Patent Grant
8642808
The present invention provides compounds, pharmaceutical compositions containing one or more of those compounds or their pharmaceutically acceptable salts, which are effective in inhibiting the binding or function of various chemokines to receptors, such the chemokine TECK to the CCR9 receptor. As antagonists or modulators for the CCR9 receptor, the compounds and compositions have utility in treating inflammatory and immune disorder conditions and diseases.
Chemokines are chemotactic cytokines that are released by a wide variety of cells and attract various types of immune system cells, such as macrophages, T cells, eosinophils, basophils and neutrophils, to sites of inflammation (reviewed in Schall, Cytokine, 3:165-183 (1991), Schall, et al., Curr. Opin. Immunol., 6:865 873 (1994) and Murphy, Rev. Immun., 12:593-633 (1994)). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca2+]), granule exocytosis, integrin up-regulation, formation of bioactive lipids (e.g., leukotrienes) and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
T lymphocyte (T cell) infiltration into the small intestine and colon has been linked to the pathogenesis of coeliac diseases, food allergies, rheumatoid arthritis, human inflammatory bowel diseases (IBD) which include Crohn's disease and ulcerative colitis. Blocking trafficking of relevant T cell populations to the intestine can lead to an effective approach to treat human IBD. More recently, chemokine receptor 9 (CCR9) has been noted to be expressed on gut-homing T cells in peripheral blood, elevated in patients with small bowel inflammation such as Crohn's disease and celiac disease. The only CCR9 ligand identified to date, TECK (thymus-expressed chemokine) is expressed in the small intestine and the ligand receptor pair is now thought to play a pivotal role in the development of IBD. In particular, this pair mediates the migration of disease causing T cells to the intestine. See for example, Zaballos, et al., J. Immunol., 162(10):5671-5675 (1999); Kunkel, et al., J. Exp. Med. 192(5):761-768 (2000); Papadakis, et al., J. Immunol., 165(9):5069-5076 (2000); Papadakis, et al., Gastroenterology, 121(2):246-254 (2001); Campbell, et al., J. Exp. Med., 195(1):135-141 (2002); Wurbel, et al., Blood, 98(9):2626-2632 (2001); and Uehara, et al., J. Immunol, 168(6):2811-2819 (2002).
Compounds that modulate the function of chemokine receptors are attractive as therapeutic agents for the treatment of inflammatory and other conditions and diseases associated with chemokine receptor activation.
The present invention is directed to compounds and pharmaceutically acceptable salts thereof, compositions, and methods useful in modulating chemokine activity. The compounds and salts thereof, compositions, and methods described herein are particularly useful in modulating CCR9 chemokine activity.
In one embodiment, the modulators of the present invention are of the formula (I):
where X, Y and Z are as defined below. Salts and N-oxides of these compounds are also within the scope of the invention.
In another aspect, the present invention provides compositions useful in modulating chemokine activity. In one embodiment, a composition according to the present invention comprises a modulator according to the invention and a pharmaceutically acceptable carrier or excipient.
In yet another aspect, the present invention provides a method of modulating chemokine function in a cell, comprising contacting the cell with a therapeutically effective amount of a modulator or composition according to the invention.
In still another aspect, the present invention provides a method for treating a chemokine-mediated condition or disease, comprising administering to a subject a safe and effective amount of a modulator or composition according to the invention.
In addition to the compounds provided herein, the present invention further provides pharmaceutical compositions containing one or more of these compounds, as well as methods for the use of these compounds in therapeutic methods, primarily to treat diseases associated with CCR9 signaling activity.
General
The present invention is directed to compounds and salts thereof, compositions and methods useful in the modulation of chemokine receptor function, particularly CCR9 function. Modulation of chemokine receptor activity, as used herein in its various forms, is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism of the activity associated with a particular chemokine receptor, preferably the CCR9 receptor. Accordingly, the compounds of the present invention are compounds which modulate at least one function or characteristic of mammalian CCR9, for example, a human CCR9 protein. The ability of a compound to modulate the function of CCR9, can be demonstrated in a binding assay (e.g., ligand binding or agonist binding), a migration assay, a signaling assay (e.g., activation of a mammalian G protein, induction of rapid and transient increase in the concentration of cytosolic free calcium), and/or cellular response assay (e.g., stimulation of chemotaxis, exocytosis or inflammatory mediator release by leukocytes).
Abbreviations and Definitions
When describing the compounds, compositions, methods and processes of this invention, the following terms have the following meanings, unless otherwise indicated.
“Alkyl” by itself or as part of another substituent refers to a hydrocarbon group which may be linear, cyclic, or branched or a combination thereof having the number of carbon atoms designated (i.e., C1-8 means one to eight carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. Alkyl groups can be substituted or unsubstituted, unless otherwise indicated. Examples of substituted alkyl include haloalkyl, thioalkyl, aminoalkyl, and the like.
“Alkenyl” refers to an unsaturated hydrocarbon group which may be linear, cyclic or branched or a combination thereof. Alkenyl groups with 2-8 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3 carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, cyclohexenyl, cyclopentenyl and the like. Alkenyl groups can be substituted or unsubstituted, unless otherwise indicated.
“Alkynyl” refers to an unsaturated hydrocarbon group which may be linear, cyclic or branched or a combination thereof. Alkynyl groups with 2-8 carbon atoms are preferred. The alkynyl group may contain 1, 2 or 3 carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like. Alkynyl groups can be substituted or unsubstituted, unless otherwise indicated.
“Aryl” refers to a polyunsaturated, aromatic hydrocarbon group having a single ring (bicyclic) or multiple rings (preferably bicyclic) which can be fused together or linked covalently. Aryl groups with 6-10 carbon atoms are preferred. Examples of aryl groups include phenyl and naphthalene-1-yl, naphthalene-2-yl, biphenyl and the like. Aryl groups can be substituted or unsubstituted, unless otherwise indicated.
“Halo” or “halogen”, by itself or as part of a substituent refers to a chlorine, bromine, iodine, or fluorine atom. Additionally, “haloalkyl”, as a substituted alkyl group, refers to a monohaloalkyl or polyhaloalkyl group, most typically substituted with from 1-3 halogen atoms. Examples include 1-chloroethyl, 3-bromopropyl, trifluoromethyl and the like.
“Heterocyclyl” refers to a saturated or unsaturated non-aromatic group containing at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen or sulfur. Preferably, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Examples of heterocycle groups include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine and the like. Preferred heterocyclic groups are monocyclic, though they may be fused or linked covalently to an aryl or heteroaryl ring system.
Exemplary heterocyclic groups may be represented by formula (AA) below:
where formula (AA) is attached via a free valence on either CR20R21, CR22R23, M1 or M2;
M1 represents O, NR24, or S(O)l;
M2 represents CR25R26, O, S(O)l, or NR24;
l is 0, 1 or 2;
j is 1, 2 or 3;
k is 1, 2 or 3,
with the proviso that j+k is 3, 4, or 5; and
R20, R21, R22, R23, R24, R25, and R26 are independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, —COR27, —CO2R27, —C(O)NR27R28, —NR27COR28, —S(O)2R28, —S(O)2NR28R29, —NS(O)2R28R29—NR28R29, —OR28, —V1COR28, —V1CO2R28, —V1C(O)NR28R29, —V1NR28COR29, —V1S(O)2R28, —V1S(O)2NR28R29, —V1NS(O)2R28R29, —V1NR28R29, and —V1OR28, where V1 is a member selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene; and R27, R28 and R29 are independently selected from the group consisting of hydrogen and C1-8 alkyl, and where the aliphatic portions of each of the R20, R21, R22, R23, R24, R25, R26, R27, R28 and R29 substituents are optionally substituted with from one to three members selected from the group consisting of halogen, —OH, —OR30, —OC(O)NHR30, —OC(O)NR30R31, —SH, —SR30, —S(O)R30, —S(O)2R30—S(O)2NHR30, —S(O)2NR30R31, —NHS(O)2R30, —NR30S(O)2R31, —C(O)NH2, —C(O)NHR30, —C(O)NR30R31, —C(O)R30, —NHC(O)R30, —NR30C(O)R31, —NHC(O)NH2, —NR30C(O)NH2, —NR30C(O)NHR31, —NHC(O)NHR30, —NR30C(O)NR30R31, —NHC(O)NR30R31, —CO2H, —CO2R30, —NHCO2R30, —NR30CO2R31, —CN, —NO2, —NH2, —NHR30, —NR30R31, —NR30S(O)NH2 and —NR30S(O)2NHR31, where R30 and R31 are independently an unsubstituted C1-6 alkyl. Additionally, any two of R20, R21, R22, R23, R24, R25, and R26 may be combined to form a bridged or spirocyclic ring system.
Preferably, the number of R20+R21+R22+R23 groups that are other than hydrogen is 0, 1 or 2. More preferably, R20, R21, R22, R23, R24, R25, and R26 are independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C1-8 alkyl, —C(O)R28, —CO2R28, —C(O)NR28R29, —NR28C(O)R29, —S(O)2R28, —S(O)2NR28R29, —NS(O)2R28R29, —NR28R29, and —OR28, where R28 and R29 are independently selected from the group consisting of hydrogen and unsubstituted C1-8 alkyl; and where the aliphatic portions of each of the R20, R21, R22, R23, R24, R25 and R26 substituents are optionally substituted with from one to three members selected from the group consisting of halogen, —OH, —OR30, —OC(O)NHR30, —OC(O)NR30R31, —SH, —SR30, —S(O)R30, —S(O)2R30, —S(O)2NH2, —S(O)2NHR30, —S(O)2NR30R31, —NHS(O)2R30, —NR30S(O)2R31, —C(O)NH2, —C(O)NHR30, —C(O)NR30R31, —C(O)R30, —NHC(O)R30, —NR30C(O)R31, —NHC(O)NH2, —NR30C(O)NH2, —NR30C(O)NHR31, —NHC(O)NHR30, —NR30C(O)NR30R31, —NHC(O)NR30R31, —CO2H, —CO2R30, —NHCO2R30, —NR30CO2R31, —CN, —NO2, —NH2, —NHR30, —NR30R31, —NR30S(O)NH2 and —NR30S(O)2NHR31, where R30 and R31 are independently an unsubstituted C1-6 alkyl.
More preferably, R20, R21, R22, R23, R24, R25, and R26 are independently hydrogen or C1-4alkyl. In another preferred embodiment, at least three of R20, R21, R22, R23, R24, R25, and R26 are hydrogen.
“Heteroaryl” refers to an aromatic group containing at least one heteroatom. Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl or thienyl. Preferred heteroaryl groups are those having at least one aryl ring nitrogen atom, such as quinolinyl, quinoxalinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, indolyl, quinolyl, isoquinolyl and the like. Preferred 6-ring heteroaryl systems include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl and the like. Preferred 5-ring heteroaryl systems include isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl and the like.
Heterocyclyl and heteroaryl can be attached at any available ring carbon or heteroatom. Each heterocyclyl and heteroaryl may have one or more rings. When multiple rings are present, they can be fused together or linked covalently. Each heterocyclyl and heteroaryl must contain at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen or sulfur. Preferably, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Heterocyclyl and heteroaryl groups can be substituted or unsubstituted, unless otherwise indicated. For substituted groups, the substitution may be on a carbon or heteroatom. For example, when the substitution is ═O, the resulting group may have either a carbonyl (—C(O)—) or a N-oxide (—N+—O−) or —S(O)— or —S(O)2—.
Suitable substituents for substituted alkyl, substituted alkenyl, and substituted alkynyl include halogen, —CN, —CO2R′, —C(O)R′, —C(O)NR′R″, oxo (═O or —O−), —OR′, —OC(O)R′, —OC(O)NR′R″-NO2, —NR′C(O)R″, —NR′″C(O)NR′R″, —NR′R″, —NR′CO2R″, —NR′S(O)2R′″, —SR′, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —SiR′R″R′″, —N3, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl, in a number ranging from zero to (2 m′+1), where m′ is the total number of carbon atoms in such radical.
Suitable substituents for substituted aryl, substituted heteroaryl and substituted heterocyclyl include halogen, —CN, —CO2R′, —C(O)R′, —C(O)NR′R″, oxo (═O or —O−), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO2, —NR′C(O)R″, —NR′C(O)NR′R″, —NR′R″, —NR′CO2R″, —NR′S(O)2R″, —SR′, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N3, substituted or unsubstituted C1-8 alkyl group, substituted or unsubstituted C6-10 aryl group, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl, in a number ranging from zero to the total number of open valences on the aromatic ring system.
As used above, R′, R″ and R′″ each independently refer to a variety of groups including hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted aryloxyalkyl. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring (for example, —NR′R″ includes 1-pyrrolidinyl and 4-morpholinyl).
Two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)—(CH2)q—U—, where T and U are independently —NR″″—, —O—, —CH2— or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A′-(CH2)r—B′—, where A′ and B′ are independently —CH2—, —O—, —NR″″—, —S—, —S(O)—, —S(O)2—, —S(O)2NR″″— or a single bond, and r is an integer from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CH2)s—X—(CH2)t—, where s and t are independently integers of from 0 to 3, and X is —O—, —NR″″—, —S—, —S(O)—, —S(O)2—, or —S(O)2NR′—. The substituent R″″ in —NR″″— and —S(O)2NR″″— is hydrogen or unsubstituted C1-6 alkyl.
“Heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
“Pharmaceutically acceptable” carrier, diluent, or excipient is a carrier, diluent, or excipient compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
“Pharmaceutically-acceptable salt” refers to a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary, tertiary and quaternary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Salts derived from pharmaceutically-acceptable acids include acetic, ascorbic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, fumaric, gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like.
Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al, “Pharmaceutical Salts”, J. Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
“Salt thereof” refers to a compound formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Preferably, the salt is a pharmaceutically-acceptable salt, although this is not required for salts of intermediate compounds which are not intended for administration to a patient.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
“Therapeutically effective amount” refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
“Treating” or “treatment” as used herein refers to the treating or treatment of a disease or medical condition (such as a bacterial infection) in a patient, such as a mammal (particularly a human or a companion animal) which includes: ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient; suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or alleviating the symptoms of the disease or medical condition in a patient.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, both solvated forms and unsolvated forms are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms (i.e., as polymorphs). In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Compounds that Modulate CCR9 Activity
The present invention provides compounds that modulate CCR9 activity. Specifically, the invention provides compounds having anti-inflammatory or immunoregulatory activity. The compounds of the invention are thought to interfere with inappropriate T-cell trafficking by specifically modulating or inhibiting a chemokine receptor function. Chemokine receptors are integral membrane proteins which interact with an extracellular ligand, such as a chemokine, and mediate a cellular response to the ligand, e.g., chemotaxis, increased intracellular calcium ion concentration, etc. Therefore, modulation of a chemokine receptor function, e.g., interference with a chemokine receptor ligand interaction, will modulate a chemokine receptor mediated response, and treat or prevent a chemokine receptor mediated condition or disease. Modulation of a chemokine receptor function includes both inducement and inhibition of the function. The type of modulation accomplished will depend on the characteristics of the compound, i.e., antagonist or full, partial or inverse agonist.
