HK1177931B - 2 -amino- pyrimidine derivatives useful as inhibitors of jnk - Google Patents

Description

2-amino-pyrimidine derivatives as inhibitors of JNK

The present invention relates generally to the fields of medicinal chemistry and the treatment of inflammatory disorders. More particularly, the present invention relates to prodrugs of JNK inhibitors, processes for preparing said inhibitors and corresponding methods, formulations, and compositions, etc., for inhibiting JNK and treating JNK-mediated disorders.

JNK, c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family, along with p38 and extracellular signal-regulated kinase (ERK). Three distinct genes have been identified (jnk1, jnk2, and jnk3), which encode 10 splice variants. JNK1 and JNK2 were expressed in a wide variety of tissues, while JNK3 was expressed primarily in neurons and to a lesser extent in the heart and testis. Members of the JNK family are activated by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF- α) and interleukin-1 β (IL-1 β) as well as environmental stress. Activation of JNK is mediated by its upstream kinases, MKK4 and MKK7, via dual phosphorylation by Thr-183 and Tyr-185. It has been shown that MKK4 and MMK7 can be activated by different upstream kinases, including MEKK1 and MEKK4, depending on the external stimulus and the cellular environment. Specificity of JNK signaling is achieved by forming JNK-specific signaling complexes containing multiple components of the kinase cascade using scaffold proteins called JNK-interacting proteins. JNK has been shown to play an important role in inflammation, T cell function, apoptosis, and cell survival by phosphorylating specific substrates, including transcription factors such as c-Jun, activator-1 (AP1) family members, and ATF2, as well as non-transcription factors such as IRS-1 and Bcl-2. Over-activation of JNK is thought to be an important mechanism in autoimmune, inflammatory, metabolic, neurological diseases, and cancer.

Rheumatoid Arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints. Most RA patients eventually develop debilitating joint damage and deformities, in addition to joint swelling and pain caused by the inflammatory process. Several convincing pharmacological and genetic evidences in cellular and animal models strongly suggest the relevance and importance of activated JNK in the pathogenesis of RA. First, abnormal activation of JNK was detected in both human arthritic joints from RA patients and rodent arthritic joints from animal models of arthritis. In addition, inhibition of JNK activation by selective JNK inhibitors blocks the production of pro-inflammatory cytokines and MMPs in human synoviocytes, macrophages and lymphocytes. Importantly, administration of selective JNK inhibitors in rats with adjuvant arthritis or in mice with collagen-induced arthritis effectively protected the joints from destruction and significantly reduced paw swelling by inhibiting cytokine and collagenase expression.

Asthma is a chronic inflammatory disease of the airways characterized by the presence of a cellular inflammatory process and bronchial hyperreactivity associated with changes in airway structure. This condition has been shown to be driven by a number of cell types in the airways, including T lymphocytes, eosinophils, mast cells, neutrophils and epithelial cells. Based on recent proof-of-concept studies, JNK has emerged as a promising therapeutic target for asthma: JNK inhibitors have been shown to significantly block RANTES production in activated human airway smooth cells. More importantly, JNK inhibitors show good efficacy in chronic rat and mouse models due to their ability to reduce cell infiltration, inflammation, hyperreactivity, smooth muscle proliferation and IgE production. These observations suggest an important role for JNK in allergic inflammation, a process of airway remodeling associated with hyperreactivity. Thus, blocking JNK activity would be expected to be beneficial for the treatment of asthma.

Type 2 diabetes is the most severe and widespread metabolic disease characterized by insulin resistance and impaired insulin secretion, which is the result of long-term low-level inflammation and abnormal lipid metabolism associated with oxidative stress. JNK activity has been reported to be abnormally elevated in various diabetic target tissues under obesity and diabetic conditions. Activation of the JNK pathway by pro-inflammatory cytokines and oxidative stress is through Ser³⁰⁷Phosphorylate insulin receptor substrate-1 (IRS-1) to negatively regulate insulin signaling, thereby promoting insulin resistance and glucose tolerance. Compelling genetic evidence comes from elaborate animal model studies using jnk crossed with genetically (ob/ob) obese mice or diet obese mice^-/-A mouse. JNK1 loss (JNK 1)^-/-) However, JNK2 function was not lost (JNK 2)^-/-) Protecting obese mice from weight gain, increasing blood glucose steady state levels, and decreasing plasma insulin levels. These studies demonstrate the potential utility of JNK inhibitors in the treatment of obesity/type 2 diabetes.

Neurodegenerative diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and stroke, are CNS diseases characterized by loss of synapses, neuronal atrophy and death. The JNK pathway leading to c-Jun activation has been shown to play a causal role in apoptosis of isolated primary embryonic neurons and a variety of neuronal cell lines after introduction of a variety of stimuli. Over-activation of JNK was observed in human brains of AD patients or in rodent brain sections derived from animal models of neurodegenerative diseases. For example, increased phospho-JNK was detected in post-hoc brains from AD patients. Administration of a JNK inhibitory peptide (JIP-1 peptide) in rodent models of AD induced by administration of □ -amyloid peptide prevented impairment of synaptic plasticity. In an animal model of PD (MPTP model), elevated phospho-MKK 4 and phospho-JNK were observed simultaneously with neuronal cell death. The behavioral impairment was alleviated by the adenoviral gene transfer of a JNK inhibitory peptide (JIP-1 peptide) into the striatum of mice, wherein neuronal cell death in the substantia nigra was blocked by inhibition of MPTP-mediated JNK, c-Jun and caspase activation. In addition, in animal models of ischemic stroke induced by glutamate excitotoxicity, mice deficient in JNK3 but not in JNK1 or JNK2 were resistant to kainic acid (glutamate receptor agonist) -mediated seizures or neuronal death. These data suggest that JNK3 is primarily responsible for glutamate excitotoxicity, an important component in ischemic disorders. Taken together, these data suggest that JNK is an attractive target for a variety of CNS diseases associated with neuronal cell death.

Uncontrolled cell growth, proliferation and migration, as well as deregulated angiogenesis, lead to malignant tumor formation. The JNK signaling pathway may not function alone in apoptosis, and sustained JNK activation leading to AP1 activation has recently been implicated in promoting cell survival in specific cancer types, such as glioblastomas and BCL-ABL transformed B lymphoblastoid cells. In the case of glia tumors, enhanced JNK/AP1 activity was seen in most primary brain tumor samples. For transformed B lymphoblasts, BCL-ABL was shown to activate the JNK pathway, which in turn upregulated the expression of the anti-apoptotic BCL-2 gene. Interestingly, the multidrug resistance and hyperproliferation seen in refractory AML (acute myeloid leukemia) patients has been causally linked to the sustained JNK activity present in these AML samples. Activation of JNK in leukemic cells leads to the induced expression of efflux pumps such as mdr1 and MRP1, which are responsible for multidrug resistance. In addition, the activated JNK pathway also upregulates genes that have a survival benefit in response to oxidative stress, including glutathione-S-transferase □ and □ -glutamylcysteine synthetase.

Renal disease is characterized by loss of nephron function caused by progressive glomerulosclerosis and tubulointerstitial fibrosis. Renal disease can develop from a number of conditions including inflammation, hypertension, diabetes or acute tissue damage caused by antibiotics, contrast agents or other nephrotoxic substances. JNK signaling has been shown to be upregulated in pathological specimens from many human kidney diseases including immune and non-immune mediated glomerulonephritis, diabetic nephropathy, hypertension, acute injury (1), and appears to play a signaling role in polycystic kidney disease (2). Convincing evidence for the important role of JNK and the therapeutic potential of JNK inhibitors is supported by studies in animal models of renal injury. JNK was increased in the rat anti-mesangial membrane-induced glomerulonephritis model and kidney function was improved by specific inhibitors in both acute and chronic disease paradigms (3). JNK was increased in Dahl salt-sensitive hypertensive rats, a model of hypertensive nephropathy (4), and in renal ischemia reperfusion injury (5, 6). JNK may contribute to the cellular mechanisms of renal injury in part by upregulating pro-inflammatory mediators in macrophages and directly activating pro-fibrotic and pro-apoptotic pathways in cells of the glomeruli and tubular epithelium (7). The ability to improve renal function by inhibiting JNK in a variety of disease models suggests JNK as an attractive target for the treatment of renal diseases of various etiologies.

