OA18716A

OA18716A - Heterobicycloaryl RORC2 inhibitors and methods of use thereof

Info

Publication number: OA18716A
Application number: OA1201600027
Authority: OA
Inventors: Andrew Christopher FLICK; Edouard Zamaratski; Marvin Jay Meyers; Atli Thorarensen; Mark Edward Schnute; Scot Richard Mente; Peter Jones; Li Xing; James Richard Kiefer, Jr.; Ravi G. Kurumbail; Mattias Wennerstal GÖRAN; Neelu Kaila; James Robert BLINN; Christoph Wolfgan ZAPF
Original assignee: Pfizer Inc.
Priority date: 2013-08-02
Filing date: 2014-07-24
Publication date: 2019-06-14

Abstract

The present invention provides compounds, pharmaceutical compositions, methods of inhibiting RORy activity and/or reducing the amount of IL-17 in a subject, and methods of treating various medical disorders using such compounds and pharmaceutical compositions.

Description

RORC2 Inhibitors and Methods of Use Thereof

BACKGROUND OF THE INVENTION

Retînoid-related orphan receptors (ROR) are reported to hâve an important rôle in numerous biological processes. Scientific investigations relating to each of retînoid-related orphan receptors RORo, RORp, and RORy hâve been described tn the literature. Continuing research in this field is spurred by the promise of developing new therapeutic agents to treat medical disorders associated with retînoid-related orphan receptor activity.

RORy has been reported to be expressed in high concentration in various tissues, such as thymus, kidney, liver, muscle, and certain fat tissue. Two isoforms of RORy hâve been identified and are referred to as y1 and γ2 (also referred to as RORyt). Expression of the γ2 isoform has been reported to appear in, for example, double-positive thymocytes. Compounds capable of modulating RORyt activity are contemplated to provide a therapeutic benefit in the treatment of multiple medical disorders, including immune and inflammatory disorders.

Numerous immune and inflammatory disorders continue to afflict millions of patients worldwide. Significant advances hâve been made in treating these disorders. However, current thérapies do not provide satisfactory results for ail patients due to, for example, detrimental side effects or insufficient efficacy. Treatments for immune and inflammatory disorders vary depending on the particular medical disorder, and often involve use of immunosuppressive drugs. Surgery (e.g., splenectomy), plasmapheresis, or radiation can be used in certain instances.

One exemplary immune disorder in need of better therapy is psoriasis. Psoriasis is a T cell-mediated inflammatory disease that affects approximately 2% to 3% of adults and has a substantial adverse impact on the quality of life for patients suffering from this disorder. Plaques resulting from psoriasis can be painful and are visually unappealing. Various therapeutics hâve been developed in an attempt to treat psoriasis. However, the traditional thérapies for psoriasis often hâve toxic adverse effects.

Accordingly, a need exists for improved treatments for psoriasis as well as other immune and inflammatory disorders. The present invention addresses this need and provides other related advantages.

SUMMARY

The présent invention provides compounds, pharmaceutical compositions, methods of inhibiting RORy activity and/or reducing the amount of 1L-17 in a subject, and methods of treating various medical disorders using such compounds. In particular, one aspect of the invention relates to compounds represented by Formulae I, II, III, IV, V, VI and Vil:

and pharmaceutically acceptable salts, pharmaceutically active métabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable soivates thereof; wherein R, X, Y and W are as defined in the Detailed Description,

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 therapeuticaily effective amount of a compound of Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable sait or solvaté thereof, as described in the Detailed Description. A large number of disorders can be treated using the compounds described herein. For example, the compounds described herein can be used to treat 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.

DETAILED DESCRIPTION

The invention provides compounds, pharmaceutical compositions, methods of inhibiting RORy activity and/or reducing the amount of IL-17 in a subject, 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 et al., eds., 1987, and periodic updates); and Current protocols in immunology (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety.

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 Controls.

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 référants 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.

)t 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.

