NZ622959B2 - Biphenylcarboxamides as rock kinase inhibitors - Google Patents

Biphenylcarboxamides as rock kinase inhibitors Download PDF

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NZ622959B2
NZ622959B2 NZ622959A NZ62295912A NZ622959B2 NZ 622959 B2 NZ622959 B2 NZ 622959B2 NZ 622959 A NZ622959 A NZ 622959A NZ 62295912 A NZ62295912 A NZ 62295912A NZ 622959 B2 NZ622959 B2 NZ 622959B2
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diseases
20alkyl
group
aryl
halo
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NZ622959A (en
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Jo Alen
Sandro Boland
Arnaud Pierre Jean Bourin
Olivier Defert
Dirk Leysen
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Amakem Nv
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Priority claimed from PCT/EP2012/067018 external-priority patent/WO2013030367A1/en
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Publication of NZ622959B2 publication Critical patent/NZ622959B2/en

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Abstract

The present disclosure relates to a compounds of formula I, as defined in the specification, as kinase inhibitors, more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present disclosure relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases, ophthalmic diseases, gastrointestinal diseases and respiratory diseases. n particular, the present disclosure relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases, ophthalmic diseases, gastrointestinal diseases and respiratory diseases.

Description

BIPHENYLCARBOXAMIDES AS ROCK KINASE INHIBITORS Field of the invention The present invention relates to new kinase inhibitors, more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such tors, and to uses of such inhibitors in the treatment and laxis of disease. In particular, the t invention relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, sing such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of e. 1O Background of the invention The serine/threonine n kinase ROCK consists in humans of two isoforms ROCK | and ROCK N. ROCK | is encoded on chromosome 18 whereas ROCK II, also called Rho-kinase, is located on chromosome 12. They both have a molecular weight close to 160kDa. They share an overall homology of 65% while being 95% homologous in their kinase s. Despite their sequence similarity, they differ by their tissue distributions. The highest levels of expression for ROCK l are observed in heart, lung and al s s ROCK N is mostly expressed in brain. Recent data indicate that these two isoforms are partially function redundant, ROCK I being more involved in immunological events, ROCK N in smooth muscle function. The term ROCK refers to ROCK | (ROK-B, p160ROCK, or Rho-kinase B) and ROCK N (ROCK-or or Rho-kinase or).
ROCK activity has been shown to be enhanced by GTPase RhoA that is a member of the Rho (Ras homologous) GTP-binding proteins. The active GTP-bound state of RhoA interacts with Rho- binding domain (RBD) of ROCK that is located in an autoinhibitory carboxyl-terminal loop. Upon binding, the interactions between the ROCK negative regulatory domain and the kinase domain are ted. The process enables the kinase to acquire an open conformation in which it is fully . The open conformation is also induced by the binding of lipid activators such as arachidonic acid to the PH domain in the kinase carboxyl-terminal domain. Another activation mechanism has been bed during apoptosis and involves the cleavage of carboxyl terminus by caspase-3 and -2 (or granzyme B) for ROCK | and II, respectively.
ROCK plays an important role in various cellular functions such as smooth muscle contraction, 3O actin cytoskeleton organization, platelet activation, downregulation of myosin phosphatase cell adhesion, -migration, -pro|iferation and survival, thrombin-induced responses of aortic smooth muscle cells, rophy of cardiomyocytes, bronchial smooth muscle contraction, smooth muscle ction and cytoskeletal reorganization of non- muscle cells, activation of volume- regulated anion channels, neurite retraction, wound healing, cell transformation and gene expression. ROCK also acts in several signaling pathways that are involved in auto-immunity and inflammation. ROCK has been shown to play a part in the activation of NF-KB, a critical molecule that leads to the production of TNF and other inflammatory cytokines. ROCK inhibitors are reported to act against TNF-alpha and lL-6 production in lipopolysaccharide (LPS)—stimulated THP-1 macrophages.
Therefore, ROCK inhibitors provide a useful therapy to treat autoimmune and inflammatory diseases as well as oxidative .
In conclusion, ROCK is a major control point in smooth muscle cell function and a key signaling ent involved in inflammatory processes in various inflammatory cells as well as fibrosis and remodeling in many diseased organs. In on, ROCK has been implicated in various diseases and disorders including eye diseases; airway diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative diseases; kidney diseases; sexual dysfunction; blood diseases; bone diseases; diabetes; benign tic hyperplasia, 1O transplant rejection, liver e, systemic lupus erythematosus, spasm, ension, chronic ctive bladder e, premature birth, infection, allergy, obesity, pancreatic disease and AIDS.
ROCK appears to be a safe target, as exemplified by knockout models and a large number of academic studies. These KO mice data, in ation with post-marketing surveillance studies with Fasudil, a tely potent ROCK inhibitor used for the treatment of vasospasm after subarachnoid hemorrhage, indicate that ROCK is a genuine and significant drug target.
ROCK tors would be useful as therapeutic agents for the treatment of disorders implicated in the ROCK pathway. Accordingly, there is a great need to develop ROCK inhibitors that are useful in treating various diseases or conditions associated with ROCK tion, particularly given the inadequate ents currently available for the majority of these disorders. Some non-limiting examples are inflammatory bowel diseases, ulcerative s, inflammatory skin diseases, glaucoma, asthma and COPD.
Glaucoma is a neurodegenerative disease that is the second most ant cause of irreversible blindness. This disease is characterized by a raised intra-ocular pressure (IOP) and by progressive retinal ganglion cell sis, resulting in irreversible visual field loss. Current treatment of this disease is directed towards the reduction of IOP, which is the main -but not only- risk factor for glaucoma. There is a need for improved treatment as the current therapy does only control and not cure the disease and r suffers from irritation, local and systemic side effects. In addition, onal positive effects, as the anti-inflammatory and nerve regenerating components of ROCK 3O inhibitors, would be highly preferred. nce ROCK inhibitors, such as Y-27632 cause changes in cell shape and decrease stress fibers, focal adhesions and MLC phosphorylation in cultured human TM cells; they relax human trabecular meshwork in vitro, relax human Schlemm’s canal endothelial cells in vitro and when topically applied to animals give a significant increase in trabecular outflow, resulting into a strong lowering of intra ocular pressure.
Inflammatory bowel disease (IBD) comprises Crohn’s disease (CD) and ulcerative colitis (UC).
Although the two diseases are grouped together as IBD, their pathophysiologies are distinct. The key feature of UC is diffuse mucosal inflammation extending ally from the rectum and which does not lly involve the small intestine. There is extensive superficial mucosal ulceration and an associated production of multiple inflammatory mediators. CD is characterized by aggregation of macrophages, frequently seen as granulomas. Unlike UC, CD is often patchy and segmental and inflammation is typically transmural. CD may be found in any site of the GI tract but involvement of the terminal ileum is the most common presentation. There are also differences in the abnormalities of adaptive immunity between UC and CD, with different lineages of T helper cells being involved. TNFCl has long been implicated in IBD, as evidenced by some current antibodybased therapies. ROCK inhibitors ively prevent TNFCl secretion from macrophages in addition to inhibiting the secretion of lL-1B, lL-6 and lL-17, which are other important ors in IBD.
Additionally, ROCK inhibitors limit the inflammatory actions of mediators such as lL-1B on intestinal 1O epithelium by preventing the tion of transcription factors such as NFKB and AP-1.
Inflammation in IBD is also ated with altered smooth muscle ctility, and the long recognized smooth muscle relaxant s of ROCK tors might alleviate tonic contractions that disrupt bowel function. Intestinal r ction is another feature of the IBD and facilitates the uptake of noxious antigens that activate the innate immune system and provoke an immune response. Barrier perturbations in IBD comprise tions in epithelial tight junctions (TJ). The tion of the TJ inflicted by a number of pathogenic inflammatory stimuli has been shown to be associated with increased activity of ROCK and is attenuated by ROCK inhibition. In addition to inflammation, fibrosis is a major complications affecting patients' quality-of-life, often leading to surgery. Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process, following injury or long term inflammation. Transforming growth factor-B1 (TGF-B1) is considered the most potent pro-fibrogenic cytokine. ROCK is a key mediator of TGFB and other fibrotic agents including LPA and S1P. ROCK tors would be expected to simultaneously reduce the inflammatory and ic processes that are observed in IBD.
Allergic asthma is a chronic inflammatory y disorder that results from maladaptive immune responses to ubiquitous environmental proteins in genetically susceptible s. Despite reasonably successful therapies, the prevalence increases as these therapies do not cure; there are still exacerbations and an increasing number of non-responders. New, effective and steroid- sparing treatments that tackle all components of the disease are required.
Chronic Obstructive Pulmonary Disease (COPD) represents a group of es characterized by 3O rsible limitation of airflow, ated with abnormal inflammatory se, bronchoconstriction and remodeling and destruction of the tissue of the lung. It is one of the leading causes of death worldwide, with a steadily increasing prevalence. There is an urgent need for novel therapeutic approaches as the current regimen is inadequate. Until now only bronchodilators are used, since glucocorticoids have limited or no effect. Reference ROCK inhibitors, such as Y-27632 relax human isolated bronchial preparations, inhibit ses in airway resistance in anaesthetised animals, potentiate relaxing effects of B-agonists in vitro and in vivo and give rapid bronchodilatation upon inhalation. In addition, ROCK inhibitors block tracheal smooth muscle contractions induced by H202, the clinical marker for oxidative stress.
Related to airway inflammation, ROCK inhibitors counteract the increase in trans-endothelial permeability mediated by inflammatory agents, maintain the endothelial barrier integrity, inhibit the influx of eosinophils after ovalbumin challenge in vivo, protect against lung edema ion and neutrophile migration, suppress airway HR to metacholine and serotonin in allergic mice and block LPS—induced TNF release. With t to airway is and ling, ROCK inhibitors block the induced ion of airway smooth muscle cells. In vitro evidences for the role of ROCK in ain/vay remodeling were obtained in human lung carcinoma cell line, bovine tracheal smooth muscle cells and human airway smooth muscle. In vivo proof for a role of ROCK in fibrosis in l was generated with mice which exhibited attenuated myocardial fibrosis in response to the 1O partial on of ROCK. The attenuation of myocardial fibrosis by Y-27632 in response to dial infarction and by l in the case of congestive heart failure in a chronic hypertensive rat model brings additional indications of ROCK importance in remodeling. Finally, ROCK tors increase apoptotic cell loss of smooth muscle cells.
Several different classes of ROCK inhibitors are known. The current focus is oncology and cardiovascular applications. Until now, the outstanding therapeutic potential of ROCK inhibitors has only been explored to a d extent because ROCK is such a potent and widespread biochemical tor that systemic tion of ROCK leads to strong biological effects which are ered as being side effects for the treatment of most of the diseases. Indeed, the medical use of ROCK inhibitors for non-cardiological tions is hampered by the pivotal role of ROCK in the regulation of the tonic phase of smooth muscle cell contraction. Systemically available ROCK inhibitors induce a marked decrease in blood re. Therefore, ROCK inhibitors with different properties are highly required.