Without intending to be bound by any particular theory, it is believed that the compounds provided herein interfere with the interaction between a chemokine receptor and one or more cognate ligands. In particular, it is believed that the compounds interfere with the interaction between CCR9 and a CCR9 ligand, such as TECK. Compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein and salts thereof.
For example, compounds of this invention act as potent CCR9 antagonists, and this antagonistic activity has been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR9. Accordingly, the compounds provided herein are useful in pharmaceutical compositions, methods for the treatment of CCR9-mediated diseases, and as controls in assays for the identification of competitive CCR9 antagonists.
CCR9 Antagonists as Treatments of Cancer
In additional to inflammatory diseases, cancers that are caused by uncontrolled proliferation of T cells may be treated with a CCR9 antagonist. Certain types of cancer are caused by T cells expressing chemokine receptor CCR9. For example, thymoma and thymic carcinoma are diseases in which cancer cells are found in the tissues of the thymus, an organ where lymphocyte development occurs. T cells in the thymus, called thymocytes, are known to express functional CCR9; its ligand is highly expressed in the thymus. Another example is the acute lymphocytic leukemia (ALL), also called acute lymphoblastic leukemia and acute, is a common leukemia, which can occur in children as well as adults. Recent studies have shown that T cells in patients with ALL selectively express high level of CCR9 (Qiuping Z et al., Cancer Res. 2003, 1; 63(19):6469-77).
Chemokine receptors have been implicated in cancer. Although the exact mechanisms of chemokine receptors' involvements have yet to be full understood, such receptors are known to promote the growth of cancer cells (proliferation), facilitate the spread of cancer cells (metastasis) or help them resist program cell death (apoptosis). For example, CCR9 in a cancer T cell line MOLT-4 provides the cells with a survival signal, allowing them to resist apoptosis (Youn B S, et al., Apoptosis. 2002 June; 7(3):271-6). In the cases of thymoma, thymic carcinoma and acute lymphocytic leukemia, it is likely that CCR9 plays a key in the survival and proliferation these cells. Thus, blocking the signaling of CCR9 should help prevent their expansion and metastasis.
Modulators of the Invention
The modulators of the present invention are of the following formula (I) or a salt or N-oxide thereof:
L is —C(O)—, —S—, —S(O)— or —S(O)2—;
X represents from 1 to 5 substituents independently selected from the group consisting of halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CN, —NO2, —C(O)R1, —CO2R1, —C(O)NR1R2, —OR1, —OC(O)R1, —OC(O)NR1R2, —NO2, —NR3C(O)R1, —NR3C(O)NR1R2, —NR1R2, —NR3CO2R1, —NR3S(O)2R1, —SR1, —S(O)R1, —S(O)2R1, —S(O)2NR1R2, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
suitable substituted C1-8 alkyl, substituted C2-8 alkenyl, or substituted C2-8 alkynyl may have from 1-5 substituents independently selected from the group consisting of halogen, —OH, —CN, —NO2, ═O, —OC(O)R1, —OR1, —C(O)R1, —C(O)NR1R2, —OC(O)NR1R2, —NR2C(O)R1, —NR1C(O)NR2R3, —CO2R1, —NR1R2, —NR2CO2R1, —SR1, —S(O)R1, —S(O)2R1, —S(O)2NR1R2, —NR1S(O)2R2, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl;
suitable substituted C6-10 aryl, substituted 5- to 10-membered heteroaryl, or substituted 3- to 10-membered heterocyclyl, may have from 1-4 substituents independently selected from the group consisting of halogen, unsubstituted C1-8 alkyl, unsubstituted C1-8 haloalkyl, unsubstituted 4- to 7-membered heterocycle, —CN, —NO2, —OR1, ═O, —OC(O)R1, —CO2R1, —C(O)R1, —C(O)NR1R2, —OC(O)NR1R2, —NR2C(O)R1, —NR1C(O)NR2R3, —NR1R2, —NR2CO2R1, —SR1, —S(O)R1, —S(O)2R1, —S(O)2NR1R2, and —NR1S(O)2R, with the proviso that if X represents a heterocycle, suitable substituents preferably do not include another heterocycle;
R1, R2 and R3 are each independently selected from the group consisting of hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl-C1-4 alkyl, aryloxy-C1-4 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycle; or R1 and R2, R3 and R2, or R1 and R3 may together with the atom(s) to which they are attached, form an substituted or unsubstituted 5-, 6-, or 7-membered ring;
and the aliphatic and aromatic portions of R1, R2 and R3 are optionally further substituted with from 1 to 3 substituents selected from the group consisting of halogen, —OH, —ORm, —OC(O)NHRm, —OC(O)NRmRn, —SH, —SRm, —S(O)Rm, —S(O)2Rm, —S(O)2NH2, —S(O)2NHRm, —S(O)2NRmRn, —NHS(O)2Rm, —NRmS(O)2Rn, —C(O)NH2, —C(O)NHRm, —C(O)N(Rm)2, —C(O)Rm, —NHC(O)Rm, —NRmC(O)Rn, —NHC(O)NH2, —NRmC(O)NH2, —NRmC(O)NHRn, —NHC(O)NHRm, —NRoC(O)NRmRn, —NHC(O)N(Rm)2, —CO2H, —CO2Rm, NHCO2Rm, —NRmCO2Rn, —CN, —NO2, —NH2, —NHRn, —NRmRn, —NRmS(O)NH2 and —NRmS(O)2NHRn, where Rm, Rn, and Ro are each independently unsubstituted C1-6 alkyl.
Y represents from 1 to 4 substituents, each independently selected from the group consisting of halogen, —CN, —NO2, —OR4, —C(O)R4, —CO2R4, —SR4, —S(O)R4, —S(O)2R4, and unsubstituted or substituted C1-4 alkyl;
suitable substituted C1-4 alkyl may have from 1 to 3 substituents independently selected from the group consisting of halogen, —OR4, —CN, —NO2, ═O, —OC(O)R4, —CO2R4, —C(O)R4, —CONR4R5, —OC(O)NR4R5, —NR4C(O)R5, —NR4C(O)NR5R6, —NR4R5, —NR4CO2R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, and —NR4SO2R5;
R4, R5 and R6 are each independently selected from the group consisting of hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C6-10 aryl, and 5- to 10-membered heteroaryl; or R4 and R5, R6 and R4 or R5 and R6, together with the atom to which they are attached, form a substituted or unsubstituted 5-, 6- or 7-membered ring;
and the aliphatic and aromatic portions of R4, R5, and R6 are optionally further substituted with from 1 to 3 substituents selected from the group consisting of halogen, —OH, —ORm, —OC(O)NHRm, —OC(O)NRmRn, —SH, —SRm, —S(O)Rm, —S(O)2Rm, —S(O)2NH2, —S(O)2NHRm, —S(O)2NRmRn, —NHS(O)2Rm, —NRmS(O)2Rn, —C(O)NH2, —C(O)NHRm, —C(O)N(Rm)2, —C(O)Rm, —NHC(O)Rm, —NRmC(O)Rn, —NHC(O)NH2, —NRmC(O)NH2, —NRmC(O)NHRn, —NHC(O)NHRm, —NRoC(O)NRmRn, —NHC(O)N(Rm)2, —CO2H, —CO2Rm, —NHCO2Rm, —NRmCO2Rn, —CN, —NO2, —NH2, —NHRm, —NRmRn, —NRmS(O)NH2 and —NRmS(O)2NHRn, where Rm, Rn, and Ro are each independently unsubstituted C1-6 alkyl;
Z represents from 0 to 5 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, —CN, —NO2, —OR7, —OC(O)R7, —CO2R7, —C(O)R7, —CONR7R8, —OC(O)NR7R8, —NR7C(O)R8, —NR7C(O)NR8R6, —NR7R8, —NR7CO2R8, —SR7, S(O)R7, —S(O)2R7, —SO2NR7R8, —NR7SO2R8, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl and unsubstituted or substituted 3- to 10-membered heterocyclyl;
suitable substituted C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl substituents on Z may have from 1 to 5 substituents independently selected from the group consisting of halogen, —OR7, —CN, —NO2, ═O, —CN, —NO2, —OC(O)R7, —CO2R7, —C(O)R7, —CONR7R8, —OC(O)NR7R8, —NR7C(O)R8, —NR7C(O)NR8R9, —NR7R8, —NR7CO2R8, —SR7, —S(O)R7, —S(O)2R7, —SO2NR7R8, —NR7SO2R8, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted 4- to 7-membered heterocyclyl;
suitable substituted aryl, heteroaryl and heterocyclyl substituents on Z may have from 1 to 5 substituents independently selected from the group consisting of halogen, —OR7, —CN, —NO2, ═O, —OC(O)R7, —OC(O)R7, —CO2R7, —C(O)R7, —CONR7R8, —OC(O)NR7R8, —NR7C(O)R8, —NR7C(O)NR8R9, —NR7R8, —NR7CO2R8, —SR7, —SOR7, —SO2R7, —SO2NR7R8, —NR7SO2R8, unsubstituted 4- to 7-membered heterocyclyl, unsubstituted C1-8 alkyl and unsubstituted C1-8 haloalkyl;
R7, R8 and R9 are each independently selected from the group consisting of hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C6-10 aryl, 5 to 10 membered heteroaryl and 3- to 10-membered heterocycle, or R7 and R8; or R8 and R9, or R7 and R9, may together with the atom(s) to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring, and;
where the aliphatic and aromatic portions of R7, R8 and R9 are optionally further substituted with 1 to 3 substituents selected from the group consisting of halogen, —OH, —ORm, —OC(O)NHRm, —OC(O)NRmRn, —SH, —SRm, —S(O)Rm, —S(O)2Rm, —S(O)2NH2, —S(O)2NHRm, —S(O)2NRmRn, —NHS(O)2Rm, —NRmS(O)2Rn, —C(O)NH2, —C(O)NHRm, —C(O)N(Rm)2, —C(O)Rm, —NHC(O)Rm, —NRmC(O)Rn, —NHC(O)NH2, —NRmC(O)NH2, —NRmC(O)NHRn, —NHC(O)NHRm, —NRoC(O)NRmRn, —NHC(O)N(Rm)2, —CO2H, —CO2Rm, NHCO2Rm, —NRmCO2Rn, —CN, —NO2, —NH2, —NHRn, —NRmRn, —NRmS(O)NH2 and —NRmS(O)2NHRn; where Rm, Rn, and Ro are each independently unsubstituted C1-6 alkyl;
with the proviso that excluded from the scope of the formulae (I-XVIII) are the following compounds:
The following compounds are known, but not as chemokine modulators, and more specifically not as CCR9 modulators (these compounds are explicitly excluded from modulators of formula (I)):
Modulators of the present invention preferably exclude compounds where:
L is carbonyl, at least one X is 2- or 4-methoxy, Y is 4-halo, and Z is 2-halo or hydrogen;
L is carbonyl, at least one X is 4-methoxy, Y is 4-amino, and Z is hydrogen;
L is carbonyl; X is 2,4,6-trialkyl, 4-ethyl, or 4-acetamido; Y is 4-chloro; and Z is hydrogen;
L is carbonyl, X is 2-amino, Y is 4-amino or 4-chloro; and Z is hydrogen;
L is carbonyl; X is 4-halo; Y is hydrogen, 4-chloro or 4-methyl; and Z is hydrogen; and
L is carbonyl; X is 2-choro; Y is 4-chloro; and Z is 2-choro.
In one embodiment, L is —CO—.
In another embodiment, the present invention provides compounds of the formula (II) and pharmaceutically acceptable salts and N-oxides thereof:
where L is defined as in formula (I);
X1, X2, X3, X4, and X5 are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OR1, —C(O)R1, —CO2R1, —O(CO)R1, —OC(O)NR1R2, —SR1, —SOR1, —SO2R1, —NR1R2, —NR1C(O)R2, —NR1C(O)2R2, —NR1(CO)NR1R2, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted 4- to 7 membered heterocyclyl, with the proviso that one of X1, X2, X3, X4, or X5 is other than hydrogen.
When X1, X2, X3, X4, or X5 is substituted C1-8 alkyl, substituted C2-8 alkenyl, or substituted C2-8 alkynyl, it may have from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, ═O, —OC(O)R1, —OR1, —C(O)R1, —CONR1R2, —NR2C(O)R1, —CO2R1, —NR1R2, —SR1, —S(O)R1, —S(O)2R1, —NR1SO2R2, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, and unsubstituted or substituted heteroaryl. Preferred substituted C1-8 alkyl have from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, ═O, —OR1, —C(O)R1, —CONR1R2, —NR2C(O)R1, —CO2R1, —NR1R2, —SO2R1, unsubstituted or substituted 5- or 6-membered heteroaryl and 5- or 6-membered unsubstituted or substituted heterocyclyl.
When X1, X2, X3, X4, or X5 is substituted C6-10 aryl, substituted 5- or 6-membered heteroaryl, or substituted 4- to 7-membered heterocycle, it may have from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —OR1, ═O, —OC(O)R1, —CO2R1, —C(O)R1, —CONR1R2, —NR2C(O)R1, —NR1R2, —SR1, —S(O)R1, —S(O)2R1, —NR1SO2R2, unsubstituted C1-8 alkyl, and unsubstituted C1-8 haloalkyl.
When X1, X2, X3, X4, or X5 is substituted 5- or 6-membered heteroaryl or substituted 4- to 7-membered heterocyclyl, it preferably has from 1 to 3 substituents independently selected from the group consisting of halogen, —OR1, —C(O)R1, —CONR1R2, —NR2C(O)R1, —NR1R2, —SO2R1, unsubstituted or substituted C1-8 alkyl, and unsubstituted or substituted C1-8 haloalkyl.
Y1, Y2, Y3 and Y4 are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OR4, —C(O)R4, —SR4, —CF3, —SOR4, and —SO2R4.
