Imidazole organic compounds and their use in inflammatory bowel disease

Abstract

The present invention relates to compounds of formula (I) or pharma- ceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof. JPEG2024528072000121.jpg39170The 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 (IBD), particularly ulcerative colitis (UC) and Crohn's disease (CD).

Description

[Technical field]

[0001] The present invention relates to compounds of formula (I) 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 comprising the compounds, and the use of the compounds in treating diseases or conditions associated with inflammatory bowel disease (IBD), in particular ulcerative colitis (UC) and Crohn's disease (CD). [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 present invention, a compound of formula (I) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, Ring A is selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each of which is optionally selected from halo, (C 1 -C 4 ) alkyl, -OR 3 , -NR 4 R 5 , -C(O)R 6 , -C(O)OR 6 , and -C(O)NR 4 R 5 and is substituted with one or more substituents selected from (C 1 -C 4 ) alkyl is optionally substituted with one or more halo; Ring B is optionally selected from halo, oxo, (C 1 -C 4 ) alkyl, -OR 7 , -NR 8 R 9 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 8 R 9 -S(O)(NR 7 )R 7 and (C 1 -C 4) alkyl is optionally substituted with one or more halo; Ring C optionally contains one or more R 2 a 5- or 6-membered carbocyclic, 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl group substituted with R 1 But H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally halo, -NR 10 R 11 and a 4- to 6-membered heterocycle; Each R 2 are independent, halo, (C 1 -C 4 ) alkyl, -OR 12 , -NR 13 R 14 , -C(O)R 12 , -C(O)OR 12 , -C(O)NR 13 R 14 , aryl, and 4- to 6-membered heterocycle, 1 -C 4 ) the alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycle; R 3 But H and (C 1 -C 4 ) alkyl, 1 -C 4 ) alkyl is optionally selected from halo, -OH, and -NR 15 R 16 and R 4 ~R 16 are each independently H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally substituted with one or more substituents selected from halo, or a group R 4 and R 5 , R 8and R 9 , R 10 and R 11 , R 13 and R 14 , R 15 and R 16 together with the atom to which they are attached, optionally halo and (C 1 -C 4 ) alkyl, which may form a 5- or 6-membered heterocyclic ring substituted with one or more substituents selected from Compound or its pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug is provided.

[0010] The compounds of formula (I) and any subformulas thereof are "compounds of the invention", or "the compounds".

[0011] A second aspect of the invention provides a pharmaceutical composition comprising a compound of the invention.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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 Hydrolyzes cAMP at 3 μM K 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] The present invention provides a compound that may be a PDE10A inhibitor for use in the prevention and / or treatment of inflammatory bowel disease. Preferably, the inflammatory bowel disease is selected from ulcerative colitis and / or Crohn's disease. This is a third aspect of the present invention. [Brief description of the drawings]

[0020] [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 (US 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]Figures 6-9 include graphs showing the effects of compounds of Reference Example A (Figure 6A), Reference Example B (Figure 6B), Reference Example C (Figure 7A), Reference Example D (Figure 7B), Reference Example E (Figure 8A), Reference Example F (Figure 8B), and Reference Example G (Figure 9) on inflammatory cytokine release from ex vivo ulcerative colitis colon tissue (UC donor 3). [Figure 7] Figures 6-9 include graphs showing the effects of compounds of Reference Example A (Figure 6A), Reference Example B (Figure 6B), Reference Example C (Figure 7A), Reference Example D (Figure 7B), Reference Example E (Figure 8A), Reference Example F (Figure 8B), and Reference Example G (Figure 9) on inflammatory cytokine release from ex vivo ulcerative colitis colon tissue (UC donor 3). [Figure 8] Figures 6-9 include graphs showing the effects of compounds of Reference Example A (Figure 6A), Reference Example B (Figure 6B), Reference Example C (Figure 7A), Reference Example D (Figure 7B), Reference Example E (Figure 8A), Reference Example F (Figure 8B), and Reference Example G (Figure 9) on inflammatory cytokine release from ex vivo ulcerative colitis colon tissue (UC donor 3). [Figure 9] Figures 6-9 include graphs showing the effects of compounds of Reference Example A (Figure 6A), Reference Example B (Figure 6B), Reference Example C (Figure 7A), Reference Example D (Figure 7B), Reference Example E (Figure 8A), Reference Example F (Figure 8B), and Reference Example G (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

[0021] The applicant has 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 (I) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein Ring A is selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each of which is optionally selected from halo, (C 1 -C 4 ) alkyl, -OR 3 , -NR 4 R 5 , -C(O)R 6 , -C(O)OR 6 , and -C(O)NR 4 R 5 and is substituted with one or more substituents selected from (C 1 -C 4 ) alkyl is optionally substituted with one or more halo; Ring B is optionally selected from halo, oxo, (C 1 -C 4 ) alkyl, -OR 7 , -NR 8 R 9 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 8 R 9 -S(O)(NR 7 )R 7 a 4- to 7-membered monocyclic carbocyclic or heterocyclic ring, or a 6- to 10-membered bicyclic carbocyclic or heterocyclic ring, each of which is substituted with one or more substituents selected from (C 1 -C 4 ) alkyl is optionally substituted with one or more halo; Ring C optionally contains one or more R 2 a 5- or 6-membered carbocyclic, 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl group substituted with R 1But H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally halo, -NR 10 R 11 and a 4- to 6-membered heterocycle; Each R 2 are independent, halo, (C 1 -C 4 ) alkyl, -OR 12 , -NR 13 R 14 , -C(O)R 12 , -C(O)OR 12 , -C(O)NR 13 R 14 , aryl, and 4- to 6-membered heterocycle; 1 -C 4 ) the alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycle; R 3 But H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally selected from halo, -OH, and -NR 15 R 16 and R 4 ~R 16 are each independently H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally substituted with one or more substituents selected from halo, or a group R 4 and R 5 , R 8 and R 9 , R 10 and R 11 , R 13 and R 14 , R 15 and R 16 together with the atom to which they are attached, optionally halo and (C1 -C 4 ) forming a 5- or 6-membered heterocyclic ring substituted with one or more substituents selected from alkyl; Compound or its pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug is provided.

[0022] 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.

[0023] As used herein, the term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I) groups. Unless otherwise specified, halo is preferably fluoro in each occurrence.

[0024] "(C 1 -C 4 The term "alkyl" means a fully saturated branched, unbranched or cyclic hydrocarbon moiety having 1, 2, 3, or 4 carbon atoms. 1 -C 4 ) Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl.

[0025] As used herein, the term "aryl" refers to benzene (C 6 H 6 ) It will be understood that this may also be referred to as phenyl.

[0026] 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.

[0027] 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.

[0028] As used herein, a "5- or 6-membered heteroaryl" is an aromatic ring system containing 5 or 6 ring atoms, at least one of which is a heteroatom. Unless otherwise stated herein, examples of 5- or 6-membered heteroaryl include pyrrole, pyrazole, imidazole, triazole, furan, thiophene, oxazole, isoxazole, isothiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0029] The term "4- to 7-membered monocyclic carbocycle" is a saturated monocyclic ring system containing 4 to 7 ring atoms, each of which is a carbon atom. Examples include cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Similarly, the term "5- or 6-membered carbocycle" is a saturated monocyclic ring system containing 5 or 6 ring atoms, each of which is a carbon atom. Examples include cyclopentane and cyclohexane.

[0030] The term "4- or 6-membered heterocycle" is a saturated monocyclic ring system containing 4 to 6 ring atoms, at least one of which is a heteroatom. Examples include azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine. The term "5- or 6-membered heterocycle" is a subset of this containing 5 to 6 ring atoms, at least one of which is a heteroatom.

[0031] The term "5- or 6-membered heteroaryl" refers to an aromatic monocyclic ring consisting of 5 or 6 ring atoms, at least one of which is a heteroatom. Examples include pyrrole, pyrazole, imidazole, triazole, furan, thiophene, oxazole, isoxazole, isothiazole, thiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

[0032] The term "6-10 membered bicyclic carbocycle or heterocycle" refers to a saturated ring system containing 6 to 10 atoms, each of which is a carbon atom in the case of a carbocycle, and at least one heteroatom in the case of a heterocycle. The ring system contains two rings that are fused together (i.e., two atoms are shared in common between the two rings), or the ring system is a spiro group in which one atom is shared in common between the two rings.

[0033] Unless otherwise specified, examples of 6-10 membered bicyclic carbocyclic rings which are spiro groups include: [ka] Examples include:

[0034] Unless otherwise specified, examples of the fused group, 6- to 10-membered bicyclic carbocyclic ring, include: [ka] Examples include:

[0035] Unless otherwise specified, examples of 6-10 membered bicyclic heterocycles that are spiro groups include: [ka] Examples include:

[0036] Unless otherwise specified, examples of the fused group are 6- to 10-membered bicyclic heterocycles: [ka] Examples include:

[0037] Ring C As noted above, ring C can be a 5- or 6-membered carbocyclic ring, a 5- or 6-membered heterocyclic ring, or a 5- or 6-membered heteroaryl group. Each of these groups can optionally be joined by one or more R 2 This means that Ring C and the adjacent pyrimidine are fused to form a fully aromatic bicyclic ring system, or that one ring (the pyrimidine) is aromatic and the other is saturated (except for the two common bridging carbons, which are unsaturated) to form a fused bicyclic ring system.

[0038] Options for the pyrimidine / Ring C bicycle of formula (I) include pyrimidines fused to a 5- or 6-membered heteroaryl group selected from optionally substituted pyrrole, pyrazole, imidazole, triazole, furan, thiophene, oxazole, isoxazole, isothiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0039] Options for the pyrimidine / Ring C bicycle of formula (I) include pyrimidines fused to a 5- or 6-membered heterocyclic group selected from optionally substituted pyrrolidine, pyrazolidine, tetrahydrofuran, dioxolane, tetrahydrothiophene, oxathiolane, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, wherein the two bridging carbons of the 5- or 6-membered carbocyclic ring are unsaturated.

[0040] Options for the pyrimidine / Ring C bicycle of formula (I) include pyrimidines fused to a 5- or 6-membered carbocyclic group selected from optionally substituted cyclopentane and cyclohexane, where the two bridging carbons of the 5- or 6-membered carbocyclic ring are unsaturated.