Ail publications and patents mentioned herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the constructs and méthodologies that are described in the publications, which might be used in connection with the methods, compositions and compounds described herein.

Chemical names, common names, and Chemical structures may be used interchangeably to describe the same structure. If a Chemical compound is referred to using both a Chemical structure and a Chemical name, and an ambiguity exists between the structure and the name, the structure prédominâtes.

“ROR stands for Retinoic acid receptor-Related Orphan Receptor. There are three forms of ROR, ROR-α, -β, and -y and each is encoded by a separate gene (RORA, RORB, and RORC respectively). There are two subtypes of RORC: 1 and 2. Subtype 2 is also called ”t. The human RORC gene is also called TOR; RORG; RZRG; NRIF3; and RZR-GAMMA. The human protein RORC is also called nuclear receptor ROR-gamma; nuclear receptor RZR-gamma; retinoic acid-binding receptor gamma; retinoid-related orphan receptor gamma; RAR-related orphan receptor C, isoform a; RAR-related orphan nuclear receptor variant 2; nuclear receptor subfamily 1 group F member 3. As used herein, RORy and “RORC2 are used interchangeably to refer to a protein from a RORC subtype 2 gene.

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. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molécule. In certain embodiments, an inhibitor completely prevents one or more activities of a molécule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molécule. In 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. In 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 ail 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 ten carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyi (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isoamyl, hexyl and the like. The ternis haloalkyi and haloalkoxy include alkyl, and alkoxy structures, respectively, in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are 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, -CFg, -CH₂CF₃, -CFaCFa, -CH₂CHaCF3 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. Cycloalkyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyi 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·¹ 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 (C4C_1o)carbocyclic ring, 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-Ci₀)carbocyclic or 4- to 10-membered heterocyclic ring may be optionally substituted with halogen, (CrCeJalkyl, (Ca-C-toJcycloalkyl, or =0. Examples of aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as tetralinyl), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyi (also known as phenalenyi), and fluorenyl.

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- to 8-membered heterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including 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 nîtrile) means CN.

The term thio means S.

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 înterchangeably 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 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. 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 alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). 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 turn 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, thiophenyi, 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, cinnolinyi, 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 turn 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 N-oxide ring.

This spécification uses the terms '‘substituent,¹' 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 nonhydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for exampfe, 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 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 if the amino nitrogen is a secondary nitrogen.

A prefix attached to a multi-moiety substituent only applies to the first moiety. To illustrate, the term alkylcycloalkyl” contains two moieties: alkyl and cycloalkyl. Thus, a (CiC₆) prefix on (Ci-C6)alkyl(C₃-Cio)cycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the (CvCgJ-prefix does not describe the cycloalkyl moiety. To illustrate further, the prefix halo on haloalkoxyaikyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents. If the halogen substitution only occurs on the alkyl moiety, the substituent would be described as alkoxyhaloalkyl. If the halogen substitution occurs on both the alkyl moiety and the alkoxy moiety. the substituent would be described as haloalkoxyhaloalkyl.

As used herein compounds of Formulae I, II, III, IV, V, VI and VII may be referred to as a compound(s) of the invention. Such terms are also defined to include all forms of the Formulae I, 11, III, IV, V, VI and VII including hydrates, solvatés, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and métabolites thereof. For example, the compounds of Formulae I, II, III, IV, V, VI and Vil, 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 stoîchiometry 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 metabolized. The term metabolized, as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis réactions and reactions catalyzed by enzymes, such as, oxidation reactions) by which a particular substance is changed by an organisai. Thus, enzymes may produce spécifie structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic-acid molécule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free suifhydryl 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-containïng compound. In some embodiments, a compound is metabolized to pharmacologicaliy active métabolites.

In some embodiments, compounds described herein could be prepared as prodrugs. A prodrug¹¹ refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also 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 carboxyiic acid, the active entity, once inside the cell where water-solubiiity 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 388-392; 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 vivota 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 in pharmaceutical compositions over the parent drug, Prodrugs may be designed as réversible drug dérivatives, for use as modifîers to enhance drug transport to site-specific tissues. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus étal., Biomed. Chrom., 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); Sinkuia étal., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Sériés; and Edward B. Floche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, ail incorporated herein in their entirety.