Z, Z1, Z2, Z3, Z4 and Z5 are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CN, ═O, —NO2, —OR10, —OC(O)R10, —CO2R10, —C(O)R10, —C(O)NR11R12, —OC(O)NR11R12, —NR10C(O)R11, —NR10C(O)NR11R12, —NR11R12, —NR10CO2R11, —SR10, —S(O)R10, —S(O)2R10, —S(O)2NR11R12, —NR10S(O)2R11, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl and substituted or unsubstituted 3- to 10-membered heterocyclyl;
suitable substituted C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl may have from 1 to 3 substituents independently selected from the group consisting of halogen, —OR10, —CN, —NO2, ═O, —OC(O)R10, —CO2R10, —C(O)R10, —C(O)NR10R11, —OC(O)NR10R11, —NR10C(O)R11, —NR10C(O)NR11R12, —NR10R11, —NR10CO2R11, —SR10, —S(O)R10, —S(O)2R10, —S(O)2NR10R11, —NR10S(O)2R11, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted 3- to 6-membered heterocyclyl;
suitable substituted aryl, heteroaryl and heterocyclyl substituents may have from 1 to 3 substituents independently selected from the group consisting of halogen, —OR10, —CN, —NO2, ═O, —OC(O)R10, —OC(O)R10, —CO2R10, —C(O)R10, —C(O)NR10R11, —OC(O)NR10R11, —NR10C(O)R11, —NR10C(O)NR11R12, —NR10R11, —NR10CO2R11, —SR10, —S(O)R10, —S(O)2R10, —S(O)2NR10R11, —NR10S(O)2R11, unsubstituted 4- to 7-membered ring heterocyclyl, unsubstituted C1-8 alkyl and unsubstituted C1-8 haloalkyl;
R10, R11 and R12 are each hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, or heteroaryl; or R10 and R11, R11 and R12, or R10 and R12, together with the atom(s) to which they are attached, form an substituted or unsubstituted 5-, 6-, or 7-membered ring; and
the aliphatic and aromatic portions of R10, R11 and R12 are optionally further substituted with from 1 to 3 substituents selected from the group consisting of halogen, —OH, —ORm, —OC(O)NHRm, —OC(O)NRmRn, —SH, —SRm, —S(O)Rm, —S(O)2Rm, —S(O)2NH2, —S(O)2NHRm, —S(O)2NRmRn, —NHS(O)2Rm, —NRmS(O)2Rn, —C(O)NH2, —C(O)NHRm, —C(O)N(Rm)2, —C(O)Rm, —NHC(O)Rm, —NRmC(O)Rn, —NHC(O)NH2, —NRmC(O)NH2, —NRmC(O)NHRn, NHC(O)NHRm, —NRoC(O)NRmRn, —NHC(O)N(Rm)2, —CO2H, —CO2Rm, —NHCO2Rm, —NRmCO2Rn, —CN, —NO2, —NH2, —NHRn, —NRmRn, —NRmS(O)NH2, and —NRmS(O)2NHRn, where Rm, Rn, and Ro are each independently unsubstituted C1-6 alkyl.
Preferred Modulators
The modulators of the present invention can have one the following formulae:
Compounds of the present invention are also represented by the following formula:
where Ar2 is selected from the following residues
The following descriptions and formulae apply only to those formulae (I-XVIII) that are applicable (i.e. those formulae with applicable substituents).
In each of the formula (III-XVIII);
X1, Xa and Xb are each independently as defined for X1 in formula (II);
Y1, Ya and Yb are each independently as defined for Y1 in formula (II); and
Z′, Z1, Za, Zb and Zc are each independently as defined for Z1 in formula (II);
In formulae (I-XVIII), U1 is selected from the group consisting of CH2, O, and NR8, where R8 is as defined in formula (I).
In formulae (I-XVIII), R8 is as defined in formula (I). In one preferred embodiment, R8 is hydrogen or unsubstituted C1-6 alkyl.
In formula (XVIII), J3, J4 and J5 are selected from the group consisting of CR30R31, O, S(O)s, and NR32, where s is 0, 1 or 2, with the proviso that p+q+r is 3, 4 or 5; and with the proviso that the resulting ring system does not contain a hydrazine functionality, a peroxide functionality nor a hydroxylamine derived functionality; and where R30, R31 and R32 are as defined for R20 in formula (AA) in paragraph [0021], [0022], [0023]. In one preferred embodiment, R30, R31 and R32 are each independently hydrogen or unsubstituted C1-6 alkyl.
In formula (XVIII), A is CZ′, where Z′ is defined as for Z1 in formula (II).
In formula (XVIII), E is CZ′ or N.
In formula (XVIII), G is O, S, or NR7, where R7 is as defined in paragraph [0051].
In the following embodiments, when one substituent is specified, the remaining substituents remain as defined during their first appearance, unless otherwise specified. For example, if X1 is defined, then X2, X3, X4, and X5 remain as defined in formula (II).
In the following embodiments, the substituents refer to formula in which they are present. Not all substituents are found in all formula
Linkers
In one embodiment of formulae (I) and (II), L is preferably —C(O)—.
In another embodiment of formulae (I) and (II), L is preferably —S—, —S(O)—, or —S(O)2—.
X Substituents
In one embodiment of formula (II), X1, X2, X3, X4, and X5 are preferably independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OR1, —C(O)R1, —SO2R1, —SR1, —NR1R2, —NC(O)R1, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C1-8 alkenyl, unsubstituted or substituted C1-8 alkynyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted 5- or 6-membered heterocyclyl. More preferably, at least one X substituent is situated para to the sulfonamido bond as defined in formula (I). Preferably, either 3 or 4 substituents represented by X1, X2, X3, X4, and X5 are hydrogen, and the remaining 1 or 2 substituents are selected from the above group with the proviso that at least one substituent is other than hydrogen.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is a 6-membered heteroaryl selected from the group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl and triazinyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is pyrimidinyl or pyridinyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is a 5-membered heteroaryl systems selected from the group consisting of isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl and thiazolyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is a substituted 5-membered heteroaryl selected from pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, furyl and thienyl. Preferably, at least one of the substituents X, Xa, Xb, X1, X2, X3, X4 and X5 is an unsubstituted 5-ring heteroaryl system selected from pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, furyl and thienyl. More preferably, at least one of the substituents X, Xa, Xb, X1, X2, X3, X4 or X5 is oxazolyl or pyrazolyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is a heterocyclic group represented by formula (AA) as defined in [0021], [0022] and [0023].
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is a substituted or unsubstituted heterocyclyl selected from the group including pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane. phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, and tetrahydrothiophene.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is a substituted or unsubstituted heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxalanyl, thiomorpholinyl, thiomorpholinyl-S,S-dioxide, piperazinyl and pyranyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, or X5 or at least one X is a substituted C1-8 alkyl, where suitable substituents are as defined for formula (II). Preferably, the substituent is a substituted or unsubstituted heterocyclic group of the formula (AA) as defined in paragraph [0021], [0022] and [0023]. More preferably, the substituent is selected from the group including pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, and tetrahydrothiophene.
In one embodiment of each of the formulae (I-XVIII), when a heterocyclic group represented by formula (AA) is present, R20, R21, R22, R23, R24, R25, and R26 are independently hydrogen or C1-4alkyl. In another preferred embodiment, at least three of R20, R21, R22, R23, R24, R25 and R26 are hydrogen; j is 1 or 2; and k is 1 or 2 with the proviso that j+k is 3 or 4. In another preferred embodiment, at least five of R20, R21, R22, R23, R24, R25, and R26 are hydrogen; j is 1 or 2; and k is 1 or 2 with the proviso that j+k is 3 or 4.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, A and X5 or at least one X is a substituted C1-8 alkyl, where suitable substituents are as defined for formula (II). In one preferred embodiment, the substituted C1-8 alkyl is substituted with a 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, and thiazolyl. More preferably, the substituted C1-8 alkyl is substituted with oxazolyl.
In one embodiment of each of the formulae (I-XVIII), a suitable substituent for substituted C1-8 alkyl (as X, X1, X2, X3, X4, X5, Xa, Xb, or X) can be selected from the group consisting of —CN, —OR1, —C(O)R1, —CO2R1, —O(CO)R1, —SO2R1 and halogen.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is an unsubstituted C1-8 alkyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is t-butyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is oxazolyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is morpholinyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is isopropoxy.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is trifluoromethoxy.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is —SO2R3.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is ethyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is isopropyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is a cyano, halogen or trifluoromethyl group.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is —C(Me)2CH2OH.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is —C(O)Me.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is —(CH2)2CO2Me.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, X5 or at least one X is isoamyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is 1-3,dioxalanyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is furyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is pyrazolyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is thienyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is methoxy.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is ethenyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is aminopyridyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is acetamido.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is unsubstituted or substituted C1-8 alkynyl.
In one embodiment of each of the formulae (I-XVIII), at least one of Xa, Xb, X1, X2, X3, X4, and X5 or at least one X is phenylacetylenyl.
In one embodiment of paragraphs [0093] to [00116], the remaining substituents are hydrogen. In another embodiment, the remaining substituents are selected from the group consisting of hydrogen, halogen, cyano, or trifluoromethyl.
In one embodiment of formula (II), at least one of X1, X2, X3, X4, and X5 is other than hydrogen.
In one embodiment of formula (II), X1 is other than hydrogen and at least 2 of X2, X3, X4, and X5 are hydrogen. Preferably, at least 3 of X2, X3, X4, and X5 are hydrogen; more preferably, X2, X3, X4, and X5 are hydrogen.
In one embodiment of each of the formulae (I-XVIII), at least one of X1, Xa, and Xb is a substituted or unsubstituted 5- or 6-membered heteroaryl ring selected from the group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, and thiazolyl; and where additional X1, Xa, and Xb, when present, are defined as for formula (II).
In one embodiment of each of the formulae (I-XVIII), at least one of X1, Xa, and Xb is a substituted or unsubstituted 5- or 6-membered heterocyclic ring, and the heterocycle is selected from the group consisting of pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, and tetrahydrothiophene; and where additional X1, Xa, and Xb, when present, are defined as for formula (II).
In one embodiment of each of the formulae (I-XVIII), at least one of X, X1, X2, X3, X4, X5, Xa, and Xb are independently selected from the group consisting of:
In one further embodiment of each of the formulae (I-XVIII), at least one of X, X1, Xa, and Xb are independently selected from this group.
In one embodiment of each of the formulae (I-XVIII), at least one of X, X1, X2, X3, X4, X5, Xa, and Xb are independently selected from the group consisting of:
In one further embodiment of each of the formulae (I-XVIII), at least one of X, X1, Xa, and Xb is independently selected from the group set forth in paragraph [00123].
In one embodiment for each of the formulae (I-XVIII), one of X1 or Xb is selected from the group defined in paragraphs [00122] or [00123], and Xa is selected from the group consisting of —F, —Cl, —CN or —CF3. In other preferred embodiments, one of X1 or Xb is selected from the group defined in paragraphs [00122] or [00123], and Xa is hydrogen.
In one embodiment of each of the formulae (I-XVIII), X, X1, Xa, and Xb are independently selected from the group consisting of hydrogen, —OH, —OR3 (but not -OMe, —OiPr, —OcycPr, —OEt, —OtBu, —OnBu, —OCF3, —OPh, —OCH2Ph, —OnPr), —C(O)R3, —CO2R3, —O(CO)R3, —OC(O)NR3R4, SR3 (but not —SiPr), —S(O)R3, —NR3R3 (but not —NHiPr, —NHEt, —NMe2), —NR5C(O)R3 (but not —NHC(O)Me), —NR5C(O)2R3, unsubstituted C1-8 alkyl (but not ethyl, methyl, iso-propyl, isoamyl, -tbutyl, cyclobutyl, cyclohexyl, -nPr), C1-8 haloalkyl (but not —CF3), unsubstituted C2-8 alkenyl, unsubstituted C2-8 alkynyl, and substituted or unsubstituted phenyl, with the proviso that at least one substituent is other than hydrogen.
In one embodiment of each of the formulae (I-XVIII), X, X1, Xa, and Xb are independently selected from the group consisting hydrogen, halogen, —CN, —NO2, —OMe, —OiPr, —OcycPr, —OEt, —OtBu, —OnBu, —OCF3, —OPh, —OCH2Ph, —OnPr, —NHC(O)Me, —SiPr, —NHiPr, —NHEt, —NMe2, ethyl, methyl, iso-propyl, isoamyl, -tbutyl, cyclobutyl, cyclohexyl, -nPr, and —CF3 with the proviso that at least one substituent is other than hydrogen.
In one embodiment of each of the formulae (I-XVIII), X1, Xa, and Xb are independently selected from the group consisting of hydrogen, —S(O)2R3, —NR5C(O)NR3R4, —NR5S(O)2R3, —S(O)2NR3R4, substituted C1-8 alkyl (but not C1-8 haloalkyl), substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocyclyl, with the proviso that at least one substituent is other than hydrogen.
In one embodiment of each of the formulae (I-XVIII), X1, Xa, and Xb are independently selected such that at least one substituent is unsubstituted C1-8 alkyl.
In one embodiment of each of the formulae (I-XVIII), X1, Xa, and Xb are independently selected from the group consisting of hydrogen, —NO2, —OR3, —C(O)R3, —S(O)2R3, —NR3R4, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 5- or 6-membered heterocyclyl. Preferably, Xa is hydrogen. In another preferred embodiment, Xa is fluorine, chlorine, —CN, or —CF3.
In one embodiment of each of the formulae (I-XVIII), each of Xa is hydrogen, and X1 is other than hydrogen.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen, and Xb is other than hydrogen.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and X1 is C1-8 alkyl, having 1 to 3 substituents independently selected from the group consisting of halogen, —CN, ═O, —OC(O)R3, —OR3, —C(O)R3, —C(O)NR3R4, —NR4C(O)R3, —CO2R3, —NR3R4, —SR3, —S(O)R3, —S(O)2R3, —NR3S(O)2R4, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocycle. In another embodiment, Xa is halogen, —CF3, or —CN.
In one embodiment of each of the formulae (I-XVIII), one of Xa is hydrogen and X1 is unsubstituted C1-8 alkyl. In another embodiment, Xa is selected from the group consisting of halogen, —CF3, or —CN.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and Xb is C1-8 alkyl, having 1 to 3 substituents independently selected from the group consisting of halogen, —CN, ═O, —OC(O)R3, —OR3, —C(O)R3, —C(O)NR3R4, —NR5C(O)R3, —CO2R3, —NR3R4, —S(O)2R3, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl and substituted or unsubstituted 4- to 7-membered heterocycle. In another embodiment, Xa is halogen, —CF3, or —CN.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and Xb is unsubstituted C1-8 alkyl. In another embodiment, Xa is halogen, —CF3, or —CN.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and X1 is C6-10 aryl or a heteroaryl, having from 0 to 3 substituents independently selected from the group consisting of halogen, —CN, —OR3, ═O, —OC(O)R3, —CO2R3, —C(O)R3, —C(O)NR3R4, —NR5C(O)R3, —NR3R4, —SR3, —S(O)R3, —S(O)2R3, —NR5S(O)2R3, and unsubstituted C1-8 alkyl or unsubstituted C1-8 haloalkyl. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and Xb is C6-10 aryl or a heteroaryl, having from 0 to 3 substituents independently selected from the group consisting of halogen, —CN, —OR3, ═O, —NO2, —OC(O)R3, —CO2R3, —C(O)R3, —C(O)NR3R4, —NR5C(O)R3, —NR3R4, —SR3, —S(O)R3, —S(O)2R3, —NR5S(O)2R3, unsubstituted C1-8 alkyl and unsubstituted C1-8 haloalkyl. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and X1 is substituted phenyl, having from 1 to 3 substituents independently selected from the group consisting of halogen, —OR3, —NO2, ═O—C(O)R3, —C(O)NR3R4, —NR5C(O)R3, —NR3R4, —SR3, —NR5S(O)2R3, —S(O)2R3, unsubstituted C1-8 alkyl, and unsubstituted C1-8 haloalkyl. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and Xb is phenyl, having from 1 to 3 substituents independently selected from the group consisting of halogen, —OR3, ═O, —NO2, —C(O)R3, —C(O)NR3R4, —NR5C(O)R3, —NR3R4, —SR3, —NR5S(O)2R3, —S(O)2R3, unsubstituted C1-8 alkyl, and unsubstituted C1-8 haloalkyl. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and X1 is substituted or unsubstituted 5- or 6-membered heteroaryl, having from 0 to 3 substituents independently selected from the group consisting of halogen, —OR3, —NO2, ═O—C(O)R3, —C(O)NR3R4, —NR5C(O)R3, —NR3R4, —SR3, —NR5S(O)2R3, —S(O)2R3, unsubstituted C1-8 alkyl, and unsubstituted C1-8 haloalkyl. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and Xb is a 5- or 6-membered substituted or unsubstituted heteroaryl, having from 0 to 3 substituents independently selected from the group consisting of halogen, —OR3, ═O, —NO2, —C(O)R3, —C(O)NR3R4, —NR5C(O)R3, —NR3R4, —SR3, —NR5S(O)2R3, —S(O)2R3, unsubstituted C1-8 alkyl, and unsubstituted C1-8 haloalkyl. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and X1 is a 4- to 7-membered heterocyclyl, having 0 to 3 substituents independently selected from the group consisting of unsubstituted C1-8 alkyl, unsubstituted C1-8 haloalkyl, —OR3, —OC(O)R3, —CO2R3, —C(O)R3, —C(O)NR3R4, —NR3R4, —NR5C(O)R3, —S(O)2R3, —SR3 and —NR5S(O)2R3. In other embodiments, Xa is selected from halogen, —CN, and —CF3.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and Xb is a 4- to 7-membered heterocyclyl, having from 0 to 3 substituents independently selected from the group consisting of unsubstituted C1-8 alkyl, unsubstituted C1-8 haloalkyl, —OR3, —OH, —NR5C(O)R3, —OC(O)R3, —CO2R3, —C(O)R3, —C(O)NR3R4, —NR3R4, —S(O)2R3, —SR3 and —NR5S(O)2R3. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and X1 is a 5- or 6-membered heterocyclyl, having 0 to 2 substituents independently selected from the group consisting of unsubstituted C1-8 alkyl and unsubstituted C1-8 haloalkyl. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment of each of the formulae (I-XVIII), Xa is hydrogen and Xb is a 5- or 6-membered heterocyclyl, having 0 to 2 substituents independently selected from the group consisting of unsubstituted C1-8 alkyl and unsubstituted C1-8 haloalkyl. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment, in each of formulae (I-XVIII), Xa is hydrogen and Xb is selected from the group consisting of —CN, —CF3, halogen, —OR3, —S(O)2R3, —C(O)R3, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocycle. In other embodiments, Xa is halogen, —CN, or —CF3.
