Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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
• • 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
  • A61P37/02—Immunomodulators
• • 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
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

• BCR B-cell receptor
• Faulty signaling through the BCR can cause disregulation of the B-cell function and/or the formation of auto-antibodies which may lead to the auto-immune and/or inflammatory diseases.
• Therapeutics, such as Rituxan which deplete B-cells are effective in the treatment of inflammatory diseases such as rheumatiod arthritis.
• Bruton's Tyrosine Kinase (BTK) is a member of the TEC family of kinases and is a regulator of B-cell development, activation, signaling and survival. BTK is downstream of the BCR.
• BTK X-linked agammaglobuliaemia results in a compromised immune system, impaired maturation of B-cells, decreased peripheral B-cell levels and reduced calcium mobilization following stimulation through the BCR. Further evidence for the role of BTK in autoimmune and inflammatory diseases has been established utilizing both BTK knock-out mouse models and pharmacological inhibitors. In addition to B-cells, BTK is expressed on several other cell types that may contribute to disease, for example: mast cells, basophils, neutrophils, monocytes and osteoclasts.
• BTK inhibitors should provided substantial therapeutic benefit for patients afflicted with, for example: multiple sclerosis, type I diabetes, rheumatoid arthritis, SLE, idiopathic thrombocytopenic purpura, myasthenia gravis, allergic rhinitis, Sjögren's syndrome, B-cell lymphoma and leukemia.
• Described herein are inhibitors of Bruton's tyrosine kinase (BTK). Also described herein are methods for synthesizing such inhibitors, methods for using such inhibitors in the treatment of diseases, including diseases wherein inhibition of BTK provides therapeutic benefit to a patient having the disease. Further described are pharmaceutical formulations that include an inhibitor of BTK.
• BTK Bruton's tyrosine kinase
• A is arylene, 5-membered heteroarylene or 6-membered heteroarylene, optionally substituted with one, two, three or four R 6 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxy and (C 1 -C 4 )alkoxy;
• W is aryl, 5-membered heteroaryl or 6-membered heteroaryl, optionally substituted with one, two, three, four or five R 7 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, and halo(C 1 -C 4 )alkoxy;
• R 1 is a 4-8 membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy;
• R is cyano, cyano(C 1 -C 3 )alkyl
• R 2a , R 2b , R 3a and R 4 are independently selected from the group consisting of hydrogen or (C 1 -C 3 )alkyl;
• R 5a and R 5b are independently selected from the group consisting of hydrogen, halo and (C 1 -C 3 )alkyl;
• R a is hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulfonyl, or (C 1 -C 6 )alkyl optionally substituted by halo, hydroxyl, (C 1 -C 6 )alkoxy or halo(C 1 -C 6 )alkoxy;
• R b and R c are independently selected from the group consisting of hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, C( ⁇ O)R d and (C 1 -C 6 )alkyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy and aryl; or R b and R c taken together with the carbon to which they are bound form a 4-7 membered carbocyclyl or heterocycyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy;
• R d is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, N(R e ) 2 or aryl;
• R e is independently selected for each occurrence from the group consisting of hydrogen and (C 1 -C 4 ) alkyl, or both R e taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl;
• G is a 5-7 membered carbocyclyl or heterocycyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy; halo(C 1 -C 6 )alkoxy and aryl.
• compositions which include a therapeutically effective amount of compound(s) of the invention, or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.
• compositions provided herein further include a pharmaceutically acceptable diluent, excipient and/or binder.
• Another aspect of the invention provides a method of treating a subject suffering from a medical disorder.
• the method comprises administering to the subject a therapeutically effective amount of a compound(s) of the invention, or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate therof.
• a compound(s) of the invention or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate therof.
• a large number of disorders can be treated using the compounds described herein.
• the compounds described herein can be used to treat a cancer, an immune disorder or inflammatory disorder, such as rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, epidermal hyperplasia, and other medical disorders described herein.
• an immune disorder or inflammatory disorder such as rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, id
• the invention provides compounds, pharmaceutical compositions, methods of inhibiting BTK activity and therapeutic uses of said compounds and pharmaceutical compositions.
• the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D. M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (F. M.
• Bruton's tyrosine kinase refers to Bruton's tyrosine kinase from Homo sapiens , as disclosed in, e.g., U.S. Pat. No. 6,326,469 (GenBank Accession No. NP. sub.-000052).
• Bruton's tyrosine kinase homolog refers to orthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse (GenBank Accession No. AAB47246), dog (GenBank Accession No. XP. sub.-549139.), rat (GenBank Accession No. NP. sub.-001007799), chicken (GenBank Accession No. NP. sub.-989564), or zebra fish (GenBank Accession No. XP. sub.-698117), and fusion proteins of any of the foregoing that exhibit kinase activity towards one or more substrates of Bruton's tyrosine kinase.
• cysteine 482 is the homologous cysteine of the rat ortholog of Bruton's tyrosine kinase
• cysteine 479 is the homologous cysteine of the chicken ortholog
• cysteine 481 is the homologous cysteine in the zebra fish ortholog.
• the homologous cysteine of TXK is Cys 350.
• Other examples of kinases having homologous cysteines are shown in FIG. 1 of U.S. Patent Application Publication No. 2012/252822, which is hereby incorporated by reference. See also the sequence alignments of tyrosine kinases (TK) published on the world wide web at kinase.com/human/kinome/phylogeny.html.
• TK tyrosine kinases
• BTK inhibitor refers to an inhibitor of BTK that can form a covalent bond with an amino acid residue of BTK.
• the inhibitor of BTK can form a covalent bond with a Cys residue of BTK.
• module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
• a modulator refers to a compound that alters an activity of a molecule.
• a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
• a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule.
• an inhibitor completely prevents one or more activities of a molecule.
• a modulator is an activator, which increases the magnitude of at least one activity of a molecule.
• the presence of a modulator results in an activity that does not occur in the absence of the modulator.
• heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be different from the others.
• alkyl refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twelve carbon atoms.
• substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isoamyl, hexyl and the like.
• haloalkyl and haloalkoxy include alkyl, and alkoxy structures, respectively, in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. In other embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.
• fluoroalkyl refers to alkyl group in which at least one hydrogen is replaced with a fluorine atom.
• fluoroalkyl groups include, but are not limited to, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , —CH 2 CH 2 CF 3 and the like.
• cycloalkyl refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule and having three to ten carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Cycloalkyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, cycloalkyl may be 2 or 3 rings fused together, such as bicyclo[4.2.0]octane and decalinyl and may also be referred to as “bicycloalkyl”.
• aryl refers to an aromatic substituent containing one ring or two or three fused rings.
• the aryl substituent may have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms.
• aryl may refer to substituents such as phenyl, naphthyl and anthracenyl.
• aryl also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C 4-10 carbocyclic ring, such as a C 5 or a C 6 carbocyclic ring, or to a 4- to 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group.
• the one or more substitutents are each bound to an aromatic carbon of the fused aryl group.
• the fused C 4-10 carbocyclic or 4- to 10-membered heterocyclic ring may be optionally substituted with halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or ⁇ O.
• aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as “phenalenyl”), and fluorenyl.
• arylene refers to a bivalent radical formed by removing a hydrogen atom from an aryl, as described above.
• the number of atoms in a cyclic substituent containing one or more heteroatoms is indicated by the prefix “A-B membered”, wherein A is the minimum and B is the maximum number of atoms forming the cyclic moiety of the substituent.
• A-B membered refers to a heterocycloalkyl containing from 5 to 8 atoms, including one or more heteroatoms, in the cyclic moiety of the heterocycloalkyl.
• hydroxy or “hydroxyl” refers to OH.
• cyano also referred to as “nitrile” means CN.
• halogen and “halo” refer to fluorine (which may be depicted as F), chlorine (which may be depicted as Cl), bromine (which may be depicted as Br), or iodine (which may be depicted as I).
• the halogen is chlorine.
• the halogen is fluorine.
• the halogen is bromine.
• heterocycloalkyl and “heterocyclyl” are used interchangeably and refer to a substituent obtained by removing a hydrogen from a saturated or partially saturated ring structure containing a total of 4 to 14 ring atoms, wherein at least one of the ring atoms is a heteroatom selected from oxygen, nitrogen, or sulfur.
• the term “4- to 10-membered heterocycloalkyl” means the substituent is a single ring with 4 to 10 total members.
• a heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur).
• the ring atom of the heterocycloalkyl substituent that is bound to the group may be one of the heteroatoms, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the heteroatom(s) or where the ring carbon atom may be in a different ring from the heteroatom(s).
• the group or substituent may be bound to the heteroatom(s), or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the heteroatom(s).
• heteroaryl refers to a substituent obtained by removing a hydrogen from an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
• a heteroaryl may be a single ring or 2 or 3 fused rings.
• heteroaryl substituents include but are not limited to: 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl;
• the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
• heteroaryl also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.
• heteroarylene refers to a bivalent radical formed by removing a hydrogen atom from a heteroaryl, as described above.
• a group of substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include: (1) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and/or (3) substitutable substituents that are substituted by one or more of the optional substituents.
• a substituent such that it “may be substituted” or as being optionally substituted with up to a particular number of non-hydrogen substituents, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less.
• a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen substituents, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions.
• tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen substituent.
• an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen.
• alkylcycloalkyl contains two moieties: alkyl and cycloalkyl.
• a (C 1 -C 6 ) prefix on (C 1 -C 6 )alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the (C 1 -C 6 )-prefix does not describe the cycloalkyl moiety.
• haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents. If the halogen substitution only occurs on the alkyl moiety, the substituent would be described as “alkoxyhaloalkyl.” If the halogen substitution occurs on both the alkyl moiety and the alkoxy moiety, the substituent would be described as “haloalkoxyhaloalkyl.”
• Form (I) and Formula (II) may be referred to as a “compound(s) of the invention.” Such terms are also defined to include all forms of the compounds of Formula (I) and Formula (II) including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
• the compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.
• the solvent or water When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity.
• the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
• a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
• active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
• metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as, oxidation reactions) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
• cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Both methods are well known in the art. In some embodiments, metabolites of a compound are formed by oxidative processes and correspond to the corresponding hydroxy-containing compound. In some embodiments, a compound is metabolized to pharmacologically active metabolites.
• compounds described herein are prepared as prodrugs.
• a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
• a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
• a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
• a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
• a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration.
• the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
• Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
• Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
• the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed.
• the compounds of the invention may have asymmetric carbon atoms.
• the carbon-carbon bonds of the compounds of the invention may be depicted herein using a solid line, a solid wedge or a dotted wedge.
• the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included.
• the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom.
• a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
• the compounds of the invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof.
• the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compounds of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
• Stereoisomers of compounds of the invention include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of the invention, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
• the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
• the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
• the present invention also includes isotopically-labeled compounds, which are identical to those recited in Formulae (I) and (II) herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F , and 36 Cl.
• isotopically-labeled compounds of Formula (I) and Formula (II), for example those into which radioactive isotopes such as 3 H and 14 O are incorporated, are useful in drug and/or substrate tissue distribution assays.
• Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
• substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
• Isotopically-labeled compounds the invention may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
• the compounds of this invention may be used in the form of salts derived from inorganic or organic acids.
• a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
• a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
• the salt preferably is pharmaceutically acceptable.
• pharmaceutically acceptable salt refers to a salt prepared by combining a compounds of Formula (I) and Formula (II) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
• Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
• salts of the compounds of this invention are non-toxic “pharmaceutically acceptable salts.”
• Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
• Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
• Suitable organic acids generally include but are not limited to aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
• suitable organic acids include but are not limited to acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, ⁇ -hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate
• suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
• base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
• Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N,N′-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
• secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, N,N′-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
• Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C 1 -C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
• C 1 -C 6 halides
• dialkyl sulfates i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates
• long chain halides i.e., decyl, lau
• hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
• BTK compounds suitable for use in the methods described herein. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the ordinary skill of the art are employed. In addition, nucleic acid and amino acid sequences for BTK (e.g., human BTK) are known in the art as disclosed in, e.g., U.S. Pat. No. 6,326,469.
• the compounds of the invention described herein are selective for BTK and kinases having a cysteine residue in an amino acid sequence position of the tyrosine kinase that is homologous to the amino acid sequence position of cysteine 481 in BTK.