[0041] Non-limiting examples of Ring C and fused pyrimidines are shown below, each of which tautomers may be substituted as described above. [ka] [ka]

[0042] The above list of bicyclic ring systems includes, where applicable but not explicitly mentioned, positional isomers of the heteroatoms in Ring C, and tautomers.

[0043] Ring C is preferably a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycle, i.e., Ring C preferably contains at least one heteroatom.

[0044] The definitions of groups in the compounds of the present invention may vary depending on the structure of Ring C, as described below. If any group below is not defined, the definition applies from above.

[0045] 1. Ring C is an optionally substituted 5- or 6-membered heteroaryl. A particular feature of the first aspect of the invention is that Ring C is a 5- or 6-membered heteroaryl, such as those mentioned above. In this case, Ring C is preferably a 5-membered heteroaryl. Particularly preferred 5-membered heteroaryl Ring C groups are pyrrole, pyrazole, imidazole and triazole, i.e. the heteroatom or heteroatoms of Ring C are preferably nitrogen. Examples of these particularly preferred 5-membered heteroaryl Ring C groups in combination with fused pyrimidines include: [ka] (each of which may optionally be one or more R 2 (which may be substituted with ), which in each case includes the replacement of NH groups with H.

[0046] The 5-membered heteroaryl of Ring C preferably contains at least two heteroatoms, i.e. at least two nitrogen atoms, which means that Ring C is a pyrazole, imidazole, or triazole.

[0047] In view of the above, the compounds of the present invention containing a 5- or 6-membered heteroaryl as ring C are compounds of formula (IA) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein X is N or CR 18 and; Y is N or CR 18 and; Ring A is selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each of which is optionally selected from halo, (C 1 -C 4 ) alkyl, -OR 3 , -NR 4 R 5 , -C(O)R 6 , -C(O)OR 6 , and -C(O)NR 4 R 5 and is substituted with one or more substituents selected from (C 1 -C 4 ) alkyl is optionally substituted with one or more halo; Ring B is optionally selected from halo, oxo, (C 1 -C 4 ) alkyl, -OR 7 , -NR 8 R 9 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 8 R 9 -S(O)(NR 7 )R 7 (C 1 -C 4 ) alkyl is optionally substituted with one or more halo; R 1 But H and (C 1 -C 4 ) alkyl; (C 1 -C4 ) alkyl is optionally halo, -NR 10 R 11 and a 4- to 6-membered heterocycle; R 3 But H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally selected from halo, -OH, and -NR 15 R 16 substituted with one or more substituents selected from R 17 But, H, (C 1 -C 4 ) alkyl, -OR 12 , -NR 13 R 14 , -C(O)R 12 , -C(O)OR 12 , -C(O)NR 13 R 14 , aryl, and 4- to 6-membered heterocycle; 1 -C 4 ) the alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycle; Each R 18 are independent of each other, H, halo, (C 1 -C 4 ) alkyl, -OR 12 , -NR 13 R 14 , -C(O)R 12 , -C(O)OR 12 , -C(O)NR 13 R 14 , aryl, and 4- to 6-membered heterocycle; 1 -C 4 ) the alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycle; and R 4 ~R 16 are each independently H and (C 1 -C 4 ) alkyl; (C 1 -C 4) alkyl is optionally substituted with one or more substituents selected from halo, or a group R 4 and R 5 , R 8 and R 9 , R 10 and R 11 , R 13 and R 14 , R 15 and R 16 together with the atom to which they are attached, optionally halo and (C 1 -C 4 ) forming a 5- or 6-membered heterocyclic ring substituted with one or more substituents selected from alkyl; Compound or its pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug It is preferable that:

[0048] A particular feature of this embodiment of the invention is that one of X and Y is N and the other is CR 18 This means that ring C is pyrazole or imidazole. These two groups are particularly preferred for ring C and are part of the compounds of formula (IA') and compounds of formula (IA''). [ka]

[0049] Each R in formula (IA), (IA') and (IA'') 18 H, halo and (C 1 -C 4 )alkyl; (C 1 -C 4 ) alkyl is optionally substituted with one or more substituents selected from halo. Each R 18 is preferably H or halo, and each R 18 More preferably, is H.

[0050] As noted above, when the compound of the invention is a compound of formula (IA), ring A can be selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each of which is optionally selected from halo, (C 1 -C 4 ) alkyl, -OR 3 , -NR 4 R 5 , -C(O)R 6 , -C(O)OR 6 , and -C(O)NR 4 R 5 and is substituted with one or more substituents selected from (C 1 -C 4 ) alkyl is optionally substituted with one or more halo. Ring A is selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each of which is optionally substituted with halo, (C 1 -C 4 ) alkyl, and -OR 3 and is substituted with one or more substituents selected from (C 1 -C 4 ) alkyl is preferably optionally substituted with one or more halo. In this case, R 3 is H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally substituted with halo and -NR 15 R 16 Particularly preferred Ring A groups are optionally substituted with one or more substituents selected from halo and -OR 3 aryl and pyridyl substituted with R 3 (C 1 -C 4 )Alkyl-NMe 2 The most preferred Ring A group is [ka] It is.

[0051] The above definition of ring A applies equally to formulae (IA') and (IA'').

[0052] When the compound of the invention is of formula (IA), ring B can be a monocyclic or bicyclic group.

[0053] If bicyclic, it optionally includes halo, oxo, (C 1 -C 4 ) alkyl, -OR 7 , -NR 8 R 9 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 8 R 9 -S(O)(NR 7 )R 7 (C 1 -C 4 ) The alkyl is optionally substituted with one or more halo. In this case, ring B is preferably an optionally substituted 7-10 membered bicyclic heterocycle.

[0054] Alternatively, when it is a monocycle, ring B may be selected from halo, oxo, (C 1 -C 4 ) alkyl, -OR 7 , -NR 8 R 9 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 8 R 9 -S(O)(NR 7 )R 7 (C 1 -C 4 ) The alkyl is optionally substituted with one or more halo.

[0055] When the compound of the invention is of formula (IA), preferred Ring B groups are [ka] each optionally substituted with one or more halo.

[0056] The above definition of ring B applies equally to formulae (IA') and (IA'').

[0057] When the compound of the invention is a compound of formula (IA), or formula (IA') or (IA''), R 7 , R 15 , and R 16 are each independently H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) Preferably, the alkyl is optionally substituted with one or more substituents selected from halo.

[0058] When the compound of the invention is a compound of formula (IA), R 17 is H, (C 1 -C 4 ) alkyl, and 4- to 6-membered heterocycle; (C 1 -C 4 ) The alkyl is preferably optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycle. 17 This definition applies equally to formulae (IA') and (IA'').

[0059] When Ring C is an optionally substituted 5- or 6-membered heteroaryl, the undefined groups above inherit their definitions from the compounds of formula (I).

[0060] 2. Ring C is an optionally substituted 5- or 6-membered carbocyclic ring or an optionally substituted 5- or 6-membered heterocyclic ring. Alternatively for ring C being an optionally substituted heteroaryl, it may be an optionally substituted 5- or 6-membered carbocyclic ring or an optionally substituted 5- or 6-membered heterocyclic ring. Carbocyclic and heterocyclic rings are usually saturated, but in the present case, as described above, the two carbon atoms common to the pyrimidine and ring C are unsaturated.

[0061] Ring C is preferably a 5- or 6-membered heterocycle. The heterocycle may optionally be one or more R 2 More preferably, ring C is optionally substituted with one or more R 2 Of the possible choices for Ring C, it is preferred that it is a piperidine (the two carbon atoms common to the pyrimidine and Ring C are unsaturated). A particularly important regioisomer is shown in the compound of formula (IB). [ka]

[0062] Thus, a preferred feature is that the compound is of formula (IB) or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide and / or prodrug thereof, wherein Ring A is selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each of which is optionally selected from halo, (C 1 -C 4 ) alkyl, -OR 3 , -NR 4 R 5 , -C(O)R 6 , -C(O)OR 6 , and -C(O)NR 4 R 5 and is substituted with one or more substituents selected from (C 1 -C 4 ) alkyl is optionally substituted with one or more halo; Ring B is optionally selected from halo, oxo, (C 1 -C 4 ) alkyl, -OR 7 , -NR 8 R 9 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 8 R 9 -S(O)(NR 7 )R 7(C 1 -C 4 ) alkyl is optionally substituted with one or more halo; R 1 But H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally halo, -NR 10 R 11 and a 4- to 6-membered heterocycle; R 3 But H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally selected from halo, -OH, and -NR 15 R 16 and R 19 But, H, (C 1 -C 4 ) alkyl, -C(O)R 12 , -C(O)OR 12 , -C(O)NR 13 R 14 , aryl, and 4- to 6-membered heterocycle; 1 -C 4 ) the alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycle; Each R 20 are independent, halo, (C 1 -C 4 ) alkyl, -OR 12 , -NR 13 R 14 , -C(O)R 12 , -C(O)OR 12 , -C(O)NR 13 R 14 , aryl, and 4- to 6-membered heterocycle; 1 -C 4) the alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycle; R 4 ~R 16 are each independently H and (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl is optionally substituted with one or more substituents selected from halo, or a group R 4 and R 5 , R 8 and R 9 , R 10 and R 11 , R 13 and R 14 , R 15 and R 16 together with the atom to which they are attached, optionally halo and (C 1 -C 4 ) alkyl; and n is 0, 1, 2, 3, 4, 5, or 6 Compound or its pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug It is to be.

[0063] In the compound of formula (IB), R 19 is H, (C 1 -C 4 ) alkyl, and 4- to 6-membered heterocycle; (C 1 -C 4 ) The alkyl is optionally substituted with one or more substituents selected from halo. R 19 is H, (C 1 -C 4 ) alkyl, or [ka] It is preferable that:

[0064] In the compound of formula (IB), each R 20are independently halo, and (C 1 -C 4 ) alkyl, (C 1 -C 4 ) The alkyl is optionally substituted with one or more substituents selected from halo.

[0065] In the compounds of formula (IB), it is preferred that n is 0, 1, 2, 3, or 4. More preferably, n is 0, 1, or 2. Most preferably, n is 0.

[0066] When ring C is a 5- or 6-membered carbocyclic or heterocyclic ring (but heterocyclic ring is preferred), ring A can be selected from the group consisting of aryl and 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo. Ring A is preferably aryl or pyridyl. When ring C is pyridyl, it is preferably 2-pyridyl. However, the most preferred group for ring A is aryl.

