OA17291A - Bruton's tyrosine kinase inhibitors. - Google Patents

Abstract

Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

Description

Bruton’s Tyrosine Kinase Inhibitors

BACKGROUND

Signaling through the B-cell receptor (BCR) can lead to a range of biological outputs depending upon, in part, the developmental stage of the B-cell. 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. In humans, mutation of BTK causes X-linked agammaglobuliaemia results in a compromised immune system, impaired maturation of B-cells, decreased peripheral B-cell Ievels and reduced calcium mobilization following stimulation through the BCR. Further evidence for the rôle of BTK in autoimmune and inflammatory diseases has been established utilizing both BTK knock-out mouse models and pharmacological inhibitors. In addition to 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. From this prespective it is clear that BTK inhibitors should provided substaintial therapeutic benefit for patients afflicted with, for example: multiple sclerosis, type I diabètes, rheumatoid arthritis, SLE, idiopathic thrombocytopénie purpura, myasthenia gravis, allergie rhinitis, Sjôgren’s syndrome, B-cell lymphoma and leukemia.

SUMMARY

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, inciuding 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.

Compounds described herein include those that hâve a structure of Formula (I) and pharmaceutically acceptable salts, solvatés, esters, acids and prodrugs thereof. In particular, one aspect of the invention relates to compounds represented by Formula (I):

or a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté therof, 5 wherein

A is arylene, 5-membered heteroarylene or 6-membered heteroarylene, optionally substituted with one, two, three or four R⁶ independently selected from the group consisting of (Ci-C4)alkyl, halo(Ci-C4)alkyl, halo, hydroxy and (Ci-C4)alkoxy;

X is O, S, C(=O), CH(OR⁴) or C(R^5a)(R^5b);

w W is aryl, 5-membered heteroaryi or 6-membered heteroaryi, optionally substituted with one, two, three, four or five R⁷ independently selected from the group consisting of (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C3-C₆)cycloalkyl, 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, hydroxy(C₂-C4)alkoxy, and halo(Ci-C4)alkoxy;

R¹ 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 (Ci-C4)alkyl, halo(Ci-C4)alkyl, halo, hydroxyl and (Ci-C4)alkoxy;

va

R is cyano, cyano(Ci-C3)alkyl, R^a or Ά ;

R^2a, R^2b, R^3a and R⁴ are independently selected from the group consisting of hydrogen or (Ci-C3)alkyl;

R^5a and R^5b are independently selected from the group consisting of hydrogen, halo and (Ci-C3)alkyl;

R^a is hydrogen, halo, cyano, (Ci-Ceîalkoxy, halo(Ci-C6)alkoxy, (Ci-C4)alkylthio, (Ci-C4)alkylsulfonyl, or (Ci-Cejalkyl optionally substituted by halo, hydroxyl, (CrCeJaIkoxy or halo(Ci-C6)alkoxy;

R^b and R° are independently selected from the group consisting of hydrogen, halo, cyano, (Ci-C₆)alkoxy, haloiCrCeJalkoxy, (C₃-C6)cycloalkyl, C(=O)R^dand (Ci-Cejalkyl optionally substituted with one, two or three R^f independently selected from

the group consisting of halo, hydroxyl, N(R^e)_2l (C_rC₆) alkoxy, halo(Ci.-C₆)alkoxy and aryl; 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°)_2| (Ci-C6)alkoxy; halo(Ci-C6)alkoxy and aryl;

R^d is (CrCeîalkyl, (CrCeîaIkoxy, N(R°)₂ or aryl;

R° is independently selected for each occurence from the group consisting of hydrogen and (CrC₄) alkyl, or both R° taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl; and

G is a 5-7 membered carbocycyl or heterocycyl optionally substituted with one, two or three R^f independently selected from the group consisting of halo, hydroxyl, N(R°)₂, (Ci-C₆)alkoxy; halo(CrC₆)alkoxy and aryl.

In a further aspect are provided pharmaceutical compositions, which include a therapeutically effective amount of compound(s) of the invention, or a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté therof. In certain embodiments, 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 sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté therof. A large number of disorders can be treated using the compounds described herein. For example, 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 thrombocytopénie thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, epidermal hyperplasia, and other medical disorders described herein.

Other objects, features and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the spécifie examples, while indicating spécifie embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the présent disclosure will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION

The invention provides compounds, pharmaceutical compositions, methods of inhibiting BTK activity and therapeutic uses of said compounds and pharmaceutical compositions. The practice of the présent 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. Ausubel étal., eds., 1987, and periodic updates); and Current protocols in immunology (J.E. Coligan étal., eds., 1991), each of which is herein incorporated by référencé in its entirety.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Ail documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by référencé in their entirety for any purpose.

Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a définition, the previous définition of the variable contrais.

Définitions

It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the spécification and the appended claims, the singular forms a, an and the include plural référents unless the context clearly dictâtes otherwise. In this application, the use of or means and/or unless stated otherwise. Furthermore, use of the term including as well as other forms, such as include, includes, and included, is not limiting.

It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods and compositions described herein, which will be limited only by the appended claims.

The term Bruton's tyrosine kinase, as used herein, refers to Bruton's tyrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Patent No. 6,326,469 (GenBank Accession No. NP.sub.--000052).

The term Bruton's tyrosine kinase homolog, as used herein, refers to orthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse (GenBank Acession No. AAB47246), dog (GenBank Acession No. XP.sub.--549139.), rat (GenBank Acession No. NP.sub.--001007799), chicken (GenBank Acession No. NP.sub.-989564), or zébra fish (GenBank Acession 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.

The term homologous cysteine, as used herein refers to a cysteine residue found with in a sequence position that is homologous to that of cysteine 481 of Bruton's tyrosine kinase, as defined herein. For example, 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; and cysteine 481 is the homologous cysteine in the zébra fish ortholog. In another example, the homologous cysteine of TXK, a Tec kinase family member related to Bruton's tyrosine, 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.

The term BTK inhibitor, as used herein, refers to an inhibitor of BTK that can form a covalent bond with an amino acid residue of BTK. In one embodiment, the inhibitor of BTK can form a covalent bond with a Cys residue of BTK.

The term modulate, as used herein, 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.

As used herein, the term modulator refers to a compound that alters an activity of a molécule. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a molécule compared to the magnitude of the activity in the absence of the modulator. ln certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molécule, ln certain embodiments, an inhibitor completely prevents one or more activities of a molécule, ln certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molécule, ln certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator.

The term 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. ln embodiments in which two or more heteroatoms are présent, the two or more heteroatoms can ail be the same as one another, or some or ali of the two or more heteroatoms can each be different from the others.

The term 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. Examples of such substituents include methyi, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isoamyl, hexyl and the like. The terms haloalkyl and haloalkoxy include alkyl, and alkoxy structures, respectively, in which at least one hydrogen is replaced with a halogen atom. ln certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are ail 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 ail the same as one another.

The term fluoroalkyl, as used herein, refers to alkyl group in which at least one hydrogen is replaced with a fluorine atom. Examples of fluoroalkyl groups include, but are not limited to, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3 and the like.

The term cycloalkyl refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molécule 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. Altematively, 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.

The term aryl refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may hâve six to eighteen carbon atoms. As an example, the aryl substituent may hâve six to fourteen carbon atoms. The term aryl may refer to substituents such as phenyl, naphthyl and anthracenyl. The term aryl also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C4.10 carbocyclic nng, such as a C₅ or a C₆ 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. When such a fused aryl group is substituted with one more substituents, the one or more substitutents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryl group. The fused C4.10 carbocyclic or 4- to 10-membered heterocyclic ring may be optionally substituted with halogen, Ci-₆alkyl, C3-i₀cycloalkyl, or =0. Examples of aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as tetralinyl), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as phenalenyl), and fluorenyl.

The term “arylene refers to a bivalent radical formed by removing a hydrogen atom from an aryl, as described above.

In some instances, the number of atoms in a cyclic substituent containing one or more heteroatoms (i.e., heteroaryl or heterocycloalkyl) 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. Thus, for example, 5-8 membered heterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, inciuding one or more heteroatoms, in the cyclic moiety of the heterocycloalkyl.

The term hydroxy or hydroxyl refers to OH.

The term cyano (also referred to as nitrile) means CN.

The terms 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). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is bromine.

The terms 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 seiected from oxygen, nitrogen, or sulfur. For example, as used herein, the term 4- to 10-membered heterocycloalkyl means the substituent is a single ring with 4 to 10 total members. A heterocycloalkyl altematively 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). In a group that has a heterocycloalkyl substituent, 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). Similarly, if the heterocycloalkyl substituent is in tum substituted with a group or substituent, 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).

The term 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. Examples of 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, and 1,4-benzoxazinyl. In a group that has a heteroaryl substituent, 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. Similarly, if the heteroaryl substituent is in tum substituted with a group or substituent, the group or substituent may be bound to the heteroatom, or it may be bound to 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 term heteroaryl also includes pyridyl N-oxides and groups containing a pyridine Noxide ring.

The term “heteroarylene” refers to a bivalent radical formed by removing a hydrogen atom from a heteroaryl, as described above.

This spécification uses the terms substituent, radical, and group interchangeably.

If 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.

If a substituent is described 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 10 positions on the substituent, whichever is less. Thus, for example, if 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. To illustrate, tetrazolyl (which has only one substitutable 15 position) would be optionally substituted with up to one non-hydrogen substituent. To illustrate further, if 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 20 if the amino nitrogen is a secondary nitrogen.

A prefix attached to a multi-moiety substituent only applles to the first moiety. To illustrate, the term alkylcycloalkyl contains two moieties: alkyl and cycloalkyl. Thus, a (Ci-C₆) prefix on (Ci-C₆)alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the (CrC₆)-prefix does not describe the cycloalkyl 25 moiety. To illustrate further, the prefix halo on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more haiogen substituents. If the haiogen substitution only occurs on the alkyl moiety, the substituent would be described as alkoxyhaloalkyl. If the haiogen substitution occurs on both the alkyl moiety and the alkoxy moiety, the substituent would be described as haloalkoxyhaloalkyl.

As used herein the term Formula (I) and Formula (II) may be referred to as a compound(s) ofthe invention. Such terms are also defined to include ail forms of the compounds of Formula (I) and Formula (II) including hydrates, solvatés, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and métabolites thereof. 35 For example, the compounds of Formula (I) and Formula (II), and pharmaceutically

acceptable salts thereof, may exist in unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will hâve a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvatés and hygroscopic compounds, the water/solvent content will be dépendent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

A métabolite of a compound disclosed herein is a dérivative of that compound that is formed when the compound is metabolized. The term active métabolite refers to a biologically active dérivative of a compound that is formed when the compound is 10 metabolized. The term metabolized, as used herein, 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 spécifie structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions 15 while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic-acid molécule 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). Métabolites 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, métabolites 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 métabolites.

In some embodiments, 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 30 parent is not. The prodrug may also hâve 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 35 entity, once inside the cell where water-solubility is bénéficiai. 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. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, 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. By virtue of knowledge of pharmacodynamie processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound. (see, for example, Nogrady (1985) Médicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 38815 392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academie Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Médicinal Chemistry Letters, Vol. 4, p. 1985).

Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a dérivative 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 dérivative 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 hâve improved solubility 25 in pharmaceutical compositions over the parent drug. Prodrugs may be designed as réversible drug dérivatives, for use as modifiers to enhance drug transport to sitespecific 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. Chrom., 30 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.

Larsen et al., Int. J. Pharmaceutics, 47,103 (1988); Sinkula et al., J. Pharm. Soi., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Sériés; and Edward B. Roche, Bioreversible Carriers in

Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, ail 35 incorporated herein in their entirety.

The compounds of the invention may hâve 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 ail possible stereoisomers (e.g. spécifie 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. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that ail possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that 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 présent.

Stereoisomers of compounds of the invention include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, géométrie isomers, rotational isomers, conformational isomers, and tautomers of the compounds of the 20 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 optîcally active, for example, Dlactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

When any racemate crystallizes, crystals of two different types are possible. The 25 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 présent 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. Examples of 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, 35 ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI. Certain isotopically-labeled

compounds of Formula (I) and Formula (II), for example those into which radioactive isotopes such as ³H and ¹⁴O are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, 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 Préparations 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. Depending on the particular compound, a sait of the compound may be advantageous due to one or more of the salt's physical properties, 15 such as enhanced pharmaceutical stability in differing températures and humidities, or a désirable solubility in water or oil. In some instances, a sait of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.

Where a sait is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the sait preferably is pharmaceutically 20 acceptable. The term pharmaceutically acceptable sait refers to a sait 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 présent invention because of their greater aqueous solubility relative to the parent 25 compound. For use in medicine, the salts of the compounds of this invention are nontoxic 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 présent 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, tartane, and trifluoroacetic acids. Suitable organic acids generally inciude but are not limited to aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.

Spécifie examples of suitable organic acids inciude 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, stéarate, salicylate, phydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 210 hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, βhydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycérophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may inciude alkali métal salts, i.e., sodium or potassium salts; alkaline earth métal salts, e.g., calcium or magnésium salts; and salts formed with suitable organic ligands, e.g., quatemary ammonium salts. In 20 another embodiment, base salts are formed from bases which form non-toxic salts, induding aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.

Organic salts may be made from secondary, tertiary or quatemary amine salts, such as tromethamine, diethylamine, Ν,Ν'-benzylethylenediamine, chloroprocaine, 25 choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl (Οι-Οθ) 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), 30 arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

Compounds

In the following description of 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 empioyed. ln 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. Patent No. 6,326,469.

In certain embodiments, the compounds of the invention described herein are sélective for BTK and kinases having a cysteine residue in an amino acid sequence position of the tyrosine kinase that !s homologous to the amino acid sequence position of cysteine 481 in BTK.

Generally, 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 usefui to détermine an in vitro IC50 for said compounds.

In some embodiments, the BTK inhibitor compound used for the methods described herein inhibits BTK or a BTK homolog kinase activity with an in vitro IC50 of less than 10 μΜ. (e.g., less than 1 μΜ, less than 0.5 μΜ, less than 0.4 μΜ, less than 0.3 μΜ, less than 0.1, less than 0.08 μΜ, less than 0.06 μΜ, less than 0.05 μΜ, less than 0.04 μΜ, less than 0.03 μΜ, less than less than 0.02 μΜ, less than 0.01, less than 0.008 μΜ, less than 0.006 μΜ, less than 0.005 μΜ, less than 0.004 μΜ, less than 0.003 μΜ, less than less than 0.002 μΜ, less than 0.001, less than 0.00099 μΜ, less than 0.00098 μΜ, less than 0.00097 μΜ, less than 0.00096 μΜ, less than 0.00095 μΜ, less than 0.00094 μΜ, less than 0.00093 μΜ, less than 0.00092, or less than 0.00090 μΜ).

Described herein are compounds of Formula (I), including those of Formula (II). Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvatés, pharmaceutically active métabolites, and pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable sait, pharmaceutically acceptable solvaté, pharmaceutically active métabolite or pharmaceutically acceptable prodrug of such compound, are provided. ln 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.

In one embodiment are compounds of Formula (I):

(D or pharmaceutically acceptable salts, pharmaceutically active métabolites, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvatés thereof, 5 as described in the Summary above.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein A is arylene optionally substituted with one, two, three or four R⁶ independently selected from the group consisting of (CrC4)alkyl, halo(CrC4)alkyl, halo, hydroxy and (CrC₄)alkoxy.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein A is

; and R⁶ is independently selected for each occurrence from the group consisting of hydrogen, (CrC4)alkyl, halo(CrC3)alkyl and halo. In certain embodiments, the présent invention relates to any

independently selected for each occurrence from the group consisting of hydrogen, (Cr C₄)alkyl, halo(CrC₃)alkyl and halo. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R⁶ is hydrogen.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein A is 5-membered heteroarylene optionally 20 substituted with one, two, three or four R⁶ independently selected from the group consisting of (CrC₄)alkyl, halo(CrC₄)alkyl, halo, hydroxy and (CrC₄)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein A is 6-membered heteroarylene, optionally substituted with one, two, three or

four R⁶ independently selected from the group consisting of (CrC^alkyl, halo(CrC4)alkyl, halo, hydroxy and (CpC^alkoxy.

In certain embodiments, the presènt invention relates to any of the aforementioned compounds, wherein X is O, CH₂ or C(=O). In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein X is S. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein X is O. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein X is C(=O). In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein X Is CH(OR⁴). In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein X is C(R^5a)(R^5b). In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein X is CH₂.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein W is aryl optionally substituted with one, two, three, four or five R⁷ independently selected from the group consisting of (CrC^alkyl, halo(CrC4)alkyl, (C₃-C6)cycloalkyl, 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(Ci-C₄)alkyl, (C1-C4)alkoxy, hydroxy(C₂-C4)alkoxy, and halo(C_rC4)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein W is phenyl optionally substituted with one, two, three, four or five R⁷ independently selected for each occurrence from the group consisting of (CrC4)alkyl, halo(CrC3)alkyl, (Ci-C4)alkoxy and halo. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein W is

présent invention relates to any of the aforementioned compounds, wherein W is

selected from the group consisting of F, Cl, methoxy and methyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds,

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein W is 5-membered heteroaryl optionally substituted 10 with one, two, three, four or five R⁷ independently selected from the group consisting of (CrC^alkyl, halo(CrC4)alkyl, (Ca-Cejcycloalkyl, 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(Ci-C₄)alkyl, (Ci-C₄)alkoxy, hydroxy(C₂-C4)alkoxy, and halo(Cr C4)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein W is 6-membered heteroaryl, optionally substituted with one, two, three, four or five R⁷ independently selected from the group consisting of (CrC4)alkyl, halo(CrC4)alkyl, (C₃-C6)cycloalkyl, 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(CrC4)alkyl, (CrC4)alkoxy, hydroxy(C₂-C4)alkoxy, and halo(CrC4)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein W is pyridine optionally substituted with one, 20 two, three, or four R⁷ independently selected from the group consisting of (Ci-C₄)alkyl, halo(C_rC4)alkyl, halo, hydroxy, hydroxy(Ci-C₄)alkyl, (Ci-C₄)alkoxy, and halo(CrC4)alkoxy. In certain embodiments, the présent invention relates to any of the

aforementioned compounds, wherein W is

R⁷ is independently selected for each occurrence from the group consisting of (Cr C^alkyl, (CrC3)haloalkyl, (CrC^alkoxy, and halo. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein W is

R⁷ is F, Cl or CF₃. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein W is

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ is a 4-membered nitrogen-containing heterocyclyl substituted on said nitrogen with R and optionally further substituted with one, two, three, four orfive substituents independently selected from the group consisting of (Ci-C^alkyl, halo(CrC4)alkyl, halo, hydroxyl and (Ci-C4)alkoxy; and R is cyano. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ 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 (CrC4)alkyl, halo(CrC4)alkyl, halo, hydroxyl and (Ci-C4)alkoxy; and R is cyano. In certain embodiments, the présent invention relates to any of the

aforementioned compounds, wherein R¹ is a 6-membered nitrogen-containing ^F 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 (Cr C4)alkyl, halo(Ci-C4)alkyl, halo, hydroxyl and (CrC4)alkoxy; and R is cyano. In certain 5 embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ 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 (Ci-C4)alkyl, halo(Ci-C4)alkyl, halo, hydroxyl and (CrC4)alkoxy; and R is cyano. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ 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 (Ci-C4)alkyl, (Ci-C4)haloalkyl, halo, hydroxyl and (Ci-C4)alkoxy; and R is cyano. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ 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 (Ci-C4)alkyl, (Ci-C4)haloalkyl, halo, hydroxyl and (Ci-C4)alkoxy; and R is cyano(Ci-C3)alkyl. In certain embodiments, the présent invention relates to any of the 20 aforementioned compounds, wherein R¹ 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 (CrC4)alkyl, (Ci-C4)haloalkyl, halo, hydroxyl and (Ci-C4)alkoxy; and R is cyano(Ci-C3)alkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ 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 (Ci-C4)alkyl, (Ci-C4)haloalkyl, halo, hydroxyl and (Ci-C4)alkoxy; and R is cyano(Ci-C₃)alkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ 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 (Ci-C₄)alkyl, halo(CrC4)alkyl, halo, hydroxyl and (CrC4)alkoxy; and R is cyano(Ci-C₃)alkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ 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 (CrC₄)alkyl, (CrC₄)haloalkyl, halo, hydroxyl and (CrC₄)alkoxy; and R is cyano(Ci-C3)alkyl. ln certain embodiments, the présent invention relates to any of the

I aforementloned compounds, wherein R¹ is

independently selected from the group consisting of (C_rC₄)alkyl, halo(CrC₄)alkyl, halo, hydroxyl and (CrC₄)alkoxy. ln certain embodiments, the présent invention relates to

any of the aforementloned compounds, wherein R¹ is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (C_rC₄)alkyl, (C_rC₄)haloalkyl, halo, hydroxyl and (CrC₄)alkoxy. In certain embodiments, the présent invention relates to any of the aforementloned

compounds, wherein R¹ is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (CrC₄)alkyl, halo(CrC₄)alkyl, halo, hydroxyl and (CrC₄)alkoxy. ln certain embodiments, the présent

invention relates to any of the aforementloned compounds, wherein R¹ is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (CrC^alkyl, halo(C_rC4)alkyl, halo, hydroxyl and (CrC^alkoxy. In certain embodiments, the présent invention relates to any of the

one, two, three, four orfive substituents independently selected from the group consisting of (Ci-C4)alkyl, halo(Ci-C4)alkyl, halo, hydroxyl and (CrC4)alkoxy.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R is cyano or cyano(CrC₃)alkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R is cyano. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R is cyano(CrC₃)alkyl; or wherein R is cyanomethyl.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^2a is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^2a is (Ci-C₃)alkyl; or wherein R²³ is methyl.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^2b is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^2b is (CrC₃)alkyl; or wherein R^2b is methyl.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R³³ is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^3a is (CrC₃)alkyl; or wherein R³³ is methyl.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^3b is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^3b is (CrC₃)alkyl; or wherein R^3b is methyl.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R⁴ is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R⁴ is (CrC₃)alkyl; or wherein R⁴ is methyl.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R⁵³ is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^5a is (CrC3)alkyI; or wherein R^5a is methyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^5a is halo.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^5b is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^5b is (Ci-C3)alkyl; or wherein R^5b is methyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^5b is halo.

In certain embodiments, the présent invention relates to any of the

O R^c (Ί R⁰ va aforementioned compounds, wherein R is R^a or ’ Ax. |_n certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R is

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^a is hydrogen, halo or (Ci-Ce)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^a is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^a is halo. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^a is (CrCe)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^a is methoxy.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is hydrogen, halo, cyano, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, or (CrC6)alkyl optionally substituted with one, two or three R^f independently seiected from the group consisting of halo, hydroxyl, N(R®)2, (CrCeJalkoxy, halo(CrC₆)alkoxy and aryl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is halo. In certain embodiments, the présent invention relates

to any of the aforementioned compounds, wherein R^b is cyano. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is hydroxyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is (Ci-C6)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is halo(Ci-C6)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is (CrC6)alkyl optionally substituted with one, two or three R^f independently selected from the group consisting of halo, hydroxyl, N(R®)2, (CrC6)alkoxy, halo(Ci-C6)alkoxy and aryl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is CH3, CHF₂, CH₂F, CH₂OH, CH₂N(CH₃)₂, CH₂OCH₃, CH₂CH₂OH, CH(OH)(CH₃) or C(OH)(CH₃)₂. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is CHF2 or CH2F. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b is CH2OCH₃.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^c is hydrogen, halo, cyano, (Οι-Οβ)alkoxy, halo(Ci-C6)alkoxy, or (Ci-C6)alkyl optionally substituted with one, two or three R^f independently selected from the group consisting of halo, hydroxyl, N(R®)2, (CrC₆)alkoxy, halo(Ci-C6)alkoxy and aryl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^c is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^c is halo. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^c is cyano. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^c is hydroxyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^c is (ΟρΟε)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^c is halo(Ci-C6)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^c is (Ci-C6)alkyl optionally substituted with one, two or three R^f independently selected from the group consisting of halo, hydroxyl, N(R®)₂, (Ci-C₆)alkoxy, halo(Ci-C₆)alkoxy and aryl.

In certain embodiments, the présent 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®)2, (CrC6)alkoxy, halo(Ci-C6)alkoxy and aryl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^b and

R 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 independentiy selected from the group consisting of halo, hydroxyl, N(R®)2, (Ci-C6)alkoxy, halo(C1.C6)alkoxy and aryl. In certain embodiments, the présent 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 independentiy selected from the group consisting of halo, hydroxyl, N(R®)2, (Ci-C₆)alkoxy, halo(CrC6)alkoxy and aryl.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^d is (CrC6)alkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^d is (CrC6)alkoxy. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^d is N(R®)2. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R^d is aryl.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R® is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein one R® is hydrogen and the other R® is (C1-C4) alkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R® is (C1-C4) alkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R® taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl.

In another embodiment are compounds of Formula (II) c

(II) or pharmaceutically acceptable salts thereof, wherein

W is phenyl or pyridyl, optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (CrC^alkyl, (Cr C₃)haloalkyl and halo.

In certain embodiments, the présent invention relates to any of the

X^y^CN aforementioned compounds, wherein R¹ is . In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ 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. .

Another embodiment of the invention is a compound represented

and pharmaceutically acceptable salts thereof. Another embodiment of the invention is a compound represented by

F and pharmaceutically acceptable salts thereof. Another embodiment of the invention is a compound represented by

and pharmaceutically acceptable salts thereof.

Another embodiment of the invention is a compound represented by

N and pharmaceutically acceptable salts thereof. Another embodiment of the invention is a compound represented by

and pharmaceutically acceptable salts thereof. In another embodiment are compounds of Formula (II)

R^a is hydrogen, halo, cyano, (CrC₆)alkoxy, halo(Ci-C₆)alkoxy, (CrC^alkylthio, (CrC^alkylsulfonyl, or (CrC₆)alkyl optionally substituted by halo, hydroxyl, (CrC₆)alkoxy or halo(Ci-C₆)alkoxy;

R^b and R^c are independently selected from the group consisting of hydrogen, halo, cyano, (CrC₆)alkoxy, halo(CrC6)alkoxy, (C3-C₆)cycloalkyl, C(=O)R^d and (Ci-C6)alkyl optionally substituted with one, two or three R^f independently selected from

the group consisting of halo, hydroxyl, N(R®)₂, (CrC₆)alkoxy and halo(CrC6)alkoxy; or

R^b and R° taken together with the carbon to which they are bound form a 4-7 membered carbocycyl or heterocycly optionally substituted with one, two or three R^f independently selected from the group consisting of halo, hydroxyl, N(R®)₂, (Ci-C₆)alkoxy and halo(CrC6)alkoxy;

R^dis (Ci.C₆)alkyl, (C^Ce)alkoxy, N(R®)₂ or aryl;

R® is independently selected for each occurence from the group consisting of hydrogen and (C1-C4) alkyl, or both R® taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl; and

W is phenyl or pyridyl, optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (Ci-C₄)alkyl, (CiC₃)haloalkyl and halo.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ is

embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ is

In certain embodiments, the présent 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.

Another embodiment of the invention is a compound represented by

Another embodiment of the invention is a compound represented by

o and pharmaceuticaily acceptable salts thereof.

Another embodiment of the invention is a compound represented by

Methods o and pharmaceutically acceptable salts thereof.

In one aspect, provided herein are methods for treating a patient by administering a compound provided herein. In some embodiments, provided herein is 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 sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté.

In another aspect, provided herein is the use of a compound disclosed herein for inhibiting Bruton's tyrosine kinase (BTK) activity or for the treatment of a disease, disorder, or condition, which would benefit from inhibition of Bruton's tyrosine kinase 15 (BTK) activity.

In some embodiments, compounds provided herein are administered to a human.

In some embodiments, compounds provided herein are orally administered.

In other embodiments, compounds provided herein are used for the formulation of a médicament for the inhibition of tyrosine kinase activity. In some other embodiments, compounds provided herein are used for the formulation of a médicament for the inhibition of Bruton's tyrosine kinase (BTK) activity.

In a further aspect, provided herein is a method for inhibiting Bruton's tyrosine kinase in a subject in need thereof by administering to the subject thereof a composition 25 containing a therapeutically effective amount of at least one compound of the invention. In some embodiments, 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, juvénile arthritis, diabètes, 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 anémia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopénie purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiteris syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anémia, Wegeneris granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

In other embodiments, 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, allergie conjunctivitis, allergie rhinitis, or atopie dermatitis.

In certain embodiments, 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, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In further embodiments, the subject in need is suffering from a cancer. In one embodiment, the cancer is a B-cell proliférative 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, médiastinal (thymie) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments, where the subject is suffering from a cancer, an anti-cancer agent is administered to the subject in addition to one of the above-mentioned compounds. In one embodiment, 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.

In further embodiments, the subject in need is suffering from a thromboembolie 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.

In a further aspect, provided herein is 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. In one embodiment, the autoimmune disease is arthritis. In another embodiment, the autoimmune disease is lupus. In some embodiments, the autoimmune disease is inflammatory bowel disease (including Crohn's disease and ulcerative colitis), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvénile arthritis, lupus, diabètes, 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 anémia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopénie purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiteris syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anémia, Wegeneris granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

In a further aspect, provided herein is 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. In some embodiments, the heteroimmune condition or disease is graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergie conjunctivitis, allergie rhinitis, or atopie dermatitis.

In a further aspect, provided herein is a method for treating an inflammatory disease by administering to a subject in need thereof a composition containing a therapeutically effective amount of at least one compound of the invention. In some embodiments, 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, ententis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In yet another aspect, provided herein is a method for treating a cancer by administering to a subject in need thereof a composition containing a therapeuticaiiy effective amount of at least one compound of the invention, ln one embodiment, the

Λ cancer is a B-cell proliférative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronîc 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, médiastinal (thymie) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments, where the subject is suffering from a cancer, an anti-cancer agent is administered to the subject in addition to one of the above-mentioned compounds. ln one embodiment, 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.

In another aspect, provided herein is a method for treating a thromboembolie disorder by administering to a subject in need thereof a composition containing a therapeuticaiiy effective amount of at least one compound of the invention. In some embodiments, the thromboembolie 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.

In a further aspect, provided herein is a method for treating an autoimmune disease by administering to a subject in need thereof a composition containing a therapeuticaiiy effective amount of a compound that forms a covalent bond with

Bruton's tyrosine kinase. In one embodiment, the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase. In a further or alternative embodiment, the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase.

In a further aspect, provided herein is 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. In one embodiment, the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase. In a further or alternative embodîment, the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase.

In a further aspect, provided herein is 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. In one embodiment, the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase. In a further or alternative embodiment, the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase. In yet another aspect, provided herein is 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. In one embodiment, the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase. In a further or alternative embodiment, the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase. In another aspect, provided herein is a method for treating a thromboembolie 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. In one embodiment, the compound forms a covalent bound with the activated form of Bruton's tyrosine kinase. In a further or alternative embodiment, the compound forms a covalent bond with a cysteine residue on Bruton's tyrosine kinase.

In any of the aforementioned aspects involving the treatment of proliférative 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, Paclitaxel™, taxol, temozolomide, thioguanine, or classes of drugs inciuding 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, topoisomerase inhibitors such as irinotecan or topotecan, tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents to treat signs or symptoms induced by such therapy inciuding allopurinol, filgrastim, granisetron/ondansetron/palonosetron, dronabinol.

In any of the aforementioned aspects involving the prévention 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. In further or alternative embodiments 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.

In a further or alternative embodiment, the compounds of the invention are inhibitors of Bruton’s tyrosine kinase (BTK), while in still further or alternative embodiments, such inhibitors are sélective for BTK. In even further or alternative embodiments, such inhibitors hâve an IC50 below 10 μΜ in enzyme assay. In one embodiment, such inhibitors hâve an IC50 of less than 1 μΜ, and in another embodiment, less than 0.25 μΜ.

Pharmaceutical Compositions and Dosing Considérations

Typically, 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 clînical approaches familiar to the médicinal 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.

The term treating, as used herein, unless otherwise indicated, 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. The term treatment, as used herein, unless otherwise indicated, refers to the act of treating as treating is defined immediately above. The term treating also includes adjuvant and neo-adjuvant treatment of a subject.

As indicated above, 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) parentéral administration, for example, by subcutaneous, intramuscuiar, intravenous or épidural injection as, for example, a stérile solution or suspension, or sustainedrelease 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; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.

The phrase 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 animais without excessive toxicity, irritation, allergie response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Wetting agents, emulsifiers and lubricants, such as sodium lauiyl sulfate and magnésium stéarate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be présent in the compositions.

Examples of pharmaceutically-acceptable antioxidants 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) métal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartane acid, phosphoric acid, and the like.

Formulations of the présent invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parentéral 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 ingrédient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particuiar mode of administration. The amount of active ingrédient 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 per cent, this amount will range from about 0.1 per cent to about ninety-nine percent of active ingrédient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

In certain embodiments, a formulation of the présent 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 présent invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the présent invention.

Methods of preparing these formulations or compositions include the step of bringing into association a compound of the présent invention with the carrier and, optionally, one or more accessory ingrédients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the présent 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 émulsion, or as an élixir 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 présent invention as an active ingrédient. A compound of the présent invention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingrédient 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 agar39 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 quatemary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stéarate, magnésium stéarate, solid polyethylene glycols, sodium lauryl sulfate, zinc stéarate, sodium stéarate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical 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 ingrédients. 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 présent invention, such as dragees, capsules, pills and granules, 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 ingrédient 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. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of stérile solid compositions which can be dissolved in stérile water, or some other stérile 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. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingrédient can also be in mïcro-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 émulsions, microemulsions, solutions, suspensions, syrups and élixirs. In addition to the active ingrédient, 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, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include 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, agaragar 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 température, but liquid at body température and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

Formulations of the présent 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 stérile 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,

paraffine, starch, tragacanth, cellulose dérivatives, 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 5 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 hâve the added advantage of providing controlled delivery of a compound of the présent invention to the body. Such dosage forms can be made 10 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.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also 15 contemplated as being within the scope of this invention. Formulations suitable for topical administration to the eye inciude, 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 aurai administration may be in the form of drops of a micronised suspension or solution in isotonie, pH-adjusted, stérile saline. Other formulations 20 suitable for ocular and aurai administration inciude ointments, biodégradable (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 25 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.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or 30 suspension from a pump spray container that is squeezed or pumped by the patient or as an aérosol spray présentation 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, 35 mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as

an aérosol 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. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

Pharmaceutical compositions of this invention suitable for parentéral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable stérile isotonie aqueous or nonaqueous solutions, dispersions, suspensions or émulsions, or stérile powders which may be reconstituted into stérile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutés which render the formulation isotonie with the biood of the intended récipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, éthanol, 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. 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.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prévention 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, phénol sorbic acid, and the like. It may also be désirable to include isotonie agents, such as sugars, sodium chloride, and the like into the compositions, ln 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.

ln some cases, in order to prolong the effect of a drug, it is désirable to slow the absorption of the drug from subeutaneous 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 dépends upon its rate of dissolution which, in tum, may dépend upon crystal size and crystalline form. Altematively, 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 biodégradable 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 biodégradable 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.

When the compounds of the présent invention are administered as pharmaceuticals, to humans and animais, 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 ingrédient in combination with a pharmaceutically acceptable carrier.

The préparations of the présent 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, 15 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.

The phrases parentéral administration and administered parenterally as used herein means modes of administration other than enterai and topical administration, 20 usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

The phrases systemic administration, administered systemically, peripheral administration and administered peripherally as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patients system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

These compounds may be administered to humans and other animais for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracistemally and topically, as by powders, ointments or drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of the présent invention, which may be used in a suitable hydrated form, and/or the pharmaceutical

compositions of the présent 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 ingrédients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingrédient 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 dépend upon a variety of factors including the activity of the particular compound of the présent invention employed, or the ester, sait or amide thereof, the route of administration, the time of administration, the rate of excrétion 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 âge, 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 détermine and prescribe the effective amount of the pharmaceutical composition required. For example, 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.

In general, 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 dépend upon the factors described above. Preferably, 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.

For example, dosing of BTK inhibitor compounds for treating an autoimmune disease can be assessed in a mouse model of rheumatoid arthritis. In this model, arthritis is induced in Balb/c mice by administering anti-collagen antibodies and lipopolysaccharide. See Nandakumaret al. (2003), Am. J. Pathol 163:1827-1837.

In another example, dosing of BTK inhibitors for the treatment of B-cell proliférative 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.

Animal models for treatment of thromboembolie disorders are also known.

The therapeutic effïcacy of the compound for one of the foregoing diseases can be optimized during a course of treatment. For example, a subject being treated can undergo a diagnostic évaluation 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 détermine in vivo activity of BTK in the presence or absence of a BTK inhibitor. For example, since 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. Soi, USA 96:2221-2226. Thus, 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.

When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.

If desired, 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 spécifie compound described herein, or pharmaceutically acceptable salts thereof, in a therapeuticaily effective amount for the treatment of an immune or inflammatory disorder, such as one of the particular immune disorders or inflammatory disorders described herein.

In addition, articles of manufacture including packaging material, a compound or composition or pharmaceutically acceptable dérivative 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 indieates that the compound or composition, or pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically

acceptable prodrug, or pharmaceutically acceptable solvaté thereof, is used for inhibiting the activity of tyrosine kinase(s), such as BTK, are provided.

Combination Treatments

The BTK inhibitor compositions described herein can also be used in combination with other well known therapeutic reagents that are seiected for their therapeutic value for the condition to be treated. In general, the compositions described herein and, in embodiments where combinational therapy is employed, other agents do not hâve to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, hâve to be administered by 10 different routes. The détermination 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 clinlcian. 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 15 skilled clinician.

In certain instances, it may be appropriate to administer at least one BTK inhibitor compound described herein in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the BTK inhibitor compounds described herein is nausea, then it may be appropriate to administer an anti-nausea agent in combination with the initial therapeutic agent. Or, by way of example only, 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 hâve minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).

Or, by way of example only, 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. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may expérience a synergistic benefit.

The particular choice of compounds used will dépend 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., slmultaneously, essentially slmultaneously 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 détermination of the order of administration, and the number of répétitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after évaluation of the disease being treated and the condition of the patient.

It is known to those of skill in the art that 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. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described extensively in the literature Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

For combination thérapies described herein, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the spécifie drug employed, on the disease or condition being treated and so forth. In addition, when co-administered with one or more biologically active agents, the compound provided herein may be administered either simultaneously with the biologically active agent(s), or sequentially. If administered sequentially, the attending physician will décidé on the appropriate sequence of administering protein in combination with the biologically active agent(s).

In any case, the multiple therapeutic agents (i.e. compounds of the invention) 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 zéro weeks to less than four weeks. In addition, 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.

It is understood that 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 âge, 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 substantîally 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 molécule concentration may also détermine the optimal dose interval.

In addition, the compounds described herein also may be used in combination with procedures that may provide additional or synergistic benefit to the patient. By way of example only, 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 détermine 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 thérapies 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. Thus, for example, 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 ofthe 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. For example, 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.

Where the subject is suffering from or at risk of suffering from an autoimmune disease, an inflammatory disease, or an allergy disease, 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, méthylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldostérone), non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, TNF-.alpha. binding proteins (e.g., infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-β, interferon-y, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta-agonists, theophylline, or anticholinergics.

Where the subject is suffering from or at risk of suffering from a B-cell proliférative disorder (e.g., plasma cell myeloma), the subjected can be treated with a BTK inhibitor compound in any combination with one or more other anti-cancer agents. In some embodiments, one or more of the anti-cancer agents are proapoptotic agents. Examples of anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, ail trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'deoxycytidine, ail trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec™), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol™, also referred to as paclitaxel, which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of Taxol™, such as Taxotere™. Compounds that hâve the basic taxane skeleton as a common structure feature, hâve also been shown to hâve the ability to arrest cells in the G2-M phases due to stabilized microtubules and may be useful for treating cancer in combination with the compounds described herein.

Further examples of anti-cancer agents for use in combination with a BTK inhibitor compound include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY

43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

Other 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; aminoglutéthimide; amsacrine;

anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bîsantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate;

cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;

estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin 11 (including recombinant interleukin II, or r1L2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1 ; interferon alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;

methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;

_ puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin;

spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;

sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride;

temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; Vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate;

vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

Other 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 protein1 ; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1 ; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin lll dérivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam dérivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene;

bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin dérivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A dérivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;

dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;

diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;

docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;

ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin;

epristeride; estramustine analogue; estrogen agonists; estrogen antagonists;

etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gélatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide;

hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;

lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilie disaccharide peptide; lipophilie platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;

molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug résistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin;

nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;

parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium;

pentostatîn; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;

phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin;

piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex;

platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin;

prednisone; propyl bis-acridone; prostaglandin J2; protéasome inhibitors; protein Abased immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonîsts; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhénium Re 186 étidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1 ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 ; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin Inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine;

synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;

titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogénital sinus-derived growth inhibitory factor; urokinase receptor antagonîsts; vapreotide; variolin B; vector system, érythrocyte gene therapy; velaresol; veramine; verdins;

verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Yet other anticancer agents that can be employed in combination with a BTK inhibitor compound include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, ete.), or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folie acid analog (e.g., methotrexate), or 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).

Examples of 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.). Examples of antimetabolites include, but are not limited to folie acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of 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). Other agents that can be used in the methods and compositions described herein for the treatment or prévention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine dérivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutéthimide).

Examples of 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 DLS10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC639829, 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 hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as

Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B),

Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-azaepothilone B, 21-aminoepothilone B (also known as BMS-310705), 21hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS39.HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as

SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC30 698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A,

TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as

NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI286 (also known as SPA-110, trifluoroacetate sait) (Wyeth), D-82317 (Zentaris), D82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

Where the subject is suffering from or at risk of suffering from a thromboembolie disorder (e.g., stroke), the subject can be treated with a BTK inhibitor compound in any combination with one or more other anti-thromboembolic agents. Examples of antithromboembolic agents include, but are not limited any of the following: thrombolytic 10 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, orBIBR 1048.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, 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 éléments to 20 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 materiais such as glass or plastic.

The articles of manufacture provided herein contain packaging materiais. Packaging materiais for use in packaging pharmaceutical products are well known to 25 those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252.

Examples of pharmaceutical packaging materiais 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 30 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.

For example, the container(s) can include one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed 35 herein. The container(s) optionally hâve a stérile access port (for example the container

can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such 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) désirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such 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 présent within a réceptacle 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 spécifie therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.

In certain embodiments, 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 métal 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 govemmental 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.

General Synthetic Procedures

The following schemes and experimental procedures are représentative of the methods that can be used to préparé compounds of Formula (I) and are not intended to be limiting. Starting materials may be obtained by procedures described in the schemes, by procedures well known to one of ordinary skill in organic chemistry, and/or may be obtained commercially.

During any of the following synthetic sequences it may be necessary and/or désirable to protect sensitive or reactive groups on any of the molécules concemed. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 2006. The need for, and the sélection of, appropriate protecting groups can be readily determined by one skilled in the art.

The compounds of Formula (I) may be prepared as single enantiomer or as a mixture of individual enantiomers which includes racemîc 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 séparation of the resulting diastereomers by common methods (e.g. crystallization, chromatographie séparation, or distillation) and chemical reversion to scalemic compound, Simulated Moving Bed technology, or high/medium-pressure liquid chromatography or supercritical fluid chromatography employing a chiral stationary phase. These techniques may be performed on the final compounds of Formula (I) or on any intermediates to compounds of Formula (I) which bear a stereogenic center. Also, to facilitate séparation by any of the methods described above, the compounds of Formula (I) or any intermediates to the compounds of Formula (I) which bear a stereogenic center may be transiently reacted with an achiral reagent, separated, and then reverted to scalemic compound by standard synthetic techniques.

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 -1. Compound A4 may be obtained by deprotection of the amine employing conditions such as catalytic hydrogénation in the case of benzyloxycarbonyl protection or trifluoroacetic acid in the case of t-butoxycarbonyl. Subséquent 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). Altematively, compounds of the formula A3 may be transformed to A5 directly under these conditions.

In certain embodiments, compound A5 is then reacted with cyanogen bromide in a polar solvent (e.g. Ν,Ν-dimethylformamide) in the presence of an inorganic base (e.g.

potassium carbonate) to afford compounds of the formula A6.1. Similarly as described in Scheme B, amine A5 is reacted with bromoacetonitrile to provide compounds of the formula B1.

In certain embodiments, 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 affoFd compounds of the formula A6.2.

A6.1 A5 A6.2

Compounds of the formula A1 empioyed in Scheme A may be prepared as described in Scheme C. Carboxylic acids of the formula C1, which are commercially available or prepared as descnbed in Schemes D - F, are converted to the correspondîng carboxylic acid chlorides C2 by the reaction with thionyl chloride or oxalyl chloride. Condensation of C2 with the sodium anion of malononitrile in anhydrous tetrahydrofuran affords compounds of the formula C3. Compounds of the formula A1 are then provided by the reaction of C3 with methyl sulfate in the presence of an inorganic base (e.g. sodium bicarbonate).

SCHEME C

C1

C2

Carboxylic acids of the formula C1 empioyed in Scheme C may be prepared as described in Schemes D - F. In Scheme D, methyl 4-hydroxybenzoate may be coupled with substituted boronic acids of the formula D1 in the presence of 4dimethylaminopyridine and copper (II) acetate to provide esters of the formula D3. Subséquent saponification of D3 employing an inorganic base such as sodium hydroxide provides carboxylic acids of the formula C1.1. Altematively as described in Scheme E, (4-(methoxycarbonyl)phenyl)boronic acid may be coupled with substituted phénols 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. Altematively as described in Scheme F, 1-(4fluorophenyl)ethanone can be heated in dimethylacetamide with substituted phénols of the formula E2 and an inorganic base such as potassium carbonate to afford ethers of the formula F2. Subséquent Baeyer Villiger oxidation of F2 with sodium hypochlorite solution provides carboxylic acids of the formula C1.1.