• an inhibitor compound of BTK used in the methods described herein is identified or characterized in an in vitro assay, e.g., an acellular biochemical assay or a cellular functional assay. Such assays are useful to determine an in vitro IC 50 for said compounds.
• the BTK inhibitor compound used for the methods described herein inhibits BTK or a BTK homolog kinase activity with an in vitro IC 50 of less than 10 ⁇ M.
• an in vitro IC 50 of less than 10 ⁇ M.
• Described herein are compounds of Formula (I), including those of Formula (II). Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound, are provided. In some embodiments, when compounds disclosed herein contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. In certain embodiments, isomers and chemically protected forms of compounds having a structure represented by Formula (I) or Formula (II), are also provided.
• the present invention relates to any of the aforementioned compounds, wherein A is arylene optionally substituted with one, two, three or four R 6 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxy and (C 1 -C 4 )alkoxy.
• the present invention relates to any of the aforementioned compounds, wherein A is
• R 6 is independently i selected for each occurrence from the group consisting of hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 3 )alkyl and halo.
• the present invention relates to any of the aforementioned compounds, wherein A is
• R 6 is independently selected for each occurrence from the group consisting of hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 3 )alkyl and halo.
• the present invention relates to any of the aforementioned compounds, wherein R 6 is hydrogen.
• the present invention relates to any of the aforementioned compounds, wherein A is 5-membered heteroarylene optionally substituted with one, two, three or four R 6 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxy and (C 1 -C 4 )alkoxy.
• the present invention relates to any of the aforementioned compounds, wherein A is 6-membered heteroarylene, optionally substituted with one, two, three or four R 6 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxy and (C 1 -C 4 )alkoxy.
• the present invention relates to any of the aforementioned compounds, wherein X is O, CH 2 or C( ⁇ O). In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is S. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is O. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is C( ⁇ O). In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is CH(OR 4 ). In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is C(R 5a )(R 5b ). In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is CH 2 .
• the present invention relates to any of the aforementioned compounds, wherein W is aryl optionally substituted with one, two, three, four or five R 7 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, and halo(C 1 -C 4 )alkoxy.
• the present invention relates to any of the aforementioned compounds, wherein W is phenyl optionally substituted with one, two, three, four or five R 7 independently selected for each occurrence from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 4 )alkoxy and halo.
• W is phenyl optionally substituted with one, two, three, four or five R 7 independently selected for each occurrence from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 4 )alkoxy and halo.
• W is phenyl optionally substituted with one, two, three, four or five R 7 independently selected for each occurrence from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 4 )alk
• the present invention relates to any of the aforementioned compounds, wherein W is
• R 7 is independently selected from the group consisting of F, Cl, methoxy and methyl.
• the present invention relates to any of the aforementioned compounds, wherein W is
• the present invention relates to any of the aforementioned compounds, wherein W is 5-membered heteroaryl optionally substituted with one, two, three, four or five R 7 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, and halo(C 1 -C 4 )alkoxy.
• the present invention relates to any of the aforementioned compounds, wherein W is 6-membered heteroaryl, optionally substituted with one, two, three, four or five R 7 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, and halo(C 1 -C 4 )alkoxy.
• the present invention relates to any of the aforementioned compounds, wherein W is pyridine optionally substituted with one, two, three, or four R 7 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxy, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and halo(C 1 -C 4 )alkoxy.
• W is pyridine optionally substituted with one, two, three, or four R 7 independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxy, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and halo(C 1 -C 4 )alkoxy.
• W is pyridine optionally substituted with one, two, three,
• the present invention relates to any of the aforementioned compounds, wherein W is
• R 7 is independently selected for each occurrence from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 4 )alkoxy, and halo.
• the present invention relates to any of the aforementioned compounds, wherein W is
• R 7 is F, Cl or CF 3 .
• the present invention relates to any of the aforementioned compounds, wherein W is
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 4-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 5-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 6-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 7-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 8-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 4-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano(C 1 -C 3 )alkyl.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 5-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano(C 1 -C 3 )alkyl.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 6-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano(C 1 -C 3 )alkyl.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 7-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano(C 1 -C 3 )alkyl.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is a 8-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano(C 1 -C 3 )alkyl.
• R 1 is a 8-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, halo, hydroxyl and (C 1 -C 4 )alkoxy; and R is cyano(C 1 -C 3 )alky
• the present invention relates to any of the aforementioned compounds, wherein R 1 is
• the present invention relates to any of the aforementioned compounds, wherein R 1 is
• the present invention relates to any of the aforementioned compounds, wherein R 1 is
• the present invention relates to any of the aforementioned compounds, wherein R 1 is
• the present invention relates to any of the aforementioned compounds, wherein R is cyano or cyano(C 1 -C 3 )alkyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R is cyano. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R is cyano(C 1 -C 3 )alkyl; or wherein R is cyanomethyl.
• the present invention relates to any of the aforementioned compounds, wherein R 2a is hydrogen. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 2a is (C 1 -C 3 )alkyl; or wherein R 2a is methyl.
• the present invention relates to any of the aforementioned compounds, wherein R 2b is hydrogen. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 2b is (C 1 -C 3 )alkyl; or wherein R 2b is methyl.
• the present invention relates to any of the aforementioned compounds, wherein R 3a is hydrogen. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 3a is (C 1 -C 3 )alkyl; or wherein R 3a is methyl.
• the present invention relates to any of the aforementioned compounds, wherein R 3b is hydrogen. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 3b is (C 1 -C 3 )alkyl; or wherein R 3b is methyl.
• the present invention relates to any of the aforementioned compounds, wherein R 4 is hydrogen. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 4 is (C 1 -C 3 )alkyl; or wherein R 4 is methyl.
• the present invention relates to any of the aforementioned compounds, wherein R 5a is hydrogen. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 5a is (C 1 -C 3 )alkyl; or wherein R 5a is methyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 5a is halo.
• the present invention relates to any of the aforementioned compounds, wherein R 5b is hydrogen. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 5b is (C 1 -C 3 )alkyl; or wherein R 5b is methyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 5b is halo.
• the present invention relates to any of the aforementioned compounds, wherein R is
• the present invention relates to any of the aforementioned compounds, wherein R is
• the present invention relates to any of the aforementioned compounds, wherein R
• the present invention relates to any of the aforementioned compounds, wherein R a is hydrogen, halo or (C 1 -C 6 )alkoxy. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R a is hydrogen. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R a is halo. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R a is (C 1 -C 6 )alkoxy. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R a is methoxy.
• the present invention relates to any of the aforementioned compounds, wherein R b is hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, or (C 1 -C 6 )alkyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy and aryl.
• the present invention relates to any of the aforementioned compounds, wherein R b is hydrogen.
• the present invention relates to any of the aforementioned compounds, wherein R b is halo. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R b is cyano. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R b is hydroxyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R b is (C 1 -C 6 )alkoxy. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R b is halo(C 1 -C 6 )alkoxy.
• the present invention relates to any of the aforementioned compounds, wherein R b is (C 1 -C 6 )alkyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy and aryl.
• the present invention relates to any of the aforementioned compounds, wherein R b is CH 3 , CHF 2 , CH 2 F, CH 2 OH, CH 2 N(CH 3 ) 2 , CH 2 OCH 3 , CH 2 CH 2 OH, CH(OH)(CH 3 ) or C(OH)(CH 3 ) 2 .
• R b is CHF 2 or CH 2 F.
• the present invention relates to any of the aforementioned compounds, wherein R b is CH 2 OCH 3 .
• the present invention relates to any of the aforementioned compounds, wherein R c is hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, or (C 1 -C 6 )alkyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy and aryl.
• the present invention relates to any of the aforementioned compounds, wherein R c is hydrogen.
• the present invention relates to any of the aforementioned compounds, wherein R c is halo. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R c is cyano. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R c is hydroxyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R c is (C 1 -C 6 )alkoxy. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R c is halo(C 1 -C 6 )alkoxy.
• the present invention relates to any of the aforementioned compounds, wherein R c is (C 1 -C 6 )alkyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy and aryl.
• the present invention relates to any of the aforementioned compounds, wherein R b and R c taken together with the carbon to which they are bound form a 4-7 membered carbocycyl or heterocycy; optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy and aryl.
• the present invention relates to any of the aforementioned compounds, wherein R b and R c taken together with the carbon to which they are bound form a 4-7 membered carbocycyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy and aryl.
• the present invention relates to any of the aforementioned compounds, wherein R b and R c taken together with the carbon to which they are bound form a 4-7 membered heterocycyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy and aryl.
• the present invention relates to any of the aforementioned compounds, wherein R d is (C 1 -C 6 )alkyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R d is (C 1 -C 6 )alkoxy. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R d is N(R e ) 2 . In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R d is aryl.
• the present invention relates to any of the aforementioned compounds, wherein R e is hydrogen. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein one R e is hydrogen and the other R e is (C 1 -C 4 ) alkyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R e is (C 1 -C 4 ) alkyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R e taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl.
• W is phenyl or pyridyl, optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 3 )haloalkyl and halo.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is
• the present invention relates to any of the aforementioned compounds, wherein R 1 is
• the present invention relates to any of the aforementioned compounds, wherein W is
• Another embodiment of the invention is a compound selected from the group consisting of the compounds of Examples 1-166 and pharmaceutically acceptable salts thereof.
• R a is hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulfonyl, or (C 1 -C 6 )alkyl optionally substituted by halo, hydroxyl, (C 1 -C 6 )alkoxy or halo(C 1 -C 6 )alkoxy;
• R b and R c are independently selected from the group consisting of hydrogen, halo, cyano, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, C( ⁇ O)R d and (C 1 -C 6 )alkyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy and halo(C 1 -C 6 )alkoxy; or R b and R c taken together with the carbon to which they are bound form a 4-7 membered carbocycyl or heterocycyl optionally substituted with one, two or three R f independently selected from the group consisting of halo, hydroxyl, N(R e ) 2 , (C 1 -C 6 )alkoxy and halo(
• R d is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, N(R e ) 2 or aryl;
• R e is independently selected for each occurrence from the group consisting of hydrogen and (C 1 -C 4 ) alkyl, or both R e taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl;
• W is phenyl or pyridyl, optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 3 )haloalkyl and halo.
• the present invention relates to any of the aforementioned compounds, wherein R 1 is
• the present invention relates to any of the aforementioned compounds, wherein R 1 is
• the present invention relates to any of the aforementioned compounds, wherein W is
• Another embodiment of the invention is a compound selected from the group consisting of the compounds of Examples 126-166 and pharmaceutically acceptable salts thereof.
• provided herein are methods for treating a patient by administering a compound provided herein.
• a method of inhibiting the activity of tyrosine kinase(s), such as BTK, or of treating a disease, disorder, or condition, which would benefit from inhibition of tyrosine kinase(s), such as BTK, in a patient which includes administering to the patient a therapeutically effective amount of at least one of any of the compounds herein, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate.
• BTK Bruton's tyrosine kinase
• compounds provided herein are administered to a human.
• compounds provided herein are orally administered.
• compounds provided herein are used for the formulation of a medicament for the inhibition of tyrosine kinase activity. In some other embodiments, compounds provided herein are used for the formulation of a medicament for the inhibition of Bruton's tyrosine kinase (BTK) activity.
• BTK Bruton's tyrosine kinase
• a method for inhibiting Bruton's tyrosine kinase in a subject in need thereof by administering to the subject thereof a composition containing a therapeutically effective amount of at least one compound of the invention.
• the subject in need is suffering from an autoimmune disease, e.g., inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, 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, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temp
• the subject in need is suffering from a heteroimmune condition or disease, e.g., graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.
• a heteroimmune condition or disease e.g., graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.
• the subject in need is suffering from an inflammatory disease, e.g., asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatiti
• the subject in need is suffering from a cancer.
• the cancer is a B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis.
• a B-cell proliferative disorder e.g., diffuse large B cell lymphoma, folli
• an anti-cancer agent is administered to the subject in addition to one of the above-mentioned compounds.
• the anti-cancer agent is an inhibitor of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002.
• the subject in need is suffering from a thromboembolic disorder, e.g., 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.
• a thromboembolic disorder e.g., 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.
