NZ622964B2 - Novel rock kinase inhibitors - Google Patents

Novel rock kinase inhibitors Download PDF

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NZ622964B2
NZ622964B2 NZ622964A NZ62296412A NZ622964B2 NZ 622964 B2 NZ622964 B2 NZ 622964B2 NZ 622964 A NZ622964 A NZ 622964A NZ 62296412 A NZ62296412 A NZ 62296412A NZ 622964 B2 NZ622964 B2 NZ 622964B2
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New Zealand
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20alkyl
group
halo
aryl
phenyl
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NZ622964A
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NZ622964A (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/EP2012/067016 external-priority patent/WO2013030365A1/en
Publication of NZ622964A publication Critical patent/NZ622964A/en
Publication of NZ622964B2 publication Critical patent/NZ622964B2/en

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Abstract

The present disclosure relates to 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 disclosure 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 and respiratory diseases. In one embodiment the compound is methyl 4-({3-[2-(aminomethyl)-5-[(3-fluoropyridin-4-yl)carbamoyl]phenyl]phenyl}amido) benzoate. rticular, 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 disclosure 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 and respiratory diseases. In one embodiment the compound is methyl 4-({3-[2-(aminomethyl)-5-[(3-fluoropyridin-4-yl)carbamoyl]phenyl]phenyl}amido) benzoate.

Description

/067016 NOVEL 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 inhibitors, and to uses of such tors in the treatment and prophylaxis of e. In particular, the present invention s to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. 1O Background of the invention The serine/threonine protein 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 domains. Despite their sequence similarity, they differ by their tissue distributions. The t levels of expression for ROCK l are ed in heart, lung and skeletal tissues whereas ROCK N is mostly expressed in brain. Recent data indicate that these two isoforms are partially on redundant, ROCK I being more involved in immunological events, ROCK N in smooth muscle function. The term ROCK refers to ROCK | , p160ROCK, or Rho-kinase B) and ROCK N 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 d in an autoinhibitory yl-terminal loop. Upon binding, the interactions between the ROCK negative regulatory domain and the kinase domain are disrupted. The process enables the kinase to acquire an open conformation in which it is fully active. The open conformation is also induced by the binding of lipid activators such as arachidonic acid to the PH domain in the kinase yl-terminal domain. Another activation mechanism has been described 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, in-induced ses of aortic smooth muscle cells, hypertrophy of cardiomyocytes, bronchial smooth muscle contraction, smooth muscle contraction and cytoskeletal reorganization of non- muscle cells, activation of volume- regulated anion channels, neurite tion, 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 es as well as oxidative stress.
In sion, ROCK is a major control point in smooth muscle cell on and a key signaling component involved in inflammatory processes in various inflammatory cells as well as fibrosis and remodeling in many diseased organs. In addition, ROCK has been implicated in various es and disorders including eye diseases; airway diseases; cardiovascular and ar diseases; inflammatory diseases; neurological and CNS disorders: erative diseases; kidney diseases; sexual dysfunction; blood diseases; bone diseases; diabetes; benign prostatic lasia, 1O transplant rejection, liver disease, systemic lupus erythematosus, spasm, hypertension, chronic obstructive r disease, 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 combination with post-marketing surveillance studies with Fasudil, a moderately potent ROCK inhibitor used for the treatment of vasospasm after subarachnoid hemorrhage, te that ROCK is a genuine and significant drug target.
ROCK inhibitors would be useful as therapeutic agents for the treatment of ers 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 treatments currently available for the majority of these ers. Some non-limiting examples include eye diseases (Age-related macular degeneration (dry or wet AMD), diabetic retinopathy, uveitis, glaucoma), or respiratory diseases (asthma, COPD...).
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 limited extent, e ROCK is such a potent and widespread biochemical regulator, that systemic inhibition of ROCK leads to strong biological effects that are considered as being side s for the treatment of most of the diseases. Indeed, the medical use of ROCK tors for rdiological indications is hampered by the pivotal role of ROCK in the regulation of the tonic phase of smooth muscle cell contraction. Systemically available ROCK 3O inhibitors induce a marked decrease in blood pressure. Therefore, ROCK inhibitors with different properties are highly required.
For the target specific treatment of ers by regulating smooth muscle function and/or atory processes and/or remodeling, it is highly desired to deliver a ROCK inhibitor to the target organ and to avoid significant amounts 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 disorders. In addition, local injection / ration into diseased tissues further extend the potential medical use of locally applied ROCK inhibitors. Given n criteria are fulfilled, these local applications allow high drug concentration WO 30365 to be reached in the target tissue. In addition, the incorporation of ROCK inhibitors into ts and stents can further expand the medical application towards the local treatment of CV diseases such as atherosclerosis, coronary es 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 e the treatment of airway diseases by local delivery by for instance inhalation, poses the risk of systemic re due to large amounts entering the GI tract and/or systemic absorption through the lungs. For the treatment of eye diseases by local delivery, also significant amounts enter the GI tract and/or systemic circulation due to the low bility of the cornea, low capacity for fluid, efficient drainage and 1O presence of blood vessels in the eyelids. Also for dermal ations, local injections and implantable medical devices, there is a severe risk of leakage into the systemic circulation.
Therefore, in addition to local ation, 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 systemic circulation. This vation can be achieved in the liver and/or in blood. These compounds, once applied y to the target tissue / organ exert their desired effect locally. When they leak out of this tissue / organ into the systemic 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 liver or in the blood to biologically inactive compounds. 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 applications and is highly desired to reduce the total load of drug and metabolites and in on will significantly increase the patient compliance.
In conclusion, there is a continuing need to design and develop soft ROCK inhibitors for the ent of a wide range of disease states. The compounds described herein and pharmaceutically acceptable compositions thereof are useful for treating or ing the severity of a y 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 es linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, 3O eactivity, barrier dysfunction, neurodegeneration and remodeling. For example, the compounds of the invention may be used in the tion and/or treatment of diseases and disorders such as: - Eye es or disorders: including but not limited to retinopathy, optic neuropathy, glaucoma and degenerative retinal diseases such as macular degeneration, proliferative vitreoretinopathy, proliferative diabetic retinopathy retinitis pigmentosa and inflammatory eye es (such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis), glaucoma filtration surgery failure, dry eye, allergic conjunctivitis, posterior capsule opacification, alities of corneal wound healing and ocular pain.
- Airway diseases; including but not limited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cytsic fibrosis, chronic obstructive pulmonary disease (COPD); bronchitis and rhinitis and respiratory distress syndrome - Throat, Nose and Ear diseases: including but not limited to sinus ms, g problems, toothache, tonsillitis, ulcer and rhinitis, - Skin diseases: including but not limited to hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis and ulceration.
- Intestinal diseases; including but not limited to inflammatory bowel disease (IBD), colitis, enteritis, ileus, ileitis, appendicitis and s disease. 1O - vascular and vascular diseases: including but not limited to, pulmonary hypertension and pulmonary vasoconstriction,.
- Inflammatory diseases: ing but not limited to contact dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile toid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, Crohn's e and ulcerative colitis.
- Neurological disorders: ing but not limited to neuropathic pain. The present compounds are therefore suitable for preventing neurodegeneration and stimulating neurogeneration in s neurological disorders.
- Proliferative diseases: such as but not limited to cancer of head , , colon, intestine, skin, and neck, nerve, uterus, kidney, lung, ovary, as, prostate, or thyroid gland; Castleman disease; sarcoma; oma; and melanoma.
- 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 ion 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 including, but not limited to, bladder e, hypertension, es, or pelvic surgery. In addition, the soft 3O ROCK inhibitors may be used to treat sexual dysfunction ated with treatment using certain drugs, such as drugs used to treat hypertension, depression or anxiety.
- Bone diseases: including but not limited to osteoporosis and osteoarthritis - In on, 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 e, and allergy.