SCHEME D

D2 D3

O

C1.1

SCHEME E

E1

SCHEME F

F2

O

C1.1

Compounds of the formula A2 employed in Scheme A may be prepared as described in Scheme G wherein ring B is an optionally substituted azetidine, pyrrolidine, piperidine, azepane and the like. The basic nitrogen atom présent in hydroxy amines of 10 the formula G1 is protected with an appropriate protecting group such as benzyloxycarbonyl, t-butoxycarbonyl, acetyl, or diphenylmethylene employing conditions well known by those skilled in the artto provide G2 whereinx = 0-2, y=1-2, and R

may include group such as (CrC^alkyl, (CrC^fluoroalkyl, halo, protected hydroxy and (Ci-C₄)alkoxy. CompoundG2 isthen oxidizedtoprovide ketonesoftheformulaG3 which is then condensed with t-butyl hydrazinecarboxylate to provide compounds of the G4. The resulting hydrazone is then reacted with an appropriate métal hydride reducing 5 agent (e.g. sodium cyanoborohydride) to provide G5. Compound G5 is then treated with an acid (e.g. hydrochloric acid) to provide hydrazines of the formula A1.1.

SCHEME G

HO

G1

HO

G2

O

G3

R

G5

G4

A1.1 G5 ^w

Additional examples of 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-l-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.

SCHEME H

OH k^NHBOC ci^^u^ci ___>.

H5

A1.2

Additional examples of A2 employed in Scheme A may be prepared as described in Scheme I wherein ring B is an azabicyclo[2.2.1]heptane. Cyclopenta-1,35 diene is reacted with ammonium chloride, formaldéhyde, and benzyl chloroformate to provide compound I2. Hydroboration of I2 employing borane methyi sulfide followed by oxidation with hydrogen peroxide provides alcohol I3 which is subsequently oxidized with Dess-Martin periodinane to provide ketone I5. The resulting ketone is then condensed with t-butyl hydrazinecarboxylate followed by treatment with sodium cyanoborohydride to provide compound I6. Compound I6 is then treated with an acid (e.g. hydrochloric acid) to provide hydrazines of the formula A1.3.

SCHEME I

Altematively, 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 methyi sulfate in the presence of an inorganic base (e.g. sodium bicarbonate) to

provide compound J3. 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. benzyloxycarbonyl, tbutoxycarbonyl, acetyl, or diphenylmethylene), to afford pyrazoles of the formula J4.

Hydrazines of the formula A2 are commercially available or may be prepared as described in Schemes G -1. Compound J4 is reacted with bis(pinacolato)diboron and potassium acetate catalyzed by PdCI₂(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 10 J6 may be coupled with optionally substituted phénols 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. Similarly, starting from 3-iodobenzoyl chloride, compounds of formula (I) in which the aryl ether substituent is at the meta-position may be prepared.

SCHEME J

R = H

R = CH₃ ,nh₂

-P

J6

A3.1

Compounds of formula (I) wherein X is CH₂ may be prepared as described in Scheme K. Compounds of the formula J4 described in Scheme J are reacted with optionally substituted benzyl zinc halides in the presence of S-PHOS and Pd₂(dba)₃ catalysts to afford compounds of the formula A3.2 which may be subsequently converted to compounds of formula (I) according to procedures described in Scheme A. Similarly, starting from 3-iodobenzoyl chloride, compounds of formula (I) in which the optionally substituted benzyl substituent is at the meta-position may be prepared.

SCHEME K

A3.2

Altematively as described in Scheme L, 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 Pd₂(dba)₃ catalysts to afford compounds of the formula L2 wherein X = CH₂. In a similar fashion compound L1 is reacted with an optionally substituted phénol in the presence of césium carbonate and copper (I) iodide to provide compounds of the formula L2 wherein X = O. In addition, 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.

SCHEME L

L1 L2

Compounds of the formula (I) wherein A is a pyridine ring are prepared as described in Scheme M. 6-Chloronicotinyl chloride (M1) is condensed with the sodium anion of malononitrile in anhydrous tetrahydrofuran to afford compound M2 which is then reacted with methyl sulfate in the presence of an inorganic base (e.g. sodium bicarbonate) to provide M3. Compound M3 is condensed with hydrazines of the formula A2, wherein the ring B is an optionally substituted 4-8 membered nitrogencontaining heterocycle and P is an appropriate amine protecting group (e.g. benzyloxycarbonyl, t-butoxycarbonyl, acetyl, or diphenylmethylene), to afford pyrazoles of the formula M4. Hydrazines of the formula A2 are commercially available or may be prepared as described in Schemes G -1. Compounds M4 are heated in a polar solvent with an optionally substituted phénol 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.

In certain embodiments, the resulting amine is then reacted with cyanogen bromide in a polar solvent (e.g. Ν,Ν-dimethylformamide) in the presence of an inorganic base (e.g. potassium carbonate) to afford compounds of the formula M7.1 (where R = CN). Similarly, the amine is reacted with bromoacetonitrile to provide compounds of the formula M7.1 (where R = CH₂CN).

In other embodiments, 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.

SCHEME Μ

M5

M6 R = H

M7.1 R = CNorCH₂CN

M7.2 R = C(=O)C(R^a)=C(R^b)(R^c)

Compounds of the formula (I) wherein W is a pyridine ring may be prepared as described in Scheme N. 4-Hydroxybenzoic acid (N1) is reacted with t-butyl dimethylsilyl chloride in the presence of imidazole to afford compound N2. Compound N2 is converted to the corresponding acid chloride by the reaction with isobutyl chloroformate which is then condensed with the sodium anion of malononitrile in anhydrous tetrahydrofuran and then treated with methyl sulfate in the presence of an inorganic base (e.g. sodium bicarbonate) to provide N3. Compound N3 is condensed 10 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 -1. Compound N4 is treated 15 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. The resulting phénols are heated in a polar solvent (e.g. N,Ndimethylformamide) with an optionally substituted 2-halopyridine and an inorganic base

(e.g. césium carbonate) to provide compounds of the formula N7. Compound N7 is reacted with concentrated sulfuric acid to provide carboxamides of the formula N8.

In certain embodiments, the resulting amines are then reacted with cyanogen bromide in a polar solvent (e.g. Ν,Ν-dimethylformamide) in the presence of an inorganic 5 base (e.g. potassium carbonate) to afford compounds of the formula N9.1 (where R = CN). Similarly, the amines are reacted with bromoacetonitrile to provide compounds of the formula N9.1 (where R = CH2CN).

In other embodiments, 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.

SCHEME N

Λ p N5 R = TBS L-*-N6 R = H r- N1 R = H L* N2 R = TBS

OTBS

LN8 R = H

N9.1 R = CNorCH₂CN

N9.2 R = C(=O)C(R^a)=C(R^b)(R^c)

Compounds of Formula (I) may also be prepared as described in Scheme O. tert-Butyl 15 3-(5-acetamido-3-bromo-4-(ethoxycarbonyl)-1 /7-pyrazol-1 -yl)piperidine-1 -carboxylate (Compound 01) prepared as described in Scheme P is reacted with a boronic acid ester of the formula 02 which may be prepared as described in Scheme Q in the presence of Pd(dppf)2Cl2 and an inorganic base (e.g. sodium carbonate) to provide

compounds of the formula 03. The resulting esters are then treated with lithium hydroxide in a mixture of methanol and tetrahydrofuran to provide carboxylic acids of the formula 04 which are then coupled with ammonia after activation with 1hydroxybenzotriazole and 3-(dimethylamino)propyl carbodiimide hydrochloride to 5 provide amide 05. Compound 05 is then treated with and acid (e.g. trifluoroacetic acid) to provide amines of the formula 06.

In certain embodiments, the resulting amines are then reacted with cyanogen bromide in a polar solvent (e.g. Ν,Ν-dimethylformamide) in the presence of an inorganic base (e.g. potassium carbonate) to afford compounds of the formula 07 (R = CN).

w Similarly, the amines are reacted with bromoacetonitrile to provide compounds of the formula 08 (R = CH2CN).

In other embodiments, 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 09.

Y=BOC,R = OH 05 Y=BOC,R = NH₂ -1 06Y=H, R = NH₂

tert-Butyl 3-(5-acetamido-3-bromo-4-(ethoxycarbonyl)-1 /-/-pyrazol-1 -yl)pipe ridine-1 carboxylate (Compound 01) empioyed in Scheme O is prepared as described in

Scheme P from ethyl 5-amino-1H-pyrazole-4-carboxylate (compound P1). Compound P1 is treated with acetyl chloride to provide compound P2 which is then reacted with bromine in a mixture of éthanol and aqueous sodium acetate to provide compound P3. Compound P3 is reacted under Mitsunobu reaction conditions with t-butyl 3hydroxypiperidine-1-carboxylate to provide compound 01.

SCHEME P

P1 |- P2 R = H

L*· P3 R = Br

Représentative examples of boronic acid esters of the formula 02 empioyed in Scheme 0 may be prepared as described in Scheme Q. Phénols 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)₂Cl2 to provide compounds of the formula 02.

SCHEME Q

Q1 Q2

EXEMPLIFICATION

The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the présent invention, and are not intended to limit the invention. The following illustrate the synthesis of various compounds of the présent invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art.

Experiments were generally carried out under inert atmosphère (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were generally used without further purification, including anhydrous solvents where appropriate. Mass spectrometry data is reported from either liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI) or gas chromatography-mass spectrometry (GCMS) instrumentation. Chemical shifts for nuclear magnetic résonance (NMR) data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents employed. Coupling constants (J values) are reported in Hertz.

For synthèses referencing procedures in other Examples or Methods, reaction conditions (length of reaction and température) may vary. In general, 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 rétention times (RetT).

Example 1 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole carboxamide

Step 1 : préparation 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 16h, 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: préparation 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. The reaction was then allowed to stir for 16 h at ambient température, cooled to 0°C and quenched with 1N hydrochloric acid (1 L). Product was extracted into ethyl acetate and the combined organic layers were washed with water, then brine, dried over sodium sulfate, and

- concentrated in vacuo to afford the title compound as an off-white solid, which was carried on to the next step without purification. MS (M-H) m/z261. ¹H NMR (CDCI₃) δ

7.74 (d, J= 8.8 Hz, 2H), 7.39 (t, J= 7.6 Hz, 2H), 7.21 (t, J= 7.2 Hz, 1H), 7.06 (d, J= 8

Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H).

Step 3: préparation of 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile.

To a solution of 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 2h, after which the reaction was warmed to 80°C and allowed to stir for an additional 12h. The reaction was cooled to ambient température, diluted with water and extracted into ethyl acetate. The combined organic layers were washed with water, then brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by silica gel coiumn chromatography to afford the title compound as an off white solid (300 g, 48%). MS (M+H) m/z277.¹H NMR (CDCI3) δ 7.47 (d, J= 8.8 Hz, 2H),

7.42 (t, J= 7.6 Hz, 2H), 7.23 (t, J= 7.6 Hz, 1H), 7.07 (t, J= 8.8 Hz, 4H), 3.97 (s, 3H).

Step 4: préparation of 3-Hydroxy-piperidine-1-carboxylic acid benzyl ester. To a suspension of piperidin-3-ol hydrochloride (134 g, 0.974 mol) and triethylamine (276 mL, 1.98 mol) in dichloromethane (2 L) at 0 °C was added a solution of benzyl chloroformate (140 mL, 0.981 mol) in dichloromethane (100 mL) drop wise over 2.5 h.

The reaction was allowed to stir for an additional 30 min at 0 °C, then allowed to warm to ambient température over 16 h, after which it was quenched with 1N hydrochloric acid (3 L) and allowed to stir for 30 min. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to afford the title compound (218 g, 95 %). ¹H-NMR (CDCI3) δ 7.29-7.41 (m, 5H), 5.14 (s, 2H), 3.59-3.85 (m, 3H), 3.13-3.27 (m,

2H), 2.18 (bs, 1H), 1.74-1.94 (m, 2H), 1.38-1.61 (m, 2H).

Step 5: préparation of 3-oxo-piperidine-1-carboxylic acid benzyl ester. To a suspension of pyridine sulfurtrioxide complex (135.6 g, 0.85 mol) in dichloromethane (1.25 L) at 0°C was added triethylamine (148 mL, 1.07 mol), followed by DMSO (151 mL, 2.13 mol). A solution of 3-hydroxy-piperidine-1-carboxylic acid benzyl ester (50.0 g, 30 0.21 mol) in dichloromethane (415 mL) was then added drop wise over 1 h, ensuring that the température did not exceed 0°C. The reaction was then allowed to warm to ambient température over 16h, after which it was cooled to 15°C and slowly quenched with saturated aqueous ammonium chloride (1 L) (exotherm!) The mixture was then allowed to stir for an additional 30 min, after which the organic layer was separated and 35 the aqueous layer was extracted with dichloromethane. The combined organic layers

were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in a 50% solution of heptane / ethyl acetate (300 mL), washed with 0.5N hydrochloric acid (600 mL), then brine. The organic layer was concentrated in vacuo and purified by silica gel column chromatography. ¹H-NMR δ (CDCI₃): 7.32-7.41 (m, 5H), 5.17 (s, 2H),

4.10 (s, 2H), 3.69 (t, 2H), 2.50 (t, 2H), 1.97-2.08 (m, 2H).

Step 6: préparation of 3-(tert-butoxycarbonyl-hydrazono)-piperidine-1 -carboxylic acid benzyl ester. To a solution of 3-oxo-piperidine-1-carboxylic acid benzyl ester (150 g, 0.64 mol) in tetrahydrofuran (1.5 L) was added fert-butyl hydrazinecarboxylate (85 g, 0.64 mol). The solution was heated to reflux for 2 h, after which it was cooled to ambient température and concentrated in vacuo to afford the title compound. MS (M+H) m/z 348.¹H-NMR (CDCI_a) δ 7.56 (s, 1H), 7.28-7.41 (m, 5H), 5.14-5.16 (d, 2H), 4.13-4.25 (d, 2H), 3.73-3.78 (m, 0.6 H), 3.53-3.61 (m, 1.4H), 2.51-2.56 (t, 0.7H), 2.33-2.37 (t, 1.3H),

1.82-1.91 (m, 2H), 1.52 (s, 9H)

Step 7: préparation of benzyl 3-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1carboxylate. To a solution of 3-(tert-butoxycarbonyl-hydrazono)-piperidine-1 -carboxylic acid benzyl ester (230 g, 0.66 mol) in tetrahydrofuran (1.5 L) was added sodium cyanoborohydride (41.6 g, 0.66 mol). A solution of para-toluenesulfonic acid monohydrate (126 g, 0.66 mol) in tetrahydrofuran (590 mL) was then added drop wise over

1.5 h, ensuring that the température did not exceed 21 °C. The reaction was then allowed to stir over 16 h. Volatiles were removed in vacuo, and the resulting residue was dissolved in ethyl acetate (2.0 L), washed with saturated aqueous sodium bicarbonate (1 L), then added to 1N sodium hydroxide (1.5 L) and allowed to stir for 1 h. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-3% dichloromethane / methanol solvent gradient) affording the title compound as a coloriess oil (169 g, 73 %). ¹H-NMR (CDCI3): δ 7.29-7.36 (m, 5H), 6.33 (bs, 1H), 5.88 (bs, 1H), 5.12 (bs, 2H), 3.42-3.64 (m, 5H), 3.02-3.17 (m, 1H),1.74-1.80 (m, 2H).

Step 8: préparation of 3-hydrazino-piperidine-1-carboxylic acid benzylester hydrochloride. To a solution of benzyl 3-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1carboxylate (50 g, 0.143 mol) in methanol (180 mL) was added a solution of 4N hydrochloric acid in dioxane (180 mL) drop wise, ensuring that the température did not exceed 10°C. The reaction was allowed to stir at ambient température over 16 h, after which a white precipitate had formed. The precipitate was filtered, then allowed to stir in ethyl acetate (700 mL) at ambient température for an additional 16h, filtered, then dried under vacuum to afford the title compound as a white powder. MS (M+H) m/z 250.2.

¹H-NMR (DMSO-î/6) δ 7.28-7.41 (m, 5H), 5.08 (s, 2H), 4.10 (d, 1 H), 3.72 (d, 1 H), 2.95 (bs, 3H), 1.98 (m, 1H), 1.70 (m, 1H), 1.29-1.37 (m, 2H).

Step 9: préparation of benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol5 1-yl]-piperidine-1-carboxylate. To a solution of 2-[(4-phenoxy-phenyl)-methoxymethylene]-malononitrile (step 3; 146 g, 0.53 mol) in éthanol (500 mL) was added benzyl 3-hydrazino-piperidine-1-carboxylate (step 8; 150.6g, 0.53 mol) and triethylamine (107g, 1.05 mol), causing the température of the solution to reach 55°C. The reaction was then allowed to cool to ambient température over 16 h, after which a precipitate had formed. The precipitate was filtered off and added to 2-methyl tetrahydrofuran (3.5 L), which dissolved the desired product, leaving behind triethyl amine hydrochloric acid, which was then removed by vacuum filtration. The filtrate was then washed with brine (1 L) and concentrated in vacuo to afford the title compound as a white solid. MS (M+H) m/z 494.

Step 10: préparation of 5-amino-3-(4-phenoxy-phenyl)-1-piperidin-3-yl-1 Hpyrazole-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 (5L) 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. MS (M+H) m/z 360.

Step 11: préparation of 5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1Hpyrazole-4-carboxylic acid amide. To a 2L SS Parr autoclave was added a solution of 5-amino-3-(4-phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazole-4-carbonitrile (189 g, 527 mmol) and éthanol (550 mL). A 2N sodium hydroxide solution (880 mL) was then added 25 and the autoclave was sealed and heated at 150°C for 30 min, after which the reaction was judged complété. The solution was cooled to ambient température and added to ethyl acetate (500 mL). The organic layer was separated, washed with brine, and concentrated in vacuo to afford a gummy solid, which was triturated with acetonitrile (500 mL), then purified further by silica gel column chromatography (15-40% methanol / 30 dichloromethane solvent gradient) to afford the title compound as a white solid (135 g, 70%). MS (M+H) m/z 360.

Step 12: préparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)1 H-pyrazole carboxamide. To a solution of 5-amino-3-(4-phenoxyphenyl)-1-piperidin-3yl-1 H-pyrazole-4- carboxylic acid amide (1.17 g, 3.10 mmol) in /V,/V-dimethylformamide 35 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. The resulting residue was dissolved in ethyl acetate, washed with brine, dried over magnésium sulfate and concentrated. The crude product was purified by reverse phase préparative HPLC to afford the title compound. MS (M+H) m/z 403.188.¹H NMR (DMSO-d6) δ 7.45 (d, «/=8.79 Hz, 2 H), 7.39 (t, «/=7.87 Hz, 2 H),

7.14 (t, «/=7.32 Hz, 1 H), 7.03 (t, «/=8.79 Hz, 4 H), 6.44 (bs, 2 H), 4.31 - 4.38 (m, 1 H),

3.48 (bs, 1 H), 3.45 (d, «/=3.66 Hz, 1 H), 2.98- 3.09 (m, 1 H), 1.90 (bs, 2 H), 1.76 -1.88 (m, 2 H), 1.68 (t, «/=12.45 Hz, 1 H).

Example 2

5-amino-1 -[(3fi)-1 -cyanopiperidin-3-yl]-3-(4-phenoxyphenyl)-1 H-pyrazole-4carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1 H-pyrazole carboxamide (prepared as described in Example 1) was chirally separated by supercritical fluid chromatography (OJ-H 30 x 250 mm col, 50% MeOH, 70 mL/min). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 403.¹H NMR (DMSO-ctâ) δ 7.45 (d, «/=8.79 Hz, 2 H), 7.39 (t, J=7.87 Hz, 2 H), 7.14 (t, J=7.32 Hz, 1 H), 7.03 (t, «/=8.79 Hz, 4 H), 6.44 (bs, 2 H), 4.31 - 4.38 (m, 1 H), 3.48 (bs, 1 H),

3.45 (d, «/=3.66 Hz, 1 H), 2.98- 3.09 (m, 1 H), 1.90 (bs, 2 H), 1.76 -1.88 (m, 2 H), 1.68 (t, «/=12.45 Hz, 1 H).

Example 3 5-amino-1 -[(3S)-1 -cyanopiperidin-3-yl]-3-(4-phenoxyphenyl)-1 H-pyrazole-4carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1 H-pyrazole carboxamide (prepared as described in Example 1) was chirally separated by supercritical fluid chromatography (OJ-H 30 x 250 mm col, 50% MeOH, 70 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 403.

¹H NMR (DMSO-de) δ 7.45 (d, J=8.79 Hz, 2 H), 7.39 (t, J=7.87 Hz, 2 H), 7.14 (t, J=7.32 Hz, 1 H), 7.03 (t, J=8.79 Hz, 4 H), 6.44 (bs, 2 H), 4.31 - 4.38 (m, 1 H), 3.48 (bs, 1 H),

3.45 (d, J=3.66 Hz, 1 H), 2.98- 3.09 (m, 1 H), 1.90 (bs, 2 H), 1.76 -1.88 (m, 2 H), 1.68 (t, J= 12.45 Hz, 1 H).

Example 4

5-amino-1 -[1 -(cyanomethyl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1 H-pyrazole-4carboxamide

A mixture of 5-amino-3-(4-phenoxy-phenyl)-1-piperidin-3-yl-1 H-pyrazole-4carboxylic acid amide (100 mg, 0.27 mmol) (Example 1, Step 11), potassium carbonate (40 mg, 0.29 mmol), and bromoacetonitrile (38 mg, 0.32 mmol) in Λ/,Λ/dimethylformamide was allowed to stir at 50°C over 16h. The suspension was cooled, diluted with water and extracted into ethyl acetate. The organic layers were combined and concentrated in vacuo. The crude product was purified by reverse phase préparative HPLC to afford the title compound. MS (M+H) m/z417.¹H NMR (DMSOî/6) δ ppm 7.47(d, J=8.79 Hz, 2 H) 7.40 (t, J=8.1 Hz, 2 H), 7.15 (t, J=7.3 Hz, 1 H), 7.06 (t, J=8.8 Hz, 4 H), 6.40 (bs, 2 H), 4.23 - 4.33 (m, 1 H), 3.77 (d, J=8.4 Hz, 2 H), 2.86 -

2.95 (m, 1 H), 2.78 (d, J=10.3 Hz, 1 H), 2.55 (bs, 1 H), 2.07 - 2.18 (m, 1 H), 1.86 (bs,1 H), 1.79 (d, J=9.9 Hz, 1 H), 1.59 -1.71 (m, 2 H).

Example 5

5-amino-1 -(1 -cyanopiperidin-4-yl)-3-(4-phenoxyphenyl)-1 H-pyrazole-4carboxamide

Step 1: préparation of benzyl 4-oxopiperidine-1-carboxylate. To a solution of piperidin-4-one hydrochloride (150 g, 0.98 mol) in saturated aqueous sodium bicarbonate (3 L) was added a solution of benzyl chlorocarbonate (192 g, 1.13 mol) in dioxane (114 mL) drop wise. The reaction was allowed to stir 16 h at ambient température. The mixture was then extracted into ethyl acetate, and the combined

organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuoto afford the title compound (236 g, >99%).

Step 2: préparation of benzyl 4-(2-(tert-butoxycarbonyl)hydrazono)piperidine-1carboxylate. 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: préparation of benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1carboxylate. A solution of benzyl 4-(2-(tert-butoxycarbonyl)hydrazono)piperidine-110 carboxylate (250 g, 0.72 mol) in tetrahydrofuran (1.7 L) was allowed to stir at ambient température for 30 min, then cooled to 4°C. Sodium cyanoborohydride (50 g, 0.79 mol) was then added portion wise, ensuring that the reaction température did not exceed 10°C. The reaction was stirred for an additional 10 min, after which a solution of paratoluene sulfonic acid (150 g, 0.79 mol) in tetrahydrofuran (700 mL) was added drop 15 wise. The reaction was allowed to stir for an additional 3 h. Solvent was removed in vacuo, and the crude residue was extracted into ethyl acetate, washed with saturated aqueous sodium bicarbonate, 1N sodium hydroxide, brine, then dried over sodium sulfate and concentrated in vacuo to afford the title compound which was taken on to the next step without purification (224 g, 90%).

Step 4: préparation 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 (2L) was allowed to stir at ambient température 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: préparation of 5-amino-3-(4-phenoxyphenyl)-1-piperidin-4-yl-1Hpyrazole-4-carboxamide. Prepared according to the procedures described for 5-amino-

3-(4-phenoxyphenyl)-1-piperidin-3-yl-1/-/-pyrazole-4-carboxylic acid amide (Example 1, steps 9-11), beginning from 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile 30 (Example 1, Step 3) and benzyl 4-hydrazinylpiperidine-1-carboxylate hydrochloride to afford the title compound.

Step 6: préparation of 5-amino-1-(1-cyanopiperidin-4-yl)-3-(4-phenoxyphenyl)1 /+pyrazole-4-carboxamide. Prepared according to the procedure for 5-amino-1 -(1 cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1/-/-pyrazole carboxamide (Example 1, Step 35 12) employing 5-amino-3-(4-phenoxyphenyl)-1-piperidin-4-yl-1H-pyrazole-4-

carboxamide to afford the title compound (9 mg, 8%). MS (M+H) m/z403.¹H NMR (DMSO-dô) δ 7.49 (d, J=8.8 Hz, 2H), 7.37 - 7.44 (m, 2H) 7.12 - 7.19 (m, 1H), 7.05 (d,

J=8.79 Hz, 2H), 7.07 (d, J=7.7 Hz, 2H), 6.35 (s, 2H), 4.21 - 4.30 (m, 1H), 3.51 (d,

J=12.8 Hz, 2H), 3.09 - 3.18 (m, 2H), 1.94-2.05 (m, 2H), 1.85 (d, JM 0.6 Hz, 2H).

Example 6

5-amino-1-[1-(cyanomethyl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-4carboxamide

Prepared according to the procedure described for 5-amino-1-[1(cyanomethyl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (Example 4) from 5-amino-3-(4-phenoxyphenyl)-1-piperidin-4-yl-1H-pyrazole-4carboxamide (Example 5, Step 5) to afford the title compound (13 mg, 12%). MS (M+H) m/z 417.¹H NMR (DMSO-dô) δ 7.47 (d, J=8.4 Hz, 2H), 7.40 (t, J=7.9 Hz, 2H),

7.16 (t, J=7.3 Hz, 1H), 7.07 (d, J=8.1 Hz, 2H), 7.04 (d, J=8.79 Hz, 2H) 6.36 (s, 2H), 4.08 - 4.18 (m, 1H), 3.76 (s, 2H), 2.88 (d, JM 1.0 Hz, 2H), 2.29 - 2.39 (m, 2 H), 1.98 (qd, JM 2.0, 3.7 Hz, 2H), 1.83 (d, JM 0.3 Hz, 2H).

Example 7 5-amino-1-(1-cyanopyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4carboxamide

Ό'

Step 1: préparation 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 température did not exceed 5°C. The reaction mixture was then allowed to stir at ambient température for 48h, after which it was poured into aqueous saturated sodium bicarbonate and extracted into dichloromethane. The combined organic layers were washed with aqueous saturated sodium bicarbonate, dried over magnésium sulfate, and concentrated in vacuo. The resulting crude oil was purified by silica gel column chromatography (50% ether/ hexanes followed by ether) to afford the title compound as a clear oil (14 g, 92%).

Step 2: préparation of benzyl 3-oxopyrrolidine-1-carboxylate. To a solution of benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate (7.5 g, 33.9 mmol) in dichloromethane (1.2 L) was added 4-methylmorpholine N-oxide (5.96 g, 50.0 mmol), tetrapropylammonium perruthenate (0.60 g, 1.7 mmol), and 4 Â 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: préparation of benzyl 3-[2-(tert-butoxycarbonyl)hydrazino]pyrrolidine-1carboxylate. To a solution of 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). The mixture was heated to reflux for 24h, then cooled to 15°C, after which sodium cyanoborohydride (0.86 g, 13.7 mmol) was added, followed by drop wise addition of para-toluene sulfonic acid (2.6 g, 15.1 mmol) in tetrahydrofuran (15 mL). The reaction mixture was allowed to stir at ambient température for an additional 16 h, then concentrated in vacuo. The resulting residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, then added to 30 mL of 1N aqueous sodium hydroxide and allowed to stir for 30 min. The aqueous layer was removed and the organic washed with water, dried over magnésium sulfate and concentrated in vacuo to afford the title compound as a clear oil (4.4 g, 97%).

Step 4: préparation of benzyl 3-hydrazinopyrrolidine-1-carboxylate. To a solution of benzyl 3-[2-(tert-butoxycarbonyl)hydrazino]pyrrolîdine-1-carboxylate (2.0 g, 6.4 mmol) in tetrahydrofuran (25 mL) was added 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: préparation of 5-amino-3-(4-phenoxyphenyl)-1-pyrrolidin-3-yl-1 Hpyrazole-4-carboxamide. Prepared according to the procedures described for 5-amino-

3-(4-phenoxyphenyl)-1-piperidin-3-yl-1/-/-pyrazole-4-carboxylic acid amide (Example 1, steps 9-11), beginning from 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile (Example 1, Step 3) and benzyl 3-hydrazinopyrrolidine-1-carboxylate to afford the title compound.

Step 6: préparation of 5-amino-1-(1-cyanopyrrolidin-3-yl)-3-(4-phenoxyphenyl)-

H-pyrazole-4-carboxamide. Prepared according to the procedure for 5-amino-1 -(1 - cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1 /7-pyrazole carboxamide (Example 1, Step

12) employing 5-amino-3-(4-phenoxyphenyl)-1 -pyrrolidin-3-yl-1 H-pyrazole-4carboxamide to afford the title compound (9 mg, 8%). MS (M+H) m/z 389.¹H NMR (DMSO-ctâ) δ 7.51 (d, J=8.8 Hz, 2H), 7.41 (t, J=7.9 Hz, 2H), 7.16 (t, J=7.5 Hz, 1 H), 7.06 (dd, J=10.8, 8.24 Hz, 4H), 6.42 (s, 2H), 4.88 - 4.98 (m, 1H), 3.74 (dd, J=10.3, 6.6 Hz,

H), 3.43 - 3.67 (m, 3H), 2.14 - 2.33 (m, 2H).

Example 8

5-amino-1 -[1 -(cyanomethyl)pyrrolidin-3-yl]-3-(4-phenoxyphenyl)-1 H-pyrazole-4carboxamide

Ό'

Prepared according to the procedure described for 5-amino-1-[1(cyanomethyl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (Example 4) from 5-amino-3-(4-phenoxyphenyl)-1-piperidin-4-yl-1H-pyrazole-4carboxamide (Example 7, Step 5) and bromoacetonitrile to afford the title compound. MS (M+H) m/z402.7.¹H NMR (DMSO-d6) m/z7.48 (d, J=8.4 Hz, 2H), 7.35 - 7.45 (m, 2H), 7.12 - 7.21 (m, 1 H), 7.00 - 7.12 (m, 4H), 6.41 (s, 2H), 4.81 - 4.96 (m, 1 H), 3.81 -

3.90 (m, 2 H), 3.01 (t, J=8.4 Hz, 1H), 2.75 - 2.88 (m, 2H), 2.64 - 2.75 (m, 1H), 2.10 -

2.36 (m, 2H).

Example 9 5-amino-1-(1-cyanoazetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

Step 1: préparation of 1-(diphenylmethyl)azetidin-3-one. To a stirred solution of sulfur trioxide-pyridine complex (69 g, 432.95 mmol) in dimethylsulfoxide (172.6 mL) was added a solution of 1-(diphenylmethyl)azetidin-3-ol hydrochloric acid (20 g, 72.52 mmol) and triethylamine (50.5 mL, 362.6 mmol) in tetrahydrofuran (69 mL) drop wise over 10 minutes. The solution was allowed to stir for 2h. The reaction mixture was then poured into water and extracted into 50% ethyl acetate / hexanes. The organic layers were combined and washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound (11.4 g, 66%).

Step 2: préparation of tert-butyl 2-[1-(diphenylmethyl)azetidin-3ylidenejhydrazinecarboxylate. 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 resultîng residue was dissolved in dichlorométhane 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, 94%).

Step 3: préparation of tert-butyl 2-[1-(diphenylmethyl)azetidin-3yljhydrazinecarboxylate. A solution of tert-butyl 2-[1-(diphenylmethyl)azetidin-3ylidenejhydrazinecarboxylate (15.8 g, 45.0 mmol) in acetic acid (120 mL) was cooled to

0°C. Sodium cyanoborohydride (2.82g, 45.0 mmol) was then added portion wise, and the reaction was allowed to warm to ambient température for 4 h. The majority of solvent was removed in vacuo, and the resultîng slurry was then neutralized to pH = 7 with 1N sodium hydroxide. The desired compound was extracted into dichlorométhane. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The resultîng residue was purified by trituration with diethyl ether to afford the title compound (15 g, 95%).

Step 4: préparation of 1-benzhydryl-3-hydrazinylazetidine. To a solution of tertbutyl 2-[1-(diphenylmethyl)azetidin-3-yl]hydrazinecarboxylate (19.3 g, 54.6 mmol) in dioxane (633 mL) at 0°C was slowly added 4M hydrochloric acid in dioxane (290 mL).

The reaction was allowed to stir at ambient température for 4 h. The solvent was removed in vacuo, and the resultîng residue was purified via trituration with diethyl ether, affording the hydrochloride sait of the title compound as a white solid (16.5 g, >99%).

Step 5: préparation of 5-amino-1-(1-benzhydrylazetidin-3-yl)-3-(430 phenoxyphenyl)-1 H-pyrazole-4-carbonitrile. Prepared according to the procedures described for benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol-1 -yl]-pipe ridine-

1-carboxylate (Example 1, step 9) employing 2-[(4-phenoxy-phenyl)-methoxymethylenej-malononitrile (Example 1, Step 3) (1.0 g, 3.25 mmol) and 1-benzhydryl-3hydrazinylazetidine (0.69g, 6.82 mmol) at ambient température to afford the title compound as the hydrochloric acid sait (1.04 g, 64%). MS (M+H) m/z 498.¹H NMR

(DMSO-î/6) δ 7.88 - 7.78 (m, 2H), 7.50 - 7.38 (m, 5H), 7.34 - 7.24 (m, 4H), 7.24 - 7.15 (m, 4H), 7.15 - 7.03 (m, 4H), 6.82 (s, 2H), 4.97 (t, J = 7.03 Hz, 1H), 4.57 (s, 1 H), 3.63 3.52 (m. 2H), 3.39 (t, J= 7.5 Hz, 2H).

Step 6: préparation of 5-amino-1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1Hpyrazole-4-carbonitrile. A solution of 5-amino-1-(1-benzhydrylazetidin-3-yl)-3-(4phenoxyphenyl)-1 H-pyrazole-4-carbonitrile (0.29 g, 0.58 mmol) and concentrated hydrochloric acid (0.5 mL) in méthanol (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: préparation of 5-amino-1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1 Hpyrazole-4-carboxamide. Prepared from 5-amino-1-(azetidin-3-yl)-3-(4-phenoxyphenyl)· 1 H-pyrazole-4-carbonitrile (414 mg, 0.580 mmol) 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) to afford the title compound (120 mg, 20%). MS (M+H) m/z 350. ¹H NMR (DMSO-cfe) δ 9.03 - 8.87 (m, 2H), 7.61 - 7.50 (m, 2H), 7.49 - 7.39 (m, 2H), 7.23 - 7.16 (m, 1H), 7.14 - 7.05 (m, 4H), 6.49 (s, 2H), 5.41 - 5.31 (m, 1H), 4.44 - 4.26 (m, 4H), 3.43 - 3.27 (m, 1H).

Step 8: préparation of 5-amino-1-(1-cyanoazetidin-3-yl)-3-(4-phenoxyphenyl)-1Hpyrazole-4-carboxamide. Prepared according to the procedure described for 5-amino-

1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole carboxamide (Example 1, Step 12) from 5-amino-1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4carboxamide to afford the title compound (32 mg, 67%). MS (M+H) m/z375.¹H NMR (DMSO-î/6) m/z7.55 (d, J= 8.79 Hz, 2H), 7.41 (t, J= 7.9 Hz, 2H), 7.17 (t, J= 7.5 Hz, 1H), 7.08 (dd, J= 8.6, 2.0 Hz, 4H), 6.41 (s, 2H), 5.28 (quin, J= 7.0 Hz, 1H), 4.50 (d, J= 7.0 Hz, 5H).

Example 10 5-amino-1 -(4-cyano-1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1 H-pyrazole-4carboxamide

Step 1: préparation of tert-butyi 6-methylene-1,4-oxazepane-4-carboxylate. To a solution of 3-chloro-2-(chloromethyl)prop-1-ene (10.0 g, 80.0 mmol) in N,N dimethylformamide (130 mL) at 0°C was added 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. The reaction was then allowed to warm to ambient température for an additional 2 h, after which solvent was removed in vacuo. The resulting residue was partitioned between water and a 2:1 ethyl acetate:hexanes mixture. After extraction the combined organic layers were washed with water, dried over magnésium sulfate and concentrated in vacuo. The resulting crude oil was purified by distillation (2 mm Hg, 85°C) to afford the title compound as a clear oil (7.9 g, 46%).

Step 2: préparation of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate. To 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 température for 48h, after which water and brine were added, and the desired product was extracted into ethyl acetate. The combined organic layers were dried over magnésium 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: préparation of tert-butyl 6-{2-[(benzyloxy)carbonyl]hydrazino}-1,4oxazepane-4-carboxylate. To a solution of tert-butyl 6-oxo-1,4-oxazepane-4carboxylate (2.0 g, 9.29 mmol) in tetrahydrofuran (30 mL) was added benzyl hydrazinecarboxylate (1.54 g, 9.29 mmol). The reaction was allowed to stir at ambient température over 24h, then cooled to 0°C, after which sodium cyanoborohydride (584 mg, 9.29 mmol) was added, followed by drop wise addition of a solution of para-toluene sulfonic acid (1.77 g, 9.29 mmol) in tetrahydrofuran (30 mL). The reaction was then allowed to warm to ambient température for an additional 24 h, then concentrated in vacuo. The resulting residue was dîssolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. To the organic layer was then added 1N sodium hydroxide (15 mL), and the mixture was allowed to stir for 3h, after which the organic layer was washed with brine, dried over magnésium sulfate and concentrated in vacuo. The resulting residue was dîssolved in diethyl ether and passed through a silica gel plug to afford the title compound as an oil (2.9 g, 89%).

Step 4: préparation of tert-butyl 6-hydrazino-1,4-oxazepane-4-carboxylate. To a solution of tert-butyl 6-{2-[(benzyloxy)carbonyl]hydrazino}-1,4-oxazepane-4-carboxylate (2.9 g, 8.3 mmol) in éthanol (30 mL) was added 10% Pd/C (500 mg, 50% wet). The mixture was placed under hydrogen (50 psi, Parr shaker) for 24h, after which it was fïltered through Celite and wash several times with éthanol. The filtrate was concentrated in vacuo to afford the title compound as an oil (1.8 g, 94%).

Step 5: préparation of tert-butyl 6-[5-amino-4-cyano-3-(4-phenoxyphenyl)-1 Hpyrazol-1-yl]-1,4-oxazepane-4-carboxylate. Prepared according to the procedure described for benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol-1-yl]-piperidine-

1-carboxyiate (Example 1, Step 9) from 2-[(4-phenoxy-phenyl)-methoxy-methyleneJmalononitrile (Example 1, Step 3) and tert-butyl 6-hydrazino-1,4-oxazepane-4carboxylate to afford the title compound. MS (M+H) m/z 475.9.

Step 6: préparation of 5-amino-1-(1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1Hpyrazole-4-carbonitrile. A solution of tert-butyl 6-[5-amino-4-cyano-3-(4phenoxyphenyl)-1 H-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 température for 1h. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated, dried over magnésium sulfate, and concentrated in vacuo, to afford the title compound. MS (M+H) m/z 376.9.

Step 7: préparation of 5-amino-1-(1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1Hpyrazole-4-carboxamide. The title compound was prepared from 5-amino-1-(1,4oxazepan-6-yl)-3-(4-phenoxyphenyl)-1 H-pyrazole-4-carbonitrile according to the procedure described for 5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1 H-pyrazole-4carboxylic acid amide (Example 1, Step 11).

Step 8: préparation of 5-amino-1-(4-cyano-1,4-oxazepan-6-yl)-3-(4phenoxyphenyl)-1 H-pyrazole-4-carboxamide. The title compound was prepared from 5amino-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-(4phenoxyphenyl)-1 /7-pyrazole carboxamide (Example 1, Step 12). MS (M+H) m/z 419. ¹H NMR (DMSO-d6) δ 7.47(d, J=8.8 Hz, 2H), 7.40 (t, J=8.1 Hz, 2H), 7.15 (t, J=7.3 Hz, 1H), 7.06 (t, J=8.8 Hz, 4H), 6.40 (bs, 2 H), 4.23 - 4.33 (m, 1 H), 3.77 (d, J=8.4 Hz, 2 H),

3.77 (d, J=8.4 Hz, 2 H), 2.86 - 2.95 (m, 1 H), 2.78 (d, J=10.3 Hz, 1 H), 2.55 (bs, 1 H), 2.07 - 2.18 (m, 1 H), 1.86 (bs,1 H), 1.79 (d, J=9.9 Hz, 1 H), 1.59 -1.71 (m, 2 H).

Example 11 5-amino-1-(2-cyano-2-azabicyclo[2.2.1]hept-5-yl)-3-(4-phenoxyphenyl)-1H· pyrazole-4-carboxamide

Step 1 : préparation of benzyl 2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate. A mixture of cyclopenta-1,3-diene (220 g, 3.33 mol), ammonium chloride (535 g, 10 mol) in water (2.5 L) and formaldéhyde solution (405 mL, 5 mol, 37%) was stirred at room température for 36 h. The mixture was neutralized with solid Na2CO₃ and cooled to 0 °C. The mixture was added benzyl chloroformate (568 g, 3.33 mol) and saturated aqueous Na₂CO₃ (1 L) with mechanical stirring for 2 h at 0 °C. Then the mixture was diluted with water (1 L) and extracted with dichloromethane (1 L x 4). The combined organic layers were dried over Na2SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc, 50:1 to 5:1) to afford the title compound (252 g, 33.0 %) as a yellow oil.

Step 2: préparation of benzyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2carboxylate. To a solution of benzyl 2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (100 g, 0.44 mol) in anhydrous tetrahydrofuran (550 mL) was added a solution of borane methylsulfide (86.3 g, 108 mL, 1.135 mol) in tetrahydrofuran (1140 mL) dropwise at -70 °C. After 15 min, the mixture was allowed to warm to room température and stirred for 3

h. 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 température for another

1 h and then concentrated. The residue was partîtioned between ether (2 L) and water (1 L). The organic layer was dried over Na2SO4, 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. ¹H NMR (400 MHz, CDCb) δ 7.30 - 7.39 (m, 5H), 5.12 - 5.22 (m, 2H), 4.05 - 4.35 (m, 2H), 3.29 - 3.32 (m, 1 H), 2.93 - 3.02 (m, 1 H), 2.51 (m, 1 H), 1.86 -1.99 (m, 2H), 1.48 -1.63 (m, 2H).

Step 3: préparation of benzyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate.

To a solution of benzyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (29 g, 0.117 mol) in anhydrous dichloromethane (600 mL) was added Dess-Martin periodinane (75 g, 0.175 mol) in portions at 10 °C. The mixture was stirred at room température for 3 h.

Aqueous Na2CO₃ (1 M, 1100 mL) and aqueous Na2S₂O₃ (1 M, 1100 mL) were added and the mixture was stirred at room température for 0.5 h. The mixture was separated and the water layer was extracted with dichloromethane (1000 mL). The combined o/ organic layers were washed with brine (500mL), dried over Na₂SO4, filtered and concentrated to afford the title compound (48 g, 82 %) as a yellow oil.

Step 4: préparation of benzyl 5-(2-(tert-butoxycarbonyl)hydrazinyl)-2azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of benzyl 5-oxo-25 azabicyclo[2.2.1]heptane-2-carboxylate (24 g, 0.098 mol) in tetrahydrofuran (380 mL x 2) was added Boc hydrazine (13 g, 0.098 mol) at room température. The mixture was heated to reflux and stirred ovemight. The reaction mixture was cooled to 15 °C and NaCNBH₃ (6.2 g, 0.098 mol) was added. A solution of p-toluenesulfonic acid (18.6 g, 0.098 mol) in tetrahydrofuran (180 mL) was added drop wise keeping the température bellow 20 °C. The mixture was stirred at room température ovemight. and then concentrated in vacuo. The residue was dissolved in EtOAc (800 mL) and the solution was washed with saturated aqueous sodium bicarbonate (800 mL). The organic layer was stirred with aqueous NaOH (1 N, 300 mL) for 1 h. After that, the organic layer was separated and dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc, 1:1 ) to afford the title compound (38 g, 53.7 %) as a white solid.

Step 5: préparation of benzyl 5-hydrazinyl-2-azabicyclo[2.2.1]heptane-2carboxylate. To a solution of benzyl 5-(2-(tert-butoxycarbonyl)hydrazinyl)-2azabicyclo[2.2.1]heptane-2-carboxylate (19 g, 0.053 mol) in methanol (200 mL) was 20 added a solution of hydrochloric acid in 1,4-dioxane (200 mL, 4 M, 0.8 mol) at -5 °C.

The mixture was stirred at room température for 4 hours and then concentrated. The residue was purified by reverse phase préparative HPLC to afford the title compound (12g, 29 %). ¹H NMR (400 MHz, D₂O) δ 7.40 - 7.45 (m, 5H), 5.10 - 5.14 (m, 2H), 4.25 -

4.36 (m, 1H), 3.68 - 3.71 (m, 1H), 3.43 - 3.52 (m, 2H), 2.89 (m, 1H), 2.12 - 2.16 (m, 2H), 25 1.69 -1.87 (m, 2H).

