WO2015151006A1 - Composés de purine substitués en tant qu'inhibiteurs de btk - Google Patents

Composés de purine substitués en tant qu'inhibiteurs de btk Download PDF

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WO2015151006A1
WO2015151006A1 PCT/IB2015/052299 IB2015052299W WO2015151006A1 WO 2015151006 A1 WO2015151006 A1 WO 2015151006A1 IB 2015052299 W IB2015052299 W IB 2015052299W WO 2015151006 A1 WO2015151006 A1 WO 2015151006A1
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Prior art keywords
amino
phenyl
purin
mmol
title compound
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PCT/IB2015/052299
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English (en)
Inventor
Milind Dattatraya Sindkhedkar
Sachin Sethi
Nabendu Nilmani Saha
Ashok Bhau Pathak
Ganesh Chandrakant KAKADE
Dagadu Ramnath DUBE
Pankaj Popatrao YENNARE
Dipali Dinesh DARANDALE
Sudhakar Maruti BALGUDE
Vilas Shivaji THANGE
Changadeo Bhanage DNYANESHWAR
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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Publication of WO2015151006A1 publication Critical patent/WO2015151006A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to substituted purine compounds of Formula (I) pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment, management, and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the inhibition of Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • the invention also relates to method of treating, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with the inhibition of Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • Background of the invention Protein kinases, the largest family of human enzymes, consisting of more than 500 proteins are responsible for the control of a variety of signal transduction processes within the cell.
  • Protein kinases exert their physiological functions by catalysing the phosphorylation of protein(s) and thereby modulating the cellular activities. Because protein kinases have profound effect on cells, their activities are highly regulated. Kinases are turned on or off by phosphorylation (sometimes by auto-phosphorylation), by binding of activator proteins or inhibitor proteins. Dysfunctions in the activities of these kinases, arising from genetic abnormalities or environmental factors are known to be associated with many diseases. Several pathological states, including cancer and chronic inflammation are associated with stimulation of intra-cellular signalling and since kinases are crucial in relaying signalling events, their inhibition/modulation offers a powerful way to control signal transduction cascades [Mohamed AJ et al, Immunol Rev.
  • BTK Tyrosine Kinase
  • Tec family of non-receptor tyrosine kinases is a key signalling enzyme expressed in all hematopoietic cell types except T lympocytes and natural killer cells.
  • BTK plays an essential role in B-cell signalling pathway thus controlling of B-cell survival in certain B-cell cancers (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm. 2000, 282-288).
  • the magnitude and duration of BCR signals must be precisely regulated.
  • BTK has been found to be an important enzyme for the survival of BCR-Abl-positive B-cell acute lymphoblastic and leukemia cells.
  • BTK enzyme activity can treat B-cell lymphoma and Leukemia [Quek et al. Current Biology (1998), 8, 1137-1140].
  • BTK is also expressed in osteoclasts, mast cells and monocytes and plays an important role in the function of these cells. Mutation of BTK in humans results in X-linked agammaglobulinaemia (XLA). Aberrant BCR-mediated signalling can cause dysregulated B-cell activation and/or the formation of pathogenic auto-antibodies leading to multiple autoimmune and/or inflammatory diseases.
  • XLA X-linked agammaglobulinaemia
  • BTK inhibition can be useful for the treatment of allergies and/or autoimmune diseases and/or inflammatory diseases. It has been further shown that selective BTK inhibitor has demonstrated dose-dependent efficacy in a mouse arthritis model [Lichuan Liu, Journal of Pharmacology and Experimental Therapeutics (2011) 338, 154-163 and Z. Pan et al., Chem. Med. Chem. 2007, 2, 58-61]. Several compounds have been reported in the art as BTK inhibitors.