SUMMARY OF THE INVENTION We have surprisingly found that the compounds described herein act as inhibitors of ROCK, in particular as soft ROCK inhibitors. The nds of the t invention are rapidly converted into functionally inactive compounds for e by carboxylic ester hydrolases (EC 3.1 .1) such as cholinesterases or carboxylesterases. 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 tic activity are of potential interest 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 terase; EC 3.1.1.3 triacylglycerol lipase; EC 3.1.1.4 ; 1O phospholipase A2; EC 3.1.1.5 ospholipase; EC 3.1.1.6 acetylesterase; EC 3.1.1.7 acetylcholinesterase; EC 3.1.1.8 cholinesterase; EC 10 tropinesterase; EC 11 pectinesterase; EC 3.1.1.13 sterol esterase; EC 3.1.1.14 chlorophyllase; EC 3.1.1.15 L- arabinonolactonase; EC 3.1.1.17 gluconolactonase; EC 3.1.1.19 uronolactonase; EC 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 3.1.1.27 4-pyridoxolactonase; EC 3.1.1.28 acylcarnitine hydrolase; EC 3.1.1.29 cyl-tRNA hydrolase; EC 3.1.1.30 D-arabinonolactonase; EC 31 6- phosphogluconolactonase; EC 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 2O 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 41 cephalosporin-C ylase; EC 3.1.1.42 chlorogenate hydrolase; EC 3.1.1.43 o-acid esterase; EC 3.1.1.44 4-methyloxaloacetate esterase; EC 3.1.1.45 carboxymethylenebutenolidase; EC 3.1.1.46 deoxylimonate A-ring-lactonase; EC 3.1.1.47 lacetylglycerophosphocholine 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 O-acetylesterase; EC 3.1.1.54 acetoxybutynylbithiophene ylase; EC 3.1.1.55 acetylsalicylate deacetylase; 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- 3O acetylgalactosaminoglycan deacetylase; EC 3.1.1.59 juvenile-hormone esterase; EC 3.1.1.60 bis(2-ethylhexyl)phthalate esterase; EC 3.1.1.61 protein-glutamate methylesterase; EC 3.1.1.63 -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 cetraxate benzylesterase; EC 3.1.1.71 acetylalkylglycerol acetylhydrolase; EC 3.1.1.72 acetylxylan esterase; EC 73 feruloyl esterase; EC 3.1.1.74 cutinase; EC 75 poly(3-hydroxybutyrate) depolymerase; EC 3.1.1.76 poly(3-hydroxyoctanoate) depolymerase; EC 3.1.1.77 acyloxyacyl hydrolase; EC 3.1.1.78 polyneuridine-aldehyde esterase; EC 3.1.1.79 hormone-sensitive lipase; EC 3.1.1.80 acetylajmaline esterase; EC 81 quorum-quenching N-acyl-homoserine lactonase; EC 82 pheophorbidase; EC 83 monoterpene s-lactone hydrolase; EC 3.1.1.84 cocaine esterase; EC 3.1.1.85 ylglycerate hydrolases.
Cholinesterases are enzymes that are primarily known for their role in the degradation of the ransmitter 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 ocyte fraction of blood. In addition to its action on acetylcholine, acetylcholinesterase hydrolyzes a variety of acetic esters, and also catalyzes transacetylations.
Acetylcholinesterase usually displays a preference for substrates with short acid chains, as the 1O acetyl group of acetylcholine. Butyrylcholinesterase (EC 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 typically carry out the hydrolysis of substrates with larger acid chains (such as the butyryl group of butyrylcholine or the benzoyl group of benzolylcholine) at a faster rate than acetylcholinesterase. In addition to its action on acetylcholine, butyrylcholinesterase is known to participate in the metabolism of several ester drugs, such as procaine.
Carboxylesterases (CES) represent a multigene family and show ubiquitous expression profiles, with high levels in liver, intestine and lungs. A majority of carboxylesterases can be classified either in carboxylesterase 1 (CES 1) or carboxylesterase 2 (CESZ) families. Interestingly, these different CES es 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 l e, hCES1 preferentially catalyzes the hydrolysis of the methyl ester of e. Human CESZ is predominantly found in ine, liver and kidney. CESZ preferentially hydrolyzes esters with r alcohol groups, and larger acid groups. As a typical example, human CESZ zes the hydrolysis of the l ester of cocaine. Another interesting ation about CES enzymes is the lack of carboxylesterase activity in human plasma. Overall, carboxylesterases can play a major 3O role in the bioconversion of ester-containing drugs and xenobiotics.
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, hydrate, or solvate thereof, YI / o R3 \R2 X NH2 N / O Wherein, X is hydrogen or halogen; A is —NH-C(=O)— or —NH-; Y is N or C; R3 is selected from the group sing hydrogen, C1_20alkyl and 03.15cycloalkyl; R1 is selected from the group comprising hydrogen, C1_20alkyl, lkoxy, and halogen; and R2 is selected from the group consisting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl, 1O heteroaryl, and 03.19heterocyclyl; wherein said C1_20alkyl, C3_20alkenyl, lkynyl, 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, heteroaryl, ycloalkyl, C3_19heterocyclyl, C1_20alkylamino, Cq_6alkyl, di(C1_20alkyl)amino, C1. goalkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, C1_20alkyl esters, carbamate, thioamido, urea, and sulfonamido; or R2 taken together with R1 forms a cyclic ester (lactone) comprising from 4 to 9 carbon atoms in the cyclic ester ring.
Viewed from a further aspect, the invention es the use of a compound of the invention, or a composition comprising such a compound, for inhibiting the activity of at least one kinase, in vitro or in vivo.
Viewed from a further 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 ms.
Viewed from a r aspect, the invention provides a pharmaceutical and/or veterinary composition sing 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 ion 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; , nose and ear diseases; intestinal diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS ers: proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive r disease, and allergy.
ED DESCRIPTION OF THE INVENTION The present invention will now be further described. In the following passages, different s of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being red or advantageous may be combined with any other feature or features ted as being red or advantageous.
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.
Undefined (racemic) asymmetric centers that may be present in the nds 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 Formulal Y' / o R3 \ R2 X NH2 N / O Wherein, X, R1, A, Y, R2 and R3 are as defined hereinbefore, including the stereo-isomeric forms, solvates, and pharmaceutically acceptable addition salts thereof.
When describing the compounds of the invention, the terms used are to be construed in accordance with the following tions, unless a context es otherwise: The term " by itself or as part of another substituent refers to a fully saturated hydrocarbon of Formula CXH2X+1 wherein 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 herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for 1O example, C1_4alkyl means an alkyl of one to four carbon atoms. Examples of alkyl groups are methyl (also shortened as Me), ethyl, n-propyl (also shortened as nPr), i-propyl, butyl, and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its s, 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 , ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its s, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene, and cyclohexyl.
The term "optionally substituted 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 substituents or 1 to 2 tuents) at any available point of attachment. Non-limiting es of such substituents include halo, hydroxyl, oxo, carbonyl, nitro, amino, amido, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl, lkyl, heterocyclyl, alkylamino, alkoxy, haloalkoxy, haloalkyl, thiol, alkylthio, carboxylic acid, ino, alkyl esters, carbamate, thioamido, urea, sulfonamido 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 yl", as used herein, unless otherwise indicated, means straight-chain, cyclic, or branched-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 3O like. An optionally substituted alkenyl refers to an l having ally 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- chain hydrocarbon radicals containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
An ally substituted alkynyl refers to an l having ally one or more substituents selected from those defined above for substituted alkyl. -1 0- 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 hydrocarbyl group having 1, 2, or 3 cyclic ure.
Cycloalkyl includes all ted or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic, or polycyclic alkyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, 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 considered to be a subset of homocyclic rings discussed hereinafter. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1O cycloheptyl, cyclooctyl, cyclononyl, adamantanyl, bicyclo(2.2.1)heptanyl and cyclodecyl with cyclopropyl, cyclopentyl, cyclohexyl, adamantanyl, and o(2.2.1)heptanyl being particularly preferred. An nally substituted cycloalkyl” refers to a cycloalkyl having optionally one or more 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 ction with a cyclic group, after 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. lkylene groups of this invention preferably se 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, ne, 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 ylene" and "alkynylene" respectively.