Step 6: préparation of benzyl 5-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1 Hpyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of benzyl 5hydrazinyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (6.5 g, 0.017 mol) and 2-((4phenoxy-phenyl)-methoxy-methylene]-malononitrile (Example 1, Step 3) (4.78 g, 0.017 30 mol) in éthanol (200 mL) was added triethylamine (5 mL, 0.035 mol) at -10 °C. The mixture was stirred at room température for 2 h and then filtered to afford the title compound (7.0 g, 80.1 %) as a white solid.

Step 7: préparation of 5-amino-1-(2-azabicyclo[2.2.1]heptan-5-yl)-3-(4phenoxyphenyl)-1H-pyrazole-4-carboxamide. A mixture of benzyl 5-(5-amino-4-cyano35 3-(4-phenoxyphenyl)-1 H-pyrazol-1 -yl)-2-azabicyclo[2.2.1 Jheptane-2-carboxylate (0.9 g,

1.78 mmol) and aqueous NaOH (2.5 N, 5 mL, 12.5 mmol) in éthanol (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 x 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: préparation of 5-amino-1-(2-cyano-2-azabicyclo[2.2.1]hept-5-yl)-3-(4phenoxyphenyl)-1 H-pyrazole-4-carboxamide. To a mixture of 5-amino-1-(2azabicyclo[2.2.1]heptan-5-yl)-3-(4-phenoxyphenyl)-1 H-pyrazole-4-carboxamide (1.2 g, 3.08 mmol) and cyanogen bromide (3.08 mmol) in N,N-dimethylformamide (20 mL) was added CS2CO3 (2 g, 6.16 mmol) at room température and the mixture was stirred at room température ovemight. The mixture was poured into water (20 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by préparative reverse phase HPLC to afford the title compound (252 mg) as a solid. MS (M+H) m/z 415.¹H NMR (400 MHz, DMSO-ctë) δ 7.59 - 7.61 (m, 2H), 7.39 - 7.43 (m, 2H), 7.03 -

7.19 (m, 5H), 6.37 (s, 2H), 4.72 - 4.75 (m, 1H), 4.02 (m, 1H), 3.17 - 3.23 (m, 2H), 2.91 (m, 1 H), 2.66 - 2.69 (m, 1H), 2.07 - 2.12 (m, 1 H), 1.77 -1.83 (m, 2H).

Example 12

5-amino-1 -[2-(cyanomethyl)-2-azabicyclo[2.2.1 ]hept-5-yl]-3-(4-phenoxyphenyl)-1 Hpyrazole-4-carboxamide

0'

The title compound was prepared according to the procedure described for 5amino-1-[1-(cyanomethyl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-4carboxamide (Example 4) from 5-amino-1-(2-azabicyclo[2.2.1]heptan-5-yl)-3-(4phenoxyphenyl)-1 H-pyrazole-4-carboxamide (Example 11, Step 7) and bromoacetonitrile. MS (M+H) m/z429.¹H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.52 (m, 4H), 7.05 - 7.19 (m, 5H), 6.36 (s, 2H), 4.57 - 4.60 (m, 1 H), 3.75 - 3.88 (m, 2H), 3.33 (m, 1 H), 2.53 - 2.63 (m, 2H), 1.84 -1.86 (m, 2H), 1.57 -1.60 (m, 1 H).

Example 13 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1 -(1 -cyanopiperidin-3-yl)-1 H-pyrazole-4carboxamide

Step 1 : préparation of methyl 4-(4-chlorophenoxy)benzoate. (4Chlorophenyl)boronic acid (25.4 g, 162.82 mmol), 4Â molecular sieves powder (16 g),

4-dimethylaminopyridine (39.5 g, 325.65 mmol) and 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 temperatuer, and the resulting mixture was stirred for 48 h. The reaction mixture was then filtered through a Celite pad. The filtrate was concentrated and the residue was purified by column chromatography on silica (8% EtOAc in petroleum ether) to afford the title compound (14 g, 48% yield) as off white solid. MS (M+H) m/z 263.¹H NMR (CDCI₃₎ 400 MHz) δ 8.02 (d, 2H), 7.35 (d, 2H), 7.02 (d, 2H), 6.97 (d, 2H), 3.88 (s, 3H).

Step 2: préparation of 4-(4-chlorophenoxy)benzoic acid. To a suspension of methyl 4-(4-chlorophenoxy)benzoate (14.0 g, 53.43mmol) in methanol-water (5:1,360 mL), NaOH (10.68 g, 267.11 mmol) was added at 0°C, the cooling batch was then removed and the reaction mixture was stirred at 60°C for 3 h. Methanol was distilled off, water (500 mL) was added to the residue and washed with diethyl ether (3x100mL).The aqueous layer was acidified with 2N HCl and then extracted with ethyl acetate (3x100mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (10.5 g, 79% yield) as off white solid. MS (M+H) m/z 247.¹H NMR (DMSO-cfe, 300 MHz) δ 12.83 (bs, 1 H), 7.95 (d, 2H), 7.51 (d, 2H), 7.17 (d, 2H), 7.07 (d, 2H).

Step 3: préparation of 4-(4-chlorophenoxy)benzoyl chloride. 4-(4chlorophenoxy)-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 25 to the next step.

Step 4: préparation 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 minerai oil, 158.4 mmol) in tetrahydrofuran (50 mL) at 0°C under nitrogen atmosphère.

After stirring for 30 min, 4-(4-chlorophenoxy)benzoyl chloride (11.0 g, 41.35 mmol) in tetrahydrofuran (35 mL) was added drop wise. Cooling bath was removed and the

reaction mixture was stirred at room température for 3 h. The reaction mixture was heated to reflux and dimethyl sulfate (28 mL, 288.89 mmol) was added drop wise, and the resulting mixture was refluxed for 18 h. After cooling to room température, water (100 mL) was added and extracted with ethyl acetate (3x100 mL). The combined organic layer was dried over sodium acetate, concentrated and purified by flash chromatography on silica (5-8 % EtOAc in petroleum ether) to afford the title compound (6.0 g, 47% yield) as pale yellow oil. ¹H NMR (DMSO-cfe, 400 MHz) δ 7.73 (d, 2H), 7.52 (d, 2H), 7.2 (d, 2H), 7.18 (d, 2H), 3.92 (s, 3H).

Step 5: préparation of benzyl 3-(5-amino-3-(4-(4-chlorophenoxy)phenyl)-4-cyano1H-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 éthanol (6 0 mL) at room température. After stirring for 3 h the precipitated solid was filtered off. The solid was washed with éthanol and dried under vacuum to afford the title compound (7.2 g, 70 % yield). MS (M+H) m/z 526.¹H NMR (DMSO-cfe, 400 MHz) δ 8.0 (d, 2H), 7.45 (d, 2H),

7.37 (m, 5H), 7.12 (d, 2H), 7.08 (d, 2H), 6.77 (s, 2H), 5.06 (bs, 2H), 4.23 (m, 1H), 4.0 (m, 2H), 2.97 (m, 2H), 1.87 (m, 3H), 1.50 (m, 1H).

Step 6: préparation of 5-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)1 H-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-1yl)piperidine-1-carboxylate (7.2 g, 13.66 mmol) in éthanol (70 mL) in a 250 mL sealed tube and the resulting mixture was heated with stirring at 140°C for 48 h. After cooling to room température water was added to the reaction mixture and extracted with ethyl acetate (3x100mL). The combined organic layer was dried over sodium sulfate, filtered, concentrated to afford the title compound (2.6 g). ¹H NMR (DMSO-cfe, 400 MHz) δ 8.21 (s, 1H), 7.49 (m, 4H), 7.45 (d, 2H), 7.10 (m, 4H), 6.36 (s, 2H), 4.20 (m, 1H), 3.11 (m, 1H), 2.97 (m, 2H), 2.50 (m, 1H), 1.93 (m, 2H), 1.76 (m, 1H), 1.60 (m, 1H).

Step 7: préparation of 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-(1cyanopiperidin-3-yl)-1 H-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-3yl)-1 H-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. The reaction mixture was cooled to room température, water was added and extracted with ethyl acetate (3x100 mL). The

combined organic layer was dried over sodium sulfate, filtered, concentrated. The crude compound was purified by flash column chromatography on silica gel (100-200 mesh) using 30-50% EtOAc in hexane to afford the title compound (6.2 g, 77 %).. MS (M+H) m/z437.¹H NMR (DMSO-cfe, 400 MHz) δ 7.5 (d, 2H), 7.45 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 6.45 (s, 2H), 5.6 (br, 1H), 4.37 (m, 1H), 3.48 (dd, 1H), 3.35 (m, 2H), 3.07 (dt, 1H), 1.87 (m, 3H), 1.70 (m, 1H).

Example 14

5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-[(3S)-1-cyanopiperidin-3-yl]-1H·

rao-5-amino-3-(4-(4-chlorophenoxy)phenyl)-1 -(1 -cyanopiperidin-3-yl)-1 Hpyrazole-4-carboxamide (prepared as described in Example 13) was chirally separated by préparative HPLC (ChiralPak IA, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 50/50, 0.8 mL/min flow rate). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z436.8. ¹H NMR (DMSO-cfô, 300 MHz) δ 7.5 (d, 2H), 7.45 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 6.45 (s, 2H), 5.6 (br, 1H), 4.37 (m, 1H), 3.48 (dd, 1H),

3.35 (m, 2H), 3.07 (dt, 1H), 1.87 (m, 3H), 1.70 (m, 1H). SOR +57.6 (c, 0.5% in MeOH) Example 15

5-amino-3-[4-(4-chlorophenoxy)phenyl]-1 -[(3R)-1 -cyanopiperidin-3-yl]-1 Hpyrazole-4-carboxamide

rao-5-amino-3-(4-(4-chlorophenoxy)phenyl)-1 -(1 -cyanopiperidin-3-yl)-1 Hpyrazole-4-carboxamide (prepared as described in Example 13) was chirally separated by préparative HPLC (ChiralPak IA, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 50/50,0.8 mL/min flow rate). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z436.8. ¹H NMR (DMSO-de, 300 MHz) δ 7.5 (d, 2H), 7.45 (d,

2H), 7.12 (d, 2H), 7.08 (d, 2H), 6.45 (s, 2H), 5.6 (br, 1H), 4.37 (m, 1H), 3.48 (dd, 1H),

3.35 (m, 2H), 3.07 (dt, 1H), 1.87 (m, 3H), 1.70 (m, 1H). SOR -56.8 (c, 0.5% in MeOH).

Example 16 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(3,4-dimethylphenoxy)phenyl]-1 //-pyrazole·

4-carboxamide

Prepared analogous to 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-(1cyanopiperidin-3-yl)-1//-pyrazole-4-carboxamide (Example 15) employing (3,4dimethylphenyl)boronic acid to afford the title compound. MS (M+H) m/z 431.¹H NMR (DMSO-c/6, 300 MHz) δ 7.45 (d, 2H), 7.17 (d, 1H), 6.98 (d, 2H), 6.90 (s, 1H), 6.80 (d, 1H), 6.42 (s, 2H), 4.37 (m, 1H), 3.44 (m, 1H), 3.35 (m, 2H), 3.07 (t, 1H), 2.20 (s, 6H),

1.7-1.97 (m, 4H).

Example 17 (R)-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(3,4-dimethylphenoxy)phenyl]-1 H-

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(3,4-dimethylphenoxy)phenyl]-1 Hpyrazole-4-carboxamide (prepared as described in Example 16) was chirally separated by préparative HPLC (ChiralPak IA, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 70/30,1.0 mL/min flow rate). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 431.¹H NMR (DMSO-ctâ,400 MHz) δ 7.45 (d, 2H), 7.17 (d, 1H), 6.98 (d, 2H), 6.90 (s, 1H), 6.80 (d, 1H), 6.42 (s, 2H), 4.37 (m, 1H), 3.44 (m, 1H),

3.35 (m, 2H), 3.07 (t, 1H), 2.20 (s, 6H), 1.7-1.97 (m, 4H).

Example 18 (S)-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(3,4-dimethylphenoxy)phenyl]-1//pyrazol e-4-carboxamide

rac-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(3,4-dimethylphenoxy)phenyl]-1/7pyrazole-4-carboxamide (prepared as described in Example 16) was chirally separated by préparative HPLC (ChiralPak IA, 4.6 x 250 mm, 5 pm coiumn, hexane/ethanol,

70/30,1.0 mL/min flow rate). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 431.¹H NMR (DMSO-c/6,400 MHz) δ 7.45 (d, 2H), 7.17 (d, 1H), 6.98 (d, 2H), 6.90 (s, 1H), 6.80 (d, 1H), 6.42 (s, 2H), 4.37 (m, 1H), 3.44 (m, 1H),

3.35 (m, 2H), 3.07 (t, 1H), 2.20 (s, 6H), 1.7-1.97 (m, 4H).

Example 19

5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(4-ethylphenoxy)phenyl]-1H-pyrazole-4carboxamide

N

Prepared analogous to 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-(1cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide (Example 15) employing (415 ethylphenyl)boronic acid to afford the title compound. MS (M+H) m/z431.¹H NMR (DMSO-c/6, 300 MHz) δ 7.46 (d, 2H), 7.21 (d, 2H), 7.0 (m, 4H), 6.35 (s, 2H), 5.06 (bs,

2H), 4.16 (m, 1H), 3.12 (m, 1H), 2.90 (m, 2H), 2.30 (s, 3H), 1.87 (m, 2H), 1.73 (m, 1H),

1.45 (m, 1H.)

Example 20

5-amino-3-[4-(4-chloro-2-methylphenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H· pyrazole-4-carboxamide

Cl

N |

Prepared analogous to 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-(1cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide (Example 15) employing (493 methylphenyl)boronic acid to afford the title compound. MS (M+H) m/z 451.¹H NMR (DMSO-d6, 300 MHz) δ 7.43 (m, 3H), 7.27 (dd, 1H), 6.90 (m, 3H), 6.43 (s, 2H), 4.35 (m,

1H), 3.50 (dd, 1H), 3.35 (m, 2H), 3.05 (dt, 1H), 2.18 (s, 3H), 1.65-1.95 (m, 4H).

Example 21 (S)-5-amino-3-[4-(4-chloro-2-methylphenoxy)phenyl]-1 -(1 -cyanopiperidin-3-yl)-1 Hpyrazole-4-carboxamide

rao-5-amino-3-[4-(4-chloro-2-methylphenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)1 H-pyrazole-4-carboxamide (prepared as described in Example 20) was chirally separated by préparative HPLC (ChiralPak IA, 4.6 x 250 mm, 5 pm coiumn, hexane/ethanol, 30/70, 0.8 mL/min flow rate). Isolation of the first eiuting isomer afforded the title compound. MS (M+H) m/z451.¹H NMR (DMSO-d6, 300 MHz) δ 7.45 (m, 3H), 7.27 (dd, 1H), 7.0 (m, 3H), 6.43 (s, 2H), 5.5-6.3 (br, 2H), 4.35 (m, 1H), 3.50 (dd, 1 H), 3.35 (m, 2H), 3.05 (dt, 1H), 2.18 (s, 3H), 1.65-1.95 (m, 4H). SOR +61.2 (c, 0.5% in chloroform)

Example 22 (R)-5-amino-3-[4-(4-chloro-2-methylphenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H·

rao-5-amino-3-[4-(4-chloro-2-methylphenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)1 H-pyrazole-4-carboxamide (prepared as described in Example 20) was chirally separated by préparative HPLC (ChiralPak IA, 4.6 x 250 mm, 5 pm coiumn, hexane/ethanol, 30/70, 0.8 mL/min flow rate). Isolation of the second eiuting isomer afforded the title compound. MS (M+H) m/z 451. ¹H NMR (DMSO-d6,300 MHz) δ 7.45 (m, 3H), 7.27 (dd, 1 H), 7.0 (m, 3H), 6.45 (s, 2H), 5.5-6.3 (br, 2H), 4.35 (m, 1 H), 3.50 (dd, 1H), 3.35 (m, 2H), 3.05 (dt, 1H), 2.18 (s, 3H), 1.65-1.95 (m, 4H). SOR -59.2 (c, 0.5% in chloroform)

Example 23

5-amino>1-(1-cyanopiperidin-3-yl)-3-[4-(2,4-dimethylphenoxy)phenyl]-1 H-pyrazole-

4-carboxamide

Prepared analogous to 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-(1cyanopiperidin-3-yl)-1H-pyrazole-4-carboxamide (Example 15) employing (2,4dimethylphenyl)boronic acid to afford the title compound. MS (M+H) m/z431.¹H NMR (400MHz, methanol-c/4) δ 7.44 (d, J = 8.4 Hz, 2H), 7.12 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H),

6.93 (d, J =8.4 Hz, 2H), 6.85 (d, J= 8.0 Hz, 1H), 4.36 (m, 1H), 3.55 (m, 1H), 3.44 (m, 2H), 3.11 (m, 1H), 2.32 (s, 3H), 2.14 (s, 3H), 2.03 (m, 2H), 1.90 (m, 2H).

Example 24 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(4-isopropylphenoxy)phenyl]-1H-pyrazole4-carboxamide

Prepared analogous to 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 15) employing (4isopropylphenyl)boronic acid to afford the title compound. MS (M+H) m/z445.¹H NMR (400MHz, methanol-cM) δ 7.46 (d, J= 8.4 Hz, 2H), 7.27 (d, J= 8.4 Hz, 2H), 7.05 (d, J=

8.4 Hz, 2H), 6.98 (d, J =8.4 Hz, 2H), 4.37 (m, 1H), 3.56 (m, 1H), 3.45 (m, 2H), 3.11 (m, 1H), 2.92 (m, 1H), 2.06 (m, 2H), 1.91 (m, 2H), 1.27 (d, 6H).

Example 25 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazole4-carboxamide

Step 1 : préparation of methyi 4-(2,4-difluorophenoxy)benzoate. 4Â 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 température, and the resulting mixture was stirred for 48 h. The reaction mixture was then filtered through celite pad, the fïltrate was concentrated and purified by column chromatography on silica (100-200 mesh), eluting with 8% EtOAc in petroleum ether to give compd-2X10 (15 g, 51.2 %) as solid. MS (M+H) m/z265.¹H NMR (DMSO-ctë, 300 MHz) δ 7.97 (d, 2H), 7.56 (m, 1H), 7.45 (m,

1 H), 7.20 (t, 1 H), 7.05 (d, 2H), 3.83 (s, 3H).

Step 2: préparation of 4-(2,4-difluorophenoxy)benzoic acid. To a suspension of methyi 4-(2,4-difluorophenoxy)benzoate (15.0 g, 56.82mmol) in methanol (525 mL) were added water (63 mL) and NaOH pellets (12.22 g, 284.11 mmol) at 0°C, the cooling batch was then removed and the reaction mixture was stirred at 50°C for 3 h. Methanol 15 was 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.

MS (M+H) m/z249. ¹H NMR (DMSO-d6, 300 MHz) δ 12.85 (bs, 1H), 7.92 (d, 2H), 7.52 (m, 1H), 7.40 (m, 1H), 7.20 (t, 1H), 7.00 (d, 2H).

Step 3: préparation of 4-(2,4-difluorophenoxy)benzoyl chloride. 4-(2,4difluorophenoxy)benzoic acid (3.0 g, 30 mmol) in thionyl chloride (80 mL) was refluxed ovemight. The volatiles were evaporated to afford the title compound.

Step 4: préparation of 2-((4-(2,4-difluorophenoxy)phenyl)(methoxy)methylene)malononitrile. A solution of malononitrile (1.0 g, 15.52 mmol) in tetrahydrofuran (10 mL) 25 was added drop wise to a stirred suspension of NaH (574 mg, 23.9 mmol) in tetrahydrofuran (50 mL) at 0°C in N₂ atmosphère. After stirring for 30 min, 4-(2,4difluorophenoxy)benzoyl chloride (3.2 g, 11.94 mmol) in tetrahydrofuran (15 mL) was added dropwise. The reaction mixture was brought to room température and stirred (~3

h). The reaction mixture was then heated to reflux and dimethyl sulfate (7.7 mL, 83.6 30 mmol) was added drop wise. The mixture was refluxed for 18 h. After cooling to room température, the mixture was quenched with ice water (100 mL) and extracted with EtOAc (2x). The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography on silica gel (100-200 mesh) eluting with 12 % EtOAc in petroleum ether to afford the title compound (1.8 g) as liquid. MS (M+H) m/z

297. ¹H NMR (DMSO-î/6, 400 MHz) δ 7.71 (d, 2H), 7.52 (m, 1H), 7.43 (m, 1H), 7.20 (t, 1H), 7.16 (d, 2H), 3.93 (s, 3H).

Step 5: préparation of benzyl 3-(5-amino-4-cyano-3-(4-(2,4difluorophenoxy)phenyl)-1 H-pyrazol-1-yl)piperidine-1-carboxylate. Triethylamine (2.2 mL 14.4 mmol) was added to a stirred mixture of 2-((4-(2,4difluorophenoxy)phenyl)(methoxy)methylene)malononitrile (1.5 g, 4.8 mmol) and 3hydrazino-piperidine-1 -carboxylic acid benzylester hydrochloride (Example 1, Step 8) (1.4 g, 4.8 mmol) in éthanol (30 mL) at room température. After stirring for 3 h the precipitate was filtered. The resulting solid was washed with éthanol and dried under vacuum to afford the title compound (1.8 g, 40%). MS (M+H) m/z530.¹H NMR (DMSOî/6, 300 MHz) δ 7.78 (d, 2H), 7.50 (m, 1H), 7.33 (m, 6H), 7.18 (m, 1H), 7.05 (d, 2H),

6.78 (s, 2H), 5.06 (bs, 2H), 4.26 (m, 1H), 3.99 (m, 2H), 3.30 (m, 1H), 2.97 (t, 1H), 2.21 (s, 3H), 1.90 (m, 3H), 1.48 (m, 1H).

Step 6: préparation of 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3yl)-1/7-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)-1/+pyrazol-1yl)piperidine-1-carboxylate (1.8 g, 3.39 mmol) in éthanol (20 mL) charged to a 100 mL sealed tube. The mixture was heated with stirring at 140°C for 24 h. After cooling to room température, the reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to afford the title compound (1.4 g). MS (M+H) m/z 414. ¹H NMR (DMSO-î/6, 300 MHz) δ 7.45 (d, 2H), 7.32 (m, 1H), 7.23 (m, 1H), 7.18 (m, 1H), 7.01 (d, 2H), 6.30 (s, 2H), 5.17 (t, 1H), 4.07 (m, 1H), 3.0 (d, 1H), 2.7-2.90 (m, 3H), 1.90 (m, 2H), 1.70 (m, 1H), 1.48 (m,

1H).

Step 7: préparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4difluorophenoxy)phenyl]-1 H-pyrazole-4-carboxamide. Potassium carbonate (450 mg,

3.3 mmol) was added to a solution of 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1(piperidin-3-yl)-1/7-pyrazole-4-carboxamide (0.9 g, 2.2 mmol) in Ν,Ν-dimethylformamide (10 mL). After stirring for 5 min, cyanogen bromide (260 mg, 2.42 mmol) was added and the resulting mixture was stirred at 60°C for 2 h. The reaction mixture was cooled to room température and water was added .The resulting precipitate was filtered. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) with 50% EtOAc/hexane as eluent to afford the title compound (1.3 g). MS (M+H) m/z 439.¹H NMR (DMSO-î/6, 400 MHz) 7.52 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.18 (t, 1 H), 7.01 (d, 2H), 6.43 (s, 2H), 4.35 (m, 1 H), 3.50 (d, 1H), 3.35 (m, 2H), 3.03 (t, 1 H), 1.92 (m, 1H), 1.80 (m, 2H), 1.48 (m, 1H).

Example 26

5-amino-1 -[(3S)-1-cyanopiperidin-3-yl]-3-[4-(2,4-difluorophenoxy)phenyl]-1 Hpyrazole-4-carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(2,4-difluorophenoxy)phenyl]-1 Hpyrazole-4-carboxamide (prepared as described in Example 25) was chirally separated by préparative HPLC (ChiralPak IA, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 30/70, 0.8 mL/min flow rate). Isolation of the first eluting isomer afforded the title compound. ¹H NMR (DMSO-c/6, 300 MHz) δ 7.52 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.18 (t, 1H), 7.01 (d, 2H), 6.43 (s, 2H), 5.2-6.2 (br, 2H), 4.35 (m, 1H), 3.50 (d, 1H), 3.35 (m, 2H), 3.03 (t, 1H), 1.92 (m, 1H), 1.80 (m, 2H), 1.48 (m, 1H). MS (M+H) m/z439. SOP: +56.8° (C=0.5% in MeOH).

Example 27 5-amino-1-[(3fi)-1-cyanopiperidin-3-yl]-3-[4-(2,4-difluorophenoxy)phenyl]-1 Hpyrazole-4-carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(2,4-difluorophenoxy)phenyl]-1 Hpyrazole-4-carboxamide (prepared as described in Example 25) was chirally separated by préparative HPLC (ChiralPak IA, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 30/70, 0.8 mL/min flow rate). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z439.¹H NMR (DMSO-c/6,300 MHz) δ 7.52 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.18 (t, 1H), 7.01 (d, 2H), 6.43 (s, 2H), 4.35 (m, 1H), 3.50 (d, 1H),

3.35 (m, 2H), 3.03 (t, 1H), 1.92 (m, 1H), 1.80 (m, 2H), 1.48 (m, 1H). SOP: -52.4° (C=0.5% in MeOH).

Example 28 .·

5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(3-fluoro-4-methylphenoxy)phenyl]-1Hpyrazole-4-carboxamide

Prepared analogous to 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4difluorophenoxy)phenyl]-1 H-pyrazole-4-carboxamide (Example 25) employing 3-fluoro4-methylphenol to afford the title compound. MS (M+H) m/z435.¹H NMR (DMSO-ctô, 400 MHz) δ 7.50 (d, 2H), 7.28 (t, 1H), 7.17 (d, 2H), 6.90 (dd, 1H), 6.82 (dd, 1H), 6.43 (s, 2H), 4.35 (m, 1H), 3.50 (dd, 1H), 3.35 (m, 2H), 3.05 (dt, 1H), 2.22 (s, 3H), 1.65-1.95 (m, 4H).

Example 29 (S)-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(3-fluoro-4-methylphenoxy)phenyl]-1Hpyrazole-4-carboxamide

rao-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(3-fluoro-4-methylphenoxy)phenyl]1 H-pyrazole-4-carboxamide (prepared as described in Example 28) was chirally separated by préparative HPLC (ChiralPak IB, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 50/50,1.0 mL/min flow rate). Isolation of the first eluting isomer afforded the title compound. ¹H NMR (DMSO-ctë, 400 MHz) δ 7.50 (d, 2H), 7.28 (t, 1H), 7.08 (d, 2H), 6.90 (dd, 1 H), 6.82 (dd, 1H), 6.43 (s, 2H), 4.35 (m, 1H), 3.50 (dd, 1H), 3.35 (m, 2H), 3.05 (dt, 1H), 2.22 (s, 3H), 1.65-1.95 (m, 4H). SOP: +59.6° (C=0.5% in MeOH). Example 30 (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(3-fluoro-4-methylphenoxy)phenyl]-1Hpyrazole-4-carboxamide

rao-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(3-fluoro-4-methylphenoxy)phenyl]1 H-pyrazole-4-carboxamide (prepared as described in Example 28) was chirally separated by preparative HPLC (ChiralPak IB, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 50/50,1.0 mL/min flow rate). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 435.¹H NMR (DMSO-c/6, 300 MHz) δ 7.50 (d, 2H), 7.28 (t, 1H), 7.08 (d, 2H), 6.90 (dd, 1H), 6.82 (dd, 1H), 6.43 (s, 2H), 4.35 (m, 1H), 3.50 (dd, 1H), 3.35 (m, 2H), 3.05 (dt, 1H), 2.22 (s, 3H), 1.65-1.95 (m, 4H). SOP: 64° (C=0.5% in MeOH).

Example 31 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(4-fluoro-3-methylphenoxy)phenyl]-1H-

Prepared analogous to 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide (Example 25) employing 4-fluoro-

3-methylphenol to afford the title compound. MS (M+H) m/z 435.¹H NMR (DMSO-c/6, 300 MHz) δ 7.48 (d, 2H), 7.18 (t, 1H), 7.03 (m, 3H), 6.92 (m, 1H), 6.43 (s, 2H), 4.36 (m, 1H), 3.50 (d, 1H), 3.35 (m, 2H), 3.04 (t, 1H), 2.21 (s, 3H), 1.65-1.95 (m, 4H).

Example 32

5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(4-fluoro-2-methylphenoxy)phenyl]-1 H-

Prepared analogous to 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide (Example 25) employing 4-fluoro-

2-methylphenol to afford the title compound. MS (M+H) m/z 435.¹H NMR (DMSO-c/6, 400 MHz) δ 7.42 (d, 2H), 7.23 (d, 1H), 7.04 (m, 2H), 6.91 (d, 2H), 6.42 (s, 2H), 4.36 (m, 1H), 3.47 (m, 1H), 3.32 (m, 2H), 3.06 (t, 1H), 2.18 (s, 3H), 1.62-1.92 (m, 4H).

Example 33

A

100 (S)-5-amino-1-(1-cyanop!per!din-3-yl)-3-[4-(4-fluoro-2-methylphenoxy)phenyl]-1//* pyrazole-4-carboxamide

rao-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(4-fluoro-2-methylphenoxy)phenyl]1 /7-pyrazole-4-carboxamide (prepared as described in Example 32) was chirally separated by préparative HPLC (ChiralPak IB, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 50/50,1.0 mL/min flow rate). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 435.¹H NMR (DMSO-de, 400 MHz) δ 7.42 (d, 2H), 7.23 (d, 1H), 7.04 (m, 2H), 6.91 (d, 2H), 6.42 (s, 2H), 5.2-6.0 (br, 2H), 4.36 (m, 1H), 3.47 (m, 1H), 3.32 (m, 2H), 3.06 (t, 1H), 2.18 (s, 3H), 1.62-1.92 (m, 4H). SOR: +53.2° (C= 0.5% in MeOH).

Example 34 (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(4-fluoro-2-methylphenoxy)phenyl]-1Hpyrazole-4-carboxamide

rao-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(4-fluoro-2-methylphenoxy)phenyl]1 A£pyrazole-4-carboxamide (prepared as described in Example 32) was chirally separated by préparative HPLC (ChiralPak IB, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 50/50,1.0 mL/min flow rate). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 435.¹H NMR (DMSO-d6,400 MHz) δ 7.42 (d, 2H), 7.23 (d, 1H), 7.04 (m, 2H), 6.91 (d, 2H), 6.42 (s, 2H), 5.2-6.0 (br, 2H), 4.36 (m, 1H), 3.47 (m, 1H), 3.32 (m, 2H), 3.06 (t, 1H), 2.18 (s, 3H), 1.62-1.92 (m, 4H). SOR: 64.8° (C= 0.5% in MeOH).

Example 35 5-am!no-3-[4-(2-chloro-4-fluorophenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H* pyrazole-4-carboxamide

101

Prepared analogous to 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4difluorophenoxy)phenyl]-1/7-pyrazole-4-carboxamide (Example 25) employing 2-chloro-

4-fluorophenol to afford the title compound. MS (M+H) m/z454.9.¹H NMR (DMSO-c/6, 300 MHz) δ 7.63 (d, 1H), 7.48 (d, 2H), 7.30 (d, 2H), 6.98 (d, 2H), 6.43 (s, 2H), 4.37 (m, 1H), 3.5 (m, 1H), 3.35 (m, 2H), 3.06 (t, 1H), 1.65-1.95 (m, 4H).

Example 36 (S)-5-amino-3-[4-(2-chloro-4-fluorophenoxy)phenyl]-1 -(1-cyanopiperidin-3-yl)-1 H-

rao5-amino-3-[4-(2-chloro-4-fluorophenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1/7pyrazole-4-carboxamide (prepared as described in Example 35) was chirally separated by préparative HPLC (ChiralPak IB, 4.6 x 250 mm, 5 pm column, hexane/ethanol, 50/50,1.0 mL/min flow rate). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 454.9. ¹H NMR (DMSO-ctë, 400 MHz) δ 7.63 (d, 1H), 7.48 (d, 2H), 7.30 (d, 2H), 6.98 (d, 2H), 6.43 (s, 2H), 5.2-6.2 (br, 2H), 4.37 (m, 1H), 3.5 (m, 1H), 3.35 (m, 2H), 3.06 (t, 1H), 1.65-1.95 (m, 4H). SOR: +49.2 (C= 0.5% in MeOH). Example 37 (R)-5-amino-3-[4-(2-chloro-4-fluorophenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H-

rao-5-amino-3-[4-(2-chloro-4-fluorophenoxy)phenyl]-1 -(1 -cyanopiperidin-3-yl)-1 Hpyrazole-4-carboxamide (prepared as described in Example 35) was chirally separated by préparative HPLC (ChiralPak IB, 4.6 x 250 mm, 5 pm column, hexane/ethanol,

102

50/50,1.0 mL/min flow rate). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 454.9.¹H NMR (DMSO-d6, 300 MHz) δ 7.63 (d, 1H), 7.48 (d, 2H), 7.30 (d, 2H), 6.98 (d, 2H), 6.43 (s, 2H), 5.2-6.2 (br, 2H), 4.37 (m, 1H), 3.5 (m,

1H), 3.35 (m, 2H), 3.06 (t, 1H), 1.65-1.95 (m, 4H).

Example 38

5-amino-3-[4-(2-chloro-4-methylphenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H-

Prepared analogous to 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4difluorophenoxy)phenyl]-1 W-pyrazole-4-carboxamide (Example 25) employing 2-chloro-

4- methylphenol to afford the title compound. MS (M+H) m/z451.¹H NMR (400MHz, methanol-d4) δ 7.47 (d, J= 8.8 Hz, 2H), 7.36 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 2H), 4.37 (m, 1 H), 3.57 (m, 1 H), 3.44 (m, 2H), 3.11 (m, 1H), 2.36 (s, 3H), 2.06 (m, 2H), 1.92 (m, 2H).

Example 39

5- amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(2-fluoro-4-methylphenoxy)phenyl]-1 H-

Prepared analogous to 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4difluorophenoxy)phenyl]-1 W-pyrazole-4-carboxamide (Example 25) employing 2-fluoro-

4- methylphenol to afford the title compound. MS (M+H) m/z435.¹H NMR (400MHz, methanol-d4) δ 7.47 (d, J= 8.8 Hz, 2H), 7.10 (m, 2H), 7.03 (m, 3H), 4.37 (m, 1 H), 3.55 (m, 1H), 3.44 (m, 2H), 3.11 (m, 1H), 2.37 (s, 3H), 2.04 (m, 2H), 1.90 (m, 2H).

Example 40

5- amino-3-[4-(4-chloro-3-methylphenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)-1H· pyrazole-4-carboxamide

103

Step 1: préparation of 1-[4-(4-chloro-3-methylphenoxy)phenyl]ethanone. To a solution of 4-fluoroacetophenone (1.0 g, 7.2 mmol) in dimethylacetamide (4 mL) was added 4-chloro-3-methylphenol (1.24 g, 8.69 mmol), followed by potassium carbonate 5 (1.38g, 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. ¹H NMR (DMSO-d6) δ 7.99 (m, 2 H) 7.48 (d, J=8.5 Hz, 1 H), 7.16 (d, J=3.1 Hz, 1 H), 7.07 (m, 2 H), 6.98 (dd, J=8.5, 3.07 Hz, 1 H) 2.55 (s, 3 H), 2.33 (s, 3 H).

Step 2: préparation of 4-(4-chloro-3-methylphenoxy)benzoic acid. To a solution of 1-[4-(4-chloro-3-methylphenoxy)phenyl]ethanone (1.8g, 6.9 mmol) in éthanol (10 mL) was added 20 mL of a 10-15% sodium hypochlorite solution and the mixture was stirred at ambient température. A solution of aqueous sodium bisulfite (50 mL) was added and the mixture was then acidified with 12N hydrochloric acid. The resulting precipitate was fîltered to afford the title compound.

Step 3: préparation 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,Ndimethylformamide to a solution of 4-(4-chloro-3-methylphenoxy)benzoic acid (1.701g, 6.475 mmol) in tetrahydrofuran (30 mL) at 0°C. The mixture was allowed to warm to 20 ambient température over 16 h and then concentrated to afford the title compound as a yellow solid.

Step 4: préparation of 2-((4-(4-chloro-3methylphenoxy)phenyl)(methoxy)methylene)-malononitrile. A solution of malononitrile (252 mg, 3.81 mmol) in anhydrous tetrahydrofuran (3 mL) was added to a suspension of 25 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) in tetrahydrofuran (5 mL) was then added drop wise over 10 min. The mixture was then treated with dimethyl sulfate and heated to reflux for 3h, after which it was quenched with saturated aqueous ammonium chloride and extracted into ethyl acetate. The combined organic layers were 30 washed with brine and concentrated in vacuo to afford the title compound as an oil.

Step 5: préparation of 1-(3-hydroxypiperidin-1-yl)ethanone. A suspension of 3hydroxy-piperdine (100 g, 0.73 mol) and triethylamine (121 mL, 0.87 mol) in

104 dichioromethane (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 température did not surpass 0°C. The mixture was allowed to stir at ambient température for an additional 16h 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 / dichioromethane. The combined organic layers were concentrated in vacuo and the resulting residue was then added to ethyl acetate (500 mL) and allowed to stir for 15 min, after which a white precipitate had formed. The precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo. The residue was purified via removal of residual anhydride by vacuum distillation (140°C, 4 mbar) to afford the title compound as a brown oil (192 g, 61 %). ¹H-NMR (CDCI3) δ 3.59-3.92 (m, 3H), 3.21-3.49 (m, 3H), 2.12 (s, 3H), 1.73-2.07 (m, 2H), 1.44-1.68 (m, 2H).

Step 6: préparation of 1-acetylpiperidin-3-one. To a cold suspension of pyridine.SO3 (372.0 g, 2.338 mol ) in dichioromethane (2.0 L) was added in sequence triethylamine (408.5 mL, 2.923 mol) and dimethylsulfoxide (414 mL, 5.846 mol) keeping the température at 0 °C. A solution of 1-(3-hydroxypiperidin-1-yl)ethanone (76.0 g, 0.531 mol) in dichioromethane (500 mL) was drop wise added over 1 h keeping the température below 0 °C. The reaction mixture was allowed to stir at room température 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 dichioromethane (4 x 250 mL). The combined organic layers were concentrated in vacuum. The residue was dissolved in ethyl acetate (1L) 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. ¹H NMR (400 MHz, CDCI3) δ 4.15 (s, 1 H),

3.98 (s, 1 H), 3.72 (t, J= 12 Hz, 2 H), 3.61 (t, J= 12 Hz, 2 H), 2.12 (s, 1.5 H), 2.06 (s,

1.5 H), 1.94-2.03 (m, 4H).

Step 7: préparation of 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 16h, after which it was cooled to 15°C and sodium cyanoborohydride (54.8 g, 0.87 mol) was added in a single portion. A solution of p-toluenesulfonic acid monohydrate (166 g, 0.87 mol) in tetrahydrofuran (700 mL) was then added drop wise over 2 h, ensuring that the température did not exceed 20°C. The mixture was allowed to stir at

105 ambient température for 16h, after which volatiles were removed in vacuo. The resulting oil was dissolved in ethyl acetate (1.5 L) and washed with saturated aqueous sodium bicarbonate (1 L). The organic layer was then added to 1N sodium hydroxide (1 L) and allowed to stir for 1 h. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (1-7% dichloromethane / 2-propanol), then re-purified using a 10-50% ethyl acetate / 2-propanol solvent gradient to afford the title compound as an oil (74.5 g, 33%). ¹H NMR (CDCI₃) δ 6.42 (bs, 1H), 6.03 (bs, 1H), 3.34-4.14 (m, 4H), 2.853.04 (m, 2H), 2.08 (ds, 3H), 1.49-1.91 (m, 3H), 1.44 (bs, 9H).

Step 8: préparation of 1-(3-hydrazinylpiperidin-1-yl)ethanone hydrochloride. To 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 température did not exceed 10°C. The mixture was allowed to stir at ambient température 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. MS (M+H) m/z 158.¹H NMR (DMSO-c/6) δ 4.15 (q, 0.5H), 4.00 (d, 0.5H), 3.85-3.92 (m, 0.5H), 3.53-

3.59 (m, 0.5H), 2.71-3.16 (m, 3H), 2.01 (ds, 3H), 1.91-2.01 (m, 1H), 1.61-1.80 (m, 1H), 1.25-1.52 (m, 2H).

Step 9: préparation of 1-(1-acetylpiperidin-3-yl)-5-amino-3-[4-(4-chloro-3methylphenoxy)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 température for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (MgSO^, filtered and concentrated to afford the title compound. MS (M+H) m/z450.

Step 10: préparation of 5-amino-3-(4-(4-chloro-3-methylphenoxy)phenyl]-1piperidin-3-yl-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1 -(piperidin-3-yl)-1 H-pyrazole-4carboxamide (Example 25, Step 6) employing 1-(1-acetylpiperidin-3-yl)-5-amino-3-[4(4-chloro-3-methylphenoxy)phenyl]-1/+pyrazole-4-carbonitrile. ¹H NMR (400 MHz, DMSO-c/6) δ ppm 7.50 (m, J=8.53 Hz, 2 H), 7.43 (d, J=8.54 Hz, 1 H), 7.08 (m, 2 H),

7.11 (d, J=3.41 Hz, 1 H), 6.90 - 6.97 (m, 1 H), 6.34 (s, 2 H), 4.13 (d, J=4.78 Hz, 1 H),

106

3.01 - 3.10 (m, 1 H), 2.80 - 2.96 (m, 2 H), 2.32 (s, 4 H), 1.90 -1.96 (m, 1 H), 1.82 -1.90 (m, 1 H), 1.68 -1.78 (m, 1 H), 1.47 -1.59 (m, 2 H),

Step 11: préparation of 5-amino-3-[4-(4-chloro-3-methylphenoxy)phenyl]-1-(1cyanopiperidin-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]-1 Hpyrazole-4-carboxamide (Example 25, Step 7) employing 5-amino-3-[4-(4-chloro-3methylphenoxy)phenyl]-1-piperidin-3-yl-1H-pyrazole-4-carboxamide. MS (M+H) m/z 451.¹H NMR (DMSO-c/6) δ 7.09 (d, 2 H), 7.06 (d, J=8.30 Hz, 2 H) 6.91 (dd, J=8.79,

2.93 Hz, 1 H), 6.43 (s, 2 H), 4.33 - 4.39 (m, 1 H), 3.49 (dd, J=12.21,3.91 Hz, 1H), 3.30 -

3.36 (m, 2 H), 3.02 - 3.09 (m, 1 H), 2.31 (s, 3 H), 1.94 (td, J=13.18, 3.42 Hz, 1 H), 1.82 -

1.89 (m, 1 H), 1.80 (bs, 1 H), 1.65 -1.74 (m, 1 H).

Example 41 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(4-fluorophenoxy)phenyl]-1 W-pyrazole-4carboxamide

N

The title compound was prepared analogous to 5-amino-3-[4-(4-chloro-3methylphenoxy)phenyl]-1 -(1 -cyanopiperidin-3-yl)-1 W-pyrazole-4-carboxamide (Example 40) employing 4-fluorophenol. MS (M+H) m/z 421.¹H NMR (DMSO-c/6) δ 7.45 (d, J=8.8 Hz, 2 H), 7.39 (t, J=7.9 Hz, 2 H), 7.14 (t, J=7.3 Hz, 1 H), 7.03 (t, J=8.8 Hz, 4 H), 6.44 (bs, 2 H), 4.31 - 4.38 (m, 1 H), 3.48 (bs, 1 H), 3.45 (d, J=3.7 Hz, 1 H), 2.98 - 3.09 (m, 1 H), 1.90 (bs, 2 H), 1.76 -1.88 (m, 2 H), 1.68 (t, J=12.5 Hz, 1 H).

Example 42 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(4-methylphenoxy)phenyl]-1 AApyrazole-4carboxamide

The title compound was prepared analogous to 5-amino-3-[4-(4-chloro-3methylphenoxy)phenyl]-1 -(1 -cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 40) employing 4-methylphenol. MS (M+H) m/z 417.¹H NMR (DMSO-c/6) δ 7.45 (d,

107

J=8.4 Hz, 2 H), 7.21 (d, J=8.4 Hz, 2 H), 6.97 (d, J=8.8 Hz, 2 H), 7.00 (d, J=8.8 Hz, 2 H),

6.73 (bs, 1 H), 6.53 - 6.67 (m, 1 H), 6.40 (d, J=8.8 Hz, 2 H), 4.95 - 5.08 (m, 1 H), 4.32 -

4.53 (m, 1 H), 4.12 (bs, 4 H), 3.40 - 3.50 (m, 1 H), 3.01 (bs, 1 H), 2.29 (s, 3 H), 1.77 2.02 (m,3H), 1.45 (bs, 1 H).

Example 43

5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(2, 5-difluorophenoxy)phenyl]-1 H-pyrazole4-carboxamide

Step 1 : préparation of 4-iodo benzoyl chloride. To a suspension of 4-iodo benzoic acid (60 g, 0.24 mol) in oxalylchloride (417 mL, 4.83 mol) at 0°C was added N,N-dimethylformamide (1 mL) drop wise. The mixture was then heated to reflux for 16 h, after which it was cooled to ambient température and concentrated in vacuo. The resulting oil was dissolved in toluene and purified by vacuum distillation to afford the title compound.

Step 2: préparation of 2-(hydroxy(4-iodophenyl)methylene)malononitrile. To a stirred suspension of sodium hydride (60%, 64.36 g, 1.61 mol) in tetrahydrofuran (600 mL) at 0°C was added a solution of malononitrile (53.09 g, 804.5 mmol) in tetrahydrofuran (600 mL) and the resulting reaction mixture was stirred for 30 min at same température. 4-lodo benzoyl chloride (214 g, 804.5 mmol) in tetrahydrofuran (600 mL) was added to the suspension at 0°C and then stirred at room température for 16 h. The reaction mixture was cooled to 0°C and quenched with saturated ammonium chloride solution (1000 ml). The resulting aqueous solution was extracted with ethyl acetate (2 x 1.5 L). The combined organic layers were washed with brine (1 L), dried over sodium sulfate and concentrated to afford the title compound (250 g) as brown solid. MS (M-H) m/z295.¹H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.0 Hz, 2 H), 7.35 (d, J =8.0 Hz, 2 H).