The compounds of the invention may hâve asymmetric carbon atoms. The carboncarbon 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 compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

Stereoisomers of compounds of the invention include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, géométrie isomers, rotational isomers, conformational isomers, and tautomers of the compounds of the invention, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

The présent invention also includes isotopically-labeled compounds, which are identical to those recited in Formulae I, II, III, IV, V, VI and VII 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, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁰0,¹⁷O, ³¹ P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI. Certain isotopicallylabeled 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 détectability. 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. Isotopicallylabeled 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, such as enhanced pharmaceutical stability in differing températures and humidifies, 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 acceptable. The term “pharmaceutically acceptable sait'¹ refers to a sait prepared by combining a compound 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 compound. For use in medicine, the salts of the compounds of this invention are non-toxic pharmaceutically acceptable salts. Salts encompassed within the term pharmaceutically acceptable salts refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the présent invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofiuoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable organic acids generally include but are not lîmited to aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.

Spécifie examples of suitable organic acids include but are not lîmited to acetate, trifluoroacetate, formate, propionate, succinate, glycoiate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stéarate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsuifonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycérophosphate, heptanoate, hexanoate, nicotinate, 218716 naphthalesulfonate, oxalats, 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 include 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 another embodiment, base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamlne, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.

Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, Ν,Ν'-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamîne), and procaine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C_rC₆) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain haiides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), 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 compounds suitabie for use in the methods described herein, définitions of referred-to standard chemistry terms may be found in reference works (if not otherwise defined herein), including Carey and Sundberg Advanced Organic Chemistry 4th Ed.” Vols. A (2000) and B (2001), Plénum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the ordinary skill of the art are employed. Unless spécifie définitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and médicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for Chemical synthèses, Chemical analyses, pharmaceutical préparation, formulation, and delivery, and treatment of patients.

In certain embodiments, the compounds of the invention described herein are sélective for RORy over RORa and/or RORp.

Generally, an inhibitor compound of RORy used in the methods described herein is identified or characterized in an in vitro assay, e.g., an acellular biochemical assay or a cellular functional assay. Such assays are useful to détermine an in vitro IC₅₀ for said compounds. In some embodiments, the RORy inhibitor compound used for the methods described herein inhibits RORy activity with an in vitro IC_S0 of less than 25 μΜ (e.g., less than 20 μΜ, less than 10 μΜ, 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). In some embodiments, the RORy inhibitor compound is a compound described in the Exemplification.

Described herein are compounds of Formulae I, II, III, IV, V, VI and VII. 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. In some embodiments, when compounds disclosed herein contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. In certain embodiments, isomers and chemîcaily protected forms of compounds having a structure represented by Formulae I, II, III, IV, V, VI and VII are also provided.

One aspect of the invention relates to a compound of Formulae I, II, Hl, IV, V, VI or VII:

or a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof, wherein,

Y is hydrogen, halo, cyano, (CrC₃)alkyl, (C_rC₃) hydroxyalkyl, (CrCsJalkenyl, (C_r

C₃)haloalkyl, (CrC₃) hydroxyhaloalkyl, (C₃-C₆)cycloalkyl, (Ci-C₃)alkoxy or (Ci-C₃)haloalkoxy;

R¹ is hydrogen, (CrCgJalkyl, (Ci-C₆)hydroxyalkyl or (Ci-C₆)haloalkyl;

X is

R³ is (CrCeJalkyl, (C₃-Ce)cycloalkyl, (C₃-Ca)heterocycloalkyl, aryl or heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (C_rC₄)alkyl, (Cr C₄)haloalkyl, (Ci-C₄)cyanoalkyl, hydroxyl, -OR, (CrC₄)hydroxyalkyl, (CrC^hydroxyalkoxy, (CrC^hydroxyalkoxytCrC^alkyl, (CrC^alkoxy, (C_rC₄)alkoxy(Ci-C₄)aIkyl, {C_r