For the target specific treatment of disorders by regulating smooth muscle function and/or inflammatory processes and/or remodeling, it is highly desired to deliver a ROCK inhibitor to the target organ and to avoid significant s of these drugs to enter other organs. Therefore, local or topical application is desired. Typically, topical administration of drugs has been applied for the treatment of airway-, eye, sexual dysfunction and skin ers. In addition, local injection / infiltration into diseased tissues further extend the ial medical use of locally applied ROCK inhibitors. Given certain criteria are fulfilled, these local applications allow high drug concentration 3O to be reached in the target tissue. In addition, the incorporation of ROCK inhibitors into implants and stents can further expand the medical application towards the local treatment of CV diseases such as atherosclerosis, coronary diseases and heart failure.
Despite the fact that direct local application is preferred in medical practice, there are concerns regarding drug levels reached into the systemic circulation. For example the treatment of airway diseases by local delivery by for instance inhalation, poses the risk of systemic exposure due to large amounts entering the GI tract and/or ic absorption through the lungs. For the treatment of eye es by local delivery, also significant amounts enter the GI tract and/or systemic circulation due to the low permeability of the cornea, low capacity for fluid, efficient drainage and presence of blood vessels in the eyelids. Also for dermal applications, local injections and implantable medical devices, there is a severe risk of leakage into the systemic circulation.
Therefore, in addition to local application, the compounds should preferably have additional properties to avoid significant systemic exposure.
Soft drugs are biologically active compounds that are inactivated once they enter the ic circulation. This inactivation can be achieved in the liver, but the preferred inactivation should occur in the blood. These compounds, once applied y to the target tissue / organ exert their desired effect locally. When they leak out of this tissue into the ic circulation, they are very rapidly inactivated. Thus, soft drugs of choice are sufficiently stable in the target tissue / organ to exert the desired biological effect, but are rapidly degraded in the blood to biologically inactive compounds. 1O In addition, it is highly preferable that the soft drugs of choice have retention at their biological target. This property will limit the number of daily applications and is highly desired to reduce the total load of drug and metabolites and in addition will significantly increase the patient compliance.
In conclusion, there is a continuing need to design and develop soft ROCK inhibitors for the treatment of a wide range of disease states. The nds described herein and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of a variety of disorders or conditions associated with ROCK activation. More specifically, the compounds of the invention are preferably used in the prevention and/or treatment of at least one disease or disorder, in which ROCK is involved, such as diseases linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, egeneration and remodeling. For example, the nds of the ion may be used in the prevention and/or treatment of diseases and disorders such as: - Eye diseases or disorders: including but not limited to retinopathy, optic neuropathy, ma and degenerative retinal diseases such as macular degeneration, proliferative vitreoretinopathy, proliferative diabetic retinopathy retinitis pigmentosa and inflammatory eye diseases (such as or uveitis, panuveitis, intermediate uveitis and posterior uveitis), ma filtration surgery e, dry eye, allergic conjunctivitis, posterior capsule opacification, abnormalities of corneal wound healing and ocular pain.
- Airway diseases; ing but not limited to ary fibrosis, emphysema, chronic 3O bronchitis, asthma, fibrosis, pneumonia, cytsic fibrosis, chronic obstructive ary disease (COPD); bronchitis and rhinitis and respiratory distress me - Throat, Nose and Ear diseases: including but not limited to sinus problems, g problems, toothache, tonsillitis, ulcer and rhinitis, - Skin diseases: including but not limited to hyperkeratosis, ratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis and ulceration.
- Intestinal diseases; including but not limited to inflammatory bowel e (IBD), colitis, gastroenteritis, ileus, ileitis, appendicitis and s disease. 2012/067018 - vascular and vascular diseases: ing but not limited to, pulmonary hypertension and pulmonary vasoconstriction,.
- Inflammatory diseases: including but not limited to t itis, atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel e, Crohn's disease and ulcerative colitis.
- Neurological disorders: ing but not limited to neuropathic pain. The present compounds are therefore le for preventing neurodegeneration and stimulating neurogeneration in various neurological disorders.
- Proliferative diseases: such as but not limited to cancer of , breast, colon, intestine, skin, 1O head and neck, nerve, uterus, kidney, lung, ovary, pancreas, prostate, or d gland; Castleman disease ; sarcoma ; malignoma; and ma.
- Kidney diseases: including but not limited to renal fibrosis or renal dysfunction - Sexual dysfunction: is meant to include both male and female sexual dysfunction caused by a defective vasoactive response. The soft ROCK inhibitors of the present invention may also be used to treat sexual dysfunction arising from a variety of causes. For example, in an embodiment, the soft ROCK inhibitors may be used to treat sexual dysfunction associated with hypogonadism and more particularly, wherein the hypogonadism is associated with reduced levels of androgen hormones. In another embodiment, the soft ROCK inhibitors may be used to treat sexual dysfunction associated with a variety of causes ing, but not limited to, bladder disease, hypertension, diabetes, or pelvic surgery. In on, the soft ROCK inhibitors may be used to treat sexual ction associated with treatment using certain drugs, such as drugs used to treat ension, depression or anxiety.
- Bone diseases: including but not limited to osteoporosis and osteoarthritis - In addition, the compounds of the invention may be used in the prevention and/or treatment of diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive bladder disease, and allergy.
SUMMARY OF THE INVENTION We have surprisingly found that the compounds described herein act as inhibitors of ROCK, in 3O particular as soft ROCK inhibitors. The compounds of the present invention are very rapidly converted into functionally inactive compounds for example by carboxylic ester hydrolases (EC 3.1.1) such as esterase or Carboxylesterases or by plasma proteins diplaying pseudoesterase activity such as Human serum albumin. Carboxylic ester hydrolases (EC 3.1.1) represent a large group of enzymes involved in the degradation of carboxylic esters into alcohols and carboxylic acids. As such, enzymes displaying this catalytic activity are of potential st for the design of soft kinase inhibitors. EC 3.1.1 includes the following sub-classes: EC 3.1.1.1 carboxylesterase; EC 3.1.1.2 arylesterase; EC 3.1.1.3 triacylglycerol lipase; EC 3.1.1.4 ; phospholipase A2; EC 5 lysophospholipase; EC 6 acetylesterase; EC 7 acetylcholinesterase; EC 3.1.1.8 cholinesterase; EC 3.1.1.10 tropinesterase; EC 3.1.1.11 pectinesterase; EC 3.1.1.13 sterol esterase; EC 3.1.1.14 chlorophyllase; EC 3.1.1.15 L- arabinonolactonase; EC 17 gluconolactonase; EC 3.1.1.19 actonase; EC 3.1.1.20 tannase; EC 3.1.1.21 retinyl-palmitate esterase; EC 3.1.1.22 hydroxybutyrate-dimer hydrolase; EC 3.1.1.23 acylglycerol lipase; EC 3.1.1.24 3-oxoadipate enol-lactonase; EC 3.1.1.25 1,4-lactonase; EC 3.1.1.26 galactolipase; EC 27 4-pyridoxolactonase; EC 3.1.1.28 acylcarnitine hydrolase; EC 3.1.1.29 aminoacyl-tRNA hydrolase; EC 3.1.1.30 D-arabinonolactonase; EC 3.1.1.31 6- 1O phosphogluconolactonase; EC 3.1.1.32 phospholipase A1; EC 3.1.1.33 6-acetylglucose deacetylase; EC 3.1.1.34 lipoprotein lipase; EC 3.1.1.35 dihydrocoumarin hydrolase; EC 3.1.1.36 limonin-D-ring-lactonase; EC 3.1.1.37 steroid-lactonase; EC 38 triacetate-lactonase; EC 3.1.1.39 actinomycin lactonase; EC 3.1.1.40 orsellinate-depside hydrolase; EC 3.1.1.41 cephalosporin-C deacetylase; EC 3.1.1.42 chlorogenate hydrolase; EC 3.1.1.43 d-amino-acid esterase; EC 3.1.1.44 4-methyloxaloacetate esterase; EC 3.1.1.45 carboxymethylenebutenolidase; EC 3.1.1.46 deoxylimonate -lactonase; EC 47 1-alkylacetylglycerophosphocholine esterase; EC 3.1.1.48 fusarinine-C ornithinesterase; EC 3.1.1.49 sinapine esterase; EC 3.1.1.50 wax-ester hydrolase; EC 3.1.1.51 phorbol-diester hydrolase; EC 3.1.1.52 phosphatidylinositol deacylase; EC 3.1.1.53 sialate ylesterase; EC 3.1.1.54 acetoxybutynylbithiophene deacetylase; EC 3.1.1.55 acetylsalicylate ylase; EC 3.1.1.56 methylumbelliferyl-acetate deacetylase; EC 3.1.1.57 2-pyrone-4,6-dicarboxylate lactonase; EC 3.1.1.58 N- acetylgalactosaminoglycan deacetylase; EC 3.1.1.59 le-hormone se; EC 3.1.1.60 bis(2-ethylhexyl)phthalate esterase; EC 61 protein-glutamate methylesterase; EC 3.1.1.63 11-cis-retinyl-palmitate hydrolase; EC 3.1.1.64 all-trans-retinyl-palmitate hydrolase; EC 3.1.1.65 L- rhamnono-1,4-lactonase; EC 3.1.1.66 5-(3,4-diacetoxybutynyl)-2,2'-bithiophene deacetylase; EC 3.1.1.67 fatty-acyl-ethyl-ester synthase; EC 3.1.1.68 xylono-1,4-lactonase; EC 3.1.1.70 ate benzylesterase; EC 3.1.1.71 alkylglycerol acetylhydrolase; EC 3.1.1.72 acetylxylan esterase; EC 3.1.1.73 feruloyl esterase; EC 3.1.1.74 cutinase; EC 3.1.1.75 poly(3-hydroxybutyrate) depolymerase; EC 3.1.1.76 -hydroxyoctanoate) depolymerase; EC 3.1.1.77 acyloxyacyl 3O hydrolase; EC 78 polyneuridine-aldehyde esterase; EC 3.1.1.79 hormone-sensitive lipase; EC 3.1.1.80 acetylajmaline esterase; EC 3.1.1.81 quorum-quenching N-acyl-homoserine lactonase; EC 3.1.1.82 pheophorbidase; EC 83 rpene s-lactone hydrolase; EC 84 cocaine esterase; EC 3.1.1.85 mannosylglycerate hydrolases.Cholinesterases are enzymes that are primarily known for their role in the degradation of the neurotransmitter acetylcholine. Acetylcholinesterase (EC 3.1.1.7) is also known as Choline esterase l, true cholinesterase, RBC cholinesterase, erythrocyte cholinesterase, or acetylcholine acetylhydrolase.