The present invention provides compounds of formula I

Or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 2;

n is 0 to 2;

p is 0 to 3;

x is CH or N;

each R is¹Independently are: hydrogen; or C_1-6An alkyl group;

each R is²Independently are: c_1-6An alkyl group; c_1-6Alkoxy halo-C_1-6An alkyl group; or halo-C_1-6An alkoxy group;

R³the method comprises the following steps: c_1-6alkylsulfonyl-C_1-6An alkyl group; tetrahydrothienyl-1, 1-oxide (1, 1-oxide) -C_1-6An alkyl group; or tetrahydrothiopyran-1, 1-oxide-C_1-6An alkyl group;

each R is⁴Independently are: c_1-6An alkyl group; c_1-6Alkoxy halo-C_1-6An alkyl group; or halo-C_1-6An alkoxy group;

R⁵is a group of formula (a) or (b):

wherein:

q is 0 or 1;

r is 0 or 1;

y is: NR (nitrogen to noise ratio)⁹(ii) a Or CR¹⁰R¹¹；

R⁶And R⁷Each independently is: hydrogen, carboxyl; carboxy-C_1-6Alkyl esters or C_1-6An alkyl group; or R⁶And R⁷Together form C_1-2An alkylene group;

R⁸the method comprises the following steps: hydrogen; or C_1-6An alkyl group;

R⁹the method comprises the following steps: hydrogen; or C_1-6An alkyl group;

R¹⁰the method comprises the following steps: hydrogen; or C_1-6An alkyl group; and is

R¹¹The method comprises the following steps: hydrogen, C_1-6Alkoxy radical, NH₂C(O)-，C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; a carboxyl group; carboxy-C_1-6An alkyl group; carboxy-C_1-6An alkyl ester; or carboxy-C_1-6Alkyl radical C_1-6An alkyl ester.

The invention also provides methods of making the subject compounds, and methods of using the subject compounds for treating JNK-mediated diseases and disorders.

All publications cited in this disclosure are incorporated herein by reference in their entirety.

Definition of

Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, the phrase "a" or "an" entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. Thus, the terms "a" (or "an"), "one or more" and "at least one" may be used interchangeably herein.

As used in this specification, the terms "comprises" and "comprising," whether in transitional phrases or in the main body of the claims, should be construed to have an open-ended meaning. That is, these terms should be construed as synonymous with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include additional steps. The term "comprising" when used in the context of a compound or composition means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

As used herein, unless specifically indicated otherwise, the use of the word "or" is in the "inclusive" sense of "and/or" and not in the "exclusive" sense of "or/and.

The term "independently" as used herein means that the variables are used in either case regardless of the presence or absence of variables having the same or different definitions within the same compound. Thus, in a compound where R "occurs twice and is defined as" independently carbon or nitrogen, "both R" can be both carbon, both R "can be nitrogen, or one R" can be carbon and the other nitrogen.

In any moiety or formula depicting or describing a compound employed or claimed in the present invention, any variable (e.g., m, n, p, Q, Q, R, R¹、R²、R³、R⁴、X、X¹、X²、X³、X⁴、X⁵、Y¹、Y²、Z¹And Z²) When occurring more than once, its definition on each occurrence is independent of its definition at each other occurrence. Moreover, combinations of substituents and/or variables are permissible only if such compounds result in stable compounds.

The symbol "" at the end of a bond or "- - - - -" across a bond, respectively, refers to the point of attachment of a functional group or other chemical moiety to the rest of the molecule that is part of the molecule. Thus, for example:

MeC(＝O)OR⁴wherein

A bond drawn into a ring system (as opposed to being attached at a distinct vertex) means that the bond can be attached to any suitable ring atom.

The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted" means that the optionally substituted moiety may incorporate hydrogen or a substituent.

The term "about" as used herein means approximately, on the left and right of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. Generally, the term "about" is used herein to change a numerical value to a 20% change above and below the stated value.

Certain compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist as two or more species that can be interconverted. Tautomers of proton transfer result from the migration of a covalently bound hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers generally produce mixtures whose chemical and physical properties are consistent with mixtures of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in the case of many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in the phenols, the enol form predominates.

Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined. Reference is made herein to various methods and materials known to those skilled in the art. Standard reference works listing general principles of pharmacology include The Pharmacological Basis of Therapeutics, 10 th edition, McGraw Hill companies Inc., New York (2001), Goodman and Gilman. Any suitable materials and/or methods known to those skilled in the art may be used in the practice of the present invention. However, preferred materials and methods are described. Materials, reagents, etc. referred to in the following description and examples are available from commercial sources unless otherwise indicated.

The definitions described herein may be appended to form chemically relevant combinations such as "heteroalkylaryl," "haloalkylheteroaryl," "arylalkyl heterocyclyl," "alkylcarbonyl," "alkoxyalkyl," and the like. When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", it is intended to indicate an alkyl group, as defined above, substituted with one to two substituents selected from the group otherwise specified. Thus, for example, "phenylalkyl" refers to an alkyl group having 1 to 2 phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl. "alkylaminoalkyl" is an alkyl group having 1 to 2 alkylamino substituents. "hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 2, 3-dihydroxybutyl, 2- (hydroxymethyl), 3-hydroxypropyl and the like. Thus, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl groups defined below. The term- (ar) alkyl refers to unsubstituted alkyl or aralkyl groups. The term (hetero) aryl or (hetero) aryl refers to aryl or heteroaryl.

The term "acyl" as used herein denotes a group of formula-C (═ O) R, wherein R is hydrogen or lower alkyl as defined herein. The term "alkylcarbonyl" as used herein denotes a group of formula C (═ O) R, wherein R is alkyl as defined herein. Term C_1-6Acyl refers to the group-C (═ O) R, containing 6 carbon atoms. The term "arylcarbonyl" as used herein denotes a group of formula C (═ O) R, wherein R is aryl; the term "benzoyl" as used herein refers to an "arylcarbonyl" group wherein R is phenyl.

The term "alkyl" as used herein denotes an unbranched or branched, saturated, monovalent hydrocarbon residue containing from 1 to 10 carbon atoms. The term "lower alkyl" denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "C" as used herein_1-10Alkyl "refers to an alkyl group consisting of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl.

When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", it is intended to indicate an alkyl group, as defined above, substituted with one to two substituents selected from the group otherwise specified. Thus, for example, "phenylalkyl" denotes the group R 'R "-, where R' is phenyl and R" is alkylene as defined herein, with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene. Examples of arylalkyl groups include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The term "arylalkyl" or "aralkyl" is similarly construed, except that R' is aryl. The terms "(hetero) arylalkyl" or "(hetero) aralkyl" are similarly construed, except that R' is optionally aryl or heteroaryl.

The term "alkylene" as used herein, unless otherwise indicated, denotes a divalent saturated straight chain hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH)₂)_n) Or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g. -CHMe-or-CH)₂CH(i-Pr)CH₂-). Except in the case of methylene, the open valences of the alkylene groups are not attached to the same atom. Examples of alkylene groups include, but are not limited to: methylene, ethylene, propylene, 2-methyl-propylene, 1, 1-dimethyl-ethylene, butylene, 2-ethylbutylene.

The term "alkenyl" denotes a straight chain monovalent hydrocarbon group of two to six carbon atoms or a branched monovalent hydrocarbon group of three to six carbon atoms containing at least one double bond, for example, vinyl, propenyl, and the like.

The term "alkoxy" as used herein denotes an-O-alkyl group wherein alkyl is as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, including isomers thereof. "lower alkoxy" as used herein denotes alkoxy having "lower alkyl" as defined before. "C" as used herein_1-10Alkoxy "means an-O-alkyl group wherein alkyl is C_1-10。

The term "alkylsulfonyl" as used herein denotes the group-SO₂R, wherein R is alkyl as defined herein.

The term "alkylsulfonylalkyl" as used herein denotes the group-R' SO₂R, wherein R is alkyl and R' is alkylene, as defined herein. Exemplary alkylsulfonylalkyl groups include 3-methanesulfonyl-propoxy, 2-methanesulfonyl-ethoxy and the like.

The term "tetrahydrothienyl-1, 1-oxide-C as used herein_1-6Alkyl "represents the group-RR ', wherein R is alkylene as defined herein and R' is tetrahydrothienyl-1, 1-oxide. Exemplary Tetrahydrothienyl-1, 1-oxide-C_1-6Alkyl groups include 1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-ylmethyl and 2- (1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-yl) -ethyl.

The term "tetrahydrothiopyran-1, 1-oxide-C as used herein_1-6Alkyl "represents the group-RR ', wherein R is alkylene as defined herein and R' is tetrahydrothiopyran-1, 1-oxide. Exemplary Tetrahydrothiopyran-1, 1-oxide-C_1-6Alkyl groups include 1, 1-dioxo-hexahydro-1 λ x 6-thiopyran-3-ylmethyl and 2- (1, 1-dioxo-hexahydro-1 λ x 6-thiopyran-3-yl) -ethyl.

The term "carboxy" as used herein denotes a group of formula-COOH.

The term "carboxyalkyl ester" as used herein denotes a group of formula-COOR, wherein R is alkyl as defined herein.

The term "carboxy-alkyl" as used herein denotes a group of formula-R '-COOH, wherein R' is alkylene as described herein.

The term "carboxy-alkyl ester" as used herein denotes a group of formula-R '-COOR, wherein R is alkyl and R' is alkylene, as described herein.

"aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi-, or tricyclic aromatic ring. Aryl groups may be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylthio, diphenylsulfonyl, diphenylisopropylidene, benzodiazepineAlkyl, benzofuranyl, benzodioxolyl, benzopyranyl, benzoAzinyl radical, benzoOxazinonyl, benzopyridyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof.