C₄)alkoxy(C_rC₄)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkoxy(C_rC₄)alkyl, (Cr-C^haloalkoxy, -NR₂, (R₂N)(C_rC₄)alkyl-, (CrC₄)alkylthio, (C₁-C₄)haloaIkylthio_I -C(=O)R, -C(=O)OR, -00(=0) R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂₁-CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂, -N(R)S(=O)₂R, -a and -CH₂A;

R is independently selected for each occurrence from the group consisting of hydrogen, (CrC₄)alkyl, (Ci-C₄)haloalkyl, (Ci-C₄)cyanoalkyl, (Ci-C₄)hydroxyalkyl, (C₃C_a)cycloalkyl or (C₃-C₈)heterocycloalkyl; or where a nitrogen is substituted with two R groups they may be taken together with the nitrogen atom to which they are attached to form a 4-, 5-, 6- or 7-membered saturated (C₃-Ca)heterocycloalkyl which, when so formed, may be optionally substituted with one, two or three substituents independently selected from the group consisting of (C_rC₄)alkyl, halo, hydroxyl, (Ci-C₄)hydroxyalkyl, (CiC₄)cyanoalkyl, (C₁-C₄)haloalkyl and =0;

A is independently selected for each occurrence from the group consisting of (C₃-C_a)cycloalkyl, (C₃-C_a)heterocycloalkyl, aryl and heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (C₁-C₄)aJkyl, (Ci-C₄)haloalkyl, (CrC^cyanoalkyl, hydroxyl, (C_rC₄)hydroxyalkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C_l-C₄)aJkyl, (C_rC₄)haloalkoxy, -NR₂, (R₂N)(Ci-C₄)alkyl-, (CrC^alkylthio, (Ci-C₄)haloalkylthio, -C(=0)R, -C(=0)0R, -0C(=0)R, -C(=0)NR₂, -N(R)C(=0)R, -CH₂C(=0)R, -CH₂C(=0)0R, -CH₂OC(=O)R, -CH₂C(=O)NR_2i -CH₂N(R)C(=0)R, -S(=O)₂R, -S(=O)₂NR₂ and -N(R)S(=O)₂R;

substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, (Ci-Cejalkyl, (C_rC₆)hydroxyalkyl and (Cr C₆)haloalkyl;

R³ is (C-i-C6)alkyi, (C3-CB)cycloalkyl, (Ca-Cajheterocycloalkyl, aryl, heteroaryl, -C(=O)R⁴, -C(=0)0R⁴, -C(=O)N(R⁵)2 or -S(=O)₂R⁴, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alkyl, (Ci-C4)haloalkyl, (Ci-C₄)cyanoalkyl, hydroxyl, (Ci

C₄)hydroxyalkyl, (C_rC₄)alkoxy, (Ci-C^alkoxyfCrC^alkyl, {CpCdhaloalkoxy, -NR₂, (R₂N)(CrC₄)alkyl-, (Cj-Cfralkylthio, (CrC^haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR_2i -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH_aC(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂, -N(R)S(=O)₂R, -a and -CH₂A;

R⁴ is hydrogen, (Ct-Cejalkyl, (C₃-C_a)cycloaJkyl, (C₃-C_B)heterocycloalkyI, (C₃Ce)cycloalkyl(Ci-C6)alkyl, (Ca-CaJheterocycloaikyifCi-CgJalkyl, aryl or heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (CrC₄)alkyl, (C₁-C₄)haloalkyl, (C_rC₄)cyanoalkyl, hydroxyl, (CrC^hydroxyalkyl, (CrC^aikoxy, (CrC6)aIkoxy(CrC6)alkyl, (Ci-Cejhaloalkoxy, -NR₂, (R₂N)(Ci-C_a)alkyl, (Ci-C_a)alkylthio, (CrCelhaloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O) R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=0)R, -CH₂C(=0)0R, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)_aNR_a, -N(R)S(=O)_aR, -A and -CH₂A; and