  • R is hydrogen or substituted or unsubstituted alkyl
  • W is hydrogen or halogen
  • Y is selected from hydrogen, halogen, cyano and substituted or unsubstituted alkoxy
  • X is selected from–O-R 1 , halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -S(O) 2 -alkyl or a group selected from (i) to (xiv):
  • R 1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heterocyclylalkyl;
  • R 2 is selected from a group consisting of (i) to (xv):
  • Z is a bond or O;
  • R 3 which may be same or different at each occurrence is independently selected from cyano, substituted or unsubstituted –C(O)-alkyl, –C(O)-haloalkyl, substituted or unsubstituted –S(O) 2 -alkyl, substituted or unsubstituted –S(O) 2 -alkenyl, substituted or unsubstituted–C(O)-alkenyl, substituted or unsubstituted–C(O)-alkynyl, substituted or unsubstituted–C(O)-cycloalkyl and substituted or unsubstituted–S(O) 2 -cycloalkyl;
  • R 4 which may be same or different at each occurrence, is independently selected from substituted or unsubstituted–C(O)-alkyl, substituted or unsubstituted–C(O)-alkenyl
  • R is hydrogen or methyl
  • W is hydrogen or halogen
  • X is selected from -O-R 1 , halogen, methyl, n-butyl, -CF 3 , -S(O) 2 -CH 3 or a group selected from (i) to (xiv):
  • R 1 is selected from methyl, -CF 3 , -CH 2 -CH 2 -O-CH 3 , -CH 2 -(CH 2 ) 2 -O-CH 3 , -CH 2 -CH 2 -
  • Y is selected from hydrogen, halogen, cyano and–O-CH 3 ;
  • R 2 is selected from a group consisting of (i) to (xxvi):
  • the invention provides compounds having the structure of Formula (II)
  • R is hydrogen or substituted or unsubstituted alkyl
  • R 1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heterocyclylalkyl;
  • R 2 is selected from the following groups (i) to (x);
  • Z is bond or O;
  • R 3 which may be same or different at each occurrence is independently selected from substituted or unsubstituted –C(O)-alkyl, substituted or unsubstituted –S(O) 2 -alkyl, substituted or unsubstituted –C(O)-alkenyl, substituted or unsubstituted–C(O)-alkynyl substituted or unsubstituted–C(O)-cycloalkyl and substituted or unsubstituted–S(O) 2 - cycloalkyl;
  • R 4 which may be same or different at each occurrence, is independently selected from substituted or unsubstituted–C(O)-alkyl, substituted or unsubstituted–C(O)-alkenyl, and substituted or unsubstituted–C(O)-alkynyl; or pharmaceutically acceptable salt thereof.
  • the invention provides compounds
  • R is hydrogen; R 1 is selected from methyl, -CF 3 , -CH 2 -CH 2 -O-CH 3 , -CH 2 -(CH 2 ) 2 -O-CH 3 , -CH 2 -CH 2 - N-(CH 3 ) 2 , and and
  • R 2 is selected from a group consisting of:
  • the invention provides compounds having the structure of Formula (I),
  • R is hydrogen or methyl
  • W is hydrogen or halogen
  • X is selected from–O-CH 2 -CH 2 -O-CH 3 , halogen, -CF 3 , n-butyl, -S(O) 2 -CH 3 or a group selected from (i) to (xiv):
  • Y is selected from hydrogen, halogen, cyano and–O-CH 3 ; and R 2 is selected from a group consisting of:
  • R is hydrogen or substituted or unsubstituted alkyl (e.g. methyl).
  • X is–O-R 1 where R 1 is selected from methyl, -
  • X is halogen, -CF 3 , n-butyl, -S(O) 2 -CH 3 or a group selected from (i) to (xiv):
  • W is hydrogen or halogen
  • Y is hydrogen, halogen, cyano and -OCH 3
  • R 2 is selected from the group consisting of:
  • Compounds of the invention include, for example, compounds of the Formulae (I) and/or Formula (II) or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of R, W, X, Y, and R 2 has any of the meanings defined hereinbefore or independently in any of paragraphs (1) to (5): 1) R is hydrogen or methyl;
  • W is hydrogen or halogen
  • X is selected from -O-R 1 , halogen, methyl, n-butyl, -CF 3 , -S(O) 2 -CH 3 or a group selected from (i) to (xiv):
  • R 1 is selected from methyl, -CF 3 , -CH 2 -CH 2 -O-CH 3 , -CH 2 -(CH 2 ) 2 -O-CH 3 , -
  • Y is selected from hydrogen, halogen, cyano and–O-CH 3 ; and 5) R 2 is selected from the following groups (i) to (xxvii); .
  • a compound of formula (I) or Formula (II) for use in treating, managing or lessening the severity of diseases, disorders, syndromes or conditions associated with BTK.