As suggested by some of its alternative names, acetylcholinesterase is not only found in brain, but also in the erythrocyte fraction of blood. In addition to its action on acetylcholine, acetylcholinesterase hydrolyzes a variety of acetic esters, and also catalyzes transacetylations. 40 Acetylcholinesterase usually displays a ence for substrates with short acid chains, as the acetyl group of acetylcholine. Butyrylcholinesterase (EC 3.1.1.8) is also known as benzoylcholinesterase, choline esterase ll, non-specific cholinesterase, pseudocholinesterase, plasma cholinesterase or acylcholine acylhydrolase, While being found primarily in liver, butyrylcholinesterase is also present in plasma. As indicated by some of its alternative names, it is less specific than acetylcholinesterase and will lly carry out the ysis of substrates with larger acid chains (such as the l group of butyrylcholine or the benzoyl group of benzolylcholine) at a faster rate than cholinesterase. In addition to its action on acetylcholine, butyrylcholinesterase is known to participate in the metabolism of several ester drugs, such as procaine. 1O ylesterases (CES) represent a multigene family and show ubiquitous expression profiles, with high levels in liver, ine and lungs. A majority of carboxylesterases can be classified either in carboxylesterase 1 (CES 1) or carboxylesterase 2 (CESZ) es. Interestingly, these different CES families show differences in tissue distribution and substrate specificity. Human CES1 is widely distributed in many tissues, but is found in low levels in the ine. CES1 preferentially hydrolyzes esters with relatively small alcohol groups and larger acid groups. As a typical e, hCES1 preferentially catalyzes the hydrolysis of the methyl ester of cocaine. Human CESZ is predominantly found in ine, liver and kidney. CESZ preferentially hydrolyzes esters with smaller l groups, and larger acid groups. As a typical example, human CESZ catalyzes the hydrolysis of the benzoyl ester of cocaine. Another interesting observation about CES enzymes is the lack of carboxylesterase activity in human plasma. Overall, carboxylesterases can play a major role in the bioconversion of ester-containing drugs and xenobiotics.
Human serum albumin (HSA) is a major component of blood plasma, accounting for approximately 60% of all plasma proteins. HSA has been found to catalyze the hydrolysis of various nds such as aspirin, cinnamoylimidazole, p-nitrophenyl acetate, organophosphate insecticides, fatty acid esters or nicotinic esters. HSA diplays multiple nonspecific catalytic sites in on to its primary reactive site. The catalytic efficiency of these sites is however low, and HSA has often been bed not as a true esterase, but as a pseudoesterase, In spite of its low catalytic efficiency, HSA can still play a significant role in the metabolism of drug-like compounds, because of its high concentration in plasma. 3O Unless a context dictates otherwise, asterisks are used herein to indicate the point at which a mono- or bivalent radical depicted is connected to the structure to which it relates and of which the radical forms part.
Viewed from a first aspect, the invention provides a compound of Formula | or a stereoisomer, tautomer, racemic, salt, e, or solvate thereof, Wherein, X is hydrogen or halogen; Y is —NH-C(=O)— or —C(=O)—NH-; R1 is ed from the group comprising hydrogen, lkyl, and 03.15cycloalkyl; R2 is ed from the group comprising hydrogen, C1_20alkyl, halogen and C1_20alkoxy; R3 is selected from the group consisting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl, heteroaryl, and 03.19heterocyclyl; wherein said C1_20alkyl, lkenyl, C3_20alkynyl, 03.15cycloalkyl, 1O aryl, heteroaryl, and C3_19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_20alkyl)amino, C1. goalkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, C1_20alkyl esters, carbamate, ido, urea, and sullfonamido; and n is an integer from 1 to 3.
Viewed from a further aspect, the invention provides the use of a compound of the ion, or a composition comprising such a compound, for inhibiting the activity of at least one , in vitro or in vivo.
Viewed from a r aspect, the invention provides the use of a compound of the invention, or a composition comprising such a compound, for inhibiting the activity of at least one ROCK kinase, for example ROCKII and/or ROCKI isoforms.
Viewed from a further aspect, the invention provides a pharmaceutical and/or veterinary composition comprising a compound of the invention.
Viewed from a still further aspect, the invention provides a compound of the invention for use in human or veterinary medicine.
Viewed from a still further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of at least one disease and/or disorder selected from the group comprising eye diseases; airway diseases; throat, nose and ear diseases; inal diseases; vascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive bladder disease, and allergy.
ED DESCRIPTION OF THE INVENTION 1O The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly ted to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
Unless a context dictates otherwise, asterisks are used herein to indicate the point at which a mono- or bivalent l ed is connected to the structure to which it relates and of which the radical forms part.
Undefined (racemic) asymmetric s that may be present in the compounds of the present invention are interchangeably indicated by drawing a wavy bonds or a straight bond in order to visualize the undefined steric character of the bond.
As already mentioned hereinbefore, in a first aspect the present invention provides compounds of Formula | Wherein, X, R1, Y, n, R2 and R3 are as d hereinbefore, including the stereo-isomeric forms, es, and pharmaceutically able addition salts thereof. -1 1- When describing the compounds of the invention, the terms used are to be construed in ance with the following definitions, unless a context dictates otherwise: The term "alkyl" by itself or as part of another substituent refers to a fully saturated hydrocarbon of Formula CXH2X+1 n x is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 20 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated . When a subscript is used herein following a carbon atom, the ipt refers to the number of carbon atoms that the named group may contain. Thus, for example, C1_4alkyl means an alkyl of one to four carbon atoms. Examples of alkyl groups are , ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g. l, i-butyl and t-butyl); pentyl and 1O its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; decyl and its isomers. C1-C6 alkyl includes all linear, branched, or cyclic alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene, and exyl.
The term "optionally tuted alkyl" refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, for example 1, 2, 3, or 4 tuents or 1 to 2 substituents) at any available point of attachment. Non-limiting examples of such substituents include halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, , haloalkoxy, haloalkyl, thiol, hio, carboxylic acid, ino, alkyl esters, carbamate, thioamido, urea, sullfonamido and the like.
The term “alkylamino”, as used herein refers to an amino group substituted with one or more alkyl chain(s). This definition includes quaternary ammonium derivatives.
The term "alkenyl", as used herein, unless othen/vise indicated, means ht-chain, cyclic, or ed-chain hydrocarbon radicals containing at least one carbon-carbon double bond.
Examples of alkenyl radicals include ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z,E-, Z,Z-hexadienyl, and the like. An optionally substituted alkenyl refers to an alkenyl having optionally one or more substituents (for example 1, 2, 3 or 4), selected from those defined above for substituted alkyl.
The term "alkynyl", as used herein, unless othen/vise indicated, means straight-chain or branched- 3O chain hydrocarbon ls containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
An optionally substituted alkynyl refers to an l having optionally one or more substituents (for example 1, 2, 3 or 4), selected from those defined above for substituted alkyl.
The term “cycloalkyl” by itself or as part of another substituent is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated arbyl group having 1, 2, or 3 cyclic structure.
Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups ning 1 to 3 rings, including monocyclic, bicyclic, or polycyclic alkyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and lly, according to this invention comprise from 3 to 15 atoms. The further rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro atoms. Cycloalkyl groups may also be ered to be a subset of homocyclic rings discussed hereinafter. Examples of cycloalkyl groups include but are not d to cyclopropyl, utyl, cyclopentyl, exyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl, o(2.2.1)heptanyl and cyclodecyl with cyclopropyl, cyclopentyl, cyclohexyl, adamantanyl, and bicyclo(2.2.1)heptanyl being particularly red. An “optionally substituted cycloalkyl” refers to a cycloalkyl having optionally one or more 1O substituents (for example 1 to 3 substituents, for example 1, 2, 3 or 4 substituents), selected from those defined above for substituted alkyl. When the suffix "ene" is used in conjunction with a cyclic group, hereinafter also referred to as “Cycloalkylene”, this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups. Cycloalkylene groups of this invention preferably comprise the same number of carbon atoms as their cycloalkyl radical counterparts.
Where alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed "alkylene" groups. Non-limiting examples of alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1,2- dimethylethylene, pentamethylene and hexamethylene. Similarly, where alkenyl groups as defined above and alkynyl groups as defined above, respectively, are divalent radicals having single bonds for attachment to two other groups, they are termed "alkenylene" and ylene" respectively.
Generally, ne groups of this ion preferably comprise the same number of carbon atoms as their alkyl counterparts. Where an alkylene or cycloalkylene biradical is present, connectivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom, preferably a common carbon atom. To illustrate this applying the asterisk nomenclature of this invention, a C3 alkylene group may be for example *-CHZCH2CH2-*, *-CH(- CHZCH3)-*, or *-CHZCH(-CH3)-*. Likewise a C3 lkylene group may be Where a cycloalkylene group is present, this is preferably a C3-C6 lkylene group, more 3O preferably a C3 cycloalkylene (i.e. cyclopropylene group) wherein its connectivity to the structure of which it forms part is through a common carbon atom. Cycloalkylene and alkylene biradicals in compounds of the invention may be, but preferably are not, substituted.
The terms "heterocyclyl" or ocyclo" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring s, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom- containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be ed at any heteroatom or carbon atom of the ring or ring , where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. An optionally substituted cyclyl refers to a cyclyl having optionally one or more substituents (for example 1 to 4 substituents, or for example 1, 2, 3 or 4), selected from those defined for substituted aryl. 1O Exemplary heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, olidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, imidyl, 3H- indolyl, isoindolinyl, chromenyl, isochromanyl, nyl, rolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3- pyrrolinyl, pyrrolidinyl, nolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, zinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, anyl, 3,4-dihydro- 2H-pyranyl, phthalazinyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,3-dioxanyl, 2,5-dioximidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 6H-1,2,5-thiadiazinyl, 2H-1,5,2-dithiazinyl, 2H-oxocinyl, 1H-pyrrolizinyl, tetrahydro- 2O 1,1-dioxothienyl, N- formylpiperazinyl, and morpholinyl.
The term “aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthalene or anthracene) or linked covalently, typically containing 6 to 10 atoms; wherein at least one ring is aromatic. The aromatic ring may optionally include one to three additional rings (either cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also ed to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl se phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1- or 2-naphthyl, 1-, 2-, or 3-indenyl, 1-, 2-, or 9-anthryl, 1- 2-, 3-, 4-, or aphtylenyl, 3-, 4-, or 5-acenaphtenyl, 1-, 2-, 3-, 4-, or 10-phenanthryl, 1- or 2-pentalenyl, 1, 2-, 3-, or 4-fluorenyl, 4- or nyl, 5-, 6-, 7-, or 3O 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, o[a,d]cylcoheptenyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl.