Step 3: préparation of 2-((4-iodophenyl)(methoxy)methylene)malononitrile. To a stirred suspension of sodium hydride (60%, 37.16 g, 929 mmol) in tetrahydrofuran (500 mL) at 0°C was added a solution of 2-(hydroxy(4-iodophenyl)methylene)malononitrile (250 g, 844.6 mmol) in tetrahydrofuran (500 mL) and the resulting reaction mixture was stirred for 30 min at same température. Dimethyl sulfate (241 mL, 253.8 mmol) in

108 tetrahydrofuran (500 mL) was added to the above stirred suspension at 0°C and the resulting reaction mixture was stirred at 80°C for 16 h. The reaction mixture was cooled to 0°C and quenched with saturated ammonium chloride solution (1000 mL). The resulting aqueous solution was extracted with ethyl acetate (2 x Î.5 L). The combined organic layers were washed with brine solution (1 L), dried over sodium sulfate and concentrated to afford the title compound (200 g). LCMS (M-H) m/z 308.

Step 4: préparation of benzyl 3-[5-amino-4-cyano-3-(4-iodophenyl)-1H-pyrazol-1yl]piperidine-1-carboxylate. To the stirred suspension of 2-((4-iodophenyl)(methoxy)methylene)malononitrile (100 g, 322.6 mmol) in éthanol (1 L) was added freshly distilled triethylamine (49.1 mL, 354.8 mmol) followed by addition of 2-(methoxy(3iodo)methylene)-malononitrile and benzyl 3-hydrazino-piperidine-1 -carboxylate (Example 1, Step 8) (91.93 g, 322.6 mmol) at room température and the resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to room température and concentrated to a volume of 500 mL. The resulting solids were filtered, washed with water (2 x 500 ml) and dried under vacuum to afford the title compound (98 gm, 58 %) as off white solid. MS (M+H) m/z527.8. ¹H NMR (400 MHz, DMSO-cf6) δ 7.82 (d, J= 8.0 Hz, 2 H), 7.57 (d, J= 8.0 Hz, 2 H), 7.34 (br, 5 H), 6.82 (s, 2 H), 5.06 (br, 2 H), 4.27 (br, 1 H), 4.01-3.91 (m, 2 H), 3.32-3.27 (m, 1 H), 2.99-2.93 (m, 1 H), 1.98-1.85 (m, 3 H), 1.54-1.48 (m, 1 H).

Step 5: préparation of benzyl 3-{5-amino-4-cyano-3-[4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl]-1H-pyrazol-1-yl}piperidine-1-carboxylate. To a stirred suspension of benzyl 3-[5-amino-4-cyano-3-(4-lodophenyl)-1 H-pyrazol-1-yl]piperidine-1carboxylate (86.7 g, 341.6 mmol), bis(pinacolato)diborane (95.4 g, 375.8 mmol), and potassium acetate (34 g, 347.2 mmol) in dimethylsulfoxide (300 mL) which had been degassed under nitrogen for 20 min, was added PdCI₂(dppf) (7.4 g, 9.1 mmol). The reaction mixture was then heated to 80°C for 2h, allowed to cool to ambient température, and filtered through Celite. The filtrate was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to afford the title compound as pale yellow oil (45 g, 75%). MS (M+H) m/z 528.¹H NMR: (400 MHz, DMSO-ctë) δ ppm: 7.83 (d, J=8 Hz, 2H), 7.57 (d, J=8 Hz, 2H), 7.36 (s, 5H), 6.83 (br s, 2H), 5.0 (bs, 2H), 4.30 (d, J=28 Hz, 2H), 3.98 (d, J=40 Hz, 2H), 3.22-3.20 (m,1H), 2.95 (t, J=24Hz, 1H), 1.97-1.84 (dd, J=52 Hz, 3H), 1.56-1.46 (bs,1H),1.30 (s, 12H).

Step 6: préparation of préparation of [4-(5-amino-1-{1[(benzyloxy)carbonyl]piperidin-3-yl}-4-cyano-1 H-pyrazol-3-yl)phenyl]boronic acid. To a

109 solution of benzyl-3-(5-amino-4-cyano-3-[4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)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). The reaction mixture was stirred at 30°C over 16 h, after which the desired product was extracted into ethyl acetate. The combined organic layers were dried over magnésium sulfate and concentrated in vacuo to afford the title compound. MS (M+H) m/z445.9.

Step 7: préparation of benzyl 3-{5-amino-4-cyano-3-[4-(2,5difluorophenoxy)phenyl]-1 H-pyrazol-1-yl}piperidine-1 -carboxylate. To a solution of 2,4difluorophenol (16 mg, 0.125 mmol) and [4-(5-amino-1-{1[(benzyloxy)carbonyl]piperidin-3-yl}-4-cyano-1 /-/-pyrazol-3-yl)phenyl]boronic acid (56 mg, 0.125 mmol) in dichloromethane (1 mL) in an 8 mL vial was added copper (II) acetate (18 mg, 0.100 mmol), 4Â molecular sieves (10 mg), and pyridine (20 pL, 0.200 mmol). The vial was capped and allowed to shake at 30°C for 16 h. The reaction mixture was then filtered and the filtrate was concentrated using a Speedvac. The resulting residue was then purified by préparative TLC to afford the title compound.

Step 8: préparation of 5-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1-piperidin-3-yl1 /+pyrazole-4-carboxamide. To a solution of benzyl 3-{5-amino-4-cyano-3-[4-(2,5difluorophenoxy)phenyl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (66 mg, 0.125 mmol) in isopropanol (1 mL) in an 8 mL vial was added 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 x 1 mL). The combined organic layers were dried over magnésium sulfate, and concentrated using a Speedvac to afford the title compound.

Step 9: préparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2, 5difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide. To an 8 mL vial containing 5amino-3-[4-(2,5-difluorophenoxy)phenyl]-1-piperidin-3-yl-1H-pyrazole-4-carboxamide (52 mg, 0.125 mmol) was added a 0.5M solution of cyanogen bromide 0.250 mmol) in Λ/,/V-dimethylformamide (0.5 mL), followed by potassium carbonate (52 mg, 0.375 mmol). The vial was capped and allowed to shake at 30°C for 16h. Solvent was removed using a Speedvac, and the resulting residue was purified via préparative HPLC to afford the title compound. LCMS (M+H) m/z 439.

Examples 44 - 66

110

The compounds in the table below were prepared analogous to 5-amino-1-(1cyanopiperidin-3-yl)-3-[4-(2, 5-difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide (Example 43).

EX	Structure	Name	MS (M+1)
44	RfeXCrV N	5-amino-1 -(1 -cyanopïperidin-3-yl)3-(4-(4isopropoxyphenoxy)phenyl]-1 Hpyrazole-4-carboxamide	461
45	h2n/^o N Cl	5-amino-3-[4-(2-chloro-5-fluorophenoxy)phenyl]-1-(1 cyanoplperidin-3-yl)-1H-pyrazole4-carboxamide	455
46	H m H2N F h2 N \ F>J r-\ 0 f^o î\f N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-{4-[4-fluoro-3-(trifluoromethoxy)phenoxy]phenyl}-1 H-pyrazole-4carboxamide	505
47	O'^ÇfyY N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-{4-[4-fluoro-2methoxyphenoxy]phenyl}-1 Hpyrazole-4-carboxamide	451
48	h2n — χ 0 fe-Vi Δ N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-[4-(3-methoxyphenoxy)phenylJ- 1 H-pyrazole-4-carboxamide	433
49	h2n . /—\ Af 0 Cl fS // νψψ	5-amino-3-[4-(5-chloro-2fluorophenoxy)phenyl]-1 -(1 cyanopiperidin-3-yl)-1 H-pyrazole4-carboxamide	455

111

50	N il	5-amino-1 -(1 -cyanopiperidin-3-yl)3-(4-(2, 4dichlorophenoxy)phenyl]-1 Hpyrazole-4-carboxamide	471
51	h2n Aâ / laaA N	5-amino-3-[4-(3-chloro-5-fluorophenoxy)phenyl]-1 -(1 cyanopiperidin-3-yl)-1 H-pyrazole4-carboxamida	455
52	Η2\.ο /=\ h2n/T W Ν^θΧλνλ0 FV	5-amino-1 -(1 -cyanopiperidin-3-yl)3-{4-[2-(trifluoromethyl)phenoxy]phenyl}-1 H-pyrazole-4carboxamide	471
53	h2n h*V A A N	5-amino-3-[4-(3-chlorophenoxy)phenyl]-1-(1-cyanopiperidin-3-yl)1 H-pyrazole-4-carboxamide	437
54		5-amino-1 -(1 -cyanopiperidin-3-yl)3-[4-(3-fluoro-2methylphenoxy)phenyl]-1 Hpyrazole-4-carboxamide	435
55	H2N /	5-amino-1 -(1 -cyanopiperidin-3-yl)- 3-(4-(2,5-dichlorophenoxy)phenyl]- 1 Mpyrazole-4-carboxamide	471
56	H,N /=\ h2nJT° ci	5-amino-3-[4-(2-chlorophenoxy)phenyl]-1 -(1 -cyanopiperidin-3-yl)1 H-pyrazole-4-carboxamide	437

112

57	VA // AA, N I	5-amino-3-(4-(3-chloro-2-fluorophenoxy)phenyl]-1 -(1 cyanopiperidin-3-yl)-1W-pyrazole4-carboxamide	455
58	*nAL0 ίΎΡ z/ UAA N	5-amino-3-[4-(3-chloro-4-fluorophenoxy) phenyl]-1-(1cyanopiperidin-3-yl)-1H-pyrazole4-carboxamide	455
59	W OfeÇ> FvrF // A0AA N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-(4-(2,4,5- trifluorophenoxy)phenyl]-1 H· pyrazole-4-carboxamide	457
60	h2n hA /Ά )==(0 cl O'Aa A // ΜΑΛ N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-(4-(3,5-dichlorophenoxy)phenyl]- 1 H-pyrazole-4-carboxamide	471
61	*nalo AA fyÇf // UA N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-(4-(2,3,4- trifluorophenoxy)phenyl]-1 H- pyrazole-4-carboxamide	457
62	VA pFp ΟΆ% A r Xço N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-(4-(2(trifluoromethoxy)phenoxy]phenyl}- 1 H-pyrazole-4-carboxamide	487
63	*CL0 Raq N Cl	5-amino-3-(4-(2-chloro-6-fluorophenoxy) phenyl]-1-(1cyanopiperidin-3-yl)-1H-pyrazole4-carboxamide	455

113

64	// N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-{4-[4-fluoro-3- (trifluoromethyl)phenoxyjphenyl}- 1 /7-pyrazole-4-carboxamide	489
65	// N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-[4-(2-methoxyphenoxy)phenyl]1 H-pyrazole-4-carboxamide	433
66	jfS N	5-amino-1-(1-cyanopiperidin-3-yl)3-(4-(3,5-difluorophenoxy)phenylJ1 A/-pyrazole-4-carboxamide	439

Example 67

5-amino-3-(4-benzylphenyl)-1-(1-cyanopiperidin-3-yl)-1AApyrazole-4-carboxamide

Step 1 : préparation of benzyl 3-(5-amino-3-(4-benzylphenyl)-4-cyano-1 /7-pyrazol1 -yl)piperidine-1 -carboxylate. To a mixture of benzyl 3-[5-amino-4-cyano-3-(4iodophenyl)-1/7-pyrazol-1-yl]piperidine-1-carboxylate (Example 43, Step 4) (1 eq), 2dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.073 eq), Pd₂(dba)₃ (0.065 eq) in N,Ndimethylformamide (50 mL) was added dropwise a solution of benzyl zinc bromide (3eq, 10 0.5 M in tetrahydrofuran) at room température under N₂. The mixture was stirred at room température overnight. The reaction mixture was quenched by saturated aqueous ammonium chloride and ethyl acetate (100 mL) was added. The mixture was filtered and the filtrate was extracted with ethyl acetate twice. The combine organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by coiumn chromatography on silica gel (CH₂CI₂/CH₃OH, 4/1-1/1) to afford the title compound as a yellow oil.

114

Step 2: préparation of 5-amino-3-(4-benzylphenyl)-1-(piperidin-3-yl)-1H-pyrazole4-carboxamide. A mixture of benzyl 3-(5-amino-3-(4-benzylphenyl)-4-cyano-1 H pyrazol-1-yl)piperidine-1 -carboxyiate (1 eq), NaOH solution(7-10 eq, 2.5M), EtOH (8 mL) was irradiated in the microware at 145 °C for 1 h. The reaction mixture was extracted with EtOAc (50 mL x 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: préparation of 5-amino-3-(4-benzylphenyl)-1-(1-cyanopiperidin-3-yl)-1Hpyrazole-4-carboxamide. A mixture of 5-amino-3-(4-benzylphenyl)-1-(piperidin-3-yl)-1Hpyrazole-4-carboxamide (1 eq.), Cs₂CO₃ (2 eq.), cyanogen bromide (1.1 eq.) in N,Ndimethylformamide (10 mL) was stirred at room température ovemight. The reaction mixture was extracted with EtOAc (50 mL x 2). The combine organic layers were washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by reverse phase préparative HPLC to afford the title compound as a white solid. LCMS (M+H): 401.¹H NMR (DMSO-d6) δ 7.05 - 7.51 (m, 9H), 6.45 (s, 2H), 4.24 -

4.43 (m, 1H), 3.97 (s, 2H), 3.47 (dd, J=12.1,4.0 Hz, 1H), 3.03 (td, J=12.5, 2.2 Hz, 1H),

1.75 - 2.01 (m, 3H), 1.58 -1.73 (m, 1 H).

Example 68 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(3-methylbenzyl)phenyl]-1 W-pyrazole-4carboxamide

The title compound was prepared analogous to 5-amino-3-(4-benzylphenyl)-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 67) employing (3methylbenzyl)zinc chloride. MS (M+H) m/z 415.¹H NMR (CDCI3,400 MHz) δ 1.77 -

1.84 (m, 2H), 2.07 - 2.11 (m, 2H), 2.25 (s, 3H), 2.93 - 2.99 (m, 1 H), 3.35 -3.53 (m, 3H),

3.90 (s, 2H), 4.0 - 4.02 (m, 1H), 5.13 (d, 2H), 5.47 (s, 2H), 6.92 - 6.97 (m, 3H), 7.10 -

7.74 (m, 1H), 7.22 (d, 2H), 7.36 (d, 2H).

Example 69 (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-(3-methylbenzyl)phenyl)-1 W-pyrazole-4carboxamide

115

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(3-methylbenzyl)phenyl]-1 /7-pyrazole4-carboxamide (prepared as described in Example 68) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 70 5 mL/min). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 415.¹H NMR (400 MHz, DMSO-ofe) δ ppm 7.39 (d, J=8.6 Hz, 2 H), 7.29 (d, J=8.1 Hz, 2 H), 7.15 - 7.21 (m, 1 H), 6.98 - 7.09 (m, 3 H), 6.46 (s, 2 H), 4.31 - 4.41 (m, 1 H),

3.94 (s, 2 H), 3.49 (dd, J=12.1,4.3 Hz, 1 H), 3.32 (m, 2 H), 3.00 - 3.10 (m, 1 H), 2.26 (s, 3 H), 1.76 - 2.00 (m, 3 H), 1.58 -1.76 (m, 1 H)

Example 70 (S)-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-(3-methylbenzyl)phenyl)-1 H-pyrazole-4carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(3-methylbenzyl)phenyl]-1 /7-pyrazole15 4-carboxamide (prepared as described in Example 68) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 70 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 415.¹H NMR (400 MHz, DMSO-ofe) δ ppm 7.39 (d, J=8.6 Hz, 2 H), 7.29 (d, J=8.1 Hz, 2 H), 7.15 - 7.21 (m, 1 H), 6.98 - 7.09 (m, 3 H), 6.46 (s, 2 H), 4.31 - 4.41 (m, 1 H), 20 3.94 (s, 2 H), 3.49 (dd, J=12.1,4.3 Hz, 1 H), 3.32 (m, 2 H), 3.00 - 3.10 (m, 1 H), 2.26 (s,

H), 1.76 - 2.00 (m, 3 H), 1.58 -1.76 (m, 1 H)

Example 71 5-amino-3-(4-(2-chlorobenzyl)phenyl)-1-(1-cyanopiperidin-3-yl)-1H-pyrazole-4carboxamide

116

The title compound was prepared analogous to 5-amino-3-(4-benzylphenyl)-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 67) employing (2chlorobenzyl)zinc chloride. MS (M+H) m/z435.¹H NMR (CDCI₃, 400 MHz) δ 1.78 -1.87 (m, 2H), 2.05 - 2.11 (m, 2H), 2.93 - 3.00 (m, 1 H), 3.35 - 3.53 (m, 3H), 4.00 - 4.05 (m, 1 H), 4.074 (s, 2H), 5.15 (d, 2H), 5.48 (s, 2H), 7.10 - 7.13 (m, 2H), 7.22 (d, 2H), 7.31 -

7.33 (m, 1H), 7.37 (d, 2H).

Example 72 (fi)-5-amino-3-(4-(2-chlorobenzyl)phenyl)-1-(1 -cyanopiperidin-3-yl)-1 H-pyrazole-410 carboxamide

rao-5-amino-3-(4-(2-chlorobenzyl)phenyl)-1 -(1 -cyanopiperidin-3-yl)-1 W-pyrazole4-carboxamide (prepared as described in Example 71) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 30% MeOH, 70 15 mL/min). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 435.¹H NMR (400 MHz, DMSO-c/₆) δ ppm 7.24 - 7.48 (m, 8 H), 6.46 (s, 2 H), 4.31 -

4.41 (m, 1 H), 4.12 (s, 2 H), 3.49 (dd, J=12.1,4.3 Hz, 1 H), 3.30 - 3.38 (m, 2 H), 3.04 (td, J=12.4, 2.9 Hz, 1 H), 1.77 - 2.00 (m, 3 H), 1.64 -1.76 (m, 1 H).

Example 73 (S)-5-amino-3-(4-(2-chlorobenzyl)phenyl)-1-(1-cyanopiperidin-3-yl)-1M-pyrazole-4carboxamide

rao-5-amino-3-(4-(2-chlorobenzyl)phenyl)-1 -(1 -cyanopiperidin-3-yl)-1 H-pyrazole4-carboxamide (prepared as described in Example 71) was chirally separated by

117 supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 30% MeOH, 70 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 435. Ή NMR (400 MHz, DMSO-cfe) δ ppm 7.24 - 7.48 (m, 8 H), 6.46 (s, 2 H), 4.31 -

4.41 (m, 1 H), 4.12 (s, 2 H), 3.49 (dd, J=12.1,4.3 Hz, 1 H), 3.30 - 3.38 (m, 2 H), 3.04 (td, J=12.4, 2.9 Hz, 1 H), 1.77-2.00 (m, 3 H), 1.64 -1.76 (m, 1 H).

Example 74

5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(2-fluorobenzyl)phenyl]-1 H-pyrazole-4carboxamide

The title compound was prepared analogous to 5-amino-3-(4-benzylphenyl)-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 67) employing (2chlorobenzyl)zinc chloride. MS (M+H) m/z 419.¹H NMR (300 MHz, DMSO-cfe) δ ppm

7.40 (d, 2 H), 7.25 - 7.37 (m, 4 H), 7.12 - 7.21 (m, 2 H), 6.46 (s, 2 H), 4.30 - 4.40 (m, 1 H), 4.02 (s, 2 H), 3.48 (dd, 1 H), 3.33 - 3.38 (m, 2 H), 3.04 (td, 1 H), 1.60 -1.99 (m, 4 H).

Example 75 (fl)-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-(2-fluorobenzyl)phenyl)-1 H-pyrazole-4carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(2-fluorobenzyl)phenyl]-1 /7-pyrazole4-carboxamide (prepared as described in Example 74) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 70 mL/min). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 419.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.40 (d, J=8.3 Hz, 2 H), 7.25 - 7.37 (m, 4 H), 7.12 - 7.21 (m, 2 H), 6.46 (s, 2 H), 4.30 - 4.40 (m, 1 H), 4.02 (s, 2 H), 3.48 (dd, J=12.3, 4.2 Hz, 1 H), 3.33-3.38 (m, 2 H), 3.04 (td, J=12.4, 2.9 Hz, 1 H), 1.76 -1.99 (m, 3 H), 1.70 (tt, J=12.5,4.1 Hz, 1 H).

118

Example 76 (S)-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-(2-fluorobenzyl)phenyl)-1 W-pyrazole-4carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(2-fluorobenzyl)phenyl]-1 /7-pyrazole-

4- carboxamide (prepared as described in Example 74) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 70 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 419.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.40 (d, J=8.3 Hz, 2 H), 7.25 - 7.37 (m, 4 H), 7.12 - 7.21 (m, 2 H), 6.46 (s, 2 H), 4.30 - 4.40 (m, 1 H), 4.02 (s, 2 H), 3.48 (dd, J=12.3,4.2 Hz, 1 H), 3.33-3.38 (m, 2 H), 3.04 (td, J=12.4, 2.9 Hz, 1 H), 1.76 -1.99 (m, 3 H), 1.70 (tt, J=12.5, 4.1 Hz, 1 H).

Example 77

5- amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(3-fluorobenzyl)phenyl]-1 W-pyrazole-4carboxamide

The title compound was prepared analogous to 5-amino-3-(4-benzylphenyl)-1-(1cyanopiperidin-3-yl)1 H-pyrazole-4-carboxamide (Example 67) employing (3fluorobenzyl)zinc chloride. MS (M+H) mZ?419.¹H NMR (CDCIa, 400 MHz) δ 1.78 -1.88 (m, 2H), 2.05 - 2.11 (m, 2H), 2.93 - 3.00 (m, 1H), 3.35 -3.53 (m, 3H), 3.94 (s, 2H), 3.98 4.06 (m, 1 H), 5.09 - 5.19 (s, 2H), 5.49 (s, 2H), 6.80 - 6.92 (m, 3H), 7.21 (d, 2H), 7.38 (d, 2H).

Example 78 (R)-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-(3-fluorobenzyl)phenyl)-1 H-pyrazole-4carboxamide

119

rao-5-amino-l -(1 -cyanopiperidin-3-yl)-3-[4-(2-f luorobenzyl)phenyl]-1 H-pyrazole4-carboxamîde (prepared as described in Example 77) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 70 5 mL/min). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 419.¹H NMR (400 MHz, DMSO-afe) δ ppm 7.38 - 7.44 (m, 2 H), 7.29 - 7.38 (m, 3 H), 7.07 - 7.13 (m, 3 H), 6.99 - 7.06 (m, 1 H), 6.46 (s, 2 H), 4.31 - 4.41 (m, 1 H), 4.01 (s, 2 H), 3.49 (dd, J=12.1, 4.5 Hz, 1 H), 3.36 (br. s., 1 H), 3.05 (td, J=12.4, 2.5 Hz, 1 H), 1.76-1.98 (m, 3 H), 1.60 -1.75 (m, 1 H).

Example 79 (S)-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-(3-fluorobenzyl)phenyl)-1 H-pyrazole-4carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(2-fluorobenzyl)phenyl]-1 H-pyrazole15 4-carboxamide (prepared as described in Example 77) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 70 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 419.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.38 - 7.44 (m, 2 H), 7.29 - 7.38 (m, 3 H), 7.07 - 7.13 (m, 3 H), 6.99 - 7.06 (m, 1 H), 6.46 (s, 2 H), 4.31 - 4.41 (m, 1 H), 4.01 (s, 20 2 H), 3.49 (dd, J=12.1,4.5 Hz, 1 H), 3.36 (br. s., 1 H), 3.05 (td, J=12.4,2.5 Hz, 1 H),

1.76 -1.98’ (m, 3 H), 1.60 -1.75 (m, 1 H)

Example 80 5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4-difluorobenzyl)phenyl]-1H-pyrazole-4carboxamide

120

F

The title compound was prepared analogous to 5-amino-3-(4-benzylphenyl)-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 67) employing (3fluorobenzyl)zinc chloride. MS (M+H) m/z437.¹H NMR (CDCh, 400 MHz) δ 1.80 -1.84 (m, 2H), 2.04 - 2.08 (m, 2H), 2.93 - 3.00 (m, 1 H), 3.35 - 3.53 (m, 3H), 3.918 (s, 2H),

3.98 - 4.05 (m, 1H), 5.14 (s, 2H), 5.49 (s, 2H), 6.72 - 6.76 (m, 2H), 7.03 - 7.09 (m, 1H),

7.22 (d, 2H), 7.37 (d, 2H).

Example 81 (/3)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-(2,4-difluorobenzyl)phenyl)-1H· pyrazole-4-carboxamîde rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(2,4-difluorobenzyl)phenyl]-1 Hpyrazole-4-carboxamide (prepared as described in Example 80) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 15 70 mL/min). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z 437.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.35 - 7.44 (m, 3 H), 7.27 (d, J=7.8 Hz, 2 H), 7.18 - 7.25 (m, 1 H), 7.05 (tt, J=8.5, 1.4 Hz, 1 H), 6.46 (s, 2 H), 4.30 - 4.40 (m, 1 H),

3.99 (s, 2 H), 3.49 (dd, J=12.4,4.3 Hz, 1 H), 3.26 - 3.38 (m, 4 H), 3.04 (td, J=12.4,2.8 Hz, 1 H), 1.77 -1.99 (m, 3 H), 1.70 (tt, J=12.8, 4.0 Hz, 1 H).

Example 82 (S)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-(2,4-difluorobenzyl)phenyl)-1Hpyrazole-4-carboxamide

121 rao-5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(2,4-difluorobenzyl)phenyl]-1Hpyrazole-4-carboxamide (prepared as described in Example 80) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 70 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z437.¹H NMR (400 MHz, DMSO-de) δ ppm 7.35 - 7.44 (m, 3 H), 7.27 (d, J=7.8 Hz, 2 H), 7.18 - 7.25 (m, 1 H), 7.05 (tt, J=8.5,1.4 Hz, 1 H), 6.46 (s, 2 H), 4.30 -

4.40 (m, 1 H), 3.99 (s, 2 H), 3.49 (dd, J=12.4, 4.3 Hz, 1 H), 3.26 - 3.38 (m, 4 H), 3.04 (td, J=12.4, 2.8 Hz, 1 H), 1.77 -1.99 (m, 3 H), 1.70 (tt, J=12.8,4.0 Hz, 1 H).

Example 83

5-amino-1 -(1 -cyanopiperidin-3-yl)-3-[4-(3,4-difluorobenzyl)phenyl]-1 H-pyrazole-4carboxamide

The title compound was prepared analogous to 5-amino-3-(4-benzylphenyl)-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 67) employing (3,4difluorobenzyl)zinc chloride. MS (M+H) m£437.¹H NMR (CDCI3, 400 MHz) δ 7.39 (d, 2H), 7.18 (d, 2H), 6.84 - 7.04 (m, 2H), 5.67 (s, 2H), 5.26 (s, 2H), 4.10-4.11 (m, 1 H),

3.89 (s, 2H), 3.34 - 3.54 (m, 3H), 2.93 - 3.00 (m, 1 H), 2.07 - 2.08 (m, 2H), 1.71-1.83 (m, 2H).

Example 84 (fl)-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-(3,4-dif luorobenzyl)phenyl)-1 H-

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-(3,4-difluorobenzyl)phenyl)-1 Hpyrazole-4-carboxamide (prepared as described in Example 83) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 70 mL/min). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z437.¹H NMR (400 MHz, DMSO-de) δ ppm 7.29 - 7.44 (m, 6 H), 7.11 (ddd, J=6.3,

4.2, 2.4 Hz, 1 H), 6.46 (s, 2 H), 4.31 - 4.41 (m, 1 H), 3.98 (s, 2 H), 3.49 (dd, </=12.1, 4.3

122

Hz, 1 H), 3.30 - 3.38 (s, 4 H), 3.05 (td, J=12.4, 2.7 Hz, 1 H), 1.76 -1.98 (m, 3 H), 1.64 -

1.76 (m, 1 H).

Example 85 (S)-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-(3,4-difluorobenzyl)phenyl)-1 Hpyrazole-4-carboxamide

rao5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-(3,4-difluorobenzyl)phenyl)-1 Hpyrazole-4-carboxamide (prepared as described in Example 83) was chirally separated by supercritical fluid chromatography (ChiralPak AD 5 μ, 21 x 250 mm col, 27% MeOH, 70 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z437.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.29 - 7.44 (m, 6 H), 7.11 (ddd, J=6.3, 4.2,2.4 Hz, 1 H), 6.46 (s, 2 H), 4.31 - 4.41 (m, 1 H), 3.98 (s, 2 H), 3.49 (dd, J=12.1, 4.3 Hz, 1 H), 3.30 - 3.38 (s, 4 H), 3.05 (td, J=12.4, 2.7 Hz, 1 H), 1.76 -1.98 (m, 3 H), 1.64-1.76 (m, 1 H).

Example 86 5-amino-3-[4-(4-ch!orobenzyl)phenyl]-1 -(1 -cyanopiperidin-3-yl)-1 H-pyrazole-4carboxamide

.Cl

Step 1 : préparation of 3-[5-acetylamino-4-cyano-3-(4-iodophenyl)-pyrazol-1 -yl]piperidine-1-carboxylic acid benzyl ester. To the stirred suspension of benzyl 3-[5amino-4-cyano-3-(4-iodophenyl)-1/-Apyrazol-1-yl]piperidine-1-carboxylate (100 g, 189.8 mmol) (Example 43, Step 4) in dichloromethane (1.6 L) was added acetyl chloride (145 mL, 1.897 mol) drop wise at 0°C under nitrogen atmosphère. After 30 min, freshly distilled triethylamine (49.1 mL, 354.8 mmol) was added drop wise at 0°C and the resulting mixture was stirred at room température for 16 hours. The reaction mixture was quenched with saturated sodium-bicarbonate solution and the aqueous part was separated. The aqueous layer was back extracted with dichloromethane (500 mL) and the combined organic layers were washed with water followed by brine and dried over

123 sodium sulfate and concentrated to afford the title compound (70 gm, 65 %) as light yellow solid. MS (M+H) m/z570. ¹H NMR (400 MHz, DMSO-ctë) δ 10.56 (s, 1 H), 7.89 (d, J= 8.0 Hz, 2 H), 7.63 (d, J= 8.0 Hz, 2 H), 7.33 (br, 5 H), 5.05 (s, 2 H), 4.29 (br, 1 H), 4.08 (m, 1 H), 3.88 (m, 1 H), 3.0 (m, 1 H), 2.13 (s, 3 H), 1.99 (m, 3 H), 1.54-1.51 (m, 1 H).

• Step 2: préparation of benzyl 3-{5-acetamido-3-[4-(4-chlorobenzyl)phenyl]-4cyano-1/7-pyrazol-1-yl}piperidine-1-carboxylate. To a solution of benzyl 3-[5-acetamido4-cyano-3-(4-iodophenyl)-1 /-/-pyrazol-1-yl]piperidine-1 -carboxylate (0.41g, 0.73mmol), palladium acetate (12mg, 0.053mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (18mg, 0.043mmol) and lithium chloride (80mg, 1.89mmol) in tetrahydrofuran (6 mL) at 0°C was added a solution of 4-chlorobenzyl zinc chloride in tetrahydrofuran (3.4 mL, 1.7 mmol). The reaction was allowed to stir at 0°C for 20 min, then allowed to stir at ambient température for 16h. A second aliquot of 4-chlorobenzyl zinc chloride solution (3 mL) was added and the reaction was then allowed to stir for an additional 27 h, after which it was quenched with saturated aqueous ammonium chloride, and extracted into ethyl acetate. The combined organic layers were washed with brine, dried over magnésium sulfate and concentrated in vacuo. The crude residue was then purified by silica gel column chromatography (60% ethyl acetate / heptanes) to afford the title compound as a brown oil. MS (M+H) m/z 568.

Step 3: préparation of 5-amino-3-[4-(4-chlorobenzyl)phenyl]-1-piperidin-3-yl-1/7pyrazole-4-carboxamide. Prepared according to the procedure described for 5-amino-

3-(4-phenoxyphenyl)-1-piperidin-3-yl-1/-/-pyrazole-4-carboxylic acid amide (Example 1, Step 11) from benzyl 3-{5-acetamido-3-[4-(4-chlorobenzyl)phenyl]-4-cyano-1/7-pyrazol-

1-yl}piperidine-1-carboxylate to afford the title compound, which was taken on to the next step without purification. MS (M+H) m/z 410.

Step 4: préparation of 5-amino-3-[4-(4-chlorobenzyl)phenyl]-1-(1-cyanopiperidin-

3-yl)-1 /7-pyrazole-4-carboxamide. Prepared according to the procedure described for 5amino-1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1/-/-pyrazole carboxamide (Example 1, Step 12) from 5-amino-3-[4-(4-chlorobenzyl)phenyl]-1-piperidin-3-yl-1/7pyrazole-4-carboxamide to afford the title compound. MS (M+H) m/z435.¹H NMR (DMSO-c/6) δ 7.39 (d, J= 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.30-7.25 (m, 4H), 6.43 (s, 2H), 4.38-4.31 (m, 1H), 3.97 (s, 2H), 3.52-3.45 (m, 1H), 3.37-3.29 (m, 2H), 3.07-3.00 (m, 1H), 1.99-1.91 (m, 1H), 1.87-1.79 (m,2H), 1.73-1.64 (m, 1H).

Example 87

124

5-Amino-3-(4-benzoyl-phenyl)-1 -(1 -cyano)-piperidin-3-yl-1 M-pyrazole-4-carboxylic acid amide

o

Step 1 : préparation 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 Ν,Ν-dimethylformamide, over 15min. The mixture was stirred at room température for 1 h and then concentrated under reduce pressure to afford the title compound (2.4 gm).

Step 2: préparation of 2-((4-benzoylphenyl)(methoxy)methylene)malononitrile.

To a suspension of sodium hydride (640 mg, 16 mmol) in dry tetrahydrofuran (10 mL) at 0°C was added a solution of malononitrile (528 mg, 8 mmol) in tetrahydrofuran (5 mL) dropwise over 15min, under nitrogen atmosphère. 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. The reaction mixture was cooled to room température and quenched with aqueous ammonium chloride and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (heptane/ethyl acetate) to afford the title compound (700mg, 30%) as an off-white solid. MS (M+H) m/z 289.2.

Step 3: préparation of benzyl 3-(5-amino-3-(4-benzoylphenyl)-4-cyano-1Hpyrazol-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 éthanol (20 mL). The mixture was heated to 70°C and stirred ovemight. After cooling to room température, the solution was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers washed with brine, dried over sodium sulfate, and concentrated to afford the title compound (1.1g, 90%). MS (M+H) m/z 506.4.

Step 4: préparation of 5-amino-3-(4-benzoyl-phenyl)-1-(1-cyano)-piperidin-3-yl1 W-pyrazole-4-carboxylic acid amide. To a into a 25mL SS Parr autoclave was added benzyl 3-(5-amino-3-(4-benzoylphenyl)-4-cyano-1 H-pyrazol-1 -yl)piperidine-1 125 carboxylate (2 g, 4 mmol) and éthanol (3 mL). A solution of sodium hydroxide (2.5 N, 10 mmol, 4 mL). The autoclave was sealed and heated until internai température reached

150°C for 15 min. After cooling to room température and the mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford the title compound (1.15g, 76%). MS (M+H) m/z 390.3.

Step 5: préparation of 5-amino-3-(4-benzoyl-phenyl)-1-(1-cyano)-piperidin-3-yl1/7-pyrazole-4-carboxylic acid amide. Cyanogen bromide (38 mg, 0.36 mmol) and potassium carbonate (62 mg, 0.45 mmol) were added to a solution of 5-amino-3-(4benzoyl-phenyl)-1-(1-cyano)-piperidin-3-yl-1/7-pyrazole-4-carboxylic acid amide (117 mg, 0.3 mmol) in N,N-dimethylformamide (4 mL). The mixture was heated to 50°C and stirred for 2 hr. After cooling to room température, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by reverse phase préparative HPLC to afford the title compound. MS (M+H) m/z515.3.¹H NMR (DMSO-d6) δ 7.76 - 7.86 (m, 4H), 7.67 - 7.76 (m, 3H), 7.54 - 7.65 (m, 2H), 6.44 (s, 2H), 4.33 - 4.49 (m, 1H), 3.55 (dd, J=12.1, 3.9 Hz, 1H), 3.02 - 3.17 (m, 1H), 1.81 - 2.07 (m, 3H), 1.67 -1.81 (m, 1H).

Example 88 5-amino-1 -(1 -cyanopiperidin-3-yl)-3-{4-[hydroxy(phenyl)methyl]phenyl}-1 Hpyrazole-4-carboxamide

Step 1: préparation of 5-amino-3-{4-[hydroxy(phenyl)methyl]phenyl}-1-piperidin-

3-yl-1 H-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 température and then filtered through Celite. The filtrate was concentrated to afford the title compound.

Step 2: préparation of 5-amino-3-(4-(hydroxy(phenyl)methyl)phenyl)-1-(piperidin-

3-yl)-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 5-

126 amino-3-(4-benzoyl-phenyl)-1 -(1 -cyano)-piperidin-3-yl-1 H-pyrazole-4-carboxylic acid amide (Example 87, Step 4) employing 5-amino-3-{4-[hydroxy(phenyl)methyllphenyl}-1piperidin-3-yl-1/+pyrazole-4-carbonitrile. MS (M+H) m/z392.3.

Step 3: préparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-{4[hydroxy(phenyl)methyl]phenyl}-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 5-amino-3-(4-benzoyl-phenyl)-1-(1-cyano)-piperidin-3-yl-1 Hpyrazole-4-carboxylic acid amide (Example 87, Step 5) employing 5-amino-3-(4(hydroxy(phenyl)methyl)phenyl)-1 -(piperidin-3-yl)-1 W-pyrazole-4-carboxamide. MS (M+H) m/z417.3.¹H NMR (DMSO-c/6) δ 7.36 - 7.45 (m, 6H), 7.34 - 7.49 (m, 6H), 7.29 (t, J=7.5 Hz, 2H), 7.25 - 7.34 (m, 2H), 7.17 - 7.23 (m, 1H), 7.14 - 7.24(m, 1H), 6.45 (s, 2H), 6.36 - 6.52 (m, 2H), 5.94 (d, J=4.1 Hz, 1H), 5.84 - 6.02 (m, 1H), 5.72 (d, J=4.0 Hz, 1 H), 5.64 - 5.79 (m, 1 H), 4.29 - 4.39 (m, 1 H), 4.23 - 4.43 (m, 1 H), 3.47 (dd, J=12.1,4.0 Hz, 1 H), 3.40 - 3.54 (m, 1 H), 3.25 - 3.31 (m, 1 H), 2.99 - 3.06 (m, 1 H), 2.99 (bs, 1 H), 1.88 (d, J=3.7 Hz, 1 H), 1.76 -1.86 (m, 2H), 1.74 -1.98 (m, 3H), 1.62 -1.73 (m, 1 H), 1.59 -1.74 (m, 1 H).

Example 89 5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(3-phenoxyphenyl)-1 H-pyrazole-4carboxamide

2-(Methoxy(3-phenoxyphenyl)methylene)malononitrile was prepared analogous to 4-(4-chloro-3-methylphenoxy)phenyl](methoxy)methylene)malononitrile (Example 40, step 4) from commercially available 3-phenoxy benzoic acid. The title compound was then prepared analogous to 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1H· pyrazole carboxamide (Example 1) to afford the title compound (23 mg, 28%). MS (M+H) m/z403.¹H-NMR (DMSO-c/6) δ 7.36 - 7.46 (Μ, 3H), 7.26 (d, J=7.69 Hz, 1H),

7.11 - 7.17 (m, 1H), 7.01 - 7.08 (m, 4H), 6.42 (s, 2H), 4.30-4.38 (m, 1H), 3.47 (dd, J=11.90, 3.84 Hz, 1H), 3.27 - 3.32 (m, 1H), 3.05 (td, J=12.5, 2.2 Hz, 1H), 1.74 - 2.00 (m, 4H), 1.62- 1.73 (m, 1H).

Example 90 5-amino-1 -[(3fi)-1 -cyanopiperidin-3-yl]-3-(3-phenoxyphenyl)-1 H-pyrazole-4carboxamide

127

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(3-phenoxyphenyl)-1 H-pyrazole-4carboxamide (prepared as described in Example 89) was chirally separated by supercritical fluid chromatography (ChiralPak 5 u, 21 x 250 mm, modifier 30% MeOH, flow rate 70 mL/min). Isolation of the first eluting isomer afforded the title compound as a white solid. MS (M+H): 403.¹H NMR (400 MHz, CDCI₃) δ ppm 7.32 - 7.46 (m, 3H) 7.21 - 7.27 (m, 1 H), 7.12 - 7.17 (m, 2 H), 7.00 - 7.08 (m, 3 H), 5.72 (s, 2 H), 5.31 (bs., 2 H), 4.08 - 4.21 (m, 1 H), 3.39 - 3.62 (m, 3 H), 2.98 - 3.11 (m, 1 H), 2.07 - 2.18 (m, 2 H),

1.82-1.94 (m,2H).

Example 91 '

5-amino-1 -[(3S)-1 -cyanopiperidin-3-yl]-3-(3-phenoxyphenyl)-1 H-pyrazole-4- “ carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(3-phenoxyphenyl)-1 H-pyrazole-415 carboxamide (prepared as described in Example 89) was chirally separated by supercritical fluid chromatography (ChiralPak 5 u, 21 x 250 mm, modifier 30% MeOH, flow rate 70 mL/min). Isolation of the second eluting isomer afforded the title compound as a white solid. MS (M+H) m/z 403.¹H NMR (400 MHz, CDCI3) δ ppm 7.31 - 7.46 (m, 3H), 7.21 - 7.28 (m, 1H), 7.12 - 7.18 (m, 2H), 7.00 - 7.09 (m, 3H), 5.72 (s, 2H), 5.31 (bs.,

2H), 4.09 - 4.21 (m, 1 H), 3.38 - 3.62 (m, 3H), 2.97 - 3.11 (m, 1H), 2.08 - 2.18 (m, 2H),

1.82-1.95 (m, 2H).

Example 92

5-amino-3-[3-(4-chlorobenzyl)phenyl]-1 -(1 -cyanopiperidin-3-yl)-1 H-pyrazole-4carboxamide

128

Step 1 : préparation 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. Ή NMR δ (300 MHz, DMSO-î/6): 8.05 (t, J=18.3 Hz, 2H), 7.70 (d, J= 8.7 Hz, 1H), 7.42 (t, J=17.4 Hz, 1H), 3.42 (s, 3H).

Step 2: préparation of benzyl 3-[5-amino-4-cyano-3-(3-iodophenyl)-1H-pyrazol-1yl]piperidine-1-carboxylate. Prepared analogous to benzyl 3-[5-amino-4-cyano-3-(4phenoxy-phenyl)-pyrazol-1-yl]-piperidine-1-carboxylate (Example 1, Step 9) from 2-((3iodophenyl)(methoxy)methylene)malononitrile and benzyl 3-hydrazino-piperidine-1carboxylate (Example 1, Step 8) to afford the title compound (80 g, 62%). MS (M+H) m/z 528.¹H NMR (300 MHz, DMSO-î/6) δ 8.12 (t, J=3.6 Hz, 1H), 7.75 - 7.81 (m, J=18 Hz, 2H), 7.24 - 7.29 (m, J=15 Hz, 5H), 6.85 (s, 1 H), 5.07 (bs, 2H), 4.27 (t, J=27 Hz, 1H), 3.98 (dd, J=41.7 Hz, 2H), 2.99 (t, J=21 Hz, 1H), 1.83 -1.98 (m, J=45 Hz, 3H), 1.51 (d, J=12Hz, 1H).

Step 3: préparation of benzyl 3-(5-acetamido-4-cyano-3-(3-iodophenyl)-1 Hpyrazol-1 -yl)piperidine-1 -carboxylate. Prepared analogous to 3-[5-acetylamino-4cyano-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)-1 H-pyrazol-1yl]piperidine-1-carboxylate to afford the title compound. MS (M+H) m/z 570.¹H NMR (400 MHz, DMSO-î/6) δ 8.24 (s, 1H), 7.89 (d, J=Q Hz, 1H), 7.74 (d, J=8 Hz, 1H), 7.74 (s, 5H), 7.17 (t, J=16 Hz, 1H), 5.13 (s, 2H), 4.07 - 4.27 (dd, J=84 Hz, 3H), 3.33 ( bs, 1H),

2.96 (d, J=12 Hz, 1H), 1.91 (d, 1H, J=12 Hz), 1.73 (s, 2H), 1.60 (d, J=16 Hz, 1H).

Step 4: préparation of benzyl 3-{5-acetamido-3-[3-(4-chlorobenzyl)phenyl]-4cyano-1 H-pyrazol-1 -ylJpiperidine-1 -carboxylate. To a solution of 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-dimethyoxybiphenyl (29.6 mg, 0.07 mmol), and tris(dibenzylideneacetone)dipalladium (55.8 mg, 0.061 mmol) in tetrahydrofuran (5 mL), was added a 0.5M solution of 4-chlorobenzylzinc chloride in tetrahydrofuran (8.0 mL) under nitrogen. The reaction was allowed to stir at ambient température over 16h, after which water (10 mL) was added and the desired product was extracted into dichloromethane (2x15 mL). The combined organic layers were concentrated in vacuo, then purified by silica gel column chromatography to afford the title compound as a light yellow solid (430 mg, 86%). MS (M+H) m/z 568.

129

Step 5: préparation 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-(4chlorobenzyl)phenyl]-4-cyano-1/7-pyrazol-1-yl}piperidine-1 -carboxylate (430 mg, 0.74 mmol) and sodium hydroxide (888 mg, 22.2 mmol) in 33% aqueous éthanol (6 mL) was heated to 165°C. After 50 min. solvents were removed în vacuo to afford the title compound as a white solid. MS (M+H) m/z 410.