  • the invention provides a pharmaceutical composition comprising at least one compound of Formula (I) or Formula (II) and at least one pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition of compound of formula (I) or Formula (II) for use in treating, managing or lessening the severity of the diseases disorders, syndromes or conditions associated with BTK in a subject, in need thereof by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause inhibition of such enzyme.
  • the disease, disorders, syndromes or conditions associated with BTK is selected from cancer, proliferative disorders, autoimmune diseases, hetero-immune diseases, and inflammatory diseases.
  • halogen or halo means fluorine, chlorine, bromine, or iodine.
  • alkyl refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from 1 to 10, 1 to 6, or from 1 to 4 carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1- dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkylene refers to a bivalent alkyl group.
  • An "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenyl refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond.
  • alkynyl groups include ethynyl, propynyl, butynyl and the like.
  • alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and -OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxyalkyl refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 and the like. Unless set forth or recited to the contrary, all alkoxyalkyl groups described or claimed herein may be substituted or unsubstituted.
  • haloalkyl refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above.
  • the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom.
  • Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms.
  • a polyhaloalkyl is substituted with up to 12 halogen atoms.
  • Non- limiting examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like.
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkoxy refers to a haloalkyl, defined herein, group attached via an oxygen linkage. Non-limiting examples of such groups are monohaloalkoxy, dihaloalkoxy or polyhaloalkoxy including perhaloalkoxy. Unless set forth or recited to the contrary, all haloalkoxy group described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • cycloalkyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms and including at least one carbon-carbon double bond, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cycloalkyl group as defined above, directly bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • aryl refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 4 C 6 H 5 .
  • heterocyclic ring or “heterocyclyl ring” or “heterocyclyl”, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S.
  • the heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states.
  • heterocyclic ring may also be fused with aromatic ring.
  • heterocyclic rings include azetidinyl, tetrahydro-2H-pyran, benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, te
  • heterocyclic ring may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted; substituents may be on same or different ring atom.
  • heteroaryl unless otherwise specified, refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more heteroatom(s) independently selected from N, O or S.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl,
  • heteroarylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • the term “chiral center” refers to a carbon atom to which four different groups are attached.
  • the term “diastereomers” refers to stereoisomers which are not enantiomers.
  • the terms “racemate” or “racemic mixture” refer to a mixture of equal parts of enantiomers.
  • the term “treating” or “treatment” of a state, disease, disorder, condition or syndrome includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease disorder or condition or at least one of its clinical or subclinical symptoms thereof; and/or (d) relieving the disease, i.e., causing regression of the state
  • subject includes mammals, preferably humans and other animals, such as domestic animals; e.g., household pets including cats and dogs.
  • a “therapeutically effective amount” refers to the amount of a compound that, when administered to a subject in need thereof, is sufficient to cause a desired effect.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity, age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds of the invention may be obtained, stored and/or administered in the form of a pharmaceutically acceptable salt.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • the invention relates to pharmaceutical compositions containing the compounds of the Formula (I) disclosed herein.
  • pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent).
  • the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to inhibit BTK associated diseases described herein when administered to a subject.
  • the subjects contemplated include, for example, a living cell and a mammal, including human mammal.
  • the compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient includes pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavouring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • compositions described herein may be prepared by conventional techniques known in the art.
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • compositions may be in conventional forms, for example, capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • Solid oral formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatine), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatine and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, caplet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the total daily dose of the compounds of the invention depends, of course, on the mode of administration.
  • oral administration may require a higher total daily dose, than an intravenous (direct into blood).
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg according to the potency of the active component or mode of administration.
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient.
  • Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.
  • the compounds and compositions, according to the method of invention may be administered using any amount and any route of administration effective for treating or lessening the severity of cancer, autoimmune disorders, inflammatory diseases, neurodegenerative or neurological disorders, bone and joints related disorders.
  • the exact amount required will vary from subject to subject, depending on the age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, depends on treatment disease, and the like.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder, the activity of the compound, the specific composition employed, the age, body weight, general health, sex and diet of the patient, the time of administration, route of administration, and rate of excretion of the compound administered, the duration of the treatment, and like factors well known in the medical arts.