The aryl ring can optionally be substituted by one or more substituents. An nally substituted aryl” refers to an aryl having ally one or more substituents (for example 1 to 5 substituents, for example 1, 2, 3 or 4) at any available point of attachment. Non-limiting examples of such substituents are selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -SOZ-NH2, aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -SOZRa, alkylthio, carboxyl, and the like, wherein Ra is alkyl or cycloal kyl.
Where a carbon atom in an aryl group is ed with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
The term “heteroaryl” as used herein by itself or as part of another group refers but is not limited to to 12 carbon-atom aromatic rings or ring systems containing 1 to 3 rings which are fused together or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by , nitrogen or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen 1O heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such aryl, e: pyrrolyl, furanyl, thiophenyl, lyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2—b]furanyl, thieno[3,2—b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, uranyl, benzopyranyl, benzopyranyl, 1(2H)—benzopyranyl, 3,4-dihydro- 1(2H)—benzopyranyl, 3,4-dihydro-1(2H)—benzopyranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2—benzisoxazolyl, 2,1- benzisoxazolyl, 1,3-benzothiazolyl, 1,2—benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2—a]pyridinyl, 6-oxo-pyridazin-1(6H)—yl, 2—oxopyridin-1(2H)—yl, 6- oxo-pyridazin-1(6H)—yl, 2—oxopyridin-1(2H)—yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, olinyl, quinoxalinyl, 7-azaindolyl, ndolyl, 5-azaindolyl, 4-azaindolyl.
The term “pyrrolyl” (also called azolyl) as used herein es pyrrolyl, pyrrolyl and yl. The term yl” (also called "furyl") as used herein includes furanyl and furanyl (also called furanyl and furanyl). The term “thiophenyl” (also called "thienyl") as used herein includes thiophenyl and thiophenyl (also called thienyl and thienyl). The term “pyrazolyl” (also called 1H-pyrazolyl and 1,2—diazolyl) as used herein includes pyrazolyl, pyrazolyl, pyrazolyl and pyrazolyl. The term “imidazolyl” as used herein es imidazolyl, ol- 3O 2—yl, imidazolyl and imidazolyl. The term “oxazolyl” (also called 1,3-oxazolyl) as used herein includes oxazolyl; oxazolyl and oxazolyl. The term “isoxazolyl” (also called 1,2—oxazolyl), as used herein includes isoxazolyl, isoxazolyl, and isoxazolyl. The term “thiazolyl” (also called 1,3-thiazolyl),as used herein includes thiazolyl, thiazolyl and thiazolyl (also called 2- thiazolyl, 4-thiazolyl and 5-thiazolyl). The term “isothiazolyl” (also called iazolyl) as used herein includes azolyl, isothiazolyl, and isothiazolyl. The term “triazolyl” as used herein includes 1H-triazolyl and 4H-1,2,4-triazolyl, “1H-triazolyl” includes 1H-1,2,3-triazolyl, 1H- 1,2,3-triazolyl, 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 1H-1,2,4-triazolyl and 1H-1,2,4- triazolyl. “4H-1,2,4-triazolyl” includes 4H-1,2,4-triazolyl, and ,4-triazolyl. The term “oxadiazolyl” as used herein includes 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazol yl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and oxadiazolyl. The term “thiadiazolyl” as used herein includes 1,2,3-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl (also called nyl) and 1,3,4-thiadiazolyl. The term zolyl” as used herein includes 1H-tetrazolyl, 1H-tetrazolyl, 2H-tetrazolyl, and 2H- tetrazolyl. The term “oxatriazolyl” as used herein includes 4-oxatriazolyl and 12,35- azolyl. The term “thiatriazolyl” as used herein es 1,2,3,4-thiatriazolyl and 12,35- thiatriazolyl. The term “pyridinyl” (also called "pyridyl") as used herein includes pyridinyl, pyridinyl and pyridinyl (also called 2—pyridyl, 3-pyridyl and 4-pyridyl). The term “pyrimidyl” as used herein includes pyrimidyl, dyl, pyrimidyl and pyrimidyl. The term “pyrazinyl” 1O as used herein includes pyrazinyl and pyrazinyl. The term “pyridazinyl as used herein includes pyridazinyl and pyridazinyl. The term “oxazinyl” (also called "1,4-oxazinyl") as used herein includes 1,4-oxazinyl and 1,4-oxazinyl. The term “dioxinyl” (also called "1,4-dioxinyl”) as used herein includes 1,4-dioxinyl and oxinyl. The term “thiazinyl” (also called "1,4- thiazinyl”) as used herein includes 1,4-thiazinyl, 1,4-thiazinyl, 1,4-thiazinyl, 1,4-thiazinyl and 1,4-thiazinyl. The term inyl” as used herein includes 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,4-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl and 1,2,3-triazinyl. The term “imidazo[2,1- b][1,3]thiazolyl” as used herein includes imidazo[2,1-b][1,3]thiazoiyl, imidazo[2,1-b][1,3]thiazol yl, o[2, 1-b][1,3]thiazolyl and imidazo[2,1-b][1,3]thiazolyl. The term o[3,2— b]furanyl” as used herein es thieno[3,2—b]furanyl, thieno[3,2—b]furanyl, thieno[3,2— b]furanyl, and thieno[3,2—b]furanyl. The term “thieno[3,2—b]thiophenyl” as used herein includes thieno[3,2—b]thienyl, thieno[3,2—b]thienyl, thieno[3,2—b]thienyl and thieno[3,2—b]thienyl.
The term “thieno[2,3-d][1,3]thiazolyl” as used herein includes thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d][1,3]thiazolyl and thieno[2,3-d][1,3]thiazolyl. The term “thieno[2,3-d]imidazolyl” as used herein includes thieno[2,3-d]imidazolyl, thieno[2,3-d]imidazolyl and [2,3- d]imidazolyl. The term “tetrazolo[1,5-a]pyridinyl” as used herein includes tetrazolo[1,5-a]pyridine- -yl, tetrazolo[1,5-a]pyridineyl, tetrazolo[1,5-a]pyridineyl, and tetrazolo[1,5-a]pyridineyl. The term “indolyl” as used herein includes indolyl, indolyl, indolyl,-indolyl, indolyl, indol yl and indolyl. The term “indolizinyl” as used herein es indolizinyl, indolizinyl, indolizinyl, indolizinyl, indolizinyl, indolizinyl, and indolizinyl. The term “isoindolyl” as 3O used herein includes isoindolyl, isoindolyl, isoindolyl, isoindolyl, isoindolyl, ol yl and isoindolyl. The term “benzofuranyl” (also called benzo[b]furanyl) as used herein includes benzofuranyl, benzofuranyl, benzofuranyl, benzofuranyl, benzofuranyl and benzofuranyl. The term “isobenzofuranyl” (also called benzo[c]furanyl) as used herein includes isobenzofuranyl, isobenzofuranyl, isobenzofuranyl, isobenzofuranyl, isobenzofuranyl and isobenzofuranyl. The term “benzothiophenyl” (also called b]thienyl) as used herein includes 2—benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and benzo[b]thiophenyl (also called benzothienyl, benzothienyl, benzothienyl, benzothienyl, benzothienyl and benzothienyl). The term “isobenzothiophenyl” (also called benzo[c]thienyl) as used herein includes isobenzothienyl, 40 isobenzothienyl, zothienyl, isobenzothienyl, isobenzothienyl and isobenzothien yl. The term “indazolyl” (also called 1H-indazolyl or 2—azaindolyl) as used herein es 1H- indazolyl, 1H-indazolyl, 1H-indazolyl, azolyl, 1H-indazolyl, 1H-indazolyl, 2H- indazolyl, 2H-indazolyl, 2H-indazolyl, 2H-indazolyl, 2H-indazolyl, and 2H-indazolyl.
The term midazolyl” as used herein includes benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl and benzimidazolyl. The term “1,3- benzoxazolyl” as used herein includes 1,3-benzoxazol-2—yl, 1,3-benzoxazolyl, nzoxazol yl, 1,3-benzoxazolyl and 1,3-benzoxazolyl. The term “1,2—benzisoxazolyl” as used herein includes 1,2—benzisoxazolyl, 1,2—benzisoxazolyl, 1,2—benzisoxazolyl, nzisoxazolyl and 1,2—benzisoxazolyl. The term “2,1-benzisoxazolyl” as used herein includes 2,1- 1O benzisoxazolyl, 2,1-benzisoxazolyl, 2,1-benzisoxazolyl, 2,1-benzisoxazolyl and 2,1- benzisoxazolyl. The term “1 ,3-benzothiazolyl” as used herein includes nzothiazolyl, 1,3- benzothiazolyl, 1,3-benzothiazolyl, 1,3-benzothiazolyl and 1,3-benzothiazolyl. The term “1 ,2—benzoisothiazolyl” as used herein includes 1,2—benzisothiazolyl, 1,2—benzisothiazolyl, 1,2- benzisothiazolyl, 1,2—benzisothiazolyl and 1,2—benzisothiazolyl. The term “2,1- sothiazolyl” as used herein includes 2,1-benzisothiazolyl, 2,1-benzisothiazolyl, 2,1- benzisothiazolyl, 2,1-benzisothiazolyl and 2,1-benzisothiazolyl. The term “benzotriazolyl” as used herein includes benzotriazolyl, benzotriazol4-yl, riazolyl, riazolyl and benzotriazolyl. The term “1 ,2,3-benzoxadiazolyl” as used herein includes 1,2,3-benzoxadiazol yl, 1,2,3-benzoxadiazolyl, 1,2,3-benzoxadiazolyl and 1,2,3-benzoxadiazolyl. The term -benzoxadiazolyl” as used herein includes 2,1,3-benzoxadiazolyl, 2,1,3-benzoxadiazol yl, benzoxadiazol-6—yl and 2,1,3-benzoxadiazolyl. The term “1,2,3-benzothiadiazolyl” as used herein includes 1,2,3-benzothiadiazolyl, 1,2,3-benzothiadiazolyl, 1,2,3-benzothiadiazol- 6-yl and 1,2,3-benzothiadiazolyl. The term “2,1,3-benzothiadiazolyl” as used herein includes 2,1,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl and 2,1,3- benzothiadiazolyl. The term “thienopyridinyl” as used herein es thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2—c]pyridinyl and thieno[3,2—b]pyridinyl. The term “purinyl” as used herein es purinyl, purinyl, purinyl and purinyl. The term “imidazo[1,2—a]pyridinyl”, as used herein includes imidazo[1,2—a]pyridinyl, imidazo[1,2—a]pyridinyl, imidazo[1,2—a]pyridin- 4-yl, imidazo[1,2—a]pyridinyl, imidazo[1,2—a]pyridinyl and imidazo[1,2—a]pyridinyl. The term 3O “1,3-benzodioxolyl”, as used herein includes 1,3-benzodioxolyl, 1,3-benzodioxolyl, 1,3- benzodioxolyl, and 1,3-benzodioxolyl. The term “quinolinyl” as used herein includes quinolin- 2—yl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl and quinolinyl. The term “isoquinolinyl” as used herein includes isoquinolinyl, nolinyl, isoquinolinyl, isoquinolin- -yl, isoquinolinyl, isoquinolinyl and isoquinolinyl. The term “cinnolinyl” as used herein includes cinnolinyl, cinnolinyl, cinnolinyl, inyl, cinnolinyl and cinnolinyl. The term “quinazolinyl” as used herein includes quinazolinyl, quiriazolinyl, quinazolinyl, quinazolinyl, quinazolinyl and quinazolinyl. The term “quinoxalinyl”. as used herein includes quinoxalinyl, quinoxalinyl, and quinoxalinyl. The term indolyl” as used herein refers to 1H-Pyrrolo[2,3-b]pyridinyl and includes 7-azaindolyl, 7-azaindolyl, ndolyl, 7- 40 azaindolyl, 7-azaindolyl, 7-azaindolyl. The term “6-azaindolyl” as used herein refers to 1H- Pyrrolo[2,3-c]pyridinyl and includes 6—azaindolyl, 6—azaindolyl, 6-azaindolyl, 6-azaindol yl, 6—azaindolyl, 6—azaindolyl. The term “5-azaindolyl” as used herein refers to 1H-Pyrrolo[3,2— c]pyridinyl and includes ndolyl, 5-azaindolyl, 5-azaindolyl, 5-azaindolyl, 5- azaindolyl, 5-azaindolyl. The term “4-azaindolyl” as used herein refers to 1H-Pyrrolo[3,2— b]pyridinyl and includes 4-azaindolyl, 4-azaindolyl, 4-azaindolyl, 4-azaindolyl, 4- azaindolyl, ndolyl.