Generally, alkylene groups of this invention preferably se the same number of carbon atoms as their alkyl counterparts. Where an alkylene or cycloalkylene biradical is present, tivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom, ably a common carbon atom. To illustrate this applying the asterisk nomenclature of this invention, a C3 alkylene group may be for example *-CHZCH2CH2-*, *-CH(- 3O CHZCH3)-*, or *-CHZCH(-CH3)-*. Likewise a C3 cycloalkylene group may be Where a cycloalkylene group is present, this is preferably a C3-C6 cycloalkylene group, more ably 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 cals in compounds of the invention may be, but preferably are not, substituted. -1 1 _ The terms ocyclyl" or "heterocyclo" 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 systems, 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 atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, d 1O and/or joined through one or more spiro atoms. An optionally substituted heterocyclyl refers to a heterocyclyl 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.
Exemplary heterocyclic groups e piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, idinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- indolyl, isoindolinyl, nyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3- inyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, perazinyl, 2-pyrazolinyl, zolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro- 2H-pyranyl, phthalazinyl, oxetanyl, thietanyl, olanyl, 1,3-dioxanyl, 2,5-dioximidazolidinyl, piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, rpholinyl, rpholinyl sulfoxide, rpholinyl sulfone, oxolanyl, 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- 1,1-dioxothienyl, N- formylpiperazinyl, and linyl.
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 intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, 3O 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 5-acenaphtylenyl, 3-, 4-, or 5-acenaphtenyl, 1-, 2-, 3-, 4-, or 10-phenanthryl, 1- or 2-pentalenyl, 1, 2-, 3-, or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7-, or ahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, dibenzo[a,d]cylcoheptenyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl.
The aryl ring can optionally be substituted by one or more substituents. An “optionally substituted aryl” refers to an aryl having optionally 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, l, alkynyl, cycloalkylalkyl, mino, alkoxy, -SOZ-NH2, aryl, -1 2- heteroaryl, l, haloalkyl, koxy, alkoxycarbonyl, alkylaminocarbonyl, arylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, arylcarbonyl, arbonyl, 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 aryl 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 1O or more carbon atoms in one or more of these rings can be replaced by oxygen, nitrogen or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting es of such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, lyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, azolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, yl, 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, zinyl, isoindolyl, benzofuranyl, benzopyranyl, 1(4H)-benzopyranyl, 1(2H)—benzopyranyl, 3,4-dihydro- 1(2H)—benzopyranyl, 3,4-dihydro-1(2H)—benzopyranyl, isobenzofuranyl, benzothiophenyl, zothiophenyl, 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, benzothiadiazolyl, pyridinyl, purinyl, imidazo[1,2—a]pyridinyl, 6-oxo-pyridazin-1(6H)—yl, yridin-1(2H)-yl, 6- oxo-pyridazin-1(6H)—yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.
The term “pyrrolyl” (also called azolyl) as used herein includes pyrrolyl, pyrrolyl and pyrrol yl. The term “furanyl” (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 enyl (also called thienyl and thienyl). The term “pyrazolyl” 3O (also called 1H-pyrazolyl and azolyl) as used herein includes pyrazolyl, pyrazolyl, pyrazolyl and pyrazolyl. The term “imidazolyl” as used herein includes imidazolyl, imidazol- 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 lyl, thiazolyl and thiazolyl (also called 2- thiazolyl, zolyl and 5-thiazolyl). The term “isothiazolyl” (also called 1,2—thiazolyl) as used herein includes isothiazolyl, isothiazolyl, and isothiazolyl. The term olyl” 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- -1 3- triazolyl. “4H-1,2,4-triazolyl” includes 4H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl. The term “oxadiazolyl” as used herein includes 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazol yl, oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-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 furazanyl) 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 1,2,3,4-oxatriazolyl and 12,35- azolyl. The term “thiatriazolyl” as used herein includes 1,2,3,4-thiatriazolyl and 12,35- thiatriazolyl. The term “pyridinyl” (also called "pyridyl") as used herein es pyridinyl, 1O pyridinyl and pyridinyl (also called 2-pyridyl, 3-pyridyl and 4-pyridyl). The term “pyrimidyl” as used herein includes pyrimidyl, pyrimidyl, pyrimidyl and dyl. The term “pyrazinyl” as used herein includes pyrazinyl and pyrazinyl. The term azinyl as used herein es pyridazinyl and zinyl. The term nyl” (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 1,4-dioxinyl. 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 “triazinyl” as used herein includes 1,3,5-triazinyl, 1,2,4-triazinyl, 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, imidazo[2, 1-b][1,3]thiazolyl and imidazo[2,1-b][1,3]thiazolyl. The term “thieno[3,2— b]furanyl” as used herein includes 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 thieno[2,3- azolyl. 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, 6- 3O yl and indolyl. The term “indolizinyl” as used herein includes indolizinyl, indolizinyl, indolizinyl, indolizinyl, indolizinyl, indolizinyl, and indolizinyl. The term “isoindolyl” as used herein includes isoindolyl, isoindolyl, isoindolyl, isoindolyl, isoindolyl, isoindol yl and isoindolyl. The term “benzofuranyl” (also called benzo[b]furanyl) as used herein includes benzofuranyl, benzofuranyl, benzofuranyl, benzofuranyl, benzofuranyl and uranyl. The term “isobenzofuranyl” (also called benzo[c]furanyl) as used herein includes isobenzofuranyl, isobenzofuranyl, isobenzofuranyl, isobenzofuranyl, isobenzofuranyl and isobenzofuranyl. The term “benzothiophenyl” (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, o[b]thiophenyl, o[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and benzo[b]thiophenyl (also called hienyl, hienyl, 40 hienyl, benzothienyl, benzothienyl and benzothienyl). The term “isobenzothiophenyl” (also called benzo[c]thienyl) as used herein includes isobenzothienyl, zothienyl, isobenzothienyl, isobenzothienyl, isobenzothienyl and isobenzothien yl. The term “indazolyl” (also called azolyl or 2-azaindolyl) as used herein includes 1H- indazolyl, 1H-indazolyl, 1H-indazolyl, 1H-indazolyl, 1H-indazolyl, 1H-indazolyl, 2H- indazolyl, 2H-indazolyl, 2H-indazolyl, azolyl, azolyl, and 2H-indazolyl.