  • the compounds of the invention are useful in treating, managing and/or lessening the diseases, disorders, syndromes or conditions associated with the inhibition of Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • the compounds of the invention are useful in treating, managing and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the inhibition of Bruton's tyrosine kinase (BTK) such as but not limited to cancer, proliferative disorders, autoimmune diseases, hetero-immune diseases and inflammatory diseases.
  • BTK Bruton's tyrosine kinase
  • the invention relates to a method of treating, managing and/or lessening the severity of one or more diseases selected from a proliferative disorder, cancers or an autoimmune disorder hetero-immune diseases, and inflammatory diseases, wherein said method comprises administering to a patient in need thereof a compound or composition of compound of Formula (I).
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition such as cancer.
  • the cancer is a B-cell proliferative disorders including but not limited to, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma,
  • the cancer is breast cancer, bone cancer, prostate cancer or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis).
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition, namely, an autoimmune disease such as, but not limited to, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, systemic lupus erythematosis (SLE), autoimmune thyroiditis some
  • an autoimmune disease such
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition such as heteroimmune conditions or diseases, which include, but are not limited to, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), allergic conjunctivitis, allergic rhinitis, atopic dermatitis, graft versus host disease, transplantation, transfusion, anaphylaxis and type I hypersensitivity.
  • allergies e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx
  • allergic conjunctivitis e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx
  • allergic conjunctivitis e.g.,
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition such as inflammatory diseases which include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, Crohn's and ulcerative colitis, conjunctivitis, cystitis, dacryo adenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, f.brositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocardi
  • COPD
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition such as thromboembolic disorder, including, but not limited to, myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombosis.
  • thromboembolic disorder including, but not limited to, myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombos
  • BTK-inhibition As used herein, the term "BTK-inhibition" "BTK-inhibition associated" diseases, disorders and/or conditions mean any disease or other disturbed condition in which BTK, or a mutant thereof, is known to play a role. It is to be understood that the invention encompasses any of the compounds of Formulae (I) or (II), or pharmaceutically acceptable salts thereof for use in the treatment of any of the conditions disclosed herein. It is to be understood that the invention encompasses the use of any of the compounds of Formulae (I) or (II) or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of any of the conditions disclosed herein.
  • the compounds described herein may be prepared by techniques known in the art.
  • the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme-1 to 4. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the isomers of the compounds in described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • the compound of formula (2) is obtained by reacting compound of formula (1) with dihydropyran in presence of p-toluene sulphonic acid.
  • Compound of formula (2) reacting with a suitable protecting group dibenzyl amine in presence of base di-isopropylethylamine at 80°C to give compound of formula (3).
  • the compound of formula (3) is converted into compound of formula (5) using compound of formula (4) under the conditions palladium catalyst such as (tris(dibenzylideneacetone)dipalladium(0), palladium (II)acetate, xantphos, rac 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, bis(tri-t-butylphosphine)palladium(0), 2- (di-t-butylphosphino)biphenyl)using suitable base e.g.
  • palladium catalyst such as (tris(dibenzylideneacetone)dipalladium(0), palladium (II)acetate, xantphos, rac 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, bis(tri-t-butylphosphine)palladium(0), 2- (di-t-butylphosphino)bipheny
  • the compound of formula (Ia) also prepared by an alternate route i.e. Scheme-2.
  • the compound of formula (3) undergoes deprotection with p-toluene sulphonic acid to give compound of formula (13) which is on reaction with Iodo aniline (7) in presence of copper (1) iodide and base N 1 ,N 2 -dimethylethane-1,2-diamine and potassium phosphate in suitable solvent 1,4-dioxane, dimethoxyethane or N,N-dimethylformamide at 90°C to give compound of formula (14).
  • the compound of formula (14) is converted into compound of formula (9) using compound of formula (4) in presence of palladium catalyst such as (tris(dibenzylideneacetone)dipalladium(0), palladium (II)acetate, xantphos, rac 2,2’- bis(diphenylphosphino)-1,1’-binaphthyl, bis(tri-t-butylphosphine)palladium(0), 2-(di-t- butylphosphino)biphenyl)using suitable base e.g.