For example, non-limiting examples of heteroaryl can be 2— or 3-furyl, 2— or 3-thienyl, 1-, 2— or 3- pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-thiazolyl, 1,2,3-triazol, or yl, 1,2,4-triazol, , or 1O yl, 1H-tetrazol, oryl, razol, or yl, 1,2,3-oxadiazol or yl, 1,2,4-oxadiazol or - -yl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazol or yl, 1,2,4-thiadiazol or yl, 1,2,5-thiadiazol or y|, thiadiazolyl, 1- or 5-tetrazolyl, 2-, 3- or dyl, 3- or 4- pyridazinyl, 2-, 4-, 5- or 6-pyrimidyl, 2-, 3-, 4-, 5- 6—2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 4- azaindol, 2-, 3-, 5-, or 7-yl, 5-azaindol, or 2-, 3-, 4-, 6-, or 7-yl, 6-azaindol-1, 2-, 3-, 4-, 5-, or 7- yl, 7-azaindol, 2-, 3-, 4, 5-, or 6-yl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 1-, 3-, 4- or enzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 3-, 4- or enzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2- or 3-pyrazinyl, 1,4-oxazin or yl, 1,4-dioxin or yl, 1,4-thiazin or yl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazin, or yl, thieno[2,3-b]furan, , , or yl, benzimidazolyl, yl, yl, yl, yl, or yl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or oxazolyl, 3-, 4-, 5-, 6- or 7-benzisothiazolyl, 1,3-benzothiazol- 2-yl, y|, yl, yl or yl, 1,3-benzodioxolyl, yl, yl, or yl, benzotriazolyl, yl, yl, yl or yl1-, nthrenyl, 3-, 4- or 5-isobenzofuranyl, 1-, 2-, 3-, 4- or 9-xanthenyl, 1-, 2-, 3- or 4-phenoxathiinyl, 2-, 3-pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or lizinyl, 2-, 3-, 4- or 5-isoindolyl, 1H- indazolyl, 3-yl, y|, yl, yl, or yl, 2H-indazolyl, 3-yl, y|, yl, yl, or yl, imidazo[2,1-b][1,3]thiazoiyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2, 1-b][1,3]thiazolyl or imidazo[2,1-b][1,3]thiazolyl, imidazo[1,2—a]pyridinyl, imidazo[1,2—a]pyridinyl, imidazo[1,2— a]pyridinyl, imidazo[1,2—a]pyridinyl, imidazo[1,2—a]pyridinyl or imidazo[1,2—a]pyridinyl, tetrazolo[1 ,5-a]pyridineyl, olo[1 ,5-a]pyridineyl, tetrazolo[1,5-a]pyridineyl, or tetrazolo[1,5-a]pyridineyl, 2-, 6-, 7- or 8-purinyl, 4-, 5- or 6-phthalazinyl, 2-, 3- or 4-naphthyridinyl, 3O 2-, 5- or 6-quinoxalinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1-, 2-, 3- or 4-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl(quinolyl), 2-, 4-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinolinyl(isoquinolyl), 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl,2-, 4-, 6- or idinyl, 1-, 2-, 3-, 4- or 9- olyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- phenanthridinyl, 1-, 2-, 3- or 4-acridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-(1,7)phenanthrolinyl, 1- or 2—phenazinyl, 1-, 2-, 3-, 4-, or 10-phenothiazinyl, 3- or 4- furazanyl, 1-, 2-, 3-, 4-, or 10-phenoxazinyl, or additionally substituted derivatives thereof.
An “optionally substituted heteroaryl” refers to a aryl having optionally one or more substituents (for example 1 to 4 substituents, for example 1, 2, 3 or 4), selected from those defined above for substituted aryl. -18— The term “oxo” as used herein refers to the group =0.
The term “alkoxy" or “alkyloxy” as used herein refers to a radical having the Formula -ORb wherein Rb is alkyl. Preferably, alkoxy is C1-C10 alkoxy, C1-C6 alkoxy, or C1-C4 alkoxy. miting examples of suitable alkoxy e methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert-butoxy, pentyloxy and hexyloxy. Where the oxygen atom in an alkoxy group is substituted with sulfur, the resultant radical is referred to as thioalkoxy. “Haloalkoxy” is an alkoxy group wherein one or more hydrogen atoms in the alkyl group are substituted with halogen. Non- limiting examples of le koxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2—trifluoroethoxy, 1,1,2,2—tetrafluoroethoxy, 2—fluoroethoxy, roethoxy, 2,2—difluoroethoxy, 1O 2,2,2—trichloroethoxy; trichloromethoxy, 2—bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.
The term "aryloxy" as used herein denotes a group -O-aryl, wherein aryl is as defined above.
The term “arylcarbonyl” or " as used herein denotes a group -C(O)—aryl, wherein aryl is as defined above.
The term “cycloalkylalkyl” by itself or as part of another substituent refers to a group having one of the aforementioned cycloalkyl groups attached to one of the aforementioned alkyl chains.
Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2—cyclopentylethyl, 2- exylethyl, cyclobutylpropyl, cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyl and the like.
The term “heterocyclyl-alkyl” by itself or as part of another substituents refers to a group having one of the aforementioned heterocyclyl group attached to one of the aforementioned alkyl group, i.e., to a group —Rd-RC wherein Rd is ne or alkylene substituted by alkyl group and Rc is a heterocyclyl group.
The term "carboxy" or “carboxyl” or “hydroxycarbonyl” by itself or as part of another substituent refers to the group -C02H. Thus, a carboxyalkyl is an alkyl group as defined above having at least one substituent that is -COZH.
The term "alkoxycarbonyl" by itself or as part of another tuent refers to a y group linked to an alkyl radical i.e. to form —C(=O)ORe, wherein R9 is as defined above for alkyl. 3O The term “alkylcarbonyloxy” by itself or as part of r substituent refers to a —O-C(=O)Re wherein R9 is as d above for alkyl.
The term “alkylcarbonylamino” by itself or as part of another substituent refers to an group of Formula -NH(C=O)R or -NR'(C=O)R, wherein R and R’ are each independently alkyl or substituted alkyl.
The term “thiocarbonyl” by itself or as part of another tuent refers to the group -C(=S)—.
The term “alkoxy” by itself or as part of another substituent refers to a group consisting of an oxygen atom ed to one optionally substituted straight or branched alkyl group, cycloalkyl group, aralkyl, or cycloalkylalkyl group. Non-limiting examples of suitable alkoxy group e methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, hexanoxy, and the like.
The term “halo” or en” as a group or part of a group is generic for fluoro, chloro, bromo, or iodo.
The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non- 1O ng examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.
The term "haloaryl" alone or in combination, refers to an aryl radical having the g as defined above wherein one or more hydrogens are replaced with a halogen as d above.
The term “haloalkoxy” alone or in combination refers to a group of Formula -O-alkyl wherein the alkyl group is substituted by 1, 2, or 3 n atoms. For example, "haloalkoxy" includes -OCF3, — OCHFz, 'OCHzF, 'O-CFz-CF3, 'O-CHz-CF3, -O-CH2—CHF2, and -O-CH2—CH2F.
Whenever the term “substituted” is used in the present invention, it is meant to te that one or more hydrogens on the atom indicated in the expression using “substituted” is ed with a selection from the indicated group, provided that the indicated atom’s normal valency is not ed, and that the substitution results in a chemically stable compound, Le. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a eutic agent.
As used herein the terms such as “alkyl, aryl, or cycloalkyl, each being optionally substituted with” or , aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl, optionally tuted aryl and optionally substituted cycloalkyl.
As bed herein, some of the compounds of the ion may contain one or more asymmetric carbon atoms that serve as a chiral center, which may lead to different optical forms (e.g. enantiomers or diastereoisomers). The invention comprises all such optical forms in all possible configurations, as well as mixtures thereof. 3O More generally, from the above, it will be clear to the skilled person that the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational s, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.
Whenever used in the present invention the term “compounds of the invention” or a similar term is meant to include the compounds of general Formula | and any subgroup thereof. This term also refers to the compounds as depicted in examples, their derivatives, N-oxides, salts, es, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, , and metabolites, as well as their quaternized nitrogen analogues. The N-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
As used in the specification and the appended claims, the singular forms "a "the" , an", and include plural referents unless the context clearly dictates otherwise. By way of example, "a 1O compound" means one compound or more than one compound.
The terms described above and others used in the specification are well understood to those in the art.
In a further embodiment, the present invention provides compounds of formula I as described hereinabove, wherein; R1 is selected from the group comprising hydrogen, Cq_6alkyl, and C3_6cycloalkyl; in particular hydrogen.
