optionally over an extended period of time, and a means for fixing the device to the skin.

[0108] As used herein, topical application may also refer to inhalation or intranasal administration. They can be conveniently delivered in the form of a dry powder (alone, in a mixture, for example, as a dry mixture with lactose, or as a mixed component particle with phospholipids) with or without the use of a suitable propellant from a dry powder inhaler, or in an aerosol spray presentation from a pressurized container, pump, spray, atomizer, or nebulizer.

[0109] Doses of the agents of the invention used in carrying out the invention will of course vary depending, for example, on the particular pathology being treated, the effect desired and the method of administration. In general, suitable daily doses for administration by inhalation are on the order of 0.0001 to 30 mg / kg, typically 0.01 to 10 mg per patient, while suitable daily doses for oral administration are on the order of 0.01 to 100 mg / kg.

[0110] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.

[0111] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. The anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Thus, the anhydrous composition is packaged using materials known to prevent exposure to water, such that it can be included in a suitable formulary kit. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (such as pill bottles), blister packs, and strip packs.

[0112] The present invention further provides pharmaceutical compositions and formulations that include one or more agents that reduce the rate at which the compounds of the present invention as an active ingredient will decompose. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0113] The compounds of the invention can be administered simultaneously with, before or after, one or more other therapeutic agents. The compounds of the invention can be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.

[0114] The present invention includes a product comprising the compound and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in treatment.The treatment can be the treatment of a disease state or disorder mediated by PDE10A.The product provided as a combined preparation includes a composition comprising the compound of the present invention and other therapeutic agent(s) together in the same pharmaceutical composition, or a composition comprising the agent of the present invention and other therapeutic agent in separate forms, for example, in the form of a kit.

[0115] Treatments and Methods The compounds of the present invention can prevent and / or treat inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. Without wishing to be bound by theory, it is believed that treatment is achieved by the ability of the compounds of the present invention to inhibit PDE10A.

[0116] As used herein, the terms "treat", "treating" or "treatment" of any disease or disorder refer, in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or suppressing the progression of the disease or at least one of its clinical symptoms). The terms "treat", "treating" or "treatment" also refer to alleviating or improving at least one physical parameter, including those that are not discernible by the patient. Treatment can be a physiological treatment (e.g., stabilization of a discernible symptom), a physical treatment (e.g., stabilization of a physical parameter), or both. Additionally, the terms "treat", "treating" or "treatment" also refer to preventing or slowing the onset or progression of a disease or disorder.

[0117] "Prevention" of a condition or disorder means delaying or preventing the onset of, or reducing the severity of, said condition or disorder as assessed by the appearance or extent of one or more symptoms of the condition or disorder.

[0118] A fourth aspect of the invention relates to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

[0119] The compounds of the invention, or pharmaceutical compositions comprising compounds of the invention, are intended for use as pharmaceuticals.

[0120] Thus, a feature of the fourth aspect of the invention is the use of a compound of the invention for the manufacture of a medicament, which may be for the prevention and / or treatment (preferably the treatment) of inflammatory bowel disease, such as ulcerative colitis and / or Crohn's disease.

[0121] The compounds of the invention, or pharmaceutical compositions comprising the compounds of the invention, may be for use in the prevention and / or treatment (preferably the treatment) of inflammatory bowel disease, such as ulcerative colitis and / or Crohn's disease.

[0122] Also described herein is a method for the prevention and / or treatment of a disease or condition that is amenable to PDE10A inhibition, comprising administering to a subject a compound of the invention, or a pharmaceutical composition comprising a compound of the invention. The disease or condition that is amenable to PDE10A inhibition may be inflammatory bowel disease, such as ulcerative colitis and / or Crohn's disease.

[0123] Another method is for preventing and / or treating inflammatory bowel disease comprising administering to a subject a compound of the invention, or a pharmaceutical composition comprising a compound of the invention.

[0124] The aforementioned method is preferably a method wherein the inflammatory bowel disease is ulcerative colitis and / or Crohn's disease.

[0125] As used herein, the term "subject" refers to an animal. Typically, an animal is a mammal. Subject also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. Preferably, the subject is a primate, and most preferably, a human.

[0126] The compounds of the present invention and related pharmaceutical compositions can be used for prophylaxis and / or treatment, but in any case, they are preferably for treatment.Accordingly, the method can be related to a subject in need of treatment.As used herein, a subject is "in need" of a treatment if such a subject would benefit biologically, medically or in quality of life from such treatment.

[0127] The compounds of the present invention and related pharmaceutical compositions should be given to a subject in a therapeutically effective amount. The term "therapeutically effective amount" of a compound of the present invention means an amount of a compound of the present invention that induces a biological or medical response, such as a reduction or inhibition of enzyme or protein activity, alleviates a pathological condition, slows or delays the progression of a disease, or prevents a disease. In one non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the present invention that is effective to at least partially alleviate, inhibit, prevent, and / or improve a PDE10A-mediated pathological condition or disorder when administered to a subject. In another non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the present invention that is effective to at least partially inhibit PDE10A activity when administered to a cell, or tissue, or non-cellular biomaterial, or culture medium.

[0128] Preparation of the Compounds of the Invention The compounds of the above formula can be prepared by conventional methods or in analogy thereto.The preparation of intermediates and compounds according to the examples of the present invention can be illustrated in particular by the following schemes.The definitions of variables in the structures in the schemes herein are the same as the definitions of variables at the corresponding positions in the formulas shown herein.

[0129] [ka]

[0130] In Scheme 1, V and W are N and NR as appropriate for formula (IA) and formula (IB). 1 The group "-OR" can be O-alkyl, such as -OMe, -OEt, and the group "-NR2" can be: [ka]

[0131] With reference to Scheme 1, compounds of general formulae (IA) and (IB) can be prepared by standard means. For example, 4-benzyloxyphenyl carboxylic acid (1-1) can be converted to the Weinreb amide using amide coupling conditions, followed by acylation with 4-methylpyridine anion to give intermediate (1-2). Intermediate (1-2) can be converted to compounds of general formula (Ic) by reaction with DMFDMA, followed by reaction with a suitable hydrazine analog. If the pyrazole nitrogen is unsubstituted, it can be alkylated or protected using standard protecting groups such as Boc and SEM. Removal of the benzyl group under hydrogenation conditions gives compounds of general formula (Id). Compounds of general formula (Id) can be reacted with compounds of general formula (Ii) (shown in Scheme 2), or intermediates 3-2, 3-5, and 3-8 (shown in Scheme 3) under alkylation or Mitsunobu coupling conditions to give compounds of general formula (Ie-Ih). Compounds of general formula (Ie) can be converted to compounds of general formula (IA) and (IB) using standard SNAr reaction conditions with a suitable nucleophile followed by oxidation and imine formation if necessary, or Buchwald coupling conditions, deprotection and urea formation if necessary. Compounds of general formula (If) can be converted to compounds of general formula (IA) and (IB) by deprotection if necessary. Compounds of general formula (Ig) can be converted to compounds of general formula (IA) and (IB) by reaction with BOP, a suitable base and a suitable amine. Compounds of general formula (Ih) can be converted to compounds of general formula (IA) and (IB) by introduction of a methyl group by Suzuki coupling if necessary, saponification, amide coupling and alkylation if necessary.

[0132] [ka]

[0133] In Scheme 2, the group "-OR" can be an O-alkyl, such as -OMe, -OEt, and the group "-NR2" can be [ka] It can be.

[0134] Referring to Scheme 2, compounds of general formula (Ii) can be prepared by standard techniques. For example, intermediate (2-2) can be prepared by reductive condensation from a suitable nitroaldehyde and acetoacetate. Intermediate (2-4) can be prepared by condensation from a suitable aminoaldehyde and acetoacetate. Intermediate (2-6) can be prepared by esterification of a carboxylic acid. Intermediate (2-8) can be prepared by SNAr of an aryl chloride with a suitable amine. Intermediate (2-10) can be prepared by ring expansion of a dicarbonyl compound followed by esterification. Intermediate (2-12) can be prepared by condensation of a chloroaniline with acetoacetate followed by bromination, carbonylation and esterification. Bromination of intermediates (2-2), (2-4), (2-6), (2-8), (2-10), (2-12) and (2-13) with NBS can provide compounds of general formula (Ii).

[0135] [ka]

[0136] In Scheme 3, the group "-NR2" can be: [ka]

[0137] According to Scheme 3, intermediates (3-2), (3-5) and (3-8) can be prepared by standard means. For example, 2-(chloromethyl)-3H-quinazolin-4-one (3-1) can be treated with POCl3 to generate an aryl chloride, which can be subjected to standard SNAr conditions with an appropriate amine to give intermediate (3-2). 2-Chloro-3-methylquinoxaline (3-3) can undergo SNAr with an appropriate amine, followed by oxidation and reduction to give alcohol intermediate (3-5). Condensation of 3-aminopicolinaldehyde (3-6) and ethyl 4-chloro-3-oxobutanoate (3-7) can give intermediate (3-8).

[0138] [ka]

[0139] Referring to Scheme 4, compounds of general formula (IIA) and (IIB) can be prepared by standard means. For example, intermediate (4-1) can be brominated using NBS, followed by alkylation with compounds of general formula (Id) to give intermediate (4-3). Saponification followed by amide coupling with an appropriate amine using standard amide coupling conditions such as HATU gives compounds of general formula (IIA) and (IIB). EXAMPLES

[0140] Exemplary compounds of the present invention and exemplary compounds useful in the methods of the present invention are described below with reference to exemplary synthetic schemes for their general preparation followed by specific examples. Those skilled in the art will recognize that starting materials can be suitably selected to obtain various compounds herein such that the final desired substituents are brought through the reaction scheme with or without protection as necessary to obtain the desired product. Alternatively, it may be necessary or desirable to use a suitable group in place of the final desired substituent that is brought through the reaction scheme and can be exchanged with the desired substituent as appropriate. The reaction can be carried out between the melting point and the reflux temperature of the solvent, or at a higher temperature by using a sealed reaction vessel, preferably between 0° C. and the reflux temperature of the solvent. The reaction can be heated using conventional heating or microwave heating. The reaction can also be carried out in a sealed pressure vessel above the normal reflux temperature of the solvent.

[0141] The compounds of the present invention, in particular all derivatives of the above formulae, can be prepared by the procedures described in the general methods presented below or routine modifications thereof. The present invention also encompasses one or more of those methods for preparing derivatives of the formulae, as well as any novel intermediates used therein.

[0142] The routes below, including those mentioned in the Examples and intermediates, illustrate methods of synthesizing the compounds of the invention. Those skilled in the art will appreciate that the compounds of the invention and intermediates thereto may be prepared by methods other than those specifically described herein, for example by modification of methods described herein, for example methods known in the art.

[0143] Furthermore, those skilled in the art will appreciate that at any stage in the synthesis of the compounds of the invention, it may be necessary or desirable to protect one or more sensitive groups to prevent undesired side reactions. In particular, it may be necessary or desirable to protect phenolic or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the invention may be used in a conventional manner.

[0144] In the general synthetic methods which follow, the substituents are as defined above with reference to the compounds of each formula above unless otherwise specified.

[0145] Where ratios of solvents are given, the ratios are by volume.

[0146] Those skilled in the art will appreciate that the experimental conditions depicted in the following schemes are illustrative of suitable conditions for carrying out the indicated transformations, and that it may be necessary or desirable to vary the exact conditions used for the preparation of the compounds of the invention. Furthermore, it will be appreciated that it may be necessary or desirable to carry out the transformations in a different order than depicted in the schemes, or to modify one or more transformations, in order to provide the desired compounds of the invention.

[0147] The compounds prepared according to the above schemes can be obtained as single enantiomers, diastereomers, or positional isomers by enantioselective, diastereoselective, or positional synthesis, or by resolution. The compounds prepared according to the above schemes can alternatively be obtained as racemic (1:1) or non-racemic (not 1:1) mixtures, or as mixtures of diastereomers or positional isomers. When mixtures of racemic and non-racemic enantiomers are obtained, single enantiomers can be isolated using conventional separation methods known to those skilled in the art, such as chiral column chromatography, recrystallization, diastereomeric salt formation, derivatization to diastereomeric adducts, biotransformation, or enzymatic conversion. When mixtures of positional or diastereomeric isomers are obtained, single isomers can be separated using conventional methods, such as chromatography or crystallization.

[0148] The compounds of the present invention can be prepared by any method known in the art for preparing compounds of similar structure. In particular, the compounds of the present invention can be prepared by the procedures described with reference to the following schemes, or by the specific methods described in the Examples, or by methods analogous to any of them.