Step 6: préparation of 5-amino-3-[2-chloro-4-(4-fluorophenoxy)phenyl]-1-(1cyanopiperidin-3-yl)-1 /£pyrazole-4-carboxamide. A solution of 5-amino-3-[3-(4chlorobenzyl)phenyl]-1-piperidin-3-yl-1/+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 température over 16h. The reaction mixture was then diluted with ethyl acetate and treated with saturated aqueous ammonium chloride. The layers were separated and the organic layer was washed with water, saturated aqueous sodium chloride, then dried over sodium sulfate, and concentrated in vacuo. The crude oil was purified by silica gel column chromatography (ethyl acetate / hexane) to afford the title compound as a light yellow solid (31 mg, 29%). MS (M+H) m/z435.¹H NMR (400 MHz, CDCh) δ ppm: 7.60 - 7.75 (m, 2H), 7.56 - 7.55 (m, 1H), 7.43 - 7.50 (m, 1H), 7.18 - 7.29 (m, 2H), 7.12 (d, J=8.28 Hz, 2H), 5.62 - 5.74 (s, 2 H), 5.20 (br. s., 2H), 4.08 - 4.20 (m, 1H), 3.98 (s, 2H), 3.96 4.02 (m, 1H), 3.36 - 3.62 (m, 4H), 3.04 (td, J=12.23, 3.89 Hz, 1H), 2.14 (dq, J=8.91, 4.56 Hz, 1H), 1.83-1.94 (m, 1H).

Example 93

5-amino-1-(1-cyanopiperidin-3-yl)-3-[3-(4-fluorobenzyl)phenyl]-1 H-pyrazole-4carboxamide

Prepared according to the procedures described for 5-amino-3-[2-chloro-4-(4fluorophenoxy)phenyl]-1 -(1 -cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 92) employing 4-fluorobenzylzinc chloride to afford the title compound. MS (M+H) m/z 418.¹H NMR (400 MHz, DMSO-d6) δ ppm 7.11 - 7.39 (m, 4H), 7.11 (t, J=8.35 Hz, 2H),

6.49 (s, 1H), 4.37 (t, J=10.40 Hz, 1H), 3.98 (s, 2H), 3.49 (d, J=8.8 Hz, 1H), 3.06 (t, </=12.1 Hz, 1H), 1.69-1.96 (m, 5H).

Example 94

130

5-Amino-1 -(1 -cyanopiperidin-3-yl)-3-(3-(4-f luorophenoxy)phenyl)-1 H-pyrazole-4carboxamide

Step 1 : préparation of benzyl 3-(5-acetamido-4-cyano-3-(3-(4fluorophenoxy)phenyl)-1 H-pyrazol-1 -yl)piperidine-1 -carboxyiate. Césium carbonate (81 mg, 250 pmol) and Cul (2.4 mg, 12.5 pmol) were added to a mixture of 4-fluorophenol (125 pmol) and benzyl 3-(5-acetamido-4-cyano-3-(3-iodophenyl)-1 H-pyrazol-1 yl)piperidine-1-carboxyiate (Example 92, step 3) (75 mg, 125 pmol) in N, Ndimethylacetamide (1 mL). A solution of 2,2,6,6-tetramethylheptane-3,5-dione (1.25 M, 100 pL) in anhydrous Λ/,/V-dimethylacetamide was added. The vial was shaken at 120°C for 16 h. The mixture was fîltered and the filtrate concentrated. The crude product was purified by préparative TLC to afford the title compound.

Step 2: préparation of 5-amino-3-(3-(4-fluorophenoxy)phenyl)-1-(piperidin-3-yl)1 /+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)-1/+pyrazol-1yl)piperidine-1-carboxyiate (125 pmol) 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 (3x1 mL). The combined organic layers were dried over magnésium sulfate, fîltered, and concentrated to afford the title compound.

Step 3: préparation of 5-amino-1-(1-cyanopiperidin-3-yl)-3-(3-(4fluorophenoxy)phenyl)-1/-/-pyrazole-4-carboxamide. 5-Amino-3-(3-(4fluorophenoxy)phenyl)-1-(piperidin-3-yl)-1 H-pyrazole-4-carboxamide (125 pmol) and K₂CO₃ (52 mg, 375 pmol) were added to a 0.5 M solution of cyanogen bromide (0.5 mL). The mixture was shaken at30°C for 16 h and then concentrated. The crude product was purified by reverse phase préparative HPLC to affoid the title compound. MS (M+H) m/z 421.

Examples 95-106

The compounds in the table below were prepared analogous to 5-amino-1-(1cyanopiperidin-3-yl)-3-(3-(4-fluorophenoxy)phenyl)-1/7-pyrazole-4-carboxamide (Example 94).

131

EX	Structure	Name	MS (M+1)
95	h2n ? FVcuî N	5-Amino-1 -(1 -cyanopiperidin-3-yl)3-{3-[4(trifluoromethoxy)phenoxy]phenyl}1 H-pyrazole-4-carboxamide	487
96	h2n r-\ >=< NHz Αχηα' N	5-amino-1-(1-cyanopiperidin-3-yl)3-[3-(3-fluoro-4methylphenoxy)phenyl]-1 Hpyrazole-4-carboxamide	435
97	H2N ? N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-[3-(2-isopropylphenoxy)phenyl]1 H-pyrazole-4-carboxamide	445
98	H2N ? r-\ >-< NHz p' ΑζΤθΧΧ N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-[3-(4-methylphenoxy)phenyl]1 H-pyrazole-4-carboxamide	417
99	h2n Z-\ >=< NHz ν'^ΎΤθΎΎ ! U Ukç, N	5-amino-3-[3-(4-chloro-3methylphenoxy)-phenyl]-1 -(1 cyanopiperidin-3-yl)-1H-pyrazole4-carboxamide	451
100	h2n r-\ >=ANH* Q-νγγθγ^ ê vur	5-amino-1 -(1 -cyanopiperidin-3-yl)3-[3-(4-isopropylphenoxy)phenyl]1 H-pyrazole-4-carboxamide	445
101	h2n ? r-\ >=< NHz pArcç	5-amino-1 -(1 -cyanopiperidin-3-yl)3-[3-(4-isopropyl-3methylphenoxy)phenyl]-1 Hpyrazole-4-carboxamide	459

132

102	h2n rviy N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-(3-(3,4- dimethylphenoxy)phenyl]-1 Hpyrazole-4-carboxamide	431
103	H2N <8 >^Anh2 cl N	5-amino-3-[3-(3-chloro-4methylphenoxy)-phenyl]-1 -(1 cyanopiperidin-3-yl)-1H-pyrazole4-carboxamide	447
104	H2N <8 N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-[3-(3-isopropyl-5methylphenoxy)phenyl]-1 Hpyrazole-4-carboxamide	459
105	H2N <8 rv-n NH2 N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-[3-(3,4-difluorophenoxy)phenyl]1 H-pyrazole-4-carboxamide	439
106	H2N N	5-amino-1 -(1 -cyanopiperidin-3-yl)3-{3-[3-fluoro-4(trifluoromethoxy)phenoxy]phenyl}- 1 H-pyrazole-4-carboxamide	505

Example 107

5-amino-1-(1-cyanopiperidin-3-yl)-3-(6-phenoxypyridin-3-yl)-1H-pyrazole-4carboxamide

Step 1: préparation of 2-((6-chloropyridin-3-yl)(methoxy)methylenemalononitrile. To a suspension of sodium hydride (454 mg, 11.4 mmol) in tetrahydrofuran (5 mL) at 0°C was added malononitrile (474 mg, 7.10 mmol) followed by a solution of 6oC

133 chloronicotinyl chloride (1.0 g, 5.7 mmol) in tetrahydrofuran (5 mL) added drop wise over five minutes, and finally, dimethyl sulfate (0.55 mL, 5.68 mmol). The reaction was allowed to stir at reflux for 3 h, then at ambient température for 18 h, after which it was quenched with saturated aqueous ammonium chloride and extracted into ethyl acetate.

The combined organic layers were washed with brine, dried over magnésium sulfate, and concentrated in vacuo to afford the title compound as an orange oil which was taken on to the next step without purification.

Step 2: préparation of benzyl 3-(5-amino-3-(6-chloropyridin-3-yl)-4-cyano-1 Hpyrazol-1 -yI)piperidine-1 -carboxylate. Prepared analogous to benzyl 3-[5-amino-410 cyano-3-(4-phenoxy-phenyl)-pyrazol-1 -y l]-piperidine-1 -carboxylate (Example 1, Step 9) by the reaction of 2-((6-chloropyridin-3-yl)(methoxy)methylenemalononitrile and 3hydrazino-piperidine-1-carboxylic acid benzyl ester (Example 1, Step 8) and 2-((6chloropyridin-3-yl)(methoxy)methylenemalononitrile at ambient température over16h with the exception of aqueous workup and purification via normal phase S1O2 column 15 chromatography to afford the title compound as a yellow solid (590 mg, 10%).

Step 3: préparation of benzyl 3-(5-amino-4-cyano-3-(6-phenoxypyridin -3-yl)-1 Hpyrazol-1-yl)piperidine-1 -carboxylate. To a solution benzyl 3-(5-amino-3-(6chloropyridin-3-yl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (590 mg, 1.35 mmol) in dimethylsulfoxide (3 mL) was added phénol (134 mg, 1.42 mmol) and potassium carbonate (280 mg, 2.02 mmol). The reaction was allowed to stir at 105°C over 72h, after which it was cooled to ambient température and partitioned between dichloromethane and water, filtered through a phase separator tube and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / heptane) to afford the title compound (260 mg, 39%).

Step 4: préparation of 5-amino-3-(6-phenoxypyridin-3-yl)-1 -(piperdin-3-yl)-1 Hpyrazole-4-carboxamide. Prepared according to the procedure described for 5-amino-

3-(4-phenoxyphenyl)-1-piperidin-3-yl-1/-Apyrazole-4-carboxylic acid amide (Example 1,

Step 11 ) from benzyl 3-(5-amino-4-cyano-3-(6-phenoxypyridin -3-yl)-1 /-Apyrazol-1 yl)piperidine-1-carboxylate to afford the title compound (150 mg, 78%).

Step 5: préparation of 5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(6-phenoxypyridin-3yl)-1 H-pyrazole-4-carboxamide. Prepared analogous to the procedures described for 5amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1 /-/-pyrazole carboxamide (Example 1, Step 12) from 5-amino-3-(6-phenoxypyridin-3-yl)-1 -(piperdin-3-yl)-1 Hpyrazole-4-carboxamide (67 mg, 0.18 mmol) to afford the title compound (3 mg, 4%).

MS (M+H) m/z 404.¹H NMR (DMSO-d6) δ 8.23 (s, 1H), 7.91 (dd, J=8.55,2.2 Hz, 1H),

134

7.42 (t, J=8.06 Hz, 2H), 7.21 (t, J=7.57 Hz, 1H), 7.15 (d, J=7.81 Hz, 2H), 7.04 (d, J=8.79 Hz, 1H), 6.37 (s, 2 H), 4.34 - 4.40 (m, 1H), 3.49 (dd, J=12.21,3.42 Hz, 1H), 3.30 - 3.38 (m, 2H), 3.03-3.10 (m, 1H), 1.91-1.97 (m, 1H), 1.83-1.90 (m, 1 H), 1.81 (bs, 1H),

1.65-1.74 (m, 1H).

Example 108

5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(1-cyanopiperidin-3-yl)-1H·

Step 1 : préparation of 4-((tert-butyldimethylsilyl)oxy)benzoic acid. To a stirred solution of 4-hydroxybenzoic acid (200 g, 1.45 mol) in N,N-dimethylformamide (3.25 L), was added imidazole (595 g, 8.67 mol) followed by addition of tert-butyl dimethylsilyl chloride (327 g, 2.17 mol) at 0 °C. The resulting reaction mixture was stirred at room température for 16 h. The reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2x2 L). The combined organic layers were washed with water (2x1 L) followed by brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography in hexanes to afford the title compound (170 g, 47 %) as white solid. ¹H NMR (400 MHz, CDCI₃): 7.96-7.98 (d, J= 8.68 Hz, 2 H), 6.86-6.88 (d, J= 8.68 Hz, 2 H), 0.98 (s, 9 H), 0.23 (s, 6 H).

Step 2: préparation of 2-((4-((tert-butyldimethylsilyl)oxy)phenyl)(methoxy)methylene)malononitrile. To a stirred suspension of sodium hydride (60%, 22.8 g, 0.95 mol) in 600 mL tetrahydrofuran, was added malononitrile (31.4 g, 0.47 mol, dissolved in 600 mL of tetrahydrofuran) at 0°C. The resulting suspension was stirred at 0 °C for 1 h. To another 3 necked round bottom flask was charged 4-((tertbutyldimethylsilyl)oxy)benzoic acid (120 g, 0.47 mol dissolved in 1200 mL of tetrahydrofuran) followed by /V-methylmorpholine (52.9 mL, 0.47 mol) and isobutylchloroformate (61.94 mL, 0.47 mol, dissolved in 600 mL tetrahydrofuran) at -30 °C. The resulting white suspension was stirred at -30 °C for 1 h. This acid chloride suspension was slowly added (through cannula) at 0 °C to the stirred suspension of NaH. The resulting suspension was stirred at room température for 3 h. Dimethyl sulfate (135.9 mL, 1.4 mol) was added to the suspension at room température and the resulting

135 φ reaction mixture was heated at reflux for 16 h. The reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2x2 L). The combined organic layers were washed with water (2 x 1 L) followed by brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the title compound (76 g, 61 %) as Iight yellow solid. MS (M+H) m/z 315.6. ¹H NMR (400 MHz, CDCI₃): 7.43 (d, J =8.68 Hz, 2 H), 6.95 (d, J =11.4 Hz, 2 H), 3.95 (s, 3 H), 0.98 (s, 9 H), 0.24 (s, 6 H).

Step 3: préparation of benzyl 3-(5-amino-3-(4-((tertbutyldimethylsilyl)oxy)phenyl)-4-cyano-1 H-pyrazol-1 -yl)piperidine-1 -carboxyiate. To a 10 stirred solution of 2-((4-((tertbutyldimethylsilyl)oxy)phenyl)(methoxy)methylene)malononitrile (76 g, 0.24 mol) in éthanol (760 mL) was added benzyl 3-hydrazinylpiperidine-1-carboxyiate (Example 1, Step 8) (68.9 g, 0.24 mol) followed by addition of triethylamine (37 mL, 0.26 mol) at room température. The resulting reaction mixture was heated to reflux for 16 h and then 15 concentrated under reduced pressure. The residue was diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with water (500 mL) followed by brine, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (102 g, 89 %) as off white solid. MS (M+H) m/z 532.¹H NMR (400 MHz, CDCI3): 7.76 (d, J = 8.48 Hz, 2 H), 7.31-7.38 (m, 5 H), 6.86 (d, J= 8.48 Hz, 2 H), 5.10-5.18 (m, 2 H), 4.44 (m, 1 H), 4.28 (m, 1 H),

4.16 (m, 1 H), 3.82 (m, 1 H), 3.2 (m, 1 H), 2.83-2.90 (t, J= 12 Hz, 1 H), 2.25 (m, 1 H), 2.09-2.12 (m, 1 H), 1.88 (m, 1 H), 0.97 (s, 9 H), 0.20 (s, 6 H).

Step 4: préparation of benzyl 3-(5-acetamido-3-(4-((tertbutyldimethylsilyl)oxy)phenyl)-4-cyano-1 H-pyrazol-1-yl)piperidine-1 -carboxyiate. To a 25 stirred solution of benzyl 3-(5-amino-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-cyano1H-pyrazol-1-yl)piperidine-1-carboxyiate (120 g, 0.19 mol) in dichloromethane (1.2 L) was added triethylamine (133 mL, 0.96 mol) followed by drop-wise addition of acetyl chloride (78.5 mL, 1.9 mol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 minutes and then at room température for 16 h. The reaction mixture was diluted with cold water (500 mL). The resulting aqueous layer was extracted with dichloromethane (2 x 500 mL). The combined organic layers were washed with water (500 mL) followed by brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (30% ethyl acetate/hexanes) to afford the title compound (100 g). MS (M+H) m/z574. ¹H

NMR (400 MHz, CDCI₃) δ 7.79 (d, J= 8.48 Hz, 2 H), 7.33 (m, 5 H), 6.88 (d, J= 8.48 Hz,

136

H), 5.11 (s, 2 H), 4.03-4.24 (m, 3 H), 3.31-3.32 (m, 2 H), 2.90 (t, J= 12 Hz, 1 H), 2.21 (m, 5 H), 1.88 (m, 1 H), 0.97 (s, 9 H), 0.20 (s, 6 H).

Step 5: préparation of benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1 Hpyrazol-1-yl)piperidine-1-carboxylate. To a stirred solution of benzyl 3-(5-acetamido-35 (4-((tert-butyldimethylsilyl)oxy)phenyl)-4-cyano-1W-pyrazol-1-yl)piperidine-1-carboxylate (165 g, 0.35 mol) in methanokwater (4:1, 2.8 L) was added LiOH«H2O (43.8 g, 1.04 mol) at 0°C. The resulting reaction mixture was stirred at 0°C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (1L) and neutralized with 1N HCl (1.8 L) to pH 6.5. The precipitated solid was filtered, washed with water (500 mL x 2) followed by hexanes and dried under vacuum. The solid was dissolved in ethyl acetate (1 L) and washed with water (2 x 500 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (104 g) as off white solid. MS (M+H) m/z460.¹H NMR (400 MHz, CDCIa): 10.48 (s, 1 H), 9.83 (s, 1 H), 7.67 (d, J= 8.48 Hz, 2 H), 7.33 (m, 5 H),

6.87 (d, J = 8.48 Hz, 2 H), 5.06 (s, 2 H), 4.23 (bs, 1 H), 4.05 (m, 1 H), 3.90 (m, 1 H), 3.00 (t, J= 11.0 Hz, 1 H), 2.17 (s, 3 H), 2.0 (m, 1 H), 1.87 (m, 1 H), 1.51 (m, 1 H).

Step 6: préparation of benzyl 3-(5-acetamido-3-{4-[(5-chloropyridin-2yl)oxy]phenyl}-4-cyano-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate. To a solution of benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1 /7-pyrazol-1 -yl)piperidine-1 20 carboxylate (500 mg, 1.20 mmol) in A/,/V-dimethylformamide (1 mL) was added 5-chloro-

2-fluoropyridine (237 mg, 1.80 mmol) and césium carbonate (1.95 g, 5.99 mmol). The 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 (3x5 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%). ¹H NMR (400 MHz, CDCI3) δ ppm 8.10 - 8.18 (m, 1H), 7.93 (d, J=8.78 Hz, 2H), 7.66 (dd, J=8.66, 2.64 Hz, 1H), 7.33 (s, 5H), 7.11 - 7.20 (m, 2H), 6.90 (d, J=8.78 Hz, 1H), 5.12 (s, 2H), 4.27 (d, J=11.04 Hz, 1H), 4.08 - 4.20 (m, 2H), 3.18 - 3.43 (m, 1H),

2.91 (t, J=11.92 Hz, 1H), 2.21 (s, 2H), 1.83-1.95 (m, 1H), 1.48-1.68 (m, 1H).

Step 7: préparation of 5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1 (piperidin-3-yl)-1 H-pyrazole-4-carboxamide. To a stirred solution of concentrated sulfuric acid (6 mL) at 0°C, was added benzyl 3-(5-acetamido-3-{4-[(5-chloropyridin-2yl)oxy]phenyl}-4-cyano-1A/-pyrazol-1-yl)piperidine-1-carboxylate (300 mg, 0.53 mmol), portion wise over 10 min. The réaction mixture was then allowed to stir at 30°C over 16 h, after which it was cooled back down to 0°C. Concentrated ammonium hydroxide was

137 carefully added to neutralize the acid to pH = 7, ensuring that the température did not exceed 5°C. The mixture was then extracted with ethyl acetate (3x5 mL), and the combined organic layers were dried over sodium sulfate, and concentrated in vacuo to afford the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ ppm: 8.19 - 8.27 (m, 1H),

7.91 - 8.02 (m, 1H), 7.48 - 7.56 (m, 2H), 7.19 - 7.22 (m, 2H), 7.16 (s, 1H), 6.32 (s, 2H), 4.03-4.16 (m, 1H), 3.31 (br. s., 1H), 3.01 (dd, <À=11.8, 3.5 Hz, 1H), 2.87 (d, <Λ=12.3 Hz, 1 H), 2.79 (dd, J=11.5,10.3 Hz, 1 H), 2.38 - 2.48 (m, 1 H), 1.81-1.96 (m, 2H), 1.71 (d, J=13.1 Hz, 1H), 1.42-1.57 (m, 1H).

Step 8: préparation of 5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide. To a solution of 5-amino-3-(4-((5chloropyridin-2-yl)oxy)phenyl)-1 -(piperidin-3-yl)-1 H-pyrazole-4-carboxamide (217 mg, 0.53 mmol) in Ν,Ν-dimethylformamide was added césium carbonate (516 mg, 1.59 mmol) and cyanogen bromide (281 mg, 2.65 mmol). The reaction was allowed to stir at ambient température for 6 h, after which water was added, and extracted into ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate / hexanes) to afford the title compound. ¹H NMR (500 MHz, DMSO-cfe) δ ppm: 8.21 (d, J=2.29 Hz, 1H), 7.96 (dd, <Λ=8.71,2.75 Hz, 1H), 7.52 (d, <Λ=8.71 Hz, 2H), 7.21 (d, <Λ=8.71 Hz, 2H),

7.13 (d, J=8.71 Hz, 1H), 6.44 (br. s., 2H), 4.26 - 4.42 (m, 1H), 3.43 - 3.52 (m, 1H), 3.25 -

3.39 (m, 2H), 2.96 - 3.11 (m, 1 H), 1.78 - 2.00 (m, 3H), 1.62 -1.77 (m, 1 H).

Example 109 (S)-5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1 -(1 -cyanopiperidin-3-yl)-1 H-

Cl rao5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}-1 -(1 -cyanopiperidin-3-yl)-1 Hpyrazole-4-carboxamide (prepared as described in Example 108) was chirally . separated by supercritical fluid chromatography (ChiralPak OD-H 30 x 250 mm column, 55% methanol, 1% isopropylamine, 80 mL/min). Isolation of the first eluting isomer afforded the title compound. ¹H NMR (500 MHz, DMSO-cfe) δ ppm: 8.21 (d, J=2.29 Hz, 1H), 7.96 (dd, <Λ=8.71, 2.75 Hz, 1H), 7.52 (d, <Λ=8.71 Hz, 2H), 7.21 (d, <À=8.71 Hz, 2H),

138

7.13 (d, </=8.71 Hz, 1H), 6.44 (br. s., 2H), 4.26 - 4.42 (m, 1H), 3.43 - 3.52 (m, 1H), 3.25 -

3.39 (m, 2H), 2.96 - 3.11 (m, 1H), 1.78 - 2.00 (m, 3H), 1.62 -1.77 (m, 1H).

Example 110 (R)-5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(1-cyanopiperidin-3-yl)-1//-

Cl rac-5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}-1-(1-cyanopiperidin-3-yl)-1/7pyrazole-4-carboxamide (prepared as described in Example 108) was chirally separated by supercritical fluid chromatography (ChiralPak OD-H 30 x 250 mm column, 55% methanol, 1% isopropylamine, 80 mL/min). Isolation of the second eluting isomer afforded the title compound. ¹H NMR (500 MHz, DMSO-cfe) δ ppm: 8.21 (d, </=2.29 Hz, 1H), 7.96 (dd, </=8.71,2.75 Hz, 1H), 7.52 (d, «/=8.71 Hz, 2H), 7.21 (d, «/=8.71 Hz, 2H),

7.13 (d, </=8.71 Hz, 1H), 6.44 (br. s., 2H), 4.26 - 4.42 (m, 1H), 3.43 - 3.52 (m, 1H), 3.25 -

3.39 (m, 2H), 2.96 - 3.11 (m, 1 H), 1.78 - 2.00 (m, 3H), 1.62 -1.77 (m, 1 H).

Example 111

5-amino-1-(1-cyanopiperidln-3-yl)-3-{4-[(5-fluoropyridin-2-yl)oxy]phenyl}-1AA

Prepared analogous to 5-amino-3-(4-[(5-chloropyridin-2-yl)oxy]phenyl}-1 -(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 108) employing 2,5difluoropyridine. ¹H NMR (500 MHz, DMSO-d₆) δ ppm: 8.16 (d, «/=3.21 Hz, 1H), 7.82 (td, J=8.48, 3.21 Hz, 1H), 7.51 (d, </=8.71 Hz, 2H), 7.10 - 7.21 (m, 3H), 6.44 (s, 1H), 4.28 -

4.44 (m, 1H), 3.49 (dd, «/=11.91,4.12 Hz, 1H), 3.28 - 3.41 (m, 2H), 3.05 (td, «/=12.49,

2.52 Hz, 1 H), 1.80 - 2.03 (m, 3H), 1.61-1.77 (m, 1 H).

Example 112 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((5-methylpyridin-2-yl)oxy)phenyl)-1AA pyrazole-4-carboxamide

139

Prepared analogous to 5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 108) employing 4-methyl-2fluoropyridine. ¹H NMR (500 MHz, DMSO-ofe) δ ppm 8.00 (s, 1 H), 7.65 - 7.77 (m, 1H), 5 7.49 (d, J=8.25 Hz, 2H), 7.14 (d, J=8.71 Hz, 2H), 6.98 (d, J=8.25 Hz, 1H), 6.45 (s, 2H),

4.30 - 4.42 (m, 1H), 3.48 (d, J=4.12 Hz, 1H), 3.29 - 3.39 (m, 2H), 3.06 (td, J=12.49, 2.52 Hz, 1 H), 2.25 (s, 3H), 1.78 - 2.01 (m, 3H), 1.64 -1.77 (m, 1 H).

Example 113 (S)-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-(4-((5-methylpyridin-2-yl)oxy)phenyl)-1 H10 pyrazole-4-carboxamide

rao-5-amino-1 -(1 -cyanopiperidin-3-yl)-3-{4-[(5-methylpyridin-2-yl)oxy]phenyl}-1 Hpyrazole-4-carboxamide (prepared as described in Example 112) was chirally separated by supercritical fluid chromatography (ChiralPak OD-H 46 x 250 mm column, 15 45% methanol, 1% isopropylamine, 4 mL/min). Isolation of the first eluting isomer afforded the title compound. ¹H NMR (500 MHz, DMSO-cfe) δ ppm 8.00 (s, 1 H), 7.65 -

7.77 (m, 1H), 7.49 (d, J=8.25 Hz, 2H), 7.14 (d, J=8.71 Hz, 2H), 6.98 (d, J=8.25 Hz, 1H),

6.45 (s, 2H), 4.30 - 4.42 (m, 1H), 3.48 (d, J=4.12 Hz, 1H), 3.29 - 3.39 (m, 2H), 3.06 (td, J=12.49, 2.52 Hz, 1H), 2.25 (s, 3H), 1.78 - 2.01 (m, 3H), 1.64-1.77 (m, 1H).

Example 114 (fî)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((5-methylpyridin-2-yl)oxy)phenyl)-1#·

rao-5-amino-1-(1-cyanopiperidin-3-yl)-3-{4-[(5-methylpyridin-2-yl)oxy]phenyl}-1H25 pyrazole-4-carboxamide (prepared as described in Example 112) was chirally

140 separated by supercritical fluid chromatography (ChiralPak OD-H 46 x 250 mm coiumn, 45% methanol, 1% isopropylamine, 4 mL/min). Isolation ofthe second eiuting isomer afforded the title compound. Ή NMR (500 MHz, DMSO-cfe) δ ppm 8.00 (s, 1 H), 7.65 -

7.77 (m, 1H), 7.49 (d, J=8.25 Hz, 2H), 7.14 (d, J=8.71 Hz, 2H), 6.98 (d, J=8.25 Hz, 1H),

6.45 (s, 2H), 4.30 - 4.42 (m, 1H), 3.48 (d, J=4.12 Hz, 1H), 3.29 - 3.39 (m, 2H), 3.06 (td, J=12.49, 2.52 Hz, 1H), 2.25 (s, 3H), 1.78 - 2.01 (m, 3H), 1.64 -1.77 (m, 1H).

Example 115

5-amino-1-(1-cyanopiperidin-3-yl)-3-{4-[(3, 5-difluoropyridin-2-yl)oxy]phenyl}-1Hpyrazole-4-carboxamide

Prepared analogous to 5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 108) employing 2,3,5trifluoropyridine. ¹H NMR (500 MHz, DMSO-cfe) δ ppm 8.15 (ddd, J=10.3, 8.0, 2.7 Hz, 1 H), 8.09 (d, J=2.7 Hz, 1 H), 7.54 (d, J=8.7 Hz, 2 H), 7.24 (d, J=8.7 Hz, 2 H), 6.45 (s, 2 H), 4.34 - 4.42 (m, 1 H), 3.51 (dd, J=12.4, 4.1 Hz, 1 H), 3.31 - 3.39 (m, 2 H), 3.07 (td, J=12.5, 2.5 Hz, 1 H), 1.81 - 2.00 (m, 3 H), 1.67 -1.76 (m, 1 H).

Example 116 (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((6-(trifluoromethyl)pyridin-2yl)oxy)phenyl)-1 H-pyrazole-4-carboxamide

Step 1 : préparation of (fi)-benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)1 H-pyrazol-1-yl)piperidine-1-carboxylate. (rac)-benzyl 3-(5-acetamido-4-cyano-3-(4hydroxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (prepared as described in Example 108) was chirally separated by supercritical fluid chromatography (ChiralPak AS-H 50 x 250 mm coiumn, 25% methanol, 250 mL/min). Isolation of the first eiuting isomer afforded the title compound. MS (M+H) m/z 460.¹H NMR (400 MHz, CDCI₃): 10.48 (s, 1 H), 9.83 (s, 1 H), 7.67 (d, J = 8.48 Hz, 2 H), 7.33 (m, 5 H), 6.87 (d, J= 8.48

141

Hz, 2 H), 5.06 (s, 2 H), 4.23 (bs, 1 H), 4.05 (m, 1 H), 3.90 (m, 1 H), 3.00 (t, J = 11.0 Hz, 1 H), 2.17 (s, 3 H), 2.0 (m, 1 H), 1.87 (m, 1 H), 1.51 (m, 1 H).

Step 2: préparation of (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((6(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-pyrazole-4-carboxamide. Prepared analogous to 5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}-1 -(1 -cyanopiperidin-3-yl)1 H-pyrazole-4-carboxamide (Example 108) employing (R)-benzyl 3-(5-acetamido-4cyano-3-(4-hydroxyphenyl)-1 H-pyrazol-1-yl)piperidine-1 -carboxylate and 2-chloro-6(trifluoromethyl)pyridine. MS (M+H) m/z472.¹H NMR (500 MHz, DMSO-cfe) δ ppm 8.09 (t, J=7.90 Hz, 1 H), 7.61 (d, J=7.33 Hz, 1 H), 7.52 (d, J=8.48 Hz, 2 H), 7.32 (d, J=8.25 Hz, 1 H), 7.23 (d, J=8.48 Hz, 2 H), 6.41 (s, 2 H), 4.30 - 4.39 (m, 1 H), 3.46 (dd, J=12.03,

3.78 Hz, 1 H), 3.28 - 3.37 (m, 2 H), 3.03 (td, J=12.50,2.50 Hz, 1 H), 1.60 -1.98 (m, 4 H).

Example 117 (S)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((6-(trifluoromethyl)pyridin-2yl)oxy)phenyl)-1H-pyrazole-4-carboxamide

Step 1 : préparation of (S)-benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)1 H-pyrazol-1 -yl)piperidine-1 -carboxylate. (rac)-benzyl 3-(5-acetamido-4-cyano-3-(4hydroxyphenyl)-1 H-pyrazol-1-yl)piperidine-1-carboxylate (prepared as described in Example 108) was chirally separated by supercritical fluid chromatography (ChiralPak AS-H 50 x 250 mm column, 25% methanol, 250 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z460.¹H NMR (400 MHz, CDCI₃): 10.48 (s, 1 H), 9.83 (s, 1 H), 7.67 (d, J= 8.48 Hz, 2 H), 7.33 (m, 5 H), 6.87 (d, J = 8.48 Hz, 2 H), 5.06 (s, 2 H), 4.23 (bs, 1 H), 4.05 (m, 1 H), 3.90 (m, 1 H), 3.00 (t, J= 11.0 Hz, 1 H), 2.17 (s, 3 H), 2.0 (m, 1 H), 1.87 (m, 1 H), 1.51 (m, 1 H).

Step 2: préparation of (S)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((6(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-pyrazole-4-carboxamide. Prepared analogous to 5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}-1-(1-cyanopiperidin-3-yl)1 H-pyrazole-4-carboxamide (Example 108) employing (S)-benzyl 3-(5-acetamido-4cyano-3-(4-hydroxyphenyl)-1 H-pyrazol-1-yl)piperidine-1-carboxylate and 2-chloro-6(trifluoromethyl)pyridine. MS (M+H) m/z472.¹H NMR (500 MHz, DMSO-cfe) δ ppm 8.09

142 (t, J=7.90 Hz, 1 H), 7.61 (d, J=7.33 Hz, 1 H), 7.52 (d, J=8.48 Hz, 2 H), 7.32 (d, J=8.25 Hz, 1 H), 7.23 (d, J=8.48 Hz, 2 H), 6.41 (s, 2 H), 4.30 - 4.39 (m, 1 H), 3.46 (dd, J=12.03,

3.78 Hz, 1 H), 3.28 - 3.37 (m, 2 H), 3.03 (td, J=12.50, 2.50 Hz, 1 H), 1.60 -1.98 (m, 4 H).

Example 118 (R)-5-amino-3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1-(1-cyanopiperidin-3yl)-1 H-pyrazole-4-carboxamide

N

Prepared analogous to (fi)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((6(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1 H-pyrazole-4-carboxamide (Example 116) employing 5-chloro-2,3-difluoropyridine. MS (M+H) m/z 456.¹H NMR (400 MHz, DMSOd₆) δ ppm 8.24 (dd, J=9.76,1.76 Hz, 1 H), 8.08 (d, J=1.76 Hz, 1 H), 7.54 (d, J=8.39 Hz, 2 H), 7.27 (d, J=8.39 Hz, 2 H), 6.44 (s, 2 H), 4.32 - 4.44 (m, 1 H), 3.50 (dd, J=11.81,

3.41 Hz, 1 H), 3.34 - 3.39 (m, 2 H), 3.07 (t, J=11.51 Hz, 1 H), 1.67 - 2.02 (m, 4 H).

Example 119 (S)-5-amino-3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1-(1-cyanopiperidin-3yl)-1 H-pyrazole-4-carboxamide

Prepared analogous to (S)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-((6(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-pyrazole-4-carboxamide (Example 117) employing 5-chloro-2,3-difluoropyridine. MS (M+H) m/z456.¹H NMR (400 MHz, DMSOd₆) δ ppm 8.24 (dd, J=9.76, 1.76 Hz, 1 H), 8.08 (d, J=1.76 Hz, 1 H), 7.54 (d, J=8.39 Hz, 2 H), 7.27 (d, J=8.39 Hz, 2 H), 6.44 (s, 2 H), 4.32 - 4.44 (m, 1 H), 3.50 (dd, J=11.81,

3.41 Hz, 1 H), 3.34 - 3.39 (m, 2 H), 3.07 (t, J=11.51 Hz, 1 H), 1.67 - 2.02 (m, 4 H). Example 120

5-amino-3-[2-chloro-4-(4-fluorophenoxy)phenyl]-1 -(1 -cyanopiperidin-3-yl)-1 Hpyrazole-4-carboxamide

143

Step 1 : préparation of 1-bromo-2-chloro-4-(4-fluorophenoxy)benzene. To a mixture of 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), and 1.5 g activated 4Â molecular sieves in 5 anhydrous dichloromethane (80 mL) at 0° C was added (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 température 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%). MS (M+H) m/z 302.

Step 2: préparation of 2-[2-chloro-4-(4-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-

1,3,2-dioxaborolane. A mixture of 1-bromo-2-chloro-4-(4-fluorophenoxy)benzene (600 mg, 1.99 mmol), bis(pinacolato)diboron (664 mg, 2.59 mmol), potassium acetate (684 mg, 6.96), and 1,r-bis-(diphenylphosino)-ferrocene)palladium dichloride (107 mg, 0.139 mmol) in anhydrous 1,4 dioxane (30 mL) was allowed to stir at 80°C under nitrogen over

16h, after which it was cooled to ambient température and filtered. The filtrate was then concentrated in vacuo and purified by silica gel column chromatography to afford the title compound as a light yellow solid (0.18 g, 26%). MS (M+H) m/z349.¹H NMR (400 MHz, CDCIa) δ ppm: 7.67 (d, J=8.34 Hz, 1H) 6.96 - 7.10 (m, 4H) 6.92 (d, J=2.53 Hz, 1H) 6.81 (dd, J=8.34, 2.27 Hz, 1H) 1.36 (s, 12H).

Step 3: préparation of ethyl 5-acetamido-1 H-pyrazole-4-carboxylate. A mixture of ethyl 5-amino-1H-pyrazole-4-carboxylate (100 g, 0.65 mol) and acetyl chloride (441.2 g, 5.62 mol) at 0°C was heated to reflux for 4h. The reaction was concentrated in vacuo to remove excess acetyl chloride. Water (1.0 L) was added and the mixture was stirred for 16 h, after which it was filtered to afford the title compound as an off white solid (120 g, 94%). MS (M+H) m/z 198.¹H NMR (400 MHz, CDCIa) δ ppm: 9.57(1 H, s), 7.75 (1H, s), 4.33-4.28 (2H, q, J= 7.08), 2.27 (3H, s), 1.37-1.34 (3H, s).

Step 4: préparation of ethyl 5-acetamido-3-bromo-1H-pyrazole-4-carboxylate. To a solution of ethyl 5-acetamido-1/-/-pyrazole-4-carboxylate (120 g, 0.61 mol) in éthanol (2.5 L) was added 4.0 L of aqueous sodium acetate (484 g, 5.91 mol), followed by drop 3o wise addition of bromine (565 g, 3.53 mol). The reaction was allowed to stir at ambient température for 3h, after which it was judged complété by TLC. The reaction was poured in water (6.8 L), and desired product was extracted into ethyl acetate (3 x 5.0 L).

144

The combined organic layers were washed with saturated aqueous sodium thiosulfate (2 x 1.5 L), dried over sodium sulfate and concentrated in vacuo. The resulting crude solid was washed with hexanes (500 mL) to afford the title compound as an off-white solid (105 g, 62.5 %). MS (M+H) m/z 278.¹H NMR (400 MHz, CDCI₃) δ ppm: 11.8 (s,

1H), 9.75 (s, 1H), 4.38-4.32 (q, J= 7.04, 2H), 2.27 (s, 3H), 1.42-1.38 (t, J= 7.04, 3H).

Step 5: préparation of tert-butyi 3-[5-acetamido-3-bromo-4-(ethoxycarbonyl)-1 Hpyrazol-1 -yl]piperidine-1 -carboxyiate. To a solution of ethyl 5-acetamido-3-bromo-1 Hpyrazole-4-carboxylate (500 mg, 1.81 mmol), triphenyl phosphine (582 mg, 2.17 mmol), and tert-butyi 3-hydroxypiperidine-1-carboxyiate (547 mg, 2.72 mmol, 1.5 equiv) in diethyl ether (5 mL) was added diisopropyl diazene-1,2-dicarboxylate (476 mg, 2.17 mmol). The reaction was then heated to 80°C for 4h, after which it was allowed to cool to ambient température and treated with saturated aqueous ammonium chloride solution. The organic layer was separated, washed with water, brine, then dried over sodium sulfate, and concentrated in vacuo. The resulting crude oil was purified by reversed phase HPLC, to afford the title compound as a light yellow solid (0.12 g, 15%). MS (M+H) m/z 459.

Step 6: préparation of tert-butyi 3-{5-acetamido-3-[2-chloro-4-(4fluorophenoxy)phenyl]-4-(ethoxycarbonyl)-1 H-pyrazol-1 -yl}piperidine-1 -carboxyiate. A solution of tert-butyi 3-[5-acetamido-3-bromo-4-(ethoxycarbonyl)-1/+pyrazol-120 yl]piperidine-1-carboxyiate (130 mg, 2.48 mmol), 2-[2-chloro-4-(4fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (98.7 mg, 0.283 mmol), sodium carbonate (60 mg, 0.566 mmol), and (1,T-bis-(diphenylphosphino)ferrocene)palladium dichloride (15.4 mg, 0.02 mmol) in a N,N-dimethylformamide (8 mL) / water (2 mL) / dioxane (16 mL) was heated to 80°C for 1 h under microwave conditions, after which it was poured into ethyl acetate and treated with saturated aqueous ammonium chloride. The organic layer was separated and washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The resulting crude oil was purified by silica gel column chromatography to afford the title compound as a light yellow solid (0.16 g, 53%). MS (M+H) m/z601.

Step 7: préparation of 5-acetamido-1 -(1 -(tert-butoxycarbonyl)piperidin-3-yl)-3-(2chloro-4-(4-fluorophenoxy)phenyl)-1A/-pyrazole-4-carboxylic acid. A solution of tertbutyi 3-{5-acetamido-3-[2-chloro-4-(4-fluorophenoxy)phenyl]-4-(ethoxycarbonyl)-1/7pyrazol-1-yl}piperidine-1-carboxyiate (110 mg, 0.18 mmol) and lithium hydroxide (268 mg, 11.0 mmol) in 50% methanolic tetrahydrofuran (8 mL) was allowed to stir at 95°C over 16h, after which it was concentrated in vacuo to a volume of 0.1 mL. Water (3 mL)

145 was added, and the mixture was cooled 0°C and acidified to pH = 3 with 1N hydrochloric acid. The resulting white precipitate was collected by vacuum filtration to afford the title compound (97 mg, >99%). MS (M+H) m/z 531.

Step 8: préparation of tert-butyl 3-{5-amino-4-carbamoyl-3-[2-chloro-4-(45 fluorophenoxy)phenyl]-1 H-pyrazol-1-yl}piperidine-1-carboxylate. To a solution of 5acetamido-1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-3-(2-chloro-4-(4-fluorophenoxy)phenyl)-1/^pyrazole-4-carboxylic acid (100 mg, 0.18 mmol), 1hydroxylbenzotriazole (38.5 mg, 0.282 mmol), 3-(dimethylamino)propyl carbodiimide hydrochloride (54.6 mg, 0.282 mmol), N,N-dimethylformamide (5 mL), was added a

0.5N solution of ammonia in 1,4-dioxane (3.76 mL, 1.88 mmol). The reaction was allowed to stir at ambient température over 16 h, after which it was concentrated in vacuo. Water (10 mL) was added, and the resulting white precipitate was collected by vacuum filtration to afford the title compound (100 mg, >99%). MS (M+H) m/z 530.

Step 9: préparation of 5-amino-3-[2-chloro-4-(4-fluorophenoxy)phenyl]-1-(115 cyanopiperidin-3-yl)-1 /7-pyrazole-4-carboxamide. To a solution of tert-butyl 3-{5-amino-

4- carbamoyl-3-[2-chloro-4-(4-fluorophenoxy)phenyl]-1 H-pyrazol-1 -yljpiperidin e-1 carboxylate (100 mg, 0.18 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction was allowed to stir at ambient température for 2h after which it was concentrated in vacuo to afford the title compound (78 mg, >99%). MS (M+H) m/z

430.

Step 10: préparation of 5-amino-3-[2-chloro-4-(4-fluorophenoxy)phenyl]-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide. Prepared analogous to the procedure described for 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1 H-pyrazole carboxamide (Example 1, Step 12) at ambient température and purified by reversed phase HPLC to afford the title compound as a light yellow solid (64 mg, 57%). MS (M+H) m/z 455.¹H NMR (400 MHz, CDCI₃) δ ppm 7.36 (d, J=8.59 Hz, 1H), 6.99 - 7.14 (m, 5H), 6.94 (dd, J=8.46, 2.40 Hz, 1H), 5.56 (s, 2H), 5.02 (s, 2H), 4.11-4.12 (m, 1H), 3.58 (d, J=4.55 Hz, 1H), 3.39 - 3.54 (m, 2H), 3.04-3.05 (m, 1 H), 2.06 - 2.21 (m, 2H), 1.92-1.93 (m, 2H).

Example 121

5- amino-1 -[(3R*,6S*)-1 -cyano-6-methylpiperidin-3-yl]-3-[4-(2,4difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide

146

Step 1 : préparation of 6-methylpiperidin-3-ol. To a solution of 6-methylpyridin-3ol (8.54 g, 77 mmol) in acetic acid (100 mL) was added platinum oxide (1.68 g, 7.4 mmol). The mixture was placed in a Parr apparatus under hydrogen pressure (50 psi) 5 and shaken for 16 h. The solvent was removed in vacuo to afford the title compound.

Step 2: préparation of benzyl 5-hydroxy-2-methylpiperidine-1 -carboxylate. To a solution of 6-methylpiperidin-3-ol (9.0 g, 78.1 mmol) in dichloromethane (100 mL) was added drop wise triethylamine (101 mL, 703 mmol), followed by benzyl chloroformate (14 mL, 93.8 mmol). The reaction was allowed to stir over 16h, after which it was 10 concentrated in vacuo, and the resulting residue purified by silica gel column chromatography to afford the title compound as colorless oil (8.1g 42%).

Step 3: préparation of benzyl 2-methyl-5-oxopiperidine-1 -carboxylate. To a solution of benzyl 5-hydroxy-2-methylpiperidine-1 -carboxylate (0.986 g, 3.96 mmol) in dichloromethane (10 mL) at 0°C was added Dess Martin reagent (3.96 mmol). The 15 reaction mixture was allowed to stir at 0°C for 30 min, then warmed to ambient température and allowed to stir for an additional 3 h. The reaction mixture was then carefully quenched with saturated aqueous sodium thiosulfate, and diluted with both water and dichloromethane. The organic layer was separated and washed with brine, water, then dried over sodium sulfate and concentrated in vacuo to afford the title 20 compound which was taken on to the next step without purification.