In a preferred embodiment, the present invention provides nds of formula I as described above, wherein; X is hydrogen or halogen; in particular n; more in particular fluoro; Y is —NH-C(=O)— or —C(=O)—NH-; R1 is ed from the group comprising hydrogen, Cq_6alkyl, and C3_8cycloalkyl; in particular hydrogen; R2 is selected from the group comprising hydrogen, Cmoalkyl, halogen and C1_20alkoxy; R3 is selected from the group ting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl, aryl, and 03.19heterocyclyl; wherein said Cmoalkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl, heteroaryl, and C3_19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, aryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, lkylamino, di(C1_20alkyl)amino, C1. goalkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, lkylthio, carboxylic acid, acylamino, Cmoalkyl , carbamate, ido, urea, and namido; and n is an integer from 1 to 3; in particular n is 1 or 2; more in particular n is 1. -21 _ In an even r embodiment, the present invention provides compounds of a I as described hereinabove, wherein; R2 is selected from hydrogen, kyl, and halogen; in particular R2 is hydrogen.
In yet another embodiment, the present invention provides nds of formula I as described hereinabove, wherein; R3 is selected from the group ting of Cmoalkyl, 03.15cycloalkyl, aryl, and C3_19heterocyclyl; wherein said Cmoalkyl, 03.15cycloalkyl, aryl, and C3_19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, Cq_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_ 1O goalkyl)amino, C1_20alkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, ino, Cmoalkyl esters, carbamate, thioamido, urea, and sullfonamido; in particular R3 is selected from the group consisting of Cmoalkyl, 03.15cycloalkyl, aryl, and C3. 19heterocyclyl; wherein said ycloalkyl, aryl, and C3_19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_20alkyl)amino, lkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, yl esters, carbamate, thioamido, urea, and sullfonamido; more in particular R3 is selected from the group ting of C1_20alkyl, 03.15cycloalkyl, aryl, and C3. 19heterocyclyl; wherein said C3_19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, aryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, lkylamino, di(C1_20alkyl)amino, C1. xy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, lkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sullfonamido; In a further embodiment, the present invention provides comounds of formula I as described hereinbefore, wherein; R3 is selected from the group consisting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl, heteroaryl, and C3_19heterocyclyl; wherein said 03.15cycloalkyl, aryl, heteroaryl, and C3. 19heterocyclyl is optionally substituted with one or more tuents ed from the group 3O consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, Cq_6alkyl, C3. 15cycloalkyl, C3_19heterocyclyl, ylamino, di(C1_20alkyl)amino, Cmoalkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sullfonamido; in particular R3 is selected from the group consisting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, C3. oalkyl, aryl, heteroaryl, and C3_19heterocyclyl; wherein said 03.15cycloalkyl and C3. 19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, Cq_6alkyl, C3. 15cycloalkyl, C3_19heterocyclyl, Cmoalkylamino, di(C1_20alkyl)amino, Cmoalkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and namido.
In a particular embodiment, the present invention es compounds of formula I as described before, wherein; said one or more optional substituents for R3 are selected from the group consisting of halo, hydroxyl, nitro, amino, cyano, aryl, heteroaryl, Cq_6alkyl, ycloalkyl, eterocyclyl, C1. 1O goalkylamino, di(C1_20alkyl)amino, C1_20alkoxy, and halo-C1_Zoalkyl; in particular halo, hydroxyl, nitro, amino, cyano, Cq_6alkyl, C1_20alkylamino, di(C1_20alkyl)amino, C1_20alkoxy, and halo-C1_Zoalkyl; more in particular C1_6alkyl.
It is also an object of the invention to provide those compounds of formula I wherein one or more of the following ction apply: 0 X is halogen; in particular fluoro; - Y is—C(=O)—NH-; - R1 is hydrogen; 0 R2 is en; 0 R3 is selected from the group consisting of Cmoalkyl, C3_20alkenyl, C3_20alkynyl, C3. 15cycloalkyl, aryl, heteroaryl, and C3_19heterocyclyl; wherein said C1_20alkyl, C3_20alkenyl, C3. goalkynyl, 03.15cycloalkyl, aryl, heteroaryl, and eterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_20alkyl)amino, Cmoalkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1. goalkylthio, carboxylic acid, acylamino, yl esters, carbamate, thioamido, urea, and sullfonamido; - R3 is selected from the group consisting of 03.15cycloalkyl, aryl, heteroaryl, and C3_19heterocyclyl; wherein said 03.15cycloalkyl, aryl, heteroaryl, and C3_19heterocyclyl is 3O optionally tuted with C1_6alkyl; in particular R3 is selected from the group consisting of indanyl, cyclohexyl, , tetrahydrofuranyl, piperidinyl, and thianyl; n said indanyl, cyclohexyl, oxanyl, tetrahydrofuranyl, piperidinyl, and thianyl is optionally substituted with kyl; more in particular R3 is selected from the group consisting of indanyl, cyclohexyl, oxanyl, tetrahydrofuranyl, dinyl, and thianyl; wherein said piperidinyl is substituted with methyl; 0 R3 is aryl; - R3 is 03.15cycloalkyl; in particular C6cycloalkyl; 0 R3 is C3_19heterocyclyl optionally substituted with C1_6alkyl; - R3 is C1_20alkyl; in particular C1_6alkyl; - said one or more optional substituents for R3 are selected from the group consisting of halo, hydroxyl, nitro, amino, cyano, aryl, heteroaryl, C1_6alkyl, C3_15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_20alkyl)amino, C1_20alkoxy, and 1_20alkyl; in particular halo, hydroxyl, nitro, amino, cyano, C1_6alkyl, C1_20alkylamino, di(C1_20alkyl)amino, C1_20alkoxy, and halo-C1_20alkyl; more in particular C1_6alkyl; - n is 1 or 2; in particular 1. 1O The compounds of the present invention can be prepared according to the reaction schemes ed in the examples hereinafter, but those skilled in the art will appreciate that these are only illustrative for the ion and that the compounds of this invention can be ed by any of several standard synthetic processes ly used by those skilled in the art of organic try.
In a preferred embodiment, the compounds of the present invention are useful as kinase inhibitors, either in vitro or in vivo, more in particular for the inhibition of at least one ROCK kinase, selected from ROCKl and , in particular soft ROCK inhibitors. Accordingly the t invention provides the compounds as defined herein, or a composition comprising said compound(s) for use as a medicine.
The present invention further provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound, as a human or veterinary medicine, in particular for prevention and/or treatment of at least one disease or disorder, in which ROCK is involved, such as diseases linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeneration, and remodeling.
In a further embodiment, the invention provides the use of a compound as defined before, or the use of a composition comprising said compound in the prevention and/or treatment of at least one disease or disorder selected from the group sing eye diseases; airway diseases; throat, nose and ear es; intestinal diseases; vascular and vascular diseases; inflammatory diseases; neurological and CNS ers: erative diseases; kidney diseases; sexual 3O dysfunction; bone diseases; benign prostatic hyperplasia, transplant rejection, spasm, hypertension, chronic obstructive bladder e, and allergy.
In a preferred embodiment, the invention es the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of eyes diseases including but not limited to retinopathy, optic neuropathy, glaucoma and degenerative retinal diseases such as macular degeneration, retinitis pigmentosa and inflammatory eye diseases (such as anterior uveitis, itis, intermediate uveitis and posterior uveitis), neurodegeneration, corneal diseases (such as but not limited to Fuch’s dystrophy and tis), abnormalities of corneal wound healing and ocular pain and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
In r preferred embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of airway diseases; including but not limited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cytsis fibrosis, chronic obstructive ary disease (COPD); itis and rhinitis and respiratory distress syndrome, and/or for preventing, treating and/or alleviating complications and/or symptoms associated ith.
In a further embodiment, the invention provides the use of a nd as defined hereinbefore or 1O the use of a composition comprising said compound in the prevention and/or treatment of cardiovascular and vascular diseases: including but not d to pulmonary hypertension and pulmonary vasoconstriction, and/or for preventing, ng and/or alleviating complications and/or symptoms associated therewith and/or alleviating complications and/or symptoms ated therewith.
In a further embodiment, the invention provides the use of a nd as defined hereinbefore or the use of a ition comprising said compound in the prevention and/or treatment of throat, nose and ear diseases: including but not limited to sinus problems, hearing problems, toothache, tonsillitis, ulcer and rhinitis, In a further embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of skin diseases: including but not limited to eratosis, parakeratosis, hypergranulosis, acanthosis, atosis, spongiosis and tion.
In a further embodiment, the ion provides the use of a compound as defined before or the use of a composition comprising said compound in the prevention and/or treatment of intestinal diseases; including but not limited to inflammatory bowel disease (IBD), colitis, gastroenteritis, ileus, ileitis, appendicitis and Crohn’s disease.
In yet another embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of inflammatory diseases: including but not limited to contact itis, atopic dermatitis, psoriasis, 3O rheumatoid arthritis, le rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis, and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.
In r ment, the invention provides the use of a compound as defined hereinbefore or the use of a ition comprising said compound in the prevention, treatment and/or management of ogical and CNS disorders: including but not limited to neuropathic pain. The present compounds are therefore suitable for preventing neurodegeneration and stimulating neurogeneration in various neurological disorders, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
In another embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or ent of proliferative diseases: such as but not limited to cancer of breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, ovary, pancreas, te, or thyroid gland; Castleman disease; sarcoma; malignoma; and melanoma; and/or for preventing, treating and/or alleviating complications and/or ms and/or matory ses associated therewith.
In another embodiment, the invention provides the use of a nd as defined hereinbefore or 1O the use of a composition comprising said compound in the prevention and/or treatment of kidney diseases: including but not limited to renal fibrosis or renal dysfunction; and/or for ting, ng and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.
In another embodiment, the invention es the use of a compound as defined before or the use of a composition comprising said compound in the prevention and/or treatment of sexual dysfunction: including but not limited to hypogonadism, bladder disease, hypertension, diabetes, or pelvic surgery; and/or to treat sexual dysfunction associated with treatment using certain drugs, such as drugs used to treat hypertension, depression or anxiety.
In r embodiment, the invention provides the use of a compound as defined before or the use of a composition comprising said nd in the prevention and/or treatment of bone diseases: including but not limited to osteoporosis and osteoarthritis; and/or for preventing, treating and/or alleviating cations and/or symptoms and/or inflammatory responses associated therewith.
In r ment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of diseases and disorders such as benign prostatic hyperplasia, lant rejection, spasm, chronic ctive bladder disease, and allergy, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
In a preferred embodiment the present invention provides the use of a compound as defined 3O hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of eye diseases.
METHOD OF TREATMENT The present invention further es a method for the prevention and/or treatment of at least one disease or disorder selected from the group comprising eye diseases; airway diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive r disease; and y; said method comprising stering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.