[0149] Those skilled in the art will appreciate that the experimental conditions depicted in the following schemes are illustrative of suitable conditions for carrying out the indicated transformations, and that it may be necessary or desirable to vary the exact conditions used for the preparation of the compounds of the invention. Furthermore, it will be appreciated that it may be necessary or desirable to carry out the transformations in a different order than depicted in the schemes, or to modify one or more transformations, in order to provide the desired compounds of the invention.

[0150] The following abbreviations are used: aq aqueous solution Boc tert-Butyloxycarbonyl Bn Benzyl BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate DCM Dichloromethane DIPEA Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMFDMA N,N-Dimethylformamide Dimethyl Acetal dppf 1,1'-bis(diphenylphosphino)ferrocene ES+ Electrospray Ionization h hour(s) HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5b]pyridinium-3-oxide hexafluorophosphate HPBC Hydroxypropyl-β-cyclodextrin HPLC High Performance Liquid Chromatography LCMS Liquid Chromatography Mass Spectrometry min Minute(s) NBS N-Bromosuccinimide NMP N-Methyl-2-pyrrolidone Rt retention time sat saturation TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography UPLC Ultra High Performance Liquid Chromatography

[0151] Experimental Method Reactions were carried out at room temperature unless otherwise stated. Microwave reactions were carried out in a Biotage microwave reactor using process vials fitted with aluminum caps and septas. Preparative chromatography was carried out using a CombiFlash® system equipped with an Isolute Flash II silica column. Reverse phase column chromatography was carried out using a CombiFlash® system equipped with a RediSep Rf C18 column. Reverse phase HPLC was carried out on either a Gilson system equipped with an ACE-5AQ, 100×21.2 mm, 5 μm column equipped with a UV detector or an ACCQPrep system equipped with a UV and mass detector. The purest fractions were collected, concentrated and dried under vacuum. Typically, compounds were dried in a vacuum oven at 50-60° C. before purity analysis. Compounds were analyzed by UPLC using an Agilent 1290 Infinity system (methods listed below). LCMS analysis was performed using a Waters UPLC Acquity H-Class system equipped with PDA and QDa detector, or an Agilent 6140 series quadrupole mass spectrometer equipped with a multimode source using a Phenomenex Kinetex XB-C18 column, or a Shimadzu LCMS-2020 system equipped with a PDA: SPD-M40 and MS: LCMS-2020 detector using a Kinetex EVO C18 column. HRMS analysis was performed using a Waters UPLC Acquity H-Class / XevoG2 QToF system and an Acquity PDA detector using a Waters HSS T3 column. The compounds prepared were named using IUPAC nomenclature. All yields indicate the purity of the product, except those marked with an asterisk.

[0152] UPLC method Method A (10 minutes, 5~100) Phenomenex Kinetex XB-C18, 1.7 μm, 2.1 × 100 mm, 40 °C, 0.5 mL / min, 5% MeCN (+0.085% TFA) in water (+0.1% TFA), 1.0 min, 5–100% over 8.0 min, 0.2 min hold, 0.8 min re-equilibration. 200~300nm. Method B (5 minutes, 5~100) Phenomenex Kinetex XB-C18, 1.7 μm, 2.1 × 50 mm, 40 °C, 0.8 mL / min, 5% MeCN (+0.1% TFA) in water (+0.1% TFA) for 1.0 min, 5–100% over 3.0 min, hold for 0.2 min, re-equilibration for 0.8 min. 200–300 nm. Method C (5 minutes, 5~100) Phenomenex Kinetex XB-C18, 1.7 μm, 2.1 × 50 mm, 40 °C, 0.8 mL / min, 5% MeCN (+0.1% formic acid) in water (+0.1% formic acid), 0.7 min, 5–100% over 3.0 min, hold 0.3 min, re-equilibrate 1.0 min. 254 nm.

[0153] Intermediate 1 [ka] 4-Benzyloxy-N-methoxy-N-methyl-benzamide Oxalyl chloride (3.76 mL, 43.8 mmol) was added dropwise to a suspension of 4-benzyloxybenzoic acid (5.00 g, 21.9 mmol) in DCM (75 mL) and DMF (400 μL) at 0° C. The reaction was allowed to warm to room temperature, stirred for 2 h, then concentrated in vacuo. The residue was dissolved in DCM (100 mL) and N,O-dimethylhydroxylamine hydrochloride (2.14 g, 21.9 mmol) was added. The reaction was cooled to 0° C., TEA (7.63 mL, 54.8 mmol) was added dropwise, allowed to warm to room temperature, and stirred for 18 h. The reaction mixture was partitioned between DCM (250 mL) and saturated aqueous NaHCO3 (250 mL). The aqueous layer was extracted with DCM (250 mL) and the organic layers were combined, washed with brine (250 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (4.53 g, 76.3%) as a white solid. UPLC (Method A) Rt 5.53 min, 100%. LCMS (ES+): 272.1 [MH] +

[0154] Intermediate 2 [ka] 1-(4-benzyloxyphenyl)-2-(4-pyridyl)ethanone Under N2, n-BuLi (2.5M in hexanes, 13.4 mL, 33.4 mmol) was added dropwise to a solution of diisopropylamine (4.71 mL, 33.4 mmol) in THF (40 mL) at -78 °C. The reaction was stirred for 30 min, warmed to 0 °C and stirred for 30 min. 4-Methylpyridine (3.28 mL, 33.4 mmol) was added dropwise and the reaction was stirred for 30 min. In a separate flask under nitrogen, intermediate 1 (4.53 g, 16.7 mmol) was dissolved in THF (100 mL) and cooled to -78 °C. A solution of 4-methylpyrine anion was added dropwise over 1 h. The reaction was stirred for 1 h. AcOH (20 mL) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo and partitioned between DCM (250 mL) and water (250 mL). The aqueous portion was extracted with DCM (250 mL). The combined organic portions were washed with saturated NaHCO3 (250 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (4.85 g, 93.0%) as a pale yellow solid. UPLC (Method A) Rt 4.67 min, 97.2%. LCMS (ES+): 304.2 [MH] +

[0155] Intermediates 3 and 4 [ka] 4-[3-(4-benzyloxyphenyl)-1-methyl-pyrazol-4-yl]pyridine and 4-[5-(4-benzyloxyphenyl)-1-methyl-pyrazol-4-yl]pyridine Intermediate 2 (3.85 g, 97.2% pure, 12.3 mmol) in DMFDMA (25 mL) was heated at reflux for 2 h and then concentrated in vacuo. The residue was dissolved in EtOH (60 mL), methylhydrazine (1.95 mL, 37.0 mmol) and concentrated sulfuric acid (138.3 μL, 2.46 mmol) were added and the reaction was heated at 70° C. for 3 h. The reaction mixture was concentrated in vacuo and partitioned between DCM (250 mL) and saturated aqueous NaHCO3 (250 mL). The aqueous layer was extracted with DCM (250 mL) and the organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (buffered with 1% TEA) to give the title compounds as yellow solids (2.84 g, 65.9%) and yellow solids (625 mg, 10.7%), respectively. UPLC Rt 4.67 min, 97.6%. LCMS(ES+):342.2[MH] + . UPLC (Method A) 4.74min, 72.2%. LCMS(ES+):342.3[MH] +

[0156] Intermediate 5 4-[3-(4-benzyloxyphenyl)-1H-pyrazol-4-yl]pyridine [ka] A mixture of intermediate 2 (8.88 g, 97.2% pure, 28.5 mmol) in DMFDMA (56.7 mL, 427 mmol) was heated at reflux for 1.5 h. The reaction mixture was concentrated in vacuo then dissolved in EtOH (250 mL) and hydrazine monohydrate (4.23 mL, 85.4 mmol) was added and the reaction was heated at 70° C. for 2 h. The reaction mixture was concentrated in vacuo then triturated with Et2O (3×100 mL) to give the title compound (8.42 g, 89.7%) as a yellow solid. UPLC (Method A) Rt 4.28 min, 99.2%. LCMS (ES+): ES+: 328.2 [MH] +

[0157] Intermediate 6 tert-Butyl 3-(4-benzyloxyphenyl)-4-(4-pyridyl)pyrazole-1-carboxylate [ka] TEA (950 μL, 6.82 mmol) was added to a solution of intermediate 5 (1.49 g, 4.55 mmol), DMAP (55.5 mg, 455 μmol) and BocO (1.49 g, 6.82 mmol) in THF (45 mL) and the reaction was stirred for 2 h. The reaction mixture was concentrated in vacuo and then purified by normal phase column chromatography to give the title compound (1.68 g, 85.9%) as a white solid. UPLC (Method A) Rt 5.58 min, 99.2%. LCMS (ES+): 428.3 [MH] +

[0158] Intermediate 7 2-[[3-(4-benzyloxyphenyl)-4-(4-pyridyl)pyrazol-1-yl]methoxy]ethyl-trimethylsilane [ka] To a stirred mixture of intermediate 5 (500 mg, 1.53 mmol) and Cs2CO3 (1.50 g, 4.58 mmol) in DMF (20 mL) was added SEMCl (306 mg, 1.83 mmol) dropwise under N2 at 0 °C and stirred for 2 days. The reaction was quenched with water, extracted with EtOAc (3 x 15 mL) and the combined organic layers were washed with water (3 x 10 mL), dried (Na2SO4) and then concentrated in vacuo. The residue was purified by preparative TLC to give the title compound (220 mg, 31.5%). * was obtained as an off-white solid. LCMS(ES+): 458.0[MH] +

[0159] Intermediate 8 4-[3-(4-benzyloxyphenyl)-1-ethyl-pyrazol-4-yl]pyridine [ka] To a solution of intermediate 5 (700 mg, 2.14 mmol) in dry DMF (15 mL) was added NaH (60% in oil, 102 mg) at 0° C. under N2. The mixture was stirred for 35 min, then ethyl iodide (500 mg, 3.21 mmol) was added and allowed to warm to room temperature for 1 h. The reaction was quenched with water, extracted with DCM (3×25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (460 mg, 60.5%). * was obtained as an off-white solid. LCMS(ES+): 356.2[MH] +

[0160] Intermediates 9 and 10 Intermediates 9 and 10 were prepared similarly to intermediate 8 by coupling intermediate 5 with the appropriate alkyl halide; see Table 1 below. [ka] X-R1 is Br-R1 or I-R1. [Table 1]

[0161] Intermediate 11 4-[1-Methyl-4-(4-pyridyl)pyrazol-3-yl]phenol [ka] Intermediate 3 (3.48 g, 97.6% purity, 9.95 mmol) was dissolved in EtOH (100 mL) and EtOAc (100 mL) and the solution was passed twice through an H-cube (70×4 mm 10% Pd / C CatCart, 1.0 mL / min, 60° C., 50 bar). The reaction mixture was concentrated in vacuo to give the title compound (2.57 g, 98.9%) as a white solid. UPLC (Method A) Rt 2.73 min, 96.1%. LCMS (ES+): 252.1 [MH] +

[0162] Intermediate 12 4-[2-Methyl-4-(4-pyridyl)pyrazol-3-yl]phenol [ka] Intermediate 4 (130 mg, 0.38 mmol) was dissolved in MeOH (15 mL) and passed through an H-cube (70×4 mm 10% Pd / C CatCart, 1.0 mL / min, 35° C.). The reaction was concentrated in vacuo to give the title compound (70.0 mg, 69.9%) as a white solid. UPLC (Method B) Rt 1.68 min, 95.5%. LCMS (ES+): 252.1 [MH] +

[0163] Intermediate 13 tert-Butyl 3-(4-hydroxyphenyl)-4-(4-pyridyl)pyrazole-1-carboxylate [ka] Intermediate 6 (1.68 mg, 99.2% purity, 3.91 mmol) was dissolved in EtOH (80 mL) and the solution was passed through an H-cube (30×4 mm 10% Pd / C CatCart, 1.0 mL / min, 22° C., full H2 mode) in a continuous loop for 6 h. The reaction mixture was concentrated in vacuo to give the title compound (1.36 g, 99.3%) as a white solid. UPLC (Method A) Rt 3.99 min, 96.2%. LCMS (ES+): 338.2 [MH] +

[0164] Intermediate 14 4-[4-(4-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenol [ka] To a solution of intermediate 7 (220 mg, 0.48 mmol) in MeOH (10 mL) was added Pd / C (10%, 200 mg) in a pressure vessel. The mixture was hydrogenated under 10 bar of hydrogen for 2.5 h, filtered through a pad of Celite and concentrated in vacuo to give the title compound. The crude material was used in the next step without further purification. LCMS (ES+): 368.1 [MH] +