In one embodiment, in each of formulae (I-XVIII), Xa is hydrogen and X1 is selected from the group consisting of —CN, —CF3, halogen, —OR3, —S(O)2R3, —C(O)R3, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocycle. In other embodiments, Xa is halogen, —CN, or —CF3.
In embodiments for each of the formulae (I-XVIII) where X1 or Xb is either a substituted C1-8 alkyl, a substituted 5- or 6-membered heteroaryl, or a substituted 4- to 7-membered heterocycle, and the aromatic or aliphatic portions of X1 or Xb may have from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, ═O, —OC(O)R3, —OR3, —C(O)R3, —C(O)NR3R4, —NR5C(O)R3, —CO2R3, —NR3R4, —S(O)2R3, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocycle.
In one embodiment of formula (II), X2, X3 and X5 are hydrogen; X1 and X4 are selected from the group consisting of halogen, —CN, —NO2, —OH, —OR3, —C(O)R3, —CO2R3, —O(CO)R3, —OC(O)NR3R4, —SR3, —S(O)R3, —S(O)2R3, —NR3R3, —NR5C(O)R3, —NR5C(O)2R3, —NR5C(O)NR3R4, —NR5S(O)2R3, —S(O)2NR3R4, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocyclyl.
In one embodiment of formula (II), X4, X2, X3 and X5 are hydrogen; and X1 is selected from the group consisting of halogen, —CN, —NO2, —OH, —OR3, —C(O)R3, —CO2R3, —O(CO)R3, —OC(O)NR3R4, —SR3, —S(O)R3, —S(O)2R3, —NR3R3, —NR5C(O)R3, —NR5C(O)2R3, —NR5C(O)NR3R4, —NR5S(O)2R3, —S(O)2NR3R4, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocyclyl.
In one embodiment of formulae (II), X2, X3 and X5 are hydrogen; X4 is selected from the group consisting of hydrogen, fluorine, chlorine, —CN and trifluoromethoxy; and X1 is selected from the group consisting of —CN, —CF3, halogen, —OR3, —S(O)2R3, —C(O)R3, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocycle.
In embodiments of each of formulae (I-XVIII), Xa and Xb are hydrogen; and X1 is selected from the group consisting of halogen, —CN, —NO2, —OH, —OR3, —C(O)R3, —CO2R3, —O(CO)R3, —OC(O)NR3R4, —SR3, —S(O)R3, —S(O)2R3, —NR3R3, —NR5C(O)R3, —NR5C(O)2R3, —NR5C(O)NR3R4, —NR5S(O)2R3, —S(O)2NR3R4, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocyclyl.
In embodiments of each of formulae (I-XVIII), X1 and Xb are hydrogen; and Xa is selected from the group consisting of halogen, —CN, —NO2, —OH, —OR3, —C(O)R3, —CO2R3, —O(CO)R3, —OC(O)NR3R4, —SR3, —S(O)R3, —S(O)2R3, —NR3R3, —NR5C(O)R3, —NR5C(O)2R3, —NR5C(O)NR3R4, —NR5S(O)2R3, —S(O)2NR3R4, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocyclyl.
In one embodiment in each of formulae (I-XVIII), Xa and Xb are selected from the group consisting of hydrogen, fluorine, chlorine, —CN and trifluoromethoxy, and X1 is selected from the group consisting of —CN, —CF3, halogen, —OR3, —S(O)2R3, —C(O)R3, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocycle.
In one preferred embodiment of formula (II), X2, X3 and X5 are hydrogen; X4 is selected from the group consisting of hydrogen, fluorine, chlorine, —CN and trifluoromethoxy; X1 is selected from one of the residues shown below:
with the proviso that at least one of the substituents is other than hydrogen; and Y3 is hydrogen; and when Y1 is chlorine or bromine, Y2 and Y4 are hydrogen, or when Y1 is fluorine, Y2 and Y4 are hydrogen or fluorine.
In one preferred embodiment of formula (II), X2, X3 and X5 are hydrogen; X4 is selected from the group consisting of hydrogen, fluorine, chlorine, —CN and trifluoromethoxy; X1 is selected from one of the residues shown below:
with the proviso that at least one of the substituents is other than hydrogen; Y3 is hydrogen, and when Y1 is chlorine or bromine, Y2 and Y4 are hydrogen, or when Y1 is fluorine, Y2 and Y4 are hydrogen or fluorine; and Z1, Z2, Z3, Z4 and Z5 are selected such that the following residues are present:
In one embodiment of each of formulae (I-XVIII), Xa is selected from the group consisting of hydrogen, fluorine, chlorine, —CN and trifluoromethoxy; X1 or Xb is selected from one of the residues shown below:
with the proviso that at least one substituent X1, Xa or Xb is other than hydrogen;
Y1 or Yb is chlorine and Ya is hydrogen; or alternatively, Y1 or Yb is fluorine and Ya is hydrogen or fluorine;
Za is hydrogen, and at least one of Z1, Z2, Z3, Z4 and Z5 or Zb is either a fluorine atom or are selected from the group consisting of methyl, chlorine and fluorine or are independently selected from the following group consisting of:
In others preferred embodiment, X1 or Xb is instead selected from one of the residues shown below.
In one embodiment in each of formulae (I-XVIII), Xa is selected from the group consisting of hydrogen, fluorine, chlorine, —CN and trifluoromethoxy, and X1 or Xb is selected from one of the residues shown below:
with the proviso that at least one substituent X1, Xa or Xb is other than hydrogen; Y1 or Yb is chlorine and Ya is hydrogen; or alternatively, Y1 or Yb is fluorine and Ya is hydrogen or fluorine; and Z1, Za and Zb are all simultaneously hydrogen.
In other preferred embodiment, X1 or Xb is instead selected from one of the residues shown below:
In one embodiment of each of the formulae (I-XVIII), X, X1, X2, X3, X4, X5, Xa, and Xb are each independently selected from the group consisting of hydrogen, —CH═CH2, phenylacetylene, -hydroxybutyl, —C(CH3)2CH2CH2OH, —CH2CH2CO2Me, phenyl (Ph), —C(O)Me, —SO2Me, pyrazole, oxazole, and morpholinyl, with the proviso that at least one non-hydrogen substituent is present.
In one embodiment of each of the formulae (I-XVIII), X, X1, X2, X3, X4, X5, Xa, and Xb are each independently selected from the group consisting of hydrogen, —CF3, isoamyl, t-butyl, ethyl (Et), —OCF3, i-propyl (iPr), —C(CH3)2CH2CH3, -OMe, —O-iPr, and —OEt, with the proviso that at least one non-hydrogen substituent is present.
Y Substituents
In one embodiment of (II), at least two substituents from the group Y1, Y2, Y3 and Y4 are hydrogen, with the proviso that at least one is other than hydrogen. Preferably, Y1, Y2, Y3 and Y4 are selected from the group consisting of halogen, —CN, —NO2, —CF3, and —SO2R4, with the proviso that only one or two substituents are other than hydrogen, and with the proviso that at least one substituent is halogen. Most preferably, at least one substituent is a halogen atom located para to the sulfonamide bond as defined in formula (I).
In one embodiment of any of formula (I) or (II), when Y, Y1, Y2, Y3 or Y4 is substituted alkyl, it preferably has from 1 to 3 substituents independently selected from the group consisting of halogen, —OR4, —CN, —NO2, ═O, —OC(O)R4, —CO2R4, —C(O)R4, —CONR4R5, —NR4C(O)R5, —NR4R5, —NR4, —SR4, —SOR4, —SO2R4, and —NR4SO2R5.
In one embodiment of any of formulae (I) and (II), at least one of Y, Y1, Y2, Y3, Y4 and Y5 is other than hydrogen.
In one embodiment of any of formulae (I) and (II), at least one of Y, Y1, Y2, Y3, Y4 and Y5 is halogen, —CN, —NO2, —OR6, —C(O)R6, —SR6, —CF3, —S(O)R6, —S(O)2R13 or substituted or unsubstituted C1-4 alkyl.
In one embodiment of any of formulae (I-XVIII), one of Y1, Ya and Yb is hydrogen and the other is not hydrogen.
In one embodiment of any of formulae (I-XVIII), Y1, Ya and Yb represent from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OR6, —C(O)R6, —SR6, —CF3, —S(O)R6, and —S(O)2R6 and substituted or unsubstituted C1-6 alkyl.
In one embodiment of any of formulae (I-XVIII), Y1, Ya and Yb represent from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —CF3, and —S(O)2Me.
In one embodiment of any of formulae (I-XVIII), one of Y1, Ya and Yb is halogen and the other is selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OH, —OR6, —C(O)R6, —CO2R6, —SR6, —S(O)R6, —S(O)2R6 and substituted or unsubstituted C1-4 alkyl.
In one embodiment in any of formulae (I-XVIII), one of Y1, Ya and Yb is substituted alkyl, having from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —ORm, —CN, —NO2, ═O, —OC(O)Rm, —CO2Rm, —C(O)Rm, —C(O)NHRn, —C(O)NH2, —C(O)NRmRn, —NRmC(O)Rn, —NHC(O)Rn, —NRmRn, —NHRm, —NH2, —SRm, —S(O)Rm, —S(O)2Rm, —NRmS(O)2Rn, and —NHS(O)2Rm where Rm and Rn are each independently unsubstituted C1-6 alkyl.
In one embodiment of any of formulae (I-XVIII), Y1 and Ya are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OH, —OR6, —C(O)R6, —CO2R6, —SR6, —S(O)R6, —S(O)2R6, and substituted or unsubstituted C1-4 alkyl, with the proviso that Y1 and Ya cannot both be hydrogen simultaneously.
In one embodiment of any of formulae (I-XVIII), Y1 and Ya are each independently hydrogen or halogen, with the proviso that one of Y1 and Ya is halogen. Preferably, one halogen atom is located para to the sulfonamide bond.
In one embodiment of any of formulae (I-XVIII), Y1 or Yb is hydrogen and Ya is chloro, fluoro or bromo; Ya is hydrogen and Y1 or Yb is chloro, fluoro or bromo; Ya and Y1 or Yb are both chloro, fluoro, or bromo (particularly fluoro).
Z Substituents
In one embodiment of any of formulae (I-XVIII), Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CN, —NO2, —OR10, —OC(O)R10, —CO2R10, —C(O)R10, —C(O)NR11R12, —NR10C(O)R11, —NR11R12, —SR10, —S(O)R10, —S(O)2R10, —S(O)2NR11R12, —NR10S(O)2R11, —OC(O)NR11R12, —NR10C(O)NR11R12, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocyclyl.
In one embodiment, any of formulae (I-XVIII), Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are independently selected from the group consisting of hydrogen, unsubstituted C1-6 alkyl (not -Me), C1-6 haloalkyl, —COON, —NO2, or —OR10, with the proviso that at least one substituent is other than hydrogen.
In one embodiment, any of formulae (I-XVIII), Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are independently selected from the group consisting of hydrogen, —CH3, —Cl, and —F. In one particular embodiment, Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are all hydrogen.
In one embodiment, any of formulae (I-XVIII), Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are independently selected from the group consisting of hydrogen, iodo, bromo, substituted C1-6 alkyl (but not C1-6 haloalkyl), unsubstituted or substituted C1-6 alkenyl, unsubstituted or substituted C1-6 alkynyl, —CN, —C(O)R10, —C(O)NR10R11, —NR10C(O)R11, —NR11R12, —SR10, —S(O)R10, —S(O)2R10, —S(O)2NR11R12, —NR10S(O)2R11, —OC(O)R10, —CO2R10 (but not —CO2H), —OC(O)NR11R12, —NR10C(O)NR11R12, —NR10CO2R11, unsubstituted or substituted 5- or 6-membered heteroaryl and unsubstituted or substituted 4- to 7-membered heterocyclyl, with the proviso that at least one substituent is other than hydrogen. Preferred substituents include hydrogen, chlorine, fluorine, —CN, —SCH3, and —SO2CH3.
In one embodiment in any of the formulae (I-XVIII), at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is cyano.
In one embodiment in any of the formulae (I-XVIII), at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is —S(O)2R7. In one particular embodiment, R7 is methyl.
In one embodiment in any of the formulae (I-XVIII), at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is halogen (in particular chlorine).
In one embodiment in any of the formulae (I-XVIII), at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is —OR7. In one particular embodiment, R7 is methyl.
In one embodiment in any of the formulae (I-XVIII), at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is —SR7. In one particular embodiment, R7 is methyl.
In one embodiment in any of the formulae (I-XVIII), at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is unsubstituted C1-6 alkyl (in particular methyl) or C1-6 haloalkyl (in particular —CF3).
In one embodiment in any of the formulae (I-XVIII), at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is substituted C1-6 alkyl (preferably not C1-6 haloalkyl).
In one embodiment in any of the formulae (I-XVIII), all substituents Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are hydrogen.