Step 4: préparation of benzyl 5-[(tert-butoxycarbonyl)hydrazono]-2methylpiperidine-1 -carboxylate. To a solution benzyl 2-methyl-5-oxopiperidine-1carboxylate (2.00 g, 8.09 mmol) in tetrahydrofuran (10 mL) was added tert-butyl hydrazinecarboxylate (1.25 g, 9.71 mmol). The reaction mixture was heated to reflux for 25 2.5 h, after which it was cooled to ambient température and concentrated in vacuo to afford the title compound as a white solid. MS (M+H) m/z 418.

Step 5: préparation of benzyl 5-[2-(tert-butoxycarbonyl)hydrazino]-2methylpiperidine-1 -carboxylate. To a solution benzyl 5-[(tertbutoxycarbonyl)hydrazono]-2-methylpiperidine-1-carboxylate (1.53 g, 4.23 mmol) in 30 tetrahydrofuran (10 mL) was added sodium cyanoborohydride (0.27 g, 4.23 mmol) was added drop wise a solution of para-toluenesulfonic acid monohydrate (0.80 g, 4.23

147 mmol) in tetrahydrofuran (2 mL). The reaction was allowed to stir at ambient température over 16 h, after which it was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate,

1N sodium hydroxide, brine and water, then dried over sodium sulfate and concentrated in vacuo to afford the title compound.

Step 6: préparation of benzyl 5-hydrazino-2-methylpiperidine-1-carboxylate. To a solution of benzyl 5-[2-(tert-butoxycarbonyl)hydrazino]-2-methylpiperidine-1-carboxylate (1.78 g, 4.9 mmol) in dichloromethane (10 mL) was added drop wise trifluoroacetic acid (5 mL). The reaction was allowed to stir at ambient température for 5 h, after which it 10 was concentrated in vacuo to afford the title compound as a pale yellow solid.

Step 7: préparation of (2S*,5R*)-benzyl 5-(5-amino-4-cyano-3-(4-(2,4difluorophenoxy)phenyl)-1 H-pyrazol-1-yl)-2-methylpiperidine-1 -carboxylate. To a solution of benzyl 5-hydrazino-2-methylpiperidine-1-carboxylate (1.71 g, 6.5 mmol) in anhydrous éthanol (30 mL) was added 2-((4-(2,4-difluorophenoxy)phenyl)(methoxy)15 methylene)malononitrile (Example 25, Step 4) (2.03 g, 6.5 mmol) and triethyl amine (4.66 mL, 32.4 mmol). The solution was stirred at ambient température over 16 h. Solvent was removed in vacuo and the crude product was purified by préparative HPLC to afford the title compound (2.12 g, 60%) as a white product. MS (M+H) m/z544.¹H NMR (400 MHz, CDCI₃) δ ppm 7.83 - 7.89 (m, 2 H), 7.30 - 7.41 (m, 5 H), 7.09 (td,

J=9.0, 5.4 Hz, 1 H), 6.93 - 7.01 (m, 3 H), 6.83 - 6.91 (m, 1 H), 5.11 - 5.20 (m, 2 H), 4.50 - 4.61 (m, 1 H), 4.39 (br. s., 2 H), 4.13 - 4.25 (m, 1 H), 3.82 (br. s., 1 H), 3.35 (t, J=11.7 Hz, 1 H), 2.36 - 2.49 (m, 1 H), 1.70 -1.95 (m, 4 H), 1.29 (d, J=7.1 Hz, 3 H)

Step 8: préparation of 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-((3S*,6R*)-6methylpiperidin-3-yl)-1H-pyrazole-4-carboxamide. To a stirred solution of concentrated 25 sulfuric acid (3 mL) at 0°C, was added (2S*,5R*)-benzyl 5-(5-amino-4-cyano-3-(4-(2,4difluorophenoxy)phenyl)-1 H-pyrazol-1-yl)-2-methylpiperidine-1-carboxylate (450 mg, 0.77 mmol), portion wise over 10 min. The reaction mixture was then allowed to stir at 30°C over 16 h, after which it was cooied to 0°C. Concentrated ammonium hydroxide was carefully added to pH = 7, ensuring that the température did not exceed 5°C. The 30 mixture was then extracted with ethyl acetate (3x10 mL), and the combined organic layers were dried over sodium sulfate, and concentrated in vacuole afford the title compound.

Step 9: préparation of 5-amino-1-[(3fî*,6S*)-1-cyano-6-methylpiperidin-3-yl]-3-[4(2,4-difluorophenoxy)phenyl]-1 H-pyrazole-4-carboxamide. To a solution of 5-amino-335 (4-(2,4-difluorophenoxy)phenyl)-1 -((3S*,6fî*)-6-methylpiperidin-3-yl)-1 H-pyrazole-4-

148 carboxamide (398 mg, 0.93 mmol) in N,N-dimethylformamide (8 mL) was added césium carbonate (911 mg, 2.77 mmol) and cyanogen bromide (586 mg, 5.54 mmol). The reaction was allowed to stir at ambient température for 6h, after which water was added, and the desired product was extracted into ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified via normal phase S1O2 column chromatography (ethyl acetate / hexanes) to afford the title compound as a white solid. MS (M+H) m/z453.¹H NMR (500 MHz, DMSO-cfe) δ ppm: 1.25 (d, J=6.9 Hz, 8 H), 1.77 -1.87 (m, 7 H), 2.04 - 2.14 (m, 2 H), 2.51 (s, 1 H), 3.36 (d, J=4.6 Hz, 2 H), 3.39 (d, J=4.6 Hz, 2 H), 3.47 - 3.57 (m, 5 H), 4.35 (ddd, J=8.4, 4.4, 4.2 Hz, 2 H),

6.43 (s, 5 H), 7.03 (d, J=8.71 Hz, 5 H), 7.11 - 7.21 (m, 2 H), 7.36 (td, J=9.2, 5.5 Hz, 2 H), 7.46 - 7.56 (m, 3 H), 7.52 (d, J=8.7 Hz, 5 H).

Example 122 5-amino-1-[(3fî,6S)-1-cyano-6-methylpiperidin-3-yl]-3-[4-(2,4difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide

rao-5-amino-1-[(3R*,6S*)-1-cyano-6-methylpiperidin-3-yl]-3-[4-(2,4difluorophenoxy)phenyl]-1 H-pyrazole-4-carboxamide (prepared as described in Example 121) was chirally separated by supercritical fluid chromatography (RegisPack 30 x 250 mm col, 23% EtOH, 80 mL/min). Isolation of the first eluting isomer afforded the title compound. MS (M+H) m/z453.¹H NMR (500 MHz, DMSO-cfe) δ ppm: 1.25 (d, J=6.9 Hz, 8 H), 1.77 -1.87 (m, 7 H), 2.04 - 2.14 (m, 2 H), 2.51 (s, 1 H), 3.36 (d, J=4.6 Hz, 2 H), 3.39 (d, J=4.6 Hz, 2 H), 3.47 - 3.57 (m, 5 H), 4.35 (ddd, J=8.4,4.4, 4.2 Hz, 2 H), 6.43 (s, 5 H), 7.03 (d, J=8.7 Hz, 5 H), 7.11 - 7.21 (m, 2 H), 7.36 (td, J=9.2, 5.5 Hz, 2 H), 7.46 - 7.56 (m, 3 H), 7.52 (d, J=8.7 Hz, 5 H).

Example 123 5-amino-1-[(3S,6R)-1-cyano-6-methylpiperidin-3-yl]-3-[4-(2,4difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide

N

F

149 rao-5-amino-1-[(3R*,6S*)-1-cyano-6-methylpiperidin-3-yl]-3-[4-(2,4difluorophenoxy)phenyl]-1 /7-pyrazole-4-carboxamide (prepared as described in

Example 121) was chirally separated by supercritical fluid chromatography (RegisPack 30 x 250 mm col, 23% EtOH, 80 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z453.¹H NMR (500 MHz, DMSO-ofe) δ ppm:

1.25 (d, J=6.9 Hz, 8 H), 1.77 -1.87 (m, 7 H), 2.04 - 2.14 (m, 2 H), 2.51 (s, 1 H), 3.36 (d, J=4.6 Hz, 2 H), 3.39 (d, J=4.6 Hz, 2 H), 3.47 - 3.57 (m, 5 H), 4.35 (ddd, J=8.4, 4.4, 4.2 Hz, 2 H), 6.43 (s, 5 H), 7.03 (d, J=8.7 Hz, 5 H), 7.11 - 7.21 (m, 2 H), 7.36 (td, J=9.2, 5.5 Hz, 2 H), 7.46 - 7.56 (m, 3 H), 7.52 (d, J=8.7 Hz, 5 H).

Example 124

5-amino-3-{4-[(4-chlorophenyl)thio]phenyl}-1 -(1 -cyanopiperidin-3-yl)-1 H-pyrazole-

4-carboxamide

Cl

Step 1 : préparation of benzyl 3-(5-acetamido-3-(4-((4-chlorophenyl)thio)phenyl)-

4-cyano-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate. A glass tube was charged with potassium carbonate (267 mg, 1.93 mmol, 1.1 eq) followed by the addition of 3-[5acetylamino-4-cyano-3-(4-iodophenyl)-pyrazol-1 -yl]-piperidine-1 -carboxylic acid benzyl ester (100 mg, 1.76 mmol, 1.0 eq) (Example 86, Step 1), 4-chlorothiophenol (330 mg, 2.28 mmol, 1.3 eq), copper iodide (191 mg, 1 mmol, 0.57 eq) and N-methylpyrrolidine (0.4 ml). The glass tube was closed and placed under stirring in a preheated 100 °C oil bath for 6-8 hr. The reaction mixture was diluted with water and was then extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography (heptane/ethyl acetate) to afford the title compound.

Step 2: préparation of 5-amino-3-(4-((4-chlorophenyl)thio)phenyl)-1-(piperidin-3yl)-1 H-pyrazole-4-carbonitrile. Benzyl 3-(5-acetamido-3-(4-((4chlorophenyl)thio)phenyl)-4-cyano-1 H-pyrazol-1-yl)piperidine-1 -carboxylate (96 mg) was added portion-wise over 10 min to a stirred solution of concentrated sulfuric acid while maintaining the température at 0°C and then stirred at 30 °C for 18 hr. The reaction mixture was cooled to 0°C and neutralized by the addition of ammonium hydroxide solution maintaining the température below 20°C. The mixture was extracted

150 with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound.

Step 3: préparation of 5-amino-3-{4-[(4-chlorophenyl)thio]phenyl}-1-(1cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1 H-pyrazole carboxamide (Example 1, Step 12) employing 5-amino-3-(4-((4-chlorophenyl)thio)phenyl)-1-(piperidin-3-yl)-1/7-pyrazole-4-carbonitrile. MS (M+H) m/z 453.

Example 125

5-amino-1-(1-cyanopiperidin-3-yl)-3-[4-(phenylthio)phenyl]-1H-pyrazole-4carboxamide

The title compound was prepared analogous to 5-amino-3-{4-[(4chlorophenyl)thio]phenyl}-1 -(1 -cyanopiperidin-3-yl)-1 H-pyrazole-4-carboxamide (Example 124) employing thiophenol. MS (M+H) m/z419.

Example 126

-[(3 S)-1 -acryloylpiperidin-3-yl]-5-amino-3-(4-phenoxyphenyl)-1 H-pyrazole-4carboxamide

Step 1 : préparation 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 16h, 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: préparation 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. The reaction was then

151 allowed to stir for 16 h at ambient température, cooled to 0°C and quenched with 1N hydrochloric acid (1L). Product was extracted into ethyl acetate and the combined organic layers were washed with water, then brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as an off-white solid, which was carried on to the next step without purification. MS (M-H) m/z261.¹H NMR (CDCI3) δ

7.74 (d, J= 8.8 Hz, 2 H), 7.39 (t, J= 7.6 Hz, 2 H), 7.21 (t, J= 7.2 Hz, 1 H), 7.06 (d, J= 8 Hz, 2 H), 7.00 (d, J= 8.8 Hz, 2 H).

Step 3: préparation of 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile

To a solution of 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 2h, after which the reaction was warmed to 80°C and allowed to stir for an additional 12h. The reaction was cooled to ambient température, diluted with 15 water and extracted into ethyl acetate. The combined organic layers were washed with water, then brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to afford the title compound as an off white solid (300 g, 48%). MS (M+H) m/z211. ¹H NMR (CDCI₃) δ 7.47 (d, J = 8.8 Hz, 2 H), 7.42 (t, J= 7.6 Hz, 2 H), 7.23 (t, J= 7.6 Hz, 1 H), 7.07 (t, J= 8.8 Hz, 4 H), 20 3.97 (s, 3 H).

Step 4: préparation of 3-Hydroxy-piperidine-1-carboxylic acid benzyl ester. To a suspension of piperidin-3-ol hydrochloride (134 g, 0.974 mol) and triethylamine (276 mL, 1.98 mol) in dichloromethane (2 L) at 0 °C was added a solution of benzyl chloroformate (140 mL, 0.981 mol) in dichloromethane (100 mL) drop wise over 2.5 h.

The reaction was allowed to stir for an additional 30 min at 0 °C, then allowed to warm to ambient température over 16 h, after which it was quenched with 1N hydrochloric acid (3 L) and allowed to stir for 30 min. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to afford the title compound (218 g, 95 %).

¹H-NMR (CDCI3) δ 7.29-7.41 (m, 5 H), 5.14 (s, 2 H), 3.59-3.85 (m, 3 H), 3.13-3.27 (m, 2 30 H), 2.18 (bs, 1 H), 1.74-1.94 (m, 2 H), 1.38-1.61 (m, 2 H).

Step 5: préparation of 3-oxo-piperidine-1-carboxylic acid benzyl ester. To a suspension of pyridine sulfur trioxide complex (135.6 g, 0.85 mol) in dichloromethane (1.25 L) at 0°C was added triethylamine (148 mL, 1.07 mol), followed by DMSO (151 mL, 2.13 mol). A solution of 3-hydroxy-piperidine-1-carboxylic acid benzyl ester (50.0 g, 35 0.21 mol) in dichloromethane (415 mL) was then added drop wise over 1 h, ensuring

152 that the température did not exceed 0°C. The reaction was then allowed to warm to ambient température over 16h, after which it was cooled to 15°C and slowly quenched with saturated aqueous ammonium chloride (1 L) (exotherm!) The mixture was then allowed to stir for an additional 30 min, after which the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in a 50% solution of heptane / ethyl acetate (300 mL), washed with 0.5N hydrochloric acid (600 mL), then brine. The organic layer was concentrated in vacuo and purified by silica gel column chromatography. ¹ H-NMR δ (CDCh): 7.32-7.41 (m, 5 H), 5.17 (s, 2 H),

4.10 (s, 2 H), 3.69 (t, 2 H), 2.50 (t, 2 H), 1.97-2.08 (m, 2 H).

Step 6: préparation of 3-(fert-butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid benzyl ester. To a solution of 3-oxo-piperidine-1-carboxylic acid benzyl ester (150 g, 0.64 mol) in tetrahydrofuran (1.5 L) was added fert-butyl hydrazinecarboxylate (85 g, 0.64 mol). The solution was heated to reflux for 2 h, after which it was cooled to ambient température and concentrated in vacuo to afford the title compound. MS (M+H) m/z 348.¹H-NMR (CDCI₃) δ 7.56 (s, 1 H), 7.28-7.41 (m, 5 H), 5.14-5.16 (d, 2 H), 4.13-4.25 (d, 2 H), 3.73-3.78 (m, 0.6 H), 3.53-3.61 (m, 1.4 H), 2.51-2.56 (t, 0.7H), 2.33-2.37 (t, 1.3 H), 1.82-1.91 (m, 2 H), 1.52 (s, 9H)

Step 7: préparation of benzyl 3-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1carboxylate. To a solution of 3-(fert-butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid benzyl ester (230 g, 0.66 mol) in tetrahydrofuran (1.5 L) was added sodium cyanoborohydride (41.6 g, 0.66 mol). A solution of para-toluenesulfonlc acid monohydrate (126 g, 0.66 mol) in tetrahydrofuran (590 mL) was then added drop wise over

1.5 h, ensuring that the température did not exceed 21 °C. The reaction was then allowed to stir over 16 h. Volatiles were removed in vacuo, and the resulting residue was dissolved in ethyl acetate (2.0 L), washed with saturated aqueous sodium bicarbonate (1 L), then added to 1N sodium hydroxide (1.5 L) and allowed to stir for 1 h. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-3% dichloromethane / methanol solvent gradient) affording the title compound as a colorless oil (169 g, 73 %). ¹H-NMR (CDCI3): δ 7.29-7.36 (m, 5 H), 6.33 (bs, 1 H), 5.88 (bs, 1 H), 5.12 (bs, 2 H), 3.42-3.64 (m, 5 H), 3.02-3.17 (m, 1 H), 1.74-

1.80 (m, 2H).

Step 8: préparation of 3-hydrazino-piperidine-1 -carboxylic acid benzylester hydrochloride. To a solution of benzyl 3-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1153 carboxylate (50 g, 0.143 mol) in methanol (180 mL) was added a solution of 4N hydrochloric acid in dioxane (180 mL) drop wise, ensuring that the température did not exceed 10°C. The reaction was allowed to stir at ambient température over 16 h, after which a white precipitate had formed. The precipitate was filtered, then allowed to stir in 5 ethyl acetate (700 mL) at ambient température for an additional 16h, filtered, then dried under vacuum to afford the title compound as a white powder. MS (M+H) m/z 250.2. ¹H-NMR (DMSO-cfe) δ 7.28-7.41 (m, 5 H), 5.08 (s, 2 H), 4.10 (d, 1 H), 3.72 (d, 1 H), 2.95 (bs, 3 H), 1.98 (m, 1 H), 1.70 (m, 1 H), 1.29-1.37 (m, 2 H).

Step 9: préparation of benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol10 1-yl]-piperidine-1-carboxylate. To a solution of 2-[(4-phenoxy-phenyl)-methoxymethylenej-malononitrile (step 3; 146 g, 0.53 mol) in éthanol (500 mL) was added benzyl 3-hydrazino-piperidine-1-carboxylate (step 8; 150.6 g, 0.53 mol) and triethylamine (107 g, 1.05 mol), causing the température of the solution to reach 55°C. The reaction was then allowed to cool to ambient température over 16 h, after which a 15 precipitate had formed. The precipitate was filtered off and added to 2-methyl tetrahydrofuran (3.5 L), which dîssolved the desired product, leaving behind triethyl amine hydrochloric acid, which was then removed by vacuum filtration. The filtrate was then washed with brine (1 L) and concentrated in vacuo to afford the title compound as a white solid. MS (M+H) m/z 494.

Step 10: préparation of 5-amino-3-(4-phenoxy-phenyl)-1 -piperidin-3-yl-1 Hpyrazole-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 (5L) 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. MS (M+H) m/z360.

Step 11 : préparation of 5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1Hpyrazole-4-carboxylic acid amide. To a 2L SS Parr autoclave was added a solution of

5-amino-3-(4-phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazole-4-carbonitrile (189 g, 527 mmol) and éthanol (550 mL). A 2N sodium hydroxide solution (880 mL) was then added 30 and the autoclave was sealed and heated at 150°C for 30 min, after which the reaction was judged complété. The solution was cooled to ambient température and added to ethyl acetate (500 mL). The organic layer was separated, washed with brine, and concentrated in vacuo to afford a gummy solid, which was triturated with acetonitrile (500 mL), then purified further by silica gel column chromatography (15-40% methanol /

154 dichloromethane solvent gradient) to afford the title compound as a white solid (135 g, 70%). MS (M+H) m/z360.

Step 12: préparation of (S)-5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1/7pyrazole-4-carboxylic acid amide. rao-5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl1 /7-pyrazole-4-carboxylic acid amide was chirally separated by supercritical fluid chromatography (Chiralpak IC, 30 x 250 mm col, 50/50, CO2/1% triethylamine in éthanol, 100 mL/min). Isolation of the first eluting isomer afforded the title compound.

Step 13: préparation of 1-[(3S)-1-acryloylpiperidin-3-yl]-5-amino-3-(4phenoxyphenyl)-1H-pyrazole-4-carboxamide. To a solution of (S)-5-amino-3-(4phenoxyphenyl)-1-piperidin-3-yl-1/7-pyrazole-4- carboxylic acid amide (377 mg, 1.0 mmol) in N,N-dimethylformamide (4.00 mL) was added 2-(1H-Benzotriazol-1yl)tris(dimethylamino)phosphonium hexafluorophosphate (486 mg, 1.1 mmol) and N,Ndiisopropylethylamine (323 mg, 2.5 mmol). The reaction mixture was cooled to 0°C and a solution of acrylic acid (79.3 mg, 1.1 mmol) in N.N-dimethylformamide (1.0 mL) was added drop wise over few minutes. The reaction was gradually warmed up to room température and stirred for 10 min, after which water was added, and extracted into ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate / 10% methanol) to afford the title compound. MS (M+H) m/z432.3.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.55 - 7.47 (m, 4 H), 7.27 (m, 1 H), 7.2 - 7.0 (m, 4 H), 6.91 - 6.77 (m, 1 H), 6.41 (br. s., 2 H), 6.19 - 6.04 (m, 1 H), 5.77 - 5.61 (m, 1 H), 4.53 - 4.03 (m, 3 H), 3.53-3.43 (m, 1 H), 3.13-2.97 (m, 1 H), 2.85-2.65 (m, 1 H), 2.08 -1.92 (m, 1 H), 1.90-

1.78 (m, 1 H), 1.55-1.45 (m, 1 H).

Example 127

1-[(3fi)-1-acryloylpiperidin-3-yl]-5-amino-3-(4-phenoxyphenyl)-1 H-pyrazole-4carboxamide

Step 1 : préparation of (R)-5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1W· pyrazole-4-carboxylic acid amide. rao-5-amino-3-(4-phenoxyphenyl)-1 -piperidin-3-yl1 /7-pyrazole-4-carboxylic acid amide was chirally separated by supercritical fluid chromatography (Chiralpak IC, 30 x 250 mm col, 50/50, CO₂/1% triethylamine in

155 éthanol, 100 mL/min). Isolation of the second eluting isomer afforded the title compound.

Step 2: préparation of 1-[(3R)-1-acryloylpiperidin-3-yl]-5-amino-3-(4phenoxyphenyl)-1H-pyrazole-4-carboxamide. To a solution of (R)-5-amino-3-(4phenoxyphenyl)-1-piperidin-3-yl-1/7-pyrazole-4- carboxylic acid amide (377 mg, 1.0 mmol) in N,N-dimethylformamide (4.00 mL) was added 2-(1H-benzotriazol-1yl)tris(dimethylamino)phosphonium hexafluorophosphate (486 mg, 1.1 mmol) and N,Ndiisopropylethylamine (323 mg, 2.5 mmol). The reaction mixture was cooled to 0°C and a solution of acrylic acid (79.3 mg, 1.1 mmol) in N,N-dimethylformamide (1.0 mL) was added drop wise over few minutes. The reaction was gradually warmed to room température and stirred for 10 min, after which water was added, and extracted into ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate / 10% methanol) to afford the title compound. MS (M+H) m/z432.3.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.55 - 7.47 (m, 4 H), 7.27 (m, 1 H), 7.2 - 7.0 (m, 4 H), 6.91 - 6.77 (m, 1 H), 6.41 (br. s., 2 H), 6.19 - 6.04 (m, 1 H), 5.77 - 5.61 (m, 1 H), 4.53 - 4.03 (m, 3 H), 3.53-3.43 (m, 1 H), 3.13 - 2.97 (m, 1 H), 2.85 - 2.65 (m, 1 H), 2.08 -1.92 (m, 1 H), 1.90-

1.78 (m, 1 H), 1.55-1.45 (m, 1 H).

Example 128 5-amino-1-{1-[(2E)-but-2-enoyl]piperidin-3-yl}-3-(4-phenoxyphenyl)-1H-pyrazole-4carboxamide

A mixture of rac-5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1/7-pyrazole-4carboxylic acid amide (prepared as described in Example 1) (200 mg, 0.53 mmol), crotonic acid (50 mg, 0.58 mmol), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (221 mg, 0.58 mmol) and N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) in tetrahydrofuran (20 mL) was stirred at room température for 24 h. The suspension was partitioned between water and ethyl acetate and the aqueous layer was further extracted with ethyl acetate (25 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The crude product was purified by reverse phase HPLC to provide the title compound. MS (M+H) m/z446.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.48 (d, J=8.79 Hz, 2 H), 7.38 - 7.44 (m, 2 H), 7.16 (s, 1 H), 7.06 (t, J=8.42 Hz, 4

156

H), 6.59 - 6.77 (m, 1 H), 6.50 - 6.58 (m, 1 H), 6.34 - 6.47 (m, 2 H), 4.27 - 4.52 (m, 1 H), 4.02 - 4.24 (m, 2 H), 3.40 - 3.52 (m, 1 H), 3.00 (m, 1 H), 2.60 - 2.73 (m, 1 H), 1.89 - 2.02 (m, 2 H), 1.82 (d, J=9.52 Hz, 4 H), 1.37 -1.51 (m, 1 H).

Example 129

5-amino-1-{(3fî)-1-[(2E)-4-hydroxybut-2-enoyl]piperidin-3-yl}-3-(4-phenoxyphenyl)1 H-pyrazole-4-carboxamide

A mixture of (R)-5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1 W-pyrazole-4carboxylic acid amide (prepared as described in Example 2, Step 1) (500 mg, 1.3 mmol), (E)-4-hydroxybut-2-enoic acid (149 mg, 1.5 mmol), O-(benzotriazol-l-yl)Ν,Ν,Ν’,Ν’-tetramethyluronium hexafluorophosphate (554 mg, 1.5 mmol) and triethylamine (335 mg, 3.3 mmol) in Λ/,/V-dimethylformamide (6 mL) was stirred at room température for 1 h. The suspension was partitioned between water and ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid solution and brine. The combined organic layers were dried (Na₂SO4), filtered and concentrated. The crude product was purified by coiumn chromatography (methanol/ethyl acetate) to provide 234 mg ofthe title compound. MS (M+H) m/z462.¹H NMR (400 MHz, DMSO-cfe) δ ppm

7.50 (d, J=8.6 Hz, 2 H), 7.44 - 7.40 (m, 2 H), 7.19 - 7.15 (m, 1 H), 7.09 - 7.05 (m, 4 H),

6.80 - 6.55 (m, 2 H), 6.41 (d, J=8.3 Hz, 2 H), 5.07 - 4.95 (m, 2 H), 4.55 - 4.47 (m, 1 H),

4.44 - 4.27 (m, 1 H), 4.02 - 4.24 (m, 2 H), 3.40 - 3.52 (m, 1 H), 3.05 (m, 1 H), 2.60 - 2.73 (m, 1 H), 2.00 -1.80 (m, 4 H), 1.37-1.51 (m, 1 H).

Example 130

-((3/7)-1 -acryloylpiperidin-3-yl]-5-amino-3-[4-(4-chlorophenoxy)phenyl]-1 Hpyrazole-4-carboxamide

Step 1 : préparation of methyl 4-(4-chlorophenoxy)benzoate. (4Chlorophenyl)boronic acid (25.4 g, 162.82 mmol), 4Â molecular sieves powder (16 g),

4-dimethylaminopyridine (39.5 g, 325.65 mmol) and anhydrous copper (II) acetate (39.0

157 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 temperatuer, and the resulting mixture was stirred for 48 h. The reaction mixture was then filtered through a Celite pad. The filtrate was concentrated and the residue was purified by column chromatography on silica (8% EtOAc in petroleum ether) to afford the title compound (14 g, 48% yield) as off white solid. MS (M+H) m/z 263.¹H NMR (CDCI₃, 400 MHz) δ 8.02 (d, 2 H), 7.35 (d, 2 H), 7.02 (d, 2 H), 6.97 (d, 2 H), 3.88 (s, 3 H).

Step 2: préparation of 4-(4-chlorophenoxy)benzoic acid. To a suspension of methyl 4-(4-chlorophenoxy)benzoate (14.0 g, 53.43mmol) in methanol-water (5:1,360 mL), NaOH (10.68 g, 267.11 mmol) was added at 0°C, the cooling batch was then removed and the reaction mixture was stirred at 60°C for 3 h. Methanol was distilled off, water (500 mL) was added to the residue and washed with diethyl ether (3x100mL).The aqueous layer was acidified with 2N HCl and then extracted with ethyl acetate (3x100mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (10.5 g, 79% yield) as off white solid. MS (M+H) m/z 247.¹H NMR (DMSO-cfe, 300 MHz) δ 12.83 (bs, 1 H), 7.95 (d, 2 H), 7.51 (d, 2 H), 7.17 (d, 2 H), 7.07 (d, 2 H).

Step 3: préparation of 4-(4-chlorophenoxy)benzoyl chloride. 4-(4chlorophenoxy)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: préparation 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 minerai oil, 158.4 mmol) in tetrahydrofuran (50 mL) at 0°C under nitrogen atmosphère. After stirring for 30 min, 4-(4-chlorophenoxy)benzoyl chloride (11.0 g, 41.35 mmol) in tetrahydrofuran (35 mL) was added drop wise. Cooling bath was removed and the reaction mixture was stirred at room température for 3 h. The reaction mixture was heated to reflux and dimethyl sulfate (28 mL, 288.89 mmol) was added drop wise, and the resulting mixture was refluxed for 18 h. After cooling to room température, water (100 mL) was added and extracted with ethyl acetate (3x100 mL). The combined organic layer was dried over sodium acetate, concentrated and purified by flash chromatography on silica (5-8 % EtOAc in petroleum ether) to afford the title compound (6.0 g, 47% yield) as pale yellow oil. ¹H NMR (DMSO-cfe, 400 MHz) δ 7.73 (d, 2 H), 7.52 (d, 2 H), 7.2 (d, 2 H), 7.18 (d, 2 H), 3.92 (s, 3 H).

158 φ Step 5: préparation of benzyl 3-(5-amino-3-(4-(4-chlorophenoxy)phenyl)-4-cyano1/-/-pyrazoI-1-yI)piperidine-1-carboxyîate. Triethylamine (8.6 mL 19.35 mmol) was added to a stirred mixture of 2-((4-(4chlorophenoxy)phenyl)(methoxy)methylene)malononitrile (6.0 g, 19.35 mmol) and 35 hydrazino-piperidine-1 -carboxylic acid benzylester hydrochloride (Example 1, Step 8) (5.5 g, 57.89 mmol) in éthanol (6 0 mL) at room température. After stirring for 3 h the precipitated solid was filtered off. The solid was washed with éthanol and dried under vacuum to afford the title compound (7.2 g, 70 % yield). MS (M+H) m/z 526.¹H NMR (DMSO-d₆,400 MHz) δ 8.0 (d, 2 H), 7.45 (d, 2 H), 7.37 (m, 5 H), 7.12 (d, 2 H), 7.08 (d,

2 H), 6.77 (s, 2 H), 5.06 (bs, 2 H), 4.23 (m, 1 H), 4.0 (m, 2 H), 2.97 (m, 2 H), 1.87 (m, 3 H), 1.50 (m, 1 H).

Step 6: préparation 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-1 H-pyrazol-115 yl)piperidine-1-carboxyîate (7.2 g, 13.66 mmol) in éthanol (70 mL) in a 250 mL sealed tube and the resulting mixture was heated with stirring at 140°C for 48 h. After cooling to room température water was added to the reaction mixture and extracted with ethyl acetate (3x100mL). The combined organic layer was dried over sodium sulfate, filtered, concentrated to afford the title compound (2.6 g). ¹H NMR (DMSO-de, 400 MHz) δ 8.21 (s, 1 H), 7.49 (m, 4 H), 7.45 (d, 2 H), 7.10 (m, 4 H), 6.36 (s, 2 H), 4.20 (m, 1 H), 3.11 (m, 1 H), 2.97 (m, 2 H), 2.50 (m, 1 H), 1.93 (m, 2 H), 1.76 (m, 1 H), 1.60 (m, 1 H).

Step 7: préparation of (R)-5-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3yl)-1 H-pyrazole-4-carboxamide. rao-5-amino-3-(4-(4-chlorophenoxy)phenyl)-1 (piperidin-3-yl)-1 H-pyrazole-4-carboxamide was chirally separated by supercritical fluid 25 chromatography (Chiralpak OJ-H, 30 x 250 mm col, 50/50, CO₂/1% triethylamine in éthanol, 70 mL/min). Isolation of the second eluting isomer afforded the title compound.

Step 8: préparation of 1-[(3R)-1-acfyloylpiperidin-3-yl]-5-amino-3-[4-(4chlorophenoxy)phenyl]-1 H-pyrazole-4-carboxamide. N,N-diisopropylethylamine (0.72 mL, 4.1 mmol) and acrylic acid (131 mg, 1.8 mmol) was added to a mixture of (R)-530 amino-3-(4-(4-chlorophenoxy)phenyl)-1 -(piperidin-3-yl)-1 H-pyrazole-4-carboxamide (675 mg, 1.6 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (740 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at room température and then purified by reverse phase HPLC to provide 250 mg ofthe title compound. MS (M+H) m/z466.¹H NMR (400 MHz, DMSO35 d₆) δ ppm 7.51 (d, J=5.77 Hz, 2 H), 7.48 - 7.40 (m, 2 H), 7.15 - 7.04 (m, 4 H), 6.93 159

6.74 (m, 1 H), 6.41 (br. s., 2 H), 6.19 - 6.01 (m, 1 H), 5.74 - 5.55 (m, 1 H), 4.59 - 4.01 (m, 3 H), 3.54 - 3.39 (m, 0.5 H), 3.12 - 2.97 (m, 1 H), 2.76 - 2.71 (m, 0.5 H), 2.05 -1.90 (m, 2 H), 1.89 -1.77 (m, 1 H), 1.56 -1.37 (m, 1 H).

Example 131

5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-{(3R)-1-[(2E)-4-hydroxybut-2enoyl]piperidin-3-yl]-1H-pyrazole-4-carboxamide

To a solution of 5-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1Hpyrazole-4-carboxamide (prepared as described in Example 13, Step 6) (844 mg, 2.05 mmol), (E)-4-hydroxybut-2-enoic acid (251 mg, 2.46 mmol) and O-(7-azabenzotriazole-

1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.07 g, 2.66 mmol) in N,Ndimethylformamide (10 mL) was added triethylamine (0.71 mL, 5.12 mmol). After 2.5 h the reaction was diluted into ethyl acetate (100 mL), washed three times with 1N HCl (15 mL) and three times with 10% Na2CO₃ (15 mL). After drying over MgSO₄, filtration and removal of the volatiles, the crude product was purified by reverse phase HPLC. The resulting solid was chirally separated by préparative HPLC (3.0 x 25.0 cm ChiralPak OD-H, 45/55, COz/isopropanol with 1% isopropyl amine at 70 mL/min flow rate). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z 496.¹H NMR (DMSO-d6,400 MHz) δ 7.52 (m, 2 H), 7.46 (m, 2 H), 7.10 (m, 4 H), 6.74 (m, 1 H), 6.60 (m, 1 H), 6.41 (m, 1 H), 4.44 (m, 1 H), 4.12 (m, 4 H), 3.06 (m, 1 H). Example 132 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-{(3fi)-1-[(2E)-4-fluorobut-2enoyl]piperidin-3-yl]-1H-pyrazole-4-carboxamide

Cl

Step 1 : préparation of (E)-ethyl 4-fluorobut-2-enoate. To the suspension of AgF (19.71 g, 155.40 mmol) in MeCN (70 mL) was added a solution of (E)-ethyl 4-bromobut-

2-enoate (10 g, 51.80 mmol) in MeCN (50 ml) under nitrogen atmosphère in the dark. The reaction mixture was stirred at room température for 24 h. The reaction mixture was

160 filtered through a short pad of celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure and low température to afford the title compound (6.83 g, 100%) as a brown liquid. ¹H NMR (400 MHz, CDCI₃) δ 1.29 (t, 3H, J = 7.1 Hz),

4.21 (q, 2H, J =4.1 Hz), 5.04 (d, 2H, J = 46.1 Hz), 6.10 (d,1 H, J = 15.8 Hz), 6.90-7.00 (m,1 H).

Step 2: préparation of (E)-4-fluorobut-2-enoic acid. To the stirred solution of (E)ethyl 4-fluorobut-2-enoate (4.4 g, 33.33 mmol) in tetrahydrofuran (30 ml), a solution of LiOH-H₂O (4.2 g, 99.99 mmol) in water (30 ml) was added and stirred at room température for 2.5 h. The reaction mixture was acidified with HCl (2N, aq, 10 ml) and 10 extracted with 10%MeOH-dichloromethane. The combined organic phase was washed with brine, dried over Na₂SO4 and concentrated to provide the title compound (1.7 g, 49%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.13 (d, J = 46.3 Hz, 2 H), 5.96 (d, J = 15.9 Hz, 1 H), 6.82-6.94 (m, 1 H), 12.54 (br s, 1 H).

Step 3: préparation of 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1 -{(3fi)-1 -[(2E)-4fluorobut-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide. To a solution of (R)-5amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (prepared as described in Example 13, step 7) (150 mg, 0.36 mmol) in N,Ndimethylformamide (2.00 mL) was cooled to 0°C. 2-(1H-Benzotriazol-120 yl)tris(dimethylamino)phosphonium hexafluorophosphate (177 mg, 0.40 mmol), N,Ndiisopropylethylamine (0.16 mL, 0.91 mmol) and (E)-4-fluorobut-2-enoic acid (41.69 mg, 0.4 mmol) were added at 0°C. The reaction mixture was stirred for 15 min at OoC and quenched with ice water (10 mL). The resulting mixture was extracted using ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (10% methanol/ ethyl acetate) followed by trituration with dichloromethane:hexane (1:5,12 mL) to afford the title compound. MS (M+H) m/z 498.¹H NMR (400 MHz, DMSO-cfc) δ ppm 7.50 (b.s, 2 H), 7.45 (d, 2 H), 7.15-7.05 (d, 4 H), 6.8-6.70 (m, 2 H), 6.40 (d, 2 H),

5.15 (d, 1 H), 5.02 (d, 1 H), 4.55-3.95 (m, 3 H), 3.49 (t, 0.5 H), 3.12 (q, 1 H), 2.76 (t, 0.5 30 H), 1.99 (bs, 2 H), 1.80-1.90 (m, 1 H), 1.47 (bs, 1 H).

Example 133 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-{(3R)-1-[(2E)-4,4-difluorobut-2enoyl]piperidin-3-yl}-1 H-pyrazole-4-carboxamide

161

F

Step 1: préparation of ethyl 4,4-difluoro-3-hydroxybutanoate. To a stirred solution of ethyl 4,4-difluoro-3-oxobutanoate (10 g, 60.19 mmol) in toluene (300 mL) was added sodium borohydride (2.4 g, 63.2 mmol) portionwise at 0 °C. The resulting mixture was stirred at room température for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with water followed by brine, dried over Na₂SO4 and concentrated to provide the title compound as a colorless liquid (9 g, 89%). ¹H NMR (400 MHz, DMSO-cfe) δ 5.89 (dt, J = 3.6 Hz, 55.7 Hz, 1 H), 5.81 (br s, 1 H), 4.11-4.02 (m, 3 H), 2.57 (dd, J = 3.9 Hz, 16 Hz, 10 1 H), 2.39 (dd, J = 9 Hz, 15.6 Hz, 1 H), 1.19 (t, J = 7 Hz, 3 H).

Step 2: préparation of (E)-ethyl 4,4-difluorobut-2-enoate. Phosphorous pentoxide (1.68 g, 11.89 mmol) was added to ethyl 4,4-difluoro-3-hydroxybutanoate (4 g, 23.78 mmol) under a nitrogen atmosphère. The mixture was stirred at 60 °C for 1h and then distilled (at 120 °C under 0.05 mm-Hg pressure) to afford the title compound (1.4 g,

39%). ¹H NMR (400 MHz, DMSO-cfe) δ 6.84-6.37 (m, 3 H), 4.19 (q, 2 H), 1.24 (t, 3 H). Step 3: Prep of (E)-4,4-difluorobut-2-enoic acid. A solution of (E)-ethyl 4,4difluorobut-2-enoate (1.3 g, 8.66 mmol) in 10% aqueous sodium hydroxide solution (13 ml) was heated to 50 °C for 1h. The reaction mixture was cooled to room température and diluted with water. The aqueous fraction was extracted with ethyl acetate and organic extract was discarded. The aqueous fraction was acidified with 1N HCl solution to pH ~4 and then extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulphate and concentrated the title compound as an off white solid (650 mg, 62 %). ¹H NMR (400 MHz, DMSO-cfe) δ 12.82 (br s, 1 H), 6.76-6.67 (m, 1 H), 6.56 (dd, 1 H, J = 4.96 Hz, 54.7 Hz), 6.37-6.33 (m, 1 H).

MS(M-H) m/z 121.

Step 4: Prep of 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-((3R)-1-[(2E)-4,4difluorobut-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide. To a solution of (R)-5amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (prepared as described in Example 13, step 7) (150 mg, 0.36 mmol) in N,N30 dimethylformamide (2.00 mL) was cooled to 0°C. 2-(1 H-benzotriazol-1yl)tris(dimethylamino)phosphonium hexafluorophosphate (177 mg, 0.40 mmol), N,N162 diisopropylethylamine (0.16 mL, 0.91 mmol) and (E)-4,4-difluorobut-2-enoic acid (41.69 mg, 0.4 mmol) were added at 0°C. The reaction mixture was stirred for 15 min at 0°C and quenched with ice water (10 mL). The resulting mixture was extracted using ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (10% methanol/ ethyl acetate) followed by trituration with dichloromethane:hexane (1:5,12 mL) to afford the title compound. MS (M+H) m/z516.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.55-7.45 (m, 4 H), 7.25-7.05 (m, 5 H), 6.7-6.35 (m, 4 H), 4.5-3.95 (m, 3 H), 3.53 (t, 0.5 H), 3.15 (q, 1 H), 2.82 (t, 0.5 H), 1.98 (b,s, 2 H), 1.95-1.80 (m, 1 H), 1.47 (bs, 1 H). Example 134

5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-[(3R)-1-(2-fluoroacryloyl)piperidin-3-yl]1 H-pyrazole-4-carboxamide

To a solution of (R)-5-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1Hpyrazole-4-carboxamide (prepared as described in Example 13, step 7) (79.1 mg, 0.192 mmol) in N,N-dimethylformamide (2.00 mL) was cooled to 0°C. 2-(1HBenzotriazol-1-yl)tris(dimethylamino)phosphonium hexafluorophosphate (106 mg, 0.24 mmol), N,N-diisopropylethylamine (65.3 mg, 0.48 mmol) and 2-fluoroacrylic acid (21.69 mg, 0.24 mmol) were added at 0°C. The reaction mixture was stirred for 15 min at 0°C and then quenched by pouring over ice water. The solid was filtered and purified by reverse phase HPLC to afford the title compound. MS (M+H) m/z484.1.

Example 135 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-{(3R)-1-[(2E)-3-cyanoprop-2enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

Step 1 : préparation of (E)-ethyl 3-cyanoacrylate. To a stirred solution of (Z)-ethyl

3-cyanoacrylate (2 g, 16 mmol) in acetonitrile (16 ml) was added triphenyl phosphine (4.2 g, 16 mmol) and heated to reflux for 5 days. The reaction mixture was cooled to λ

163 room température and volatiles were removed under reduced pressure. The residue was purified by silica gel column chromatography in hexane to afford the title compound as colorless liquid (370 mg, 19 %). ¹H NMR (400 MHz, CDCI₃) δ 6.69 (d,1 H), 6.48 (d, 1 H), 4.28 (q, 2 H), 1.32 (t, 3 H). GCMS: Rt = 6.71 min; m/z 125

Step 2: préparation of (E)-3-cyanoacrylic acid. A solution of (E)-ethyl 3cyanoacrylate (1.3 g, 10.38 mmol) in hydrochloric acid (6N, aq, 20 ml) was heated to 100 °C for 4 h. The reaction mixture was cooled to room température and evaporated to dryness. The residue was triturated with ether to afford the title compound as a white solid (900 mg, 89%). ¹H NMR (400 MHz, CDCI₃) δ 7.99 (br s, 1 H), 6.72 (d, 1 H), 6.57 (d, 1 H). MS (M+H) m/z 98.

Step 3: préparation of 5-amino-3-[4-(4-chlorophenoxy)phenyl]-1-{(3R)-1-[(2E)-3cyanoprop-2-enoyl]piperidin-3-yl}-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 1-[(3R)-1-acryloylpiperidin-3-yl]-5-amino-3-[4-(4chlorophenoxy)phenyl]-1H-pyrazole-4-carboxamide (Example 13) employing (E)-3cyanoacrylic acid. ¹H NMR (400 MHz, DMSO-cfe) δ 1.50 (m, 1 H), 1.85-2.07 (m, 3 H),

2.91 (t, 0.5 H), 3.14 (t, 1 H), 3.55 (dd, 0.5 H), 4.07-4.45 (m, 3 H), 6.38-6.42 (m, 2 H),

6.52 (dd, 1 H), 7.08-7.12 (m, 4 H), 7.44-7.52 (m, 4 H), 7.83 (dd, 1 H). MS (M+H) m/z 491.

Example 136

1-[(3S)-1-acryloylpiperidin-3-yl]-5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1Hpyrazole-4-carboxamide

Step 1 : préparation of methyl 4-(2,4-difluorophenoxy)benzoate. 4Â molecular sieves powder (17 g), (4-(methoxycarbonyl)phenyl)boronic acid (17.34 g, 133.33 mmol),

4-dimethylaminopyridine (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 température, and the resulting mixture was stirred for 48 h. The reaction mixture was then filtered through celite pad, the filtrate was concentrated and purified by column chromatography on silica (100-200 mesh), eluting with 8% EtOAc in petroleum ether to give compd-2X10 (15 g, 51.2 %) as solid.