[0165] Intermediates 15-17 Intermediates 15-17 were prepared similarly to intermediate 14 by deprotection of the benzyl group via hydrogenation; see Table 2 below. [ka] [Table 2]

[0166] Intermediate 18 tert-Butyl 2-methylquinoline-4-carboxylate [ka] N,N'-Dicyclohexylcarbodiimide (1.65 g, 8.01 mmol) was added portionwise to a suspension of 2-methylquinoline-4-carboxylic acid (1.00 g, 5.34 mmol), DMAP (65.3 mg, 534 μmol) and tert-butanol (1.02 mL, 10.7 mmol) in DCM (60 mL) and the mixture was stirred for 16 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (539 mg, 41.2%) as a yellow oil. UPLC (Method A) Rt 4.31 min, 99.4%. LCMS (ES+): 244.2 [MH] +

[0167] Intermediate 19 Ethyl 7-fluoro-2-methyl-quinoline-3-carboxylate [ka] Ethyl acetoacetate (1.85 g, 14.2 mmol) was added to a stirred mixture of 4-fluoro-2-nitrobenzaldehyde (2.00 g, 11.8 mmol) and Fe (3.30 g, 59.1 mmol) in AcOH (20 mL) and stirred at 50° C. for 2 h. The resulting mixture was filtered, the filter cake was washed with DCM (3×30 mL), and the combined organic layers were washed with water (3×30 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (760 mg, 27.6%). * was obtained as a white solid. LCMS(ES+): 234.1[MH] +

[0168] Intermediates 20 and 21 Intermediates 20 and 21 were prepared similarly to intermediate 19 by condensation of the appropriate benzaldehyde with ethyl acetoacetate; see Table 3 below. [ka] [Table 3]

[0169] Intermediate 22 Methyl 6-bromo-2-methyl-quinoline-3-carboxylate [ka] Water (30 μL) was added dropwise to a stirred solution of 2-amino-5-bromobenzaldehyde (1.70 g, 8.50 mmol) in methyl acetoacetate (10 mL) and then heated at 80° C. for 3 h. EtOAc (50 mL) was added, washed with H2O (3×20 mL) and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (1.80 g, 75.6%). * was obtained as a yellow solid. LCMS(ES+): 280.0[MH] +

[0170] Intermediate 23 Methyl 5-bromo-2-methyl-quinoline-3-carboxylate [ka] A mixture of 2-amino-6-bromobenzaldehyde (1.00 g, 5.00 mmol), methyl acetoacetate (6.0 mL), and HO (0.1 mL) was stirred at 80° C. for 3 h. The resulting mixture was concentrated in vacuo and then purified by silica gel column chromatography to give the title compound (0.90 g, 64.3%). * was obtained as a yellow solid. LCMS(ES+): 280.2[MH] +

[0171] Intermediate 24 Ethyl 6-fluoro-2-methyl-quinoline-4-carboxylate [ka] Acetone (1.41 g, 24.2 mmol) was added dropwise to a stirred mixture of 5-fluoro-1H-indole-2,3-dione (2.00 g, 12.1 mmol) and KOH (3.40 g, 60.6 mmol) in EtOH (165 mL) and then heated at 80 °C for 2 h. The reaction was neutralized to pH 7 with concentrated HCl and then concentrated in vacuo. The residue was dissolved in EtOH:toluene (1:1) and H2SO4 (2.0 mL) was added and then heated at 80 °C overnight. The reaction was neutralized to pH 7 with NaOH and extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with water (3 x 20 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (720 mg, 25.5%). * was obtained as an off-white solid. LCMS(ES+): 233.9[MH] +

[0172] Intermediate 25 4-Bromo-5-chloro-2-methyl-quinoline [ka] To a stirred mixture of 3-chloroaniline (1.85 g, 14.5 mmol) and ethyl acetoacetate (1.89 g, 14.5 mmol) in dioxane (40 mL) was added polyphosphoric acid (10.0 g, 86.9 mmol) and the reaction was heated at 100 °C overnight. The mixture was basified to pH 14 with aqueous NaOH and then extracted with EtOAc (3 x 30 mL). The aqueous phase was acidified to pH 5 with hydrochloric acid and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 20 mL), dried (Na2SO4) and concentrated in vacuo. The residue (600 mg, 3.10 mmol) was dissolved in MeCN (20 mL) and PBr3 (2.10 g, 7.75 mmol) was added and then heated at 80 °C for 3 h. The mixture was basified to pH 9 with saturated aqueous NaHCO3 and extracted with EtOAc (3 x 15 mL), and the combined organic layers were washed with water (3 x 10 mL), dried (Na2SO4), and then concentrated in vacuo. The residue was purified by preparative TLC to give the title compound (310 mg, 39.0%). * was obtained as a yellow solid. LCMS(ES+): 258.6[MH] +

[0173] Intermediate 26 Methyl 5-chloro-2-methyl-quinoline-4-carboxylate [ka] To a solution of intermediate 25 (290 mg, 1.13 mmol) and TEA (172 mg, 1.70 mmol) in MeOH (10 mL) was added Pd(dppf)Cl2 (92.1 mg, 0.11 mmol) in a pressure vessel. The mixture was purged with N2 for 5 min and pressurized to 10 bar with carbon monoxide for 6 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 5 mL) and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (170 mg, 63.8%). * was obtained as a yellow oil. LCMS(ES+): 236.0[MH] +

[0174] Intermediate 27 tert-Butyl 4-(3-methylquinoxalin-2-yl)piperazine-1-carboxylate [ka] To a stirred solution of 2-chloro-3-methylquinoxaline (200 mg, 1.12 mmol) and tert-butyl piperazine-1-carboxylate (209 mg, 1.12 mmol) in DMF, DIPEA (289 mg, 2.24 mmol) was added dropwise and stirred at 80° C. for 3 h. The reaction was quenched with water, extracted with EtOAc (2×40 mL), and then concentrated in vacuo. The residue was purified by preparative TLC to give the title compound (140 mg, 38.1%) as a pale yellow solid. LCMS (ES+): 329.2 [MH] +

[0175] Intermediate 28 Methyl 2-(bromomethyl)quinoline-3-carboxylate [ka] Azobisisobutyronitrile (44.1 mg, 269 μmol) was added to a solution of methyl 2-methylquinoline-3-carboxylate (548 mg, 98.8% purity, 2.69 mmol) and NBS (718 mg, 4.03 mmol) in CCl4 (13 mL) and the reaction was heated at reflux for 4 h. The reaction mixture was filtered, concentrated in vacuo, and then purified by normal phase column chromatography to give the title compound (492 mg, 60.9%) as a yellow solid. UPLC (Method A) Rt 5.55 min, 93.2%. LCMS (ES+): 280.0 [MH] +

[0176] Intermediates 29-32 Intermediates 29-32 were prepared similarly to intermediate 28 by bromination of the appropriate intermediate with NBS; see Table 4 below. [ka] [Table 4]

[0177] Intermediate 33 Methyl 2-(bromomethyl)quinazoline-4-carboxylate [ka] Oxalyl chloride (0.19 mL, 2.23 mmol) was added to a solution of 2-methylquinazoline-4-carboxylic acid hydrochloride (250 mg, 1.11 mmol) in DCM (11 mL) and DMF (10 μL) at 0° C. The reaction was stirred for 30 min. MeOH (1.0 mL) was added and the reaction was allowed to warm to room temperature and stirred for 30 min. The mixture was concentrated in vacuo, diluted with EtOAc (30 mL), washed with saturated aqueous NaHCO3 (30 mL), dried (MgSO4), and concentrated in vacuo. The residue was dissolved in CCl4 (5.0 mL) and the mixture was sparged with N2 for 5 min. Azobisisobutyronitrile (15.5 mg, 9.45 μmol) and NBS (210 mg, 1.18 mmol) were added and the reaction was heated under reflux for 20 h. The mixture was filtered and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (58.0 mg, 20.0%) as a white solid. UPLC (Method B) Rt 2.46 min, 91.5%. LCMS (ES+): 281.0 [MH] +

[0178] Intermediate 34 Ethyl 2-(chloromethyl)-1,5-naphthyridine-3-carboxylate [ka] 3-Aminopicolinaldehyde (500 mg, 4.09 mmol) and ethyl 4-chloro-3-oxobutanoate (0.66 mL, 4.91 mmol) were dissolved in EtOH (27 mL) and heated under reflux for 18 h. The mixture was concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (100 mL), the aqueous portion was extracted with EtOAc (100 mL) and the combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by trituration in isohexane to give the title compound (724 mg, 69.5%) as a brown solid. UPLC (Method B) Rt 2.46 min, 98.5%. LCMS (ES+): 251.0 [MH] +

[0179] Intermediate 35 Ethyl 2-(bromomethyl)-7-fluoroquinoline-3-carboxylate [ka] To a stirred mixture of intermediate 19 (757 mg, 3.25 mmol) and benzoyl peroxide (83.2 mg, 0.33 mmol) in CCl4 (15 mL) was added NBS (520 mg, 2.92 mmol) and stirred at 80 °C for 2 days. The mixture was allowed to cool to room temperature, quenched with saturated aqueous Na2S2O3, and extracted with DCM (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by reverse phase column chromatography to give the title compound (540 mg, 53.3%). * was obtained as a white solid. LCMS(ES+): 312.1[MH] +

[0180] Intermediates 36-42 Intermediates 36-42 were prepared similarly to intermediate 35 by brominating intermediates 20-24 and 26-27 with NBS; see Table 5 below. [ka] [Table 5]

[0181] Intermediate 43 4-[2-(chloromethyl)quinazolin-4-yl]-1,4-thiazinane-1,1-dioxide [ka] 2-(Chloromethyl)-3H-quinazolin-4-one (500 mg, 2.57 mmol) was dissolved in POCl3 (12 mL, 129 mmol). IPEA (0.3 mL, 1.72 mmol) was added at 0° C. under N2 and the reaction was heated at 100° C. for 3 h. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in dioxane (20 mL) and thiomorpholine-1,1-dioxide (485 mg, 3.59 mmol) and DIPEA (619 mg, 4.79 mmol) were added at 0° C. under N2 and heated at 60° C. for 2 days. The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (3×10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (145 mg, 19.4%). * was obtained as a dark red solid. LCMS(ES+): 312.1[MH] +

[0182] Intermediate 44~45 Intermediates 44-45 were prepared similarly to intermediate 43 by chlorination followed by SNAr with the appropriate amine; see Table 6 below. [ka]

[0183] In that case, the group "NR2" is [ka] It is possible. [Table 6]

[0184] Intermediate 46 tert-Butyl N-[1-(3-methylquinoxalin-2-yl)azetidin-3-yl]carbamate [ka] To a stirred solution of 2-chloro-3-methylquinoxaline (530 mg, 2.97 mmol) and tert-butyl N-(azetidin-3-yl)carbamate (511 mg, 2.97 mmol) in DMF was added DIPEA (959 mg, 7.42 mmol) dropwise and stirred for 3 h. The reaction was quenched with water at room temperature and extracted with EtOAc (2×100 mL). The combined organic layers were concentrated in vacuo. The residue was purified by preparative TLC to give the title compound (500 mg, 53.6%). * was obtained as a yellow solid. LCMS(ES+): 315.2[MH] +

[0185] Intermediate 47 tert-Butyl N-[1-[3-(hydroxymethyl)quinoxalin-2-yl]azetidin-3-yl]carbamate [ka] To a stirred solution of intermediate 46 (200 mg, 0.64 mmol) in 1,4-dioxane, SeO2 (141 mg, 1.27 mmol) and H2O (115 mg, 6.36 mmol) were added dropwise and then heated at 60 °C overnight. The reaction was quenched with water, extracted with EtOAc (2 x 30 mL) and the combined organic layers were concentrated in vacuo. The residue was dissolved in THF:MeOH (1:1, 3.0 mL) and then NaBH(OAc)3 (238 mg, 1.13 mmol) was added and stirred for 20 min. The reaction was quenched with water, extracted with EtOAc (2 x 30 mL) and the combined organic layers were concentrated in vacuo and then purified by preparative TLC to give the title compound (110 mg, 59.1%). * was obtained as a yellow solid. LCMS(ES+): 331.2[MH] +