The term "base" includes, but is not limited to, NaOH, KOH, LiOH and alkali metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, cesium carbonate and the like.

"cycloalkyl" or "carbocycle" refers to a monovalent saturated carbocyclic moiety consisting of a single ring or two rings. Cycloalkyl groups may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated derivatives thereof.

"Heterocycloalkyl-lower alkyl" means a compound of formula-R^a-R^bWherein R is^aIs lower alkylene and R^bIs heterocycloalkyl as defined herein.

The term "heteroaryl" or "heteroaromatic (heteroaromatic)" as used herein refers to a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring, each ring containing four to eight atoms, combined with one or more N, O or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl group will be on the aromatic ring. As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counterparts. Thus, for the purposes of the present invention, a heteroaryl group need only have some degree of aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms, including, but not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl,oxazole, isoOxazole, thiazole, isothiazole, triazoline, thiadiazole andbisoxazolines (oxadixolines) which may be optionally substituted by one or more, preferably one or two substituents selected from: hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoAzole, benzilOxazoles, benzothiazoles, and benzisothiazoles. The bicyclic moiety may be optionally substituted on either ring; however the point of attachment is on the heteroatom containing ring.

The terms "heterocyclyl", "heterocycle" or "heterocycloalkyl" as used herein denote a monovalent saturated cyclic group consisting of one or more rings (preferably one to two rings), each ring having three to eight atoms, combined with one or more ring heteroatoms (selected from N, O or S (O))_0-2) And which may be optionally independently substituted with one or more (preferably one or two) substituents selected from: hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise specified. Examples of heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinylAn oxetanyl group, a tetrahydrofuryl group, a tetrahydrothienyl group,Oxazolidinyl, thiazolidinyl, isooxazolidinylOxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl, and imidazolinyl.

The term "hydroxyalkyl" as used herein denotes an alkyl group as defined herein wherein one to three hydrogen atoms on different carbon atoms are substituted by a hydroxyl group.

In generalAbbreviations used include: acetyl (Ac), Azobisisobutyronitrile (AIBN), atmospheric pressure (Atm), 9-borabicyclo [3.3.1 ]]Nonane (9-BBN or BBN), tert-butyloxycarbonyl (Boc), di-tert-butyl pyrocarbonate or Boc anhydride (BOC)₂O), benzyl (Bn), butyl (Bu), chemical abstracts accession number (CASRN), benzyloxycarbonyl (CBZ or Z), Carbonyldiimidazole (CDI), 1, 4-diazabicyclo [2.2.2]Octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU), N, N ' -Dicyclohexylcarbodiimide (DCC), 1, 2-Dichloroethane (DCE), Dichloromethane (DCM), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), diisobutylaluminum hydride (DIBAL or DIBAL-H), Diisopropylethylamine (DIPEA), N, N-Dimethylacetamide (DMA), 4-N, N-Dimethylaminopyridine (DMAP), N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1, 1 ' -bis- (diphenylphosphino) ethane (dppe), 1, 1 ' -bis- (diphenylphosphino) ferrocene (dppf), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acid Ethyl Ester (EEDQ), diethyl ether (Et)₂O), O- (7-azabenzotriazol-1-yl) -N, N, N 'N' -tetramethylureaHexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), High Pressure Liquid Chromatography (HPLC), Isopropanol (IPA), lithium hexamethyldisilazide (LiHMS), methanol (MeOH), melting point (mp), MeSO₂- (methylsulfonyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrometry (Ms), methyl tert-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (NMP)(PCC), pyridine dichromate(PDC), phenyl (Ph), propyl (Pr), isopropyl (i-Pr), pounds per square inch (psi), pyridine (pyr), room temperature (RT or RT), tert-butyldimethylsilyl or t-BuMe₂Si (TBDMS), triethylamine (TEA or Et)₃N), 2, 2, 6, 6-tetramethylpiperidine 1-oxyl (TEMPO), trifluoromethanesulfonate or CF₃SO₂- (Tf), trifluoroacetic acid (TFA), 1, 1 ' -bis-2, 2, 6, 6-tetramethylheptane-2, 6-dione (TMHD), O-benzotriazol-1-yl-N, N, N ', N ' -tetramethylureaTetrafluoroborate (TBTU), thin-layer chromatography (TLC), Tetrahydrofuran (THF), trimethylsilyl or Me₃Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C₆H₄SO₂-or tosyl (Ts), N-urethane-N-carboxy anhydride (UNCA). When used for alkyl moieties, conventional Nomenclature including the prefixes positive (n), iso (i-), sec-, tert (tert-) and neo have their customary meaning (J.Rigaudy and D.P.Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford).

"heteroaryl" means a monocyclic or bicyclic moiety of 5 to 12 ring atoms having at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl group will be on the aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl,azolyl radical, isoAn azole group, a thiazole group, an isothiazole group,oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl (thiophenyl), furyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuranyl (benzofuranyl), benzothienyl, benzothiopyranyl, benzimidazolylAzolyl radical, benzoOxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, indazolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza-azanylRadical, diazaMesityl, acridinyl and the like, including partially hydrogenated derivatives thereof.

The terms "halo," "halogen," and "halide" are used interchangeably herein and refer to fluorine, chlorine, bromine, and iodine.

"haloalkyl" means an alkyl group, as defined herein, wherein one or more hydrogens have been replaced with the same or different halogen. The term "lower haloalkyl" refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms substituted with one or more halogen atoms. Exemplary haloalkyl groups include-CH₂Cl，-CH₂CF₃，-CH₂CCl₃，-CF₂CF₃，-CF₃And the like.

"Heterocyclyl" or "heterocycloalkyl" refers to a monovalent saturated moiety consisting of one to two rings, incorporating one, two, or three or four heteroatoms selected from nitrogen, oxygen or sulfur. The heterocyclyl ring may be as defined hereinOptionally substituted. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl (homopiperazinyl), azaA group, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridyl, pyridazinyl, pyrimidinyl,oxazolidinyl, isoOxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolidinyl, benzothiazolinyl, benzimidazolyl, thiadiazolidinyl, quinolizidinyl, quinolizidinOxazolidinyl (benzolylidinyl), dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl (thiomorpholinyl), thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Preferred groups for the chemical groups for which definitions are given above are those specifically exemplified in the examples.

"optionally substituted" means a substituent independently substituted with 0-3 substituents selected from lower alkyl, halo, OH, cyano, amino, nitro, lower alkoxy, or halo-lower alkyl.

Preferred "oxidants" include peracids such as meta-chloroperbenzoic acid (MCPBA) and peracetic acid, but other oxidants such as hydrogen peroxide, permanganate or persulfate may also be used to oxidize the thioether to the sulfone.

"leaving group" means a group having the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group that is replaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkyl-or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, methylthio, phenylsulfonyloxy, toluenesulfonyloxy and thienyloxy, dihalophosphonooxy, optionally substituted benzyloxy, isopropyloxy, acyloxy and the like.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

An "agonist" refers to a compound that enhances the activity of another compound or receptor site.

An "antagonist" refers to a compound that reduces or prevents the action of another compound or receptor site.

The term "drug candidate" refers to a compound or agent that is to be tested for a possible effect in the treatment of a disease state in an animal, whether or not the drug candidate has any known biological activity.

The term "homologous" as used herein refers to a protein that functions substantially the same and shares substantial sequence homology to the following degrees in another subject species: they are considered in the art as different forms of the same protein, differing primarily in the species in which they are found. Thus, for example, human ERG, mouse ERG and rat ERG are all considered homologous to each other.

"modulator" means a molecule that interacts with a target. Such interactions include, but are not limited to, agonists, antagonists, and the like, as defined herein.

"disease" and "disease state" refer to any disease, condition, symptom, disorder, or indication.

The term "cell line" refers to a clone of immortalized mammalian cells. A "stable" cell line is one that exhibits substantially consistent characteristics over time (e.g., at each replication). A stable cell line within the scope of the present invention provides a significant proportion of cells capable of providing a tight resistance (seal resistance) of greater than about 50MOhm, a current amplitude of greater than about 200pA, and a current amplitude that does not vary by more than about 20% within 1 hour under controlled conditions.

By "pharmaceutically acceptable salt" of a compound is meant a pharmaceutically acceptable salt as defined herein, and which salt possesses the desired pharmacological activity of the parent compound. Such salts include:

(1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or acid addition salts with organic acids; such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid (hydroxyynaphtoic acid), 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or

(2) Salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or is coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine (tromethamine), and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

It is understood that the recitation of all pharmaceutically acceptable salts includes the solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein of the same acid addition salt.

Preferred pharmaceutically acceptable salts are those formed from acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium.

"solvate" means a solvent addition formulation containing a stoichiometric or non-stoichiometric amount of solventFormula (II) is shown. Some compounds have a tendency to form solvates by trapping solvent molecules in a fixed molar ratio in the crystalline solid state. If the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. The hydrate is obtained by mixing one or more molecules of water with one of the water in the form of H₂The species retaining the molecular state of O are bound, such binding being capable of forming one or more hydrates.