[0067] When Ring C is a 5- or 6-membered carbocyclic or heterocyclic ring (but heterocyclic rings are preferred), Ring B is halo, oxo, (C 1 -C 4 ) alkyl, -OR 7 , -NR 8 R 9 , -C(O)R 7 , -C(O)OR 7 , Optionally, -C(O)NR 8 R 9 -S(O)(NR 7 )R 7 (C 1 -C 4 ) alkyl is optionally substituted with one or more halo. Ring B is preferably an optionally substituted 4-7 membered monocyclic heterocycle. In particular, Ring B is optionally substituted with halo, and (C 1 -C 4) alkyl; 1 -C 4 ) alkyl is optionally substituted with one or more halo. In this case, ring B is morpholine, preferably [ka] The structure may be as follows:

[0068] The morpholine is optionally substituted with halo, and 1 -C 4 ) alkyl; 1 -C 4 ) alkyl is optionally substituted with one or more halo. Particular examples of ring B are: [ka] It is.

[0069] When Ring C is a 5- or 6-membered carbocyclic or heterocyclic ring (but a heterocyclic ring is preferred), R 1 is H and (C 1 -C 4 ) alkyl, (C 1 -C 4 ) The alkyl is optionally substituted with one or more substituents selected from halo. R 1 is H, Me or -CF 3 It is preferable that:

[0070] When Ring C is an optionally substituted 5- or 6-membered carbocyclic ring or an optionally substituted 5- or 6-membered heterocyclic ring, such as in compounds of formula (IB), any undefined groups above inherit their definitions from compounds of formula (I).

[0071] In view of all of the above, specific compounds of formula (I) that are particularly useful in the present invention are: 6-[9-methyl-2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane 6-[9-methyl-2-[2-[1-methyl-4-(3-pyridyl)imidazol-2-yl]ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane 6-[1-methyl-6-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane 6-[9-methyl-2-[2-[4-phenyl-1-(tetrahydropyran-4-ylmethyl)imidazol-2-yl]ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane 6-[9-methyl-2-[2-[1-(2-morpholinoethyl)-4-phenyl-imidazol-2-yl]ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane 6-[6-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane 6-[9-methyl-2-[2-(4-phenyl-1H-imidazol-2-yl)ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane 6-[1-(azetidin-3-ylmethyl)-6-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane (3aS,6aR)-5-[1-methyl-6-[2-(4-phenyl-1H-imidazol-2-yl)ethynyl]pyrazolo[3,4-d]pyrimidin-4-yl]-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole 2-[3-[2-[2-[4-[(3aS,6aR)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-1-methyl-pyrazolo[3,4-d]pyrimidin-6-yl]ethynyl]-1H-imidazol-4-yl]phenoxy]-N,N-dimethyl-ethanamine 4-[2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]morpholine (3R)-3-Methyl-4-[2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]morpholine (3S)-3-Methyl-4-[2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]morpholine 4-[2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-7-(oxetan-3-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]morpholine 4-[7-(cyclopropylmethyl)-2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]morpholine (3aR,6aS)-5-(1-(cyclopropylmethyl)-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole (3aR,6aS)-5-(1-ethyl-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole (3aR,6aS)-5-(1-isopropyl-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole (3aR,6aS)-5-(6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole (3aR,6aS)-5-(9-methyl-2-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)hexahydro-1H-furo[3,4-c]pyrrole (R)-3-Methyl-4-(9-methyl-2-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine (S)-3-Methyl-4-(9-methyl-2-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine (3aR,6aS)-5-(1-methyl-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole 1-Imino-4-(1-methyl-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1l6-thiomorpholine-1-oxide (3aR,6aS)-5-(1-isopropyl-6-((4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole (3aR,6aS)-5-(1-(cyclopropylmethyl)-6-((4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole (3aR,6aS)-5-(1-(oxetan-3-yl)-6-((4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole (3aR,6aS)-5-(9-methyl-2-((4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)hexahydro-1H-furo[3,4-c]pyrrole (R)-3-Methyl-4-(9-methyl-2-((4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine (S)-3-Methyl-4-(9-methyl-2-((4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine (3aR,6aS)-5-(9-methyl-2-((4-(pyridin-3-yl)-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)hexahydro-1H-furo[3,4-c]pyrrole (R)-3-methyl-4-(9-methyl-2-((4-(pyridin-3-yl)-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine and (S)-3-Methyl-4-(9-methyl-2-((4-(pyridin-3-yl)-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof. It is.

[0072] Further definitions 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.

[0073] 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.

[0074] 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.

[0075] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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]

[0086] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0087] 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).

[0088] 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.

[0089] Mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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)).

[0099] A "pharmacologically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and typically biologically suitable for administration to a subject.

[0100] 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.

[0101] 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).

[0102] 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.

[0103] 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]

[0104] 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 ( 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.

[0105] 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.

[0106] 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.

[0107] Pharmaceutically acceptable solvates according to the invention include those in which the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -Acetone, d 6 -Contains DMSO.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] Tablets may be film coated or enteric coated according to methods known in the art.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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 passing through the host's skin. For example, a transdermal device is in the form of a dressing and includes a backing member, a reservoir that contains 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] "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.

[0131] 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.

[0132] The compounds of the invention, or pharmaceutical compositions comprising compounds of the invention, are intended for use as pharmaceuticals.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] The aforementioned method is preferably a method wherein the inflammatory bowel disease is ulcerative colitis and / or Crohn's disease.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] [ka] In Scheme 1, X and Y are selected from CH or N, and at least one CR 18 and there is one N. Ring A, ring B, R 1 , R 17 and R 18 is as defined above.

[0143] Compounds of general formula (IA) and (IB) can be readily prepared by standard techniques. For example, 4-phenyl-3-H-imidazole (1-1) can be converted to compounds of general formula (Ib) via alkylation with a suitable alkyl halide. Furthermore, compounds of general formula (Ia) can be converted to compounds of general formula (Ib) via Suzuki-Miyaura coupling with a suitable imidazole halide. Compounds of general formula (Ib) can be reacted with iodine to give compounds of general formula (Ic). Compounds of general formula (Ic) can be reacted with intermediates (Ig) or (Ii) under Sonogashira coupling conditions to give compounds of general formula (Id) or (IA) after optional Boc or SEM deprotection. Compounds of general formula (Id) can be converted to compounds of general formula (IB) via TFA-mediated Boc deprotection and optional alkylation with a suitable alkyl halide or reductive amination with a suitable ketone.

[0144] [ka] In Scheme 2, X and Y are CR 18 or N, where at least one CH and one N are present. Ring B, R 17 , and R 18 is as defined above.

[0145] Compounds of general formula (1g) can be readily prepared by standard techniques. Intermediate (2-1) can be methylated to give intermediate (2-2), which can then be converted to intermediate (2-3) via a Sandmeyer reaction. Intermediate (2-3) or compounds of general formula (Ie) can be converted to compounds of general formula (If) via nucleophilic aromatic substitution and optional alkylation. Compounds of general formula (If) can be converted to compounds of general formula (Ig) via Sonogashira coupling with trimethylsilylacetylene, followed by deprotection with potassium carbonate.

[0146] [ka] In Scheme 2, Ring B is as defined above.

[0147] Compounds of general formula (1i)) can be readily prepared by standard techniques. Intermediate (3-1) can be converted to compounds of general formula (Ih) via nucleophilic aromatic coupling. Compounds of general formula (Ih) can be converted to compounds of general formula (Ig) via Sonogashira coupling with trimethylsilylacetylene, followed by deprotection with potassium carbonate. EXAMPLES

[0148] The compounds of formula (I), including formula (IA) and (IB) above, can be prepared by conventional methods or in analogy thereto. The preparation of intermediates 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.

[0149] The following abbreviations have been used: aq aqueous solution Boc tert-Butyloxycarbonyl DCM Dichloromethane DIPEA Diisopropylethylamine DMF Dimethylformamide dppf 1,1'-bis(diphenylphosphino)ferrocene ES+ Electrospray Ionization h hour(s) HPLC High Performance Liquid Chromatography LCMS Liquid Chromatography Mass Spectrometry min Minute(s) PE Petroleum Ether Rt retention time sat saturation SEM Trimethylsilylethoxymethyl TBAF Tetrabutylammonium fluoride TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TMS Trimethylsilane UPLC Ultra High Performance Liquid Chromatography XantPhos-Pd-G2 Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0150] Examples and intermediate compounds Experimental Method Reactions were carried out at room temperature unless otherwise stated. Preparative chromatography was performed using a CombiFlash® system equipped with an Isolute Flash II silica column. Reverse phase column chromatography was performed using a CombiFlash® system equipped with a RediSep Rf C18 column. Reverse phase HPLC was performed on either a Gilson system equipped with an ACE-5AQ, 100×21.2 mm, 5 μm column with UV detector or an ACCQPrep system with UV and mass detector. Compounds were analyzed by UPLC using an Agilent 1290 Infinity system (methods listed below). LCMS analysis was performed using a Shimadzu LCMS-2020 system equipped with a PDA: SPD-M40 and MS: LCMS-2020 detector using a Kinetex EVO C18 column. The compounds prepared were named using IUPAC nomenclature.