[0186] Intermediate 48 2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline [ka] A mixture of intermediate 13 (100 mg, 96.2% pure, 285 μmol), 2-bromomethylquinoline (69.7 mg, 314 μmol) and Cs2CO3 (102 mg, 314 μmol) in DMF (3.0 mL) was stirred for 1 h. 1M Hydrochloric acid (3.0 mL) was added and the reaction was stirred for 3 days. The reaction mixture was partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with DCM (50 mL) and the organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (37.4 mg, 34.5%) as a white solid. UPLC (Method A) Rt 3.37 min, 99.6%. LCMS (ES+): 379.1 [MH] +

[0187] Intermediate 49 Ethyl 2-[4-(4-pyridyl)-3-[4-(2-quinolylmethoxy)phenyl]pyrazol-1-yl]acetate [ka] Ethyl bromoacetate (47.7 μL, 431 μmol) was added to a suspension of intermediate 48 (150 mg, 98.9% pure, 392 μmol), K2CO3 (65.0 mg, 470 μmol) and tetrabutylammonium iodide (14.5 mg, 39.2 μmol) in DMF (4.0 mL) and heated at 80 °C for 1 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organics were washed with water (2 x 50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (134 mg, 35.8%) as an orange solid. UPLC (Method B) Rt 2.16 min, 48.6%. LCMS (ES+): 465.2 [MH] +

[0188] Intermediate 50 Methyl 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylate [ka] A solution of intermediate 11 (300 mg, 96.1% purity, 1.15 mmol) in DMF (4.0 mL) was added dropwise under N2 to a suspension of NaH (60% in mineral oil, 50.5 mg, 1.26 mmol) in DMF (8.0 mL) at 0 °C and stirred for 30 min. Intermediate 28 (345 mg, 93.2% purity, 1.15 mmol) was added and the mixture was allowed to warm to room temperature over 16 h. The reaction mixture was partitioned between DCM (100 mL), H2O (100 mL) and brine (50 mL), the aqueous layer was extracted with DCM (100 mL), the organic layers were combined, washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (439 mg, 82.5%) as a yellow solid. UPLC (Method A), Rt 4.52 min, 97.1%. LCMS(ES+):451.2[MH] +

[0189] Intermediates 51-64 Intermediates 51-64 were prepared similarly to intermediate 50 by alkylating the appropriate phenol intermediate with the appropriate bromide intermediate using NaH; see Table 7 below. [ka] [Table 7-1] [Table 7-2]

[0190] Intermediate 65 Methyl 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazoline-4-carboxylate [ka] A mixture of intermediate 11 (56.1 mg, 99.2% pure, 0.22 mmol), intermediate 33 (68.0 mg, 91.5% pure, 0.22 mmol) and Cs2CO3 (79.3 mg, 0.24 mmol) in DMF (3.0 mL) was stirred for 16 h. The mixture was diluted with DCM (20 mL), washed with saturated aqueous NaHCO3 (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (35.0 mg, 34.6%) as a yellow solid. UPLC (Method B) Rt 2.24 min, 98.7%. LCMS (ES+): 452.1 [MH] +

[0191] Intermediate 66-72 Intermediates 66-72 were prepared similarly to intermediate 65 by alkylating the appropriate phenol intermediate with the appropriate bromide / chloride intermediate using Cs2CO3; see Table 8 below. [ka] [Table 8-1] [Table 8-2]

[0192] Intermediate 73 tert-Butyl N-[1-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]azetidin-3-yl]carbamate [ka] A mixture of intermediate 44 (50.0 mg, 0.14 mmol) and intermediate 11 (36.0 mg, 0.14 mmol) and K2CO3 (39.6 mg, 0.29 mmol) in MeCN (2.0 mL) was heated at 80 °C for 2 h. The reaction was concentrated in vacuo and then purified by preparative TLC to give the title compound (59.1 mg, 73.2%).* was obtained as a pale yellow solid. LCMS(ES+): 564.3[MH] +

[0193] Intermediate 74 tert-Butyl 4-[2-[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]piperazine-1-carboxylate [ka] Intermediate 74 was prepared similarly to intermediate 73 by alkylating intermediate 11 with intermediate 45 to give the title compound (28.0 mg, 40.6%). * was obtained as a brown oil. LCMS(ES+): 578.3[MH] +

[0194] Intermediate 75 Methyl 6-methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylate [ka] To a solution of intermediate 55 (100 mg, 0.19 mmol) and potassium difluoro(methyl)borane fluoride (23.0 mg, 0.19 mmol) in anhydrous dioxane (3.0 mL) was added Cs2CO3 (123 mg, 0.38 mmol) and Pd(dppf)Cl2.DCM (15.0 mg, 0.02 mmol) and the reaction was heated at 80 °C under N2 for 16 h. The reaction was concentrated in vacuo and then purified by silica gel column chromatography to give the title compound (120 mg) as a yellow solid. This material was carried on to the next reaction without further purification. LCMS (ES+): 465.15 [MH] +

[0195] Intermediate 76 5-Methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid [ka] A mixture of intermediate 56 (100 mg, 0.19 mmol) and potassium trifluoro(methyl)borane wide (35.0 mg, 0.29 mmol), Pd(PPh3)2Cl2 (27.0 mg, 0.04 mmol) and Cs2CO3 (126 mg, 0.39 mmol) in anhydrous 1,4-dioxane was stirred at 100 °C overnight under N2. The resulting mixture was filtered, the filter cake was washed with 1,4-dioxane (2 × 5 mL) and concentrated in vacuo. The residue was purified by reverse phase column chromatography to give the title compound (20.0 mg, 22.9%) as a yellow oil. LCMS (ES+): 451.1 [MH] +

[0196] Intermediate 77 tert-Butyl N-[1-[3-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoxalin-2-yl]azetidin-3-yl]carbamate [ka] To a stirred solution of intermediate 47 (45.0 mg, 0.14 mmol), intermediate 11 (51.3 mg, 0.20 mmol) and PPh3 (53.6 mg, 0.20 mmol) in anhydrous THF, diisopropyl azodicarboxylate (41.3 mg, 0.20 mmol) was added dropwise under N2 at 0 °C and stirred overnight. The reaction was quenched with water, extracted with EtOAc (2 x 30 mL), the organic layer was concentrated in vacuo and then purified by preparative TLC to give the title compound (40.0 mg, 52.1%). * was obtained as a yellow solid. LCMS(ES+): 564.3[MH] +

[0197] Intermediate 78 4-Methylsulfanyl-2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline [ka] A solution of intermediate 71 (154 mg, 93.1% purity, 257 μmol) in DMF (2.6 mL) was sparged with N2 for 5 min. Sodium thiomethoxide (39.7 μmg, 566 μmol) was added and the reaction was stirred at 100 °C for 19 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (20 mL). The aqueous layer was extracted with EtOAc (20 mL) and the organic layers were combined, dried (MgSO4) and concentrated in vacuo to give the title compound (109 mg, 80.6%) as a yellow solid. UPLC (Method A) Rt 3.52 min, 80.7%. LCMS (ES+): 425.1 [MH] +

[0198] Intermediate 79 4-Methylsulfanyl-2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline [ka] 3-Chloroperbenzoic acid (61.3 mg, 70-75% purity, 249 μmol) was added portionwise to a solution of intermediate 78 (109 mg, 80.7% purity, 207 μmol) in DCM (4.1 mL) at 0 °C and the reaction was stirred for 10 min. The reaction was warmed to room temperature and stirred for 1 h. The reaction mixture was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with DCM (20 mL) and the organic layers were combined, dried (MgSO4) and concentrated in vacuo to give the title compound (91.0 mg, 61.1%) as a yellow solid. UPLC (Method A) Rt 3.62 min, 61.3%. LCMS (ES+): 441.0 [MH] +

[0199] Intermediate 80 N-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]-1,1-diphenyl-methanimine [ka] To a stirred solution of diphenylmethanimine (61.5 mg, 0.34 mmol), intermediate 68 (80.0 mg, 0.17 mmol), K2CO3 (46.9 mg, 0.34 mmol) in dioxane (3.0 mL), Pd2(dba)3.CHCl3 (17.6 mg, 0.02 mmol) and XPhos (16.2 mg, 0.03 mmol) were added in small portions under N2 and heated at 100 °C overnight. The reaction was concentrated in vacuo and then purified by preparative TLC to give the title compound (70.0 mg, 72.1%). * was obtained as a yellow solid. LCMS(ES+): 572.4[MH] +

[0200] Intermediate 81 N-[Dimethyl(oxo)-lambda^{6}-sulfanylidene]-2-[[4-[4-(4-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide [ka] Intermediate 62 (32.0 mg, 0.06 mmol) was dissolved in THF:H2O (1:1) and LiOH (4.00 mg, 0.17 mmol) was added and stirred for 3 h. The mixture was acidified to pH 5 with hydrochloric acid, extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine (3 x 5 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in DCM (5.0 mL) and S,S-dimethylsulfoximine (8.40 mg, 0.09 mmol), DMAP (6.60 mg, 0.05 mmol), 2-chloro-1-methylpyridine-1-potassium iodide (23.1 mg, 0.09 mmol) and DIPEA (17.5 mg, 0.14 mmol) were added and stirred for 2 h. The reaction was quenched with water and extracted with DCM (3×5 mL), and the combined organic layers were washed with brine (3×5 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC to give the title compound (15.0 mg, 52.8%). * was obtained as a yellow solid. LCMS(ES+): 628.3[MH] +

[0201] Example 1 2-[[4-[2-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylic acid [ka] A mixture of intermediate 12 (150 mg, 0.60 mmol), methyl 2-(chloromethyl)quinoline-4-carboxylate (159 mg, 97.1% purity, 0.66 mmol), and Cs2CO3 (391 mg, 1.19 mmol) in DMF (3.0 mL) was stirred at 40 °C for 3 days. The reaction was diluted with DCM (20 mL), washed with water (2 x 10 mL), and concentrated in vacuo. The residue was suspended in THF (5.0 mL) and aqueous NaOH (2.00 mL, 1.0 M, 2.00 mmol) was added and stirred at 30 °C overnight. The reaction was concentrated in vacuo and purified by reverse phase HPLC (buffered with formic acid) and then isolated using SPE on a Biotage SCX-II column to give the title compound (65.0 mg, 24.7%) as a pale-yellow solid. UPLC (Method A) Rt 3.92 min, 98.9%. HRMS(ES+ / QToF)m / z:[M+H] + C 26 H 21 N4O3 theoretical value 437.1614; measured value 437.1608

[0202] Example 2 2-[[4-[2-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid [ka] Example 2 was prepared similarly to Example 1 from intermediates 12 and 28 to give the title compound (35.5 mg, 13.4%) as a pale yellow solid. LCMS (Method A) Rt 3.93 min, 98.6%. HRMS (ES+ / QToF) m / z: [M+H] + C 26 H 21 N4O3 theoretical value 437.1614; measured value 437.1605

[0203] Example 3 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid [ka] LiOH.HO (119 mg, 2.84 mmol) was added to a solution of intermediate 50 (439 mg, 97.1% purity, 946 μmol) in THF (5.0 mL) and water (5.0 mL) and stirred for 2 h. The volatiles were removed in vacuo. To the remaining aqueous portion was added 1 M hydrochloric acid (2.84 mL). The resulting solid was collected by filtration and washed with water (2×5 mL) to give 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid (370 mg, 87.8%) as a white solid. UPLC (Method A) Rt 3.78 min, 98.0%. HRMS (ES+ / QToF) m / z: [M+H] + C 26 H 21 N4O3 theoretical value 437.1614; measured value 437.1615

[0204] Example 4 Ammonium 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylate [ka] 1,4-Dioxane (5.0 mL) and hydrochloric acid (4 M in 1,4-dioxane, 5.0 mL, 20 mmol) were added to intermediate 51 (500 mg, 909 μmol) in water (5.0 mL) and the reaction was heated at 60° C. for 3 h. The reaction mixture was concentrated in vacuo to give 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylic acid dihydrochloride (510 mg, 99.8%) as a brown solid. 50 mg was dissolved in THF (2.0 mL) and water (2.0 mL), neutralized to pH 7, then purified by reverse phase HPLC (buffered with ammonia) to give the title compound (14.8 mg, 3.58%) as a white solid. UPLC (Method A), Rt 3.77 min, 99.6%. HRMS(ES+ / QToF)m / z:[M+H] + C 26 H 21 N4O3 theoretical value 437.1614; measured value 437.1611