"subject" includes mammals and birds. "mammal" means any member of the mammalia class, including but not limited to: a human being; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs; and the like. The term "subject" does not denote a particular age or gender.

"therapeutically effective amount" refers to the amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinary practitioner, and other factors.

"pharmacological effect" as used herein includes an effect produced in a subject that achieves the intended therapeutic goal. For example, the pharmacological effect will be one that results in the prevention, reduction, or diminution of urinary incontinence in the subject being treated.

"disease state" refers to any disease, disorder, symptom, or indication.

"treatment" or "therapy" of a disease state includes: (i) preventing a disease state, i.e., such that clinical symptoms of a disease state do not develop in a subject that may be exposed to or predisposed to the disease state but does not yet experience or develop symptoms of the disease state; (ii) inhibiting a disease state, i.e., arresting the development of the disease state or its clinical symptoms; or (iii) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

All patents and publications identified herein are hereby incorporated by reference in their entirety.

Nomenclature and Structure

Generally, the nomenclature used in this application is based on AUTONOM^TMv.4.0, a Beilstein Institute computerized system for generating IUPAC systematic nomenclature. Chemical Structure uses illustrated hereinVersion 2.2 was made. Unless otherwise indicated, any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. The nitrogen-containing heteroaromatic ring exhibits an open valence at the nitrogen atom, and the variable is R^a、R^bOr R^cWhere indicated on the heteroaromatic ring, such variable may be bonded or bound to the open valence nitrogen. In the case where a chiral center is present in a structure but the chiral center does not exhibit a particular stereochemistry, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein can exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms represented in the structures herein are intended to encompass all natural isotopes of such atoms. Thus, for example, hydrogen atoms represented herein are intended to include deuterium and tritium, while carbon atoms are intended to include C¹³And C¹⁴An isotope.

In certain embodiments of formula I or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 2;

n is 0 to 2;

p is 0 to 3;

x is CH or N;

each R is¹Independently are: hydrogen; or C_1-6An alkyl group;

each R is²Independently are: c_1-6An alkyl group; c_1-6Alkoxy halo-C_1-6An alkyl group; or halo-C_1-6An alkoxy group;

R³the method comprises the following steps: c_1-6alkylsulfonyl-C_1-6An alkyl group; thienyl-1, 1-oxide-C_1-6An alkyl group; or tetrahydrothiopyran-1, 1-oxide-C_1-6An alkyl group;

each R is⁴Independently are: c_1-6An alkyl group; c_1-6Alkoxy halo-C_1-6An alkyl group; or halo-C_1-6An alkoxy group;

R⁵is a group of formula (a) or (b):

wherein:

q is 0 or 1;

r is 0 or 1;

y is: NR (nitrogen to noise ratio)⁹(ii) a Or CR¹⁰R¹¹；

R⁶And R⁷Each independently is: hydrogen; or C_1-6An alkyl group; or R⁶And R⁷Together form C_1-2An alkylene group;

R⁸the method comprises the following steps: hydrogen; or C_1-6An alkyl group;

R⁹the method comprises the following steps: hydrogen; or C_1-6An alkyl group;

R¹⁰the method comprises the following steps: hydrogen; or C_1-6An alkyl group; and is

R¹¹The method comprises the following steps: c_1-6An alkyl group; hydroxy-C_1-6An alkyl group; a carboxyl group; carboxy-C_1-6An alkyl group; carboxy-C_1-6An alkyl ester; or carboxy-C_1-6Alkyl radical C_1-6An alkyl ester.

In certain embodiments of formula I, m is 0 or 1.

In certain embodiments of formula I, m is 0.

In certain embodiments of formula I, m is 1.

In certain embodiments of formula I, n is 0 or 1.

In certain embodiments of formula I, n is 0.

In certain embodiments of formula I, n is 1.

In certain embodiments of formula I, p is 0 to 2.

In certain embodiments of formula I, p is 0 or 1.

In certain embodiments of formula I, p is 0.

In certain embodiments of formula I, p is 1.

In certain embodiments of formula I, q is 0.

In certain embodiments of formula I, q is 1.

In certain embodiments of formula I, r is 0.

In certain embodiments of formula I, r is 1.

In certain embodiments of formula I, X is CH.

In certain embodiments of formula I, X is N.

In certain embodiments of formula I, R¹Is hydrogen.

In certain embodiments of formula I, R¹Is C_1-6An alkyl group.

In certain embodiments of formula I, each R is²Independently is C_1-6Alkyl radical, C_1-6Alkoxy or halogen.

In certain embodiments of formula I, each R is²Independently is C_1-6Alkyl or halogen.

In certain embodiments of formula I, R²Is C_1-6An alkyl group.

In certain embodiments of formula I, R³Is C_1-6alkylsulfonyl-C_1-6An alkyl group.

In certain embodiments of formula I, R³Is tetrahydrothienyl-1, 1-oxide-C_1-6An alkyl group.

In certain embodiments of formula I, R³Is tetrahydrothiopyran-1, 1-oxide-C_1-6An alkyl group.

In certain embodiments of formula I, R³The method comprises the following steps: 3-methanesulfonyl-propyl; or 1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-ylmethyl.

In certain embodiments of formula I, R³Is 3-methanesulfonyl-propyl.

In certain embodiments of formula I, R³Is 1, 1-dioxo-tetrahydro-1. lamda.6-thiophen-3-ylmethyl.

In certain embodiments of formula I, each R is⁴Independently is C_1-6Alkyl or halogen.

In certain embodiments of formula I, R⁴Is C_1-6An alkyl group.

In certain embodiments of formula I, R⁵Is a radical of formula (a).

In certain embodiments of formula I, R⁵Is a radical of formula (b).

In certain embodiments of formula I, R⁶And R⁷Each independently is: hydrogen; or C_1-6An alkyl group; or R⁶And R⁷Together form C_1-2An alkylene group.

In a certain embodiment of formula I, R⁶The method comprises the following steps: hydrogen; a carboxyl group; carboxy-C_1-6An alkyl ester.

In certain embodiments of formula I, R⁶Is hydrogen.

In certain embodiments of formula I, R⁶Is C_1-6An alkyl group.

In certain embodiments of formula I, R⁷Is hydrogen or methyl.

In certain embodiments of formula I, R⁷Is hydrogen.

In certain embodiments of formula I, R⁷Is C_1-6An alkyl group.

In certain embodiments of formula I, R⁶And R⁷Together form C_1-2An alkylene group.

In certain embodiments of formula I, R⁶And R⁷Together form a methylene group.

In certain embodiments of formula I, R⁶And R⁷Together form an ethylene group.

In certain embodiments of formula I, R⁸Is hydrogen.

In certain embodiments of formula I, R⁸Is C_1-6An alkyl group.

In certain embodiments of formula I, Y is NR⁹。

In certain embodiments of formula I, Y is CR¹⁰R¹¹。

In certain embodiments of formula I, R⁹Is hydrogen.

In certain embodiments of formula I, R⁹Is C_1-6An alkyl group.

In certain embodiments of formula I, R¹⁰Is hydrogen.

In certain embodiments of formula I, R¹⁰Is C_1-6An alkyl group.

In certain embodiments of formula I, R¹¹The method comprises the following steps: c_1-6An alkyl group; hydroxy-C_1-6An alkyl group; a carboxyl group; carboxy-C_1-6An alkyl group; carboxy-C_1-6An alkyl ester; or carboxy-C_1-6Alkyl radical C_1-6An alkyl ester.

In certain embodiments of formula I, R¹¹The method comprises the following steps: c_1-6An alkyl group; or hydroxy-C_1-6An alkyl group.

In certain embodiments of formula I, R¹¹Is C_1-6An alkyl group.

In certain embodiments of formula I, R¹¹Is hydroxy-C_1-6An alkyl group.

In certain embodiments of formula I, R¹¹Is a carboxyl group.

In certain embodiments of formula I, R¹¹Is a carboxyl group C_1-6An alkyl ester.

In certain embodiments of formula I, R¹¹Is carboxy-C_1-6An alkyl group.

In certain embodiments of formula I, R¹¹Is carboxy-C_1-6alkyl-C_1-6An alkyl ester.

Representative compounds encompassed by and within the scope of the present invention are provided in table 1 below, along with the melting point and IC50 affinity values for the selected compounds.

TABLE 1

TABLE 1

Method of producing a composite material

In one aspect, the present application provides a method of treating a JNK-mediated disorder in a subject having a JNK-mediated disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described above.

In certain embodiments of the methods of treating a JNK-mediated disorder, the JNK-mediated disorder is characterized by cell proliferation.

In certain embodiments of the methods of treating a JNK-mediated disorder, the JNK-mediated disorder is arthritis.

In certain embodiments of the methods of treating a JNK-mediated disorder, the arthritis is rheumatoid arthritis.

In certain embodiments of the methods of treating a JNK-mediated disorder, the JNK-mediated disorder is asthma.

In certain embodiments of the methods of treating a JNK-mediated disorder, the JNK-mediated disorder is diabetes.