[0151] UPLC method Method A (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-equilibration 1.0 min, 254 nm 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. Method C (3 minutes, 5~50) HALO C18, 2.0 μm, 3.0 × 50 mm, 40 °C, 1.5 mL / min, 5% MeCN (+0.1% formic acid) in water (+0.1% formic acid), 5–50% over 3.0 min, 254 nm Method D (3 minutes, 10~70) Titan C18, 1.9μm, 3.0×50mm, 40℃, 1.5mL / min, water (+0.04%NH3 H 2 10% MeCN in O), 10–70% over 3.0 min, 254 nm Method E (3 minutes, 10~95) Kinetex EVO C18, 2.6μm, 3.0×50mm, 40℃, 1.2mL / min, water (5mM NH 4 HCO 3 ) in 10% MeCN, 10–70% over 3.0 min, 254 nm Method F (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) for 1.0 min, 5–100% over 8.0 min, hold for 0.2 min, re-equilibration 0.8 min, 200–300 nm Method G (3 minutes, 5~50) HALO C18, 2.0 μm, 3.0 × 50 mm, 40 °C, 1.5 mL / min, 5% MeCN (+0.05% TFA) in water (+0.05% TFA), 5–95% over 3.0 min, 254 nm

[0152] Experimental procedure Intermediate 1 [ka] 1-Methyl-4-phenyl-imidazole N 2 Under an atmosphere of 0° C., NaH (60% in mineral oil, 3.33 g, 83.2 mmol) was added to a solution of 4-phenyl-3H-imidazole (10 g, 69.4 mmol) in DMF (70 mL) at 0.5° C. The solution was stirred for 30 min, then the temperature was maintained at 0° C. while the CH 3 I (5.2 mL, 83.5 mmol) was added dropwise over 10 min. The resulting mixture was stirred for an additional 1 h without cooling. The reaction was then quenched by adding water (100 mL) and extracted with EtOAc (5×100 mL). The combined organic layers were washed with brine (30 mL) and diluted with anhydrous Na 2 SO 4The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (7.80 g, 71.1%) as a yellow solid. LCMS (ES+): 159.0 [MH] +

[0153] Examples 2-5 were prepared similarly to intermediate 1 by alkylation of imidazole; see Table 1 below. Table 1: Alkylation of imidazole with sodium hydride [ka] [Table 1]

[0154] Intermediate 6 [ka] 3-(1-Methylimidazol-4-yl)pyridine N 2 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.00 g, 9.80 mmol), 4-iodo-1-methylimidazole (2.28 g, 11.0 mmol), Pd(dppf)Cl in 1,4-dioxane (40 mL) and water (4.0 mL) under 2 ·CH 2 Cl 2 (0.81 g, 1.00 mmol) and K 2 CO 3 A mixture of (4.14 g, 30.0 mmol) was heated to 100° C. for 4 h. The reaction was concentrated in vacuo, diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (590 mg, 38.0%) as a brown oil. LCMS (ES+): 160.2 [MH] +

[0155] Intermediates 7 and 48 were prepared similarly to intermediate 6 via Suzuki-Miyaura coupling: see Table 2 below. Table 2: Suzuki-Miyaura coupling leading to imidazoles [ka] [Table 2]

[0156] Intermediate 8 [ka] N,N-Dimethyl-2-[3-[1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenoxy]ethanamine N 2 (2-Bromoethyl)dimethylamine hydrobromide (2.69 g, 11.6 mmol) was added to Intermediate 7 (2.8 g, 9.64 mmol) and Cs in DMF (30 mL) under 2 CO 3 (6.28 g, 19.3 mmol) was added to a suspension of 1,2-dichlorophenyl ether (6.28 g, 19.3 mmol). The resulting mixture was stirred at 100° C. for 16 h, then quenched with water (50 mL) and extracted with EtOAc (5×50 mL). The combined organic layers were washed with brine (30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (570 mg, 16.0%) as a brown oil. LCMS (ES+): 362.2 [MH] +

[0157] Intermediate 9 [ka] 2-Iodo-1-methyl-4-phenyl-imidazole N 2Under an atmosphere of 0.1 M, n-BuLi (2.5 M in hexane, 29.6 mL, 74.0 mmol) was added dropwise over 10 min to a solution of intermediate 1 (7.8 g, 49.3 mmol) in THF (80 mL) at -78 °C. The solution was stirred at -78 °C for 1 h, and then dissolved in I in THF (20 mL). 2 (13.8 g, 54.2 mmol) was added dropwise over 10 min. The resulting mixture was warmed to 0° C. and stirred for an additional 1 h before being quenched with water (100 mL) and extracted with EtOAc (5×100 mL). The combined organic layers were washed with brine (30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (7.70 g, 55.0%) as a yellow solid. LCMS (ES+): 285.0 [MH] +

[0158] Examples 10-14 and 49 were prepared similarly to intermediate 9 by iodination of imidazole; see Table 3 below. Table 3: Iodination of imidazole using n-butyllithium and iodine [ka] [Table 3]

[0159] Intermediate 15 [ka] 6-Chloro-9-methyl-purin-2-amine N 2 6-Chloro-9H-purin-2-amine (15.0 g, 59.0 mmol) in DMF (100 mL) under an atmosphere of 3 I (3.67 mL, 59.0 mmol) and K 2 CO 3(16.3 g, 118 mmol) suspension was stirred for 16 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (3.4 g, 24.9%) as a yellow solid. LCMS (ES+): 184.0 [MH] +

[0160] Intermediate 50 [ka] 4-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine N 2 Methylhydrazine sulfate (3.75 g, 26.0 mmol) was added to a solution of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (5.00 g, 26.0 mmol) and TEA (10.9 mL, 78.2 mmol) in DMF (50 mL) under an atmosphere of 0.1%. The resulting mixture was stirred at 50° C. for 1 h and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give the title compound (3.82 g, 79.9%) as a yellow solid. LCMS (ES+): 184.1 [MH] +

[0161] Intermediate 51 was prepared similarly to intermediate 50 by pyrazole formation via cyclization; see Table 12 below. Table 12: Pyrazole formation via cyclization [ka] [Table 4]

[0162] Intermediate 16 [ka] 6-Chloro-2-iodo-9-methyl-purine N 2Isoamyl nitrite (7.47 mL, 55.6 mmol) was dissolved in THF (70 mL) with intermediate 15 (3.4 g, 18.5 mmol, 1.0 equiv.), CuI (3.53 g, 18.5 mmol), and CH 2 I 2 (7.47 mL, 92.6 mmol) was added to a suspension and the reaction was heated to 80° C. for 2 h. The reaction was then concentrated in vacuo and the resulting residue was purified by silica gel column chromatography to give the title compound (3.2 g, 58.7%) as a yellow solid. LCMS (ES+): 295.1 [MH] +

[0163] Intermediate 52 was prepared similarly to intermediate 16 by iodination of pyrimidine via the Sandmeyer reaction; see Table 13 below. Table 13: Iodination of pyrimidines via the Sandmeyer reaction [ka] [Table 5]

[0164] Intermediate 17 [ka] 6-(6-chloro-1-methyl-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane A solution of 4,6-dichloro-1-methylpyrazolo[3,4-d]pyrimidine (3.00 g, 14.9 mmol), 2-oxa-6-azaspiro[3.3]heptane (1.47 g, 14.9 mmol), and DIPEA (7.76 mL, 44.6 mmol) in EtOH (30 mL) was stirred for 16 h and then concentrated in vacuo. The resulting residue was washed with PE (3×5 mL) and dried under vacuum to give the title compound (1.92 g, 48.8%) as a yellow solid. The material was carried on to the next reaction without further purification. LCMS (ES+): 266.1 [MH] +

[0165] Examples 18-23 and 53-55 were prepared similarly to intermediate 17 with SnAr on halogenated pyrimidines; see Table 4 below. Table 4: SnAr of halogenated pyrimidines [ka] [Table 6-1] [Table 6-2]

[0166] Intermediate 24 [ka] 6-(6-chloro-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane N 2 NaH (60% in mineral oil, 239 mg, 5.98 mmol) and 4-bromooxane (784 mg, 4.78 mmol) were added sequentially to a solution of Intermediate 19 (1.00 g, 3.98 mmol) in DMF (10 mL) under an atmosphere of 0.1%. The reaction was then heated to 100° C. for 5 h before being quenched with water (10 mL) and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (400 mg, 30.0%) as a yellow solid. LCMS (ES+): 336.2 [MH] +

[0167] Intermediate 25 [ka] 6tert-Butyl 3-[[6-chloro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carboxylate 3-(Iodomethyl)azetidine (1.17 g, 5.96 mmol) was dissolved in DMF (15 mL) with intermediate 19 (1.00 g, 3.97 mmol), Cs 2 CO 3 (2.59 g, 7.95 mmol) was added to a suspension of 100 ml of ethyl acetate (1.0 g, 1.0 mmol). The reaction was then heated to 80° C. for 2 h before being quenched with water (20 mL) and then extracted with DCM (3×20 mL). The combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (660 mg, 51.8%) as a yellow solid. LCMS (ES+): 421.2 [MH] +

[0168] Intermediates 56 and 57 were prepared by the synthesis of Cs 2 CO 3 Prepared similarly to intermediate 25 by alkylation of pyrazolopyrimidine with; see Table 14 below. Table 14: Cs 2 CO 3 Alkylation of pyrazolopyrimidines using [ka] [Table 7]

[0169] Intermediate 26 [ka] Trimethyl-[2-[1-methyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-6-yl]ethynyl]silane N 2TEA (996 μL, 7.15 mmol) and trimethylsilylacetylene (848 μL, 5.96 mmol) were successively added to intermediate 17 (600 mg, 2.26 mmol), CuI (90.8 mg, 0.48 mmol), and Pd(dppf)Cl in DMF (25 mL) under an atmosphere of 2 ·CH 2 Cl 2 (583 mg, 0.72 mmol) was added dropwise over 10 min. The resulting mixture was stirred for 1 h, then diluted with water (15 mL) and extracted with DCM (3×15 mL). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (625 mg, 84.5%) as a yellow solid. LCMS (ES+): 328.3 [MH] +

[0170] Examples 27-33 and 58-63 were prepared similarly to intermediate 17 via Sonogashira coupling with trimethylsilylacetylene; see Table 5 below. Table 5: Sonogashira coupling leading to TMS-alkynes [ka] [Table 8-1] [Table 8-2] [Table 8-3]

[0171] Intermediate 34 [ka] 6-(6-ethynyl-1-methyl-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane Intermediate 26 (625 mg, 1.91 mmol) and K in MeOH (5.0 mL) and DCM (5.0 mL) 2 CO 3 A suspension of (551 mg, 3.99 mmol) was stirred for 1 h, then diluted with water (15 mL) and extracted with DCM (3×15 mL). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (380 mg, 78.0%) as a yellow solid. LCMS (ES+): 256.1 [MH] +

[0172] Examples 35-40 and 64-69 were prepared similarly to intermediate 34 by removal of the alkynyl TMS group; see Table 6 below. Table 6: Alkynyl TMS deprotection [ka] [Table 9-1] [Table 9-2]