• a method for treating an autoimmune disease by administering to a subject in need thereof a composition containing a therapeutically effective amount of at least one compound of the invention.
• the autoimmune disease is arthritis.
• the autoimmune disease is lupus.
• the autoimmune disease is inflammatory bowel disease (including Crohn's disease and ulcerative colitis), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, 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, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arte
• a method for treating a heteroimmune condition or disease by administering to a subject in need thereof a composition containing a therapeutically effective amount of at least one compound of the invention.
• the heteroimmune condition or disease is graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.
• the inflammatory disease is asthma, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, men
• the cancer is a B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid
• a B-cell proliferative disorder e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lympho
• an anti-cancer agent is administered to the subject in addition to one of the above-mentioned compounds.
• the anti-cancer agent is an inhibitor of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002.
• a method for treating a thromboembolic disorder by administering to a subject in need thereof a composition containing a therapeutically effective amount of at least one compound of the invention.
• the thromboembolic disorder is 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.
• a method for treating an autoimmune disease by administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with Bruton's tyrosine kinase.
• the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase.
• the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase.
• a method for treating a heteroimmune condition or disease by administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with Bruton's tyrosine kinase.
• the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase.
• the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase.
• a method for treating an inflammatory disease by administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with Bruton's tyrosine kinase.
• the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase.
• the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase.
• a method for treating a cancer by administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with Bruton's tyrosine kinase.
• the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase.
• the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase.
• a method for treating a thromboembolic disorder by administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with Bruton's tyrosine kinase.
• the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase.
• the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase.
• any of the aforementioned aspects involving the treatment of proliferative disorders, including cancer are further embodiments comprising administering at least one additional agent selected from the group consisting of alemtuzumab, arsenic trioxide, asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, PaclitaxelTM, taxol, temozolomide, thioguanine, or classes of drugs including hormones (an antiestrogen, an antiandrogen, or gonadotropin releasing hormone analogues, interferons such as alpha interferon, nitrogen mustards such as busulfan or melphalan or mechlorethamine, retinoids such as tretinoin
• any of the aforementioned aspects involving the prevention or treatment of BTK-dependent or tyrosine kinase mediated diseases or conditions are further embodiments comprising identifying patients by screening for a tyrosine kinase gene haplotype.
• the tyrosine kinase gene haplotype is a tyrosine kinase pathway gene, while in still further or alternative embodiments, the tyrosine kinase gene haplotype is a BTK haplotype.
• the compounds of the invention are inhibitors of Bruton's tyrosine kinase (BTK), while in still further or alternative embodiments, such inhibitors are selective for BTK.
• BTK Bruton's tyrosine kinase
• such inhibitors have an IC 50 below 10 ⁇ M in enzyme assay. In one embodiment, such inhibitors have an IC 50 of less than 1 ⁇ M, and in another embodiment, less than 0.25 ⁇ M.
• a compound of the invention is administered in an amount effective to treat a condition as described herein.
• the compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
• Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
• the term “therapeutically effective amount” as used herein refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
• treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
• treatment refers to the act of treating as “treating” is defined immediately above.
• treating also includes adjuvant and neo-adjuvant treatment of a subject.
• the invention provides pharmaceutical compositions, which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
• the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam
• phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
• Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
• a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
• an aforementioned formulation renders orally bioavailable a compound of the present invention.
• Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
• the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
• Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
• a compound of the present invention may also be administered as a bolus, electuary or paste.
• the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxa
• pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
• compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
• compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• embedding compositions which can be used include polymeric substances and waxes.
• the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
• Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
• Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
• the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
• Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
• Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
• dosage forms can be made by dissolving or dispersing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
• Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable carrier.
• a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
• formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
• a polymer such as crossed-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
• Such formulations may also be delivered by iontophoresis.
• the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
• Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone; as a mixture, for example, in a dry blend with lactose; or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
• the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
• compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
• aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
• the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
• the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
• the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
• systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
• These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
• the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
• a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
• the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
• the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
• a number of animal models of are useful for establishing a range of therapeutically effective doses of BTK inhibitor compounds for treating any of the foregoing diseases.
• BTK inhibitor compounds for treating an autoimmune disease can be assessed in a mouse model of rheumatoid arthritis.
• arthritis is induced in Balb/c mice by administering anti-collagen antibodies and lipopolysaccharide. See Nandakumar et al. (2003), Am. J. Pathol 163:1827-1837.
• dosing of BTK inhibitors for the treatment of B-cell proliferative disorders can be examined in, e.g., a human-to-mouse xenograft model in which human B-cell lymphoma cells (e.g. Ramos cells) are implanted into immunodeficient mice (e.g., “nude” mice) as described in, e.g., Pagel et al. (2005), Clin Cancer Res 11(13):4857-4866.
• human B-cell lymphoma cells e.g. Ramos cells
• the therapeutic efficacy of the compound for one of the foregoing diseases can be optimized during a course of treatment.
• a subject being treated can undergo a diagnostic evaluation to correlate the relief of disease symptoms or pathologies to inhibition of in vivo BTK activity achieved by administering a given dose of a BTK inhibitor.
• Cellular assays known in the art can be used to determine in vivo activity of BTK in the presence or absence of a BTK inhibitor.
• activated BTK is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551)
• phospho-specific immunocytochemical staining of P-Y223 or P-Y551-positive cells can be used to detect or quantify activation of Bkt in a population of cells (e.g., by FACS analysis of stained vs unstained cells). See, e.g., Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226.
• the amount of the BTK inhibitor inhibitor compound that is administered to a subject can be increased or decreased as needed so as to maintain a level of BTK inhibition optimal for treating the subject's disease state.
• the effective amount may be less than when the agent is used alone.
• the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
• the invention further provides a unit dosage form (such as a tablet or capsule) comprising a compound of any one of Formula (I) and Formula (II) or a specific compound described herein, or pharmaceutically acceptable salts thereof, in a therapeutically effective amount for the treatment of an immune or inflammatory disorder, such as one of the particular immune disorders or inflammatory disorders described herein.
• a unit dosage form such as a tablet or capsule
• an immune or inflammatory disorder such as one of the particular immune disorders or inflammatory disorders described herein.
• articles of manufacture including packaging material, a compound or composition or pharmaceutically acceptable derivative thereof provided herein, which is effective for inhibiting the activity of tyrosine kinase(s), such as BTK, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for inhibiting the activity of tyrosine kinase(s), such as BTK, are provided.
• the BTK inhibitor compositions described herein can also be used in combination with other well known therapeutic reagents that are selected for their therapeutic value for the condition to be treated.
• the compositions described herein and, in embodiments where combinational therapy is employed, other agents do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes.
• the determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition is well within the knowledge of the skilled clinician.
• the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
• the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
• the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
• another therapeutic agent which also includes a therapeutic regimen
• the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
• the particular choice of compounds used will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
• the compounds may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the disease, disorder, or condition, the condition of the patient, and the actual choice of compounds used.
• the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.
• therapeutically-effective dosages can vary when the drugs are used in treatment combinations.
• Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature.
• metronomic dosing i.e., providing more frequent, lower doses in order to minimize toxic side effects
• Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
• dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
• the compound provided herein may be administered either simultaneously with the biologically active agent(s), or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein in combination with the biologically active agent(s).
• the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than zero weeks to less than four weeks.
• the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations are also envisioned.
• the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought can be modified in accordance with a variety of factors. These factors include the disorder from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the dosage regimens set forth herein.
• the pharmaceutical agents which make up the combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration.
• the pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration.
• the two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents.
• the time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Circadian variation of the target molecule concentration may also determine the optimal dose interval.
• the compounds described herein also may be used in combination with procedures that may provide additional or synergistic benefit to the patient.
• patients are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical composition of a compound disclosed herein and/or combinations with other therapeutics are combined with genetic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.
• the compounds described herein and combination therapies can be administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary.
• the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
• the compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
• the administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
• the initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or combination thereof.
• a compound should be administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
• the length of treatment can vary for each subject, and the length can be determined using the known criteria.
• the compound or a formulation containing the compound can be administered for at least 2 weeks, between about 1 month to about 5 years, or from about 1 month to about 3 years.
• a BTK inhibitor compound can be used in with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthrani
• immunosuppressants e.g., tacrolimus, cyclosporin, rap
• binding proteins e.g., infliximab, etanercept, or adalimumab
• abatacept anakinra
• interferon- ⁇ interferon- ⁇
• interleukin-2 interleukin-2
• allergy vaccines antihistamines, antileukotrienes, beta-agonists, theophylline, or anticholinergics.
• the subjected can be treated with a BTK inhibitor compound in any combination with one or more other anti-cancer agents.
• one or more of the anti-cancer agents are proapoptotic agents.
• anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (GleevecTM), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, TaxolTM, also referred to as “paclitaxel”, which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation
• mitogen-activated protein kinase signaling e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002
• Syk inhibitors e.g., mTOR inhibitors
• mTOR inhibitors e.g., rituxan
• anti-cancer agents that can be employed in combination with a BTK inhibitor compound include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmus
• anti-cancer agents that can be employed in combination with a BTK inhibitor compound include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-C
• nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.
• alkyl sulfonates e.g., busulfan
• nitrosoureas e.g., carmustine, lomusitne, etc.
• triazenes decarbazine, etc.
• antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
• folic acid analog e.g., methotrexate
• pyrimidine analogs e.g., Cytarabine
• purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
• Examples of natural products useful in combination with a BTK inhibitor compound include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
• vinca alkaloids e.g., vinblastin, vincristine
• epipodophyllotoxins e.g., etoposide
• antibiotics e.g., daunorubicin, doxorubicin, bleomycin
• enzymes e.g., L-asparaginase
• biological response modifiers e.g., interferon alpha
• alkylating agents that can be employed in combination a BTK inhibitor compound include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, ete.).
• nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.
• ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
• antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
• folic acid analog e.g., methotrexate
• pyrimidine analogs e.g., fluorouracil, floxouridine, Cytarabine
• purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
• hormones and antagonists useful in combination with a BTK inhibitor compound include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).
• adrenocorticosteroids e.g., prednisone
• progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate
• estrogens e
• platinum coordination complexes e.g., cisplatin, carboblatin
• anthracenedione e.g., mitoxantrone
• substituted urea e.g., hydroxyurea
• methyl hydrazine derivative e.g., procarbazine
• adrenocortical suppressant e.g., mitotane, aminoglutethimide
• anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with a BTK inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as Cl-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochlor
• anti-thromboembolic agents include, but are not limited any of the following: thrombolytic agents (e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran
• kits and articles of manufacture are also described herein.
• Such kits can include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein.
• Suitable containers include, for example, bottles, vials, syringes, and test tubes.
• the containers can be formed from a variety of materials such as glass or plastic.
• the articles of manufacture provided herein contain packaging materials.
• Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.
• Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
• a wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by inhibition of BTK, or in which BTK is a mediator or contributor to the symptoms or cause.
• the container(s) can include one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein.
• the container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
• kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
• a kit will typically may include one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
• materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
• a set of instructions will also typically be included.
• a label can be on or associated with the container.
• a label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
• a label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.
• the pharmaceutical compositions can be presented in a pack or dispenser device which can contain one or more unit dosage forms containing a compound provided herein.
• the pack can for example contain metal or plastic foil, such as a blister pack.
• the pack or dispenser device can be accompanied by instructions for administration.
• the pack or dispenser can also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, can be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
• Compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
• the compounds of Formula (I) may be prepared as single enantiomer or as a mixture of individual enantiomers which includes racemic mixtures.
• Methods to obtain preferentially a single enantiomer from a mixture of individual enantiomers or a racemic mixture are well known to those ordinarily skilled in the art of organic chemistry. Such methods include but are not limited to preferential crystallization of diastereomeric salts (e.g. tartrate or camphor sulfonate), covalent derivatization by a chiral, non-racemic reagent followed by separation of the resulting diastereomers by common methods (e.g.
• Compounds of formula (I) may be prepared as described in Scheme A.
• Compounds of the formula A1, prepared as described in Scheme C are condensed with hydrazines of the formula A2, wherein the ring B is an optionally substituted 4-8 membered nitrogen-containing heterocycle and P is an appropriate amine protecting group (e.g. benzyloxycarbonyl, t-butoxycarbonyl, acetyl, or diphenylmethylene), to afford pyrazoles of the formula A3.