In certain embodiments of the methods of treating a JNK-mediated disorder, the JNK-mediated disorder is alzheimer's disease.

In certain embodiments of the methods of treating a JNK-mediated disorder, the JNK-mediated disorder is parkinson's disease.

In certain embodiments of the methods of treating a JNK-mediated disorder, the JNK-mediated disorder is ischemic stroke.

In certain embodiments of the methods of treating a JNK-mediated disorder, the JNK-mediated disorder is cancer.

In certain embodiments of the methods of treating a JNK-mediated disorder, wherein the JNK-mediated disorder is a cancer and the cancer is a brain cancer.

In certain embodiments of the methods of treating a JNK-mediated disorder, wherein the JNK-mediated disorder is a cancer and the cancer is leukemia.

In one aspect, the present application provides a pharmaceutical composition comprising a compound of any one of the above embodiments admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

In another aspect, the present application provides the use of any one of the above compounds for the preparation of a medicament for the therapeutic and/or prophylactic treatment of a JNK-mediated disorder.

In certain embodiments of the use of the above compound for the preparation of a medicament, wherein the JNK-mediated disorder is an autoimmune disorder, an inflammatory disorder, a metabolic disorder, a neurological disease, or cancer.

In certain embodiments of the use of the above compounds for the preparation of a medicament, wherein the JNK-mediated disorder is rheumatoid arthritis, asthma, type II diabetes, alzheimer's disease, parkinson's disease or stroke.

In another aspect, the present application provides a compound of any of the above embodiments for use in treating a JNK-mediated disorder.

The compounds of the invention are JNK modulators and are therefore expected to be effective in the treatment of a wide variety of JNK-mediated diseases. Exemplary JNK-mediated disorders include, but are not limited to, autoimmune diseases, inflammatory diseases, metabolic diseases, neurological diseases, and cancer. Accordingly, the compounds of the present invention may be used to treat one or more of such disorders. In some embodiments, the compounds of the invention may be used to treat JNK mediated diseases, such as rheumatoid arthritis, asthma, type II diabetes, alzheimer's disease, parkinson's disease, or stroke.

Administration and pharmaceutical compositions

The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt or solvate thereof, in association with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.

In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration of agents that serve similar utilities. Suitable dosage ranges are typically from 1 to 500mg per day, preferably from 1 to 100mg per day, and most preferably from 1 to 30mg per day, depending on a number of factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication for which the administration is being made, and the preference and experience of the physician concerned. One of ordinary skill in the art of treating such diseases will be able to determine, without undue experimentation and relying on personal knowledge and the disclosure of the present application, a therapeutically effective amount of a compound of the present invention for a given disease.

The compounds of the invention may be administered in the form of pharmaceutical formulations including those suitable for: oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is generally oral, using a convenient daily dosage regimen which can be adjusted to the degree of affliction.

The compounds of the present invention may be incorporated into pharmaceutical compositions and unit dosage forms with one or more conventional adjuvants, carriers or diluents. The pharmaceutical compositions and unit dosage forms can comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed in the form of solids such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of a sterile injectable solution for parenteral use.

Formulations containing about one (1) milligram of active ingredient per tablet, or more broadly, from about 0.01 to about one hundred (100) milligrams of active ingredient, are accordingly suitable representative unit dosage forms.

The compounds of the present invention may be formulated into a wide variety of orally administered dosage forms. Pharmaceutical compositions and dosage forms may comprise one or more compounds of the present invention or pharmaceutically acceptable salts thereof as an active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid support may be one or more substances which may also act as: diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is usually a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is usually mixed with a carrier having the required binding capacity in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "formulation" is intended to include the formulation of the active compound with encapsulating material as a carrier, providing a capsule in which the active component with or without a carrier is surrounded by a carrier with which it is associated. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted into liquid form preparations immediately prior to use. Emulsions may be prepared in solution, for example in aqueous propylene glycol, or may contain emulsifying agents, for example lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners. Aqueous suspensions may be formulated by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusions or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example as solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preservatives, wetting agents, emulsifying or suspending agents, stabilizing agents and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by sterile isolation of a sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

The compounds of the present invention may be formulated for topical administration to the epidermis as an ointment, cream or lotion, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include: lozenges comprising the active pharmaceutical agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may also be formulated for administration as suppositories. A low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool, and solidified.

The compounds of the present invention may be formulated for vaginal administration. Suitable are known in the art as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient, for example, a carrier.

The subject compounds can be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The formulations may be provided in single or multiple dose forms. In the latter case of a dropper or pipette, this can be achieved by the patient administering an appropriate, predetermined volume of solution or suspension. In the case of a nebulizer, this can be achieved by, for example, a metered spray pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract, and include intranasal administration. The compounds typically have small particle sizes, for example about five (5) microns or less. Such particle sizes may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized container with a suitable propellant, such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dosage of the medicament may be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, for example in capsules or cartridges of, for example, gelatin, or in blister packs, from which the powder may be administered by means of an inhaler.

If desired, the formulations may be prepared with an enteric coating suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated in a transdermal or subcutaneous drug delivery device. These delivery systems are advantageous when sustained release of the compound is desired, and when patient compliance with the treatment regimen is critical. Often the compounds in transdermal delivery systems are adheredOnto a skin-adherent solid support. The compound of interest may also be combined with a penetration enhancer such as lauryl nitrogenA ketone (1-dodecyl azepan-2-one) combination. The sustained release delivery system is inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate the compound in a lipid-soluble membrane such as silicone rubber or a biodegradable polymer such as polylactic acid.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Other suitable pharmaceutical carriers and their formulations are described in: remington: pharmaceutical Science and Practice (Remington: The Science and Practice of Pharmacy 1995, edited by E.W. Martin, Mack publishing company, 19 th edition, Iston, Pa. Representative pharmaceutical formulations containing the compounds of the present invention are described below.

Additional objects, advantages and novel features of the present invention will become apparent to one skilled in the art upon examination of the following examples of the invention, which are not intended to be limiting.

Synthesis of

The compounds of the present invention can be prepared by various methods depicted in the exemplary synthetic reaction schemes shown and described below.

The starting materials and Reagents used in the preparation of these compounds are generally available from commercial suppliers such as Aldrich Chemical Co, or prepared by methods known to those skilled in the art according to the procedures set forth in the references, such as Fieser and Fieser's Reagents for Organic Synthesis; wiley & Sons: new York, 1991, Volumes 1-15; rodd's Chemistry of carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and suppl; and Organic Reactions, Wiley & Sons: new York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some of the methods by which the compounds of the present invention may be synthesized and various modifications may be made to these synthetic reaction schemes and will be suggested to one skilled in the art in view of the disclosure contained herein.

If desired, starting materials and intermediates in the synthesis reaction schemes can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Unless stated to the contrary, the reactions described herein are preferably carried out under the following conditions: the reaction temperature ranges from about-78 ℃ to about 150 ℃, more preferably from about 0 ℃ to about 125 ℃, and most preferably and suitably is about room (or ambient) temperature, e.g., about 20 ℃, under an inert atmosphere at atmospheric pressure.

Scheme a below illustrates one synthetic procedure that may be used to prepare specific compounds of formula I, wherein R is lower alkyl and may be the same or different at each occurrence, and m, n, p, q, R, X, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹As defined herein.

Scheme A

In step 1 of scheme A, an O-alkylation reaction occurs wherein the oxindole compoundaWith halide compoundsbReact to produce indole compoundsc. The reaction may be carried out in the presence of, for example, potassium carbonate and potassium iodide in a polar aprotic solvent such as acetonitrile.

In step 2, indolecWith dichloropyrimidinesdReacted to produce an indole pyrimidine compounde. The reaction of step 2 can be carried out in the presence of HOBt and potassium carbonate in a polar solvent.

In step 3, the compoundeWith cyclohexylaminefReacted to produce an indole pyrimidine amine compoundg. The reaction of step 3 may be carried out in the presence of potassium carbonate under polar solvent conditions.

Compound (I)gIs subjected to hydrolysis in step 4 to give the corresponding carboxylic acid compoundh. The hydrolysis in this step can be accomplished, for example, in the presence of a base such as sodium hydroxide and under polar protic solvent conditions.

Amide formation takes place in step 5, where the compoundhWith aminesiReacting to obtain an amide compoundjWhich are compounds of formula I according to the invention. Amide formation may occur via an acid chloride intermediate (not shown), or by using various amide coupling agents such as ECDI or other carbodiimides.

Many variations to the procedure of scheme a are possible and will suggest themselves to those skilled in the art. Specific details for the preparation of the compounds of the present invention are described in the following examples.

The following abbreviations may be used in the preparations and examples below.