  • palladium catalyst such as (tris(dibenzylideneacetone)dipalladium(0), palladium (II)acetate, xantphos, rac 2,2’- bis(diphenylphosphino)-1,1’-binaphthyl, bis(tri-t-butylphosphine)palladium(0), 2-(di-t- butylphosphino)biphen
  • Formula (Ia) is obtained by reacting compound of formula (9) with an acid chloride of formula (10) or acid of formula (11 ) in presence of base like N- methylpyrrolidone, potassium carbonate, diisopropylethylamine, triethylamine and ⁇ or coupling reagent like BOP, HBTU, DCC to afford compound of formula (12), followed by deprotection of benzyl group of compound of formula (12) using triflic acid to give the compound of formula (Ia).
  • the compound of formula (17) is converted into compound of formula (18) using compound of formula (4) under the conditions palladium catalyst such as (tris(dibenzylideneacetone)dipalladium(0), palladium (II)acetate, xantphos, rac 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, bis(tri-t-butylphosphine)palladium(0) or 2- (di-t-butylphosphino)biphenyl) using suitable base (cesium carbonate, sodium tert-butoxide or potassium tert-butoxide) in suitable solvent such as 1,4-dioxane, dimethoxye
  • the compounds of formula (Ic), wherein R 1 and R 3 , X, Y and Z are as described herein above, is prepared by following the sequential transformation as depicted in Scheme-4.
  • the compound of formula (1) reacting with compound of formula (20) in presence of diisopropyl azodicarboxylate, diethyl azodicarboxylate and base such as triphenyl phosphine at an ambient temperature to afford compound of formula (21 and 22).
  • Compound of formula (21) reacting with benzyl amine in presence of base diisopropylethylamine at 80°C to afford compound of formula (23).
  • the compound of formula (23) is converted into compound of formula (24) using compound of forrmula (4) under the conditions palladium catalyst such as (tris(dibenzylideneacetone)dipalladium(0), palladium (II)acetate, xantphos, rac-2,2’- bis(diphenylphosphino)-1,1’-binaphthyl, bis(tri-t-butylphosphine) palladium(0) or 2-(di-t- butylphosphino)biphenyl) using suitable base (cesium carbonate, sodium tert-butoxide or potassium tert-butoxide in suitable solvent such as 1,4-dioxane, dimethoxyethane or N,N- dimethylformamide.
  • palladium catalyst such as (tris(dibenzylideneacetone)dipalladium(0), palladium (II)acetate, xantphos, rac-2,2’- bis(diphenyl
  • the title compound was prepared by following a procedure similar to that described in Intermediate-155 using 2,6-dichloro-9H-purine (2.5 g, 13.23 mmol), (S)-tert-butyl 3- hydroxypiperidine-1-carboxylate (5.32 g, 26.5 mmol), Triphenylphosphine (6.94 g, 26.5 mmol) and DIAD (Diisopropyl azodicarboxylate)(4.01 g, 19.84 mmol) to give title compound (0.6 g, 12.19% yield) as white solid.
  • the tide compound was prepared by following a procedure similar to that described in Intermediate- 157 using Intermediate- 169 (7 g, 15.80 mmol), 4-morpholinoaniline (3.38 g, 18.96 mmol), Palladium(II) acetate (0.355 g, 1.580 mmol), BINAP (1.968 g, 3.16 mmol) and cesium carbonate (10.30 g, 31.6 mmol) to affored title compound (8 g, 87.0%) as a off white solid.
  • the title compound was prepared by following a procedure similar to that described in Intermediate-155 using 2,6-dichloro-9H-purine (5 g, 26.5 mmol), tert-butyl 4- hydroxypiperidine-1-carboxylate (7.99 g, 39.7 mmol), Triphenylphosphine (13.88 g, 52.9 mmol) and DIAD (8.02 g, 39.7 mmol) to give title compound (3 g, 30.5% yield) as white solid.
  • the title compound was prepared by following a procedure similar to that described in Intermediate-155 using 2,6-dichloro-9H-purine (6 g, 31.7 mmol), tert-butyl 3- hydroxypyrrolidine-1-carboxylate (8.92 g, 47.6 mmol) and TRIPHENYLPhOSPHINE (12.49 g, 47.6 mmol) and DIAD (9.63 g, 47.6 mmol) to give title compound (5 g, 44% yield) as white solid.