The term “benzimidazolyl” as used herein includes benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl and benzimidazolyl. The term “1,3- benzoxazolyl” as used herein es 1,3-benzoxazol-2—yl, 1,3-benzoxazolyl, 1,3-benzoxazol yl, 1,3-benzoxazolyl and 1,3-benzoxazolyl. The term “1,2—benzisoxazolyl” as used herein 1O includes 1,2—benzisoxazolyl, 1,2—benzisoxazolyl, 1,2—benzisoxazolyl, 1,2—benzisoxazolyl and 1,2—benzisoxazolyl. The term “2,1-benzisoxazolyl” as used herein includes 2,1- benzisoxazolyl, 2,1-benzisoxazolyl, 2,1-benzisoxazolyl, 2,1-benzisoxazolyl and 2,1- benzisoxazolyl. The term “1 ,3-benzothiazolyl” as used herein includes 1,3-benzothiazolyl, 1,3- benzothiazolyl, 1,3-benzothiazolyl, 1,3-benzothiazolyl and 1,3-benzothiazolyl. The term “1 zoisothiazolyl” as used herein includes 1,2—benzisothiazolyl, 1,2—benzisothiazolyl, 1,2- benzisothiazolyl, 1,2—benzisothiazolyl and 1,2—benzisothiazolyl. The term “2,1- benzoisothiazolyl” as used herein includes 2,1-benzisothiazolyl, nzisothiazolyl, 2,1- othiazolyl, nzisothiazolyl and 2,1-benzisothiazolyl. The term “benzotriazolyl” as used herein includes benzotriazolyl, benzotriazol4-yl, benzotriazolyl, benzotriazolyl and benzotriazolyl. The term “1 ,2,3-benzoxadiazolyl” as used herein es 1,2,3-benzoxadiazol yl, 1,2,3-benzoxadiazolyl, 1,2,3-benzoxadiazolyl and 1,2,3-benzoxadiazolyl. The term “2,1,3-benzoxadiazolyl” as used herein includes 2,1,3-benzoxadiazolyl, 2,1,3-benzoxadiazol yl, 2,1,3-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 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 includes 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 includes purinyl, purinyl, purinyl and purinyl. The term “imidazo[1,2—a]pyridinyl”, 3O as used herein es 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 “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, inyl, quinolinyl, quinolinyl, quinolinyl and quinolinyl. The term inolinyl” as used herein includes isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolin- -yl, isoquinolinyl, isoquinolinyl and isoquinolinyl. The term “cinnolinyl” as used herein includes cinnolinyl, cinnolinyl, cinnolinyl, cinnolinyl, cinnolinyl and cinnolinyl. The term “quinazolinyl” as used herein includes quinazolinyl, quiriazolinyl, olinyl, quinazolinyl, quinazolinyl and quinazolinyl. The term “quinoxalinyl”. as used herein es 40 quinoxalinyl, quinoxalinyl, and quinoxalinyl. The term “7-azaindolyl” as used herein refers WO 30365 2012/067016 -1 5- to 1H-Pyrrolo[2,3-b]pyridinyl and es 7-azaindolyl, 7-azaindolyl, 7-azaindolyl, 7- azaindolyl, 7-azaindolyl, 7-azaindolyl. The term “6-azaindolyl” as used herein refers to 1HPyrrolo [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 5-azaindolyl, 5-azaindolyl, 5-azaindolyl, 5-azaindolyl, 5- azaindolyl, 5-azaindolyl. The term “4-azaindolyl” as used herein refers to 1H-Pyrrolo[3,2— dinyl and includes ndolyl, 4-azaindolyl, 4-azaindolyl, 4-azaindolyl, 4- azaindolyl, 4-azaindolyl.
For example, miting examples of heteroaryl can be 2— or 3-furyl, 2— or 3-thienyl, 1-, 2— or 3- 1O 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 zolyl, 1,2,3-triazol, or yl, 1,2,4-triazol, , or yl, 1H-tetrazol, oryl, 2H-tetrazol, or yl, 1,2,3-0xadiazol or yl, 1,2,4-oxadiazol or - -yl, 1,2,5-0xadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazol or yl, 1,2,4-thiadiazol or yl, 1,2,5-thiadiazol or yl, 1,3,4-thiadiazolyl, 1- or 5-tetrazolyl, 2—, 3- or 4-pyridyl, 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, ndol-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 5-isobenzofuryl, 2—, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 3-, 4- or 5-isobenzothienyl, 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 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisothiazolyl, 1,3-benzothiazol- 2—yl, yl, 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 8-indolizinyl, 2—, 3-, 4- or 5-isoindolyl, 1H- indazolyl, 3-yl, yl, yl, yl, or yl, 2H-indazolyl, 3-yl, yl, 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, o[1,2—a]pyridinyl or imidazo[1,2—a]pyridinyl, 3O tetrazolo[1 ,5-a]pyridineyl, tetrazolo[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, 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 7-pteridinyl, 1-, 2—, 3-, 4- or 9- carbazolyl, 1-, 2—, 3-, 4-, 5-, 6-, 7-, 8- or olinyl, 1-, 2—, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- thridinyl, 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- nyl, 1-, 2—, 3-, 4-, or 10-phenoxazinyl, or additionally substituted tives thereof. -1 5- An “optionally substituted heteroaryl” refers to a heteroaryl 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.
The term “oxo” as used herein refers to the group =0.
The term “alkoxy" or “alkyloxy” as used herein refers to a l having the Formula -ORb wherein Rb is alkyl. ably, alkoxy is C1-C10 , C1-C6 alkoxy, or C1-C4 alkoxy. miting examples of suitable alkoxy include 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 ant radical is referred to as thioalkoxy. “Haloalkoxy” is an alkoxy 1O group wherein one or more hydrogen atoms in the alkyl group are substituted with halogen. Non- limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2—trifluoroethoxy, 1,1,2,2—tetrafluoroethoxy, roethoxy, 2—chloroethoxy, fluoroethoxy, 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 "aroyl" 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- cyclohexylethyl, cyclobutylpropyl, entylpropyl, 3-cyclopentylbutyl, exylbutyl 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 alkylene or alkylene tuted 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 substituent refers to a carboxy group linked to an alkyl l i.e. to form —C(=O)ORe, wherein R9 is as defined above for alkyl.
The term “alkylcarbonyloxy” by itself or as part of another tuent refers to a —O-C(=O)Re wherein R9 is as defined above for alkyl. -1 7- 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 r substituent refers to the group -C(=S)—.
The term “alkoxy” by itself or as part of r substituent refers to a group consisting of an oxygen atom attached to one optionally substituted straight or branched alkyl group, cycloalkyl group, l, 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. 1O The term “halo” or en” as a group or part of a group is generic for fluoro, , 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- limiting examples of such haloalkyl radicals e 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 meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined 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 halogen atoms. For example, "haloalkoxy" includes -OCF3, — OCHFz, 'OCHzF, -CF3, 'O-CHz-CF3, -O-CH2—CHF2, and -O-CH2—CH2F.
Whenever the term “substituted” is used in the t invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the ted group, provided that the indicated atom’s normal valency is not exceeded, 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 therapeutic agent.
As used herein the terms such as “alkyl, aryl, or lkyl, each being optionally substituted with” or “alkyl, aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl, ally tuted aryl and optionally substituted cycloalkyl. 3O As described herein, some of the compounds of the invention may contain one or more tric 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 l forms in all possible configurations, as well as mixtures thereof.
More lly, 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 isomers, E/Z-isomers, stereochemical isomers (i.e. -1 8- 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 s, 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 Tables 1 to 11, their derivatives, es, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, ues, pro-drugs, esters, 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 1O atoms are oxidized to the so-called N-oxide.
As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a 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 bed herein, wherein; R3 is selected from the group comprising hydrogen, Cq_6alkyl, and C3_6cycloalkyl, in ular hydrogen or C1_3alkyl; more in ular hydrogen.
In a preferred embodiment, the present invention provides nds of formula I, n; X is hydrogen or n; in particular halogen; more in particular fluoro; A is —NH-C(=O)— or —C(=O)—NH-; Y is N or C; R3 is selected from the group comprising en, C1_20alkyl, and 03.15cycloalkyl; in particular hydrogen or C1_6alkyl; more in ular hydrogen or C1_6alkyl; even more in particular hydrogen; R1 is selected from the group comprising en, Cmoalkyl, C1_20alkoxy, and halogen; in particular hydrogen, C1_6alkyl, and halogen; more in particular hydrogen, methyl, and halogen; and R2 is selected from the group consisting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl, heteroaryl, and 03.19heterocyclyl; wherein said Cmoalkyl, C3_20alkenyl, C3_20alkynyl, 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, ycloalkyl, C3_19heterocyclyl, C1_20alkylamino, Cq_6alkyl, di(C1_20alkyl)amino, C1. -1 9- goalkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; Or R2 taken together with R1 form a cyclic ester (Iactone) comprising from 4 to 9 carbon atoms in the cyclic ester ring.