• Hydrazines of the formula A2 are commercially available or may be prepared as described in Schemes G-I.
• Compound A4 may be obtained by deprotection of the amine employing conditions such as catalytic hydrogenation in the case of benzyloxycarbonyl protection or trifluoroacetic acid in the case of t-butoxycarbonyl. Subsequent hydrolysis of the nitrile to afford carboxamides of the formula A5 may be accomplished by heating compounds A4 in the presence of strong base (e.g. sodium hydroxide) or strong acid (e.g. sulfuric acid). Alternatively, compounds of the formula A3 may be transformed to A5 directly under these conditions.
• strong base e.g. sodium hydroxide
• strong acid e.g. sulfuric acid
• compound A5 is then reacted with cyanogen bromide in a polar solvent (e.g. N,N-dimethylformamide) in the presence of an inorganic base (e.g. potassium carbonate) to afford compounds of the formula A6.1.
• a polar solvent e.g. N,N-dimethylformamide
• an inorganic base e.g. potassium carbonate
• amine A5 is reacted with bromoacetonitrile to provide compounds of the formula B1.
• compound A5 is then reacted with an alkenoic acid or alkenoic acid chloride in the presence of an amine and an appropriate coupling agent as needed to afford compounds of the formula A6.2.
• Carboxylic acids of the formula C1 employed in Scheme C may be prepared as described in Schemes D-F.
• methyl 4-hydroxybenzoate may be coupled with substituted boronic acids of the formula D1 in the presence of 4-dimethylaminopyridine and copper (II) acetate to provide esters of the formula D3.
• Subsequent saponification of D3 employing an inorganic base such as sodium hydroxide provides carboxylic acids of the formula C1.1.
• (4-(methoxycarbonyl)phenyl)boronic acid may be coupled with substituted phenols of the formula E2 in the presence of 4-dimethylaminopyridine and copper (II) acetate to provide esters of the formula D3 which can be further transformed to acids C1.1 as described in Scheme D.
• 1-(4-fluorophenyl)ethanone can be heated in dimethylacetamide with substituted phenols of the formula E2 and an inorganic base such as potassium carbonate to afford ethers of the formula F2.
• Subsequent Baeyer Villiger oxidation of F2 with sodium hypochlorite solution provides carboxylic acids of the formula C1.1.
• Compound G2 is then oxidized to provide ketones of the formula G3 which is then condensed with t-butyl hydrazinecarboxylate to provide compounds of the G4.
• the resulting hydrazone is then reacted with an appropriate metal hydride reducing agent (e.g. sodium cyanoborohydride) to provide G5.
• an appropriate metal hydride reducing agent e.g. sodium cyanoborohydride
• Compound G5 is then treated with an acid (e.g. hydrochloric acid) to provide hydrazines of the formula A1.1.
• A2 employed in Scheme A may be prepared as described in Scheme H wherein ring B is an oxazepane.
• Condensation of 3-chloro-2-(chloromethyl)prop-1-ene and N-(t-butoxycarbonyl)-2-aminoethanol in the presence of sodium hydride base provides compound H3.
• Oxidative cleavage of the olefin with sodium periodate and osmium tetroxide provides ketone H4.
• Compound H4 is condensed with benzyl hydrazinecarboxylate followed by treatment with sodium cyanoborohydride to provide compound H5.
• Compound H5 is then treated with hydrogen gas in the presence of palladium on carbon to afford hydrazine A1.2.
• A2 employed in Scheme A may be prepared as described in Scheme I wherein ring B is an azabicyclo[2.2.1]heptane.
• Cyclopenta-1,3-diene is reacted with ammonium chloride, formaldehyde, and benzyl chloroformate to provide compound 12.
• Hydroboration of 12 employing borane methyl sulfide followed by oxidation with hydrogen peroxide provides alcohol 13 which is subsequently oxidized with Dess-Martin periodinane to provide ketone 15.
• the resulting ketone is then condensed with t-butyl hydrazinecarboxylate followed by treatment with sodium cyanoborohydride to provide compound 16.
• Compound 16 is then treated with an acid (e.g. hydrochloric acid) to provide hydrazines of the formula A1.3.
• an acid e.g. hydrochloric acid
• compounds of formula (I) may be prepared as described in Scheme J.
• Condensation of 4-iodobenzoyl chloride with the sodium anion of malononitrile in anhydrous tetrahydrofuran affords compound J2 which is then reacted with methyl sulfate in the presence of an inorganic base (e.g. sodium bicarbonate) to provide compound J3.
• an inorganic base e.g. sodium bicarbonate
• Compound J3 is condensed with hydrazines of the formula A2, wherein the ring B is an optionally substituted 4-8 membered nitrogen-containing heterocycle and P is an appropriate amine protecting group (e.g.
• Hydrazines of the formula A2 are commercially available or may be prepared as described in Schemes G-I.
• Compound J4 is reacted with bis(pinacolato)diboron and potassium acetate catalyzed by PdCl 2 (dppf) 2 to provide compounds of the formula J5.
• the resulting boronates depicted by J5 are then hydrolyzed in the presence of sodium periodate and ammonium acetate to afford boronic acids of the formula J6.
• Compound J6 may be coupled with optionally substituted phenols in the presence of copper (II) acetate and pyridine to afford aryl ethers of the formula A3.1 which may be subsequently converted to compounds of formula (I) according to procedures described in Scheme A.
• aryl ethers of the formula A3.1 which may be subsequently converted to compounds of formula (I) according to procedures described in Scheme A.
• compounds of formula (I) in which the aryl ether substituent is at the meta-position may be prepared.
• the amino substituent of J4 may be transiently protected as the corresponding N-acetyl to provide compounds of the formula L1.
• Compound L1 is reacted with optionally substituted benzyl zinc halides in the presence of S-PHOS and Pd 2 (dba) 3 catalysts to afford compounds of the formula L2 wherein X ⁇ CH 2 .
• compound L1 is reacted with an optionally substituted phenol in the presence of cesium carbonate and copper (I) iodide to provide compounds of the formula L2 wherein X ⁇ O.
• compound L1 is reacted with an optionally substituted thiophenol in the presence of potassium carbonate and copper (I) iodide to provide compounds of the formula L2 wherein X ⁇ S.
• Compound L2 may then be treated with a strong base (e.g. sodium hydroxide) or a strong acid (e.g. concentrated sulfuric acid) to provide compounds of the formula A5 which may be subsequently converted to compounds of formula (I) according to procedures described in Scheme A.
• a strong base e.g. sodium hydroxide
• a strong acid e.g. concentrated sulfuric acid
• Hydrazines of the formula A2 are commercially available or may be prepared as described in Schemes G-I.
• Compounds M4 are heated in a polar solvent with an optionally substituted phenol and an inorganic base (e.g. potassium carbonate) to provide compounds of the formula M5.
• Compound M5 is then heated in an ethanolic solution of sodium hydroxide to provide carboxamides M6.
• the resulting amine is then reacted with cyanogen bromide in a polar solvent (e.g. N,N-dimethylformamide) in the presence of an inorganic base (e.g. potassium carbonate) to afford compounds of the formula M7.1 (where R ⁇ CN).
• a polar solvent e.g. N,N-dimethylformamide
• an inorganic base e.g. potassium carbonate
• the amine is reacted with bromoacetonitrile to provide compounds of the formula M7.1 (where R ⁇ CH 2 CN).
• the resulting amine is then reacted with an alkenoic acid or alkenoic acid chloride in the presence of an amine and an appropriate coupling agent as needed to afford compounds of the formula M7.2.
• Compound N3 is condensed with hydrazines of the formula A2, wherein the ring B is an optionally substituted 4-8 membered nitrogen-containing heterocycle and P is an appropriate amine protecting group (e.g. benzyloxycarbonyl, t-butoxycarbonyl, acetyl, or diphenylmethylene), to afford pyrazoles of the formula N4.
• Hydrazines of the formula A2 are commercially available or may be prepared as described in Schemes G-I.
• Compound N4 is treated with acetyl chloride and triethylamine to afford compounds of the formula N5 which when treated with lithium hydroxide in a mixture of methanol and water provide compound N6.
• a polar solvent e.g. N,N-dimethylformamide
• an optionally substituted 2-halopyridine and an inorganic base e.g. cesium carbonate
• Compound N7 is reacted with concentrated sulfuric acid to provide carboxamides of the formula N8.
• the resulting amines are then reacted with cyanogen bromide in a polar solvent (e.g. N,N-dimethylformamide) in the presence of an inorganic base (e.g. potassium carbonate) to afford compounds of the formula N9.1 (where R ⁇ CN).
• a polar solvent e.g. N,N-dimethylformamide
• an inorganic base e.g. potassium carbonate
• the amines are reacted with bromoacetonitrile to provide compounds of the formula N9.1 (where R ⁇ CH 2 CN).
• the resulting amines are then reacted with an alkenoic acid or alkenoic acid chloride in the presence of an amine and an appropriate coupling agent as needed to afford compounds of the formula M9.2.
• esters are then treated with lithium hydroxide in a mixture of methanol and tetrahydrofuran to provide carboxylic acids of the formula O4 which are then coupled with ammonia after activation with 1-hydroxybenzotriazole and 3-(dimethylamino)propyl carbodiimide hydrochloride to provide amide O5.
• Compound O5 is then treated with and acid (e.g. trifluoroacetic acid) to provide amines of the formula O6.
• the resulting amines are then reacted with cyanogen bromide in a polar solvent (e.g. N,N-dimethylformamide) in the presence of an inorganic base (e.g. potassium carbonate) to afford compounds of the formula O7 (R ⁇ CN).
• a polar solvent e.g. N,N-dimethylformamide
• an inorganic base e.g. potassium carbonate
• the amines are reacted with bromoacetonitrile to provide compounds of the formula O8 (R ⁇ CH 2 CN).
• the resulting amines are then reacted with an alkenoic acid or alkenoic acid chloride in the presence of an amine and an appropriate coupling agent as needed to afford compounds of the formula O9.
• boronic acid esters of the formula O2 employed in Scheme O may be prepared as described in Scheme Q.
• Phenols of the formula Q1 are reacted with boronic acids of the formula D1 in the presence of copper (II) acetate and triethylamine to provide ethers of the formula Q2.
• Aryl bromides such as Q2 are then reacted with bis(pinacolato)diboron in the presence of an inorganic base (e.g. potassium acetate) and Pd(dppf) 2 Cl 2 to provide compounds of the formula O2.
• reaction conditions length of reaction and temperature
• reaction conditions may vary.
• reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate.
• Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluants/gradients were chosen to provide appropriate Rf's or retention times (RetT).
• Step 1 preparation of 4-phenoxy benzoyl chloride.
• a solution of 4-phenoxy benzoic acid (500 g, 2.33 mol) in thionyl chloride (1.2 L) was refluxed for 16 h, after which volatiles were removed in vacuo to afford the title compound as a brown gum, which was taken on to the next step without purification.
• Step 2 preparation of 2-[hydroxy-(4-phenoxy-phenyl)-methylene]malononitrile.
• a solution of malononitrile (154 mL, 2.55 mol) in anhydrous tetrahydrofuran (500 mL) was added drop wise under nitrogen to a suspension of sodium hydride (205 g, 5.12 mol) in tetrahydrofuran (2 L) over 1.5 h at 0° C.
• the reaction mixture was allowed to stir for an additional 30 min, after which addition of a solution of 4-phenoxy benzoyl chloride (540 g, 2.32 mol) in tetrahydrofuran (750 mL) was added.
• Step 3 preparation of 2-[(4-phenoxy-phenyl)methoxy-methylene]-malononitrile.
• 2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile (600 g, 2.29 mol) in a mixture of dioxane/water (4/1.5, L) at 0° C. was added sodium bicarbonate (1.34 kg, 16 mol) portion wise.
• Dimethyl sulfate (1.2 L, 13.74 mol) was added drop wise over 2 h, after which the reaction was warmed to 80° C. and allowed to stir for an additional 12 h.
• the reaction was cooled to ambient temperature, diluted with water and extracted into ethyl acetate.
• Step 4 preparation of 3-Hydroxy-piperidine-1-carboxylic acid benzyl ester.