[0173] Intermediate 41 [ka] Trimethyl-[2-[[2-[2-[9-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)purin-2-yl]ethynyl]-4-phenyl-imidazol-1-yl]methoxy]ethyl]silane N 2 Pd(PPh) in THF (5 mL) was added under 3 ) 2 Cl 2 A solution of Intermediate 10 (50.0 mg, 196 μmol), Cs (27.5 mg, 39.0 μmol) and Intermediate 35 (78.4 mg, 196 μmol) in THF (10 mL) was added to 2 CO3 To a suspension of 128 mg (392 μmol) and CuI (14.9 mg, 78 μmol) was added dropwise over 10 min. The resulting mixture was stirred for 2 h, diluted with water (5 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (10 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (45.0 mg, 43.5%) as a yellow solid. LCMS (ES+): 527.6 [M] +

[0174] Intermediate 42 and Examples 1 to 4 are prepared by the reaction of Pd(PPh 3 ) 2 Cl 2 Prepared similarly to intermediate 41 via Sonogashira coupling with; see Table 7 below (table is divided into two parts). Table 7: Pd(PPh 3 ) 2 Cl 2 Sonogashira coupling using [ka] [Table 10] Table 7 continued – Examples of Compounds [Table 11]

[0175] Intermediate 43 [ka] tert-Butyl 2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-4-morpholino-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate N 2A solution of intermediate 9 (455 mg, 1.32 mmol) in DMF (2.5 mL) was added dropwise to a solution of intermediate 38 (150 mg, 0.53 mmol), CuI (5.0 mg, 26 μmol), XantPhos-Pd-G2 (74.0 mg, 79 μmol), and XantPhos (45.8 mg, 79 μmol) in TEA (2.0 mL) and DMF (7.5 mL) under an atmosphere of 0.1%. The resulting mixture was stirred at 80 °C for 2 h, then diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (202 mg, 76.6%) as a brown solid. LCMS (ES+): 501.25 [MH] +

[0176] Examples 44-47 and 70-76 as well as Examples 6 and 16-19 were prepared similarly to intermediate 43 via Sonogashira coupling using XantPhos-Pd-G2; see Table 8 below (the table is divided into two parts). Table 8: Sonogashira coupling using XantPhos-Pd-G2 [ka] [Table 12-1] [Table 12-2] Table 8 continued – Examples of Compounds [Table 13]

[0177] Example 20 [ka] (3aR,6aS)-5-(9-methyl-2-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)hexahydro-1H-furo[3,4-c]pyrrole A solution of intermediate 70 (60 mg, 0.17 mmol), (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (39 mg, 0.34 mmol), and TEA (76 μL, 0.51 mmol) in DMF (1.0 mL) was stirred for 1 h, then quenched with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated NH 4 Wash with aqueous Cl (3 × 5 mL) and anhydrous Na 2 SO 4 The residue was purified by reverse phase HPLC (NH 4 HCO 3 Purification by HPLC (buffered with ethyl acetate) afforded the title compound (19.9 mg, 26.8%) as a yellow solid. UPLC (Method C): Rt 1.39 min. HRMS (ES+ / QToF) m / z: [M+H] + C 24 H 24 N 7 O theoretical value 426.2042; measured value 426.2048

[0178] Examples 77-82 and Examples 21-24 were prepared similarly to Example 20 with later SnAr treatment of the halogenated pyrimidines; see Table 15 below. Table 15: Halogenated pyrimidine late SnAr Scheme [Table 14] Table 15 continued – Examples of Compounds [Table 15]

[0179] Example 7 [ka] 6-[9-methyl-2-[2-(4-phenyl-1H-imidazol-2-yl)ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane TBAF (5.00 mL, 19.1 mmol) was added to a solution of intermediate 41 (45 mg, 85 μmol) in THF (5.0 mL) and the reaction was stirred for 16 h. The reaction was quenched by the addition of water (5 mL) and extracted with DCM (5×5 mL). The combined organic layers were washed with saturated NH 4 Wash with aqueous Cl (3 × 5 mL) and anhydrous Na 2 SO 4 The residue was purified by reverse phase HPLC (NH 4 HCO 3 Purification by HPLC (buffered with HPLC) afforded the title compound (8.3 mg, 24.5%) as a white solid. UPLC (Method A): Rt 1.81 min. HRMS (ES+ / QToF) m / z: [M+H] + C 22 H 20 N 7 O theoretical value 398.1729; measured value 398.1727

[0180] Example 8 [ka] 6-[1-(azetidin-3-ylmethyl)-6-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane TFA (2.0 mL) was added to a solution of Intermediate 42 (80.0 mg, 141 μmol) in DCM (4.0 mL). The reaction was stirred for 1 h, then concentrated in vacuo and purified by reverse phase HPLC (NH 4 HCO 3 Purification by HPLC (buffered with ethyl acetate) afforded the title compound (40.6 mg, 59.9%) as a yellow solid. UPLC (Method C): Rt 0.99 min. LCMS (ES+): 467.3 [MH] +

[0181] Examples 9-13 and 25-33 were prepared similarly to Example 8 by TFA-mediated deprotection; see Table 9 below. Table 9: Deprotection of SEM or Boc with TFA [ka] [Table 16-1] [Table 16-2] [Table 16-3]

[0182] Example 14 [ka] 4-[2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-7-(oxetan-3-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]morpholine A solution of Example 11 (120 mg, 300 μmol) and 3-oxetane (176 μL, 3.00 mmol) in THF (5.0 mL) was stirred at 70 °C for 30 h and then cooled to room temperature. 3 CN (94.2 mg, 1.50 mmol) was added in portions and the reaction was stirred for 16 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were concentrated in vacuo and the residue was purified by reverse phase HPLC (buffered with HCOOH) to give the title compound (26.4 mg, 19.0%) as a brown solid. UPLC (Method E): Rt 1.57 min. HRMS (ES+ / QToF) m / z: [M+H] + C 26 H 29 N 6 O 2 Theoretical value: 457.2352; measured value: 457.2348

[0183] Example 15 [ka] 4-[7-(cyclopropylmethyl)-2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]morpholine N 2 Example 11 (140 mg, 350 μmol) in DMF (10 mL) under an atmosphere of 2 CO 3 A suspension of (144 mg, 1.05 mmol) and (iodomethyl)cyclopropane (191 mg, 1.05 mmol) was stirred at 37 °C for 1 h. The reaction was then concentrated in vacuo and the residue was purified by reverse phase HPLC (NH 4 HCO 3 Purification by HPLC (buffered with ethyl acetate) afforded the title compound (28.7 mg, 17.8%) as a yellow solid. UPLC (Method E): Rt 1.68 min. LCMS (ES+): 455.3 [MH] +

[0184] Biochemical Human PDE10A Activity Assay - PDE10A2 Phosphosensor 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 Ex430nm / Em450nm optical filter on a BMG CLARIOStar plate reader. Data were analyzed using a four-parameter fit.

[0185] 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 10: PDE10 inhibition data for compounds of the invention [Table 17-1] [Table 17-2]

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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 stock. 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. Diluent 1:1 MeOH:H 2 The resulting supernatant was diluted with O at a ratio of 1:2.

[0190] 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.

[0191] 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).

[0192] 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 analyte in a 96-well plate in the range of 25-150,000 pg. Calibration standards of appropriate concentrations across the calibration curve range were prepared by adding a volume of 25 μL of control male Sprague-Dawley Rat brain homogenate (containing 8.33 mg of brain tissue) to each well.

[0193] To prepare control and experimental brain homogenates, brains were thawed at room temperature, weighed, and diluted with diluent (50:50 MeCN / HCO3) in a ratio of 2 mL per gram of brain. 2 Brain homogenization was performed by bead beater homogenization using Precellys Evolution and CKMix50 7mL mixed ceramic bead homogenization tubes.

[0194] Aliquots of 25 μL of experimental samples were extracted along the standard 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). The protein precipitate was separated from the extracted test compound by centrifugation at 4000 rpm for 5 minutes at 4° C. The diluent was 1:1 MeOH:H 2 The resulting supernatant was diluted with O at a ratio of 1:2.

[0195] 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.

[0196] 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 calibrator 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).

[0197] 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 clear indication of which time point was used).

[0198] 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.

[0199] 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 11: Brain to plasma partitioning (Kpuu) of compounds of the invention [Table 18]

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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)).

[0204] 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)).

[0205] 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.

[0206] 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.

[0207] The effect of selective PDE10A inhibition was examined in inflamed colonic mucosa from patients with ulcerative colitis, obtained 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)).

[0208] 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.

[0209] PDE10A inhibitors, Reference Examples A-G (the syntheses of which are outlined below along with their PDE10A inhibitory activity), were tested at a concentration of 100 nM (a concentration selective for PDE10A inhibition) and were found to significantly reduce IL-6 and IL-8 secretion levels compared to vehicle controls. 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.

[0210] The structure of PF-02545920 is shown below. PF-02545920 is an IC 50 PF-02545920 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]

[0211] 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.

[0212] 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]

[0213] 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.

[0214] 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).

[0215] 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.

[0216] 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.

[0217] 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).

[0218] 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.

[0219] 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.

[0220] Protocol 2 Ulcerative colitis donor samples were obtained with full ethical consent from patients undergoing curative resection for ulcerative colitis. Tissues were placed on Netwell filters with the top (mucosal) side facing up. Biopsy tissues were then incubated at 37°C in high O in control medium or medium containing the test compound. 2 The cells were cultured in an atmospheric incubator. To minimize variability, biopsies were also cultured in the presence of the inflammatory stimulant Staphylococcal 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.

[0221] 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.