In an even r embodiment, the present invention provides compounds of formula I as described herein, wherein; R1 is selected from the group comprising hydrogen, C1_6alkyl, C1_6alkoxy, and halogen; in particular hydrogen, C1_6alkyl, and halogen; more in particular hydrogen, methyl, and halogen. 1O In an even further red embodiment, the present invention provides compounds of formula I as described herein, wherein; R1 is selected from the group sing hydrogen, Cmoalkyl, C1_20alkoxy, and halogen; in particular hydrogen, methyl, and n; more in particular R1 is methyl or fluoro; and R2 is selected from the group ting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl, heteroaryl, and 03.19heterocyclyl; wherein said Cmoalkyl, C3_20alkenyl, and C3_20alkynyl is optionally substituted with one or more substituents selected from the group ting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1. goalkylamino, di(C1_20alkyl)amino, C1_20alkoxy, 1_20alkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, yl esters, carbamate, ido, urea, and sulfonamido; in particular R2 is selected from the group consisting of lkyl, C3_20alkenyl, C3_20alkynyl, C3. 15cycloalkyl, aryl, heteroaryl, and C3_19heterocyclyl; wherein said Cmoalkyl is optionally substituted with one or more substituents selected from the group ting of halo, yl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_ goalkyl)amino, C1_20alkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, ino, yl esters, carbamate, thioamido, urea, and sulfonamido. or R2 taken together with R1 form a cyclic ester (Iactone) comprising from 4 to 5 carbon atoms in the cyclic ester ring.
In a further ment, the present invention provides compounds of formula I as described 3O herein, wherein; R1 is selected from the group comprising hydrogen, Cmoalkyl, C1_20alkoxy, and n; in particular hydrogen, methyl or halogen, more in particular methyl or fluoro; and R2 is selected from the group consisting of Cmoalkyl, C3_20alkenyl, C3_20alkynyl, and aryl; wherein said Cmoalkyl, C3_20alkenyl, C3_20alkynyl, and aryl 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, 03.19heterocyclyl, C1_20alkylamino, di(C1_ goalkyl)amino, lkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; in particular R2 is selected from the group consisting of Cmoalkyl, C3_20alkenyl, C3_20alkynyl, and aryl; wherein said Cmoalkyl is optionally substituted with one or more tuents selected from the group consisting of halo, yl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C3. 15cycloalkyl, C3_19heterocyclyl, Cmoalkylamino, di(C1_20alkyl)amino, oxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, lkylthio, ylic acid, acylamino, Cmoalkyl esters, ate, ido, urea, and sulfonamido; 1O or R2 taken together with R1 form a cyclic ester (lactone) sing from 4 to 5 carbon atoms in the cyclic ester ring.
In another preferred embodiment, the present invention provides nds of formula I as described herein, wherein; R1 is selected from the group comprising hydrogen, yl, lkoxy, and halogen; in particular hydrogen, methyl or halogen, more in particular methyl or fluoro; and R2 is ed from the group consisting of Cq_6alkyl, Cg_6alkenyl, Cg_6alkynyl, and aryl; n said C1_6alkyl, C3_6alkenyl, Cg_6alkynyl, and aryl is ally 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, Cmoalkyl , carbamate, thioamido, urea, and sulfonamido; in particular selected from the group consisting of C1_6alkyl, C3_6alkenyl, and Cg_6alkynyl; wherein said Cq_6alkyl, C3_6alkenyl, and Cg_6alkynyl 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, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; more in particular R2 is C1_6alkyl optionally substituted with a substituent selected from the group 3O 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 sulfonamido; or R2 taken together with R1 form a cyclic ester (lactone) comprising from 4 to 5 carbon atoms in the cyclic ester ring. -21 _ In a particular embodiment, the present invention provides nds of a I as described herein, wherein; said one or more al substituents for R2 are selected from the group consisting of halo, hydroxyl, nitro, amino, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_20alkyl)amino, C1_20alkoxy, and halo-C1_Zoalkyl; in particular from the group consisting of cyano, C3_6cycloalkyl, C3_6heterocyclyl, C1_6alkoxy, di(C1_6alkyl)amino, aryl, and aryl; more in particular from C3_6heterocyclyl, and C1_6alkoxy.
It is also an object of the invention to provide those compounds of formula I wherein one or more of 1O the following ction apply: 0 X is halogen; in particular fluoro; - A is —C(=O)—NH-; - Y is C; 0 R3 is hydrogen; 0 R1 is selected from the group comprising hydrogen, Cmoalkyl, and halogen; in particular hydrogen, C1_6alkyl, and halogen; more in particular hydrogen, methyl and fluoro - R1 is hydrogen; 0 R1 is fluoro; - R2 is selected from the group ting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, C3. oalkyl, aryl, heteroaryl, and 03.19heterocyclyl; wherein said C1_20alkyl, C3_20alkenyl, and C3_20alkynyl 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, 03.15cycloalkyl, C3_19heterocyclyl, lkylamino, di(C1_20alkyl)amino, C1_20alkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; in particular R2 is selected from the group consisting of Cmoalkyl, lkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl, heteroaryl, and C3_19heterocyclyl; wherein said Cmoalkyl is optionally substituted with one or more substituents selected from the group ting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_ 3O goalkyl)amino, C1_20alkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; - R2 is selected from the group consisting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, and aryl; wherein said lkyl, lkenyl, C3_20alkynyl, and aryl 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, ycloalkyl, C3_19heterocyclyl, C1. lamino, di(C1_20alkyl)amino, C1_20alkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, C1. goalkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; in particular R2 is selected from the group consisting of C1_20alkyl, C3.
WO 30365 2012/067016 goalkenyl, C3_20alkynyl, and aryl; wherein said Cmoalkyl is optionally substituted with one or more substituents selected from the group consisting of halo, yl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_20alkyl)amino, oxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; R2 is selected from the group consisting of Cq_6alkyl, C3_6alkenyl, Cg_6alkynyl, and aryl; wherein said Cq_6alkyl, C3_6alkenyl, Cg_6alkynyl, and aryl 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. 1O goalkylamino, di(C1_20alkyl)amino, lkoxy, 1_20alkoxy, halo-C1_Zoalkyl, thiol, C1. goalkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; in particular selected from the group consisting of C1_6alkyl, C3_6alkenyl, and Cg_6alkynyl; wherein said C1_6alkyl, C3_6alkenyl, and kynyl is optionally substituted with one or more substituents ed 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, Cmoalkyl esters, carbamate, ido, urea, and sulfonamido; more in particular R2 is C1_6alkyl optionally tuted with a substituent 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_ goalkyl)amino, C1_20alkoxy, halo-C1_Zoalkoxy, 1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; even more in particular R2 is C1_6alkyl. said one or more optional substituents for R2 are selected from the group consisting of halo, hydroxyl, nitro, amino, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1. goalkylamino, di(C1_20alkyl)amino, C1_20alkoxy, and 1_Zoalkyl; in particular from the group consisting of cyano, cloalkyl, terocyclyl, C1_6alkoxy, di(C1_6alkyl)amino, aryl, and heteroaryl; more in particular from C3_6heterocyclyl, and C1_6alkoxy; said one or more optional substituents for R2 are selected from C3_19heterocyclyl and C1. 3O goalkoxy; more in particular from oxolanyl and methoxy; R1 and R2 taken er form a cyclic ester comprising 4 carbon atoms in the cyclic ester ring.
In another particular embodiment, the present invention provides a compound selected from the group consisting of: methyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) benzoate; methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—3- fluorobenzoate; 0 methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—2— fluorobenzoate; - propyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—3- fluorobenzoate; - methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—2— methylbenzoate; - propyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—2— methylbenzoate; - methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}carbamoyl) 1O benzoate; - methyl 6-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}carbamoyl) pyridinecarboxylate; - 2—methoxyethyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl} amido)benzoate; - oxolanylmethyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl} amido)benzoate; - 4-(aminomethyl)-N-(3-fluoropyridinyl){3-[(1-oxo-1,3-dihydrobenzofuranyl) carbamoyl]phenyl}benzamide; and - N-{3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}oxo-1,3-dihydro- 2-benzofurancarboxamide.
The nds 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 rative for the invention and that the compounds of this invention can be prepared by any of several standard synthetic processes ly used by those skilled in the art of organic chemistry.
In a red embodiment, the compounds of the t invention are useful as kinase inhibitors, either in vitro or in vivo, more in particular for the inhibition of at least one ROCK kinase, ed from ROCKl and ROCKll, in particular soft ROCK inhibitors. Accordingly the present invention 3O 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 before 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 ed, such as diseases linked to smooth muscle cell function, mation, 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 hereinbefore, or the use of a composition comprising said compound in the tion and/or treatment of at least one disease or disorder selected from the group comprising eye diseases; airway diseases; throat, nose and ear diseases; intestinal diseases; vascular and ar diseases; inflammatory diseases; neurological and CNS disorders: proliferative es; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia, transplant rejection, spasm, hypertension, chronic obstructive bladder disease, and allergy.