[0205] Example 5 2-[4-(4-pyridyl)-3-[4-(2-quinolylmethoxy)phenyl]pyrazol-1-yl]acetic acid [ka] 1.0M NaOH (1.50mL, 1.50mmol) was added to a solution of intermediate 49 (134mg, 48.6% purity, 140μmol) in THF (1.5mL) and MeOH (0.5mL) and stirred for 1h. 1M HCl was added to neutralize the mixture and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (43.0mg, 70.2%) as a yellow solid. UPLC (Method A) Rt 3.44min, 99.9%. HRMS (ES+ / QToF) m / z: [M+H] + C 26 H 21 N4O3 theoretical value 437.1614; measured value 437.1612

[0206] Example 6 2-[[4-[1-Methylsulfonyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline [ka] Methanesulfonyl chloride (11.1 μL, 144 μmol) was added to a solution of Intermediate 48 (50.0 mg, 98.9% purity, 131 μmol) and TEA (27.3 μL, 196 μmol) in DCM (5.0 mL) at 0° C. and the reaction was stirred for 30 min. The reaction was then concentrated in vacuo and stirred with 10% MeOH / water (3.0 mL) for 10 min before the resulting solid was collected by filtration. The solid was then purified by reverse phase HPLC to give the title compound (8.50 mg, 13.6%) as a white solid. UPLC (Method A) Rt 3.92 min, 95.4%. HRMS (ES+ / QToF) m / z: [M+H] + C 25 H 21 N4O3S theoretical value 457.1334; measured value 457.1331

[0207] Example 7 N-[Dimethyl(oxo)-λ6-sulfanylidene]-5-methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide [ka] A mixture of intermediate 76 (20.0 mg, 0.04 mmol), iminodimethyl-λ6-sulfanone (8.00 mg, 0.08 mmol), DMAP (6.00 mg, 0.05 mmol), 2-chloro-1-methylpyridin-1-ium iodide (22.0 mg, 0.08 mmol) and TEA (13.0 mg, 0.13 mmol) in DCM was stirred overnight. The reaction mixture was concentrated in vacuo and then purified by Prep-HPLC (buffered with NH4HCO3) to give the title compound (4.40 mg, 18.7%). * was obtained as a pale yellow solid. UPLC (Method C) Rt 1.73 min, 99.7%. HRMS (ES+ / QToF) m / z: [M+H] + C 29 H 28 N5O3S theoretical value 526.1913; measured value 526.1915

[0208] Example 8 N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[4-(4-pyridyl)-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide [ka] A mixture of intermediate 61 (45.0 mg, 0.09 mmol), iminodimethyl-λ6-sulfanone (16.6 mg, 0.18 mmol), DMAP (13.0 mg, 0.11 mmol), 2-chloro-1-methylpyridin-1-ium iodide (45.5 mg, 0.18 mmol), DIPEA (34.5 mg, 0.27 mmol) in DMF (5.0 mL) was stirred for 2 h. The reaction was quenched with water, extracted with EtOAc (2×5 mL), and the combined organic layers were washed with brine (2×5 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative HPLC (buffered with NH4HCO3) to give the title compound (2.00 mg, 3.7%). * was obtained as a purple solid. UPLC (Method C) Rt 1.89 min, 97.3%. HRMS (ES+ / QToF) m / z: [M+H] + C 29 H 25 Theoretical value of N5O3F3S is 580.1630; measured value is 580.1627

[0209] Example 9 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-methylsulfonyl-quinoline-3-carboxamide [ka] DIPEA (58.7 μL, 337 μmol) was added to a suspension of Example 3 (50.0 mg, 98.0% purity, 112 μmol), methanesulfonamide (21.4 mg, 224 μmol) and HATU (85.4 mg, 224 μmol) in DCM (1.2 mL) and stirred for 6.5 h. The reaction mixture was partitioned between DCM (30 mL) and H2O (30 mL). The aqueous layer was extracted with DCM (30 mL) and the organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (18.8 mg, 32.1%) as a white solid. UPLC (Method A), Rt 3.96 min, 98.4%. HRMS (ES+ / QToF) m / z: [M+H] + C 27 H 24 N5O4S theoretical value 514.1549; measured value 514.1542

[0210] Examples 10 to 14 Examples 10-14 were prepared similarly to Example 9 by amide coupling of the appropriate intermediate with the appropriate amine using HATU; see Table 9 below. [ka]

[0211] In the above scheme, R 4 and R 5 is -C(O)N=S(O)R e It could be 2. [Table 9]

[0212] Example 15 N-Methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-methylsulfonyl-quinoline-3-carboxamide [ka] MeI (5.89 μL, 94.6 μmol) was added to the formate salt of Example 9 (48.0 mg, 99.5% purity, 78.9 μmol) and K2CO3 (16.4 mg, 118 μmol) in acetone:DMF (2:1, 1.5 mL) and stirred for 42 h. The mixture was concentrated in vacuo and then purified by reverse phase HPLC (buffered with NH3) to give the title compound (15.7 mg, 37.4%) as a white solid. UPLC (Method A) Rt 3.93 min, 99.1%. HRMS (ES+ / QToF) m / z: [M+H] + C 28 H 26 N5O4S theoretical value 528.1706; measured value 528.1713

[0213] Example 16 N-Methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-methylsulfonyl-quinoline-4-carboxamide [ka] DIPEA (0.10 mL, 0.57 mmol) was added to a solution of Example 4 (102 mg, 98.2% pure, 0.23 mmol) and T3P (50 wt% solution in EtOAc, 0.28 mL, 0.47 mmol) in DMF (1.5 mL), the mixture was stirred for 5 min, and then N-methylmethanesulfonamide (40.0 μL, 0.47 mmol) was added. The reaction mixture was stirred at 40° C. for 3 h. The mixture was diluted with DCM (20 mL), washed with 1 M aqueous NaOH (25 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by reverse phase HPLC (buffered with NH3) to give the title compound (19.7 mg, 16.3%) as a white solid. UPLC (Method A) Rt 4.26 min, 99.7%. HRMS (ES+ / QToF) m / z: [M+H] + C 28 H 26 N5O4S theoretical value 528.1706; measured value 528.1705

[0214] Example 17 N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazoline-4-carboxamide [ka] Intermediate 65 (35.0 mg, 98.7% pure, 76.5 μmol) was dissolved in THF (2.0 mL) and water (2.0 mL). LiOH.H2O (3.85 mg, 91.8 μmol) was added and the reaction was stirred for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in DMF (2.0 mL) and HATU (58.2 mg, 0.15 mmol), S,S-dimethylsulfoximine (14.3 mg, 0.15 mmol) and DIPEA (26.7 μL, 0.15 mmol) were added and the reaction was stirred for 1.5 h. The mixture was diluted with DCM (30 mL), washed with saturated aqueous NaHCO3 (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (buffered with NH3) to give the title compound (24.4 mg, 61.8%) as a yellow solid. UPLC (Method A) Rt 3.68 min, 99.4%. HRMS(ES+ / QToF)m / z:[M+H] + C 27 H 25 N6O3S theoretical value 513.1709; measured value 513.1710

[0215] Examples 18 to 20 Examples 18-20 were prepared similarly to Example 17 by saponification of the appropriate intermediate followed by amide coupling with the appropriate amine using HATU; see Table 10 below. [ka] [Table 10]

[0216] Example 21 N-[Dimethyl(oxo)-λ6-sulfanylidene]-7-fluoro-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide [ka] Intermediate 52 (110 mg, 0.23 mmol) was dissolved in THF:H2O (1:1) and LiOH (10.9 mg, 0.46 mmol) was added and stirred for 12 h. The residue was acidified to pH 4 with hydrochloric acid. The resulting mixture was extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine (3 x 3 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in DCM (5.0 mL) and S,S-dimethylsulfoximine (6.20 mg, 0.07 mmol), 2-chloro-1-methylpyridin-1-ium iodide (16.9 mg, 0.07 mmol), DMAP (4.80 mg, 0.04 mmol) and DIPEA (12.8 mg, 0.10 mmol) were added and stirred for 2 h. The resulting mixture was extracted with DCM (3×5 mL) and the combined organic layers were washed with water (3×5 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (2.80 mg, 16.0%). * was obtained as a white solid. UPLC (Method C) Rt 1.79 min, 96.5%. HRMS (ES+ / QToF) m / z: [M+H] + C 28 H 25 N5O3FS theoretical value 530.1662; measured value 530.1657

[0217] Examples 22 to 28 Examples 22-28 were prepared similarly to Example 21 by saponification of the appropriate intermediates followed by amide coupling with S,S-dimethylsulfoximine using 2-chloro-1-methylpyridin-1-ium iodide; see Table 11 below. [ka]

[0218] In the above scheme, the "OR" group can be an O-alkyl, such as -OMe or -OEt. [Table 11-1] [Table 11-2]

[0219] Example 29 2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid [ka] HCl (4M in 1,4-dioxane) (3.00 mL, 12.0 mmol) was added to a solution of intermediate 69 (70.0 mg, 88.6% purity, 116 μmol) in 1,4-dioxane (3.0 mL) and the reaction was stirred for 16 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in THF (1.0 mL) and water (1.0 mL) and LiOH.H2O (24.2 mg, 578 μmol) was added and the reaction was stirred for 2 h. 1.0 M hydrochloric acid was added to neutralize the reaction mixture to pH 7 and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (16.1 mg, 32.9%) as a white solid. UPLC (Method A) Rt 3.58 min, 99.6%. HRMS (ES+ / QToF) m / z: [M+H] + C 25 H 19 N4O3FS theoretical value 423.1457; measured value 423.1455

[0220] Example 30 2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylic acid [ka] LiOH·HO (31.4 mg, 749 μmol) was added to a solution of intermediate 70 (153 mg, 87.5% purity, 250 μmol) in THF (2.5 mL) and water (2.5 mL) and the reaction was stirred for 16 h. THF was removed in vacuo. The remaining aqueous portion was neutralized to pH 7 with 1 M hydrochloric acid and the resulting precipitate was collected by filtration. The product was purified by reverse phase HPLC to give the title compound (8.27 mg, 7.76%) as a white solid. UPLC (Method A) Rt 3.48 min, 98.9%. HRMS (ES+ / QToF) m / z: [M+H] + C 25 H 19 N4O3 theoretical value 423.1457; measured value 423.1459

[0221] Example 31 N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide [ka] Intermediate 81 (20.0 mg) was dissolved in DCM (1.0 mL) and TFA (0.2 mL) and stirred for 45 min. The reaction was concentrated in vacuo and then purified by preparative HPLC (buffered with TFA) to give the title compound (7.90 mg, 49.8%). * was obtained as a yellow solid. LCMS(ES+): 498.2[MH] + . UPLC (Method C) Rt 1.60 min, 88.3%. HRMS(ES+ / QToF)m / z:[M+H] + C 27 H 24 N5O3S theoretical value 498.1600; measured value 498.1604

[0222] Example 32 Dimethyl-oxo-[[2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]imino]-lambda 6-sulfane [ka] A mixture of intermediate 71 (155 mg, 93.1% pure, 259 μmol), S,S-dimethylsulfoximine (96.5 mg, 1.04 mmol), Pd(OAc) (2.91 mg, 12.9 μmol), BINAP (24.2 mg, 38.8 μmol) and CsCO (169 mg, 518 μmol) in toluene (2.6 mL) was sparged with N for 5 min. The reaction was heated at reflux for 18 h and then heated at 120 °C in a microwave reactor for 30 min. MeOH (10 mL) was added and the mixture was filtered, concentrated in vacuo and then purified by normal phase column chromatography and reverse phase HPLC (buffered with ammonia) to give the title compound (1.92 mg, 1.57%) as a yellow solid. UPLC (Method A) Rt 3.31 min, 99.3%. HRMS(ES+ / QToF)m / z:[M+H] + C 26 H 24 N5O2S theoretical value 470.1651; measured value 470.1650

[0223] Example 33 Imino-methyl-oxo-[2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]-lambda 6-sulfane [ka] A mixture of intermediate 79 (91.0 mg, 61.3% purity, 127 μmol), ammonium acetate (117 mg, 1.52 mmol) and iodobenzene diacetate (367 mg, 1.14 mmol) in MeOH (1.0 mL) was stirred for 48 h. Ammonium acetate (39.0 mg, 507 umol) and iodobenzene diacetate (122 mg, 380 umol) were added and the reaction was stirred for 24 h. DCM (10 mL) and saturated aqueous NaHCO3 (10 mL) were added. The organic and aqueous layers were decanted off and then purified by normal phase column chromatography and reverse phase HPLC (buffered with ammonia) to give the title compound (3.52 mg, 6.02%) as a yellow solid. UPLC (Method A) Rt 3.48 min, 98.6%. HRMS (ES+ / QToF) m / z: [M+H] + C 25H 22 N5O2S theoretical value 456.1494; measured value 456.1492