In a preferred embodiment, the ion provides a method for the prevention and/or treatment of eye es including but not limited to retinopathy, optic neuropathy, glaucoma and degenerative retinal diseases such as macular degeneration, retinitis tosa and matory eye diseases (such as or uveitis, panuveitis, intermediate uveitis and posterior uveitis), corneal es (such as but not limited to Fuch’s dystrophy and keratitis), abnormalities of corneal wound healing 1O and ocular pain; said method comprising administering to a t in need thereof a therapeutic effective amount of a compound or a composition as defined herein.
In another preferred embodiment, the invention provides a method for the prevention and/or treatment of airway diseases including but not limited to pulmonary fibrosis, emphysema, c bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonary disease (COPD) bronchitis, rhinitis, and respiratory distress syndrome; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a ition as defined herein.
In another embodiment, the ion provides a method for the prevention and/or treatment of cardiovascular and ar diseases: including but not limited to pulmonary ension and pulmonary vasoconstriction; said method comprising administering to a t in need thereof a therapeutic effective amount of a nd or a composition as defined herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of inflammatory diseases: ing but not limited to contact dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis; said method comprising administering to a subject in need thereof a therapeutic effective amount of a nd or a composition as defined herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of neurological and CNS disorders: including but not limited to neuropathic pain. The t 3O compounds are therefore suitable for preventing neurodegeneration and stimulating neurogeneration in various neurological disorders; said method comprising administering to a subject in need thereof a therapeutic ive amount of a compound or a composition as defined herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of erative diseases: such as but not limited to cancer of breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate, or thyroid gland; Castleman e; leukemia; sarcoma; lymphoma; malignoma; and melanoma; said method comprising administering to a subject in need thereof a therapeutic ive amount of a compound or a composition as defined herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of kidney diseases: including but not limited to renal fibrosis or renal dysfunction; said method comprising administering to a subject in need f a therapeutic effective amount of a compound or a composition as d herein.
In another embodiment, the invention provides a method for the prevention and/or ent of sexual dysfunction: including but not limited to hypogonadism, bladder disease, hypertension, diabetes, or pelvic surgery; and/or to treat sexual ction associated with treatment using 1O certain drugs, such as drugs used to treat ension, sion or anxiety; said method comprising administering to a subject in need f a therapeutic effective amount of a compound or a composition as defined herein.
In another embodiment, the invention provides a method for the prevention and/or ent of bone diseases: including but not limited to osteoporosis and osteoarthritis; said method sing administering to a subject in need thereof a therapeutic ive amount of a compound or a composition as defined herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of diseases and ers such as benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive bladder disease, and allergy; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.
In a preferred embodiment, the invention provides a method for the prevention and/or treatment of glaucoma, asthma, sexual dysfunction or COPD; said method comprising stering to a subject in need thereof a eutic effective amount of a compound or a composition as defined herein.
In the invention, particular preference is given to compounds of a | or any subgroup thereof that in the inhibition assay for ROCK described below inhibit ROCK with an IC5O value of less than uM, preferably less than 1 uM, even more preferably less than 0.1uM.
Said inhibition may be ed in vitro and/or in vivo, and when effected in vivo, is preferably effected in a selective manner, as defined above. 3O The term "ROCK-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which is known to play a role. The term "ROCK-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a ROCK inhibitor. Accordingly, another embodiment of the t invention relates to treating or lessening the severity of one or more diseases in which ROCK is known to play a role.
For pharmaceutical use, the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable ddition and/or base-addition salt (e.g. ed with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form or a pro-drug or pre-drug. As used herein and unless otherwise stated, the term “solvate” es any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like. Such salts, hydrates, solvates, etc. and the preparation thereof will be clear to the d person.
The ceutically acceptable salts of the compounds ing to the invention, i.e. in the form 1O of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. es of such acid addition salts include acetate, adipate, alginate, ate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, onate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, oate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2—hydroxyethanesulfonate, lactate, maleate, methanesulfonate, malonate, thalene-sulfonate, nicotinate, e, te, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the invention and at least one ceutically acceptable carrier, diluent or ent and/or adjuvant, and optionally one or more r pharmaceutically active compounds.
By means of non-limiting examples, such a formulation may be in a form suitable for oral stration, for eral administration (such as by intramuscular or subcutaneous injection), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.. Such suitable administration forms — which may be solid, semi-solid or liquid, depending on the manner of administration — as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the standard handbooks, such as the latest edition of Remington’s Pharmaceutical 3O Sciences.
Some preferred, but non-limiting examples of such ations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, sions, emulsions, solutions, syrups, aerosols, ointments, creams, s, soft and hard n capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such ations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, ble oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other nces that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and ding agents, dispersing agents, desintegrants, bulking agents, s, preserving , sweetening , flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated so as to provide rapid, sustained or d release of the active compound(s) contained therein, for example using liposomes or hilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a 1O pharmaceutical composition ing to the invention, it can be advantageous to employ Cl-, [3- or y-cyclodextrins or their derivatives.
In addition, co-solvents such as alcohols may improve the solubility and/or the stability of the compounds. In the ation of aqueous compositions, addition of salts of the nds of the invention can be more suitable due to their increased water solubility.
For the treatment of pain, the compounds of the invention may be used locally. For local administration, the compounds may advantageously be used in the form of a spray, ointment or ermal patch or r suitable form for topical, transdermal and/or intradermal administration.
For ophthalmic application, solutions, gels, s and the like are often prepared using a physiological saline solution, gel or excipient as a major vehicle. Ophthalmic formulations should preferably be prepared at a comfortable pH with an appropriate buffer system.
More in particular, the compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of les consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.
The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one ent is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically m or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid sion is referred to as "a solid 3O solution". Solid solutions are preferred physical systems because the ents therein are usually readily bioavailable to the organisms to which they are administered.
It may further be convenient to formulate the compounds in the form of nanoparticles which have a surface er adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Suitable surface modifiers can preferably be ed from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
Yet r interesting way of formulating the compounds according to the invention involves a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing ceutical dosage forms for oral administration. Materials suitable for use as cores in the beads are manifold, provided that said als are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and tives thereof.
The preparations may be prepared in a manner known per se, which usually involves mixing at 1O least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in ation with other pharmaceutical active compounds, when necessary under aseptic conditions.
The compounds can be administered by a variety of routes including the oral, rectal, ocular, transdermal, subcutaneous, intramuscular or asal routes, ing mainly on the ic ation used and the condition to be treated or prevented, and with oral and intravenous stration usually being preferred. The at least one compound of the invention will generally be administered in an “effective amount”, by which is meant any amount of a compound of the Formula | or any subgroup thereof that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is stered. In ance with the method of the present ion, said pharmaceutical ition can be administered separately at different times during the course of therapy or concurrently in divided or single ation forms. The present invention is therefore to be understood as embracing all such s of simultaneous or alternating treatment and the term istering" is to be interpreted accordingly.
For an oral administration form, the compositions of the present invention can be mixed with le additives, such as ents, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, 3O corn starch. In this case, the preparation can be carried out both as dry and as moist granules.
Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for s or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, ing benzyl alcohol or other le preservatives, absorption promoters to enhance bioavailability, carbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable t, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
For subcutaneous administration, the compound according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought 1O into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lizates obtained used, for example, for the production of ion or infusion ations. le ts are, for example, water, physiological saline solution or alcohols, e.g. l, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, tanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When ly administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the ion with a suitable non-irritating excipient, such as cocoa butter, synthetic ide esters or polyethylene s, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
In red embodiments, the compounds and compositions of the invention are used locally, for instance topical or in both absorbed and non-adsorbed applications.
The compositions are of value in the veterinary field, which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also — for economically important animals such as cattle, pigs, sheep, chicken, fish, etc. — enhancing the growth and/or weight of the animal and/or the amount and/or the quality of the meat or other products obtained from the animal. Thus, in a further aspect, the invention relates to a composition for veterinary use 3O that contains at least one compound of the invention and at least one suitable carrier (Le. a carrier suitable for veterinary use). The invention also relates to the use of a compound of the invention in the preparation of such a composition.
The invention will now be illustrated by means of the following synthetic and biological examples, which do not limit the scope of the invention in any way.
EXAMPLES A. ochemical properties of the compounds A. 1. Compound ,Qurity Unless indicated otherwise, the purity of the compounds was confirmed by liquid chromatography/mass spectrometry (LC/MS).
A.2. Attribution of the ration: The Cahn-lngold-Prelog system was used to attribute the absolute configuration of chiral center, in which the four groups on an asymmetric carbon are ranked to a set of sequences rules. Reference is made to Cahn; ; Prelog Angew. Chem. Int. Ed. Engl. 1966, 5, 385-415. 1O A.3. Stereochemistry: It is known by those skilled in the art that specific enantiomers (or diastereoisomers) can be ed by different methods such as, but not d to chiral resolution (for example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula | or any subgroup thereof), assymetric synthesis or preparative chiral chromatography (using different column such as Chiralcel OD-H (tris-3,5-dimethylphenylcarbamate, 46 x 250 or 100 x 250 mm, 5 pm), Chiralcel OJ (tris-methylbenzoate, 46 x 250 or 100 x 250 mm, 5 pm), Chiralpak AD (tris-3,5- dimethylphenylcarbamate, 46 x 250 mm, 10 pm) and Chiralpak AS (tris-(S) phenylethylcarbamate, 46 x 250 mm, 10 pm) from Chiral Technologies Europe (lllkirch, France)).
Whenever it is convenient, isomers can be obtained starting from commercial materials with known configuration (such compounds include cid for instance). 2012/067018 B. Compound synthesis B. 1. Compounds of the invention The compounds of the invention can be made according to the following general procedures: 0 0mg, O OH R2 N O I 0 H + O F NH I\ 00 \N 00 N/ o u< | N / o X Intermediate Reaction a: To a on of carboxylic acid (1eq) in an organic t such as DMF at room temperature was added an appropriate coupling reagent (such as TBTU (1.5 eq)/ HOBt (0.3 eq)) and DIEA (3 to 10 eq) as required. After 5 min the corresponding aniline (1.5 eq) was added and the e stirred at room temperature until completion of the reaction. Then the solvent was removed under vacuum and the residue diluted in EtOAc. The organic phase was washed with saturated NaHC03, brine, dried over NaZSO4 and filtered. After evaporation of the solvent, the residue was purified by flash chromatography, eluted for instance with DCM/EtOAc (100/0 to 50/50) to give the expected product as a white powder.
Reaction b : To a on or suspension of the corresponding methyl ester in acetonitrile/water 2/1 was added dropwise a solution 1.6M of LiOH in water. The mixture was stirred at room temperature until tion of the reaction. Then a solution 0.5M of HCI in water was added until pH = 4 and the mixture extracted with EtOAc (x3). The combined organic phases were washed with brine, dried over NaZSO4 and filtered. The solvent was removed under vacuum to give the ed compound as a white powder. The compound was usually used in the next step without further purification.