164

MS (M+H) m/z 265.¹H NMR (DMSO-cfe, 300 MHz) δ 7.97 (d, 2 H), 7.56 (m, 1 H), 7.45 (m, 1 H), 7.20 (t, 1 H), 7.05 (d, 2 H), 3.83 (s, 3 H).

Step 2: préparation of 4-(2,4-difluorophenoxy)benzoic acid. To a suspension of methyl 4-(2,4-difluorophenoxy)benzoate (15.0 g, 56.82mmol) in methanol (525 mL) were added water (63 mL) and NaOH pellets (12.22 g, 284.11 mmol) at 0°C, the cooling batch was then removed and the reaction mixture was stirred at 50°C for 3 h. Methanol was 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. MS (M+H) m/z249. ¹H NMR (DMSO-cfe, 300 MHz) δ 12.85 (bs, 1 H), 7.92 (d, 2 H),

7.52 (m, 1 H), 7.40 (m, 1 H), 7.20 (t, 1 H), 7.00 (d, 2 H).

Step 3: préparation of 4-(2,4-difluorophenoxy)benzoyl chloride. 4-(2,4difluorophenoxy)benzoic acid (3.0 g, 30 mmol) in thionyl chloride (80 mL) was refluxed ovemight. The volatiles were evaporated to afford the title compound.

Step 4: préparation 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 N₂ atmosphère. After stirring for 30 min, 4-(2,4difluorophenoxy)benzoyl chloride (3.2 g, 11.94 mmol) in tetrahydrofuran (15 mL) was added dropwise. The reaction mixture was brought to room température and stirred (~3 h). The reaction mixture was then heated to reflux and dimethyl sulfate (7.7 mL, 83.6 mmol) was added drop wise. The mixture was refluxed for 18 h. After cooling to room température, the mixture was quenched with ice water (100 mL) and extracted with EtOAc (2x). The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography on silica gel (100-200 mesh) eluting with 12 % EtOAc in petroleum ether to afford the title compound (1.8 g) as liquid. MS (M+H) m/z 297. ¹H NMR (DMSO-cfe, 400 MHz) δ 7.71 (d, 2 H), 7.52 (m, 1 H), 7.43 (m, 1 H), 7.20 (t, 1 H), 7.16 (d, 2 H), 3.93 (s, 3 H).

Step 5: préparation of benzyl 3-(5-amino-4-cyano-3-(4-(2,4difluorophenoxy)phenyl)-1 H-pyrazol-1-yl)piperidine-1-carboxylate. Triethylamine (2.2 mL 14.4 mmol) was added to a stirred mixture of 2-((4-(2,4difluorophenoxy)phenyl)(methoxy)methylene)malononitrile (1.5 g, 4.8 mmol) and 3hydrazino-piperidine-1-carboxylic acid benzylester hydrochloride (Example 1, Step 8) (1.4 g, 4.8 mmol) in éthanol (30 mL) at room température. After stirring for 3 h the precipitate was filtered. The resulting solid was washed with éthanol and dried under

165 vacuum to afford the title compound (1.8 g, 40%). MS (M+H) m/z 530.¹H NMR (DMSOde, 300 MHz) δ 7.78 (d, 2 H), 7.50 (m, 1 H), 7.33 (m, 6 H), 7.18 (m, 1 H), 7.05 (d, 2 H),

6.78 (s, 2 H), 5.06 (bs, 2 H), 4.26 (m, 1 H), 3.99 (m, 2 H), 3.30 (m, 1 H), 2.97 (t, 1 H), 2.21 (s, 3 H), 1.90 (m, 3 H), 1.48 (m, 1 H).

Step 6: préparation of 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3yl)-1 H-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-1yl)piperidine-1-carboxylate (1.8 g, 3.39 mmol) in éthanol (20 mL) charged to a 100 mL sealed tube. The mixture was heated with stirring at 140°C for 24 h. After cooling to room température, the reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were dried over Na₂SO4, filtered, and concentrated to afford the title compound (1.4 g). MS (M+H) m/z 414. ¹H NMR (DMSO-cfe, 300 MHz) δ 7.45 (d, 2 H), 7.32 (m, 1 H), 7.23 (m, 1 H), 7.18 (m, 1 H), 7.01 (d, 2 H), 6.30 (s, 2 H),

5.17 (t, 1 H), 4.07 (m, 1 H), 3.0 (d, 1 H), 2.7-2.90 (m, 3 H), 1.90 (m, 2 H), 1.70 (m, 1 H), 1.48 (m, 1 H).

Step 7: préparation of (S)-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1(piperidin-3-yl)-1H-pyrazole-4-carboxamide. rao-5-amino-3-(4-(2,4difluorophenoxy)phenyl)-1-(piperidin-3-yl)-1 H-pyrazole-4-carboxamide was chirally separated by supercritical fluid chromatography (ChiralPak OJ-H, 4.6 x 250 mm, 15/85, CO₂/ethanol with 0.2% isopropylamine, 2.5 mL/min flow rate). Isolation of the second eluting isomer afforded the title compound.

Step 8: préparation of 1-[(3S)-1-acryloylpiperidin-3-yl]-5-amino-3-[4-(2,4difluorophenoxy)-phenyl]-1H-pyrazole-4-carboxamide. Triethylamine (1.69 mL, 12.1 mmol) and N-[(dimethylamino)-1 H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-Nmethylmethanaminium hexafluorophosphate N-oxide (2.02 g (5.3 mmol) were added to a solution of (S)-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)-1H· pyrazole-4-carboxamide (2.0 g, 4.8 mmol) and acrylic acid (0.38 g, 5.3 mmol) in N,Ndimethylformamide (20 mL). After stirring at room température for 3 h, mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid solution and brine and then dried (Na₂SO₄), filtered and concentrated. The crude product was purified by column chromatography (methanol/ethyl acetate) to afford the title compound. MS (M+H) m/z468.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.42 - 7.59 (m, 3 H), 7.30 - 7.41 (m, 1 H), 7.11 - 7.21 (m, 1 H), 7.02 (d, J=8.20 Hz, 2 H), 6.74 - 6.92 (m, 1 H), 6.40 (br. s., 2 H), 6.10 (t, J=18.70 Hz, 1

166

H), 5.67 (dd, </=25.37,10.54 Hz, 1 H), 4.01 - 4.55 (m, 2 H), 3.39 - 3.52 (m, 1 H), 2.96 -

3.11 (m, 1 H), 2.73 (t, J=11.51 Hz, 1 H), 1.78 - 2.07 (m, 3 H), 1.47 (br. s., 1 H)

Example 137

1-[(3fi)-1-acryloylpiperidin-3-yl]-5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1H pyrazole-4-carboxamide

Step 1 : préparation of (fî)-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1(piperidin-3-yl)-1H-pyrazole-4-carboxamide. rao-5-amino-3-(4-(2,4difluorophenoxy)phenyl)-1-(piperidin-3-yl)-1 H-pyrazole-4-carboxamide (prepared as described in Example 25, Step 6) was chirally separated by supercritical fluid chromatography (ChiralPak OJ-H, 4.6 x 250 mm, 15/85, CO₂/ethanol with 0.2% isopropylamine, 2.5 mL/min flow rate). Isolation of the first eluting isomer afforded the title compound.

Step 2: préparation of 1 -[(3fi)-1 -acryloylpiperidin-3-yl]-5-amino-3-[4-(2,4difluorophenoxy)-phenyl]-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 1 -[(3S)-1 -acryloylpiperidin-3-yl]-5-amino-3-[4-(2,4difluorophenoxy)-phenyl]-1 H-pyrazole-4-carboxamide (Example 25, Step 8). MS (M+H) m/z468.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.42 - 7.59 (m, 3 H), 7.30 - 7.41 (m, 1 H), 7.11 - 7.21 (m, 1 H), 7.02 (d, J=8.20 Hz, 2 H), 6.74 - 6.92 (m, 1 H), 6.40 (br. s., 2 H),

6.10 (t, J=18.70 Hz, 1 H), 5.67 (dd, J=25.37,10.54 Hz, 1 H), 4.01 - 4.55 (m, 2 H), 3.39 -

3.52 (m, 1 H), 2.96 - 3.11 (m, 1 H), 2.73 (t, J=11.51 Hz, 1 H), 1.78 - 2.07 (m, 3 H), 1.47 (br. s., 1 H)

Example 138

5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2E)-4-methoxybut-2enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

167

To a solution of (fi)-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)1 H-pyrazole-4-carboxamide (prepared as described in Example 26, Step 1) (50 mg,

0.12 mmol), (E)-4-methoxybut-2-enoic acid (15 mg, 0.13 mmol, prepared according to J. Org. Chem. 1981,46, 940-948) and O-(7-azabenzotriazole-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate (53 mg, 0.13 mmol) in N.N-dimethylformamide (1 mL) was added triethylamine (25 mg, 0.24 mmol). After 3 h the reaction was diluted into ethyl acetate (10 mL), washed three times with aqueous 1N hydrochloric acid (2 mL) and three times with 10% Na₂CO3 (2 mL). After drying over magnésium sulfate, filtration and concentration, the crude product was purified by reverse phase HPLC to afford the title compound. MS (M+H) m/z512.¹H NMR (DMSO-de, 400 MHz) δ 7.49 (m, 3 H), 7.36 (m, 1 H), 7.16 (m, 1 H), 7.03 (m, 2 H), 6.65 (m, 2 H), 4.40 (m, 1 H), 4.20 (m, 1 H), 4.04 (m, 3 H), 3.28 (m, 3 H), 3.06 (m, 1 H), 1.92 (m, 3 H), 1.47 (m, 1 H).

Example 139 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-[(3R)-1-(2-methylacryloyl)piperidin-3yl]-1 H-py razole-4-carboxamide -

To a solution of (R)-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)1 H-pyrazole-4-carboxamide (prepared as described in Example 26, Step 1) (69 mg, 0.17 mmol), methacrylic acid (15 mg, 0.17 mmol) and O-ibenzotriazol-l-ylJ-N.N.N’.N’tetramethyluronium hexafluorophosphate (67 mg, 0.17 mmol) in Λ/,Λ/dimethylformamide (2 mL) was added N.N-diisopropylethylamine (0.1 mL). After 18 h the crude reaction mixture was purified by reverse phase HPLC to afford the title compound. MS (M+H) m/z 482.¹H NMR (DMSO-de, 400 MHz) δ 7.54 - 7.46 (m, 3 H), 7.35 (td, */=9.1, 5.6 Hz, 1 H), 7.16 (t, «7=8.5 Hz, 1 H), 7.03 (d, «7=8.5 Hz, 2 H), 6.4 (br s,2 H), 5.17 (br s, 1 H), 5.01 (s, 1 H), 4.40 (m,1 H), 4.23 (m, 1 H), 3.90 (m, 1 H), 3.3 (m, 1 H), 3.10 (m, 1 H), 2.05 -

1.80 (m,6H), 1.49 (m, 1 H).

Example 140 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3fî)-1-[(2E)-4-(dimethylamino)but-2enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

168

The title compound was prepared analogous to 5-amino-3-[4-(2,4difluorophenoxy)phenyl]-1 -((3/7)-1 -(2-methylacryloyl)piperidin-3-yl]-1 H-pyrazole-4carboxamide (Example ) employing (E)-4-(dimethylamino)but-2-enoic acid. MS (M+H) m/z 526.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.47 - 7.53 (m, 2 H), 7.24 (td, J=9.1,

5.4 Hz, 1 H), 7.16 (ddd, J=11.0, 8.4, 3.0 Hz, 1 H), 6.97 - 7.07 (m, 3 H), 6.55 - 6.83 (m, 2 H), 4.63 (d, J=12.0 Hz, 1 H), 4.34 (d, J=13.0 Hz, 1 H), 4.09 - 4.27 (m, 4 H), 3.65 (dd, J=13.1, 10.0 Hz, 1 H), 2.27 (s, 3 H), 2.24 (s, 2 H), 1.93 - 2.18 (m, 3 H), 1.56 -1.70 (m, 1 H).

Example 141 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2E)-5-hydroxypent-2enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

Step 1: Préparation of (E)-ethyl 5-hydroxypent-2-enoate. To a solution of propane-1,3-diol (9.0 g, 118.42 mmol) in dichloromethane (1.2 L), was added ethyl 2(triphenylphosphoranylidene)acetate (99.03 g, 284.21 mmol) and manganèse dioxide (206.5 g, 2368.42 mmol) at room température. Resulting mixture was stirred at room température for 48 h. After completîon of reaction (monitored by TLC) the mixture was filtered through a short pad of celite bed and washed with dichloromethane. The fïltrate was concentrated under reduced pressure. The crude material was purified by column chromatography (13% ethyl acetate/hexane) to afford the title compound (12 g, 70.5) as colorless liquid. ¹H NMR (400 MHz, CDCI₃) δ 6.97-6.87 (m, 1 H), 5.90 (d, J = 15.6 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.75 (m, 2 H) 2.45 (q, J = 6.2 Hz, 2 H), 1.89 (br s, 1 H),

1.26 (t, J =7.2 Hz, 3 H).

Step 2: Préparation of (E)-ethyl 5-hydroxypent-2-enoic acid. To a solution of (E)ethyl 5-hydroxypent-2-enoate (1.5 g, 10.41 mmol) in tetrahydrofuran (6 mL), a solution of lithium hydroxide-hydrate (1.31 g, 31.24 mmol) in water (6 mL) was added at room

169 température. The resulting reaction mixture was stirred at room température for 2 h. The mixture was acidified with 1N-HCI (15 mL) and extracted with ethyl acetate (3x50 mL).

The combined organic portion was dried over sodium sulfate, fîltered and concentrated to afford the title compound (0.6 g, 50%) as a colorless liquid. ¹H NMR (400 MHz, CDCI₃) δ 12.1 (br s, 1 H), 6.97-6.87 (m, 1 H), 5.79 (d, J = 15.6 Hz, 1 H), 3.50 (t, J = 6.2 Hz, 2 H) 2.31 (q, J = 6.2 Hz, 2 H),

Step 3: Préparation of 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2E)5-hydroxypent-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide. A solution of (R)-5amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (prepared as described in Example 26, Step 1) (100 mg, 0.24 mmol) in N,Ndimethylformamide (0.5 mL) was cooled to 0°C. (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (118 mg, 0.27 mmol) and N,Ndiisopropylethylamine (0.1 mL, 0.61 mmol) were added followed by (E)-5-hydroxypent-

2-enoic acid (30.89 mg, 0.27 mmol). The mixture was stirred at same température for 15 min. The reaction mixture was quenched with ice water (10 mL) and was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water (2 x 10 mL), brine (2x10 mL), dried over sodium sulfate and concentrated under vacuo. The crude residue was purified by silica gel column chromatography (1% MeOH in EtOAc) followed by trituration with (1:5 dichloromethane:Hexane, 12 mL) to afford the title compound as off white solid. MS (M+H) m/z 512.¹H NMR (400 MHz, DMSO- cfe) δ 7.55-7.45 (m, 3 H), 7.40-7.30 (m, 1 H), 7.15 (t, 1 H), 7.01 (d, 2 H), 6.75-6.60 (m, 1 H), 6.60-6.50 (m, 1 H), 6.39 (bs, 2 H), 4.70-4.00 (m, 5 H), 3.49 (bs, 2 H), 3.10-2.95 (m, 1 H), 2.32 (bs, 2 H), 2.01 (bs, 2 H), 1.90-1.75 (m, 1 H), 1.45 (bs, 1 H).

Example 142

5-amino-1 -{(3R)-1 -[(2E)-but-2-enoyl]piperidin-3-yl}-3-[4-(2,4difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide

The title compound was prepared analogous to 5-amino-3-[4-(2,4dif luorophenoxy)phenyl]-1 -{(3R)-1 -[(2E)-5-hydroxypent-2-enoyl]piperidin-3-yl}-1 Hpyrazole-4-carboxamide (Example ) employing (E)-but-2-enoic acid. MS (M+H) m/z 482.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.55-7.45 (m, 3 H), 7.40-7.30 (m, 1 H), 7.15

170 (t, 1 H), 7.02 (d, 2 H), 6.75-6.60 (m, 1 H), 6.60-6.50 (m, 1 H), 6.39 (bs, 2 H), 4.50-4.00 (m, 3 H), 3.55-3.35 (m, 1 H), 3.10-2.90 (m, 1 H), 1.97 (bs, 2 H), 1.82 (bs, 4 H), 1.45 (bs,

H).

Example 143

5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2E)-pent-2-enoyl]piperidin

3-yl}-1 H-pyrazole-4-carboxamide

The title compound was prepared analogous to 5-amino-3-[4-(2,4dif luorophenoxy)phenyl]-1 -{(3fi)-1 -[(2E)-5-hydroxypent-2-enoyl]piperidin-3-yl}-1 Hpyrazole-4-carboxamide (Example ) employing (E)-pent-2-enoic acid. MS (M+H) m/z 496.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.55-7.45 (m, 3 H), 7.40-7.30 (m, 1 H), 7.15 (t, 1 H), 7.02 (d, 2 H), 6.75-6.60 (m, 1 H), 6.60-6.50 (m, 1 H), 6.39 (bs, 2 H), 4.50-4.05 (m, 3 H), 3.55-3.40 (m, 0.5 H), 3.10-2.95 (m, 1 H), 2.80-2.65 (m, 0.5 H), 2.55-2.10 (m, 2 H), 1.97 (bs, 2 H), 1.90-1.80 (m, 1 H), 1.45 (bs, 1 H), 0.99 (bs, 3 H).

Example 144 5-amino-1-{(3R)-1-[(2E)-4,4-difluorobut-2-enoyl]piperidin-3-yl}-3-[4-(2,4difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide

The title compound was prepared analogous to 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1 -{(3fi)-1 -[(2E)-5-hydroxypent-2-enoyl]piperidin-3-yl}-1 H-pyrazole-4carboxamide (Example ) employing (E)-4,4-difluorobut-2-enoic acid (prepared as described in Example 133, step 3). MS (M+H) m/z518.¹H NMR (400 MHz, DMSO-cfe) δ 7.55-7.45 (m, 3 H), 7.40-7.30 (m, 1 H), 7.23-7.11 (m, 2 H), 7.02 (d, 2 H), 6.70-6.35 (m, 4 H), 4.50-3.95 (m, 3 H), 3.53 (t, 0.5 H), 3.12 (q, 1 H), 2.81 (t, 0.5 H), 1.98 (bs, 2 H), 1.95-1.80 (m, 1 H), 1.48 (bs, 1 H).

Example 145

171

5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2E)-4-fluorobut-2enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

The title compound was prepared analogous to 5-amino-3-[4-(2,4difluorophenoxy)phenyl]-1 -((3/7)-1 -[(2E)-5-hydroxypent-2-enoyl]piperidin-3-yl}-1 Hpyrazole-4-carboxamide (Example ) employing (E)-4-fluorobut-2-enoic acid (Example, step 2). MS (M+H) m/z 500.¹H NMR (400 MHz, DMSO- d₆) δ 7.55-7.45 (m, 3 H), 7.40-

7.30 (m, 1 H), 7.15 (t, 1 H), 7.02 (d, 2 H), 6.80-6.70 (m, 2 H), 6.39 (d, 2 H), 5.15 (d, 1 H), 5.02 (d, 1 H), 4.60-4.00 (m, 3 H), 3.48 (t, 0.5 H), 3.07 (q, 1 H), 2.76 (t, 0.5 H), 1.98 (bs, 2 H), 1.80-1.90 (m, 1 H), 1.47 (bs, 1 H).

Example 146 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2Z)-2-fluoro-4-hydroxybut-2‘ enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

HO

Step 1 : préparation of (Z)-ethyl 2-fluorobut-2-enoate. To a stirred suspension of sodium hydride (50% in minerai oil, 11.3 g, 235.6 mmol) in tetrahydrofuran (125 mL) were added diethyl oxalate (35.4 mL, 259.2 mmol) and ethyl 2-fluoroacetate (5 g, 47.1 mmol). When the reaction was initiated (reaction mixture observed to be refluxing), the balance of ethyl 2-fluoroacetate (20 g, 188.5 mmol) was slowly added (to maintain 4045°C) and the whole reaction mixture was heated for 3 h at 60°C. The reaction mixture was allowed to attain room température and cooled to 0°C. Acetaldehyde (13.6 mL, 240.35 mmol) was added and resulting mixture was brought slowly to the boiling point (80°C) and continued for additional 1 h. After cooling, it was poured into water and extracted with dichloromethane. The combined organic layer was washed with 5% aqueous sodium carbonate solution, water, dried over sodium sulfate and concentrated to afford the title compound (21 g, 68%) as a brown liquid. GCMS m/z 132.¹H NMR (400 MHz, CDCI₃): 6.23-6.09 (m, 1 H). 4.35 (q, 2 H), 1.79 (dd, 3 H), 1.37 (t, 3 H).

172 φ Step 2: préparation of (Z)-ethyl 4-bromo-2-fluorobut-2-enoate. To a stirred solution of (Z)-ethyl 2-fluorobut-2-enoate (2 g, 15.15 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (2.98 g, 16.66 mmol) and benzoyl peroxide (2.5 mg). The mixture was heated to reflux and continued for 6 h. The reaction mixture was filtered and the filtrate was concentrated. The crude material thus obtained was purified by column chromatography (1% ethyl acetate/hexane) to afford the title compound (0.4 g, 13%) as a yellow liquid. ¹H NMR (400 MHz, CDCI₃): 6.41-6.30 (m, 1 H). 4.30 (q, 2 H), 4.05 (dd, 2 H), 1.34 (t, 3 H).

Step 3: préparation of (Z)-ethyl 4-acetoxy-2-fluorobut-2-enoate. To a stirred solution of (Z)-ethyl 4-bromo-2-fluorobut-2-enoate (2.5 g, 11.84 mmol) in Ν,Νdimethylformamide (25 mL) was added sodium acetate (1.94 g, 23.69 mmol) and resulting solution heated at 70°C for 6 h. The reaction mixture was allowed to attain room température, diluted with water and extracted with diethyl ether. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (2.5% ethyl acetate/hexane) to afford the title compound (0.75 g, 33%) as a yellow liquid. ¹H NMR (400 MHz, CDCI₃) δ 6.26-6.14 (m, 1 H). 4.79 (dd, 2 H), 4.29 (q, 2 H), 2.07 (s, 3 H), 1.34 (t, 3 H).

Step 4: préparation of (Z)-2-fluoro-4-hydroxybut-2-enoic acid. To a solution of lithium hydroxide-hydrate (0.99 g, 23.68 mmol) in water (12 mL) was added solution of (Z)-ethyl 4-acetoxy-2-fluorobut-2-enoate (1.5 g, 7.89 mmol) in tetrahydrofuran (12 mL) and stirred at room température for 2.5 h. The reaction mixture was acidified with 2NHCI and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to afford the title compound (0.45g, 48%) as a yellow solid. ¹H NMR (400 MHz, CDCI3) δ 13.45 (b,s, 1 H), 6.18-6.06 (m, 1

H), 5.06 (bs,1 H), 4.15 (m, 2 H).

Step 5: préparation of 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2Z)-

2-fluoro-4-hydroxybut-2-enoyl]piperidin-3-yl}-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1{(3H)-1-[(2E)-5-hydroxypent-2-enoyl]piperidin-3-yl}-1 H-pyrazole-4-carboxamide (Example ) employing (Z)-2-fluoro-4-hydroxybut-2-enoic acid. MS (M+H) m/z516.¹H NMR (400 MHz, DMSO- ofe) δ 7.55-7.45 (m, 3 H), 7.40-7.34 (m, 1 H), 7.15 (t, 1 H), 7.01 (d, 2 H), 6.40 (bs, 2 H), 5.66-5.50 (m, 1 H), 4.97 (t, 1 H), 4.27 (bs, 1 H), 4.10 (bs, 2 H), 4.00 (br, 1 H), 3.55 (br, 1 H), 3.00 (br, 1 H), 1.98 (bs, 2 H), 1.95-1.80 (m, 1 H), 1.52 (bs, 1 H).

Example 147

173

5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2E)-4-hydroxy-4methylpent-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

HO

Step 1 : préparation of 1,1,1-trichloro-4-methylpent-3-en-2-ol. To a stirred solution of 3-methylbut-2-enal (4 g, 47.55 mmol) in anhydrous Ν,Ν-dimethylformamide (80 mL) was added trichloroacetic acid (11.65 g, 71.32 mmol) and sodium trichloroacetate (13.22 g, 71.32 mmol) at room température. After 3 h of stirring at room température the reaction mixture was diluted with diethyl ether (200 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The precipitated solids were filtered and washed with diethyl ether (3x50 mL). The combined organics were again washed with saturated aqueous sodium bicarbonate (2x50 mL), brine, dried over sodium sulfate and filtered. The solvent was evaporated to afford the title compound as light yellow solid. ¹H NMR (400 MHz, CDCI₃) δ 5.45-5.35 (m, 1 H), 4.11 (bs, 2 H), 1.73 (s, 3 H), 1.67 (s, 3 H).

Step 2: préparation of (E)-4-hydroxy-4-methylpent-2-enoic acid. To a stirred solution of compound 1,1,1-trichloro-4-methylpent-3-en-2-ol (7 g, 34.39 mmol) in dimethoxyethane:water (4:3,140 mL) was added powdered NaOH (8.25 g, 206.38 mmol) and the resulting mixture was stirred at room température for 5 mins and then heated at 55°C for 12 h. The mixture was allowed to attain room température and excess dimethoxyethane was evaporated under reduced pressure. The remaining aqueous phase was acidified to pH = 1 by slow addition of 2N aqueous HCl and extracted with ethylacetate (2x 200 mL). Evaporation of solvent followed by purification by silica gel coiumn chromatography (15% EtOAc-Hexane) afforded the title compound as light yellow solid. ¹H NMR (400 MHz, CDCI₃) δ 7.12 (d, 1 H), 6.03 (d, 1 H), 1.38 (s, 6 H).

Step 3: préparation of 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2E)-

4-hydroxy-4-methylpent-2-enoyl]piperidin-3-yl}-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1{(3R)-1-[(2E)-5-hydroxypent-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide (Example ) employing (E)-4-hydroxy-4-methylpent-2-enoic acid. MS (M+H) m/z 526.¹H NMR (400 MHz, DMSO- cfe) δ 7.55-7.45 (m, 3 H), 7.40-7.30 (m, 1 H), 7.15 (t, 1 H), 7.02

174 (d, 2 H), 6.80-6.65 (m, 1 H), 6.55-6.37 (m, 3 H), 4.83 (d, 1 H), 4.55-4.00 (m, 3 H), 3.42 (t, 0.5 H), 3.15-2.95 (m, 1 H), 2.75-2.65 (m, 0.5 H), 2.05-1.80 (m, 3 H), 1.47 (bs, 1 H),

1.20 (d, 6 H).

Example 148

5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2E,4S)-4-hydroxypent-2enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

HQ

Step 1 : Préparation of (E)-4-oxopent-2-enoic acid. To a mixture of 2-oxoacetic acid (11.17 g, 121.45 mmol) and ground morpholinium hydrochloride (15 g, 121.45 mmol) was stirred in acetone (120 mL) at room température for 1 h and then heated at reflux for another 16 h. The reaction mixture was cooled and concentrated under vacuo to remove excess acetone. The crude residue thus obtained was dissolved in water (100 mL) and the aqueous phase was extracted with 10% IPA in dichlorométhane (5x 100 mL). The combined organic layer was dried over sodium sulfate and filtered. Evaporation of solvent afforded title as off white solid. This material was used for next step without further purification. ¹H NMR (400 MHz, DMSO-de) δ ppm 13.06 (bs, 1 H),

6.79 (d, 1 H), 6.67 (d, 1 H), 2.33 (s, 3 H).

Step 2: Préparation of (E)-4-hydroxypent-2-enoic acid. To a stirred solution of (E)-4-oxopent-2-enoic acid (7.6 g, 66.61 mmol) in 10% aqueous potassium hydrogen carbonate (133 mL) was added potassium borohydride (4.02 g, 74.60 mmol) at 4-5°C in portions and the resultîng reaction mixture was allowed to stir at room température for 4 h. The reaction mixture was cooled to 0°C and acidified with 6N aqueous HCl to pH = 5-

6. The aqueous phase was extracted with 10% IPA in dichlorométhane (8x100 mL). The combined organic layer was dried over sodium sulfate and filtered. Evaporation of solvent followed by purification using column chromatography (1.5% methanoldichloromethane) afforded the title compound (5g, 65%) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.20 (bs, 1 H), 6.80 (dd, 1 H), 5.84 (dd, 1 H), 5.04 (bs, 1 H), 4.25-4.35 (m, 1 H), 1.15 (d, 3 H).

Step 3: préparation of rac-5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-((3R)-1[(2E,4S)-4-hydroxypent-2-enoyl]piperidin-3-yl}-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1175 {(3R)-1-[(2£)-5-hydroxypent-2-enoyl]piperidin-3-yl}-1 H-pyrazole-4-carboxamide (Example ) employing (E)-4-hydroxypent-2-enoic acid. MS (M+H) m/z 512.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.55-7.45 (m, 3 H), 7.40-7.30 (m, 1 H), 7.15 (t, 1 H), 7.02 (d, 2 H), 6.70-6.60 (m, 1 H), 6.60-6.50 (m, 1 H), 6.39 (bs, 2 H), 4.96 (d, 1 H), 4.55-4.00 (m, 4 H), 3.43 (t, 0.5 H), 3.10-3.05 (m, 1 H), 2.75-2.60 (m, 0.5 H), 2.00-1.75 (m, 3 H),

1.47 (bs, 1 H), 1.15 (bs, 3 H).

Step 4: préparation of 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1[(2E,4S)-4-hydroxypent-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide. rac-5amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-((3R)-1-((E)-4-hydroxypent-2enoyl)piperidin-3-yl)-1 H-pyrazole-4-carboxamide was chirally separated by supercritical fluid chromatography (Chiralcel OD-H, 20 x 250 mm, 50, hexane.ethanol, methanol, N,N-diisopropylethylamine (70:20:10:0.1), 18 mL/min). Isolation ofthe first eluting isomer afforded the title compound. MS (M+H) m/z 512.¹H NMR (400 MHz, DMSO-cfe) δ ppm 7.55-7.45 (m, 3 H), 7.40-7.30 (m, 1 H), 7.15 (t, 1 H), 7.02 (d, 2 H), 6.70-6.60 (m, 1 H), 6.60-6.50 (m, 1 H), 6.39 (d, 2 H), 4.96 (d, 1 H), 4.55-4.00 (m, 4 H), 3.43 (t, 0.5 H), 3.10-3.05 (m, 1 H), 2.75-2.60 (m, 0.5 H), 2.00-1.75 (m, 3 H), 1.47 (bs, 1 H), 1.15 (bs, 3 H).

Example 149 5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-((R)-1-((R,E)-4-hydroxypent-2enoyl)piperidin-3-yl)-1H-pyrazole-4-carboxamide

rac-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-((3R)-1-((E)-4-hydroxypent-2enoyl)piperidin-3-yl)-1 H-pyrazole-4-carboxamide (prepared as described in Example , step 3) was chirally separated by supercritical fluid chromatography (Chiralcel OD-H, 20 x250 mm, 5D, hexane.ethanol, methanol, N,N-diisopropylethylamine (70:20:10:0.1), 18 mL/min). Isolation of the second eluting isomer afforded the title compound. MS (M+H) m/z512.¹H NMR (400 MHz, DMSO-cfe) δ 7.55-7.45 (m, 3 H), 7.40-7.30 (m, 1 H), 7.15 (t, 1 H), 7.02 (d, 2 H), 6.70-6.60 (m, 1 H), 6.60-6.50 (m, 1 H), 6.39 (bs, 2 H), 4.96 (d, 1 H), 4.55-4.00 (m, 4 H), 3.43 (t, 0.5 H), 3.10-3.05 (m, 1 H), 2.75-2.60 (m, 0.5 H), 2.00-

1.75 (m, 3 H), 1.47 (bs, 1 H), 1.15 (bs, 3 H).

Example 150

176

5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-[(3R)-1-(2-fluoroacryloyl)piperidin-3y l]-1 H-pyrazole-4-carboxamide

To a solution of (fi)-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)1 H-pyrazole-4-carboxamide (prepared as described in Example 26, step 1) (200 mg, 0.48 mmol) in Λ/,/V-dimethylformanide (3 mL) at 0 °C was added (benzotriazol-1 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (235 mg, 0.53 mmol), N,Ndiisopropylethylamine (0.22 mL, 1.21 mmol) and 2-fluoroacrylic acid (43.6 mg, 0.48 mmol). After 30 min, the mixture was poured into water/ethyl acetate and the layers seperated. The organic layer was dried (Na₂SO₄) and concentrated. The crude product was purified by reverse-phase HPLC to afford the title compound. ¹H NMR (600 MHz, DMSO-de) δ ppm 1.57 (m, 1 H), 1.89 - 2.09 (m, 3 H), 2.97 (m, 0.5 H), 3.22 (m, 1 H), 3.61 (m, 0.5 H), 3.97 (m, 1 H), 4.13 - 4.42 (m, 2 H), 5.11 - 5.38 (m, 2 H), 6.45 (br. s., 2 H), 7.00 - 7.09 (m, 2 H), 7.15 - 7.24 (m, 1 H), 7.42-7.38 (m, 1 H), 7.51 - 7.59 (m, 3 H). MS (M+H) m/z 486.1.

Example 151 5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-{(3R)-1-[(2E)-4-hydroxybut-2-enoylJpiperidin-3-yl}-1H-pyrazole-4-carboxamide

HQ

To a solution of (R)-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)1 H-pyrazole-4-carboxamide (prepared as described in Example 26, step 1) (100 mg, 0.24 mmol), 0-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (112 mg, 0.29 mmol), (E)-4-hydroxybut-2-enoic acid (98 mg, 0.97 mmol) in 2 mL of N,Ndimethylformamide was added N,N-diisopropylethylamine (0.13 mL, 0.73 mmol) dropwise. The solution was stirred ovemight at room température. The reaction mixture was poured into water/ethyl acetate and the layers seperated. The organic extract was dried (NaaSO^, filtered and concentrated. The crude product was purified

177 by reverse-phase HPLC to afford the title compound. ¹H NMR (400 MHz, methanol-cQ δ ppm 1.64 (d, J=12.88 Hz, 1 H) 1.97 (dt, J=13.64, 3.03 Hz, 1 H) 2.06 - 2.25 (m, 2 H)

2.76 - 2.95 (m, 0.5 H) 3.07 - 3.24 (m, 1 H) 3.52 - 3.71 (m, 0.5 H) 4.05 - 4.30 (m, 4 H)

4.37 - 4.72 (m, 1 H) 6.56 - 6.72 (m, 1 H) 6.75 - 6.93 (m, 1 H) 6.96 - 7.08 (m, 3 H) 7.10 -

7.32 (m, 2 H) 7.50 (d, J=8.34 Hz, 2 H). MS (M+H) m/z 498.2.

Example 152

5-amino-1-{(3R)-1-[(2E)-3-cyanoprop-2-enoyl]piperidin-3-yl}-3-[4-(2,4difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide

A solution of (R)-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-3-yl)-1Hpyrazole-4-carboxamide (prepared as described in Example 26, step 1) (0.19 g, 0.468 mmol) in Λ/,/V-dimethylformamide (4 mL) was cooled to -10 °C (ice-salt). Benzotriazol-1yloxy)tris (dimethylamino) phosphonium hexafluorophosphate (228 mg, 0.515 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.17 mmol) were added followed by (E)-3cyanoacrylic acid (prepared as described in Example, step 2) (50 mg, 0.515 mmol) and the mixture was stirred at -10 °C for additional 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by préparative TLC (5% MeOH-dichloromethane) to afford the title compound (80 mg, 35%) as off white solid. MS (M+H) m/z493.4.¹H NMR (400 MHz, DMSO-cfe) δ 1.46 (m, 1 H), 1.82 (m, 1 H), 1.96 (m, 2 H), 2.86 (m, 0.5 H), 3.07-3.13 (m, 1 H), 3.48-3.53 (m, 0.5 H), 3.98-4.42 (m, 3 H), 6.37 (m, 2 H), 6.49 (dd, 1 H), 6.98-7.00 (m, 2 H), 7.12 (t, 1 H), 7.29-7.34 (m, 1 H), 7.42-7.48 (m, 3 H), 7.75-7.84 (m, 1 H).

Example 153 1-[(3R)-1-acryloylpiperidin-3-yl]-5-amino-3-{4-[(5-chloro-3-fluoropyridin-2yl)oxy]phenyl}-1H-pyrazole-4-carboxamide

178

Step 1 : préparation of 4-((tert-butyldimethylsilyl)oxy)benzoic acid. To a stirred solution of 4-hydroxybenzoic acid (200 g, 1.45 mol) in Ν,Ν-dimethylformamide (3.25 L), was added imidazole (595 g, 8.67 mol) followed by addition of tert-butyl dimethylsilyl chloride (327 g, 2.17 mol) at 0 °C. The resulting reaction mixture was stirred at room température for 16 h. The reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2x2 L). The combined organic layers were washed with water (2 x 1 L) followed by brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography in hexanes to afford the title compound (170 g, 47 %) as white solid. ¹H NMR (400 MHz, CDCI₃): 7.96-7.98 (d, J = 8.68 Hz, 2 H), 6.86-6.88 (d, J= 8.68 Hz, 2 H), 0.98 (s, 9 H), 0.23 (s, 6

H).

Step 2: préparation of 2-((4-((tertbutyldimethylsilyl)oxy)phenyl)(methoxy)methylene)malononitrile. To a stirred suspension of sodium hydride (60%, 22.8 g, 0.95 mol) in 600 mL tetrahydrofuran, was added malononitrile (31.4 g, 0.47 mol, dissolved in 600 mL of tetrahydrofuran) at 0°C. The resulting suspension was stirred at 0 °C for 1 h. To another 3 necked round bottom flask was charged 4-((tert-butyldimethylsilyl)oxy)benzoic acid (120 g, 0.47 mol dissolved in 1200 mL of tetrahydrofuran) followed by N-methylmorpholine (52.9 mL, 0.47 mol) and isobutyl-chloroformate (61.94 mL, 0.47 mol, dissolved in 600 mL tetrahydrofuran) at -30 °C. The resulting white suspension was stirred at -30 °C for 1 h. This acid chloride suspension was slowly added (through cannula) at 0 °C to the stirred suspension of NaH. The resulting suspension was stirred at room température for 3 h. Dimethyl sulfate (135.9 mL, 1.4 mol) was added to the suspension at room température and the resulting reaction mixture was heated at reflux for 16 h. The reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2x2 L). The combined organic layers were washed with water (2 x 1 L) followed by brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the title compound (76 g, 61 %) as light yellow solid. MS (M+H) m/z315.6. ¹H NMR (400 MHz, CDCI₃) δ 7.43 (d, J =8.68 Hz, 2 H), 6.95 (d, J =11.4 Hz, 2 H), 3.95 (s, 3 H), 0.98 (s, 9 H), 0.24 (s, 6 H).

Step 3: préparation of benzyl 3-(5-amino-3-(4-((tertbutyldimethylsilyl)oxy)phenyl)-4-cyano-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate. To a stirred solution of 2-((4-((tert-butyldimethylsilyl)oxy)phenyl)(methoxy)methylene)malononitrile (76 g, 0.24 mol) in éthanol (760 mL) was added benzyl 3hydrazinylpiperidine-1-carboxylate (Example 1, Step 8) (68.9 g, 0.24 mol) followed by

179 addition of triethylamine (37 mL, 0.26 mol) at room température. The resulting reaction mixture was heated to reflux for 16 h and then concentrated under reduced pressure.

The residue was diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with water (500 mL) followed by brine, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (102 g, 89 %) as an off white solid. MS (M+H) m/z 532.¹H NMR (400 MHz, CDCh) δ 7.76 (d, J= 8.48 Hz, 2 H), 7.31-7.38 (m, 5 H), 6.86 (d, J = 8.48 Hz, 2 H), 5.10-

5.18 (m, 2 H), 4.44 (m, 1 H), 4.28 (m, 1 H), 4.16 (m, 1 H), 3.82 (m, 1 H), 3.2 (m, 1 H),

2.83-2.90 (t, J= 12 Hz, 1 H), 2.25 (m, 1 H), 2.09-2.12 (m, 1 H), 1.88 (m, 1 H), 0.97 (s, 9 10 H), 0.20 (s, 6 H).

Step 4: préparation of benzyl 3-(5-acetamido-3-(4-((tertbutyldimethylsilyl)oxy)phenyl)-4-cyano-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate. To a stirred solution of benzyl 3-(5-amino-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-cyano1/+pyrazol-1-yl)piperidine-1-carboxylate (120 g, 0.19 mol) in dichloromethane (1.2 L) 15 was added triethylamine (133 mL, 0.96 mol) followed by drop-wise addition of acetyl chloride (78.5 mL, 1.9 mol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 minutes and then at room température for 16 h. The reaction mixture was diluted with cold water (500 mL). The resulting aqueous layer was extracted with dichloromethane (2 x 500 mL). The combined organic layers were washed with water 20 (500 mL) followed by brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (30% ethyl acetate/hexanes) to afford the title compound (100 g). MS (M+H) m/z 574. ¹H NMR (400 MHz, CDCIa) δ 7.79 (d, J = 8.48 Hz, 2 H), 7.33 (m, 5 H), 6.88 (d, J= 8.48 Hz, 2 H), 5.11 (s, 2 H), 4.03-4.24 (m, 3 H), 3.31-3.32 (m, 2 H), 2.90 (t, J= 12 Hz, 1 H), 2.21 25 (m, 5 H), 1.88 (m, 1 H), 0.97 (s, 9 H), 0.20 (s, 6 H).

Step 5: préparation of benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1 Hpyrazol-1-yl)piperidine-1-carboxylate. To a stirred solution of benzyl 3-(5-acetamido-3(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-cyano-1 /7-pyrazol-1 -yl)piperidine-1 -carboxylate (165 g, 0.35 mol) in methanokwater (4:1, 2.8 L) was added LiOHH₂O (43.8 g, 1.04 mol) 30 at 0°C. The resulting reaction mixture was stirred at 0°C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (1L) and neutralized with 1N HCl (1.8 L) to pH 6.5. The precipitated solid was filtered, washed with water (500 mL x 2) followed by hexanes and dried under vacuum. The solid was dissolved in ethyl acetate (1 L) and washed with water (2 x 500 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure

180 to afford the title compound (104 g) as off white solid. MS (M+H) m/z 460.¹H NMR (400 MHz, CDCI3) δ 10.48 (s, 1 H), 9.83 (s, 1 H), 7.67 (d, J= 8.48 Hz, 2 H), 7.33 (m, 5 H),

6.87 (d, J= 8.48 Hz, 2 H), 5.06 (s, 2 H), 4.23 (bs, 1 H), 4.05 (m, 1 H), 3.90 (m, 1 H), 3.00 (t, J = 11.0 Hz, 1 H), 2.17 (s, 3 H), 2.0 (m, 1 H), 1.87 (m, 1 H), 1.51 (m, 1 H).

Step 6: préparation of (fi)-benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)1 H-pyrazol-1 -yl)piperidine-1 -carboxylate. raobenzyl 3-(5-acetamido-4-cyano-3-(4hydroxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate was chirally separated by supercritical fluid chromatography (ChiralPak AS-H, 50 x 250 mm, 86/14, COa/methanol, 235 mL/min flow rate). Isolation of the first eluting isomer afforded the title compound.

Step 7; préparation of (R)-benzyl 3-(5-acetamido-3-(4-((5-chloro-3-fluoropyridin-

2-yl)oxy)phenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate. A solution of (fi)benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1H-pyrazol-1-yl)piperidine-1carboxylate (1 g, 2.2 mmol), césium carbonate (1.06 g, 3.3. mol), 5-chloro-2,3difluoropyridine (369 mg, 2.4 mmol) in DMSO (7.25 mL) was heated to 80 °C for 3 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (Na₂SO₄), filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/dichloromethane) to afford 0.86 g of the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 10.57 (br. s., 1 H), 8.26 (dd, J=9.85,2.20 Hz, 1 H), 8.10 (d, J=2.26 Hz, 1 H), 7.84 - 7.91 (m, 2 H), 7.25 - 7.42 (m, 7 H), 5.07 (br. s., 2 H), 4.30 (br. s., 1 H), 4.04 - 4.15 (m, 1 H), 3.90 (br. s., 1 H), 3.04 (t, J=11.04 Hz, 1 H), 2.15 (br. s., 3 H), 2.04 (d, J=5.02 Hz, 2 H), 1.89 (br. s., 1 H), 1.46 1.61 (m, 1 H)

Step 8: préparation of (R)-5-amino-3-(4-((5-chloro-3-fluoropyridin-2yl)oxy)phenyl)-1 -(piperidin-3-yl)-1 H-pyrazole-4-carboxamide. (R)-benzyl 3-(5acetamido-3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-4-cyano-1H-pyrazol-1yl)piperidine-1-carboxylate (860 mg, 1.46 mmol) was dissolved in 80% sulfuric acid (20 mL) and stirred at room température for 18 h. The reaction mixture was poured into ice and concentrated ammonium hydroxide was added slowly until the pH reached 10. The mixture was extracted with ethyl acetate. The organic layer was dried (Na₂SO4), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 8.25 (dd, J=9.9, 2.1 Hz, 1 H), 8.08 (d, J=2.3 Hz, 1 H), 7.51 - 7.56 (m, 2 H), 7.24 - 7.29 (m, 2 H), 7.06 (m, 2 H), 6.31 (s, 2 H), 4.03 - 4.13 (m, 2 H), 3.00 (dd, J=11.7, 3.5 Hz, 1 H), 2.87 (d, J=12.1 Hz, 1 H), 2.74 - 2.83 (m, 1 H), 2.36 - 2.47 (m, 1 H), 1.85 -1.95 (m, 2 H), 1.70 (m, 1 H), 1.43 -1.57 (m, 1 H)

181

Step 9: préparation of 1-[(3fi)-1-acryloylpiperidin-3-yl]-5-amino-3-{4-[(5-chloro-3fluoropyridin-2-yl)oxy]phenyl}-1 H-pyrazole-4-carboxamide. Diisopropylamine (0.61 mL,

3.5 mmol) was added to a solution of (fi)-5-amino-3-(4-((5-chloro-3-fluoropyridin-2yl)oxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (600 mg, 1.4 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (691 mg,

1.5 mmol) and acrylic acid (0.11 mL, 1.5 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room température for 30 min and then purified by reverse-phase HPLC to afford the title compound. MS (M+H) m/z 485.¹H NMR (400 MHz, DMSO-ofe) δ ppm 8.25 (dd, J=9.91, 2.26 Hz, 1 H), 8.09 (d, J=2.26 Hz, 1 H), 7.55 (d, J=6.27 Hz, 2 H), 7.24 - 7.29 (m, 2 H), 6.77 - 6.91 (m, 1 H), 6.40 (br. s., 2 H), 6.05 -

6.18 (m, 1 H), 5.61 - 5.74 (m, 1 H), 4.52 (d, J=10.04 Hz, 1 H), 4.01 - 4.38 (m, 2 H), 3.43 - 3.53 (m, 1 H), 3.01 - 3.13 (m, 1 H), 2.72 - 2.79 (m, 1 H), 1.81 - 2.05 (m, 3 H), 1.47 (br. s., 1 H).