R⁵ is independently selected for each occurrence from the group consisting of hydrogen, (Ci-C6)alkyl, (C3-Ca)cycloalkyl, (C3-CB)heterocycloalkyl, (C3-Ca)cycloalkyl(Ci-Cs)alkyl, (C3-Ca)heterocycIoalkyl(CrC6)alkyl, aryl and heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (CrC4)alkyl, (Cr C4)haloalkyl, (CrC4)cyanoalkyl, hydroxyl, (CrC4)hydroxyalkyl, (CrC^alkoxy, (0,C4)alkoxy(C1-C4)alkyl, (CrC4)haloalkoxy, -NR2r (R2N)(CrC4)aIkyl-, (CrC4)alkyithio, (Cr C4)haloalkylthio, -C(=0)R, -C(=O)OR, -OC(=O)R, -C(=O)NR2> -N(R)C(=0)R, -CH2C(=0)R, -CH2C(=O)OR, -CH20C(=0)R, -CH2C(=O)NR2, -CH2N(R)C(=0)R, -S(=O)2R, -S(=O)2NR2i -N(R)S(=O)2R, -A and -CH2A; or where a nitrogen is substituted with two R⁵ groups may be taken together with the nitrogen atom to which they are attached to form a 4-, 5-, 6- or 7membered saturated C3._Bheterocycloalkyl which, when so formed, may be optionally substituted with one, two or three substituents independently selected from the group consisting of (C_rC₄)alkyl, halo, hydroxyl, (Ci-C₄)hydroxyalkyl, (CrC^haloalkyl and =0.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein the compound is represented by Formula I or is a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof, in certain embodiments, the present invention relates to any of the aforementioned compounds, wherein the compound is represented by Formula II or is a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein the compound is represented by Formula III or is a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein the compound is represented by Formula IV or is a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein the compound is represented by Formula V or is a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein the compound is represented by Formula VI or is a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein the compound is represented by Formula VU or is a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ is (CrC₆)alkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R¹ is methyl.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein Y is hydrogen. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein Y is (Ci-C₃)alkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein Y is methyl.

In certain embodiments, the présent invention relates to any of the aforementioned .p r² p r² o r^!-^ j J J _ZN—I H N—j H₃C N—ί compounds, wherein X is h I, h I _or H^Z J, incertain embodiments, the présent invention relates to any of the aforementioned compounds, o

^R2-< j /N—| wherein Xis h î. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein X is

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

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

NC

compounds, wherein X is selected from the group consisting of

O

invention relates to any of the aforementioned compounds, wherein X is selected from the

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is

NC

In certain embodiments, the present invention relates to any of the aforementioned o ^R2-^ J ί

N -j I—( N—R³ compounds, wherein X is H ijandWis? '—^z . In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is

O ^R2^ J /H |—( N—R³

H ?;Wisi '—t ; and R³ is-C(=O)R⁴.

In certain embodiments, the present invention relates to any of the aforementioned

R² Q „

H₃c n—j ^H Incertain ^R -^sx j ,^N~^sr s N—| H N—I compounds, wherein X is H î₍ h ? or embodiments, the present invention relates to any of the aforementioned compounds, o wherein X is H In certain embodiments, the present invention relates to any of the R² P. h /^N i aforementioned compounds, wherein X is H L In certain embodiments, the present

R² O

N-S'' i

H₃C N—5 invention relates to any of the aforementioned compounds, wherein X is h' I.

compounds, wherein X is selected from the group consisting of

ln certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein X is

O

R²-S^ < d .