In one embodiment of any of formulae (I-XVIII), where at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is a substituted or unsubstituted 4- to 7-membered heterocycle. Such suitable heterocyclic groups are represented by formula (AA) as defined in [0021], [0022], and [0023]. Preferably, R20, R21, R22, R23, R24, R25, and R26 are independently hydrogen or C1-4alkyl. In another preferred embodiment, at least three of R20, R21, R22, R23, R24, R25, and R26 are hydrogen; j is 1 or 2; and k is 1 or 2 with the proviso that j+k is 3 or 4. In other preferred embodiments, at least five of R20, R21, R22, R23, R24, R25, and R26 are hydrogen; j is 1 or 2; and k is 1 or 2 with the proviso that j+k is 3 or 4.
In one embodiment of any of formulae (I-XVIII), at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is a unsubstituted or substituted heterocyclyl selected from the group including pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, and tetrahydrothiophene.
In one embodiment of any of formulae (I-XVIII), at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is a substituted or unsubstituted 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, and thiazolyl.
In one embodiment of any of formulae (I-XVIII), Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are substituted C1-8 alkyl, substituted C2-8 alkenyl or substituted C2-8 alkynyl, it preferably has from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR10, ═O, —CO2R10, —C(O)R10, —C(O)NR11R12, —NR10C(O)R11, —NR11R12, —SR10, —S(O)R10, —S(O)2R10, —NR10S(O)2R11, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to 7-membered heterocyclyl. More preferably, it has from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR10, ═O, —C(O)R10, —CO2R10, —C(O)NR11R12, —NR10C(O)R11, —NR11R12, —SR10, —S(O)R10, —S(O)2R10, —S(O)2NR11R12, —NR10S(O)2R11, and 4- to 7-membered heterocyclyl.
In one embodiment of each of the formulae (I-XVIII) when at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is a substituted C1-8 alkyl, at least one substituent is a substituted or unsubstituted 4- to 7-membered heterocyclyl represented by formula (AA) as defined in [0021], [0022], and [0023]. Preferably, R20, R21, R22, R23, R24, R25, and R26 are independently hydrogen or C1-4alkyl. In another preferred embodiment, at least three of R20, R21, R22, R23, R24, R25, and R26 are hydrogen; j is 1 or 2; and k is 1 or 2 with the proviso that j+k is 3 or 4. In another preferred embodiments, at least five of R20, R21, R22, R23, R24, R25, and R26 are hydrogen; j is 1 or 2; and k is 1 or 2 with the proviso that j+k is 3 or 4.
In one embodiment of each of the formulae (I-XVIII) when at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is a substituted C1-8 alkyl, at least one substituent is selected from the group consisting of pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane. phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, and tetrahydrothiophene.
In one embodiment of each of the formulae (I-XVIII) when at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is a substituted C1-8 alkyl, at least one substituent is a substituted or unsubstituted 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, and thiazolyl.
In one embodiment of the formulae (I-XVIII), Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are selected from one of the following residues
with the proviso that at least one of Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is other than hydrogen.
In one embodiment of the formulae (I-XVIII), Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are each hydrogen.
In one embodiment of any of formulae (I-XVIII), when Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc is substituted heterocyclyl or heteroaryl, it preferably has from 0 to 2 substituents independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, —OR10, ═O—OH, —C(O)R10, —C(O)NR11R12, —NR11R12, and —S(O)2R10.
In one embodiment of any of formulae (I-XVIII), Z, Z′, Z1, Z2, Z3, Z4, Z5, Za, Zb and Zc are each independently hydrogen, halogen, —CN, —OR4, —NR7R8, —SR7 (e.g., thiomethyl), —SOR7, —SO2R7 (e.g., methylsulfonyl), unsubstituted or substituted C1-6 alkoxyl (e.g., methoxy), unsubstituted or substituted C1-6 alkyl (e.g., methyl), unsubstituted or substituted phenyl, or unsubstituted or substituted 5- or 6-membered heterocyclyl.
In another group of embodiments, the compounds are represented by the formula (XIX):
where X is OCF3, tert-butyl, ethyl, isopropyl, oxazole, C(O)CH3, CN, fluorine, CF3, isopropoxy, isoamyl, or hydroxybutyl.
Compositions that Modulate CCR9 Activity
In another aspect, the present invention provides compositions that modulate CCR9 activity. Generally, the compositions for modulating chemokine receptor activity in humans and animals will comprise a pharmaceutically acceptable excipient or diluent and a compound having the formula provided above as formula (I).
The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self emulsifications as described in U.S. Patent Application 2002/0012680, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated enterically or otherwise by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Additionally, emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil in water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative. and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, axed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Additionally, the compounds can be administered via ocular delivery by means of solutions or ointments. Still further, transdermal delivery of the subject compounds can be accomplished by means of iontophoretic patches and the like.
For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present invention are employed. As used herein, topical application is also meant to include the use of mouth washes and gargles.
The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds as noted herein, such as those applied in the treatment of the above mentioned pathological conditions.
Methods of Treating CCR9-Mediated Conditions or Diseases
In yet another aspect, the present invention provides methods of treating or preventing a CCR9-mediated condition or disease by administering to a subject having such a condition or disease a therapeutically effective amount of any compound of formula (I) above. Compounds for use in the present methods include those compounds according to formula (I), those provided above as embodiments, those specifically exemplified in the Examples below, and those provided with specific structures herein. The “subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
As used herein, the phrase “CCR9-mediated condition or disease” and related phrases and terms refer to a condition or disease characterized by inappropriate, i.e., less than or greater than normal, CCR9 functional activity. Inappropriate CCR9 functional activity might arise as the result of CCR9 expression in cells which normally do not express CCR9, increased CCR9 expression (leading to, e.g., inflammatory and immunoregulatory disorders and diseases) or decreased CCR9 expression. Inappropriate CCR9 functional activity might also arise as the result of TECK secretion by cells which normally do not secrete TECK, increased TECK expression (leading to, e.g., inflammatory and immunoregulatory disorders and diseases) or decreased TECK expression. A CCR9-mediated condition or disease may be completely or partially mediated by inappropriate CCR9 functional activity. However, a CCR9-mediated condition or disease is one in which modulation of CCR9 results in some effect on the underlying condition or disease (e.g., a CCR9 antagonist results in some improvement in patient well being in at least some patients).
The term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a cell, tissue, system, or animal, such as a human, that is being sought by the researcher, veterinarian, medical doctor or other treatment provider.
Diseases and conditions associated with inflammation, immune disorders, infection and cancer can be treated or prevented with the present compounds, compositions, and methods. In one group of embodiments, diseases or conditions, including chronic diseases, of humans or other species can be treated with inhibitors of CCR9 function. These diseases or conditions include: (1) allergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies and food allergies, (2) inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria and pruritus, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma, (8) asthma and respiratory allergic diseases such as allergic asthma, allergic rhinitis, hypersensitivity lung diseases and the like, (9) autoimmune diseases, such as fibromyalagia, scleroderma, ankylosing spondylitis, juvenile RA, Still's disease, polyarticular juvenile RA, pauciarticular juvenile RA, polymyalgia rheumatica, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, polyarticular arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, type II diabetes, glomerulonephritis, and the like, (10) graft rejection (including allograft rejection), (11) graft-v-host disease (including both acute and chronic), (12) other diseases in which undesired inflammatory responses are to be inhibited, such as atherosclerosis, myositis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome and gout, (13) immune mediated food allergies such as Coeliac (Celiac) disease (14) pulmonary fibrosis and other fibrotic diseases, and (15) irritable bowel syndrome.
In another group of embodiments, diseases or conditions can be treated with modulators and agonists of CCR9 function. Examples of diseases to be treated by modulating CCR9 function include cancers, cardiovascular diseases, diseases in which angiogenesis or neovascularization play a role (neoplastic diseases, retinopathy and macular degeneration), infectious diseases (viral infections, e.g., HIV infection, and bacterial infections) and immunosuppressive diseases such as organ transplant conditions and skin transplant conditions. The term “organ transplant conditions” is means to include bone marrow transplant conditions and solid organ (e.g., kidney, liver, lung, heart, pancreas or combination thereof) transplant conditions.
Preferably, the present methods are directed to the treatment of diseases or conditions selected from inflammatory bowel disease including Crohn's disease and Ulcerative Colitis, allergic diseases, psoriasis, atopic dermatitis and asthma, autoimmune disease such as rheumatoid arthritis and immune-mediated food allergies such as Coelaic disease.
Depending on the disease to be treated and the subject's condition, the compounds and compositions of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each rouse of administration. The present invention also contemplates administration of the compounds and compositions of the present invention in a depot formulation.
In the treatment or prevention of conditions which require chemokine receptor modulation an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, hereditary characteristics, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
In still other embodiments, the present methods are directed to the treatment of allergic diseases, wherein a compound or composition of the invention is administered either alone or in combination with a second therapeutic agent, wherein said second therapeutic agent is an antihistamine. When used in combination, the practitioner can administer a combination of the compound or composition of the present invention and a second therapeutic agent. Also, the compound or composition and the second therapeutic agent can be administered sequentially, in any order.
In yet other embodiments, the present methods are directed to the treatment of psoriasis wherein a compound or composition of the invention is used alone or in combination with a second therapeutic agent selected from a corticosteroid, a lubricant, a keratolytic agent, a vitamin D3 derivative, PUVA and anthralin.
In other embodiments, the present methods are directed to the treatment of atopic dermatitis using a compound or composition of the invention either alone or in combination with a second therapeutic agent selected from a lubricant and a corticosteroid.
In further embodiments, the present methods are directed to the treatment of asthma using a compound or composition of the invention either alone or in combination with a second therapeutic agent selected from a β2-agonist and a corticosteroid.
The compounds and compositions of the present invention can be combined with other compounds and compositions having related utilities to prevent and treat the condition or disease of interest, such as inflammatory conditions and diseases, including inflammatory bowel disease, allergic diseases, psoriasis, atopic dermatitis and asthma, and those pathologies noted above.
The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). 1H-NMR were recorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are reported as the ratio of mass over charge, followed by the relative abundance of each ion (in parenthesis). In tables, a single m/e value is reported for the M+H (or, as noted, M−H) ion containing the most common atomic isotopes. Isotope patterns correspond to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSD electrospray mass spectrometer using the HP1100 HPLC for sample delivery. Normally the analyte was dissolved in methanol at 0.1 mg/mL and 1 μL was infused with the delivery solvent into the mass spectrometer, which scanned from 100 to 1500 daltons. All compounds could be analyzed in the positive ESI mode, using acetonitrile/water with 1% formic acid as the delivery solvent. The compounds provided below could also be analyzed in the negative ESI mode, using 2 mM NH4OAc in acetonitrile/water as delivery system.
Compounds within the scope of this invention can be synthesized as described below, using a variety of reactions known to the skilled artisan. A sample of useful routes to both the benzophenone and heteroaryl derived subunits and to fully elaborated sulfonamide molecules of formula (I) within this claim are provided below. In the descriptions of the syntheses that follow, some precursors were obtained from commercial sources. These commercial sources include Aldrich Chemical Co., Acros Organics, Ryan Scientific Incorporated, Oakwood Products Incorporated, Lancaster Chemicals, Sigma Chemical Co., Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, and GFS Chemicals.
Compounds of the invention can be prepared using conventional synthetic methodology. Examples of approaches that may be taken to synthesize these compounds are shown below. Nonetheless, one skilled in the art will recognize that alternative methods may be employed to synthesize the target compounds of this invention, and that the approaches described within the body of this document are not exhaustive, but do provide broadly applicable and practical routes to compounds of interest.
Certain molecules claimed in this patent can exist in different enantiomeric and diastereomeric forms and all such variants of these compounds are within the scope of the invention.
The detailed description of the experimental procedures used to synthesize key compounds in this text lead to molecules that are described by the physical data identifying them as well as by the structural depictions associated with them.
Those skilled in the art will also recognize that during standard work up procedures in organic chemistry, acids and bases are frequently used. Salts of the parent compounds are sometimes produced, if they possess the necessary intrinsic acidity or basicity, during the experimental procedures described within this patent.
The following examples are offered to illustrate, but not to limit, the claimed invention.
Additionally, those skilled in the art will recognize that the molecules claimed in this patent may be synthesized using a variety of standard organic chemistry transformations.
Certain general reaction types employed widely to synthesize target compounds in this invention are summarized in the examples. Specifically, generic procedures for sulfonamide formation, pyridine N-oxide formation and 2-aminophenyl-arylmethanone synthesis via Friedel-Crafts type approaches are given, but numerous other standard chemistries are described within and were employed routinely.
While not intended to be exhaustive, representative synthetic organic transformations which can be used to prepare compounds of the invention are included below.
These representative transformations include; standard functional group manipulations; reduction such as nitro to amino; oxidations of functional groups including alcohols and pyridines; aryl substitutions via IPSO or other mechanisms for the introduction of a variety of groups including nitrile, methyl and halogen; protecting group introductions and removals; Grignard formation and reaction with an electrophile; metal-mediated cross couplings including but not limited to Buckvald, Suzuki and Sonigashira reactions; halogenations and other electrophilic aromatic substitution reactions; diazonium salt formations and reactions of these species; etherifications; cyclative condensations, dehydrations, oxidations and reductions leading to heteroaryl groups; aryl metallations and transmetallations and reaction of the ensuing aryl-metal species with an electrophile such as an acid chloride or Weinreb amide; amidations; esterifications; nucleophilic substitution reactions; alkylations; acylations; sulfonamide formation; chlorosulfonylations; ester and related hydrolyses, and the like.
Compounds of the invention, including those listed in the table of activities, can be made by the methods and approaches described in the following experimental section and by the use of standard organic chemistry transformations well known to those skilled in the art.
The following general procedures summarize methodologies frequently utilized to synthesize the intermediates and compounds of the invention. Specific examples of the use of these general methodologies is given in the detailed experimental sections for individual compounds.
Additionally, various organic chemistry transformations are described, as they relate to the synthesis of specific compounds of the invention. These specific synthetic approaches and methodologies can also be applied, in a general sense, to access general classes of compounds claimed in this invention.
Additionally, it is envisaged that many standard organic chemistry transformations, well known to those skilled in the art, including but not limited to those outlined previously in the introductory comments section to the preparation of CCR9 modulators, can be applied to enable the synthesis of broad classes of compounds and intermediates of the invention.
To the desired aniline (0.5 mmol) dissolved in pyridine and cooled in an ice-water bath was added a solution of an aryl sulfonyl chloride (0.5 mmol) dissolved in cold pyridine. The reaction mixture was then heated to 60° C. with gentle shaking for 16 h. Evaporation of the solvent with standard workup followed by either flash chromatography or reversed phase HPLC yielded the corresponding N-aryl-benzenesulfonamides.