List of abbreviations

Ac₂O acetic anhydride

AcOH acetic acid

BOP benzotriazol-1-yl-Oxy-tris- (dimethylamino) -acetic acidHexafluorophosphates

DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene

DCE 1, 2-dichloroethane

DCM dichloromethane/methylene dichloride

DIPEA diisopropylethylamine

DMA dimethyl acetamide

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

Et₂O diethyl ether

EtOH ethanol/alcohol

EtOAc ethyl acetate

HOBt 1-hydroxybenzotriazole

LDA lithium diisopropylamide

LiHMDS lithium bis (trimethylsilyl) amide

m-CPBA 3-chloroperoxybenzoic acid

MeOH methanol/xylitol

MW microwave

NMP 1-methyl-2-pyrrolidone

PMB 4-methoxybenzyl

PyBOP benzotriazol-1-yl-oxytripyrrolidinylHexafluorophosphates

RT Room temperature

TBME Tert-butyl methyl Ether

TFA trifluoroacetic acid

Tf₂O-Trifluoromethanesulfonic anhydride

THF tetrahydrofuran

TLC thin layer chromatography

Examples

The following preparations and examples are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being exemplary and representative thereof.

Example 1: (1, 1-dioxo-tetrahydro-1. lamda. 6. ang. -thiophen-3-yl) -methanol

LAH (35mL of 1M THF solution) was added dropwise to a solution of 1, 1-dioxo-tetrahydro-1 λ 6-thiophene-3-carboxylic acid (5.0g) in THF (100 mL). The mixture was stirred at room temperature for 5 hours and then cooled in an ice bath. Water (3mL) and NaOH (6mL of a 15% aqueous solution) were added, and the mixture was stirred at room temperature for 60 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to yield 3.59g of (1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-yl) -methanol.

Example 2: toluene-4-sulfonic acid 1, 1-dioxo-tetrahydro-1. lambda. 6-thiophen-3-ylmethyl ester

A mixture of (1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-yl) -methanol (3.59g), 4-tosyl chloride (9.11g) and pyridine 5.8mL) in chloroform (50mL) was heated to 60 ℃ and stirred overnight. The reaction mixture was cooled and diluted with 100mL 1N HCl and extracted with dichloromethane. The combined organic extracts were washed with brine and dried (MgSO)₄) Filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% EtOAc in hexanes) to give 4.012g of toluene-4-sulfonic acid 1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-ylmethyl ester.

Example 3: 4- (3-methylsulfanyl-propoxy) -1- (2-methylsulfanyl-pyrimidin-4-yl) -1H-indole

4- (3-methylthio-propoxy) -1H-indole (400.88g), 2L of 1N K in 250mL THF^tBuO and 381g of 4-chloro-2-methylthio-pyrimidine in 350mL of THF are combined while cooling to keep below 40 ℃ and allowed to stir at room temperature for 1 hour. The solvent was then removed in vacuo and the solid suspended in MeOH, filtered, washed with MeOH and water, and dried to yield 87.56% 4- (3-methylsulfanyl-propoxy) -1- (2-methylsulfanyl-pyrimidin-4-yl) -1H-indole.

Example 4: 1- (2-Methylsulfinyl-pyrimidin-4-yl) -4- (3-methanesulfonyl-propoxy) -1H-indole

MCPBA (204.3g, 77%) in DCM (310mL) and MeOH (155mL) was added dropwise over-1.5H at-5 ℃ to 100.0g4- (3-methylsulfanyl-propoxy) -1- (2-methylsulfanyl-pyrimidin-4-yl) -1H-indole in DCM (590mL) and methanol (145 mL). Additional MCPBA (12.0g) was added at 2 deg.C and after 20 minutes the reaction mixture was diluted with 900mL of MTBE added slowly over 20 minutes at 12 deg.C. The mixture was allowed to stir at 20-22 ℃ for 1.5 h. MTBE (300mL) was then added and after 20 minutes the mixture was filtered, the solid rinsed with MTBE (2x200mL) and the solvent removed in vacuo to give 1- (2-methanesulfinyl-pyrimidin-4-yl) -4- (3-methanesulfonyl-propoxy) -1H-indole (90.2%).

Example 5: 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid methyl ester

4-amino-cyclohexanecarboxylic acid ethyl ester (550g) and 815mL of DIPEA were added to 1- (2-methanesulfinyl-pyrimidin-4-yl) -4- (3-methanesulfonyl-propoxy) -1H-indole (746.7g) in 2.5LDMA and the mixture was allowed to heat to 120 ℃ for 4H before being allowed to cool to room temperature. Water (3L) was added dropwise and the resulting precipitate was collected by filtration and washed with H₂O and MeOH, and dried under vacuum at 48 deg.C overnight to yield 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl]-pyrimidin-2-ylamino } -cyclohexanecarboxylic acid methyl ester (90%).

Example 6: 4- (3-methanesulfonyl-propoxy) -1H-indole

1-chloro-3- (methylsulfonyl) -propane (160g) was added to 1H-indol-4-ol (108.77) in 1L MeCNg) Adding 338g K₂CO₃And 13.36g KI. The reaction mixture was stirred at 80 ℃ overnight, then cooled and filtered through celite. The filtrate was distilled in vacuo and the solvent was replaced with DCM (700 mL). The mixture was filtered and the solvent was removed under vacuum and replaced with MeOH (600 mL). The solvent was partially removed under vacuum at 40 ℃ and crystallization occurred. After cooling, additional MeOH was added and the slurry was filtered. The collected solid was rinsed with cold MeOH and N at 35 deg.C under vacuum₂Drying overnight afforded 4- (3-methanesulfonyl-propoxy) -1H-indole (82%).

Example 7: 1- (2-chloro-pyrimidin-4-yl) -4- (3-methanesulfonyl-propoxy) -1H-indole

A mixture of 4- (3-methanesulfonyl-propoxy) -1H-indole (188.1g), 2, 4-dichloropyrimidine (221.25g), HOBT (20.08g), K₂CO₃(143.68g) and DMA (1.6L) were heated to 85 ℃ for 20 h. IPA (5L) was then added and the mixture was stirred for 20min, then cooled to 0 deg.C for 3h and filtered. The collected solid was rinsed with IPA and water, and the solid was dried under vacuum at 55 ℃ for 4 days to yield 1- (2-chloro-pyrimidin-4-yl) -4- (3-methanesulfonyl-propoxy) -1H-indole (94%).

Example 8: (2-propylsulfanyl-pyrimidin-4-yl) -hydrazine

4-chloro-2-propylthio-pyrimidine (15.03g), hydrazine (10.69g) and potassium carbonate (15.37g) were added to ethanol (150mL) and the mixture was heated to 80 ℃ for 3 hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. Chromatographic purification of the residue: (CH₂Cl₂Hexane, over silica) to give 7.036g of (2-propylsulfanyl-pyrimidin-4-yl) -hydrazine.

Example 9: 4-methoxy-1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazole

(2-propylsulfanyl-pyrimidin-4-yl) -hydrazine (7.036g), 2-fluoro-6-methoxy-4-propylsulfanyl-benzaldehyde 5.524g) and DB 16.373g) were added to DMSO (70mL) and the mixture was stirred at room temperature for 1 hour, then at 80 ℃ for 1 hour. The mixture was cooled, diluted with water, and filtered. The collected solid was washed with water and then dried under reduced pressure to give 4-methoxy-1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazole.

Example 10: 1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazol-4-ol

4-methoxy-1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazole was dissolved in dichloromethane (100mL) and the mixture was cooled to-78 ℃ and stirred. Addition of BBR₃(152.62uL), and the mixture was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane and the combined organic layers were washed with water, saturated NaHCO₃The aqueous solution and brine were washed and dried (MgSO)₄) Filtered and concentrated under reduced pressure to give 1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazol-4-ol.

Example 11: 4- (2-methylsulfanyl-ethoxy) -1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazole

1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazol-4-ol (600mg), potassium carbonate (1.104g), and 1-chloro-2-methylsulfanyl-ethane 401.9mg) were added to NMP (6mL), and the mixture was heated to 80 ℃ for 3 hours. The mixture was cooled, diluted with water and filtered. The collected solid was washed with water and dried under reduced pressure to give 705mg of 4- (2-methylsulfanyl-ethoxy) -1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazole.

Example 12: methanesulfonyl-ethoxy) -1- [2- (propane-1-sulfonyl) -pyrimidin-4-yl ] -1H-indazole

4- (2-methylsulfanyl-ethoxy) -1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazole (705mg) and m-perchlorobenzoic acid (2.109g of 77% solid) were added to dichloromethane (10mL) and the mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 10% aqueous sodium bisulfite and extracted with dichloromethane. The combined organic layers were washed with water, saturated NaHCO₃The aqueous solution and brine were washed and dried (MgSO)₄) Filtered and concentrated under reduced pressure to give 4- (2-methanesulfonyl-ethoxy) -1- [2- (propane-1-sulfonyl) -pyrimidin-4-yl]-1H-indazole.

Example 13: 4- {4- [4- (2-methanesulfonyl-ethoxy) -indazol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ethyl ester

Following the procedure of example 5 generally, 4- {4- [4- (2-methanesulfonyl-ethoxy) -indazol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ethyl ester was prepared by reaction of 4-amino-cyclohexanecarboxylic acid ethyl ester with 4- (2-methanesulfonyl-ethoxy) -1- [2- (propane-1-sulfonyl) -pyrimidin-4-yl ] -1H-indazole.