[0224] Example 34 N-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]methanesulfonamide [ka] A mixture of intermediate 68 (113 mg, 96.0% pure, 230 umol), Pd2(dba)3 (12.6 mg, 13.8 μmol), tBuXPhos (17.6 mg, 41.1 μmol), K2CO3 (63.6 mg, 460 umol) and methanesulfonamide (21.9 mg, 230 umol) in 1,4-dioxane (1.2 mL) under N2 was sparged with N2 for 5 min. The reaction was heated at 60-90 °C for 19 h. The reaction mixture was filtered through Celite, concentrated in vacuo, and then purified by reverse phase HPLC to give the title compound (28.8 mg, 25.6%) as a white solid. UPLC (Method A), Rt 3.62 min, 99.3%. HRMS (ES+ / QToF) m / z: [M+H] + C 26 H 24 N5O2S theoretical value 486.1600; measured value 486.1603

[0225] Example 35 1-Methyl-3-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]urea [ka] A mixture of intermediate 68 (113 mg, 96.0% purity, 230 μmol), N-methylurea (85.3 mg, 1.15 mmol), Pd2(dba)3 (21.1 mg, 23.0 μmol), Xantphos (26.6 mg, 46.0 μmol), CuI (13.1 mg, 69.0 μmol) and NaOtBu (111 mg, 1.15 mmol) in 1,4-dioxane (2.0 mL) was sparged with N2 for 5 min. The reaction was heated at 110 °C for 30 min in a microwave reactor. The reaction mixture was diluted with MeOH (10 mL), filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase column chromatography and reverse phase HPLC (buffered with formic acid). The fractions were pooled, neutralized with saturated aqueous NaHCO3 (25 mL), extracted with DCM (2 x 25 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (16.5 mg, 15.4%) as a white solid. UPLC (Method A) Rt 3.33 min, 99.5%. HRMS (ES+ / QToF) m / z: [M+H] + C 27 H 25 N6O2 theoretical value 465.2039; measured value 465.2042

[0226] Example 36 1-[Dimethyl(oxo)-λ6-sulfanylidene]-3-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]urea [ka] To a stirred solution of intermediate 80 (70.0 mg, 0.12 mmol) in THF (1.0 mL) was added HCl (2M, 1.0 mL) and stirred for 20 min. The reaction was concentrated in vacuo. The residue was dissolved in DCM and DIPEA (108 mg, 0.83 mmol) and triphosgene (12.4 mg, 0.04 mmol) were added dropwise at 0° C. under N2, then stirred at 0° C. for 30 min. Iminodimethyl-λ6-sulfanone (15.5 mg, 0.17 mmol) was added and stirred for 1 h. The reaction was concentrated in vacuo and then purified by preparative HPLC (buffered with NH4HCO3) to give the title compound (2.80 mg, 6.37%). *was obtained as a white solid. UPLC (Method C) Rt 1.41 min, 96.1%. HRMS (ES+ / QToF) m / z: [M+H] + C 28 H 27 N6O2S theoretical value 527.1865; measured value 527.1868

[0227] Example 37 4-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]-1,4-thiazinane-1,1-dioxide [ka] To a solution of intermediate 11 (50.0 mg, 0.20 mmol) in dry DMF (8.0 mL) was added NaH (60% in oil, 16.0 mg) at 0° C. and stirred for 30 min. Intermediate 43 (93.0 mg, 0.30 mmol) was added and the mixture was allowed to warm to room temperature for 1 h. The reaction mixture was quenched with water and extracted with EtAOc (3×25 mL) and the combined organic layers were washed with water (3×10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (36.0 mg, 34.4%). * was obtained as a white solid. UPLC (Method C) Rt 1.49 min, 99.0%. HRMS (ES+ / QToF) m / z: [M+H] + C 28 H 27 N6O2S theoretical value 527.1865; measured value 527.1863

[0228] Example 38 4-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]piperazin-2-one [ka] A mixture of intermediate 64 (30.0 mg, 0.07 mmol), piperazine-2-one (11.0 mg, 0.11 mmol), BOP (38.9 mg, 0.09 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (33.5 mg, 0.21 mmol) in DMF was stirred for 2 h. The resulting mixture was quenched with water (5.0 mL), extracted with EtOAc (2×5.0 mL) and the combined organic layers were washed with water (2×5.0 mL), dried (Na2SO4) and then concentrated in vacuo. The residue was purified by silica gel column chromatography and preparative HPLC (buffered with NH4HCO3) to give the title compound (6.30 mg, 17.5%). * was obtained as a white solid. UPLC (Method C) Rt 1.32 min, 99.3%. HRMS (ES+ / QToF) m / z: [M+H] + C 28 H 26 N7O2 theoretical value 492.2148; measured value 492.2147

[0229] Example 39 1-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]azetidin-3-amine [ka] A solution of intermediate 73 (50.0 mg, 0.09 mmol) and TFA (2.0 mL) in DCM (4.0 mL) was stirred for 1 h. The reaction was concentrated in vacuo and then purified by preparative HPLC (buffered with NH4HCO3) to give the title compound (6.30 mg, 15.1%). * was obtained as a yellow solid. UPLC (Method C) Rt 1.10 min, 89.0%. HRMS (ES+ / QToF) m / z: [M+H] + C 27 H 26 N7O theoretical value 464.2199; measured value 464.2199.

[0230] Examples 40 to 42 Examples 40-42 were prepared similarly to Example 39 by Boc deprotection of the appropriate intermediates with TFA; see Table 12 below. [ka]

[0231] In the above scheme, X is [ka] It is. [Table 12]

[0232] Biochemical human PDE10A activity assay - PDE10A2 phosphate sensor assay Half-log dilutions of compound starting at a final concentration of 50 μM were dispensed into black 384-well plates using an Echo Acoustic dispenser along with DMSO and inhibitor controls. Human PDE10A2 and CD73 were both diluted in Tris-based assay buffer to final concentrations of 0.25 nM and 1 nM, respectively, and incubated with compound for 15 min at room temperature, followed by addition of substrate cGMP and phosphate sensor diluted in Tris-based assay buffer to final concentrations of 3 μM and 0.9 μM, respectively. Plates were incubated for a further 35 min at room temperature before measuring fluorescence intensity using an Ex 430 nm / Em 450 nm optical filter on a BMG CLARIOStar plate reader. Data were analyzed using a four-parameter fit.

[0233] Cell-based human PDE10A activity assay – cAMP HTRF assay in HEK293 rhPDE10A2 cell line Half-log dilutions of compound starting at a final concentration of 10 μM were dispensed into white 384-well plates using a Tecan D300e digital dispenser along with DMSO and inhibitor controls. HEK293 cells overexpressing recombinant human PDE10A2 were seeded with compound at 2500 cells / well in a volume of 5 μL / well. Plates were incubated at room temperature for 60 minutes. To induce endogenous cAMP, 5 μL / well of forskolin was added to the plate for a final assay concentration of 10 μM. Plates were incubated at room temperature for an additional 45 minutes. cAMP HTRF detection reagent was added and plates were incubated at room temperature for 60 minutes. FRET signals were measured on a BMG PHERAstar FS plate reader using HTRF optical filters (337 / 620 / 665). Data were analyzed using a 4-parameter fit. [Table 13-1] [Table 13-2]

[0234] The data in the above table show that the compounds of the present invention, compounds of formula (IA), (IB), (IIA) and (IIB), are potent PDE10A inhibitors and may therefore be suitable for use in the treatment of inflammatory bowel diseases such as ulcerative colitis and / or Crohn's disease.

[0235] Measurement of CNS permeability in vivo Male Sprague Dawley rats (Charles River, UK) weighing 300–350 g were group-housed (n=3) under a 12-h light / dark cycle with free access to food and water. Two days prior to dosing, animals were anesthetized with inhaled isoflurane and the right jugular vein was exposed and surgically cannulated. Animals were then housed singly for recovery and throughout the remainder of the procedure. On the day of dosing, animals were weighed, tail-marked, and administered 1 mg / kg compound intravenously through an indwelling venous cannula in a volume of 3–5 mL / kg. Animals were killed 10–30 min after dosing by intravenous administration of pentobarbital. Postmortem blood was collected by cardiac puncture and briefly stored on ice in K2 EDTA blood tubes before being spun at 14,000 g for 4 min at 4°C. Plasma was removed into a 96-well plate, placed on dry ice, and stored at -80°C. Brains were quickly dissected, placed on dry ice and stored at -80°C.

[0236] Male Sprague-Dawley rats are dosed (intravenously) with test compounds and the animals are sacrificed at certain time points. Plasma is isolated from whole blood after cardiac exsanguination by centrifugal blood fractionation, and whole brains are isolated. Samples are stored on ice and transferred to a bioanalysis lab storage unit at -80°C. Bioanalysis of plasma and brain samples is performed as detailed below.

[0237] Plasma Bioanalysis Typically, calibration curve standards of test compounds were prepared in the range of 1.00-6,000 ng / mL using 1.00 mg / mL DMSO stocks. Calibration curves were prepared by printing known masses of analytes in a 96-well plate ranging from 25-150,000 pg. 25 μL of control male Sprague-Dawley Rat plasma was added to each well to prepare calibration curve standards of appropriate concentrations across the calibration curve range. Experimental samples were thawed to room temperature and 25 μL aliquots were added to the 96-well precipitation plate alongside the calibration curve. Samples were extracted using protein precipitation (400 μL MeCN containing 25 ng / mL tolbutamide as an internal standard, stirred at room temperature for at least 5 minutes). Protein precipitates were separated from the extracted test compounds by centrifugation at 4000 rpm for 5 minutes at 4°C. The resulting supernatant was diluted 1:2 with diluent 1:1 MeOH:H2O.

[0238] Samples were analyzed by UPLC-MS / MS on either an AB Sciex API6500 QTrap or a Waters TQ-S mass spectrometer using pre-optimized analytical MRM (multiple reaction monitoring) methods specific for the test compounds.

[0239] Using appropriate regression and weighting, concentrations of test compounds in isolated samples were determined after analysis of samples against duplicate replicates of the calibration curve, injected before and after the sample set. Only calibration standards within ±15% (±20% at LLoQ) of the expected test substance concentration value were included in the calibration curve; samples outside the limits of the calibration curve were considered below or above the limit of quantitation (LLoQ / ALoQ).

[0240] Brain Bioanalysis Typically, calibration curve standards of test compounds were prepared in the range of 3.00-18,000 ng / mL using 1.00 mg / mL DMSO stocks. Calibration curves were prepared by printing known masses of analytes in a 96-well plate ranging from 25-150,000 pg. A volume of 25 μL of control male Sprague-Dawley Rat brain homogenate (containing 8.33 mg of brain tissue) was added to each well to prepare calibration curve standards of appropriate concentrations across the calibration curve range.

[0241] To prepare control and experimental brain homogenates, brains were thawed at room temperature, weighed, and diluent (50:50 MeCN / HO) was added at a ratio of 2 mL per gram of brain. Brain homogenization was performed by bead beater homogenization using Precellys Evolution and CKMix50 7 mL mixed ceramic bead homogenization tubes.

[0242] Aliquots of 25 μL of experimental samples were extracted along the calibration curve using protein precipitation (400 μL MeCN containing 25 ng / mL tolbutamide as an internal standard, stirred at room temperature for at least 5 minutes). Protein precipitates were separated from the extracted test compounds by centrifugation at 4000 rpm for 5 minutes at 4° C. The resulting supernatant was diluted in a ratio of 1:2 using diluent 1:1 MeOH:H2O.

[0243] Samples were analyzed by UPLC-MS / MS using previously optimized analytical MRM (multiple reaction monitoring) methods specific for the test compounds on either an AB Sciex API6500 QTrap or a Waters TQ-S mass spectrometer.

[0244] The concentration of test compounds in isolated samples was determined after analysis of the samples against two replicates of the calibration curve injected before and after the sample set, using appropriate regression and weighting. Only calibration samples within ±15% (±20% at LLoQ) of the expected test concentration value were included in the calibration curve; samples outside the limits of the calibration curve were considered below or above the limit of quantitation (LLoQ / ALoQ).

[0245] Measurement of brain / plasma ratio and free brain concentration Total CNS penetration was calculated by dividing the brain concentration by the plasma concentration at each time point, and these ratios were averaged to calculate the mean brain:plasma ratio (Br:Pl) (with the time points used clearly stated).