In the above general scheme, R represents 1 to 5 substituents consistent with the definitions provided above. To 12.5 mL 1 M BCl3 (12 mmol, 1.2 eq.) in methylene chloride stirred at 0° C. was added a solution of the desired haloaniline (10 mmol, 1.0 eq.) in 15 mL of TCE drop wise over 20 minutes. After 10 minutes the desired benzonitrile (11 mmol, 1.1 eq.) was added followed by AlCl3 (15 mmol, 1.5 eq.). The reaction was brought to room temperature, stirred for an hour then heated at 80-90° C. until all of the DCM was distilled off. The reaction mixture was then refluxed at 160° C. for 4 hours, cooled to RT and stirred overnight. 10 mL 3 M HCl were carefully added and the mixture was refluxed at 120° C. for 2-3 hours while reaction progress was monitored by LC/MS. The crude reaction was cooled to RT and 100 mL water was added. The crude mixture was extracted with DCM (2×50 mL), the aqueous layer was set aside and the organic layer was back extracted with 50 mL 1 M HCl (aq.). All aqueous layers were combined, brought to pH 12 with 3 M NaOH (aq.) and extracted with DCM (4×50 mL). The DCM layer was dried on Na2SC4, filtered and concentrated by rotary evaporation. The crude product was washed liberally with Et2O and dried under vacuum, and further purified by conventional techniques such as column chromatography when necessary.
To a solution of desired aniline (40 mmol) in 25 mL pyridine was added 5.3 mL (43.1 mmol) of pivaloyl chloride and the reaction mixture stirred overnight at room temperature. The mixture was poured into vigorously stirring 6M HCl, and the solids were collected by vacuum filtration, washed well with H2O, and dried in vacuo.
2,2-dimethyl propanamide protected aniline (0.0095 mol) in dry THF (40 ml) was cooled to −5° C. n-Butyl lithium (24 ml, 1.2 M, 0.0284 mol) was added dropwise and the reaction stirred at the same temperature for 2 h. The reaction mixture was cooled to −70° C. and to this was added the desired phenyl carboxylic acid (0.0142 mol), dissolved in dry THF (10 ml), dropwise. The mixture was stirred at room temperature for 18 h, quenched with water and extracted with ethyl acetate. The extract was washed with brine solution and concentrated. The product was purified by column using 5-10% of ethyl acetate in pet ether as eluent.
Removal of the pivaloyl protecting group form the amino ketone (0.4 g, 0.0013 mol) in 2 ml of methanol was effected via addition of potassium hydroxide (0.48 g, 0.00857 mol) in 1.2 ml of water. The reaction mixture was heated at 70° C. for 6 h, diluted with water and extracted with ethyl acetate. The extract was washed with water, brine and concentrated. The crude material was purified by column chromatography.
Alternatively, 6N HCl (10 ml) and intermediate pivaloyl protected aminoketone (1.2 g, 3.755 mmol) were heated at 90° C. overnight, cooled to room temperature, the reaction mixture basified by adding saturated sodium bicarbonate solution and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The product was purified by column chromatography.
Trimethylacetyl chloride was added drop wise to a solution of desired aniline in dry pyridine and the reaction was stirred under nitrogen overnight. About half of the pyridine was removed by rotary evaporation, then the mixture was treated with 6M hydrochloric acid and extracted with ethyl acetate. The extracts were washed with saturated aqueous NaHCO3 and with water, then were dried (MgSO4), filtered and concentrated by rotary evaporation.
EDC and desired heteroaryl carboxylic acid were stirred in acetonitrile-THF with N,O-dimethylhydroxylamine hydrochloride and triethylamine. After stirring overnight at ambient temperature, the resulting reaction mixture was added to ice water and extracted with ethyl acetate (3×100 mL). The extracts were dried, filtered, and concentrated.
To a stirred solution of the pivaloyl protected intermediate in dry THF was added 2.5M n-butyllithium in hexane at −40° C. and the mixture was stirred at 0° C. for 2 h. A solution of the Weinreb amide in dry THF was added dropwise and the reaction was stirred at ambient temp overnight. The mixture was diluted with water and extracted with ethyl acetate and the organic layer was dried (MgSC4), filtered and concentrated, to yield, after purification by HPLC or column chromatography, the pivaloyl protected aminoketone intermediate.
Deprotection with 70% sulfuric acid was carried out at 75° C. and progress monitored by LC/MS. The reaction was allowed to cool to ambient temperature, and was washed with ether-hexane. The acidic aqueous layer was cooled in an ice bath and aqueous NaOH was added drop wise to basify the mixture. The product was extracted with ethyl acetate and the extracts were washed with saturated aqueous NaHCO3 (2×100 mL), with saturated aqueous sodium chloride, dried (MgSC4), filtered and concentrated, yielding the desired (2-Amino-phenyl)-heteroaryl-methanone.
The desired benzene derivative (1.4 mmol) was dissolved in CHCl3 (15 mL) at 0° C., and to this was added chlorosulfonic acid (4.2 mmol). After 30 minutes, the reaction mixture was warmed to room temperature, and additional chlorosulfonic acid (4.2 mmol) was added. After a further hour, the reaction mixture was cooled to 0° C., and crushed ice added to the reaction. The reaction mixture was partitioned between 1M pH7 phosphate buffer and ether, and the ether layer washed with saturated aqueous NaCl, dried over Na2SC4, filtered, and concentrated in vacuo to yield crude product.
The desired aniline (0.0848 mol) was added slowly to concentrated HCl (109.2 ml), the reaction stirred at room temperature for 15 min, then cooled to 0° C., sodium nitrite (6.2 g, 0.1103 mol in 26 ml of water) added dropwise and the reaction stirred for 15 min.
Separately, distilled water (0.198 ml) was cooled to 0° C. and thionyl chloride (42.9 g, 0.3605 mol) was added dropwise, the mixture warmed to and stirred at room temperature for 17 h, then re-cooled to 0° C., and copper (I) chloride (0.120 g) added in small portions with further stirring for 30 mins to yield a yellowish green solution (Solution A).
This Cu(I) solution (A) was added dropwise to the aniline/HCl solution at −5° C., and stirring continued at 0° C. for 75 min. The reaction mixture was diluted with chloroform. The organic layer was separated, washed with brine, dried over sodium sulphate and concentrated in vacuo.
The desired bromobenzenesulfonamide derivative (0.22 mmol) was dissolved in 6 ml anhydrous dioxane, and to this solution was added potassium phosphate tribasic monohydrate (1.32 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.032 mmol), followed by the desired heterocycle (1.1 mmol). The mixture was purged under nitrogen, and Pd (dba)3 (0.01 mmol) was added. The reaction mixture was heated overnight at 90° C., cooled, water (5 mL) added, and extracted with ethyl acetate 3 times. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude reaction mixture was purified using HPLC.
The desired bromobenzenesulfonamide derivative (0.25 g, 0.55 mmol) was dissolved in 2.5 ml of anhydrous dimethylformamide. To this solution was added 0.14 g (1.3 mmol) sodium carbonate, suitable heteroaryl-3-boronic acid (0.68 mmol), and Pd(PPh3)4 19 mg (0.014 mmol). The reaction mixture was heated overnight at 80° C. under a nitrogen atmosphere. The mixture was quenched with water and extracted 3 times with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated, and the crude product purified by flash column chromatography.
To a solution of 4-chloroaniline (5.0 g, 39.2 mmol) in 25 mL pyridine was added 5.3 mL (43.1 mmol) of pivaloyl chloride and the reaction mixture stirred overnight at room temperature. The mixture was poured into vigorously stirring 6M HCl, and the solids were collected by vacuum filtration, washed well with H2O, and dried in vacuo to yield the title compound. 1H NMR (CDCl3) δ 7.47 (d, J=9.2 Hz, 2H) 7.30 (s, 1H) 7.27 (d, J=8.8 Hz, 2H) 1.32 (s, 9H) MS (ES) m/z=212.1
Following the general procedure for the synthesis of (2-Amino-phenyl)-aryl-methanones, a solution of BCl3 (1M in DCM) (24 mL, 24 mmol), cooled to 0° C., was added dropwise a solution of 4-fluoroaniline (1.77 g, 16 mmol) in 30 mL of TCE over a period of 15 min and the resulting reaction mixture stirred at that temperature for an additional 10 min. Benzonitrile (2.06 g, 20 mmol) and AlCl3 (3.0 g, 22 mmol) were added under ice-water cooling. The solution was allowed to warm to rt and stirred for 30 min. The solution was then heated at 80-90° C. for 1 h and the DCM distilled off. The resulting solution was refluxed at 160° C. for 4 h and stirred at RT overnight. 3N HCl (20 ml approx.) was added to the reaction mixture and refluxed at 100° C. for 1 hr. The reaction mixture was allowed to cool down and the solution was made basic (pH 12) with 6N NaOH. The reaction mixture was diluted with water and DCM. The resulting two layers were separated and the aqueous layer was extracted with DCM (2×150 mL) and dried over Na2SC4. After removal of solvent, the residue was purified by flash chromatography using ethyl acetate/hexane (1:12) as eluent. 630 mg of the pure product was obtained (yield=18%).
To BCl3 (1M in DCM) (48 mL, 48 mmol), cooled to 0° C., was added dropwise a solution of 4-bromoaniline (5.5 g, 32 mmol) in 60 mL of TCE over a period of 15 min and stirred at that temperature for an additional 10 min. Benzonitrile (4.12 g, 40 mmol) and AlCl3 (6.0 g, 45 mmol) were added under ice-water cooling. The solution was allowed to warm to RT and stirred for 30 min. The solution was then heated at 80-90° C. for 1 h and the DCM distilled off. The resulting solution was refluxed at 160° C. for 4 h and stirred at rt overnight. 3N HCl (40 ml approx.) was added and the reaction mixture stirred at 90° C. for 1 hr. The reaction mixture was allowed to cool to RT and the solution was brought to pH12 by addition of 6N aq. NaOH soln. The reaction mixture was diluted with water and DCM. The resulting two layers were separated and the aqueous layer was extracted with DCM (2×150 mL) and dried over Na2SC4. After removal of solvent, the residue was purified by the flash chromatography using ethyl acetate/hexane (1:12) as eluent. 1.2 g of the pure product was obtained as yellow solid (yield=14%).
To a solution of BCl3 (1M in DCM) (31.97 mL, 32 mmol) in 20 mL of TCE, cooled in an ice-water bath, was added a solution of 3-bromoaniline (5.0 g, 29 mmol) in 20 mL of TCE dropwise over a period of 15 min and the resulting reaction mixture stirred at that temperature for an additional 15 min. Benzonitrile (6 mL, 58 mmol) and AlCl3 (4.26 g, 32 mmol) were added under ice-water cooling. The solution was allowed to warm to RT and stirred for 20 min. The solution was then heated at 80-90° C. for 1 h and the DCM distilled off. The resulting solution was refluxed at 150° C. for 4 h and then stirred at RT overnight. 3N HCl was added to the reaction mixture (25 mL approx.) and the reaction mixture refluxed at 90° C. for 1 h. The reaction mixture was allowed to cool to RT and the solution was adjusted to pH9 with 6N NaOH. The resulting two layers were separated and the basic layer was extracted with DCM (6×50 mL), dried (Na2SC4) and concentrated. The product was purified using column chromatography (EA: Hex, 1:9). 2.95 g of the pure product was isolated (yield=37%). TLC analysis (EA: Hex, 1:3) Product Rf=0.65 (yellow spot). 1H NMR (500 MHz, DMSO-d6) δ 6.66 (dd, 1H, J=2.5, 8 Hz), 7.11 (d, 1H, 2 Hz), 7.19 (d, 1H, 8 Hz), 7.26 (s, 2H), 7.56 (m, 5H). 13C NMR (125 MHz, DMSO-d6) δ 197.27, 152.67, 139.49, 135.60, 131.13, 128.51, 128.27, 128.03, 118.62, 116.93, 115.44.