Example 14: 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid methyl ester

1- (2-chloro-pyrimidin-4-yl) -4- (3-methanesulfonyl-propoxy) -1H-indole (300g), 4-amino-cyclohexanecarboxylic acid ethyl ester HCl salt (155g) and K in NMP (2.35L)₂CO₃(170g) Stirred at 80 ℃ for 5h and then at room temperature overnight. The reaction mixture was then stirred on an ice bath and 2.5L of water was added slowly while stirring and cooling continued until the exothermic reaction was complete. After cooling, the mixture was filtered and the resulting solid was taken up in H₂O rinse and dry overnight under vacuum to give 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl]-pyrimidin-2-ylamino } -cyclohexanecarboxylic acid methyl ester (97%).

Example 15: 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid sodium salt

50% (w/w) NaOH in H₂O (198.95g) in water was added to 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl in IPA (7.5L)]-pyrimidin-2-ylamino } -cyclohexanecarboxylic acid methyl ester (830.0g), and the mixture was allowed to stir at 82 ℃ for 1h, then at room temperature overnight. The mixture is then filtered and the solid is washed withIPA rinse and drying at 60 deg.C for 3 days under vacuum to give 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl]-pyrimidin-2-ylamino } -cyclohexanecarboxylic acid sodium salt (96.9%).

Example 16: 4- (1, 1-dioxo-tetrahydro-1. lamda. 6. ang-thiophen-3-ylmethoxy) -1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indole

1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indol-4-ol (1.56g) and toluene-4-sulfonic acid 1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-ylmethyl ester (2.37g) were added to NMP (20mL), followed by cesium carbonate (5.08 g). The mixture was stirred at 70 ℃ for 60 hours, after which the solvent was removed by distillation. The residue was diluted with 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO)₄) Filtered and concentrated under reduced pressure to give 2.96g of 4- (1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-ylmethoxy) -1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indole.

Example 17: 4- (1, 1-dioxo-tetrahydro-1. lamda. 6. ang-thiophen-3-ylmethoxy) -1- [2- (prop-1-sulfinyl) -pyrimidin-4-yl ] -1H-indole

A solution of 4- (1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-ylmethoxy) -1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indole (1.16g) in dichloromethane (40mL) was cooled to 0 ℃ and m-chlorobenzoic acid (3.58g) was added. The mixture was stirred for 45 minutes and then purified by addition of saturated NaHCO₃The aqueous solution was quenched. The mixture was extracted with dichloromethane and the combined organic layers were dried (MgSO₄) Filtering and concentrating under reduced pressure to obtainTo 1.2g of 4- (1, 1-dioxo-tetrahydro-1. lamda. 6. lamda. -thiophen-3-ylmethoxy) -1- [2- (propane-1-sulfinyl) -pyrimidin-4-yl]-1H-indole.

Example 18: 4- {4- [4- (1, 1-dioxo-tetrahydro-1. lamda. 6. ang. -thiophen-3-ylmethoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ethyl ester

To 4- (1, 1-dioxo-tetrahydro-1. lamda. 6. lamda. -thiophen-3-ylmethoxy) -1- [2- (prop-1-sulfinyl) -pyrimidin-4-yl]1.2g of-1H-indole) and 4-amino-cyclohexanecarboxylic acid ethyl ester HCl salt (1.12g) in NMP (5mL) diisopropylethylamine (1.4mL) was added. The mixture was heated to 80 ℃ for 18 hours, then cooled and poured into 75mL of water. The mixture was extracted with dichloromethane and the combined organic layers were dried (MgSO₄) Filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% EtOAc in hexanes) to give 1.069g of 4- {4- [4- (1, 1-dioxo-tetrahydro-1. lambda.6-thiophen-3-ylmethoxy) -indol-1-yl]-pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ethyl ester

Example 19: 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid sodium salt

50% (w/w) NaOH in H₂O (198.95g) in water was added to 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl in IPA (7.5L)]-pyrimidin-2-ylamino } -cyclohexanecarboxylic acid methyl ester (830.0g), and the mixture was allowed to stir at 82 ℃ for 1h, then at room temperature overnight. The mixture was then filtered and the solids were rinsed with IPA and under vacuumDrying at 60 ℃ for 3 days gave 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl]-pyrimidin-2-ylamino } -cyclohexanecarboxylic acid sodium salt (96.9%).

Example 20: (R) -1- (4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarbonyl) -piperidine-3-carboxylic acid ethyl ester

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid sodium salt (0.4g), (R) -piperidine-3-carboxylic acid ethyl ester (0.165g), BOP (0.537g) and DIPEA (0.56mL) were added to DMF (3mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water, dried under reduced pressure and purified by flash chromatography (DCM/MeOH) to give 39.6mg of (R) -1- (4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarbonyl) -piperidine-3-carboxylic acid ethyl ester, MP ═ 175.0-177.0 ℃.

Other compounds prepared using the above procedure are shown in table 1.

Biological assay

Example 21: in vitro JNK assay

By using [ gamma-³³P]ATP phosphorylates GST-ATF2(19-96) to measure JNK activity. The enzyme reaction was carried out in a final volume of 40. mu.l with ATP and substrate at a concentration of Km in a buffer containing 25mM HEPES, pH 7.5, 2mM dithiothreitol, 150mM NaCl, 20mM MgCl₂0.001% Tween20, 0.1% BSA and 10% DMSO. Human JNK2 α 2 assay contained 1nM enzyme, 1 μ M ATF2, 8 μ MATP and 1uCi [ gamma-³³P]ATP. Human JNK1 α 1 assay containing 2nM enzyme, 1 μ M ATF2, 6 μ M ATP and 1 μ Ci [ γ -³³P]ATP. Human JNK3(Upstate Biotech #14-501M) assay containing 2nM enzyme, 1 μ MATF2, 4 μ M ATP and 1 μ Ci [ γ -³³P]ATP. The enzyme assay is performed in the presence or absence of several compound concentrations. JNK and compound were preincubated for 10min, followed by initiation of enzymatic reaction by addition of ATP and substrate. The reaction mixture was incubated at 30 ℃ for 30 min. At the end of the incubation, 25. mu.l of the reaction mixture was transferred to 150. mu.l of 10% glutathione containing 135mM EDTAThe reaction was stopped with a slurry (Amersham # 27-4574-01). The reaction product was captured on an affinity resin and washed 6 times with phosphate buffered saline on a filter plate (Millipore, MABVNOB50) to remove free radionucleotides. Will be on a microplate scintillation counter (PackardTopcount)³³Binding of P to ATF2 was quantified. Through IC₅₀Value measurement of inhibitory potency of Compounds on JNK, the IC₅₀Values were generated from 10 concentration inhibition curves fitted to the following 3-parameter model: % inhibition-max/(1 + (IC)₅₀/[ inhibitors of the enzyme])^{Slope of}). Data were analyzed on microsoft Excel for parameter evaluation. Representative results are shown in table 1 below:

example 22: TNF α -induced IL-6 production assay in rats:

female Wistar-Han rats obtained from the Charles River Laboratories (Charles River Laboratories) were acclimated for one week and reached a body weight of approximately 101-. Test compound (N ═ 8/compound) was administered to rats by oral gavage 30 minutes prior to intraperitoneal challenge with 0.5 μ g of recombinant rat TNF- α (Biosource). Blood was collected by cardiac puncture 90 minutes after TNF-a challenge. Plasma was prepared using a lithium heparin separator tube (BD microtainer) and frozen at-80 ℃ until analysis. Determination of IL-6 Water Using a rat-specific IL-6ELISA kit (Biosource)And (7) flattening. Determination of percent inhibition and ED₅₀Values (calculated as the dose of compound when TNF- α production was 50% of control values).

Example 23: TNF α -induced IL-6 production assay in rats:

female Wistar-Han rats obtained from the Charles River Laboratories (Charles River Laboratories) were acclimated for one week and reached a body weight of approximately 114-. Compound 18(N ═ 8/dose) was administered subcutaneously to rats 30 minutes prior to intraperitoneal challenge with 0.5 μ g of recombinant rat TNF- α (Biosource). Blood was collected by cardiac puncture 90 minutes after TNF-a challenge. Plasma was prepared using a lithium heparin separator tube (BD microtainer) and frozen at-80 ℃ until analysis. IL-6 levels were determined using a rat-specific IL-6ELISA kit (Biosource). Determination of percent inhibition and ED₅₀Values (calculated as the dose of compound when TNF- α production was 50% of control values).