[0246] The free drug hypothesis states that only unbound compounds can interact and cause pharmacological effects. Therefore, it is desirable for compounds to have high free brain concentrations. To calculate the free concentration in each matrix, the determined concentrations are multiplied by the % free values ​​determined by plasma protein binding and brain tissue binding studies using rapid equilibrium dialysis. The values ​​are then converted to molar concentrations to obtain nanomolar free concentrations at each time point.

[0247] Kpuu was calculated as the ratio of the fraction of free drug unbound in the brain to the fraction of free drug unbound in plasma. [Table 14]

[0248] The data in the above table demonstrate that the compounds of the present invention, compounds of formulae (IA), (IB), (IIA), and (IIB), do not significantly penetrate the central nervous system.

[0249] In vitro incubations for screening reactive metabolites: GSH trapping assay To test for the formation of reactive metabolites, each compound was incubated at a concentration of 10 μM with human liver microsomes (HLM, 1 mg / mL protein) or human liver S9 (1.5 mg / ml protein) in 100 mM phosphate buffer (pH 7.4) in the presence of NADPH (1 mM) and GSH (1 mM) as a trapping agent. Incubations were performed for 0 min (T0) and 60 min (T60) in a shaking incubator at 37 °C. The reactions were stopped by adding 2 volumes of 75% MeCN, vortexing, and centrifuging at 5-13K rpm for 5-10 min. The supernatants were analyzed using HRMS analysis and LC-MS / MS. The formation of the GSH conjugate peak is reported as % of the parent compound peak at T0. [Table 15]

[0250] The data in the above table show that the compounds of the present invention, compounds of formula (IA), (IB), (IIA), and (IIB), do not significantly form reactive metabolites that may cause idiosyncratic adverse drug reactions that are often associated with, for example, drug-induced skin, liver, and hematopoietic toxicity. The compounds of the present invention form less reactive metabolites than PF-02545920.

[0251] Evaluation of PDE10A inhibitors for use in the treatment of ulcerative colitis To investigate the role of PDE10A in ulcerative colitis (UC), we investigated the RNA expression of PDE10A in normal and diseased tissues using the Genotype-Tissue Expression (GTEx) database, and in parallel, assessed the expression levels of guanylate cyclase 2C (GUCY2C), an enzyme that synthesizes cGMP in response to the endogenous peptides guanylin and uroguanylin, as well as the heat-stable entrotoxin of Escherichia coli.

[0252] As previously described in the literature, PDE10A is expressed at low levels in normal tissues, except in the brain (shown in Figure 1). However, in colonic mucosa and colonic tissues from ulcerative colitis patients, the expression levels of PDE10A were significantly elevated compared to normal controls (shown in Figure 2). This is a finding not previously reported in the literature and highlights a possible undiscovered role of PDE10A in IBD pathology.

[0253] GUCY2C was found to be specifically expressed at high levels in the normal colon and small intestine (shown in Figure 1), suggesting a role for this enzyme in normal intestinal homeostasis. GUCY2C was significantly down-regulated in the colonic mucosa and colon of UC (shown in Figure 2), a finding that has been previously reported in the literature.

[0254] Guanylate cyclase-C and cGMP signaling are downregulated in ulcerative colitis (Brenna et al. The guanylate cyclase-C signaling pathway is down-regulated in inflammatory bowel disease Scand J Gastroenterol. 50(10), 1241-52 (2015)), and reduced expression of guanylate cyclase-2C, guanylin, and uroguanylin correlates with disease severity (Lan et al. Expression of guanylate cyclase-C, guanylin, and uroguanylin is downregulated proportionally to the ulcerative colitis disease activity index Sci Rep. 6, 25034, (2016) published online 29 April 2016 doi: 10.1038 / srep25034), suggesting that reduced cGMP signaling is involved in UC pathology. cGMP in the gastrointestinal tract has also been shown to be involved in fluid and electrolyte secretion, barrier function, inflammation, and proliferation (Waldman et al. Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders., Gut. 67(8), 1543-1552 (2018)).

[0255] Although less studied in inflammation than cAMP, reduced cGMP signaling has also been shown to increase inflammation in other systems (Ahluwalia et al. Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment. Proc Natl Acad Sci US A. 101(5), 1386-91 (2004); Raposo et al. Role of iNOS-NO-cGMP signaling in modulation of inflammatory and myelination processes. Brain Res Bull. 104, 60-73 (2014)).

[0256] Taken together, it is believed that in the UC colon and colonic mucosa, cGMP hydrolysis activity by PDE10A is increased and cGMP synthesis activity by guanylate cyclase 2C is decreased, ultimately resulting in decreased cGMP levels and signaling.

[0257] The therapeutic potential of inhibitors of PDE10A for the treatment of inflammatory bowel disease was evaluated using tissue samples of inflamed colonic mucosa from patients with ulcerative colitis.

[0258] The effect of selective PDE10A inhibition was examined in inflamed colonic mucosa from patients with ulcerative colitis, collected during routine endoscopy (Protocol 1 detailed below). These samples retain the disease phenotype in ex vivo culture, secrete high basal levels of inflammatory cytokines, and are highly relevant translational disease models. The effect of PDE10A inhibitors on the levels of the inflammatory cytokines IL-6 and IL-8 released from these tissue samples was measured. Both IL-6 and IL-8 are key regulators in ulcerative colitis pathology and their levels correlate with disease severity (Waldner MJ et al. Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development. Semin Immunol. 26(1), 75-9 (2014); Bernardo D et al. IL-6 promotes immune responses in human ulcerative colitis and induces a skin-homing phenotype in the dendritic cells and T-cells they stimulate. Eur J Immunol. 42(5),1337-53 (2012); Pearl DS, Cytokine mucosal expression in ulcerative colitis, the relationship between cytokine release and disease activity. J Crohns Colitis. 7(6), 481-9 (2013)).

[0259] The structurally distinct PDE10A inhibitors PF-02545920 and TAK-063 were tested alongside two positive control compounds, the steroid prednisolone and the Janus kinase inhibitor tofacitinib, in colon biopsy samples from two ulcerative colitis patients. These colon biopsies retain an inflammatory phenotype and secrete high levels of inflammatory cytokines in ex vivo culture. Selective PDE10A inhibition significantly reduced the secreted levels of IL-6 and IL-8 compared to DMSO vehicle (Figures 4 and 5). This reduction was comparable to that seen with the positive controls. PF-02545920 was tested at concentrations of 0.1 μM and 1 μM. TAK-063 was tested at a concentration of 1 uM. The doses tested of each inhibitor will result in selective inhibition of PDE10A relative to other PDE family members.

[0260] The compounds of the present invention of Examples 4, 9, 10, 11, 17, 19 and 20 were tested at a concentration of 100 nM (a concentration selective for PDE10A inhibition) and were found to significantly reduce the secretion levels of IL-6 and IL-8 compared to vehicle control. The ability of selective PDE10A inhibition by the compounds of the present invention to significantly reduce the levels of pathological inflammatory cytokines in colonic tissue from UC patients ex vivo indicates the therapeutic utility of PDE10A inhibitors for the treatment of UC. The results are shown in Figures 6-9.

[0261] The structure of PF-02545920 is shown below. PF-02545920 is an IC 50 It is a potent and selective cyclic nucleotide PDE10A competitive inhibitor with a reported activity of 1.26 nM. PF-02545920 is being studied in clinical trials for the treatment of Huntington's disease. Patients received 5 mg or 20 mg of PF-02545920 twice daily. [ka]

[0262] In isolated enzyme biochemical assays, PF-02545920 had IC 50<5 nM, IC against other PDE family members 50 It has been shown to be a highly selective PDE10A inhibitor with a potency of >1 μM (Grauer SM et.al. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther. 2009 331(2), 574-90). Thus, at test concentrations of 0.1 μM and 1 μM in in vitro tissue assays, PF-02545920 selectively inhibits PDE10A.

[0263] The structure of TAK-063 is shown below. TAK-063 was studied in a Phase 2 clinical trial for people with schizophrenia. TAK-063 was administered at 20 mg once daily, but could be reduced to 10 mg once daily if higher doses were not tolerated. [ka]

[0264] In isolated enzyme biochemical assays, TAK-063 demonstrated IC 50 IC of 0.3 nM and IC against other PDE family members 50It has been shown to be a highly selective PDE10A inhibitor with a potency of >5μM (Kunitomo J et.al. Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor. J Med.Chem. 57(22), 9627-43 (2014)). Therefore, TAK-063 selectively inhibits PDE10A at a test concentration of 1uM in an in vitro tissue assay.

[0265] The effect of selective PDE10A inhibition was also investigated in inflamed colonic mucosa from patients with pharmacotherapy-refractory ulcerative colitis, taken during colectomy (Protocol 2, detailed below). The PDE10A inhibitor PF-02545920 (1 μM) was tested in colonic samples from two patients with ulcerative colitis. The effect of selective PDE10A inhibition on the levels of the inflammatory cytokine TNFα released from these tissue samples was measured. TNFα is a pro-inflammatory mediator that is highly expressed in the colonic mucosa of patients with UC and is the target of anti-TNFα biologics that have shown efficacy in the treatment of UC (Pugliese D. et al. Anti TNF-α therapy for ulcerative colitis: current status and prospects for the future., Expert Rev Clin Immunol. 13(3), 223-233 (2017)). Selective PDE10A inhibition significantly reduced the secreted levels of TNFα compared to DMSO vehicle (FIG. 10).

[0266] The ability of selective PDE10A inhibition to significantly reduce levels of proinflammatory cytokines in colonic mucosa from UC patients indicates the therapeutic utility of PDE10A inhibitors for the treatment of UC.

[0267] Evaluation of PDE10A inhibitors for use in the treatment of Crohn's disease. As mentioned above, treatments for UC should also be effective in treating CD. In particular, cGMP signaling has been shown to be reduced in both UC and CD (Brenna, et al. The guanylate cyclase-C signaling pathway is down-regulated in inflammatory bowel disease. Scand J Gastroentero 50, 1241-1252 (2015)), and the mechanism is closely related to PDE10A.

[0268] Additionally, we tested the effect of selective PDE10A inhibition using 0.1 uM PF-2545920 on inflamed colonic mucosa from Crohn's disease patients obtained during routine endoscopy (Protocol 1). Selective PDE10A inhibition significantly reduced IL-6 and IL-8 secretion levels from two independent CD patient biopsies compared to DMSO vehicle (Figure 11).

[0269] The ability of selective PDE10A inhibition to significantly reduce the levels of inflammatory cytokines in colonic mucosa from CD patients indicates the therapeutic utility of PDE10A inhibitors for the treatment of CD in addition to UC. Just as PF-2545920 can treat CD by inhibiting PDE10A, the compounds of the present invention can also treat CD.

[0270] Protocol 1 Biopsies were obtained from inflamed colonic mucosa of patients with ulcerative colitis or Crohn's disease during routine endoscopy. Ex vivo biopsy cultures for analysis of inflammatory cytokine biomarkers were performed as previously described (Vossenkamper A. et al. A CD3-specific antibody reduces cytokine production and alters phosphoprotein profiles in intestinal tissues from patients with inflammatory bowel disease. Gastroenterology, 147, 172-183 (2014)). Biopsies were cultured in organ culture for 24 h with the addition of a positive control compound or a specific PDE10A inhibitor. Supernatants collected at the end of the experiment were snap frozen and stored at -70°C. For cytokine measurements, frozen culture supernatants were thawed and analyzed for inflammatory cytokine levels using Luminex cytokine assay kits (R&D Systems) and an R&D Systems MAGPIX® analyzer. Mean ± SD values ​​were calculated for the levels of spontaneous cytokine production measured in biopsy culture supernatants from each treatment group.

[0271] Protocol 2 Ulcerative colitis donor samples were obtained with full ethical consent from patients undergoing therapeutic resection for ulcerative colitis. Tissues were placed on a Netwell filter with the top (mucosal) side facing up. Biopsy tissues were then cultured in control medium or medium containing test compound at 37°C in an incubator with high O2 atmosphere. To minimize variability, biopsies were also cultured in the presence of the inflammatory stimulant Staphylococcus enterotoxin B (SEB) to aid in normalization of cytokine levels. Media samples were collected approximately 18 hours after the start of culture, protease inhibitors were added, and samples were stored at -80°C. Supernatants were then subjected to ELISA analysis to measure cytokines.

[0272] Evaluation of PDE10A inhibitors in IL-8 neutrophil activation The PDE10A compound PF-02545920 was evaluated in an in vitro assay of IL-8 neutrophil activation. PF-02545920 dose-dependently inhibited IL-8-induced neutrophil activation (as shown in Figure 3). This is an interesting result, as a role for PDE10A in neutrophil function has not been previously reported, and further suggests a role for PDE10A in regulating inflammation and that PDE10A inhibitors may be suitable as therapeutics for inflammatory bowel disease.