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.28-7.34 (m, 3H), 7.37-7.44 (m, 4H), 7.48 (dd, 1H, J=8.8, 2.4 Hz), 7.54-7.62 (m, 3H), 7.78 (d, 1H, J=8.8 Hz), 9.89 (s, 1H). MS: m/z 428.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 87 mg of 4-fluoro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 6.90 (t, 1H, J=8.8 Hz, 4.4 Hz), 7.17 (t, 1H, J=7.6 Hz), 7.38-7.46 (m, 5H), 7.52 (d, 2H, J=8 Hz), 7.60 (t, 1H, J=7.2 Hz), 7.70 (d, 1H, J=8.8 Hz), 7.83 (td, 1H, J=8.4, 1.8 Hz), 10.09 (s, 1H). MS: m/z 390.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 2,4-dichloro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.24 (m, 1H), 7.31 (m, 1H), 7.45 (m, 2H), 7.54 (m, 2H), 7.60-7.65 (m, 2H), 7.97 (d, 1H, J=8.4 Hz), 10.23 (s, 1H). MS: m/z 440.7 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 3,4-Dichloro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.25 (d, 1H, J=8.8 Hz), 7.36-39 (m, 3H), 7.43-47 (m, 3H), 7.53 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.61 (m, 1H), 7.65 (m, 1H), 7.73 (d, 1H, J=8.8 Hz), 9.56 (s, 1H). MS: m/z 440.7 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 102 mg of 4-ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.13 (t, 3H, J=8.0 Hz), 2.53 (q, 2H, J=15.3 Hz, 7.6 Hz), 7.07 (d, 2H, J=8.4 Hz), 7.32 (d, 1H, J=2.8 Hz), 7.34-7.42 (m, 4H), 7.48 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.56 (m, 3H), 7.76 (d, 1H, J=8.8 Hz), 9.75 (s, 1H). MS: m/z 400.8 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 116 mg of 4-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.90 (t, 3H, J=6.8 Hz), 1.29 (m, 2H), 1.46 (m, 2H), 2.49 (t, 2H, J=7.6 Hz), 7.05 (d, 2H, J=8.4 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.40 (m. 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.56 (m, 3H), 7.76 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). MS: m/z 428.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 109 mg of 2,3-dihydro-benzofuran-6-sulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.80 (t, 2H, J=8.8 Hz), 4.42 (t, 2H, J=9.2 Hz), 6.57 (d, 1H, J=8.4 Hz), 7.35 (m, 3H), 7.43 (m, 3H), 7.48 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.6 (m, 1H), 7.74 (d, 1H, J=8.8 Hz), 9.48 (s, 1H). MS: m/z 414.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 124 mg of 4-butoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.98 (t, 3H, J=7.6 Hz), 1.45 (m, 2H), 1.72 (m, 2H), 3.79 (t, 2H, J=6.6 Hz), 6.66 (d, 2H, J=8.8 Hz), 7.31 (d, 1H, J=2.8 Hz), 7.35-7.42 (m, 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.53-7.60 (m, 3H), 7.75 (d, 1H, J=8.8 Hz), 9.62 (s, 1H). MS: m/z 444.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 133 mg of 4-acetylamino-3-chloro-benzenesulfonyl chloride 1H-NMR (400 MHz, CDCl3): δ 2.24 (s, 3H), 7.36 (d, 1H, J=2.4), 7.40-7.60 (m, 8H), 7.66 (d, 1H, J=2.0 Hz), 7.71 (d, 1H, J=8.8 Hz), 8.36 (d, 1H, J=8.8 Hz), 9.63 (s, 1H). MS: m/z 463.0 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-fluoro-phenyl)-phenyl-methanone and 101 mg of 4-methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.64 (s, 3H), 6.62 (d, 2H, J=9.2 Hz), 7.02 (m, 1H), 7.25 (m, 1H), 7.31 (m, 2H), 7.37 (m, 2H), 7.48 (m, 2H), 7.56 (m, 1H), 7.79 (q, 1H, J=9.2 Hz, 4.8 Hz), 9.34 (s, 1H). MS: m/z 386.0 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 121 mg of 4-Pyrazol-1-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 6.47 (m, 1H), 7.25 (m, 2H), 7.30-7.35 (m, 3H), 7.41 (m, 1H), 7.49-7.55 (m, 3H), 7.67-7.72 (m, 3H), 7.75-7.78 (m, 2H), 9.62 (s, 1H). MS: m/z 438.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.30 (d, 2H, J=8.8 Hz), 7.36-7.44 (m, 4H), 7.47 (d, 1H, J=2.4 Hz), 7.54-7.63 (m, 4H), 7.21 (d, 1H, J=8.8 Hz), 9.92 (s, 1H). MS: m/z 473.4 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-phenyl-methanone and 121 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.25-7.35 (m, 5H), 7.45-7.49 (m, 4H), 7.63-7.71 (m, 4H), 7.95 (s, 1H), 9.67 (s, 1H). MS: m/z 484.3 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-phenyl-methanone and 102 mg of 4-Ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.13 (t, 3H, J=7.6 Hz), 2.54 (q, 2H, 14.8 Hz, 7.6 Hz), 7.08 (d, 2H, J=8.8 Hz), 7.35-7.43 (m, 4H), 7.46 (d, 1H, J=2.4 Hz), 7.55-7.63 (m, 4H), 7.69 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). m/z 445.3 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-Amino-5-methoxy-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.60 (s, 3H), 3.72 (s, 3H), 6.55 (d, 2H, J=8.8 Hz), 6.78 (d, 1H, J=2.8 Hz), 7.07 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.28-7.37 (m, 4H), 7.42 (d, 2H, J=6.8 Hz), 7.54 (m, 1H), 7.72 (d, 1H, J=8.8 Hz), 9.05 (s, 1H). MS: m/z 398.3 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-4-bromo-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.72 (s, 3H), 6.75 (d, 2H, J=8.8 Hz), 7.19-7.26 (m, 2H), 7.37-7.43 (m, 4H), 7.57 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.96 (s, 1H), 10.09 (s, 1H). MS: m/z 447.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 125 mg of (2-Amino-5-chloro-phenyl)-(4-fluoro-phenyl)-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.09 (t, 2H, J=8.8 Hz), 7.29 (m, 3H), 7.43-7.50 (m, 3H), 7.59 (m, 2H), 7.77 (d, 1H, J=8.8 Hz), 9.72 (s, 1H). MS: m/z 446.0 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 131 mg of ((6-Amino-3-chloro-2-methoxy-phenyl)-phenyl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.23 (s, 9H), 3.74 (s, 3H), 6.73 (d, 1H, J=2.8 Hz), 7.16 (dd, 1H, J=9.2 Hz, 3.2 Hz), 7.33 (d, 2H, J=8.4 Hz), 7.50 (d, 2H, J=6.0 Hz), 7.56 (d, 2H, J=8.8 Hz), 7.68 (d, 1H, J=9.2 Hz), 8.82 (d, 2H, J=6.4 Hz), 9.38 (s, 1H). MS: m/z 458.1 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.56 (t, 3H, J=7.2 Hz), 1.18 (s, 6H), 1.54 (q, 2H, J=7.2 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.34 (d, 1H, J=2.8 Hz), 7.40 (m, 4H), 7.45 (dd, 1H, J=8.8 Hz, 2.0 Hz), 7.56-7.62 (m, 3H, 7.78 (d, 1H, J=8.8 Hz), 9.95 (s, 1H). MS: m/z 442.0 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 131 mg of 3-(4-chlorosulfonyl-phenyl)-propionic acid methyl ester. 1H-NMR (400 MHz, CDCl3): δ 2.50 (t, 2H, J=8.0 Hz), 2.83 (t, 2H, J=8.0 Hz), 3.64 (s, 3H), 7.08 (d, 2H, J=8.8 Hz), 7.33 (d, 1H, J=2.8 Hz), 7.36-7.42 (m, 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.58 (m, 3H), 7.75 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). MS: m/z 458.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 117 mg of 4-Acetylamino-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.16 (s, 3H), 7.26 (b, 1H), 7.33 (d, 1H, J=2.4 Hz), 7.39 (m, 6H), 7.46 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.55 (m, 3H), 7.71 (d, 1H, J=8.8 Hz), 9.74 (s, 1H). MS: m/z 429.0 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 127 mg of 4-Methanesulfonyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.92 (s, 3H), 7.34 (m, 3H), 7.434 (m, 2H), 7.51 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.60 (m, 1H), 7.75 (d, 1H, J=8.8 Hz), 7.80-7.86 (m, 4H), 9.86 (b, 1H). MS: m/z 450.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.78 (s, 3H), 6.83 (d, 2H, J=9.2 Hz), 7.39 (b, 1H), 7.49 (d, 2H, J=6.4 Hz), 7.68 (m, 4H), 8.85 (d, 2H, J=6.0 Hz), 9.96 (b, 1H). MS: m/z 447.0 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 3-Cyano-benzenesulfonyl chloride. 1H NMR (CDCl3): δ 7.39-7.45 (m, 6H), 7.53-7.62 (m, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.91 (bs, 2H), 9.77 (s, 1H). MS: m/z 396.9 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)phenyl-methanone and 4-Trifluoromethoxy-benzenesulfonyl chloride. 1H NMR (CDCl3): δ 7.06 (d, J=8.0 Hz, 2H), 7.36 (m, 3H), 7.40-7.44 (m, 2H), 7.49 & 7.52 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.58-7.62 (m, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 1H), 9.81 (s, 1H). MS: m/z 456.0 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)phenyl-methanone and 2-fluoro-benzenesulfonyl chloride. 1H NMR (CDCl3): δ (ppm): 6.88-6.93 (m, 1H), 7.16-7.20 (m, 1H), 7.38 (d, J=6.4 Hz, 1H), 7.41-7.46 (m, 4H), 7.52 (m, 2H), 7.58-7.62 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.81-7.85 (m, 1H), 10.10 (s, 1H). MS: m/z 390.0 (M++1).
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 3-fluoro-benzenesulfonyl chloride. 1H NMR (CDCl3): δ (ppm): 7.00-7.05 (m, 1H), 7.35 (m, 1H), 7.37 (m, 1H), 7.39-7.44 (m, 4H), 7.37-7.43 (m, 4H), 7.45-7.46 (m, 1H), 7.49-7.50 (m, 1H), 7.51-7.52 (m, 2H), 7.58-7.62 (m, 1H), 9.80 (s, 1H). MS: m/z 390.0 (M++1).
The known compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-phenyl-methanone and 4-methoxy-benzenesulfonyl chloride and purified by flash chromatography (20% EtOAc.Hexane). 1H NMR (CDCl3) δ 9.63 (s, 1H) 7.75 (d, J=12 Hz, 1H) 7.57 (m, 3H) 7.49-7.35 (m, 5H) 7.33 (d, J=4 Hz, 1H) 6.69 (d, J=12 Hz, 2H) 3.67 (s, 3H). MS: m/z=402.0 (M++1).
2-Amino-5-chlorobenzophenone (5.33 g, 23 mmol) was dissolved in 100 mL pyridine and stirred at room temperature. 4-Bromobenzenesulfonyl chloride (6.17 g, 24.1 mmol) was added and the mixture was stirred overnight. The mixture was poured in a steady stream into 350 mL vigorously stirring chilled 6M HCl which resulted in the precipitation of a reddish oil. The solution was diluted with 100 mL EtOAc and 200 mL H2O, shaken in a separating funnel and the aqueous layer discarded. The organics were dried and reduced in vacuo to yield title compound (10.2 g, 98%). 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 7.43-7.48 (m, 5H), 7.62 (t, 1H), 7.74 (d, 1H), 9.62 (s, 1H). MS: m/z=449.9 (M++1).
2-Amino-5-chlorobenzophenone (2.92 g, 12.60 mmol) was dissolved in 60 mL of pyridine and 4-cyanobenzenesulfonyl chloride (2.66 g, 13.2 mmol) in 10 mL pyridine was then added. The mixture was stirred overnight at room temperature under N2, then poured in a steady stream into 350 mL vigorously stirring chilled 6M HCl which resulted in the precipitation of a yellow solid which was collected by vacuum filtration, washed well with H2O, then dissolved in 50 mL EtOAc and the solvents removed under vacuum to get a reddish powder which was dissolved in 75 mL boiling acetone. 150 mL of H2O was added in a slow stream to the hot, stirring acetone solution. A yellow precipitate formed upon cooling which was collected by vacuum filtration and dried overnight under vacuum to get 5.7 g product as a reddish powder (quant). 1H NMR (DMSO) δ 10.28 (s, 1H) 7.92 (dd, J=1.6, 8.8, 2H) 7.70 (d, 2H) 7.64 (t, 1H) 7.58-7.52 (m, 3H) 7.50-7.46 (m, 2H) 7.42 (d, J=2.8 Hz, 1H) 7.03 (d, 8.8 Hz, 1H). MS: m/z=397.0 (M++1).
To a magnetically stirred solution of 2-amino-5-chlorobenzophenone (1.62 g, 7.0 mmol) in dry pyridine (30 mL) was added dropwise a solution of pipsyl chloride in toluene (12 mL) and the reaction was stirred at ambient temperature. The reaction was added to cold (ice bath) 6M hydrochloric acid with stirring and the mixture was extracted with ethyl acetate (3×50 mL). The extracts were washed with water and with saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated to give a crystalline solid. The product was filtered, washed with hexane and dried (vacuum) to get white crystalline solid. 1H NMR (CDCl3) δ 9.63 (br s, 1H, NH), 7.75 (dm, 1H, J=8.8 Hz), 7.62 (tm, 1H, J=7.6 Hz), 7.56 (dm, 1H, J=7.6 Hz), 7.48 (m, 3H), 7.32 (m, 5H). MS: m/z 498.0 (M+1).
To a magnetically stirred mixture of N-(2-Benzoyl-4-chloro-phenyl)-4-iodo-benzenesulfonamide (497 mg, 1.0 mmol), [1,1′ Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.037 mmol) and dry cesium carbonate (511 mg, 1.57 mmol) in NMP (3 mL), was added DME (3 mL) and dry triethylamine (3 mL) under dry nitrogen. To this stirred mixture was added (4-methoxyphenyl)boronic acid (202 mg) and the mixture was stirred at 55° C. overnight. The reaction was worked up by addition to crushed ice and extracted with ethyl acetate (3×75 mL), and the organic layer was dried (MgSC4), filtered and concentrated. The crude product was chromatographed on silica gel using 10-30% EtOAc/Hexane. 1H NMR (CDCl3) δ 9.64 (br s, 1H, NH), 7.75 (dm, 1H), 7.75 (dm, 2H, J=8.8 Hz), 7.48 (m, 3H), 7.56 (dm, 2H, J=8.4 Hz), 7.51 (m), 7.32 (d 1H, J=2.2 Hz), 7.26 (d, 1H, J=7 Hz), 7.09 (d, 2H, J=8.4 Hz), 3.65 (s, 3H). MS: m/z 478.0 (M+1).
To a magnetically stirred mixture of the N-(2-Benzoyl-4-chloro-phenyl)-4-bromo-benzenesulfonamide (450 mg, 1.0 mmol), [1,1′ Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.037 mmol) and copper (I) iodide (100 mg, 0.52 mmol) was added DME (6 mL) and dry triethylamine (3 mL) under dry nitrogen. To this stirred mixture was added tetrabutylammonium iodide (250 mg), followed by the addition of phenylacetylene (0.240 mL). The dark green mixture was stirred at ambient temp overnight. The reaction was worked up by addition to crushed ice and extracted with ethyl acetate (3×75 mL), and the organic layer was dried (MgSC4), filtered and concentrated. The crude product was chromatographed on silica gel using 10-30% EtOAc/Hexane. 1H NMR (CDCl3) δ 9.64 (br s, 1H, NH), 7.75 (d, 1H, J=Hz), 7.75 (d, 1H, J=8.8 Hz), 7.48 (m, 8H), 7.36 (m, 7H). MS: m/z 472 (M+1)
In Vitro Assays
A variety of assays can be used to evaluate the compounds provided herein, including signaling assays, migration assays, and other assays of cellular response. CCR9 receptor signaling assays can be used to measure the ability of a compound, such as a potential CCR9 antagonist, to block CCR9 ligand-(e.g. TECK)-induced signaling. A migration assay can be used to measure the ability of a compound of interest, such as a possible CCR9 antagonist, to block CCR9-mediated cell migration in vitro. The latter is believed to resemble chemokine-induced cell migration in vivo.
In a suitable assay, a CCR9 protein (whether isolated or recombinant) is used which has at least one property, activity, or functional characteristic of a mammalian CCR9 protein. The property can be a binding property (to, for example, a ligand or inhibitor), a signaling activity (e.g., activation of a mammalian G protein, induction of rapid and transient increase in the concentration of cytosolic free calcium [Ca++]), cellular response function (e.g., stimulation of chemotaxis or inflammatory mediator release by leukocytes), and the like.
The assay can be a cell based assay that utilizes cells stably or transiently transfected with a vector or expression cassette having a nucleic acid sequence which encodes the CCR9 receptor. The cells are maintained under conditions appropriate for expression of the receptor and are contacted with a putative agent under conditions appropriate for binding to occur. Binding can be detected using standard techniques. For example, the extent of binding can be determined relative to a suitable control (for example, relative to background in the absence of a putative agent, or relative to a known ligand). Optionally, a cellular fraction, such as a membrane fraction, containing the receptor can be used in lieu of whole cells.
Detection of binding or complex formation can be detected directly or indirectly. For example, the putative agent can be labeled with a suitable label (e.g., fluorescent label, chemiluminescent label, isotope label, enzyme label, and the like) and binding can be determined by detection of the label. Specific and/or competitive binding can be assessed by competition or displacement studies, using unlabeled agent or a ligand (e.g., TECK) as a competitor.
Binding inhibition assays can be used to evaluate the present compounds. In these assays, the compounds are evaluated as inhibitors of ligand binding using, for example, TECK. In this embodiment, the CCR9 receptor is contacted with a ligand such as TECK and a measure of ligand binding is made. The receptor is then contacted with a test agent in the presence of a ligand (e.g., TECK) and a second measurement of binding is made. A reduction in the extent of ligand binding is indicative of inhibition of binding by the test agent. The binding inhibition assays can be carried out using whole cells which express CCR9, or a membrane fraction from cells which express CCR9.
The binding of a G protein coupled receptor by, for example, an agonist, can result in a signaling event by the receptor. Accordingly, signaling assays can also be used to evaluate the compounds of the present invention and induction of signaling function by an agent can be monitored using any suitable method. For example, G protein activity, such as hydrolysis of GTP to GDP, or later signaling events triggered by receptor binding can be assayed by known methods (see, for example, PCT/US97/15915; Neote, et al., Cell, 72:415425 (1993); Van Riper, et al., J. Exp. Med., 177:851-856 (1993) and Dahinden, et al., J. Exp. Med., 179:751-756 (1994)).