• piperidin-3-ol hydrochloride 134 g, 0.974 mol
• triethylamine 276 mL, 1.98 mol
• dichloromethane 2 L
• benzyl chloroformate 140 mL, 0.981 mol
• dichloromethane 100 mL
• Step 5 preparation of 3-oxo-piperidine-1-carboxylic acid benzyl ester.
• pyridine sulfur trioxide complex 135.6 g, 0.85 mol
• dichloromethane 1.25 L
• DMSO 151 mL, 2.13 mol
• a solution of 3-hydroxy-piperidine-1-carboxylic acid benzyl ester (50.0 g, 0.21 mol) in dichloromethane (415 mL) was then added drop wise over 1 h, ensuring that the temperature did not exceed 0° C.
• Step 6 preparation of 3-(tert-butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid benzyl ester.
• 3-oxo-piperidine-1-carboxylic acid benzyl ester 150 g, 0.64 mol
• tetrahydrofuran 1.5 L
• tert-butyl hydrazinecarboxylate 85 g, 0.64 mol
• Step 7 preparation of benzyl 3-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate.
• 3-(tert-butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid benzyl ester 230 g, 0.66 mol
• sodium cyanoborohydride 41.6 g, 0.66 mol
• Step 8 preparation of 3-hydrazino-piperidine-1-carboxylic acid benzylester hydrochloride.
• benzyl 3-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate 50 g, 0.143 mol
• methanol 180 mL
• 4N hydrochloric acid 4N hydrochloric acid in dioxane
• Step 9 preparation of benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol-1-yl]-piperidine-1-carboxylate.
• 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile step 3; 146 g, 0.53 mol
• benzyl 3-hydrazino-piperidine-1-carboxylate step 8; 150.6 g, 0.53 mol
• triethylamine 107 g, 1.05 mol
• Step 10 preparation of 5-amino-3-(4-phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazole-4-carbonitrile.
• a solution of benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol-1-yl]-piperidine-1-carboxylate (260 g, 527 mmol) in 2-methyl tetrahydrofuran (5 L) was passed through a Midi apparatus at 65° C., 7 mL/min, under full hydrogen, using a 10% Pd/C cartridge over a period of 16 h. Solvent was removed in vacuo to afford the title compound as a tan solid.
• Step 11 preparation of 5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide.
• a solution of 5-amino-3-(4-phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazole-4-carbonitrile 189 g, 527 mmol
• ethanol 550 mL
• a 2N sodium hydroxide solution (880 mL) was then added and the autoclave was sealed and heated at 150° C. for 30 min, after which the reaction was judged complete.
• the solution was cooled to ambient temperature and added to ethyl acetate (500 mL).
• Step 12 preparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole carboxamide.
• 5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide (1.17 g, 3.10 mmol) in N,N-dimethylformamide was added potassium carbonate (643 mg, 4.65 mmol) followed by cyanogen bromide (398 mg, 3.72 mmol). The mixture was stirred at 50° C. over 16 h, after which volatiles were removed in vacuo.
• Step 1 preparation of benzyl 4-oxopiperidine-1-carboxylate.
• piperidin-4-one hydrochloride 150 g, 0.98 mol
• saturated aqueous sodium bicarbonate 3 L
• benzyl chlorocarbonate 192 g, 1.13 mol
• dioxane 114 mL
• the reaction was allowed to stir 16 h at ambient temperature.
• the mixture was then extracted into ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound (236 g, >99%).
• Step 2 preparation of benzyl 4-(2-(tert-butoxycarbonyl)hydrazono)piperidine-1-carboxylate.
• a solution of benzyl 4-oxopiperidine-1-carboxylate (236 g, 1.01 mol) and tert-butyl hydrazine carboxylate (133 g, 1.01 mol) in heptane (6.5 L) was heated to reflux for 1 h.
• the resulting precipitate was filtered affording the title compound (296 g, 0.84 mol).
• Step 3 preparation of benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate.
• a solution of benzyl 4-(2-(tert-butoxycarbonyl)hydrazono)piperidine-1-carboxylate (250 g, 0.72 mol) in tetrahydrofuran (1.7 L) was allowed to stir at ambient temperature for 30 min, then cooled to 4° C.
• Sodium cyanoborohydride 50 g, 0.79 mol
• Step 4 preparation of benzyl 4-hydrazinylpiperidine-1-carboxylate hydrochloride.
• a solution of benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate (174 g, 0.5 mol) in a 50% solution of methanol/4N hydrochloric acid in dioxane (2 L) was allowed to stir at ambient temperature for 48 h, after which it was concentrated in vacuo.
• the resulting crude white solid was triturated with warm dichloromethane, to afford the title compound (131 g, 96%).
• Step 5 preparation of 5-amino-3-(4-phenoxyphenyl)-1-piperidin-4-yl-1H-pyrazole-4-carboxamide.
• Step 6 preparation of 5-amino-1-(1-cyanopiperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide.
• Step 1 preparation of benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate.
• a solution of (3S)-pyrrolidin-3-ol (10.0 g, 0.12 mol) in dichloromethane (130 mL) was cooled to 5° C.
• Triethylamine (16.9 mL, 0.12 mol) was added, followed by drop wise addition of benzyl chloroformate (13.9 mL, 0.10 mol), ensuring that the temperature did not exceed 5° C.
• the reaction mixture was then allowed to stir at ambient temperature for 48 h, after which it was poured into aqueous saturated sodium bicarbonate and extracted into dichloromethane.
• Step 2 preparation of benzyl 3-oxopyrrolidine-1-carboxylate.
• benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate 7.5 g, 33.9 mmol
• dichloromethane 1.2 L
• 4-methylmorpholine N-oxide 5.96 g, 50.0 mmol
• tetrapropylammonium perruthenate 0.60 g, 1.7 mmol
• 4 ⁇ molecular sieves 7.0 g.
• the reaction mixture was allowed to stir under nitrogen for 2 h, after which it was filtered through a silica gel plug and eluted with diethyl ether.
• the filtrate can concentrated to afford the title compound as clear oil (6.5 g, 88%).
• Step 3 preparation of benzyl 3-[2-(tert-butoxycarbonyl)hydrazino]pyrrolidine-1-carboxylate.
• benzyl 3-oxopyrrolidine-1-carboxylate (3.0 g, 13.7 mmol) in tetrahydrofuran (30 mL) was added tert-butyl hydrazinecarboxylate (1.81 g, 13.7 mmol).
• Step 4 preparation of benzyl 3-hydrazinopyrrolidine-1-carboxylate.
• benzyl 3-[2-(tert-butoxycarbonyl)hydrazino]pyrrolidine-1-carboxylate 2.0 g, 6.4 mmol
• 4M hydrochloric acid in dioxane 6.0 mL
• the solution was allowed to stir at 60° C. for 3 h.
• the solvent was removed in vacuo, and the resulting residue was partitioned between water and ethyl acetate.
• the organic layer was discarded and the aqueous layer then concentrated in vacuo to afford the title compound as a white foam (1.7 g, >99%).
• Step 5 preparation of 5-amino-3-(4-phenoxyphenyl)-1-pyrrolidin-3-yl-1H-pyrazole-4-carboxamide.
• Step 6 preparation of 5-amino-1-(1-cyanopyrrolidine-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide.
• Step 1 preparation of 1-(diphenylmethyl)azetidin-3-one.
• sulfur trioxide-pyridine complex 69 g, 432.95 mmol
• dimethylsulfoxide 172.6 mL
• a solution of 1-(diphenylmethyl)azetidin-3-ol hydrochloric acid 20 g, 72.52 mmol
• triethylamine 50.5 mL, 362.6 mmol
• tetrahydrofuran 69 mL
• Step 2 preparation of tert-butyl 2-[1-(diphenylmethyl)azetidin-3-ylidene]hydrazinecarboxylate.
• a solution of 1-(diphenylmethyl)azetidin-3-one (11.4 g, 48.0 mmol) in methanol (110 mL) was cooled to 0° C.
• tert-Butyl hydrazinecarboxylate (6.3 g, 48.0 mmol) was added, followed by drop wise addition of acetic acid (5.56 mL).
• the reaction was allowed to stir over 16 h.
• the solvents were removed in vacuo, and the resulting residue was dissolved in dichloromethane and washed with 1N sodium hydroxide, then with brine.
• the organic layer was dried over sodium sulfate and concentrated in vacuo.
• the crude solid was purified by trituration with diethyl ether to afford the title compound as a white solid (15.8 g
• Step 3 preparation of tert-butyl 2-[1-(diphenylmethyl)azetidin-3-yl]hydrazinecarboxylate.
• a solution of tert-butyl 2-[1-(diphenylmethyl)azetidin-3-ylidene]hydrazinecarboxylate (15.8 g, 45.0 mmol) in acetic acid (120 mL) was cooled to 0° C.
• Step 4 preparation of 1-benzhydryl-3-hydrazinylazetidine.
• tert-butyl 2-[1-(diphenylmethyl)azetidin-3-yl]hydrazinecarboxylate (19.3 g, 54.6 mmol) in dioxane (633 mL) at 0° C.
• 4M hydrochloric acid in dioxane (290 mL).
• the reaction was allowed to stir at ambient temperature for 4 h.
• the solvent was removed in vacuo, and the resulting residue was purified via trituration with diethyl ether, affording the hydrochloride salt of the title compound as a white solid (16.5 g, >99%).
• Step 5 preparation of 5-amino-1-(1-benzhydrylazetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile.
• benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol-1-yl]-piperidine-1-carboxylate (Example 1, step 9) employing 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile (Example 1, Step 3) (1.0 g, 3.25 mmol) and 1-benzhydryl-3-hydrazinylazetidine (0.69 g, 6.82 mmol) at ambient temperature to afford the title compound as the hydrochloric acid salt (1.04 g, 64%).
• Step 6 preparation of 5-amino-1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile.
• a solution of 5-amino-1-(1-benzhydrylazetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (0.29 g, 0.58 mmol) and concentrated hydrochloric acid (0.5 mL) in methanol (30 mL) was run through a 20% palladium hydroxide cartridge in an H-cube apparatus at 50° C. twice. The solution was then concentrated in vacuo to afford the title compound (0.19 g, 98%).
• Step 7 preparation of 5-amino-1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide.
• Step 8 preparation of 5-amino-1-(1-cyanoazetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide.
• MS (M+H) m/z 375 Example 1, Step 12
• Step 1 preparation of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate.
• 3-chloro-2-(chloromethyl)prop-1-ene (10.0 g, 80.0 mmol) in N,N-dimethylformamide (130 mL) at 0° C.
• sodium hydride (5.8 g, 174.0 mmol) in a single portion.
• the reaction was allowed to stir at 0° C. for 10 min, after which a solution of N-(tert-butoxycarbonyl)-2-aminoethanol (12.9 g, 80.0 mmol) in tetrahydrofuran (100 mL) was added slowly via cannula.
• Step 2 preparation of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate.
• a solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (4.0 g, 18.76 mmol) in dioxane (80 mL) was added a solution of sodium periodate (8.0 g, 37.4 mmol) in water (80 mL), followed by 1.2 mL of a 2.5% wt solution of osmium tetroxide in tert-butanol.
• the reaction was allowed to stir at ambient temperature for 48 h, after which water and brine were added, and the desired product was extracted into ethyl acetate.
• the combined organic layers were dried over magnesium sulfate and concentrated in vacuo.
• the resulting brown oil was passed through a silica gel plug to afford the title compound as a clear oil.
• Step 3 preparation of tert-butyl 6- ⁇ 2-[(benzyloxy)carbonyl]hydrazino ⁇ -1,4-oxazepane-4-carboxylate.
• tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate 2.0 g, 9.29 mmol
• benzyl hydrazinecarboxylate 1.54 g, 9.29 mmol
• Step 4 preparation of tert-butyl 6-hydrazino-1,4-oxazepane-4-carboxylate.
• a solution of tert-butyl 6- ⁇ 2-[(benzyloxy)carbonyl]hydrazino ⁇ -1,4-oxazepane-4-carboxylate (2.9 g, 8.3 mmol) in ethanol (30 mL) was added 10% Pd/C (500 mg, 50% wet). The mixture was placed under hydrogen (50 psi, Parr shaker) for 24 h, after which it was filtered through Celite and wash several times with ethanol. The filtrate was concentrated in vacuo to afford the title compound as an oil (1.8 g, 94%).