[0273] The above described embodiments are not intended to limit the scope of protection afforded by the claims, but rather to illustrate examples of how the invention may be practiced.

Claims

1. A compound of formula (IA) or (IB) 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein X is selected from N and CR ４ and; Y is selected from N and CR ５ and is selected from; CR ４ and CR ５ at least one of which is present; Z is selected from N and CR ６ and; R １ is selected from the group consisting of H, C １ -C ６ alkyl and -SO ２ R ７ and the C １ -C ６ alkyl is optionally substituted with one or more substituents independently selected from halo, oxo, -NR ａ R ｂ , -C(O)NR ａ R ｂ , -C(O)OR ｃ , -OR ｃ ; R ２ and R ３ are each independently selected from the group consisting of H, halo, and C １ -C ６ alkyl, and said C １ -C ６ alkyl is optionally substituted with one or more halo atoms; R ４ and R ５ are H, -C(O)OR ｃ , -C(O)N(R ｄ )SO ２ R ｅ 、-C(O)N=S(O)R ｅ ２ 、-N=S(O)R ｅ ２ 、-N(R ｄ )C(O)N=S(O)R ｅ ２ 、 -N(R ｄ ), C(O)NR ｅ ２ ,-N(R ｄ ), SO ２ R ｅ ,-S(O)(=NR ｄ )R ｅ , 【Chemical 2】 is independently selected from the group consisting of; R ６ is selected from H, F, Cl and C １ -C ６ alkyl, and said C １ -C ６ alkyl is optionally substituted with one or more halo atoms; R ７ is selected from H and C １ -C ６ alkyl, said C １ -C ６ alkyl being optionally substituted with one or more halo atoms; R ８ is C １ -C ６ alkyl, -OH, and -NR ａ R ｂ selected from, said C １ -C ６ alkyl is optionally substituted with one or more halo atoms; R ９ is C １ -C ６ alkyl, -OH, oxo, and -NR ａ R ｂ selected from, said C １ -C ６ alkyl is optionally substituted with one or more halo atoms; R １０ is selected from H and C １ -C ６ alkyl, said C １ -C ６ alkyl is optionally substituted with one or more halo atoms; R ａ , R ｂ , R ｃ , R ｄ and R ｅ are each independently selected from H and C １ -C ６ alkyl, and said C １ -C ６ alkyl is optionally substituted with one or more halo atoms or R ａ and R ｂ can together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle or two Rs bonded to the same atom can together with the atom to which they are bonded form a 5- or 6-membered heterocycle; ｅ ​ m is 0, 1, 2, 3 or 4; n is 1 or 2; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4; R １ is H or optionally substituted C １ -C ６ is alkyl, at least one of R ４ and R ５ is present and is not H; and wherein C1-C6 alkyl is a fully saturated branched, unbranched or cyclic hydrocarbon,[[]]END]] a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

2. R ４ and R ５ at least one of which is present, -C(O)OR ｃ , -C(O)N(R ｄ )SO ２ R ｅ 、-C(O)N=S(O)R ｅ ２ 、-N=S(O)R ｅ ２ 、-N(R ｄ )C(O)N=S(O)R ｅ ２ 、 -N(R ｄ )(C(O)NR ｅ ２ 、-N(R ｄ )(SO ２ R ｅ 、-S(O)(=NR ｄ )(R ｅ 、 【Chemical Formula 3】 The compound according to claim 1, selected from the group consisting of.

3. R ２ The compound according to claim 1, wherein R is H.

4. R ３ The compound according to claim 1, wherein R is H.

5. R １ is selected from the group consisting of H, C １ -C ３ alkyl and -SO ２ Me, and the C １ -C ３ alkyl is optionally substituted with one or more substituents independently selected from halo and -C(O)OH, the compound according to claim 1.

6. R １ is H, Me, Et, -CH ２ CF ３ CH ２ C(O)OH, cyclopropyl, and -SO ２ The compound according to claim 1, selected from the group consisting of Me.

7. Z is selected from N and CR ６ and R ６ is selected from H, F, Cl and Me; preferably, Z is CR ６ The compound according to claim 1, wherein.

8. Each R ｄ is selected from H and Me, and each R ｅ is Me, the compound according to claim 1.

9. X is selected from N and CR ４ ; R ４ is H, -C(O)OR ｃ , -C(O)N(R ｄ )SO ２ R ｅ ; -C(O)N=S(O)R ｅ ２ ; 【Chemical Formula 4】 The compound according to claim 1, selected from.

10. X is selected from N and CR ４ ; R ４ is selected from H, -C(O)OH, -C(O)NHSO ２ Me -C(O)NMeSO ２ Me, -C(O)N=S(O)Me ２ , 【Chemical Formula 5】 The compound according to claim 1, selected from.

11. Y is selected from N and CR ５ and R ５ is selected from H, -C(O)OH, -C(O)N(Me)SO ２ Me -C(O)N=S(O)Me ２ 、-N=S(O)Me ２ 、-NH-C(O)N=S(O)Me ２ 、-NH-C(O)NHMe、 -NHSO ２ Me, -S(O)(=NH)Me, 【Chemical Formula 6】 The compound according to claim 1, selected from.

12. (i) X is selected from N and CR4; and R4 is H, -C(O)ORc, -C(O)N(Rd)SO2Re; -C(O)N=S(O)Re2, 【Chemical 7】 selected from; (ii) Y is selected from N and CR5; and R5 is H, -C(O)OH, -C(O)N(Me)SO2Me, -C(O)N=S(O)Me2, -N=S(O)Me2, -NHC(O)N=S(O)Me2, -NHC(O)NHMe, -NHSO2Me, -S(O)(=NH)Me, 【Chemical 8】 selected from; (iii) Z is selected from N and CR6; and R6 is selected from H, F, Cl, and Me, preferably where Z is CR6; (iv) R1 is selected from the group consisting of H, Me, Et, -CH2CF3, CH2C(O)OH, cyclopropyl, and -SO2Me; (v) R2 and R3 are independently selected from the group consisting of H, halo, and C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with one or more halo atoms; (vi) R8 is selected from C1-C6 alkyl, -OH, and -NRaRb, said C1-C6 alkyl being optionally substituted with one or more halo atoms; (vii) R9 is selected from C1-C6 alkyl, -OH, oxo, and -NRaRb; (viii) R10 is selected from H and C1-C6 alkyl, and said C1-C6 alkyl is optionally substituted with one or more halo atoms; (ix) Ra, Rb, and Rc are each independently selected from H and C1-C6 alkyl, and said C1-C6 alkyl is optionally substituted with one or more halo atoms, or Ra and Rb together with the nitrogen atom to which they are attached can form a 5- or 6-membered heterocyclic ring; and (x) Rd is selected from H and Me, and each Re is independently Me, The compound according to claim 1.

13. 2-[[4-[2-Methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylic acid; 2-[[4-[2-Methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid; 2-[[4-[1-Methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid; Ammonium 2-[[4-[1-Methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylate; 2-[4-(4-Pyridyl)-3-[4-(2-quinolylmethoxy)phenyl]pyrazol-1-yl]acetic acid; 2-[[4-[1-Methylsulfonyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline; N-[Dimethyl(oxo)-λ6-sulfanilidene]-5-methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide; N-[Dimethyl(oxo)-λ6-sulfanilidene]-2-[[4-[4-(4-pyridyl)-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide; 2-[[4-[1-Methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-methylsulfonyl-quinoline-3-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide; 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-(1-oxothiolan-1-ylidene)quinoline-3-carboxamide; N-(cyclopropyl-methyl-oxo-λ6-sulfanilylidene)-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide; N-methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-methylsulfonyl-quinoline-3-carboxamide; N-methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-methylsulfonyl-quinoline-4-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazoline-4-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-3-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoxaline-2-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-1,5-naphthyridine-3-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-7-fluoro-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-6-fluoro-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-5-fluoro-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-6-methyl-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-6-fluoro-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide; 5-chloro-N-[dimethyl(oxo)-λ6-sulfanilylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide; N-[dimethyl(oxo)-λ6-sulfanilylidene]-2-[[4-[1-ethyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxamide; 2-[[4-[1-cyclopropyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-N-[dimethyl(oxo)-λ6-sulfanilylidene]quinoline-4-carboxamide; 2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid; 2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylic acid; N-[dimethyl(oxo)-λ6-sulfanilylidene]-2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxamide; dimethyl-oxo-[[2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]imino]-λ6-sulfane; imino-methyl-oxo-[2-[[4-[4-(4-pyridyl)-1H-pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]-λ6-sulfane; N-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]methanesulfonamide; 1-methyl-3-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]urea; 1-[dimethyl(oxo)-λ6-sulfanilylidene]-3-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-quinolyl]urea; 4-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]-1,4-thiazinane-1,1-dioxide; 4-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]piperazin-2-one; 1-[2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazolin-4-yl]azetidin-3-amine; 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-4-piperazin-1-yl-quinazoline; 1-[3-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoxalin-2-yl]azetidin-3-amine; and 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]-3-piperazin-1-yl-quinoxaline, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, the compound according to claim 1, selected from the group consisting of.

14. A compound of formula (IIA) or (IIB) 【Chemical Formula 7】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein R １１ is selected from the group consisting of H, C １ -C ６ alkyl and -SO ２ R ７ and the C １ -C ６ alkyl is optionally substituted with one or more substituents independently selected from halo, oxo, -NR ａ R ｂ , -C(O)NR ａ R ｂ , -C(O)OR ｃ , -OR ｃ and is preferably selected from the group consisting of H and C １ -C ６ alkyl, more preferably C １ -C ６ alkyl, even more preferably Me, and the C １ -C ６ alkyl or Me is optionally substituted with one or more halo, preferably F; R １２ is H, -C(O)OR ｃ , -C(O)N(R ｄ ), SO ２ R ｅ , -C(O)N=S(O)R ｅ ２ 、-N=S(O)R ｅ ２ 、-N(R ｄ )C(O)N=S(O)R ｅ ２ 、-N(R ｄ )C(O)NR ｅ ２ 、 -N(R ｄ )SO ２ R ｅ 、-S(O)(=NR ｄ )R ｅ 、 【Chemical Formula 8】 selected from the group consisting of, preferably -C(O)N=S(O)R ｅ ２ , more preferably -C(O)N=S(O)Me ２ and; R １３ is halo, -OR ｆ and C １ -C ６ selected from the group consisting of alkyl, wherein said C １ -C ６ alkyl is optionally substituted with one or more halo, preferably F; R ｆ is selected from the group consisting of H and C １ -C ６ alkyl, and said C １ -C ６ alkyl is optionally substituted with one or more halo, preferably F; and r is 0, 1, 2, 3, or 4, preferably 0; and R ７ 、 R ８ 、 R ９ 、 R １０ 、 R ａ 、 R ｂ 、 R ｃ 、 R ｄ 、 R ｅ 、 m, n, p, and q are as described in any of claims 1 to 12 the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

15. R １２ is -C(O)OR ｃ -C(O)N(R ｄ )SO ２ R ｅ -C(O)N=S(O)R ｅ ２ -N=S(O)R ｅ ２ and -N(R ｄ )C(O)N=S(O)R ｅ ２ 、-N(R ｄ )C(O)NR ｅ ２ 、-N(R ｄ )SO ２ R ｅ 、-S(O)(=NR ｄ )R ｅ 、 【Chemical Formula 9】 selected from the group consisting of Preferably -C(O)N=S(O)R ｅ ２ More preferably -C(O)N=S(O)Me ２ The compound according to claim 14, wherein it is

16. The compound according to claim 14, which is N-[dimethyl(oxo)-λ6-sulfanilylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]imidazo[1,2-a]pyridine-3-carboxamide, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

17. A pharmaceutical composition comprising the compound according to claim 1 and one or more excipients.

18. The pharmaceutical composition according to claim 17 for use as a medicament.

19. The pharmaceutical composition according to claim 17 for use in the prevention and / or treatment of inflammatory bowel disease.

20. The pharmaceutical composition for use according to claim 19, wherein the inflammatory bowel disease is ulcerative colitis and / or Crohn's disease.

21. Use of the compound according to claim 1 for the manufacture of a medicament.

22. The use according to claim 21, wherein the medicament is for the prevention and / or treatment of inflammatory bowel disease.

23. The use according to claim 22, wherein the inflammatory bowel disease is ulcerative colitis and / or Crohn's disease.

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