Example 24: rodent collagen-induced arthritis:

female Lewis rats obtained from Harlan Laboratories (Harlan Laboratories) at the age of 7-8 weeks were acclimated for one week and reached a body weight of approximately 120-140g prior to use. On study day 0, rats were exposed intradermally (i.d.) to the antigen at several sites on the back using 100 μ g of bovine collagen type II (Chondrex) in incomplete Freund's adjuvant emulsion (IFA; 0.1ml total at 2-3 sites). Arthritis induction is usually observed 12-14 days after antigen exposure; however, a booster injection of 100 μ g collagen/IFA (up to 0.1ml total i.d.) was provided at an alternative site on the base or back of the tail on about days 7-10 to synchronize disease induction. Compound dosing can be prophylactic (starting at or 1-2 days prior to boost) or therapeutic (starting after boost and meeting an initial disease score of 1-2-see clinical scores below). Animals were evaluated for disease development and progression over the next 21 days.

Rats were evaluated using a scoring system (described below) using a plethysmometer to measure paw volume for each paw, or caliper to measure paw or joint thickness. Baseline measurements were taken on day 0, starting again at the first signs of swelling, up to three times per week, until the end of the experiment. The score was evaluated for each paw as follows:

1 ═ swollen and/or reddened paw or toe.

2 ═ two or more joints swollen.

Severe swelling of the paw involves more than two joints.

4-severe arthritis of the entire paw and toe.

The arthritis index of each rat was evaluated by summing the four single paw scores, giving a maximum score of 16. To continuously measure the onset and progression of the disease, the paw volume of the hind paw was also determined by using a plethysmometer.

At the end of the study, the hind paws (and other tissues) were collected for gravimetric, histological, cellular and/or molecular analysis. In addition, blood was collected by cardiac puncture, plasma was prepared using a lithium heparin separator tube (BDmicrotainer), and frozen at-70 ℃ until analysis. Levels of inflammatory cytokines (e.g., TNF-. alpha., IL-1 and IL-6) from the plasma or from homogenized joint tissue were determined using a rat-specific ELISA kit (R & D). The level of disease protection or inhibition is determined by combining the changes in clinical score, paw volume and histopathology relative to control animals.

Example 25: rat pharmacokinetic study:

female Wistar/Han (CRL: WI) rats (Charles River, Hollister, Calif.) weighing between 180 and 220g were used. Animals were allowed free access to standard laboratory food and tap water and were housed in a constant temperature-humidity environment. Three rats per dose group (dose region) were dosedIndividual IV bolus doses of 10mg/kg (50% cyclodextrin/water) or individual doses of 10mg/kg oral suspension prepared in an aqueous vehicle containing 0.9% NaCl, 0.5% sodium carboxymethylcellulose, 0.4% polysorbate 80 and 0.9% benzyl alcohol. From each individual CO₂∶O₂(60: 40) anesthetized rats blood was collected via orbital sinus or cardiac puncture at 1, 3, 6, 8 and 24h post-dose. Plasma levels of test compounds were determined by LC/MS method. In this way, an aliquot of plasma was treated by mixing with acetonitrile to precipitate the protein, centrifuged to clarify the supernatant, then further diluted with formate buffer (50mM) and injected onto HPLC. Test compounds were isolated from endogenous interferents and subsequently eluted from the HPLC column for mass spectrometry quantitation.

While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be included within the scope of the appended claims.

Claims (18)

1. A compound of formula I

Or a pharmaceutically acceptable salt thereof,

wherein:

m is 0;

n is 0;

p is 0;

x is CH or N;

R³the method comprises the following steps: c_1-6alkylsulfonyl-C_1-6Alkyl or tetrahydrothienyl-1, 1-oxide-C_1-6An alkyl group;

R⁵is a group of formula (a) or (b):

wherein:

q is 0 or 1;

r is 0 or 1;

y is: NR (nitrogen to noise ratio)⁹；R⁶And R⁷Each independently is: hydrogen, carboxyl; carboxy-C_1-6Alkyl esters or C_1-6An alkyl group; or R⁶And R⁷Together form C_1-2An alkylene group;

R⁸the method comprises the following steps: hydrogen; or C_1-6An alkyl group; and is

R⁹The method comprises the following steps: hydrogen; or C_1-6An alkyl group.

2. The compound of claim 1, wherein,

m is 0;

n is 0;

p is 0;

x is CH or N;

R³the method comprises the following steps: c_1-6alkylsulfonyl-C_1-6Alkyl or tetrahydrothienyl-1, 1-oxide-C_1-6An alkyl group; r⁵Is a group of formula (a) or (b):

wherein:

q is 0 or 1;

r is 0 or 1;

y is: NR (nitrogen to noise ratio)⁹；R⁶And R⁷Each independently is: hydrogen; or C_1-6An alkyl group; or R⁶And R⁷Together form C_1-2An alkylene group;

R⁸the method comprises the following steps: hydrogen; or C_1-6An alkyl group; and is

R⁹The method comprises the following steps: hydrogen; or C_1-6An alkyl group.

3. The compound according to any one of claims 1 to 2, wherein q is 1.

4. The compound according to any one of claims 1 to 2, wherein q is 0.

5. The compound according to any one of claims 1 to 4, wherein X is CH.

6. The compound according to any one of claims 1 to 4, wherein X is N.

7. A compound according to any one of claims 1 to 6, wherein R³Is C_1-6alkylsulfonyl-C_1-6An alkyl group.

8. A compound according to any one of claims 1 to 6, wherein R³Is tetrahydrothienyl-1, 1-oxide-C_1-6An alkyl group.

9. A compound according to any one of claims 1 to 8, wherein R⁵Is a radical of formula (a).

10. A compound according to any one of claims 1 to 8, wherein R⁵Is a radical of formula (b).

11. The compound of claim 1, wherein the compound is selected from the group consisting of:

(4- {4- [4- (1, 1-dioxo-tetrahydro-1. lambda.) -⁶-thien-3-ylmethoxy) -indol-1-yl]-pyrimidin-2-ylamino } -cyclohexyl) - ((R) -4-ethyl-3-methyl-piperazin-1-yl) -methanone;

(4- {4- [4- (1, 1-dioxo-tetrahydro-1. lambda.) -⁶-thien-3-ylmethoxy) -indol-1-yl]-pyrimidin-2-ylamino } -cyclohexyl) - ((S) -4-ethyl-3-methyl-piperazin-1-yl) -methanone;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ((R) -1-propyl-pyrrolidin-3-yl) -amide;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ((R) -1-ethyl-pyrrolidin-3-yl) -amide;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ((S) -1-ethyl-pyrrolidin-3-yl) -amide;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ((R) -1-propyl-piperidin-3-yl) -amide;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ((R) -1-ethyl-piperidin-3-yl) -amide;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ((S) -1-propyl-piperidin-3-yl) -amide;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ((S) -1-ethyl-piperidin-3-yl) -amide;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid methyl- (1-methyl-piperidin-2-ylmethyl) -amide;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid (1-ethyl-pyrrolidin-2-ylmethyl) -amide;

(1R, 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl- (4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexyl) -methanone;

(4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexyl) - (8-methyl-3, 8-diaza-bicyclo [3.2.1] oct-3-yl) -methanone;

(4- {4- [4- (3-methanesulfonyl-propoxy) -indazol-1-yl ] -pyrimidin-2-ylamino } -cyclohexyl) - ((S) -3-methyl-piperazin-1-yl) -methanone;

(4- {4- [4- (3-methanesulfonyl-propoxy) -indazol-1-yl ] -pyrimidin-2-ylamino } -cyclohexyl) - ((R) -3-methyl-piperazin-1-yl) -methanone;

(4- {4- [4- (1, 1-dioxo-tetrahydro-1. lambda.) -⁶-thiophen-3-ylmethoxy) -indazol-1-yl]-pyrimidin-2-ylamino } -cyclohexyl) - ((S) -3-methyl-piperazin-1-yl) -methanone;

(4- {4- [4- (1, 1-dioxo-tetrahydro-1. lambda.) -⁶-thiophen-3-ylmethoxy) -indazol-1-yl]-pyrimidin-2-ylamino } -cyclohexyl) - ((S) -3-methyl-piperazin-1-yl) -methanone;

(3, 3-dimethyl-piperazin-1-yl) - (4- {4- [4- (1, 1-dioxo-tetrahydro-1. lambda⁶-thien-3-ylmethoxy) -indol-1-yl]-pyrimidin-2-ylamino } -cyclohexyl) -methanone;

4- {4- [4- (1, 1-dioxo-tetrahydro-1. lamda.) -⁶-thien-3-ylmethoxy) -indol-1-yl]-pyrimidin-2-ylamino } -cyclohexanecarboxylic acid (1-ethyl-piperidin-3-yl) -amide;

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ((S) -1-ethyl-pyrrolidin-2-ylmethyl) -amide; and

4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -pyrimidin-2-ylamino } -cyclohexanecarboxylic acid ((R) -1-ethyl-pyrrolidin-2-ylmethyl) -amide.

12. A composition comprising a compound according to any one of claims 1-11 in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent.

13. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of a JNK-mediated disorder.

14. The use according to claim 13, wherein the JNK-mediated disorder is arthritis.

15. Use according to claim 14, wherein the arthritis is rheumatoid arthritis.

16. The use according to claim 13, wherein the JNK-mediated disorder is asthma.

17. The use according to claim 13, wherein the JNK-mediated disorder is diabetes.

18. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of an inflammatory disorder.