Example 154 5-amino-3-{4-[(5-chloro-3-fluoropyridin-2-yl)oxy]phenyl}-1-{(3R)-1-[(2E)-4hydroxybut-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

A solution of (R)-5-amino-3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1(piperidin-3-yl)-1 H-pyrazole-4-carboxamlde in N,N-dimethylformamide (2 mL) was cooled to 0 °C and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (265 mg, 0.6 mmol), N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) and (E)-4-hydroxybut-2-enoic acid (61.3 mg, 0.6 mmol) were added. After 30 min, the reaction was poured into water/ethyl acetate and the layers seperated. The organic layer was dried (Na₂SO4) and the solvent removed. The crude product was purified by reverse-phase-HPLC to afford the title compound (50 mg). MS (M+H) m/z 515.

Example 155 5-amino-3-{4-[(5-chloro-3-fluoropyridin-2-yl)oxy]phenyl}-1-{(3R)-1-[(2E)-4,4difluorobut-2-enoyl]piperidin-3-yl}-1 H-pyrazole-4-carboxamide

182

F (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (274 mg, 0.62 mmol), Ν,Ν-diisopropylethylamine ( 0.24 mL, 1.4 mmol) and (E)-4,4difluorobut-2-enoic (prepared as described in Example 133, step 3) (100 mg, 0.82 mmol) were added to a solution of (R)-5-amino-3-(4-((5-chloro-3-fluoropyridin-2yl)oxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (0.32 g, 0.745 mmol) in

N, N-dimethylfomnamide (4 mL) at -10 °C. After 15 min, the reaction was diluted with water/ethyl acetate. The layers were separated and the organic extract washed with brine, dried (Na₂SO4) and concentrated. The crude product was purified by silica gel column chromatgraphy (3.5% MeOH/dichloromethane) to afford the title compound (120 mg, 30%). ¹H NMR (400 MHz, DMSO-cfe) δ 1.49 (m, 1 H), 1.87-2.32 (m, 3 H), 2.83 (t,

O. 5 H), 3.09-3.17 (m, 1 H), 3.52-3.58 (m, 0.5 H), 3.99-4.49 (m, 3 H), 6.39 6.68 (m, 4 H), 7.13-7.21 (m, 1 H), 7.27 (d, 2 H), 7.53-7.56 (m, 2 H), 8.08 (d, 1 H), 8.25 (dd, 1 H). MS (M+H) m/z535.

Example 156

5-amino-3-{4-[(5-chloro-3-fluoropyridin-2-yl)oxy]phenyl}-1-{(3R)-1-[(2E)-4fluorobut-2-enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

The title compound was prepared analogous to 5-amino-3-(4-[(5-chloro-320 fluoropyridin-2-yl)oxy]phenyl}-1 -{(3R)-1 -[(2E)-4,4-difluorobut-2-enoyl]piperidin-3-yl)-1 Hpyrazole-4-carboxamide (Example ) employing (E)-4-fluorobut-2-enoic acid (prepared as described in Example , step 2). ¹H NMR (400 MHz, DMSO-cfe) δ 8.24 (dd, 1 H), 8.08 (d, 1 H), 7.55 (d, 2 H), 7.27 (d, 2 H), 6.67-6.77 (m, 2 H), 6.38 (br s, 2 H), 5.10 (dd, 2 H), 4.18-4.52 (m, 2 H), 4.05 (m, 1 H), 3.52 (t, 0.5 H), 3.04-3.12 (m, 1 H), 2.79 (t, 0.5 H),

1.84-1.99 (m, 2 H), 1.48 (m, 1 H). MS (M+H) m/z 517.

Example 157

183

1-[(3R)-1-acryloylpiperidin-3-yl]-5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}1 H-pyrazole-4-carboxamide

Step 1 : préparation of (R)-benzyl 3-(5-acetamido-3-(4-((5-chloropyridin-2yl)oxy)phenyl)-4-cyano-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate. 5-Chloro-2fluoropyridine (237 mg, 1.80 mmol) and CS2CO3 (1.95 g, 5.99 mmol) were added to a solution of (R)-benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1 H-pyrazol-1 yl)piperidine-1-carboxylate (prepared as described in Example, step 6) (500 mg, 1.20 mmol) in A/./V-dimethylformamide (1 mL) was added. The 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 (3x5 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%). ¹H NMR (400 MHz, CDCI3) δ ppm 8.10 - 8.18 (m, 1 H), 7.93 (d, J=8.78 Hz, 2 H), 7.66 (dd, J=8.66, 2.64 Hz, 1 H),

7.33 (s, 5 H), 7.11 - 7.20 (m, 2 H), 6.90 (d, J=8.78 Hz, 1 H), 5.12 (s, 2 H), 4.27 (d, J=11.04 Hz, 1 H), 4.08-4.20 (m, 2 H), 3.18-3.43 (m, 1 H), 2.91 (t, J=11.92 Hz, 1 H),

2.21 (s, 2 H), 1.83 -1.95 (m, 1 H), 1.48 -1.68 (m, 1 H).

Step 2: préparation of (R)-5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1(piperidin-3-yl)-1 H-pyrazole-4-carboxamide. (R)-benzyl 3-(5-acetamido-3-(4-((5chloropyridin-2-yl)oxy)phenyl)-4-cyano-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate (300 mg, 0.53 mmol) was added portion wise over 10 min to a stirred solution of concentrated sulfuric acid (6 mL) at 0°C. The reaction mixture was then allowed to stir at 30°C over 16 h, after which it was cooled to 0°C. Concentrated ammonium hydroxide was carefully added until pH = 7, ensuring that the température did not exceed 5°C. The mixture was then extracted with ethyl acetate (3x5 mL), and the combined organic layers were dried over sodium sulfate, and concentrated in vacuo to afford the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ ppm: 8.19 - 8.27 (m, 1 H), 7.91 - 8.02 (m, 1 H), 7.48 - 7.56 (m, 2 H), 7.19 - 7.22 (m, 2 H), 7.16 (s, 1 H), 6.32 (s, 2 H), 4.03 - 4.16 (m, 1 H), 3.31 (br. s., 1 H), 3.01 (dd, J=11.8, 3.5 Hz, 1 H), 2.87 (d, J=12.3 Hz, 1 H), 2.79 (dd, J=11.5,10.3 Hz, 1 H), 2.38-2.48 (m, 1 H), 1.81 -1.96 (m, 2 H), 1.71 (d, J=13.1 Hz, 1 H), 1.42-1.57,(m, 1 H).

184

Step 3: préparation of 1-[(3R)-1-acryloylpiperidin-3-yl]-5-amino-3-{4-[(5chloropyridin-2-yl)oxy]phenyl}-1 H-pyrazole-4-carboxamide. The title compound was prepared analogous to 1-[(3R)-1-acryloylpiperidin-3-yl]-5-amino-3-{4-[(5-chloro-3fluoropyridin-2-yl)oxy]phenyl}-1H-pyrazole-4-carboxamide (Example ) employing (R)-5amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(piperidin-3-yl)-1 H-pyrazole-4carboxamide to afford the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 8.30 (d, J=2.34 Hz, 1 H), 8.04 (dd, J=8.59,2.73 Hz, 1 H), 7.53 - 7.65 (m, 2 H), 7.28 (d, J=8.20 Hz, 2 H), 7.21 (d, J=8.59 Hz, 1 H), 6.79 - 6.98 (m, 1 H), 6.41 - 6.49 (m, 2 H), 6.06 - 6.26 (m, 1 H), 5.60 - 5.80 (m, 1 H), 4.05 - 4.61 (m, 3 H), 3.47 - 3.60 (m, 0.5 H), 3.05 - 3.20 (m, 1 H), 2.71 - 2.87 (m, 0.5 H), 1.83 - 2.12 (m, 3 H), 1.54 (br. s., 1 H). MS (M+H) m/z467.

Example 158 5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}-1-{(3R)-1-[(2E)-4-hydroxybut-2enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

The title compound was prepared analogous to 5-amino-3-{4-[(5-chloro-3fluoropyridin-2-yl)oxy]phenyl}-1-{(3R)-1-[(2E)-4-hydroxybut-2-enoyl]piperidin-3-yl}-1Hpyrazole-4-carboxamide (Example ) employing (R)-5-amino-3-(4-((5-chloropyridin-2yl)oxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (prepared as described in Example , Step 2) to afford the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ ppm

8.30 (d, J=2.34 Hz, 1 H), 8.04 (dd, J=8.59,2.73 Hz, 1 H), 7.53 - 7.65 (m, 2 H), 7.28 (d, J=8.20 Hz, 2 H), 7.21 (d, J=8.59 Hz, 1 H), 6.79 - 6.98 (m, 1 H), 6.41 - 6.49 (m, 2 H), 6.06 - 6.26 (m, 1 H), 5.60 - 5.80 (m, 1 H), 4.05 - 4.61 (m, 3 H), 3.47 - 3.60 (m, 0.5 H), 3.05 - 3.20 (m, 1 H), 2.71 - 2.87 (m, 0.5 H), 1.83 - 2.12 (m, 3 H), 1.54 (br. s., 1 H). MS (M+H) m/z467.

Example 159 5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}-1-{(3R)-1-[(2E)-4,4-difluorobut-2enoyl]plperidin-3-yl}-1H-pyrazole-4-carboxamide

185

F

The title compound was prepared analogous to 5-amino-3-{4-[(5-chloro-3fluoropyridin-2-yl)oxy]phenyl}-1 -{(3R)-1 -[(2E)-4,4-difluorobut-2-enoyl]piperidin-3-yl}-1 Hpyrazole-4-carboxamide (Example ) employing (R)-5-amino-3-(4-((5-chloropyridin-25 yl)oxy)phenyl)-1 -(pipe rid in-3-yl) -1 H-pyrazole-4-carboxamide (prepared as described in Example , Step 2) to afford the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ 8.23 (d, 1 H), 7.99 (dd, 1 H), 7.53 (t, 2 H), 7.21 (d, 2 H), 7.18 (m, 1 H), 7.15 (d, 1 H), 6.52-

6.60 (m, 2 H), 6.37-6.42 (m, 2 H), 4.19-4.49 (m, 2 H), 3.99-4.08 (m, 1 H), 3.55 (dd, 0.5 H), 3.05-3.17 (m, 1 H), 2.86 (m, 0.5 H), 1.99 (m, 2 H), 1.86-1.90 (m, 1 H), 1.50 (m, 1 H).

MS (M+H) m/z 517.

Example 160 5-amino-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}-1-{(3R)-1-[(2E)-4,4-dlfluorobut-2enoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide

The title compound was prepared analogous to 5-amino-3-[4-[(5-chloro-3-fluoropyridin2-yl)oxy]phenyl}-1 -{(3R)-1 -[(2E)-4-fluorobut-2-enoyl]piperidin-3-yl}-1 H-pyrazole-4carboxamide (Example ) employing (R)-5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (prepared as described in Example, Step 2) to afford the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ 8.23 (d, 1 H), 7.98 (dd,

1 H), 7.54 (d, 2 H), 7.21 (d, 2 H), 7.15 (d, 1 H), 6.74 (d, 2 H), 6.40 (d, 2 H), 5.10 (dd, 2 H), 4.18-4.52 (m, 2 H), 4.06 (m, 1 H), 3.51 (t, 0.5 H), 3.08 (q, 1 H), 2.79 (t, 0.5 H), 1.99 (m, 2 H), 1.86 (d, 1 H), 1.48 (m, 1 H). MS (M+H) m/z499.

Example 161 1-[(3R)-1-acryloylpiperidin-3-yl]-5-amino-3-(4-{[6-(trifluoromethyl)pyridin-225 yl]oxy}phenyl)-1 H-pyrazole-4-carboxamide

186

Step 1 : préparation of (R)-benzyl 3-(5-acetamido-4-cyano-3-(4-((6(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate. 2Chloro-6-(trifluoromethyl)pyridine (11.4 g, 62.6 mmol) and Cs₂CO₃ (55.6 g, 171 mmol) were added to a solution of (R)-benzyl 3-(5-acetamido-4-cyano-3-(4-hydroxyphenyl)-1 H· pyrazol-1-yl)piperidine-1-carboxylate (prepared as described Example , step 6) (26.2 g, 56.9 mmol) in DMSO (60 mL). The reaction mixture was heated to 110 °C for 3 hours and then allowed to cool to room température. The mixture was poured into water/ethyl acetate and the layers separated. The organic layer was dried (Na₂SO₄) and the solvent evaloprated to afford the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ ppm

8.16 (t, J=7.91 Hz, 1 H), 7.85 - 7.95 (m, 2 H), 7.68 (d, J=7.28 Hz, 1 H), 7.23 - 7.44 (m, 8 H), 5.07 (br. s., 2 H), 4.30 (br. s., 1 H), 4.09 (d, J=12.05 Hz, 1 H), 3.91 (br. s., 1 H), 3.41 (s, 1 H), 3.04 (t, J=10.67 Hz, 1 H), 1.82 - 2.19 (m, 7 H), 1.54 (br. s., 1 H). MS (M+H) m/z 605.4.

Step 2: préparation of (R)-5-amino-1 -(piperidin-3-yl)-3-(4-((6(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-pyrazole-4-carboxamide. To a round bottom flask containing (R)-benzyl 3-(5-acetamido-4-cyano-3-(4-((6(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate (26 g, 43 mmol) was added dropwise 80% sulfuric acid (160 mL) slowly at room température.

After addition was complété the reaction was warmed to 40 °C for 3 h. The mixture was then cooled to 0 °C and ice added to the mixture. The solution was then neutralized by slow addition of concentrated ammonium hydroxide. The resulting suspension was extracted with ethyl acetate. The combined organic layers were washed with water, dried (Na₂SO₄) and concentrated to afford the title compound. ¹H NMR (400 MHz,

DMSO-cfe) δ ppm 8.15 (t, J=8.00 Hz, 1 H), 7.68 (d, J=7.41 Hz, 1 H), 7.54 - 7.61 (m, 2 H), 7.34 - 7.40 (m, 1 H), 7.25 - 7.31 (m, 2 H), 7.03 - 7.20 (m, 2 H), 6.35 (s, 2 H), 4.09 -

4.18 (m, 1 H), 3.72 - 3.90 (m, 1 H), 3.03 (dd, J=11.71, 3.90 Hz, 1 H), 2.77 - 2.93 (m, 2 H), 2.37-2.50 (m, 1 H), 1.88 -1.98 (m, 2 H), 1.68-1.77 (m, 1 H), 1.45 -1.58 (m, 1 H). MS (M+H) m/z447.3.

Step 3: préparation of 1 -[(3R)-1 -acryloylpiperidin-3-yl]-5-amino-3-(4-{[6“ (trifluoromethyl)pyridin-2-yl]oxy}phenyl)-1 H-pyrazole-4-carboxamide. (Benzotriazol-1 -

187 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (5.45 g, 12.3 mmol), N,Ndïisopropylethylamine (5.10 mL, 28.0 mmol) and then acrylic acid (0.85 mL, 12.3 mmol) were added to a solution of (R)-5-amino-1-(piperidin-3-yl)-3-(4-((6(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-pyrazole-4-carboxamide (5.0 g, 11.2 mmol) in Ν,Ν-dimethylformamide (35 mL) at 0 °C. After 15 min, the reaction mixture was poured into water/ethyl acetate and the layers separated. The organic layer was dried (Na₂SO₄) and concentrated. The crude product was purified by reverse phase HPLC to afford the title compound. ¹H NMR (400 MHz, DMSO-de) δ ppm 8.15 (t, «/=8.00 Hz, 1 H), 7.49 - 7.77 (m, 3 H), 7.19 - 7.44 (m, 3 H), 6.73 - 7.02 (m, 1 H), 6.42 (br. s., 2 H),

6.13 (t, «/=19.51 Hz, 1 H), 5.55 - 5.80 (m, 1 H), 3.90 - 4.69 (m, 3 H), 3.50 (d, J=11.32 Hz, 1 H), 2.98 - 3.21 (m, 1 H), 2.76 (br. s., 1 H), 2.02 (br. s., 1 H), 1.87 (d, J=12.10 Hz, 1 H),

1.23 -1.60 (m, 1 H). MS (M+H) m/z 501.3.

Example 162 5-amino-1-{(3R)-1-[(2E)-4-hydroxybut-2-enoyl]piperidin-3-yl}-3-(4-{[6(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-1H-pyrazole-4-carboxamide

HO

N,N-diisopropylethylamine (0.13 mL, 0.72 mmol) was added dropwise to a solution of (R)-5-amino-1 -(piperidin-3-yl)-3-(4-((6-(trifluoromethyl)pyridin-2yl)oxy)phenyl)-1H-pyrazole-4-carboxamide (prepared as described in Example, step 2) (108 mg, 0.24 mmol), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (112 mg, 0.29 mmol), and (E)-4-hydroxybut-2-enoic acid (98.7 mg, 0.96 mmol) in DMF (2 mL). After 14 hrs, the reaction was poured into water/ethyl acetate and the layers separated. The organic layer was dried (Na₂SO₄) and concentrated. The crude product was purified by reverse phase HPLC to afford the title compound. ¹H NMR (600 MHz, DMSO-ofe) δ ppm 7.71 (d, «/=7.47 Hz, 1 H), 7.63 (d, «/=8.35 Hz, 2 H), 7.41 (d, J=8.35 Hz, 1 H), 7.28 - 7.35 (m, 2 H), 6.71 - 6.85 (m, 2 H), 6.65 (t, «/=13.62 Hz, 1 H), 6.46 (d, J=14.50 Hz, 2 H), 4.97 - 5.10 (m, 1 H), 4.59 (br. s., 1 H), 4.44 (br. s., 1 H), 4.04 - 4.32 (m, 4 H), 3.56 (br. s., 1 H), 3.12 (d, J=12.74 Hz, 1 H), 2.73 (br. s., 1 H), 1.96 - 2.11 (m, 1 H), 1.90 (br. s., 1 H), 1.53 (br. s., 1 H). MS (M+H) m/z 531.1.

Example 163

188

5-amino-1-{(3R)-1-[(2E)-4,4-difluorobut-2-enoyl]piperidin-3-yl}-3-(4-{[6 (trifluoromethyl)pyridin-2-yl]oxy}phenyl)-1H-pyrazole-4-carboxamide

F (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (163.4 mg, 0.37 mmol), N,N-diisopropylethylamine (0.15 mL, 0.85 mmol) and (E)-4,4difluorobut-2-enoic acid (prepared as described in Example 133, step 3) (45 mg, 0.37 mmol) were added to a solution of (R)-5-amino-1-(piperidin-3-yl)-3-(4-((6(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1 H-pyrazole-4-carboxamide (prepared as described in Example , step 2) (150 mg, 0.34 mmol) in N,N-dimethylformamide (3 mL).

After 30 min, the reaction was poured into water/ethyl acetate. The layers were separated and the organic layer was washed with brine, dried (Na₂SO4) and concentrated. The crude product was purified by silica gel coiumn chromatography (3% MeOH/dichloromethane) to afford the title compound (70 mg, 38%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.13 (t, 1 H), 7.66 (d, 1 H), 7.56 (t, 2 H), 7.36 (d, 1 H), 7.27 (d, 2 H),

7.13-7.25 (m, 1 H), 6.30-6.80 (m, 4 H), 3.95-4.55 (m, 3 H), 3.57 (dd, 0.5 H), 3.14 (t, 1 H), 2.78 (m, 0.5 H), 2.07 (bs, 2 H), 1.75-1.95 (m, 1 H), 1.49 (bs, 1 H). MS (M+H) m/z 551.

Example 164 5-amino-1-{(3R)-1-[(2E)-4-fluorobut-2-enoyl]piperidin-3-yl}-3-(4-{[620 (trifluoromethyl)pyridin-2*yl]oxy}phenyl)-1H-pyrazole-4-carboxamide

The title compound was prepared analogous to 5-amino-1-{(3R)-1-[(2E)-4,4dÎfluorobut-2-enoyl]piperidin-3-yl}-3-(4-{[6-(trifluoromethyl)-pyridin-2-yl]oxy}phenyl)-1Hpyrazole-4-carboxamide (Example) employing (E)-4-fluorobut-2-enoic acid (prepared 25 as described in Example , Step 2) to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (bs, 1 H), 1.80-1.90 (m, 1 H), 1.99 (bs, 2 H), 2.76 (t, 0.5 H), 3.08 (t, 1 H), 3.52 (t, 0.5 H), 4.00-4.60 (m, 3 H), 5.04 (d, 1 H), 5.15 (d, 1 H), 6.40 (bs, 2 H),

189

6.65-6.80 (m, 2 H), 7.27 (d, 2 H), 7.36 (d, 1 H), 7.57 (d, 2 H), 7.66 (d, 1 H), 8.13 (t, 1 H). MS (M+H) m/z 533.

Example 165

5-amino-1-[(3R)-1-(2-fluoroacryloyl)piperidin-3-yl]-3-(4-{[6-(trifluoromethyl)pyridin

2-yl]oxy}phenyl)-1H-pyrazole-4-carboxamide

(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (218 mg, 0.49 mmol), diisopropylamine (0.2 mL, 1.12 mmol) and 2-fluoroacrylic acid (40.3 mg, 0.45 mmol) were added to a solution of (R)-5-amino-1-(piperidin-3-yl)-3-(4((6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1 H-pyrazole-4-carboxamide (prepared as described in Example , step 2) (200 mg, 0.45 mmol) in N,N-dimethylformamide (3 mL) at 0 °C. After 30 min, the mixture was poured into water/ethyl acetate and the layers separated. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by reverse phase HPLC to afford the title compound. ¹H NMR (600 MHz, DMSO-cfe) δ ppm 8.18 (t, /=7.69 Hz, 1 H), 7.70 (d, /=7.47 Hz, 1 H), 7.62 (d, /=8.35 Hz, 2 H), 7.41 (d, /=8.35 Hz, 1 H), 7.27 - 7.34 (m, 2 H), 6.45 (s, 2 H), 5.31 (br. s., 1 H), 5.11 - 5.26 (m, 2 H), 4.10-4.44 (m, 3 H), 3.79-4.06 (m, 1 H), 3.66 (m, 1 H), 3.26 (m, 1 H),

2.96 (m., 1 H), 2.07 (m, 1 H), 1.95 (d, /=12.30 Hz, 1 H), 1.58 (m, 1 H). MS (M+H) m/z 519.1.

Example 166 5-amino-1-{(3R)-1-[(2E)-3-cyanoprop-2-enoyl]piperidin-3-yl}-3-(4-{[6(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-1H-pyrazole-4-carboxamide

The title compound was prepared analogous to 5-amino-1-{(3R)-1-[(2E)-4,4difluorobut-2-enoyl]piperidin-3-yl}-3-(4-{[6-(trifluoromethyl)-pyridin-2-yl]oxy)phenyl)-1Hpyrazole-4-carboxamide (Example) employing (E)-3-Cyanoacrylic acid (prepared as described in Example , Step 2) to afford the title compound. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 8.14 (t, 1 H), 7.83 (t, 1 H), 7.66 (d, 1 H), 7.55-7.58 (m, 2 H), 7.36 (d, 1

190

H), 7.26-7.29 (m, 2 H), 6.52 (dd, 1 H), 6.37-6.41 (m, 2 H), 4.07-4.48 (m, 3 H), 3.58 (dd, * 0.5 H), 3.14-3.20 (m, 1 H), 2.90 (t, 0.5 H), 2.01 (m, 2 H), 1.85 (m, 1 H), 1.49 (m, 1 H).

MS (M+H) m/z 526.4.

Example 167

In Vitro Pharmacology

Human BTK LanthaScreen Assay

TR-FRET LanthaScreen assays were performed by incubating a dilution sériés of inhibitor concentrations with 50 μΜ ATP, 100 nM FAM-Srctide peptide substrate (5FAMGEEPLYWSFPAKKK-NH2, SEQ ID NO,: 1, Molecular Devices, RP7595) and 70 pM of 10 human full-length BTK Kinase (expressed in Sf9 insect cells and purified in-house). The assays were performed with and without pre-incubating the inhibitors with the enzyme for 60 minutes before starting the kinase reaction by adding ATP and the peptide substrate. Samples containing enzyme but no inhibitor were included to détermine the maximal extent of reaction. Samples containing no enzyme served as the négative 15 control. The kinase reaction mixtures were incubated at room température for 60 minutes before stopping the kinase activity by the addition of 15 mM EDTA. The extent of peptide phosphorylation by BTK was detected using a Terbium-conjugated antiphospho-Tyrosine antibody (Tb-PT66 antibody, Invitrogen # PV3557). Phosphorylation of peptide substrate was measured by determining the ratio of 520/495 nm on an

Envision Multi-label Reader (Perkin Elmer) and IC50 values were calculated by fitting the data to a four-parameter équation using XLFit4 (IDBS).

EX	IC50 (nM)
1	1.4
2	0.37
3	3.3
4	35.0
5	32.1
6	11.7
7	16.2
8	16.5
9	23.3

EX	IC50 (nM)
10	13.5
11	5.9
12	54.2
13	2.6
14	12.5
15	0.64
16	1.28
17	0.4
18	3

Table 1. BTK Inhibition

EX	IC50 (nM)
19	1.0
20	3.4
21	22.5
22	1.0
23	9.2
24	5.0
25	2.18
26	17.3
27	1.3

EX	IC50 (nM)
28	1.0
29	2.9
30	0.43
31	2.8
32	4.1
33	24.1
34	3.8
35	1.7
36	25.3

EX	IC50 (nM)
37	0.79
38	2.5
39	1.1
40	1.5
41	6.3
42	1.2
43	0.77
44	24.4
45	0.81

191

'------------------------------------------------ EX	IC50 (nM)
46	6.4
47	1.6
48	0.44
49	2.2
50	1.8
51	1.9
52	2.9
53	1.7
54	1.2
55	2.2
56	1.3
57	3.1
58	1.8
59	8.5
60	4.8
61	5.1
62	3.3
63	4.9
64	8.7
65	10.6
66	7.2
67	2.4
68	1.9
69	0.6
70	21.9

EX	IC50 (nM)
71	2.7
72	0.54
73	6.1
74	1.0
75	0.81
76	12.0
11	2.3
78	1.4
79	31.0
80	15.6
81	5.7
82	126
83	15.3
84	5.6
85	212
86	26.8
87	1.3
88	5.7
89	7.7
90	3.2
91	154
92	73.4
93	35
94	50.2
95	79.2

EX	IC50 (nM)
96	21.9
97	52.8
98	27.3
99	15.6
100	16.3
101	5.3
102	7.6
103	13.4
104	53.1
105	55.5
106	58
107	171
108	7.8
109	128
110	9.2
111	119
112	16.5
113	264
114	10.1
115	3.7
116	2.6
117	18.9
118	7.6
119	60.5
120	141

EX	IC50 (nM)
121	9.9
122	0.46
123	396
124	0.74
125	0.40
126	1.3
127	0.18
128	4.5
129	1.0
130	0.17
131	2.3
132	1.1
133	0.38
134	5.0
135	1.2
136	7.8
137	0.25
138	21.8
139	247
140	3.7
141	58
142	61
143	125
144	0.41
145	2.8

EX	ICSO (nM)
146	48
147	241
148	39
149	52
150	5.3
151	2.3
152	1.5
153	0.48
154	49
155	0.7
156	1.4
157	1.3
158	71
159	1.3
160	5.5
161	1.2
162	9.8
163	1.3
164	3.2
165	4.4
166	2.2

Human Primary B cell Prolifération Assay

Human B cells were purified from buffy coats using the human B cell RosetteSep kit per manufacturées instructions. Purified cells were resuspended in RPMI5 10%HIFCS, 2 mM L-glutamine, 100 U/mL penicillin, 100 pg/ml streptomycin, incubated with compounds for 1 hour at 37°C and then stimulated with 50 pg/mL anti-human IgM F(ab’)2 for 72 hours. ³H-thymidine was included in the culture media for the final 8-16

192 • hours. Cells were harvested and ³H-thymidine incorporation was measured. Inhibition was calculated using DMSO + 50 pg/ml anti-human IgM F(ab’)2 stimulated B cells as the 0% inhibition control, and DMSO + assay buffer stimulated B cells as the 100% inhibition control.

Human Primary T cell Prolifération Assay

Human CD4⁺ T cells were purified from buffy coats using the human cell RosetteSep CD4⁺ T cells kit per manufacturées instructions. Purified cells were resuspended in RPMI-10%HIFCS, 2 mM L-glutamine, 100 U/mL penicillin, 100 pg/ml streptomycin, plated at 200,000 cells/well in 96-well round-bolltom plates, incubated 10 with compounds for 1 hour at 37°C and then stimulated with an equal number of antiCD3/anti-CD28-coated beads (Invitrogen) for 72 hours. ³H-thymidine was included in the culture media for the final 8-16 hours. Cells were harvested and ³H-thymidine incorporation was measured. Inhibition was calculated using DMSO + bead- stimulated CD4⁺ T cells as the 0% inhibition control, and DMSO + assay buffer stimulated CD4⁺ T 15 cells as the 100% inhibition control.

Human B cell Prolifération Assay

Human B cells were purified from buffy coats using the human B cell RosetteSep kit per manufacturées instructions. Purified cells were resuspended in RPMI10%HIFCS, 2 mM L-glutamine, 100 U/mL penicillin, 100 pg/ml streptomycin, incubated 20 with compounds for 1 hour at 37°C and then stimulated with 50 pg/mL anti-human IgM F(ab’)2 for 72 hours. ³H-thymidine was included in the culture media for the final 8-16 hours. Cells were harvested and ³H-thymidine incorporation was measured. Inhibition was calculated using DMSO + 50 pg/ml anti-human IgM F(ab’)2 stimulated B cells as the 0% inhibition control, and DMSO + assay buffer stimulated B cells as the 100% inhibition control.

Human Whole Blood Histamine Assay

Heparinized human whole blood (200 pl) was plated in 96-well V-bottom assay plates (VWR). Compounds diluted in 100% DMSO (1 μΙ) were added and incubated at 37°C for 120 miniutes. Anti-human-lgE antibody (KPL) was added to a final concentration of 2 μg/ml and assay plates incubated for 30 minutes at 37°C. Plates were spun at 2000 rpm for 8 minutes and the analyzed for histamine release by ELISA kits (Beckman Coulter). For each inhibitor tested, inhibition of histamine release is normalized as a percentage of control histamine based on the formula: % of Control = 100 x (A-B)/(C-B) where A is the histamine from wells containing inhibitor and anti-lgE

193

antibody, B is the histamine from wells without anti-lgE antibody(minimum histamine) and C is the histamine from wells containing anti-lgE antibody but no inhibitor (maximum). Inhibition curves and IC50 values are determined using Excel-fit. Human EGFR LanthaScreen Selectivity Assay

TR-FRET LanthaScreen assays were performed by incubating a dilution sériés of inhibitor concentrations with 20 μΜ ATP, 100 nM peptide substrate (FITC-C6KKAEEEEYFELVAKK-NH2 (SEQ ID NO.: 2, American Peptide, #333778) and 600 pM of human EGFR kinase domain (Invitrogen). The assays were performed with and without pre-incubating the inhibitors with the enzyme for 60 minutes before starting the kinase reaction by adding ATP and the peptide substrate. Samples containing enzyme but no inhibitor were included to détermine the maximal extent of reaction. Samples containing no enzyme served as the négative control. The kinase reaction mixtures were incubated at room température for 60 minutes before stopping the kinase activity by the addition of 15 mM EDTA. The extent of peptide phosphorylation by EGFR was detected using a Terbium-conjugated anti-phospho-Tyrosine antibody (Tb-PT66 antibody, Invitrogen # PV3557). Phosphorylation of peptide substrate was measured by determining the ratio of 520/495 nm on an Envision Multi-label Reader (Perkin Elmer) and IC50 values were calculated by fitting the data to a four-parameter équation using XLFit4 (IDBS).

Table 2.

Example	B Cell IC50 (nM)	HWB IC50 (nM)	EGFR IC50 (nM)
2	0.5	33.3	1,710
15	1.7	20.6	3,890
27	2.7	64.3	16,800
110	1.6	94.7	>15,400
116	14.9	41.8	>26,800
118	29.6	50	>50,000
126	20.9	201	802
130	0.15	133	7.9
131	1.6	259	2200
136	0.44	570	214
137	0.63	31.4	25.6
144	0.84		274

194

145	11.8	126	2180
151	0.22	258	12100
153	0.56		2.9
155	2.0		106
156	2.5		381
157	24.2	98.7	29.7
159	2.8		311
160	2.9		890
161	3.0	52.7	89.8
162	103	343	14100
163	0.92		1190
164	11.4		3360

Example 168

In Vivo Pharmacology

N P Ficoll Model

Type 2 T cell independent antibody responses were induced by immunizing 8 to week old C57BI/6 female mice i.p. with 100 pg of NP-Ficoll in PBS (day 0). BTK inhibitors were prepared in methylcellulose tween and mice were dosed QD with compounds starting on day -1. Mice were euthanized and sérum collected 6 days postNP-Ficoll immunization. Sera from immunized mice were then tested in an ELISA to measure NP-specific IgM and lgG3 titers. Briefly, to assess NP-specific antibody titers Nunc Maxi-Sorp plates (VWR International) were coated ovemight at room température with 20 pg/mL of BSA:NP (Biosearch Technologies). Plates were washed with PBS Tween 0.05% buffer (PBS-T) and blocked with PBS containing 0.5% gelatin for 2 hours. Sérum samples were then diluted in PBS-T and incubated for 1 hour. Bound antibody was detected using goat anti-mouse IgM-HRP or lgG3-HRP antibodies (Southem Biotech) diluted in PBS-T. ELISA plates were developed using TMB Sure Blue reagent (Kirkegaard & Perry Labs), reactions were stopped by adding 1.0M sulfuric acid to sample wells and absorbances assessed at 450nm on a Spectramax Plus 384 microplate reader (Molecular Devices).

Mouse Collage-lnduced Arthritis (CIA) Model ofArthritis

Arthritis was induced by immunizing DBA/1 mice with bovine type II collagen (Cil) emulsified in complété Freund’s adjuvant and by a boost 21 days later with Cil

195 emulsified in incomplète Freund's adjuvant. Efficacy was assessed in a semitherapeutic dosing regimen, which involved assignment to treatment groups when 10% of the mice showed disease symptoms. Mice were dosed orally one a day. Disease severity was evaluated by scoring ail four paws for each animal, with a maximum possible score being 16 according to the following classification: 0, no arthritis; 1, one or two swollen digits; 2, three or more swollen digits or mild to moderate swelling of the entire paw; 3, extensive swelling of the entire paw; 4, resolution of swelling, ankylosis of the paw. At the end of the study, ail four paws from each animal were collected for microscopie analysis. Tissue samples were decalcified and embedded in paraffin, sectioned at 6 pm, stained with hematoxylin and eosin (H&E), and examined microscopically. Each section from each paw was examined for the presence of arthritis, and the severity of arthritis, when présent, was subjectively scored according to the following criteria: Grade 0, normal synovial membrane (1-3 synoviocytes thick) and absence of inflammatory cells; Grade 1, synoviocyte hypertrophy, slight synovial membrane fibrosis, and slight to mild inflammatory cell infiltrâtes into the synovial membrane/articular capsule and/or synovial fluid; Grade 2, grade 1 plus mild to moderate inflammatory cell infiltrâtes, absence or minimal pannus formation, and superficial cartilage érosion; Grade 3: grade 2 plus marked inflammatory cell infiltrâtes, fibrosis, and mild to severe érosion of cartilage extending into subchondral bone; Grade 4, loss of joint integrity through érosion or destruction with bone remodeling, fibrosis, and ankylosis.

K/BxN Sérum Transfer Model of Arthritis

In the K/BxN sérum transfer model, 6 week old male BTKxid, CBA/CaJ, and C57BL/6 mice, from Jackson Laboratory, were injected with pooled sérum from 8-weekold arthritic K/BxN mice (150 pL sérum i.p. on days 0 and 2). Hind ankle width was measured with a pocket thickness gauge and the average change in ankle thickness in both ankles was calculated for each animal. Animais were measured Monday through Friday for 14 days. At the end of the study, ail four paws from each animal were collected for microscopie analysis.

For treatment studies, 6 week old male C57BL/6 mice, from Jackson Laboratory, were injected with pooled sérum from 8-week-old arthritic K/BxN mice (150 pL sérum

i.p. on days 0 and 2). Mice were dosed orally once a day starting on day 0. Hind ankle width was measured with a pocket thickness gauge and the average change in ankle thickness in both ankles was calculated for each animal. Animais were measured

196

Monday through Friday for 14 days. At the end of the study, ail four paws from each animal were collected for microscopie analysis as described above.

INCORPORATION BY REFERENCE

Ail publications and patent applications mentioned in this spécification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims (23)

1. We claim:

   1. A compound having Formula (I)

   R³* _P3b

   W
2. 2_r A A or a pharmaceuticaily acceptable sait thereof, wherein

   A is arylene, 5-membered heteroarylene or 6-membered heteroarylene, optionally substituted with one, two, three or four R⁶ independently selected from the group consisting of (CrC₄)alkyl, halo(Ci-C₄)alkyl, halo, hydroxy and (Cr C₄)alkoxy;

   X is O, S, C(=O), C(OR⁴) or C(R^5a)(R^5b);

   W is aryl, 5-membered heteroaryl or 6-membered heteroaryl, optionally substituted with one, two, three, four or five R⁷ independently selected from the group consisting of (CrC₄)alkyl, halo(CrC₄)alkyl, (C
3. 3-C6)cycloalkyl,
4. 4-6 membered saturated heterocycle, halo, hydroxy, hydroxy(CrC₄)alkyl, (Cr C₄)alkoxy, hydroxy(C₂-C₄)alkoxy, and halo(CrC₄)alkoxy;

   R¹ 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 (CrC₄)alkyl, halo(Ci-C₄)alkyl, halo, hydroxyl and (CrC₄)alkoxy;

   o R^c o R^c

   R is cyano, cyano(Ci-C3)alkyl, R^a or ^Λ ;

   R^2a, R^2b, R^3a, R^3b and R⁴ are independently selected from the group consisting of hydrogen or (Ci-C₃)alkyl;

   R^5a and R^5b are independently selected from the group consisting of hydrogen, halo and (Ci-Cs)alkyl;

   R^a is hydrogen, halo, cyano, (CrC6)alkoxy, halo(CrC₆)alkoxy, (Ci-C₄)alkylthio, (CrC₄)alkylsulfonyl, or (CrC₆)alkyl optionally substituted by halo, hydroxyl, (Ci-C₆)alkoxy or halo(CrC6)alkoxy;

   198

   R^b and R^c are independently selected from the group consisting of hydrogen, halo, cyano, (CrCeJalkoxy, haloiCi-Ceîalkoxy, (C3-C6)cycloalkyl, C(=O)R^dand (CrCejalkyl optionally substituted with one, two or three R^f independently selected from the group consisting of halo, hydroxyl, N(R®)2, (C_rC6)alkoxy, halo(Ci-C₆)alkoxy and aryl; 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®)2, (CrCeJalkoxy; halo(Ci-C6)alkoxy and aryl; R^dis (Ci-C6)alkyl, (CrC6)alkoxy, N(R®)₂ or aryl;

   R® is independently selected for each occurence from the group consisting of hydrogen and (CrC₄) alkyl, or both R® taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl; and

   G is a 5-7 membered carbocycyl or heterocycyl optionally substituted with one, two or three R^f independently selected from the group consisting of halo, hydroxyl, N(R®)₂, (CrCeJalkoxy; halo(Ci-C₆)alkoxy and aryl.

   The compound of claim 1, wherein R is cyano or cyanoiCpCaJalkyl.

   O R^c n R^c

   The compound of claim 1, wherein R is R^a or *

   The compound of any one of claims 1 -3, wherein A is ; and R⁶ is independently selected for each occurrence from the group consisting of hydrogen, (Ci-C₄)alkyl, halo(Ci-C3)alkyl and halo.
5. 5.

   The compound of any one of claims 1-3, wherein A is
6. 6.

   independently selected for each occurrence from the group consisting of hydrogen, (CrC^alkyl, halo(Ci-C3)alkyl and halo.

   The compound of claim 4 or 5, wherein R⁶ is hydrogen.
7. 7. The compound of any one of claims 1 -6, wherein X is O, CH₂ or C(=O).

   199
8. 8. The compound of any one or claims 1 -6, wherein X is O.
9. 9. The compound of any one of claims 1-6, wherein X is CH2.
10. 10. The compound of any one of claims 1 -9, wherein W is phenyl optionally substituted with one, two, three, four or five R⁷ independently selected for each occurrence from the group consisting of (CrC^alkyl, halo(CrC3)alkyl, (C_r C₄)alkoxy, and halo.
11. 11.

    The compound of claim 10, wherein W is and R⁷ is independently selected from the group consisting of F, Cl, methoxy and methyi.
12. 12.

    The compound of any one of claims 1-9, wherein W is pyridiyl optionally substituted with one, two, three, or four R⁷ independently selected from the group consisting of (CpC^alkyl, halo(Ci-C4)alkyl, halo, hydroxy, hydroxy(Ci-4)alkyl, (CrC₄)alkoxy, and (Ci-C₄)haloalkoxy.
13. 13.

    selected for each occurrence from the group consisting F, Cl and CF₃.

    200 three, four or five substituents independently selected from the group consisting of (CrC^alkyl, halo(Ci-C₄)alkyl, halo, hydroxyl and (CrC₄)alkoxy.
14. 15. A compound having Formula (II) o-w (H) or a pharmaceutically acceptable sait thereof, wherein

    W is phenyl or pyridyl, optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (CrC4)alkyl, (Ci-C3)haloalkyl and halo.

    201

    F F and pharmaceutically acceptable salts thereof. A compound having formula (II) o-w

    202 or pharmaceutically acceptable salts thereof, wherein

    R^a is hydrogen, halo, cyano, (Ci-C₆)alkoxy, halo(Ci-C₆)alkoxy, (CrC^alkylthio, (CrC^alkylsulfonyl, or (Ci-C₆)alkyl optionally substituted by halo, hydroxyl, (CrC₆)alkoxy or halo(C_rC6)alkoxy;

    R^b and R^c are independently selected from the group consisting of hydrogen, halo, cyano, (Ci-C6)alkoxy, halo(CrC6)alkoxy, (C3-C6)cycloalkyl, C(=O)R^dand (CrC6)alkyl optionally substituted with one, two or three R^f independently selected from the group consisting of halo, hydroxyl, N(R®)₂, (Ci-C₆)alkoxy and halo(Ci-C₆)alkoxy;

    R^dis (Ci-Ce)alkyl, (Ci-C₆)alkoxy, N(R®)₂ or aryl;

    R® is independently selected for each occurence from the group consisting of hydrogen and (C1-C4) alkyl, or both R® taken together with the nitrogen atom to which they are bound form a 4-7 membered heterocycyl; and

    W is phenyl or pyridyl, optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (Ci-C4)alkyl, (CrC3)haloalkyl and halo.

    203
15. 20. A compound represented by o

    C'A O-A^0H CA ο , o or o and pharmaceutically acceptable salts thereof.
16. 21. A pharmaceutical composition comprising a compound according to any one of

    5 claims 1,15,17,18 or 20, or a pharmaceutically acceptable sait thereof, admixed with a pharmaceutically acceptable carrier, excipient or dilutant.
17. 22. Use of a compound according to any one of claims 1,15,17,18 or 20, or a pharmaceutically sait thereof and a pharmaceutically acceptable carrier in the manufacture of a pharmaceutical composition for inhibiting Bruton's Tyrosine

    10 kinase wherein said composition is for administration to a patient.
18. 23. Use of a compound according to any one of claims 1,15,17,18 or 20, or a pharmaceutically sait thereof and a pharmaceutically acceptable carrier in the manufacture of a pharmaceutical composition for treating an autoimmune disease wherein said composition is for administration to a subject in need

    15 thereof.
19. 24. Use of a compound according to any one of claims 1,15,17,18 or 20, or a pharmaceutically sait thereof and a pharmaceutically acceptable carrier in the manufacture of a pharmaceutical composition for treating a heteroimmune

    204 condition or disease wherein said composition is for administration to a subject in need thereof. .
20. 25. Use of a compound according to any one of claims 1, 15, 17, 18 or 20, or a pharmaceutically sait thereof and a pharmaceutically acceptable carrier in the

    5 manufacture of a pharmaceutical composition for treating an inflammatory disease wherein said composition is for adminstration to a subject in need thereof.
21. 26. Use of a compound according to any one of claims 1,15,17,18 or 20, or a pharmaceutically sait thereof and a pharmaceutically acceptable carrier in the

    1 o manufacture of a pharmaceutical composition for treating a cancer wherein said composition is for adminstration to a subject in need thereof.
22. 27. The use of claim 26, wherein the cancer is a B-cell proliférative disorder.
23. 28. The use of claim 27, wherein the B-cell proliférative disorder is chronic lymphocytic lymphoma, diffuse large B cell lymphoma, follicular lymphoma or

    15 chronic lymphocytic leukemia.