  • the title compound was prepared by following a procedure similar to that described in Intermediate-155 using 2,6-dichloro-9H-purine (10 g, 52.9 mmol), (S)-tert-butyl 3- hydroxypyrrolidine-1-carboxylate (9.91 g, 52.9 mmol), Triphenylphosphine (20.82 g, 79 mmol) and DIAD (16.05 g, 79 mmol) to give title compound (8.0 g, 42.2% yield) as a white solid.
  • the title compound was prepared by following a procedure similar to that described in Intermediate-155 using 2,6-dichloro-9H-purine (10g, 52.9 mmol), (R)-tert-butyl 3- hydroxypyrrolidine-1-carboxylate (9.91 g, 52.9 mmol) and Triphenylphosphine (20.82 g, 79 mmol) and DIAD (16.05 g, 79 mmol) to give title compound (8 g, 42.2% yield) as white solid.
  • reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water, organic layer was concentrated in vacuo and residue obtained was purified by column chromatography using 20% EtOAc/Hexane as a eluent afforded title compound (0.619 g, 0.974 mmol, 46.8 % yield) as a off-white solid.
  • Step-1 0.5 g, 0.786 mmol
  • Dioxane Volume: 20 ml
  • HCl in Dioxane (0.197 ml, 0.786 mmol) was added dropwise at 0 °C and stirred for overnight.
  • solvent was removed in vacuo furnished title compound (0.407 g, 0.711 mmol, 90 % yield) as a off-white solid and which was used for next step.
  • Step-2 To a stirred solution of Step-2 (0.4 g, 0.699 mmol) in THF (Volume: 10 ml), DIPEA (0.611 o ml, 3.50 mmol) and acryloyl chloride (0.057 ml, 0.699 mmol) were added dropwise at 0 C and stirred for 3 hrs. Reaction mixture was partitioned between ethyl acetate and water, organic layer was concentrated in vacuo, resulted residue was purified by column chromatography using 60% EtOAc/Hexane as a eluent furnished titled compound (0.407 g, 0.690 mmol, 99 % yield) as a brown coloured solid.
  • reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water, organic layer was concentrated in vacuo and residue obtained was purified by column chromatography using 30% EtOAc/Hexane as a eluent afforded tert-butyl 3-(2-chloro-6- (dibenzylamino)-9H-purin-9-yl)azetidine-1-carboxylate (1.019 g, 2.018 mmol, 70.6 % yield) as a off-white solid.
  • reaction mixture was washed with saturated sodium bicarbonate solution and total organic layer was dried over sodium sulfate and evaporated under reduced pressure. Residue was triturated with hexane furnished title compound 525 mg as a white solid.
  • Example-1 (E)-N-(3-(6-Amino-2-((4-(2-methoxyethoxy) phenyl) amino)-9H-purin-9-yl) phenyl) but-2-enamide
  • Example-2 N-(3-(6-Amino-2-((4-(2-methoxyethoxy) phenyl) amino)-9H-purin-9-yl)phenyl) acrylamide
  • Example-3 N-(3-(6-Amino-2-((4-phenoxyphenyl) amino)-9H-purin-9-yl)phenyl) acrylamide
  • Example-7 1-(3-(6-Amino-2-((4-(2-methoxyethoxy)phenyl)amino)-9H-purin-9- yl)piperidin-1-yl)-2-methylprop-2-en-1-one
  • Example-8 1 -(3-(6-Amino-2-((4-(2-methoxyethoxy)phenyl)amino)-9H-purin-9-yl) piperidine-1-carbonyl)cyclopropanecarbonitrile
  • Example-9 1-(3-(6-Amino-2-((4-(2-methoxyethoxy)phenyl)amino)-9H-purin-9- yl)piperidin-1-yl)-3-methylbut-2-en-1-one
  • Example 53 and 54 were prepared by methylation of Example-31 using methyl iodide and NaH in DMF.
  • the biochemical assay uses ADP-GloTM Kinase Assay (Promega) to measure the ADP formed from a kinase reaction.
  • the assay carries three steps. First, the kinase enzyme reaction is carried out in presence or absence of test and reference compounds. ADP-GloTM Reagent is added to terminate the kinase reaction and deplete the remaining ATP. The Kinase detection reagent converts back the ADP formed during the kinase reaction to ATP, which is converted into light by Ultra-GloTM Luciferase, which is measure using BioTek Synergy 2 multimode plate reader. The luminescent signal positively correlates with kinase activity.