In a preferred embodiment, the invention es the use of a nd as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of eyes 1O diseases including but not limited to pathy, optic neuropathy, glaucoma and degenerative retinal diseases such as macular degeneration, retinitis pigmentosa and inflammatory eye diseases (such as or uveitis, panuveitis, intermediate uveitis and posterior uveitis), 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 treatment of airway diseases; including but not limited to ary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonary e (COPD); bronchitis and is and respiratory distress syndrome, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
In a further 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 cardiovascular and vascular diseases: including but not d to pulmonary hypertension and pulmonary vasoconstriction, and/or for preventing, treating and/or alleviating complications and/or symptoms ated therewith and/or alleviating complications and/or symptoms associated therewith.
In a further 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 throat, nose and ear diseases: including but not limited to sinus ms, hearing problems, toothache, tonsillitis, ulcer and is, 3O In a further 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 skin diseases: including but not limited to eratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis and ulceration.
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 intestinal diseases; including but not limited to inflammatory bowel disease (IBD), colitis, gastroenteritis, ileus, ileitis, icitis and Crohn’s disease. 2012/067016 In yet another embodiment, the invention es the use of a compound as defined before or the use of a composition comprising said compound in the tion and/or treatment of inflammatory diseases: including but not d to t dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoid tis, sing litis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis, and/or for preventing, treating and/or ating complications and/or symptoms and/or inflammatory responses associated therewith.
In another embodiment, the invention es the use of a compound as defined hereinbefore or the use of a composition sing said compound in the prevention, treatment and/or 1O management of neurological 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 r 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 proliferative diseases: such as but not limited to cancer of breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, ovary, pancreas, prostate, or thyroid gland; man disease; sarcoma; malignoma; and melanoma; and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses ated therewith.
In r embodiment, the invention provides the use of a compound as d hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of kidney diseases: including but not d to renal fibrosis or renal dysfunction; and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses 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 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 n drugs, such as drugs used to treat hypertension, depression or anxiety. 3O 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 treatment of bone diseases: including but not limited to osteoporosis and osteoarthritis; and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.
In another embodiment, the invention provides the use of a compound as d before or the use of a composition comprising said compound in the prevention and/or treatment of diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive bladder e, 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 hereinbefore or the use of a ition comprising said compound in the prevention and/or treatment of eye diseases.
METHOD OF TREATMENT The present invention further provides a method for the prevention and/or treatment of at least one disease or disorder ed from the group comprising eye diseases; airway es; 1O 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; c obstructive bladder disease; and allergy; said method comprising stering to a subject in need f 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 diseases including but not limited to retinopathy, optic neuropathy, ma and degenerative retinal diseases such as macular degeneration, retinitis tosa and inflammatory eye diseases (such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis), said method comprising administering to a subject in need thereof a therapeutic effective amount of a nd or a composition as defined .
In another embodiment, the invention provides a method for the prevention and/or treatment of ain/vay diseases including but not d to pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonary disease (COPD) bronchitis, rhinitis, and respiratory distress syndrome; said method comprising stering to a subject in need thereof 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 treatment of cardiovascular and vascular diseases: including but not limited to pulmonary hypertension and pulmonary vasoconstriction; said method comprising administering to a subject in need thereof a 3O 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 treatment of inflammatory diseases: including but not d to contact itis, atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease and ulcerative s; said method comprising stering to a subject in need thereof a therapeutic effective amount of a nd or a composition as defined herein.
In another ment, the invention es a method for the tion and/or treatment of neurological 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; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as d herein.
In another embodiment, the invention provides a method for the tion and/or treatment of proliferative es: such as but not limited to cancer of , colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate, or thyroid gland; Castleman 1O disease; leukemia; sarcoma; lymphoma; oma; and melanoma; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.
In another embodiment, the invention es 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 thereof 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 treatment of sexual ction: including but not limited to hypogonadism, bladder e, 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; 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 bone es: including but not limited to osteoporosis and osteoarthritis; said method comprising stering to a subject in need thereof 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 treatment of diseases and disorders such as benign prostatic hyperplasia, lant ion, spasm, chronic obstructive bladder disease, and allergy; said method comprising stering to a subject in need 3O thereof a therapeutic ive 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 eye diseases; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.
In the invention, particular preference is given to compounds of Formula | or any subgroup thereof that in the inhibition assay for ROCK described below t 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 effected in vitro and/or in vivo, and when effected in vivo, is preferably effected in a selective manner, as defined above.
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 es or conditions that are alleviated by treatment with a ROCK inhibitor. Accordingly, another embodiment of the present invention relates to treating or ing 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 acid-addition and/or base-addition salt (e.g. 1O obtained 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, such as an ester. As used herein and unless otherwise stated, the term “solvate” includes 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, s, esters and the like. Such salts, hydrates, solvates, etc. and the preparation thereof will be clear to the skilled person.
The pharmaceutically acceptable salts of the compounds ing to the ion, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from nic or organic acids or bases. lly, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation or ceutical composition comprising at least one nd of the invention and at least one pharmaceutically acceptable r, diluent or excipient and/or adjuvant, and ally one or more further pharmaceutically active compounds.
By means of non-limiting es, such a formulation may be in a form suitable for oral administration, for parenteral stration (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, olid or liquid, ing 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.
Some preferred, but non-limiting examples of such preparations e tablets, pills, powders, 3O lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged s (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 formulations, such as lactose, dextrose, e, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, anth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, le) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable 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, g agents, emulsifying and suspending agents, sing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, ing agents, flow regulators, release agents, etc. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for e using liposomes or hydrophilic ric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ Cl-, [3- or 1O y-cyclodextrins or their derivatives.ln on, co-solvents such as alcohols may improve the lity and/or the ity of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.
For ophthalmic application, solutions, gels, tablets 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 particles 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) sing at least two components, wherein one component 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 uniform or homogenous throughout or ts of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid on". Solid solutions are preferred physical systems because the components n are y readily bioavailable to the organisms to which they are stered.
It may further be convenient to formulate the compounds in the form of nanoparticles which have a surface modifier ed 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 selected 3O from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural ts and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
The preparations may be prepared in a manner known per se, which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically able carriers, and, if desired, in combination with other pharmaceutical active compounds, when ary under aseptic conditions.
The compounds can be administered by a variety of routes including the oral, rectal, ocular, transdermal, subcutaneous, intramuscular or intranasal routes, ing mainly on the specific 2012/067016 preparation used and the condition to be treated or prevented. The at least one compound of the ion will generally be administered in an “effective ”, by which is meant any amount of a compound of the Formula | or any subgroup thereof that, upon le administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
In accordance with the method of the present invention, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be 1O interpreted accordingly.
In preferred embodiments, the nds and itions of the invention are used locally, for instance topical or in both absorbed and sorbed 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 ts obtained from the animal. Thus, in a further aspect, the invention relates to a composition for veterinary use that contains at least one compound of the invention and at least one suitable r (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 rated by means of the following synthetic and ical examples, which do not limit the scope of the invention in any way.
A. Physicochemical ties of the compounds A. 1. Compound purity Unless indicated otherwise, the purity of the compounds was confirmed by liquid chromatography/mass spectrometry (LC/MS).
A.2. Attribution of the configuration: 3O 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; lngold; Prelog Angew. Chem. Int. Ed. Engl. 1966, 5, 385-415.
A.3. Stereochemistrv: It is known by those skilled in the art that specific enantiomers (or diastereoisomers) can be obtained by different methods such as, but not limited to chiral resolution (for example, salts formed 2012/067016 with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the tion 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 3,5-dimethylphenylcarbamate, 46 x 250 or 100 x 250 mm, 5 pm), Chiralcel OJ methylbenzoate, 46 x 250 or 100 x 250 mm, 5 pm), Chiralpak AD (tris-3,5- dimethylphenylcarbamate, 46 x 250 mm, 10 um) and Chiralpak AS (tris-(S) phenylethylcarbamate, 46 x 250 mm, 10 pm) from Chiral Technologies Europe (lllkirch, France)).