[0222] Synthesis of PDE10A inhibitors (reference examples) A ​​to G Reference 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 and 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. and TEA (7.63 mL, 54.8 mmol) was added dropwise, then allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with DCM (250 mL) and saturated NaHCO 3 The aqueous solution (250 mL) was separated into 100 mL of DCM and 150 mL of ethyl acetate. The aqueous layer was extracted with DCM (250 mL) and the organic layers were combined, washed with brine (250 mL) and dried (MgSO 4 ) 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 F) Rt 5.53 min, 100%. LCMS (ES+): 272.1 [MH] +

[0223] Reference intermediate 2 [ka] 1-(4-benzyloxyphenyl)-2-(4-pyridyl)ethanone N 2 Under reduced pressure, n-BuLi (2.5 M 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, N 2 Reference 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 then 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 NaHCO 3 (250 mL) and dried (MgSO 4 ) and concentrated in vacuo to give the title compound (4.85 g, 93.0%) as a pale yellow solid. UPLC (Method F) Rt 4.67 min, 97.2%. LCMS (ES+): 304.2 [MH] +

[0224] Reference intermediate 3 (and by-products) 4-[3-(4-benzyloxyphenyl)-1-methyl-pyrazol-4-yl]pyridine and 4-[5-(4-benzyloxyphenyl)-1-methyl-pyrazol-4-yl]pyridine (by-product) [ka] Reference intermediate 2 (3.85 g, 97.2% purity, 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) and 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 then diluted with DCM (250 mL) and saturated NaHCO 3 The mixture was partitioned between aqueous (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 a yellow solid (2.84 g, 65.9%) and a yellow solid (625 mg, 10.7%), respectively. UPLC Rt 4.67 min, 97.6%. LCMS (ES+): 342.2 [MH] + . UPLC (Method F) 4.74 min, 72.2%. LCMS(ES+):342.3[MH] +

[0225] Reference intermediate 4 4-[1-Methyl-4-(4-pyridyl)pyrazol-3-yl]phenol [ka] Reference intermediate 3 (3.48 g, 97.6% purity, 9.95 mmol) was dissolved in EtOH (100 mL) and EtOAc (100 mL) and 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 F) Rt 2.73 min, 96.1%. LCMS (ES+): 252.1 [MH] +

[0226] Reference intermediate 5 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 F) Rt 4.31 min, 99.4%. LCMS (ES+): 244.2 [MH] +

[0227] Reference intermediate 6 Methyl 2-(bromomethyl)quinoline-3-carboxylate [ka] Azobisisobutyronitrile (44.1 mg, 269 μmol) was dissolved in CCl 4 A solution of methyl 2-methylquinoline-3-carboxylate (548 mg, 98.8% purity, 2.69 mmol) and NBS (718 mg, 4.03 mmol) in (13 mL) was added 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 F) Rt 5.55 min, 93.2%. LCMS (ES+): 280.0 [MH] +

[0228] Reference Intermediates 7A and 7B Reference intermediates 7A and 7B were prepared similarly to Reference intermediate 6 by bromination of the appropriate intermediate with NBS. [Table 19]

[0229] Reference intermediate 8 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 (MgSO 4 ) 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] +

[0230] Reference Intermediate 9 Methyl 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylate [ka] N 2 Under the conditions below, a solution of Reference Intermediate 4 (300 mg, 96.1% purity, 1.15 mmol) in DMF (4.0 mL) was added dropwise 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. Reference Intermediate 6 (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 diluted with DCM (100 mL), H 2 Partition between 2H2O (100 mL) and brine (50 mL), extract the aqueous layer with DCM (100 mL), combine the organic layers, wash with brine (100 mL) and dry (MgSO 4 ) 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 F), Rt 4.52 min, 97.1%. LCMS (ES+): 451.2 [MH] +

[0231] Reference Intermediate 10 tert-Butyl 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-4-carboxylate [ka] Reference intermediate 10 was prepared similarly to reference intermediate 9 by alkylation of reference intermediate 4 and reference intermediate 7A with NaH. Yellow gum. Yield 500 mg, 90.1%; LCMS (ES+): 493.3 [MH] + ;UPLC (Method F), Rt5.23 min, 89.5%

[0232] Reference Intermediate 11 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinoline-3-carboxylic acid [ka] LiOH.H 2 O (119 mg, 2.84 mmol) was added to a solution of Reference Intermediate 9 (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 F) Rt 3.78 min, 98.0%. LCMS (ES+): 437.1 [MH] +

[0233] Reference intermediate 12 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 Reference Intermediate 10 (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 F), Rt 3.77 min, 99.6%. LCMS(ES+):437.1[MH] +

[0234] Reference Intermediate 13 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) and saturated NaHCO 3 aqueous solution (30 mL) and dried (MgSO 4 ) and concentrated in vacuo. The residue was diluted with CCl 4 (5.0 mL) and the mixture was purified with N 2 The mixture was sparged with 500 mL of ethyl acetate 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]+

[0235] Reference intermediate 14 Methyl 2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazoline-4-carboxylate [ka] Intermediate 4 (56.1 mg, 99.2% purity, 0.22 mmol), intermediate 13 (68.0 mg, 91.5% purity, 0.22 mmol) and Cs in DMF (3.0 mL). 2 CO 3 (79.3 mg, 0.24 mmol) was stirred for 16 h. The mixture was diluted with DCM (20 mL) and saturated NaHCO 3 aqueous solution (20 mL) and dried (MgSO 4 ) 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] +

[0236] Reference Intermediates 15 and 16 Reference intermediates 15 and 16 are Cs 2 CO 3 Prepared similarly to intermediate 14 by alkylation of the appropriate phenol intermediate with the appropriate bromide / chloride intermediate using [Table 20]

[0237] Reference Intermediate 17 [ka] Trimethyl(2-quinazolin-2-ylethynyl)silane N 2Trimethylsilylacetylene (2.6 mL, 18.4 mmol) and DIPEA (3.0 mL, 17.2 mmol) were successively added to 2-chloroquinoxaline (1.50 g, 9.11 mmol), CuI (174 mg, 0.91 mmol), and Pd(dppf)Cl in DMF (15 mL) under an atmosphere of 2 ·CH 2 Cl 2 (1.48 g, 1.82 mmol) was added to a suspension of 1.2 mL of ethyl acetate (1.48 g, 1.82 mmol). The mixture was stirred at 80° C. for 1 h, then quenched with water (30 mL) and extracted with EtOAc (5×30 mL). The combined organic layers were washed with brine (50 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (1.40 g, 65.8%) as a yellow solid. LCMS (ES+): 227.2 [MH] +

[0238] Reference Intermediate 18 [ka] 2-Ethynylquinazoline Reference intermediate 17 (600 mg, 2.65 mmol) and K in MeOH (5.0 mL) and DCM (5.0 mL) 2 CO 3 After stirring for 1 h, a suspension of (366 mg, 2.65 mmol) was added to water (40 mL) and extracted with EtOAc (5×40 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (360 mg, 88.1%) as a white solid. LCMS (ES+): 155.3 [MH] +

[0239] Reference Intermediate 19 [ka] 1-Methyl-4-phenyl-imidazole N2 Under an atmosphere of 0° C., NaH (60% in mineral oil, 3.33 g, 83.2 mmol) was added to a solution of 4-phenyl-3H-imidazole (10 g, 69.4 mmol) in DMF (70 mL) at 0.5° C. The solution was stirred for 30 min, then the temperature was maintained at 0° C. while the CH 3 I (5.2 mL, 83.5 mmol) was added dropwise over 10 min. The resulting mixture was stirred for an additional 1 h without cooling. The reaction was then quenched by adding water (100 mL) and extracted with EtOAc (5×100 mL). The combined organic layers were washed with brine (30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (7.80 g, 71.1%) as a yellow solid. LCMS (ES+): 159.0 [MH] +

[0240] Reference intermediate 20 [ka] 2-Iodo-1-methyl-4-phenyl-imidazole N 2 Under an atmosphere of 0.1% N, n-BuLi (2.5 in hexane, 29.6 mL, 74.0 mmol) was added dropwise to a solution of Reference Intermediate 19 (7.8 g, 49.3 mmol) in THF (80 mL) over 10 min at -78 °C. The solution was stirred at -78 °C for 1 h, and then dissolved in I in THF (20 mL). 2 (13.8 g, 54.2 mmol) was added dropwise over 10 min. The resulting mixture was warmed to 0° C. and stirred for an additional 1 h before being quenched with water (100 mL) and extracted with EtOAc (5×100 mL). The combined organic layers were washed with brine (30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (7.70 g, 55.0%) as a yellow solid. LCMS (ES+): 285.0 [MH] +

[0241] Reference intermediate 21 [ka] 4-(6-chloro-1,3-dimethyl-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine 4,6-Dichloro-1,3-dimethylpyrazolo[3,4-d]pyrimidine (300 mg, 1.38 mmol), TEA (578 μL, 4.15 mmol) and morpholine (143 μL, 1.66 mmol) in DMF (10 mL) were stirred at room temperature for 2 h, then concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (200 mg, 54.1%) as a yellow solid. LCMS (ES+): 268.2 [MH] +

[0242] Reference intermediate 22 [ka] 1-Methyl-4-phenyl-imidazole-2-carbaldehyde N 2 n-BuLi (2.5 M in hexanes, 1.5 mL, 3.8 mmol) was added dropwise over 10 min to a solution of reference intermediate 19 (500 mg, 3.16 mmol) in THF (10 mL) under an atmosphere of -40°C, stirred for 30 min, then cooled to -78°C. DMF (300 μL, 4.11 mmol) was added dropwise over 10 min, then stirred for an additional 1 h, after which the solution was allowed to warm to room temperature over 2 h. The reaction was quenched by the addition of water (30 mL) and extracted with EtOAc (5 x 50 mL). The combined organic layers were washed with brine (3 x 10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (450 mg, 75.5%) as a white solid. LCMS (ES+): 187.3 [MH] +

[0243] Reference intermediate 23 [ka] (1-methyl-4-phenyl-imidazol-2-yl)methanol NaBH 4 (183 mg, 4.84 mmol) was added to a solution of Reference Intermediate 22 (450 mg, 2.42 mmol) in MeOH (5.0 mL) and stirred for 1 h, after which water (20 mL) was added and extracted with EtOAc (5×30 mL). The combined organic layers were washed with brine (3×10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (440 mg, 96.7%) as a white solid. LCMS (ES+): 189.2 [MH] +

[0244] The following compounds are reference examples: Reference example A 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 Reference Intermediate 10 (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 F), Rt 3.77 min, 99.6%. LCMS(ES+):437.1[MH] +

[0245] Reference example B 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 reference intermediate 11 (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 diluted with DCM (30 mL) and H 2 The aqueous layer was extracted with DCM (30 mL) and the organic layers were combined and dried (MgSO 4 ) 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 F), Rt 3.96 min, 98.4%. LCMS (ES+): 514.1 [MH] +

[0246] Reference Examples C and D Examples C and D were prepared similarly to Example B by amide coupling of the appropriate intermediate with the appropriate amine using HATU. [Table 21]

[0247] Reference example E N-[Dimethyl(oxo)-λ6-sulfanylidene]-2-[[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenoxy]methyl]quinazoline-4-carboxamide [ka] Reference intermediate 14 (35.0 mg, 98.7% purity, 76.5 μmol) was dissolved in THF (2.0 mL) and water (2.0 mL). 2O (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) and saturated NaHCO 3 aqueous solution (30 mL) and dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (NH 3 Purification by HPLC (buffered with HPLC) afforded the title compound (24.4 mg, 61.8%) as a yellow solid. UPLC (Method F) Rt 3.68 min, 99.4%. LCMS (ES+): 513.1 [MH] +