• Step 5 preparation of tert-butyl 6-[5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl]-1,4-oxazepane-4-carboxylate.
• Step 6 preparation of 5-amino-1-(1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile.
• a solution of tert-butyl 6-[5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl]-1,4-oxazepane-4-carboxylate in equal parts dichloromethane, trifluoroacetic acid, and triethyl silane (30 mL) was allowed to stir at ambient temperature for 1 h. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo, to afford the title compound.
• Step 7 preparation of 5-amino-1-(1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide.
• the title compound was prepared from 5-amino-1-(1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to the procedure described for 5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide (Example 1, Step 11).
• Step 8 preparation of 5-amino-1-(4-cyano-1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide.
• the title compound was prepared from 5-amino-1-(1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide according to the procedures described for 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole carboxamide (Example 1, Step 12).
• Step 1 preparation of benzyl 2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate.
• the mixture was neutralized with solid Na 2 CO 3 and cooled to 0° C.
• the mixture was added benzyl chloroformate (568 g, 3.33 mol) and saturated aqueous Na 2 CO 3 (1 L) with mechanical stirring for 2 h at 0° C.
• Step 2 preparation of benzyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate.
• benzyl 2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate 100 g, 0.44 mol
• anhydrous tetrahydrofuran 550 mL
• borane methylsulfide 86.3 g, 108 mL, 1.135 mol
• the reaction mixture was quenched by sequential addition of water (250 mL), aqueous NaOH (250 mL, 6M, 1.54 mol) and then hydrogen peroxide (250 mL, 250 g, 30%, 2.2 mol) between 0-10° C.
• the mixture was stirred at room temperature for another 1 h and then concentrated.
• the residue was partitioned between ether (2 L) and water (1 L).
• the organic layer was dried over Na 2 SO 4 , filtered and concentrated.
• the crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc, 4:1; 1/1) to afford the title compound (58 g, 26.6%) as a colorless oil.
• Step 3 preparation of benzyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate.
• benzyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate 29 g, 0.117 mol
• Dess-Martin periodinane 75 g, 0.175 mol
• the mixture was stirred at room temperature for 3 h.
• Aqueous Na 2 CO 3 (1M, 1100 mL) and aqueous Na 2 S 2 O 3 (1 M, 1100 mL) were added and the mixture was stirred at room temperature for 0.5 h.
• Step 4 preparation of benzyl 5-(2-(tert-butoxycarbonyl)hydrazinyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate.
• benzyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate 24 g, 0.098 mol
• Boc hydrazine 13 g, 0.098 mol
• the reaction mixture was heated to reflux and stirred overnight.
• the reaction mixture was cooled to 15° C. and NaCNBH 3 (6.2 g, 0.098 mol) was added.
• Step 5 preparation of benzyl 5-hydrazinyl-2-azabicyclo[2.2.1]heptane-2-carboxylate.
• benzyl 5-(2-(tert-butoxycarbonyl)hydrazinyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate 1942 g, 0.053 mol
• methanol 200 mL
• hydrochloric acid in 1,4-dioxane
• Step 6 preparation of benzyl 5-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate.
• benzyl 5-hydrazinyl-2-azabicyclo[2.2.1]heptane-2-carboxylate 6.5 g, 0.017 mol
• 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile (Example 1, Step 3) (4.78 g, 0.017 mol) in ethanol (200 mL) was added triethylamine (5 mL, 0.035 mol) at ⁇ 10° C.
• the mixture was stirred at room temperature for 2 h and then filtered to afford the title compound (7.0 g, 80.1%) as a white solid.
• Step 7 preparation of 5-amino-1-(2-azabicyclo[2.2.1]heptan-5-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide.
• a mixture of benzyl 5-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.9 g, 1.78 mmol) and aqueous NaOH (2.5N, 5 mL, 12.5 mmol) in ethanol (10 mL) was treated with microwave irradiation at 145° C. for 20 min.
• the mixture was poured into water (10 mL) and extracted with EtOAc (20 mL ⁇ 3).
• the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (0.69 g).
• Step 8 preparation of 5-amino-1-(2-cyano-2-azabicyclo[2.2.1]hept-5-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide.
• To a mixture of 5-amino-1-(2-azabicyclo[2.2.1]heptan-5-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (1.2 g, 3.08 mmol) and cyanogen bromide (3.08 mmol) in N,N-dimethylformamide (20 mL) was added Cs 2 CO 3 (2 g, 6.16 mmol) at room temperature and the mixture was stirred at room temperature overnight.
• Step 1 preparation of methyl 4-(4-chlorophenoxy)benzoate.
• anhydrous copper (II) acetate (39.0 g, 217.11 mmol) were added to a solution of methyl 4-hydroxybenzoate (16.5 g, 108.55 mmol) in dry dichloromethane (1000 mL) at room temperature, and the resulting mixture was stirred for 48 h.
• the reaction mixture was then filtered through a Celite pad.
• Step 2 preparation of 4-(4-chlorophenoxy)benzoic acid.
• methanol-water 5:1, 360 mL
• NaOH 10.68 g, 267.11 mmol
• Methanol was distilled off, water (500 mL) was added to the residue and washed with diethyl ether (3 ⁇ 100 mL).
• the aqueous layer was acidified with 2N HCl and then extracted with ethyl acetate (3 ⁇ 100 mL).
• Step 3 preparation of 4-(4-chlorophenoxy)benzoyl chloride.
• 4-(4-chlorophenoxy)-benzoic acid (10.5 g, 42.33 mmol) in thionyl chloride (110 mL) was refluxed for 4 h. The volatiles were evaporated and the crude title compound was taken to the next step.
• Step 4 preparation of 2-((4-(4-chlorophenoxy)phenyl)(methoxy)methylene)-malononitrile.
• a solution of malononitrile (3.54 g, 53.66 mmol) in tetrahydrofuran (25 mL) was added drop wise to a stirred suspension of sodium hydride (3.96 g, 60% in mineral oil, 158.4 mmol) in tetrahydrofuran (50 mL) at 0° C. under nitrogen atmosphere.
• 4-(4-chlorophenoxy)benzoyl chloride (11.0 g, 41.35 mmol) in tetrahydrofuran (35 mL) was added drop wise.
• Step 5 preparation of benzyl 3-(5-amino-3-(4-(4-chlorophenoxy)phenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• Triethylamine (8.6 mL 19.35 mmol) was added to a stirred mixture of 2-((4-(4-chlorophenoxy)phenyl)(methoxy)methylene) malononitrile (6.0 g, 19.35 mmol) and 3-hydrazino-piperidine-1-carboxylic acid benzylester hydrochloride (Example 1, Step 8) (5.5 g, 57.89 mmol) in ethanol (6.0 mL) at room temperature.
• Step 6 preparation of 5-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide.
• a cold 2.5M aq. NaOH solution 70 mL was added to a solution of benzyl 3-(5-amino-3-(4-(4-chlorophenoxy)phenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (7.2 g, 13.66 mmol) in ethanol (70 mL) in a 250 mL sealed tube and the resulting mixture was heated with stirring at 140° C. for 48 h.
• Step 7 preparation of 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide.
• Potassium carbonate (1.33 g, 9.52 mmol) was added to a solution of 5-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (2.6 g, 6.35 mmol) in N,N-dimethylformamide (20 mL), after stirring for 5 minutes cyanogen bromide (670 mg, 6.99 mmol) was added and the resulting mixture was stirred at 60° C. for 3 h.
• Step 1 preparation of methyl 4-(2,4-difluorophenoxy)benzoate.
• 4 ⁇ molecular sieves powder (17 g), (4-(methoxycarbonyl)phenyl)boronic acid (17.34 g, 133.33 mmol), DMAP (27.13 g, 222.22 mmol) and anhydrous copper (II) acetate (30.3 g, 166.7 mmol) were added to a solution of 2,4-difluorophenol (20.0 g, 111.11 mmol) in dry dichloromethane (800 mL) at room temperature, and the resulting mixture was stirred for 48 h.
• Step 2 preparation of 4-(2,4-difluorophenoxy)benzoic acid.
• methanol 525 mL
• water 63 mL
• NaOH pellets 12.22 g, 284.11 mmol
• Methanol distilled off and water was added.
• the residue was acidified with 1N HCl and then extracted with EtOAc. The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (12.0 g, 91.5%) as white solid.
• Step 3 preparation of 4-(2,4-difluorophenoxy)benzoyl chloride.
• 4-(2,4-difluorophenoxy)benzoic acid (3.0 g, 30 mmol) in thionyl chloride (80 mL) was refluxed overnight. The volatiles were evaporated to afford the title compound.
• Step 4 preparation of 2-((4-(2,4-difluorophenoxy)phenyl)(methoxy)methylene)-malononitrile.
• a solution of malononitrile (1.0 g, 15.52 mmol) in tetrahydrofuran (10 mL) was added drop wise to a stirred suspension of NaH (574 mg, 23.9 mmol) in tetrahydrofuran (50 mL) at 0° C. in N 2 atmosphere. After stirring for 30 min, 4-(2,4-difluorophenoxy)benzoyl chloride (3.2 g, 11.94 mmol) in tetrahydrofuran (15 mL) was added dropwise.
• Step 5 preparation of benzyl 3-(5-amino-4-cyano-3-(4-(2,4-difluorophenoxy)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• Triethylamine (2.2 mL 14.4 mmol) was added to a stirred mixture of 2-((4-(2,4-difluorophenoxy)phenyl)(methoxy)methylene)malononitrile (1.5 g, 4.8 mmol) and 3-hydrazino-piperidine-1-carboxylic acid benzylester hydrochloride (Example 1, Step 8) (1.4 g, 4.8 mmol) in ethanol (30 mL) at room temperature.
• Step 6 preparation of 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide.
• a cold 2.5M aq. NaOH solution (20 mL) was added to a mixture of benzyl 3-(5-amino-4-cyano-3-(4-(2,4-difluorophenoxy)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.8 g, 3.39 mmol) in ethanol (20 mL) charged to a 100 mL sealed tube. The mixture was heated with stirring at 140° C. for 24 h.
• Step 7 preparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide.
• Potassium carbonate 450 mg, 3.3 mmol
• 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide 0.9 g, 2.2 mmol
• N,N-dimethylformamide 10 mL
• cyanogen bromide 260 mg, 2.42 mmol
• Step 1 preparation of 1-[4-(4-chloro-3-methylphenoxy)phenyl]ethanone.
• 4-fluoroacetophenone 1.0 g, 7.2 mmol
• dimethylacetamide 4 mL
• 4-chloro-3-methylphenol 1.24 g, 8.69 mmol
• potassium carbonate 1.38 g, 9.99 mmol
• the reaction mixture was heated at 100° C. for 3 h and then allowed to cool, quenched with water and extracted into ethyl acetate. The combined organic layers were concentrated in vacuo to afford the title compound.
• MS (M+H) m/z 260.9.
• Step 2 preparation of 4-(4-chloro-3-methylphenoxy)benzoic acid.
• a solution of 1-[4-(4-chloro-3-methylphenoxy)phenyl]ethanone (1.8 g, 6.9 mmol) in ethanol (10 mL) was added 20 mL of a 10-15% sodium hypochlorite solution and the mixture was stirred at ambient temperature.
• a solution of aqueous sodium bisulfite (50 mL) was added and the mixture was then acidified with 12N hydrochloric acid. The resulting precipitate was filtered to afford the title compound.
• Step 3 preparation of 4-(4-chloro-3-methylphenoxy)benzoyl chloride.
• Anhydrous oxalyl chloride (1.23 g, 9.71 mmol) was added drop-wise followed by 4 drops of N,N-dimethylformamide to a solution of 4-(4-chloro-3-methylphenoxy)benzoic acid (1.701 g, 6.475 mmol) in tetrahydrofuran (30 mL) at 0° C.
• the mixture was allowed to warm to ambient temperature over 16 h and then concentrated to afford the title compound as a yellow solid.
• Step 4 preparation of 2-((4-(4-chloro-3-methylphenoxy)phenyl)(methoxy)methylene)-malononitrile.