  • ADP-GloTM Kinase Assay Promega
  • test and reference compound s are pre incubated for 30 min with 1.5 ng/ml BTK kinase enzyme in 96 half area white opaque plate, followed by addition of 0.2 ⁇ g/ml substrate and 100 ⁇ M ultra-pure ATP.
  • the reaction mixture is incubated in a shaking incubator for 30 min at room temperature at 250 rpm.
  • Equal volumes of ADP-GloTM Reagent is added and incubated in shaking for 40 min.
  • double the volume of Kinase detection reagent is added and the luminescence is measured after 30 min. Percentage incubation is calculated against positive control value.
  • This ELISA based assay measures tyrosine-phosphorylated Epidermal Growth Factor Receptor (phospho-EGF R) in cell lysates.
  • An immobilized capture antibody specific for EGFR binds both phosphorylated and unphosphorylated EGF R.
  • HRP-conjugated detection antibody specific for phosphorylated tyrosine is used to detect only phosphorylated protein, utilizing a standard HRP format.
  • A431 cells are pre incubated with desired concentration of test and reference compounds in serum free media for 30 min, followed by stimulation with 400 ng/ml EGF.
  • Spend media is removed after 6 to 8 min and cells lysed in ice cold 1X lysis buffer containing protease and phosphatese inhibitor cocktails.
  • Phosphorylated EGFR in the lysate supernatant is measured by ELISA. Inhibition of EGFR Phosphorylation is calculated by comparing OD values of test against positive control values.
  • Table-4 In vitro activity of BTK (IC 50 ) and % inhibition of phosho EGFR.
  • the biochemical assay uses ADP-GloTM Kinase Assay (Promega) to measure the ADP formed from a kinase reaction.
  • the assay carries three steps. First, the kinase enzyme reaction is carried out in presence or absence of test and reference compounds. ADP-GloTM Reagent is added to terminate the kinase reaction and deplete the remaining ATP. The Kinase detection reagent converts back the ADP formed during the kinase reaction to ATP, which is converted into light by Ultra-GloTM Luciferase, which is measure using BioTek Synergy 2 multimode plate reader. The luminescent signal positively correlates with kinase activity.
  • ADP-GloTM Kinase Assay Promega
  • test and reference compound s are pre incubated for 30 min with 1.5 ng/ml BTK kinase enzyme in 96 half area white opaque plate, followed by addition of 0.2 ⁇ g/ml substrate and 30 ⁇ M ultra-pure ATP.
  • the reaction mixture is incubated in a shaking incubator for 30 min at room temperature at 250 rpm.
  • Equal volumes of ADP-GloTM Reagent is added and incubated in shaking for 40 min. Next, double the volume of Kinase detection reagent is added and the luminescence is measured after 30 min. Percentage incubation is calculated against positive control value.
  • kinase reaction was initiated by a freshly prepared mixture containing the substrate U Light polyGT Lance ultra (Cat# TRF 0100- M, Perkin Elmer) and Km concentration of ATP followed by incubation for 2 hours with shaking at 250rpm. 10mM EDTA was added to terminate the kinase reaction, followed by 2nM Anti- phosphotyrosine antibody (Cat # AD 0068, Perkin Elmer), and incubated at room temperature for 1 hour with shaking at 250rpm. FRET signal was measured in PHERAStar FS. The ratio of signals obtained at 620 nm and 665 nm were used to compute percent inhibition. Table-5: BTK, EGFR, phoshoEGFR and JAK3 activity data for representative compounds.

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Abstract

La présente invention concerne le composé de formule (I) dans laquelle les substituants sont tels que décrits dans la description, et leur utilisation dans un médicament destiné au traitement de maladies, de troubles associés à l'inhibition de la tyrosine kinase de Bruton (BTK). L'invention concerne en outre les composés décrits dans la description et leurs sels pharmaceutiquement acceptables, des compositions pharmaceutiques de ces derniers utiles dans le traitement de maladies, de troubles, de syndromes et/ou d'états associés à l'inhibition de la BTK.
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