[0248] Reference Examples F and G Examples F and G were prepared similarly to Example E by saponification of the appropriate intermediate, followed by amide coupling with the appropriate amine using HATU. [Table 22]

[0249] Reference example H [ka] 2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]quinazoline N 2A mixture of Reference Intermediate 18 (150 mg, 0.97 mmol), Reference Intermediate 20 (332 mg, 1.17 mmol), 2nd Generation XantPhos Precatalyst (86 mg, 0.10 mmol), XantPhos (56 mg, 0.10 mmol), CuI (9.00 mg, 0.05 mmol), and TEA (500 μL, 3.63 mmol) in DMF (5.0 mL) was stirred for 1 h under an atmosphere of 0.05%. Water (20 mL) was then added and extracted with EtOAc (5×30 mL). The combined organic layers were concentrated in vacuo and the residue was purified by reverse phase HPLC (buffered with HCOOH) to give the title compound (27.9 mg, 9.21%) as a brown solid. UPLC (Method E): Rt 1.39 min. LCMS (ES+): 311.10 [MH] +

[0250] Reference example J [ka] 4-[1,3-Dimethyl-6-[(1-methyl-4-phenyl-imidazol-2-yl)methoxy]pyrazolo[3,4-d]pyrimidin-4-yl]morpholine Intermediate 23 (150 mg, 0.80 mmol), Intermediate 21 (200 mg, 0.80 mmol), and Cs in DMF (3.0 mL) 2 CO 3 A suspension of (520 mg, 1.57 mmol) was stirred at 100° C. for 16 h, then water (20 mL) was added and extracted with EtOAc (5×30 mL). The combined organic layers were washed with brine (3×10 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by reverse phase HPLC (NHHCO 3 Purification by HPLC (buffered with ethyl acetate) afforded the title compound (104 mg, 32.3%) as a white solid. UPLC (Method E): Rt 1.50 min. LCMS (ES+): 402.1 [MH] +

[0251] These reference examples have the following activities in the above human PDE10A activity assay and in the cell-based human PDE10A activity assay: [Table 23]

[0252] The data in the above table show that the Reference Examples are potent PDE10A inhibitors and therefore may be suitable for use in the treatment of inflammatory bowel diseases such as ulcerative colitis and / or Crohn's disease.

[0253] 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 (I) 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein Ring A is selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from halo, (C １ -C ４ )alkyl, -OR ３ , -NR ４ R ５ , -C(O)R ６ , -C(O)OR ６ , and -C(O)NR ４ R ５ , and the (C １ -C ４ )alkyl is optionally substituted with one or more halos; Ring B is optionally a halo, oxo, (C １ -C ４ )alkyl, -OR ７ , -NR ８ R ９ , -C(O)R ７ , -C(O)OR ７ , -C(O)NR ８ R ９ , and -S(O)(NR ７ )R ７ substituted with one or more substituents selected from, a 4- to 7-membered monocyclic carbocyclic or heterocyclic ring, or a 6- to 10-membered bicyclic carbocyclic or heterocyclic ring, wherein the (C １ -C ４ )alkyl is optionally substituted with one or more halos; Ring C is an optionally one or more R ２ substituted 5- or 6-membered carbocyclic ring, 5- or 6-membered heterocyclic ring or 5- or 6-membered heteroaryl group; R １ is selected from the group consisting of H and (C １ -C ４ )alkyl, said (C １ -C ４ )alkyl being optionally substituted with one or more substituents selected from halo, -NR １０ R １１ , and 4- to 6-membered heterocycles; Each R ２ is independently selected from the group consisting of halo, (C １ -C ４ )alkyl, -OR １２ , -NR １３ R １４ , -C(O)R １２ , -C(O)OR １２ , -C(O)NR １３ R １４ , aryl, and 4- to 6-membered heterocycles, and the (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycles; R ３ is selected from H and (C １ -C ４ )alkyl, said (C １ -C ４ )alkyl being optionally substituted with one or more substituents selected from halo, -OH, and -NR １５ R １６ ; and R ４ ~R １６ are each independently selected from H and (C １ -C ４ ), and the (C １ -C ４ ) alkyl is optionally substituted with one or more substituents selected from halo, or the groups R ４ and R ５ , R ８ and R ９ , R １０ and R １１ , R １３ and R １４ , R １５ and R １６ together with the atoms to which they are attached optionally form a 5- or 6-membered heterocycle substituted with one or more substituents selected from halo and (C １ -C ４ ) alkyl a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

2. A compound of formula (IA) 【Chemical 2】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein X is N or CR １８ wherein; Y is N or CR １８ wherein, preferably, one of X and Y is N and the other is CR １８ ; Ring A is selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from halo, (C １ -C ４ )alkyl, -OR ３ , -NR ４ R ５ , -C(O)R ６ , -C(O)OR ６ , and -C(O)NR ４ R ５ , and the (C １ -C ４ )alkyl is optionally substituted with one or more halo; Ring B is optionally a halo, oxo, (C １ -C ４ )alkyl, -OR ７ , -NR ８ R ９ , -C(O)R ７ , -C(O)OR ７ , -C(O)NR ８ R ９ , and -S(O)(NR ７ )R ７ substituted with one or more substituents selected from, a 4- to 7-membered monocyclic carbocyclic or heterocyclic ring, or a 6- to 10-membered bicyclic carbocyclic or heterocyclic ring, wherein the (C １ -C ４ )alkyl is optionally substituted with one or more halos; R １ is selected from the group consisting of H and (C １ -C ４ )alkyl, said (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo, -NR １０ R １１ , and 4- to 6-membered heterocycles; R ３ is selected from H and (C １ -C ４ )alkyl, said (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo, -OH, and -NR １５ R １６ ; R １７ is selected from the group consisting of H, (C １ -C ４ )alkyl, -OR １２ , -NR １３ R １４ , -C(O)R １２ , -C(O)OR １２ , -C(O)NR １３ R １４ , aryl, and 4- to 6-membered heterocycles, and the (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycles; Each R １８ is independently selected from the group consisting of H, halo, (C １ -C ４ )alkyl, -OR １２ , -NR １３ R １４ , -C(O)R １２ , -C(O)OR １２ , -C(O)NR １３ R １４ , aryl, and 4- to 6-membered heterocycles, wherein said (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycles, preferably each R １８ is H or halo, more preferably each R １８ is H; and R ４ to R １６ are each independently selected from H and (C １ -C ４ )alkyl, wherein the (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo, or the groups R ４ and R ５ , R ８ and R ９ , R １０ and R １１ , R １３ and R １４ , R １５ and R １６ together with the atoms to which they are attached optionally form a 5- or 6-membered heterocycle substituted with one or more substituents selected from halo and (C １ -C ４ )alkyl the compound according to claim 1.

3. Ring B is (i) Optionally, halo, oxo, (C １ -C ４ ) alkyl, -OR ７ , -NR ８ R ９ , -C(O)R ７ , -C(O)OR ７ , -C(O)NR ８ R ９ , and -S(O)(NR ７ )R ７ substituted with one or more substituents selected from; a 6- to 10-membered bicyclic heterocycle, preferably a 7- to 10-membered bicyclic heterocycle, wherein the (C １ -C ４ ) alkyl is optionally substituted with one or more halos; or (ii) halo, oxo, (C １ -C ４ )alkyl, -OR ７ , -NR ８ R ９ , -C(O)R ７ , -C(O)OR ７ , -C(O)NR ８ R ９ , and -S(O)(NR ７ )R ７ ; a 4- to 7-membered monocyclic heterocycle substituted with at least one substituent selected from the group consisting of; wherein the (C １ -C ４ )alkyl is optionally substituted with one or more halos the compound according to claim 2.

4. Ring B is (i) Optionally, a 7- to 10-membered bicyclic heterocycle substituted with one or more substituents selected from halo, (C １ -C ４ )alkyl, and -S(O)(NR ７ )R ７ , wherein the (C １ -C ４ )alkyl is optionally substituted with one or more halos; or (ii) a 4- to 7-membered monocyclic heterocyclic ring substituted with at least one substituent selected from halo, (C １ -C ４ )alkyl, and -S(O)(NR ７ )R ７ , wherein the (C １ -C ４ )alkyl is optionally substituted with one or more halos the compound according to claim 2.

5. Ring A is selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from halo, (C １ -C ４ )alkyl, and -OR ３ , wherein said (C １ -C ４ )alkyl is optionally substituted with one or more halo; R ３ is selected from H and (C １ -C ４ )alkyl, said (C １ -C ４ )alkyl being optionally substituted with one or more substituents selected from halo and -NR １５ R １６ ; R １７ is selected from the group consisting of H, (C １ -C ４ )alkyl, and a 4- to 6-membered heterocyclic ring, and the (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo and a 4- to 6-membered heterocyclic ring; Each R １８ is independently selected from the group consisting of H, halo, and (C １ -C ４ )alkyl, wherein said (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo, and preferably each R １８ is H or halo, more preferably each R １８ is H; and R ７ 、R １５ 、and R １６ are each independently selected from H and (C １ -C ４ ), and the (C １ -C ４ ) alkyl is optionally substituted with one or more substituents selected from halo the compound according to claim 1.

6. Ring A is selected from the group consisting of aryl and pyridyl, optionally substituted with one or more halo and -OR ３ and R ３ is (C １ -C ４ )alkyl-NMe ２ wherein Preferably ring A is 【Chemical Formula 3】 the compound according to claim 2, selected from

7. Ring B is 【Chemical Formula 4】 selected from the group consisting of each being optionally, substituted with one or more halos the compound according to claim 1.

8. (i) Ring A is selected from the group selected from aryl and pyridyl, optionally substituted with one or more halos and -OR3, wherein R3 is (C1-C4)alkyl-NMe2, Preferably ring A is 【Chemical Formula 5】 selected from (ii) Ring B is ​ selected from the group consisting of, each being optionally substituted with one or more halos; (iii) Each R7 is independently selected from H and (C1-C4)alkyl, and (C1-C4)alkyl is optionally substituted with one or more substituents selected from halos; (iv) R17 is selected from the group consisting of H, (C1-C4)alkyl, and a 4- to 6-membered heterocycle, and (C1-C4)alkyl is optionally substituted with one or more substituents selected from halos and a 4- to 6-membered heterocycle; (v) Each R18 is independently selected from the group consisting of H, halo, and (C1-C4)alkyl, and (C1-C4)alkyl is optionally substituted with one or more substituents selected from halos, preferably each R18 is H or halo, more preferably R18 is H, the compound according to claim 2.