• a solution of malononitrile (252 mg, 3.81 mmol) in anhydrous tetrahydrofuran (3 mL) was added to a suspension of sodium hydride (183 mg, 3.807 mmol) in tetrahydrofuran (15 mL) at 0° C.
• a solution of 4-(4-chloro-3-methylphenoxy)benzoyl chloride 1.0 g, 3.81 mmol
• tetrahydrofuran 5 mL
• Step 5 preparation of 1-(3-hydroxypiperidin-1-yl)ethanone.
• a suspension of 3-hydroxy-piperdine (100 g, 0.73 mol) and triethylamine (121 mL, 0.87 mol) in dichloromethane (1 L) was cooled to 0° C.
• Acetic anhydride (79 mL, 0.84 mol) was then added drop wise over 1.5 h, ensuring that the temperature did not surpass 0° C.
• the mixture was allowed to stir at ambient temperature for an additional 16 h and then was washed with water, saturated aqueous sodium bicarbonate, and finally brine.
• the combined aqueous layers were then re-extracted with a solution of 10% methanol/dichloromethane.
• Step 6 preparation of 1-acetylpiperidin-3-one.
• SO 3 372.0 g, 2.338 mol
• dichloromethane 2.0 L
• triethylamine 408.5 mL, 2.923 mol
• dimethylsulfoxide 414 mL, 5.846 mol
• a solution of 1-(3-hydroxypiperidin-1-yl)ethanone (76.0 g, 0.531 mol) in dichloromethane (500 mL) was drop wise added over 1 h keeping the temperature below 0° C.
• the reaction mixture was allowed to stir at room temperature for 16 h.
• the reaction mixture was quenched with saturated ammonium chloride (1 L) at 0-5° C. and stirred for another 1 h.
• the organic layer was separated and the aqueous layer was extracted with 10% methanol in dichloromethane (4 ⁇ 250 mL).
• the combined organic layers were concentrated in vacuum.
• the residue was dissolved in ethyl acetate (1 L) and filtered through glass sintered and concentrated in vacuum. Residual dimethylsulfoxide and triethylamine were removed by high vacuum distillation.
• the crude product was purified by silica gel column chromatography to afford the title compound (16 g) as a brown semi solid.
• Step 7 preparation of tert-butyl 2-(1-acetylpiperidin-3-yl)hydrazinecarboxylate.
• tert-butyl 2-(1-acetylpiperidin-3-yl)hydrazinecarboxylate To a solution of 1-acetyl-piperidin-3-one (123 g, 0.87 mol) in tetrahydrofuran (1.5 L) was added tert-butyl hydrazinecarboxylate (115 g, 0.87 mol). The solution was heated to reflux for 16 h, after which it was cooled to 15° C. and sodium cyanoborohydride (54.8 g, 0.87 mol) was added in a single portion.
• Step 8 preparation of 1-(3-hydrazinylpiperidin-1-yl)ethanone hydrochloride.
• a solution of tert-butyl 2-(1-acetylpiperidin-3-yl)hydrazinecarboxylate (45.1 g, 0.18 mol) in methanol (220 mL) at 0° C. was added 4N hydrochloric acid in dioxane (221 mL) ensuring that the temperature did not exceed 10° C.
• the mixture was allowed to stir at ambient temperature for 16 h, after which volatiles were removed in vacuo.
• the residue was dissolved in water (75 mL), extracted into 10% dichloromethane/methanol. The combined organic layers were concentrated to afford the title compound.
• Step 9 preparation of 1-(1-acetylpiperidin-3-yl)-5-amino-3-[4-(4-chloro-3-methylphenoxy)phenyl]-1H-pyrazole-4-carbonitrile.
• Triethylamine (156 mg, 1.54 mmol) was added to a slurry of 1-(3-hydrazinylpiperidin-1-yl)ethanone hydrochloride (133 mg, 0.68 mmol) and 2-((4-(4-chloro-3-methylphenoxy)phenyl)(methoxy)methylene)-malononitrile (200 mg, 0.62 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (MgSO 4 ), filtered and concentrated to afford the title compound. MS (M+H) m/z 450.
• Step 10 preparation of 5-amino-3-[4-(4-chloro-3-methylphenoxy)phenyl]-1-piperidin-3-yl-1H-pyrazole-4-carboxamide.
• the title compound was prepared analogous to 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (Example 25, Step 6) employing 1-(1-acetylpiperidin-3-yl)-5-amino-3-[4-(4-chloro-3-methylphenoxy)phenyl]-1H-pyrazole-4-carbonitrile.
• Step 11 preparation of 5-amino-3-[4-(4-chloro-3-methylphenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide.
• the title compound was prepared analogous to 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide (Example 25, Step 7) employing 5-amino-3-[4-(4-chloro-3-methylphenoxy)phenyl]-1-piperidin-3-yl-1H-pyrazole-4-carboxamide.
• Step 1 preparation of 4-iodo benzoyl chloride.
• 4-iodo benzoic acid 60 g, 0.24 mol
• oxalylchloride 417 mL, 4.83 mol
• N,N-dimethylformamide 1 mL
• the mixture was then heated to reflux for 16 h, after which it was cooled to ambient temperature and concentrated in vacuo.
• the resulting oil was dissolved in toluene and purified by vacuum distillation to afford the title compound.
• Step 2 preparation of 2-(hydroxy(4-iodophenyl)methylene)malononitrile.
• sodium hydride 50%, 64.36 g, 1.61 mol
• tetrahydrofuran 600 mL
• malononitrile 53.09 g, 804.5 mmol
• tetrahydrofuran 600 mL
• 4-lodo benzoyl chloride 214 g, 804.5 mmol
• Step 3 preparation of 2-((4-iodophenyl)(methoxy)methylene)malononitrile.
• sodium hydride 50%, 37.16 g, 929 mmol
• tetrahydrofuran 500 mL
• 2-(hydroxy(4-iodophenyl)methylene)malononitrile 250 g, 844.6 mmol
• tetrahydrofuran 500 mL
• Step 4 preparation of benzyl 3-[5-amino-4-cyano-3-(4-iodophenyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate.
• 2-((4-iodophenyl)(methoxy)-methylene)malononitrile 100 g, 322.6 mmol
• ethanol 1 L
• 2-(methoxy(3-iodo)methylene)-malononitrile and benzyl 3-hydrazino-piperidine-1-carboxylate (Example 1, Step 8) (91.93 g, 322.6 mmol) at room temperature and the resulting mixture was stirred at 80° C.
• Step 5 preparation of benzyl 3- ⁇ 5-amino-4-cyano-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazol-1-yl ⁇ piperidine-1-carboxylate.
• Step 6 preparation of preparation of [4-(5-amino-1- ⁇ 1-[(benzyloxy)carbonyl]piperidin-3-yl ⁇ -4-cyano-1H-pyrazol-3-yl)phenyl]boronic acid.
• benzyl-3- ⁇ 5-amino-4-cyano-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazol-1-yl ⁇ piperidine-1-carboxylate (2.97 g, 5.63 mmol) in 33% aqueous acetone (67.5 mL) was added sodium periodate (3.61 g, 16.88 mmol) and ammonium acetate (1.30 g, 16.88 mmol).
• Step 7 preparation of benzyl 3- ⁇ 5-amino-4-cyano-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazol-1-yl ⁇ piperidine-1-carboxylate.
• 2,4-difluorophenol (16 mg, 0.125 mmol) and [4-(5-amino-1- ⁇ 1-[(benzyloxy)carbonyl]piperidin-3-yl ⁇ -4-cyano-1H-pyrazol-3-yl)phenyl]boronic acid (56 mg, 0.125 mmol) in dichloromethane (1 mL) in an 8 mL vial
• copper (II) acetate 18 mg, 0.100 mmol
• pyridine 20 ⁇ L, 0.200 mmol
• Step 8 preparation of 5-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1-piperidin-3-yl-1H-pyrazole-4-carboxamide.
• benzyl 3- ⁇ 5-amino-4-cyano-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazol-1-yl ⁇ piperidine-1-carboxylate 66 mg, 0.125 mmol
• 5M aqueous sodium hydroxide 0.5 mL, 2.50 mmol
• the vial was capped and allowed to shake at 155° C. for 48 h. Water was added to the vial (1 mL) and the desired product was extracted into ethyl acetate (3 ⁇ 1 mL).
• the combined organic layers were dried over magnesium sulfate, and concentrated using a Speedvac to afford the title compound.
• Step 9 preparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide.
• 5-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1-piperidin-3-yl-1H-pyrazole-4-carboxamide 52 mg, 0.125 mmol
• a 0.5M solution of cyanogen bromide 0.250 mmol) in N,N-dimethylformamide 0.5 mL
• the vial was capped and allowed to shake at 30° C. for 16 h. Solvent was removed using a Speedvac, and the resulting residue was purified via preparative HPLC to afford the title compound.
• Step 1 preparation of benzyl 3-(5-amino-3-(4-benzylphenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• benzyl 3-[5-amino-4-cyano-3-(4-iodophenyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (Example 43, Step 4) (1 eq), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.073 eq), Pd 2 (dba) 3 (0.065 eq) in N,N-dimethylformamide (50 mL) was added dropwise a solution of benzyl zinc bromide (3eq, 0.5 M in tetrahydrofuran) at room temperature under N 2 .
• Step 2 preparation of 5-amino-3-(4-benzylphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide.
• a mixture of benzyl 3-(5-amino-3-(4-benzylphenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (1 eq), NaOH solution (7-10 eq, 2.5M), EtOH (8 mL) was irradiated in the microwave at 145° C. for 1 h.
• the reaction mixture was extracted with EtOAc (50 mL ⁇ 3).
• the combine organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuum to afford the title compound as a yellow oil.
• Step 3 preparation of 5-amino-3-(4-benzylphenyl)-1-(1-cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide.
• a mixture of 5-amino-3-(4-benzylphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (1 eq.), Cs 2 CO 3 (2 eq.), cyanogen bromide (1.1 eq.) in N,N-dimethylformamide (10 mL) was stirred at room temperature overnight.
• the reaction mixture was extracted with EtOAc (50 mL ⁇ 2). The combine organic layers were washed with brine, dried over sodium sulfate, and concentrated.
• Step 1 preparation of 3-[5-acetylamino-4-cyano-3-(4-iodophenyl)-pyrazol-1-yl]-piperidine-1-carboxylic acid benzyl ester.
• Step 2 preparation of benzyl 3- ⁇ 5-acetamido-3-[4-(4-chlorobenzyl)phenyl]-4-cyano-1H-pyrazol-1-yl ⁇ piperidine-1-carboxylate.
• benzyl 3-[5-acetamido-4-cyano-3-(4-iodophenyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.41 g, 0.73 mmol)
• palladium acetate (12 mg, 0.053 mmol)
• 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl 18 mg, 0.043 mmol
• lithium chloride 80 mg, 1.89 mmol
• Step 3 preparation of 5-amino-3-[4-(4-chlorobenzyl)phenyl]-1-piperidin-3-yl-1H-pyrazole-4-carboxamide.
• Step 4 preparation of 5-amino-3-[4-(4-chlorobenzyl)phenyl]-1-(1-cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide.
• MS (M+H) m/z 435 MS (M+H) m/z 435.
• Step 1 preparation of 4-benzoylbenzoyl chloride.
• Oxalyl chloride (1.3 mL, 15 mmol) was added dropwise to a solution of 4-benzoylbenzoic acid (2.2 gm, 10 mmol) in tetrahydrofuran, with few drops of N,N-dimethylformamide, over 15 min.
• the mixture was stirred at room temperature for 1 h and then concentrated under reduce pressure to afford the title compound (2.4 gm).
• Step 2 preparation of 2-((4-benzoylphenyl)(methoxy)methylene)malononitrile.
• sodium hydride 640 mg, 16 mmol
• malononitrile 528 mg, 8 mmol
• tetrahydrofuran 5 mL
• 4-Benzoylbenzoyl chloride (2.45 g, 10 mmol) in tetrahydrofuran was then added dropwise followed by dimethyl sulfate (528 mg, 8 mmol). The mixture was then heated to reflux for 18 h.