Chemotaxis assays can also be used to assess receptor function and evaluate the compounds provided herein. These assays are based on the functional migration of cells in vitro or in vivo induced by an agent, and can be used to assess the binding and/or effect on chemotaxis of ligands, inhibitors, or agonists. A variety of chemotaxis assays are known in the art, and any suitable assay can be used to evaluate the compounds of the present invention. Examples of suitable assays include those described in PCT/US97/15915; Springer, et al., WO 94/20142; Berman et al., Immunol. Invest., 17:625-677 (1988); and Kavanaugh et al., J. Immunol., 146:4149-4156 (1991)).
Calcium signaling assays measure calcium concentration over time, preferably before and after receptor binding. These assays can be used to quantify the generation of a receptor signaling mediator, Ca++, following receptor binding (or absence thereof). These assays are useful in determining the ability of a compound, such as those of the present invention, to generate the receptor signaling mediator by binding to a receptor of interest. Also, these assays are useful in determining the ability of a compound, such as those of the present invention, to inhibit generation of the receptor signaling mediator by interfering with binding between a receptor of interest and a ligand.
In calcium signaling assays used to determine the ability of a compound to interfere with binding between CCR9 and a known CCR9 ligand, CCR9-expressing cells (such as a T cell line MOLT-4 cells) are first incubated with a compound of interest, such as a potential CCR9 antagonist, at increasing concentrations. The cell number can be from 105 to 5×105 cells per well in a 96-well microtiter plate. The concentration of the compound being tested may range from 0 to 100 μM. After a period of incubation (which can range from 5 to 60 minutes), the treated cells are placed in a Fluorometric Imaging Plate Reader (FLIPR®) (available from Molecular Devices Corp., Sunnyvale, Calif.) according to the manufacturer's instruction. The FLIPR® system is well known to those skilled in the art as a standard method of performing assays. The cells are then stimulated with an appropriate amount of the CCR9 ligand TECK (e.g. 5-100 nM final concentration) and the signal of intracellular calcium increase (also called calcium flux) is recorded. The efficacy of a compound as an inhibitor of binding between CCR9 and the ligand can be calculated as an IC50 (the concentration needed to cause 50% inhibition in signaling) or IC50 (at 90% inhibition).
In vitro cell migration assays can be performed (but are not limited to this format) using the 96-well microchamber (called ChemoTX™). The ChemoTX™ system is well known to those skilled in the art as a type of chemotactic/cell migration instrument. In this assay, CCR9-expressing cells (such as MOLT-4) are first incubated with a compound of interest, such as a possible CCR9 antagonist, at increasing concentrations. Typically, fifty thousand cells per well are used, but the amount can range from 103-106 cells per well. CCR9 ligand TECK, typically at 50 nM (but can range from 5-100 nM), is placed at the lower chamber and the migration apparatus is assembled. Twenty microliters of test compound-treated cells are then placed onto the membrane. Migration is allowed to take place at 37 C for a period of time, typically 2.5 hours. At the end of the incubation, the number of cells that migrated across the membrane into the lower chamber is then quantified. The efficacy of a compound as an inhibitor of CCR9-mediated cell migration is calculated as an IC50 (the concentration needed to reduce cell migration by 50%) or IC50 (for 90% inhibition).
In Vivo Efficacy Models for Human IBD
T cell infiltration into the small intestine and colon have been linked to the pathogenesis of human inflammatory bowel diseases which include Coeliac disease, Crohn's disease and ulcerative colitis. Blocking trafficking of relevant T cell populations to the intestine is believed to be an effective approach to treat human IBD. CCR9 is expressed on gut-homing T cells in peripheral blood, elevated in patients with small bowel inflammation such as Crohn's disease and Coeliac disease. CCR9 ligand TECK is expressed in the small intestine. It is thus believed that this ligand-receptor pair plays a role in IBD development by mediating migration of T cells to the intestine. Several animal models exist and can be used for evaluating compounds of interest, such as potential CCR9 antagonists, for an ability to affect such T cell migration and/or condition or disease, which might allow efficacy predictions of antagonists in humans.
Animal Models with Pathology Similar to Human Ulcerative Colitis
A murine model described by Panwala and coworkers (Panwala, et al., J Immunol., 161(10):5733-44 (1998)) involves genetic deletion of the murine multi-drug resistant gene (MDR). MDR knockout mice (MDR−/−) are susceptible to developing a severe, spontaneous intestinal inflammation when maintained under specific pathogen-free facility conditions. The intestinal inflammation seen in MDR−/− mice has a pathology similar to that of human inflammatory bowel disease (IBD) and is defined by Th1 type T cells infiltration into the lamina propria of the large intestine.
Another murine model was described by Davidson et al., J Exp Med., 184(1):241-51(1986). In this model, the murine IL-10 gene was deleted and mice rendered deficient in the production of interleukin 10 (IL-10−/−). These mice develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD.
Another murine model for IBD has been described by Powrie et al., Int Immunol., 5(11):1461-71(1993), in which a subset of CD4+ T cells (called CD45RB(high)) from immunocompetent mice are purified and adoptively transferred into immunodeficient mice (such as C.B-17 scid mice). The animal restored with the CD45RBhighCD4+ T cell population developed a lethal wasting disease with severe mononuclear cell infiltrates in the colon, pathologically similar with human IBD.
Murine Models with Pathology Similar to Human Crohn's Disease
The TNF ARE(−/−) Model.
The role of TNF in Crohn's disease in human has been demonstrated more recently by success of treatment using anti-TNF alpha antibody by Targan et al., N Engl J Med., 337(15):1029-35 (1997). Mice with aberrant production of TNF-alpha due to genetic alteration in the TNF gene (ARE−/−) develop Crohn's-like inflammatory bowel diseases (see Kontoyiannis et al., Immunity, 10(3):387-98 (1999)).
The SAMP/Yit Model.
This is model described by Kosiewicz et al., J Clin Invest., 107(6):695-702 (2001). The mouse strain, SAMP/Yit, spontaneously develops a chronic inflammation localized to the terminal ileum. The resulting ileitis is characterized by massive infiltration of activated T lymphocytes into the lamina propria, and bears a remarkable resemblance to human Crohn's disease.
This example illustrates the activity associated with representative compounds of the invention.
Materials and Methods (In Vitro Assays)
Reagents and Cells
MOLT-4 cells were obtained from the American Type Culture Collection (Manassas, Va.) and cultured in RPMI tissue culture medium supplemented with 10% fetal calf serum (FCS) in a humidified 5% CO2 incubator at 37° C. Recombinant human chemokine protein TECK was obtained from R&D Systems (Minneapolis, Minn.). ChemoTX® chemotaxis microchambers were purchased from Neuro Probe (Gaithersburg, Md.). CyQUANT® cell proliferation kits were purchased from Molecular Probes (Eugene, Oreg.). Calcium indicator dye Fluo-4 AM was purchased from Molecular Devices (Mountain View, Calif.).
Conventional Migration Assay
Conventional migration assay was used to determine the efficacy of potential receptor antagonists in blocking migration mediated through CCR9. This assay was routinely performed using the ChemoTX® microchamber system with a 5-μm pore-sized polycarbonate membrane. To begin such an assay, MOLT-4 cells were harvested by centrifugation of cell suspension at 1000 PRM on a GS-6R Beckman centrifuge. The cell pellet was resuspended in chemotaxis buffer (HBSS with 0.1% BSA) at 5×106 cells/mL. Test compounds at desired concentrations were prepared from 10 mM stock solutions by serial dilutions in chemotaxis buffer. An equal volume of cells and compounds were mixed and incubated at room temperature for 15 minutes. Afterwards, 20 μL of the mixture was transferred onto the porous membrane of a migration microchamber, with 29 μL of 50 nM chemokine TECK protein placed at the lower chamber. Following a 150-minute incubation at 37° C., during which cells migrated against the chemokine gradient, the assay was terminated by removing the cell drops from atop the filter. To quantify cells migrated across the membrane, 5 μL of 7X CyQUANT® solution was added to each well in the lower chamber, and the fluorescence signal measured on a Spectrafluor Plus fluorescence plate reader (TECAN, Durham, N.C.). The degree of inhibition was determined by comparing migration signals between compound-treated and untreated cells. IC50 calculation was further performed by non-linear squares regression analysis using Graphpad Prism (Graphpad Software, San Diego, Calif.).
RAM Assay
The primary screen to identify CCR9 antagonists was carried out using RAM assay (WO 02101350), which detects potential hits by their ability to activate cell migration under inhibitory TECK concentration. To begin such an assay, MOLT-4 cells were harvested by centrifugation of cell suspension at 1000 RPM on a GS-6R Beckman centrifuge. The cell pellet was resuspended in chemotaxis buffer (HBSS/0.1% BSA) at 5×106 cells/mL. Twenty-five microliters of cells was mixed with an equal volume of a test compound diluted to 20 μM in the same buffer. Twenty microliters of the mixture was transferred onto the filter in the upper chemotaxis chamber, with 294 of 500 nM chemokine protein TECK placed in the lower chamber. Following a 150-minute incubation at 37° C., the assay was terminated by removing the cell drops from atop the filter. To quantify cells migrated across the membrane, 5 μL of 7X CyQUANT® solution was added to each well in the lower chamber, and the fluorescence signal measured on a Spectrafluor Plus fluorescence plate reader (TECAN, Durham, N.C.).
For selection of potential hits, the level of migration activation was calculated as a RAM index—the ratio between the signal of a particular well and the median signal of the whole plate. Compounds with a RAM index of greater than 1.8 were regarded as RAM positive, and were selected for IC50 determinations in conventional functional assays.
Calcium Flux Assay
Calcium flux assay measures an increase in intracellular calcium following ligand-induced receptor activation. In the screen of CCR9 antagonists, it was used as a secondary assay carried out on a FLIPR® machine (Molecular Devices, Mountain View, Calif.). To begin an assay, MOLT-4 cells were harvested by centrifugation of cell suspension, and resuspended to 1.5×106 cells/mL in HBSS (with 1% fetal calf serum). Cells were then labeled with a calcium indicator dye Fluo-4 AM for 45 minutes at 37° C. with gentle shaking. Following incubation, cells were pelletted, washed once with HBSS and resuspended in the same buffer at a density of 1.6×106 cells/mL. One hundred microliters of labeled cells were mixed with 104 of test compound at the appropriate concentrations on an assay plate. Chemokine protein TECK was added at a final concentration of 25 nM to activate the receptor. The degree of inhibition was determined by comparing calcium signals between compound-treated and untreated cells. IC50 calculations were further performed by non-linear squares regression analysis using Graphpad Prism (Graphpad Software, San Diego, Calif.).
The discovery of CCR9 antagonists was carried out in two steps: First, RAM assay was used to screen a compound library in a high-throughput manner. The assay detected compounds by their ability to cause a positive migration signal under RAM condition. Secondly, RAM positive compounds were tested to determine their IC50s using the conventional migration and calcium flux assays.
For instance, in a screen of approximately 100,000 compounds, 2000 individual wells representing approximately 2% of total compounds showed a RAM index greater than 1.8. These compounds were cheery-picked and retested in duplicate wells by RAM assay. A total of 270 compounds, or 0.27% of the library, were confirmed RAM positives.
Since a RAM positive signal indicates only the presence of a receptor antagonist and not how strongly it blocks receptor functions, the RAM positive compounds were further tested for potency in calcium flux assay using MOLT-4 cells. IC50 determinations on this subset discovered several compounds with IC50s less than 1 μM and that did not inhibit other chemokine receptors examined at significant levels.
The MDR1α-knockout mice, which lack the P-glycoprotein gene, spontaneously develop colitis under specific pathogen-free condition. The pathology in these animals has been characterized as Th1-type T cell-mediated inflammation similar to ulcerative colitis in humans. Disease normally begins to develop at around 8-10 weeks after birth. But the ages at which disease emerges and the ultimate penetrance level often vary considerably among different animal facilities.
In a study using the MDR1α-knockout mice, the known compound shown below was tested for its ability to delay disease onset during a short treatment regimen.
This compound is structurally similar to the claimed modulators (I) of the present invention. Female mice (n=15) were dosed with 50 mg/kg twice a day by intraperitonial injection, starting at age 13 weeks for 14 consecutive days. The study was terminated when the mice reached age 17 weeks at which point the disease penetrance level measured by diarrhea incidence reached 55%. The study showed that the compound was well tolerated; mice in the compound-treated group showed a significant delay in the onset of IBD symptoms. This protection extended one to two weeks after treatment stopped (
In the table below, structures and activity are provided for representative compounds described herein. Activity is provided as follows for either or both of the chemotaxis assay and/or calcium mobilization assays, described above: + 1000 nM<IC50<10000 nM; ++, 100 nM<IC50<1000 nM; and +++, IC50<100 nM.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.
This application is a Continuation of U.S. patent application Ser. No. 12/780,390, filed May 14, 2010 now abandoned, which application is a Continuation of U.S. patent application Ser. No. 12/024,860, filed Feb. 1, 2008 now U.S. Pat. No. 7,741,519, which application is a Continuation of U.S. patent application Ser. No. 11/789,304, filed Apr. 23, 2007, now U.S. Pat. No. 7,335,653, which application is a Continuation of U.S. patent application Ser. No. 10/848,836, filed May 19, 2004, now U.S. Pat. No. 7,227,035, which application is a Continuation-In-Part of U.S. patent application Ser. No. 10/716,183, filed Nov. 18, 2003 now abandoned, which application claims the benefit of U.S. Provisional Application No. 60/427,670, filed Nov. 18, 2002. The disclosures of the priority applications are incorporated by reference herein in their entirety.
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| WO 9938845 | Aug 1999 | WO |
| WO 9942465 | Aug 1999 | WO |
| WO 9955324 | Nov 1999 | WO |
| WO 9955663 | Nov 1999 | WO |
| WO 0005214 | Feb 2000 | WO |
| WO 0062778 | Oct 2000 | WO |
| WO 0100579 | Jan 2001 | WO |
| WO 0109097 | Feb 2001 | WO |
| WO 0117971 | Mar 2001 | WO |
| WO 0119788 | Mar 2001 | WO |
| WO 0119798 | Mar 2001 | WO |
| WO 0132646 | May 2001 | WO |
| WO 0156607 | Aug 2001 | WO |
| WO 0156989 | Aug 2001 | WO |
| WO 0157003 | Aug 2001 | WO |
| WO 0157020 | Aug 2001 | WO |
| WO 0160319 | Aug 2001 | WO |
| WO 0200633 | Jan 2002 | WO |
| WO 0218326 | Mar 2002 | WO |
| WO 0230358 | Apr 2002 | WO |
| WO 02054867 | Jul 2002 | WO |
| WO 02055501 | Jul 2002 | WO |
| WO 02059080 | Aug 2002 | WO |
| WO 03099773 | Dec 2003 | WO |
| WO 2005004810 | Jan 2005 | WO |
| Entry |
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| Number | Date | Country | |
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| 20110257183 A1 | Oct 2011 | US |
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|---|---|---|---|
| 60427670 | Nov 2002 | US |
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| Parent | 11789304 | Apr 2007 | US |
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| Parent | 10848836 | May 2004 | US |
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| Parent | 10716183 | Nov 2003 | US |
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