9. Ring C is an optionally 1- or multi-R ２ substituted 5- or 6-membered heterocyclic ring, preferably Ring C is an optionally 1- or multi-R ２ substituted 6-membered heterocyclic ring, the compound according to claim 1.

10. A compound of formula (IB) 【Chemical Formula 7】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein Ring A is selected from the group consisting of aryl and 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents selected from halo, (C １ -C ４ )alkyl, -OR ３ , -NR ４ R ５ , -C(O)R ６ , -C(O)OR ６ , and -C(O)NR ４ R ５ , and the (C １ -C ４ )alkyl is optionally substituted with one or more halo; Ring B is optionally a halo, oxo, (C １ -C ４ )alkyl, -OR ７ , -NR ８ R ９ , -C(O)R ７ , -C(O)OR ７ , -C(O)NR ８ R ９ , and -S(O)(NR ７ )R ７ substituted with one or more substituents selected from, a 4- to 7-membered monocyclic carbocyclic or heterocyclic ring, or a 6- to 10-membered bicyclic carbocyclic or heterocyclic ring, wherein the (C １ -C ４ )alkyl is optionally substituted with one or more halos; R １ is selected from the group consisting of H and (C １ -C ４ )alkyl, said (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo, -NR １０ R １１ , and 4- to 6-membered heterocycles; R ３ is selected from H and (C １ -C ４ )alkyl, said (C １ -C ４ )alkyl being optionally substituted with one or more substituents selected from halo, -OH, and -NR １５ R １６ ; and R １９ is selected from the group consisting of H, (C １ -C ４ ), alkyl, -C(O)R １２ , -C(O)OR １２ , -C(O)NR １３ R １４ , aryl, and a 4- to 6-membered heterocyclic ring, and the (C １ -C ４ ) alkyl is optionally substituted with one or more substituents selected from halo and a 4- to 6-membered heterocyclic ring; Each R ２０ is independently selected from the group consisting of halo, (C １ -C ４ )alkyl, -OR １２ , -NR １３ R １４ , -C(O)R １２ , -C(O)OR １２ , -C(O)NR １３ R １４ , aryl, and 4- to 6-membered heterocycles, and the (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo and 4- to 6-membered heterocycles; R ４ ~R １６ are each independently selected from H and (C １ -C ４ )alkyl, wherein the (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo, or groups R ４ and R ５ , R ８ and R ９ , R １０ and R １１ , R １３ and R １４ , R １５ and R １６ together with the atoms to which they are attached optionally form a 5- or 6-membered heterocycle substituted with one or more substituents selected from halo and (C １ -C ４ )alkyl; and n is 0, 1, 2, 3, 4, 5, or 6 The compound according to claim 9.

11. R １９ is selected from the group consisting of H, (C １ -C ４ ), alkyl, and 4- to 6-membered heterocycles, and the (C １ -C ４ ) alkyl is optionally substituted with one or more substituents selected from halo; Each R ２０ is independently selected from the group consisting of halo and (C １ -C ４ )alkyl, wherein said (C １ -C ４ )alkyl is optionally substituted with one or more substituents selected from halo; and n is 0, 1, 2, 3, or 4, preferably n is 0, 1, or 2, and most preferably n is 0 The compound according to claim 10.

12. R １９ is H, (C １ -C ４ )alkyl, and 【Chemical 8】 The compound according to claim 10, selected from the group consisting of

13. Ring A is selected from the group consisting of aryl and 6-membered heteroaryl, each optionally substituted with one or more substituents selected from halo, preferably ring A is aryl or pyridyl, more preferably aryl, or 2-pyridyl, and most preferably aryl, the compound according to claim 9.

14. Ring B is optionally a halo, oxo, (C １ -C ４ )alkyl, -OR ７ , -NR ８ R ９ , -C(O)R ７ , -C(O)OR ７ , -C(O)NR ８ R ９ , and -S(O)(NR ７ )R ７ substituted with one or more substituents selected from, a 4- to 7-membered monocyclic carbocyclic or heterocyclic ring, preferably a 4- to 7-membered monocyclic heterocyclic ring, wherein the (C １ -C ４ )alkyl is optionally substituted with one or more halos The compound according to claim 9.

15. Ring B is optionally a 6-membered heterocyclic ring substituted with one or more substituents selected from halo and (C １ -C ４ )alkyl, and the (C １ -C ４ )alkyl is optionally substituted with one or more halos. The compound according to claim 14.

16. Ring B is optionally substituted with one or more substituents selected from halo and (C １ -C ４ )alkyl, morpholine, preferably 【Chemical Formula 9】 and said (C １ -C ４ ) alkyl is optionally substituted with one or more halos, and most preferably ring B is 【Chemical Formula 10】 The compound according to claim 15, selected from the group consisting of

17. R １ is selected from the group consisting of H and (C １ -C ４ )alkyl, said (C １ -C ４ )alkyl being optionally substituted with one or more substituents selected from halo, preferably R １ is H, Me or -CF ３ , the compound according to claim 9.

18. (i) R19 is selected from the group consisting of H, (C1-C4) alkyl, and 【Chemical 11】 selected from the group consisting of; (ii) Ring A is selected from the group consisting of aryl and 6-membered heteroaryl, each optionally substituted with one or more substituents selected from halo, preferably ring A is aryl or pyridyl, more preferably aryl, or 2-pyridyl, and most preferably aryl; (iii) Ring B is morpholine, preferably 【Chemical 12】 and is optionally substituted with one or more substituents selected from halo and (C1-C4) alkyl, (C1-C4) alkyl is optionally substituted with one or more halo, and most preferably, ring B is 【Chemical 13】 selected from the group consisting of, The compound according to claim 10.

19. ・ 6-[9-Methyl-2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane; ・ 6-[9-Methyl-2-[2-[1-methyl-4-(3-pyridyl)imidazol-2-yl]ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane; ・ 6-[1-Methyl-6-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane; ・ 6-[9-Methyl-2-[2-[4-phenyl-1-(tetrahydropyran-4-ylmethyl)imidazol-2-yl]ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane; ・ 6-[9-Methyl-2-[2-[1-(2-morpholinoethyl)-4-phenyl-imidazol-2-yl]ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane; ・ 6-[6-[2-(1-Methyl-4-phenyl-imidazol-2-yl)ethynyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane; ・ 6-[9-Methyl-2-[2-(4-phenyl-1H-imidazol-2-yl)ethynyl]purin-6-yl]-2-oxa-6-azaspiro[3.3]heptane; ・ 6-[1-(Azetidin-3-ylmethyl)-6-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane; ・ (3aS,6aR)-5-[1-Methyl-6-[2-(4-phenyl-1H-imidazol-2-yl)ethynyl]pyrazolo[3,4-d]pyrimidin-4-yl]-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole; ・ 2-[3-[2-[2-[4-[(3aS,6aR)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]-1-methyl-pyrazolo[3,4-d]pyrimidin-6-yl]ethynyl]-1H-imidazol-4-yl]phenoxy]-N,N-dimethyl-ethanamine; ・ 4-[2-[2-(1-Methyl-4-phenyl-imidazol-2-yl)ethynyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]morpholine; ・ (3R)-3-Methyl-4-[2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]morpholine; ・ (3S)-3-Methyl-4-[2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]morpholine; ・ 4-[2-[2-(1-Methyl-4-phenyl-imidazol-2-yl)ethynyl]-7-(oxetan-3-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]morpholine; - 4-[7-(Cyclopropylmethyl)-2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethynyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]morpholine; - (3aR,6aS)-5-(1-(Cyclopropylmethyl)-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole; - (3aR,6aS)-5-(1-Ethyl-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole; - (3aR,6aS)-5-(1-Isopropyl-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole; - (3aR,6aS)-5-(6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole; - (3aR,6aS)-5-(9-Methyl-2-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)hexahydro-1H-furo[3,4-c]pyrrole; - (R)-3-Methyl-4-(9-methyl-2-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine; - (S)-3-Methyl-4-(9-methyl-2-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine; - (3aR,6aS)-5-(1-Methyl-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole; - 1-Imino-4-(1-methyl-6-((1-methyl-4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1l6-thiomorpholine-1-oxide; ・ (3aR,6aS)-5-(1-Isopropyl-6-((4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole; ・ (3aR,6aS)-5-(1-(Cyclopropylmethyl)-6-((4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole; ・ (3aR,6aS)-5-(1-(Oxetan-3-yl)-6-((4-phenyl-1H-imidazol-2-yl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hexahydro-1H-furo[3,4-c]pyrrole; (3aR,6aS)-5-(9-Methyl-2-((4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)hexahydro-1H-furo[3,4-c]pyrrole; ・ (R)-3-Methyl-4-(9-methyl-2-((4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine; ・ (S)-3-Methyl-4-(9-methyl-2-((4-phenyl-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine; ・ (3aR,6aS)-5-(9-Methyl-2-((4-(pyridin-3-yl)-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)hexahydro-1H-furo[3,4-c]pyrrole; ・ (R)-3-Methyl-4-(9-methyl-2-((4-(pyridin-3-yl)-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine; and ・ (S)-3-Methyl-4-(9-methyl-2-((4-(pyridin-3-yl)-1H-imidazol-2-yl)ethynyl)-9H-purin-6-yl)morpholine 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

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 and one or more excipients.

21. The pharmaceutical composition according to claim 20, for use as a medicament.

22. The compound according to any one of claims 1 to 17, or the pharmaceutical composition according to claim 18, for use in the prevention and / or treatment of inflammatory bowel disease, preferably wherein the inflammatory bowel disease is ulcerative colitis and / or Crohn's disease.

23. Use of the compound according to any one of claims 1 to 19 for the manufacture of a medicament.

24. The use according to claim 23, wherein the medicament is for the prevention and / or treatment of inflammatory bowel disease, preferably wherein the inflammatory bowel disease is ulcerative colitis and / or Crohn's disease.

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