• Step 3 preparation of benzyl 3-(5-amino-3-(4-benzoylphenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• Benzyl 3-hydrazino-piperidine-1-carboxylate (Example 1, Step 8) (694 mg, 2.43 mmol) and triethylamine (1.2 mL, 8.5 mmol) were added to a solution of 2-((4-benzoylphenyl)(methoxy)methylene)malononitrile (700 mg, 2.43 mmol) in ethanol (20 mL). The mixture was heated to 70° C. and stirred overnight.
• Step 4 preparation of 5-amino-3-(4-benzoyl-phenyl)-1-(1-cyano)-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide.
• benzyl 3-(5-amino-3-(4-benzoylphenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (2 g, 4 mmol)
• ethanol 3 mL
• a solution of sodium hydroxide 2.5N, 10 mmol, 4 mL.
• the autoclave was sealed and heated until internal temperature reached 150° C. for 15 min.
• Step 5 preparation of 5-amino-3-(4-benzoyl-phenyl)-1-(1-cyano)-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide.
• Cyanogen bromide 38 mg, 0.36 mmol
• potassium carbonate 62 mg, 0.45 mmol
• 5-amino-3-(4-benzoyl-phenyl)-1-(1-cyano)-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide 117 mg, 0.3 mmol
• N,N-dimethylformamide 4 mL
• Step 1 preparation of 5-amino-3- ⁇ 4-[hydroxy(phenyl)methyl]phenyl ⁇ -1-piperidin-3-yl-1H-pyrazole-4-carbonitrile.
• Methanol (20 mL) was added to benzyl 3-(5-amino-3-(4-benzoylphenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 87, Step 3) and 10% palladium on carbon in a Fisher-Porter bottle. A few drops of acetic acid were added and the bottle was charged with hydrogen gas (43 psi). The mixture was stirred 18 h at room temperature and then filtered through Celite. The filtrate was concentrated to afford the title compound.
• Step 2 preparation of 5-amino-3-(4-(hydroxy(phenyl)methyl)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide.
• the title compound was prepared analogous to 5-amino-3-(4-benzoyl-phenyl)-1-(1-cyano)-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide (Example 87, Step 4) employing 5-amino-3- ⁇ 4-[hydroxy(phenyl)methyl]phenyl ⁇ -1-piperidin-3-yl-1H-pyrazole-4-carbonitrile.
• MS (M+H) m/z 392.3.
• Step 3 preparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3- ⁇ 4-[hydroxy(phenyl)methyl]phenyl ⁇ -1H-pyrazole-4-carboxamide.
• the title compound was prepared analogous to 5-amino-3-(4-benzoyl-phenyl)-1-(1-cyano)-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide (Example 87, Step 5) employing 5-amino-3-(4-(hydroxy(phenyl)methyl)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide.
• MS (M+H) m/z 417.3.
• Step 1 preparation of 2-((3-iodophenyl)(methoxy)methylene)malononitrile. Prepared analogous to 2-[(4-phenoxy-phenyl)-methoxy-methylene]malononitrile (Example 1, step 3) from 3-iodo benzoic acid to afford the title compound.
• Step 2 preparation of benzyl 3-[5-amino-4-cyano-3-(3-iodophenyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate.
• benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol-1-yl]-piperidine-1-carboxylate (Example 1, Step 9) from 2-((3-iodophenyl)(methoxy)methylene)malononitrile and benzyl 3-hydrazino-piperidine-1-carboxylate (Example 1, Step 8) to afford the title compound (80 g, 62%).
• Step 3 preparation of benzyl 3-(5-acetamido-4-cyano-3-(3-iodophenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• Prepared analogous to 3-[5-acetylamino-4-cyano-3-(4-iodophenyl)-pyrazol-1-yl]-piperidine-1-carboxylic acid benzyl ester (Example 86, Step 1) employing benzyl 3-[5-amino-4-cyano-3-(3-iodophenyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate to afford the title compound.
• Step 4 preparation of benzyl 3- ⁇ 5-acetamido-3-[3-(4-chlorobenzyl)phenyl]-4-cyano-1H-pyrazol-1-yl ⁇ piperidine-1-carboxylate.
• benzyl 3-(5-acetamido-4-cyano-3-(3-iodophenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 498 mg, 0.875 mmol
• 2′-dicyclohexylphosphino-2,6-dimethoxybiphenyl 29.6 mg, 0.07 mmol
• tris(dibenzylideneacetone)dipalladium 55.8 mg, 0.061 mmol) in tetrahydrofuran (5 mL)
• Step 5 preparation of 5-amino-3-[3-(4-chlorobenzyl)phenyl]-1-piperidin-3-yl-1H-pyrazole-4-carboxamide.
• a solution of benzyl 3- ⁇ 5-acetamido-3-[3-(4-chlorobenzyl)phenyl]-4-cyano-1H-pyrazol-1-yl ⁇ piperidine-1-carboxylate (430 mg, 0.74 mmol) and sodium hydroxide (888 mg, 22.2 mmol) in 33% aqueous ethanol (6 mL) was heated to 165° C. After 50 min. solvents were removed in vacuo to afford the title compound as a white solid.
• Step 6 preparation of 5-amino-3-[2-chloro-4-(4-fluorophenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide.
• a solution of 5-amino-3-[3-(4-chlorobenzyl)phenyl]-1-piperidin-3-yl-1H-pyrazole-4-carboxamide (100 mg, 0.24 mmol), cyanogen bromide (40 mg, 0.37 mmol), and sodium carbonate (78 mg, 0.73 mmol) in N,N-dimethylformamide (5 mL) was allowed to stir at ambient temperature over 16 h.
• Step 1 preparation of benzyl 3-(5-acetamido-4-cyano-3-(3-(4-fluorophenoxy)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• Cesium carbonate (81 mg, 250 ⁇ mol) and Cul (2.4 mg, 12.5 ⁇ mol) were added to a mixture of 4-fluorophenol (125 ⁇ mol) and benzyl 3-(5-acetamido-4-cyano-3-(3-iodophenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 92, step 3) (75 mg, 125 ⁇ mol) in N,N-dimethylacetamide (1 mL).
• Step 2 preparation of 5-amino-3-(3-(4-fluorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide.
• a 5 N aqueous solution of NaOH 2.5 mL was added to a solution of benzyl 3-(5-acetamido-4-cyano-3-(3-(4-fluorophenoxy)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (125 ⁇ mol) in isopropanol (1 mL).
• the mixture was shaken at 155° C. for 48 h. Water (1 mL) was added and the mixture was extracted with EtOAc (3 ⁇ 1 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the title compound.
• Step 3 preparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-(3-(4-fluorophenoxy)phenyl)-1H-pyrazole-4-carboxamide.
• 5-Amino-3-(3-(4-fluorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (125 ⁇ mol) and K 2 CO 3 (52 mg, 375 ⁇ mol) were added to a 0.5 M solution of cyanogen bromide (0.5 mL). The mixture was shaken at 30° C. for 16 h and then concentrated. The crude product was purified by reverse phase preparative HPLC to afford the title compound. MS (M+H) m/z 421.
• Step 1 preparation of 2-((6-chloropyridin-3-yl)(methoxy)methylenemalononitrile.
• Step 2 preparation of benzyl 3-(5-amino-3-(6-chloropyridin-3-yl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol-1-yl]-piperidine-1-carboxylate (Example 1, Step 9) by the reaction of 2-((6-chloropyridin-3-yl)(methoxy)methylenemalononitrile and 3-hydrazino-piperidine-1-carboxylic acid benzyl ester (Example 1, Step 8) and 2-((6-chloropyridin-3-yl)(methoxy)methylenemalononitrile at ambient temperature over 16 h with the exception of aqueous workup and purification via normal phase SiO 2 column chromatography to afford the title compound as a yellow solid (590 mg, 10%).
• Step 3 preparation of benzyl 3-(5-amino-4-cyano-3-(6-phenoxypyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• benzyl 3-(5-amino-3-(6-chloropyridin-3-yl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate 590 mg, 1.35 mmol
• phenol 134 mg, 1.42 mmol
• potassium carbonate 280 mg, 2.02 mmol
• Step 4 preparation of 5-amino-3-(6-phenoxypyridin-3-yl)-1-(piperdin-3-yl)-1H-pyrazole-4-carboxamide.
• Step 5 preparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-(6-phenoxypyridin-3-yl)-1H-pyrazole-4-carboxamide.
• Step 1 preparation of 4-((tert-butyldimethylsilyl)oxy)benzoic acid.
• 4-hydroxybenzoic acid 200 g, 1.45 mol
• N,N-dimethylformamide 3.25 L
• imidazole 595 g, 8.67 mol
• tert-butyl dimethylsilyl chloride 327 g, 2.17 mol
• the resulting reaction mixture was stirred at room temperature for 16 h.
• the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2 ⁇ 2 L).
• the combined organic layers were washed with water (2 ⁇ 1 L) followed by brine, dried over sodium sulfate and concentrated under reduced pressure.
• Step 2 preparation of 2-((4-((tert-butyldimethylsilyl)oxy)phenyl)(methoxy)-methylene)malononitrile.
• sodium hydride 60%, 22.8 g, 0.95 mol
• malononitrile 31.4 g, 0.47 mol, dissolved in 600 mL of tetrahydrofuran
• the resulting suspension was stirred at 0° C. for 1 h.
• Step 3 preparation of benzyl 3-(5-amino-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• Step 4 preparation of benzyl 3-(5-acetamido-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• Step 5 preparation of benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• benzyl 3-(5-acetamido-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate 165 g, 0.35 mol
• methanol:water (4:1, 2.8 L LiOH.H 2 O (43.8 g, 1.04 mol) at 0° C.
• the resulting reaction mixture was stirred at 0° C. for 2 h.
• Step 6 preparation of benzyl 3-(5-acetamido-3- ⁇ 4-[(5-chloropyridin-2-yl)oxy]phenyl ⁇ -4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 500 mg, 1.20 mmol
• N,N-dimethylformamide (1 mL) was added 5-chloro-2-fluoropyridine (237 mg, 1.80 mmol) and cesium carbonate (1.95 g, 5.99 mmol).
• reaction mixture was then heated to 100° C. for 30 minutes under microwave conditions, after which it was diluted with water and extracted into ethyl acetate (3 ⁇ 5 mL). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to afford the title compound (300 mg, 44%).
• Step 7 preparation of 5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide.
• benzyl 3-(5-acetamido-3- ⁇ 4-[(5-chloropyridin-2-yl)oxy]phenyl ⁇ -4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate 300 mg, 0.53 mmol
• Step 8 preparation of 5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(1-cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide.
• To a solution of 5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (217 mg, 0.53 mmol) in N,N-dimethylformamide was added cesium carbonate (516 mg, 1.59 mmol) and cyanogen bromide (281 mg, 2.65 mmol).
• Step 1 preparation of (R)-benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• (rac)-benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate was chirally separated by supercritical fluid chromatography (ChiralPak AS-H 50 ⁇ 250 mm column, 25% methanol, 250 mL/min). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 460.
• Step 2 preparation of (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-pyrazole-4-carboxamide.
• Step 1 preparation of (S)-benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.
• (rac)-benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate prepared as described in Example 108, was chirally separated by supercritical fluid chromatography (ChiralPak AS-H 50 ⁇ 250 mm column, 25% methanol, 250 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 460.
• Step 2 preparation of (S)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-pyrazole-4-carboxamide.
• Step 1 preparation of 1-bromo-2-chloro-4-(4-fluorophenoxy)benzene.
• 4-bromo-3-chlorophenol 1.2 g, 5.8 mmol
• copper (II) acetate 1.79 g, 9.83 mmol
• triethylamine 4.82 mL, 34.7 mmol
• activated 4 ⁇ molecular sieves in anhydrous dichloromethane (80 mL) at 0° C.
• 4-fluorophenyl)boronic acid (2.43 g, 17.4 mmol, 3.0 equiv) portion-wise over 30 min.
• the reaction mixture was allowed to warm to ambient temperature over 16 h, after which it was filtered.
• the filtrate concentrated in vacuo and purified by silica gel column chromatography to afford the title compound as a light yellow oil (0.60 g, 35%).
• Step 2 preparation of 2-[2-chloro-4-(4-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

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