Reaction c: Through a on or suspension of the Boc-protected amine in DCM (or dioxane, or dietyl-ether), HCI (gas) was bubbled at room temperature for 5 to 10 min. The e was stirred 1O at room temperature until tion of the reaction. The resulting precipitate was filtered, washed with Ether (x3) and dried under vacuum to give the HCI salt of the expected compound as a white powder.
Reaction d: To a solution of carboxylic acid (1eq) in in an organic solvent such as DMF at room temperature was added an riate coupling reagent (such as TBTU (1.5 eq)/ HOBt (0.3 eq)) and DIEA (3 to 10 eq) as required.. After 5 min the alcohol (R3-OH; 6 eq) was added and the e stirred at room temperature until completion of the reaction. The solvent was subsequently removed under vacuum and the residue diluted in EtOAc. The organic phase was washed with saturated NaHC03, brine, dried over NaZSO4 and filtered. After evaporation of the solvent, the residue was purified by flash chromatography, eluted for instance with DCM/EtOAc (100/0 to 50/50) to give the expected product as a white powder.
For the preparation of the required intermediate(s), reference is made to the PCT application WO 2011/107608 A1.
In the table that is set forth below, exemplary compounds of the ion are set out in tabulated form. In this table, an arbitrarily assigned nd number and structural information are set out.
Table 1 Of)Y 2 F NH N/ O n—n— —-_-—__ -H —-_-—__ —--__—— —-_-—_—— “-—I-— -'C‘ZOWH' —'WH' * —---——-CH2-COO-iPent —---——--CH2-COO-cclobut I —---——--CH2-COO-c cIOpentI -COO-c clohex I - --_14 -C(=O)NH- -H -H 'C‘ZOWH' ° 'WH' 'WH' C. In vitro and in vivo assays C. 1. ROCK inhibitory activity screening C. 1.1 . Kinase inhibition (ROCKI or ROCK/l) On-target activity against ROCK was measured in a biochemical assay, using the following reagents: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCIZ, 1mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO. ed cofactors are added dually to each kinase reaction. The reaction procedure first involved the preparation of a peptide substrate in a freshly prepared reaction buffer. Required cofactors were then added to the 1O substrate solution. ROCK (1nM final concentration) was then delivered to the substrate solution.
After gentle mix, DMSO solutions of the test compounds were added to the enzyme. Substrate mix 33P-ATP (specific ty 0.01 uCi/ul final) was then delivered into the reaction mixture to initiate the reaction. The kinase reaction was incubated for 120 min. at room temperature. Reactions were then d onto P81 ion exchange paper (Whatman # 3698-915). Filters were washed extensively in 0.1% Phosphoric acid. A etric count was then performed and IC5O values were subsequently determined.
When evaluated under such conditions, compounds of the invention inhibit ROCK2 with an |C50 < 100nM.
C. 1.2. Myosin Light Chain Phosphorylation assay Rat smooth muscle cell line A7r5 is used. The nous expression of ROCK results in a constitutive phosphorylation of the tory myosin light chain at T18/S19. A7r5 cells were plated in DMEM supplemented with 10%FCS in multiwall cell culture plates. After serum starvation ght, cells were incubated with compounds in serum-free .
Quantification of MLC-T18/S19 orylation is assessed in 96 well-plates via ELISA using a phspho-MLC-T18/S19 specific antibody and a secondary detection antibody. Raw data were converted into percent substrate phosphorylation relative to high ls, which were set to 100%.
|C50 values were determined using GraphPad Prism 5.01 re using a nonlinear regression curve fit with variable hill slope.
When evaluated under such conditions, compounds of the invention display EC50 values under 10uM. Preferred compounds display EC50 values under 0.5uM. C.2. Pharmacological 1O Characterization C2. 1. Stability assay in human and/or rat plasma Compounds are incubated at a concentration of 1 uM in human plasma (or rat, mice, dog, monkey, minipig or rabbit). Samples are taken at fixed time points and the t of compound is determined by LC-MS/MS after protein precipitation. Half life for compounds of the invention is reported in Table 2.
Table 2 # des t1,2(min) in human plasma C. 2. 2. Stability assay in rabbit s humor Compounds are incubated at a concentration of 1 uM in rabbit aqueous humor (AH). Samples are taken at fixed time points and the remnant of compound is determined by LC-MS/MS after protein precipitation. Half life for compounds of the invention is reported in Table 3 WO 30367 Table 3 # des W: rabbit AH (min)

Claims (14)

1. A compound of a I or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof, ( )n O X Y N N R1 O NH Wherein, X is hydrogen or halogen; Y is –NH-C(=O)- or –C(=O)-NH-; R1 is selected from the group comprising hydrogen, lkyl, and C3-15cycloalkyl; R2 is selected from the group comprising hydrogen, lkyl, halogen and C1-20alkoxy; R3 is selected from the group consisting of C1-20alkyl, lkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said C1-20alkyl, C3-20alkenyl, lkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl is optionally substituted with one or more tuents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1- 6alkyl, C3-15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1- 20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sullfonamido; and n is an integer from 1 to 3.
2. A compound of formula I according to any one of the previous claims, wherein; R1 is selected from the group comprising hydrogen, C1-6alkyl, and C3-6cycloalkyl; in particular
3. A compound of a I according to any one of the previous claims, wherein; X is halogen; more in particular fluoro; Y is –NH-C(=O)- or –C(=O)-NH-; R1 is selected from the group comprising hydrogen, C1-6alkyl, and C3-8cycloalkyl; in particular hydrogen; R2 is selected from the group comprising hydrogen, C1-20alkyl, halogen and C1-20alkoxy; R3 is selected from the group consisting of C1-20alkyl, C3-20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said lkyl, C3-20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1- 6alkyl, C3-15cycloalkyl, eterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1- 20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sullfonamido; and n is an integer from 1 to 3; in particular n is 1 or 2; more in particular n is 1.
4. A nd of a I according to any one of the previous claims, wherein; R2 is selected from hydrogen, C1-6alkyl, and halogen; in particular R2 is en.
5. A compound of formula I according to any one of the previous claims, wherein; R3 is selected from the group consisting of C1-20alkyl, C3-15cycloalkyl, aryl, and C3-19heterocyclyl; wherein said lkyl, C3-15cycloalkyl, aryl, and C3-19heterocyclyl is ally substituted with one or more tuents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1-6alkyl, C3-15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1-20alkoxy, 1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, ino, C1-20alkyl esters, carbamate, thioamido, urea, and sullfonamido.
6. A compound of formula I according to any one of the previous claims, wherein one or more of the following restrictions apply: • X is halogen; in ular fluoro; • Y is–C(=O)-NH-; • R1 is en; • R2 is hydrogen; • R3 is selected from the group consisting of C1-20alkyl, C3-20alkenyl, C3-20alkynyl, C3- 15cycloalkyl, aryl, heteroaryl, and eterocyclyl; wherein said C1-20alkyl, lkenyl, C3- 20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, yl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1-6alkyl, C3-15cycloalkyl, C3-19heterocyclyl, C1- 20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1-20alkoxy, halo-C1-20alkyl, thiol, C1- 20alkylthio, carboxylic acid, ino, C1-20alkyl esters, carbamate, thioamido, urea, and sullfonamido; • R3 is selected from the group consisting of C3-15cycloalkyl, aryl, heteroaryl, and C3- 19heterocyclyl; wherein said C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl is optionally substituted with C1-6alkyl; in particular R3 is selected from the group ting of l, cyclohexyl, oxanyl, tetrahydrofuranyl, piperidinyl, and thianyl; wherein said indanyl, cyclohexyl, oxanyl, tetrahydrofuranyl, piperidinyl, and thianyl is optionally substituted with C1-6alkyl; more in particular R3 is selected from the group consisting of indanyl, cyclohexyl, , tetrahydrofuranyl, piperidinyl, and thianyl; wherein said piperidinyl is substituted with methyl; • R3 is aryl; • R3 is C3-15cycloalkyl; in particular oalkyl; • R3 is C3-19heterocyclyl ally substituted with kyl; • R3 is lkyl; in particular C1-6alkyl; • said one or more optional substituents for R3 are selected from the group consisting of halo, hydroxyl, nitro, amino, cyano, aryl, heteroaryl, C1-6alkyl, C3-15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, 20alkyl)amino, C1-20alkoxy, and halo-C1-20alkyl; in particular halo, hydroxyl, nitro, amino, cyano, C1-6alkyl, C1-20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, and halo-C1-20alkyl; more in particular kyl; • n is 1 or 2; in particular 1.
7. A compound according to any one of claims 1 to 6 for use as a medicine.
8. A composition comprising a compound as defined in any one of claims 1 to 6, for use as a human or veterinary medicine.
9. A compound according to any one of claims 1 to 6, or a composition according to claim 8, for use in the prevention and/or treatment of a disease or disorder, in which ROCK is involved, such as diseases linked to smooth muscle cell on, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeneration and ling.
10. A compound according to any one of claims 1 to 6, or a composition according to claim 8, for use in the prevention and/or treatment of at least one disease or disorder according to claim 9 selected from the group comprising eye diseases; airway diseases; throat, nose and ear diseases; intestinal diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia, transplant ion, spasm, hypertension, chronic obstructive bladder disease, and allergy.
11. A compound according to any one of claims 1 to 6, or a composition according to claim 8, for use in the prevention and/or treatment of an eye diseases according to claim 9 or 10; including but not limited to retinopathy, optic neuropathy, glaucoma and rative retinal diseases such as macular degeneration, retinitis pigmentosa and inflammatory eye diseases (such as anterior uveitis, panuveitis, ediate uveitis and posterior uveitis), neurodegeneration, corneal diseases (such as but not limited to Fuch’s dystrophy and keratitis), abnormalities of corneal wound healing and ocular pain and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
12. A compound ing to any one of claims 1 to 6, or a composition according to claim 8, for use in the prevention and/or treatment of Intestinal es; ing but not d to inflammatory bowel disease (IBD), colitis, ulcerative s, gastroenteritis, ileus, ileitis, appendicitis and Crohn’s disease.
13. Use of a compound according to any one of claims 1 to 6, or a composition according to claim 8, for inhibiting the activity of at least one kinase in vitro.
14. Use of a nd ing to any one of claims 1 to 6, or a composition according to claim 8, for the manufacture of a medicament for the prevention and/or treatment of at least one disease or disorder selected from the group comprising eye diseases; airway diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive bladder disease; intestinal diseases and allergy.
NZ622959A 2011-08-31 2012-08-31 Biphenylcarboxamides as rock kinase inhibitors NZ622959B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP11179491 2011-08-31
EP11179491.3 2011-08-31
PCT/EP2012/067018 WO2013030367A1 (en) 2011-08-31 2012-08-31 Biphenylcarboxamides as rock kinase inhibitors

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NZ622959B2 true NZ622959B2 (en) 2015-06-30

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