Whenever it is convenient, stereoisomers can be obtained starting from commercial materials with known configuration (such compounds e aminoacid for instance). 1O B. Compound synthesis B. 1. Compounds of the invention The compounds of the invention can be made according to the ing general procedures: R1 O O o \ 0/ 0 / OH 0 R1 0 i Y R3 / \ o 3 + R I a / —> X NH HN Y F NH H A 2 N A |\ O O X |\ o o N / O N / O K Intermediate R1 O o \ OH o N Y/ 0 H R1 R3 o \ o/ x NH N Y \ GAO 3 d,c N/ O R1 0 0 I\ o’ O N Y x NH2 N/ 0 Reaction a: To a solution or suspension of the ylic acid intermediate in an organic solvent such as DMF or DCM at room temperature were added an appropriate coupling reagent (e.g TBTU/HOBt, HATU or T3P) and a base such as DIEA or DMAP. After 5 min the selected amine was added and the mixture stirred at the appropriate temperature (e.g rt or 60°C) until completion of the reaction. After an riate work up, the residue could be purified following different methods such as flash chromatography eluted for instance with DCM/EtOAc or precipitation in a solvent (e.g DCM or water) to give the expected product as a white powder.
Reaction b: To a solution or suspension of the ester intermediate in an organic t (e.g THF, Dioxane or Acetonitrile) was added dropwise an aqueous solution of an appropriate base such as LiOH. The resulting e was stirred at room temperature until completion of the reaction. Then the on mixture was acidified until pH 4 using an appropriate acid such as HCI (0.5M in water) or KHSO4 (0.5M in water). The white suspension was ted by filtration, washed with water and an riate organic solvent such as AcOEt or DCM, and dried under vacuum to give the 1O expected t as a white powder.
Reaction c: h a solution or suspension of the Boc-protected amine in an organic solvent (e.g DCM, AcOEt, diethyl ether or e) was bubbled HCI (gas) at room temperature for 5 to 10 min.
The resulting mixture was stirred at an appropriate temperature (e.g 0°C or rt) until completion of the reaction. Then the white suspension was collected by filtration, washed with an organic solvent such as diethyl ether and dried under vacuum to give the HCI salt of the expected product as a white powder.
Reaction d: To a solution or suspension of the carboxylic acid intermediate in an organic t (e.g THF, DMF or DCM) at room temperature were added an appropriate coupling reagent (e.g TBTU/HOBt, HATU, DIC or T3P) and a base such as DIEA or DMAP. After 5 min the selected alcohol was added and the mixture stirred at the appropriate temperature (e.g rt or 60°C) until completion of the on. After an appropriate work up, the residue was purified by flash chromatography using an appropriate eluent such as DCM/EtOAc or Heptane/EtOAc to give the expected product as a white powder.
If A = -NHC(O)—, the final compounds can be made from the required aniline intermediate and the appropriate carboxylic acid, following similar protocols.
For the ation of the required intermediate(s), reference is made to the PCT application W02011/107608.
In the table that is set forth below, exemplary compounds of the invention are set out in tabulated form. In this table, an arily assigned compound number and structural information are set out.
Table1 A 1R; ORsYl / Osz x NH2 “I.“ — iI--—_ IN“I--—— --'CIOIN“I--—— --I-_'H --I-_——“H ———_l-———_I—-—— _I—-—— «CH:ll:l:v'l'l Compound 11: F Q O — O o NH2 Compound 11 is obtained by first coupling the Intermediate carboxylic acid (as described in the general scheme / Intermediate described in /107608) with the corresponding commercially available lactone and then removing Boc protection as described in the general scheme (step c).
Compound 12: nd 12 is obtained by first coupling the Intermediate aniline (as described in W02011/107608) with the corresponding commercially available lactone and then removing Boc protection as described in the general scheme (step c).
WO 30365 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 , 2 mM DTT, 1% DMSO. ed cofactors are added individually to each kinase reaction. The reaction procedure first ed the ation of a peptide substrate in a freshly prepared reaction buffer. Required cofactors were then added to the substrate solution. ROCK (1nM final tration) was then delivered to the substrate solution. 1O After gentle mix, DMSO solutions of the test compounds were added to the . Substrate mix 33P-ATP (specific activity 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 spotted onto P81 ion exchange paper (Whatman # 3698-915). Filters were washed ively in 0.1% oric acid. A radiometric count was then performed and IC5O values were uently ined.
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 endogenous expression of ROCK results in a tutive phosphorylation of the regulatory myosin light chain at T18/S19. A7r5 cells were plated in DMEM supplemented with 10%FCS in multiwall cell culture plates. After serum starvation overnight, cells were ted with compounds in serum-free medium.
Quantification of MLC-T18/S19 phosphorylation 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 controls, which were set to 100%.
IC5O values were determined using GraphPad Prism 5.01 software using a nonlinear regression curve fit with variable hill slope. The EC50 values are below 500nM for the compounds of the invenfion.
C. 2. Pharmacological Characterization 3O 0.2. 1. Stability assay in human hepatocytes.
Compounds are incubated at a concentration of 1 uM with human cytes (2 106 cells/ml in buffer solution). At fixed time points (ex: 1, 30, 60 & 120 minutes), an incubation mixture (200ul) is cooled down on ice and 100u| of acetonitrile is added. After vortex-mixing, the sample is centrifuged for 5 minutes at 16000rpm. The remnant of compound in each sample is determined by LC-PDA-MS/MS analysis and half-life of the compound is subsequently calculated. Formation of the acid metabolite resulting from ester hydrolysis can be performed simultaneously. Peak areas for appearance of the acid are first recorded, and the corresponding concentrations are then back- calculated from ation curve.
When evaluated under such conditions, compounds of the invention are rapidly degraded in the corresponding acid (primary metabolite). For instance, compound 1 has a t1/2 of 14 minutes, as illustrated in table in Table 2: Table2 de 1 (% remaining) Acid (corresponding %) 4.8 +/- 0.1 99.7 +/- 0.8 2.4 +/- 1.3 99.3 +/- 0.8 C. 2. 2. Stability assay in rabbit s or vitreous humor Compounds are incubated at a concentration of 1 uM in rabbit aqueous humor (AH) or rabbit 1O vitreous (VH). Samples are taken at fixed time points and the remnant of compound is determined by LC-MS/MS after protein precipitation. Half-life values for compounds of the invention are provided in table 3.
Table 3 C. 2.3. Pharmacokinetics after intravenous and oral administration in mice.
The bioavailability of compound 1 was evaluated after intravenous and oral dosing in male CD-1 mice. The nd was dosed at 0.1 mg/kg intravenously and 1 mg/kg . Plasma levels were ined by LC-MS/MS and pharmacokinetic parameters were ted by a non- compartmental model using WinNonlin v5.2.1 software.
After intravenous dosing of compound 1 at 0.1 mg/kg, Cmax of 16.3 ng/mL was reached. The clearance and volume of distribution were 15.4 g and 100 L/kg, respectively. The intravenous exposure as ed by AUClast was found to be 4.82 i 0.276 hr*ng/mL. The corresponding metabolite was detectable till 1 hour post dose with maximum concentration of 16.3 ng/mL.
Metabolite had 1.47-fold higher exposure (7.10 i 0.920 hr*ng/mL) compared to parent compound.
Following oral dosing of nd 1 at 1 mg/kg, a Cmax of 22.4 i 22 ng/mL, was observed at 15 minutes post dose. AUClast was found to be 6.20 i 5.50 hr*ng/mL. The percent oral bioavailability was found to be 12.9%. Following oral dosing of Compound 1, its metabolite was detectable at 15 min only with Cmax of 4.53 i 3.83 ng/mL. These data confirm that Compound 1 is y metabolized and excreted from the body very rapidly.