N-j |—/ N-R³

H i; W is I '—/ ; and R³ is -C(=O)R⁴.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R² is (Ci-C6)alkyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (CrC^alkyl, (CrC4)haloalkyl, (Ci-C4)cyanoalkyl, hydroxyl, -OR, hydroxyl(CiC4)alkyl, (CrC4)hydroxyalkoxy, (CrC^hydroxyalkoxyfCrCAjalkyl, (CrC4)alkoxy, (Cr C4)alkoxy(C1-C4)a[kyl, (Ci-C4)alkoxy(Ci-C4)alkoxy, (C1-C4)alkoxy(Ci-C4)alkoxy(C1-C4)alkyl, (CrC4)haloalkoxy, -NR2, (R2N)(CrC4)alkyl-, (CrC4)alkylthio, (C1-C4)haloalkylthio, -C(=O)R, -C(=O)OR, -0C(=O)R, -C(=O)NR2, -N(R)C(=O)R, -CH2C(=O)R, -CH2C(=O)OR, -CH20C(=O)R, -CH2C(=O)NR2, -CH2N(R)C(=O)R, -S(=O)2R, -S(=O)2NR2, -N(R)S(=O)2R, -A and -CH2A. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R² is (CrC6)alkyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, hydroxyl, -C(=O)R, -C(=O)OR, -C{=O)NR₂, -S(=O)₂R, -S(=O)₂NR₂, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R² is (C3-C8)cycloalkyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (CpC^alkyl, (Ci-C4)haloalkyl, (Ci-C/cyanoalkyl, hydroxyl, -OR, hydroxyl(CrC4)alkyl, (CrC4)hydroxyalkoxy, (CrC4)hydroxyalkoxy(C1-C4)a!kyl, (Cr C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkoxy, (CrC4)alkoxy(C1C4)alkoxy(C1-C4)alkyl, (Ci-C4)haloalkoxy, -NR2, (R2N)(CrC4)alkyl-, (CrC4)alkylthio, (Cr C4)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR21 -N(R)C(=O)R, -CH2C(=O)R, -CH2C(=O)OR, -CH2OC(=O)R, -CH2C(=O)NR2, -CH2N(R)C(=O)R, -S(=O)2R, -S(=O)2NR2, -N(R)S(=O)2R, -A and -CH2A. In certain embodiments, the present invention relates to any of the aforementioned compounds. wherein R² is (C3-C_a)cycloalkyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, hydroxyl, -C(=O)R, -C(=O)OR, -C(=O)NR₂₁-S(=O)₂R, -S(=O)₂NR₂, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R² is (C₃-C₈)heterocycloalkyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alkyl, (C_rC₄)cyanoalkyl, (Ci-C₄)haloalkyl, hydroxyl, -OR, hydroxyl(Ci-C₄)alkyl, (C_rC₄)hydroxyalkoxy, (Ci-C₄)hydroxyalkoxy(C₁-C₄)alkyl, (Ct C₄)alkoxy_t (Ci-C₄)alkoxy(Ci-C₄)alkyl, (Ci-C₄)alkoxy(C₁-C₄)alkoxy, (C_l-C₄)alkoxy(C₁C₄)alkoxy(Ci-C₄)alkyl, (C₁-C₄)haloalkoxy, -NR₂, (R₂N)(Ci-C₄)alkyl-, (CrC^alkylthio, (C_vC₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR_2î -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂, -N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R² is aryl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (CrCAjalkyl, (C₁-C₄)haloalkyl, (Ci-C₄)cyanoalkyl, hydroxyl, -OR, hydroxyl(C_rC₄)alkyl, (C_rC₄)hydroxyalkoxy, (C₁-C₄)hydroxyalkoxy(C₁-C₄)alkyl, (Ci-C₄)alkoxy, (C_rC₄)alkoxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C4)alkoxy, (C₁-C₄)alkoxy(C_rC₄)alkoxy(C_rC₄)alkyl, (CrC₄)haIoalkoxy, -NR₂, (R₂N)(CrC₄)alkyl-, (CrC^alkyithio, (CrC₄)haloalkylthio,