Claims (14)

1. A compound of Formula I or a isomer, tautomer, racemic, salt, hydrate, or solvate thereof, Y O R3 R2 X NH H 2 N O Wherein, X is hydrogen or halogen; A is –NH-C(=O)- or –C(=O)-NH-; Y is N or C; R3 is selected from the group comprising en, C1-20alkyl and C3-15cycloalkyl; R1 is selected from the group comprising hydrogen, C1-20alkyl, C1-20alkoxy, and halogen; and R2 is selected from the group consisting of C1-20alkyl, C3-20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said C1-20alkyl, 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, C3- 15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, C1-6alkyl, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1- xy, halo-C1-20alkyl, thiol, C1-20alkylthio, ylic acid, ino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; or R2 taken together with R1 forms a cyclic ester ne) comprising from 4 to 9 carbon atoms in the cyclic ester ring.
2. The compound of formula I according to claim 1, n; R3 is selected from the group comprising hydrogen, C1-6alkyl, and C3-6cycloalkyl, in particular hydrogen or C1-3alkyl; more in particular hydrogen.
3. The compound of a I according to claim 1, wherein; X is halogen; more in particular fluoro; A is =O)- or –C(=O)-NH-; Y is N or C; R3 is ed from the group comprising hydrogen, C1-20alkyl, and C3-15cycloalkyl; in particular hydrogen or C1-6alkyl; more in particular hydrogen or C1-6alkyl; even more in particular hydrogen; R1 is ed from the group sing hydrogen, C1-20alkyl, C1-20alkoxy, and halogen; in ular hydrogen, C1-6alkyl, and halogen; more in particular hydrogen, methyl, and halogen; and R2 is selected from the group consisting of C1-20alkyl, C3-20alkenyl, lkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said C1-20alkyl, 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, yl, amino, amido, cyano, aryl, heteroaryl, C3- 15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, C1-6alkyl, 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 sulfonamido; or R2 taken together with R1 form a cyclic ester (lactone) comprising from 4 to 9 carbon atoms in the cyclic ester ring.
4. The nd of formula I ing to claim 1, wherein; R1 is selected from the group comprising hydrogen, C1-6alkyl, C1-6alkoxy, and halogen; in particular hydrogen, C1-6alkyl, and halogen; more in particular hydrogen, methyl, and halogen.
5. The compound of formula I according to claim 1, n; R1 is selected from the group comprising hydrogen, C1-20alkyl, C1-20alkoxy, and halogen; in particular hydrogen, methyl, and halogen; more in particular R1 is methyl or ; and R2 is selected from the group ting of lkyl, C3-20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said C1-20alkyl, 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, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1- 20alkoxy, halo-C1-20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, ylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; or R2 taken together with R1 form a cyclic ester ne) comprising from 4 to 5 carbon atoms in the cyclic ester ring.
6. The compound of formula I according to claim 1, wherein one or more of the following restrictions apply: • X is halogen; in particular fluoro; • A is –C(=O)-NH-; • Y is C; • R3 is hydrogen; • R1 is selected from the group comprising hydrogen, C1-20alkyl, and halogen; in ular hydrogen, C1-6alkyl, and n; more in particular hydrogen, methyl and fluoro • R1 is hydrogen; • R1 is fluoro; • R2 is ed from the group ting of lkyl, C3-20alkenyl, C3-20alkynyl, ycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; n said C1-20alkyl, C3-20alkenyl, and C3-20alkynyl 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, C3-19heterocyclyl, lkylamino, di(C1-20alkyl)amino, lkoxy, halo-C1-20alkoxy, halo-C1- 20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; in particular R2 is selected from the group consisting of C1-20alkyl, C3- 20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said C1- 20alkyl is optionally substituted with one or more tuents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, aryl, 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 sulfonamido; • R2 is selected from the group consisting of C1-20alkyl, lkenyl, lkynyl, and aryl; wherein said C1-20alkyl, C3-20alkenyl, C3-20alkynyl, and aryl 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, 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 sulfonamido; in particular R2 is selected from the group consisting of C1-20alkyl, C3-20alkenyl, C3-20alkynyl, and aryl; wherein said C1-20alkyl is optionally substituted with one or more substituents ed from the group consisting of halo, yl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, 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 sulfonamido; • R2 is selected from the group consisting of C1-6alkyl, C3-6alkenyl, C3-6alkynyl, and aryl; wherein said C1-6alkyl, C3-6alkenyl, C3-6alkynyl, and aryl 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, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, lkoxy, halo-C1-20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; in ular selected from the group consisting of C1-6alkyl, C3-6alkenyl, and C3-6alkynyl; wherein said C1- 6alkyl, C3-6alkenyl, and C3-6alkynyl 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, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1- 20alkoxy, halo-C1-20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, ino, C1- 2 is C 20alkyl esters, carbamate, ido, urea, and sulfonamido; more in ular R 1-6alkyl optionally substituted with a substituent 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, 1-20alkoxy, halo-C1- 20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl , carbamate, thioamido, urea, and sulfonamido; even more in particular R2 is C1-6alkyl. • said one or more optional substituents for R2 are selected from the group consisting of halo, hydroxyl, nitro, amino, cyano, aryl, heteroaryl, C3-15cycloalkyl, C3-19heterocyclyl, C1- 20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, and halo-C1-20alkyl; in particular from the group consisting of cyano, C3-6cycloalkyl, terocyclyl, C1-6alkoxy, di(C1-6alkyl)amino, aryl, and heteroaryl; more in particular from C3-6heterocyclyl, and C1-6alkoxy; • said one or more optional substituents for R2 are selected from C3-19heterocyclyl and C1- 20alkoxy; more in ular from oxolanyl and methoxy; • R1 and R2 taken together form a cyclic ester sing 4 carbon atoms in the cyclic ester ring.
7. The compound according to claim 1, selected from the group consisting of • methyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) benzoate; • methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) fluorobenzoate; • methyl [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) fluorobenzoate; • propyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) fluorobenzoate; • methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) methylbenzoate; • propyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) methylbenzoate; • methyl [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}carbamoyl) benzoate; • methyl 6-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}carbamoyl) pyridinecarboxylate; • 2-methoxyethyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl} amido)benzoate; • oxolanylmethyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl} amido)benzoate; • 4-(aminomethyl)-N-(3-fluoropyridinyl){3-[(1-oxo-1,3-dihydrobenzofuranyl) carbamoyl]phenyl}benzamide; and • N-{3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}oxo-1,3-dihydro benzofurancarboxamide.
8. A compound according to any one of claims 1 to 7 for use as a medicine.
9. A ition comprising a nd as defined in any one of claims 1 to 7, for use as a human or veterinary medicine.
10. A compound according to any one of claims 1 to 7, or a composition according to claim 9, 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 function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeneration, and remodeling.
11. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of at least one disease or disorder selected from the group comprising eye diseases; airway diseases; throat, nose and ear diseases; intestinal es; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative es; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia, transplant rejection, spasm, hypertension, chronic obstructive bladder disease, and allergy.
12. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of an eye e; including but not limited to retinopathy, optic neuropathy, glaucoma, degenerative retinal diseases such as macular degeneration, retinitis pigmentosa and inflammatory eye es (such as anterior uveitis, itis, intermediate s and posterior uveitis), and/or for ting, ng and/or alleviating complications and/or symptoms ated therewith.
13. Use of a compound according to any one of claims 1 to 7, or a composition according to claim 9, for inhibiting the activity of at least one kinase in vitro.
14. Use of a nd according to any one of claims 1 to 7, or a composition according to claim 9, for the preparation of a medicament for the prevention and/or treatment of at least one e or disorder ed 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; and allergy.
NZ622964A 2011-08-31 2012-08-31 Novel rock kinase inhibitors NZ622964B2 (en)

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EP11179491 2011-08-31
EP11179491.3 2011-08-31
PCT/EP2012/067016 WO2013030365A1 (en) 2011-08-31 2012-08-31 Novel rock kinase inhibitors

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NZ622964B2 true NZ622964B2 (en) 2015-06-30

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