-C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR_2i -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂₁ -N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R² is phenyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (C_rC₄)alkyl, (C-i-C₄)haloalkyl, (Gi-C₄)cyanoalkyl, hydroxyl, -OR, hydroxyl(CiC₄)alkyl, (CrC₄)hydroxyalkoxy, (CrC₄)hydroxyalkoxy(Ci-C₄)aIkyl, (CrC₄)alkoxy, (C_rC₄)alkoxy(C_rC₄)alkyl, (C₁-C₄)alkoxy(C_rC₄)alkoxy, (C₁-C₄)alkoxy(C_rC₄)alkoxy(C₁-C₄)a!kyl, (Ci-C₄)haloalkoxy, -NR₂, (R₂N)(Ci-C₄)alkyl-, (C_rC₄)alkylthio, (Ci-C₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂ and -N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R² is heteroaryl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alkyl, (CrC₄)haioalkyl, (C-i-C₄)cyanoalkyl, hydroxyl, -OR, hydroxyl(Cr C₄)alkyl, (C₁-C₄)hydroxyalkoxy, (C_rC₄)hydroxyalkoxy(Ci-C₄)alkyl, (Ci-C₄)alkoxy, (CiC₄)alkoxy(Ci-C₄)alkyl, (C₁-C₄)alkoxy(Ci-C₄)alkoxy_I (C₁-C₄)alkoxy(Ci-C₄)alkoxy(C₁-C₄)alkyl, (CrC^haloalkoxy, -NR₂, (R_aN)(Ci-C₄)alkyl-, (C_rC₄)alkylthio, (C_rC₄)haloalkylthio, -C(=O)R, -C(=O)OR, -0C(=0)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂₁ N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R² is pyridyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alkyl, (Ci-C₄)haloalkyl, (Ci-C₄)cyanoalkyl, hydroxyl, -OR, hydroxyl(Cr C₄)alkyl, (Ci-C₄)hydroxyalkoxy, (C_rC₄)hydroxyalkoxy(C_rC₄)alkyl, (C_rC₄)alkoxy, (C_rC₄)alkoxy(Ci-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkoxy, (Ci-C₄)alkoxy(Ci-C₄)alkoxy(C₁-C₄)alkyl, (CrC₄)haloalkoxy_t -NR₂, (R₂N)(C_rC₄)alkyl-, (C_rC₄)alkylthio, (Ci-C₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR,

-CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂, N(R)S(=O)₂R, -A and -CH_ZA.

Ç N-R³ compounds, wherein W is » '—optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, (Ci-C₆)alkyl, (CvCeJhydroxyalkyl and (CrCsJhaloalkyl.

In certain embodiments, the présent invention relates to any of the aforementioned |—Ç N-R³ compounds, wherein W is f '—substituted with methyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, |—Ç N-R³ wherein W is ? '—

In certain embodiments, the présent invention relates to any of the aforementioned !—Ç N-R³ compounds, wherein W is ? ; and R³ is -C(=0)R⁴. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein W is

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

Kj4~ ⁰ . In certain embodiments, the present invention relates to any of the

I—( aforementioned compounds, wherein W is ’ '—' o

In certain embodiments, the present invention relates to any of the aforementioned |—/ N-R³ compounds, wherein W is i '—; and R³ is -S(=O)₂R⁴.

In certain embodiments, the present invention relates to any of the aforementioned R³ y—N compounds, wherein W is ? '—' optionaîly substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, (Ci-C₆)alkyl, (C_rC₆)hydroxyalkyl and (Ci-C₆)haloalkyl.

In certain embodiments, the present invention relates to any of the aforementioned > ,R³ compounds, wherein W is i optionaîly substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, (C-t-CeJalkyl, (Ci-C₆)hydroxyalkyl and (C-t-CeJhaloalkyl.

In certain embodiments, the present invention relates to any of the aforementioned |—<fVl-R³ compounds, wherein W is ? optionaîly substituted with one, two, three, four or five substitutents independently selected for each occumence from the group consisting of halo, (Ci-C₅)alkyl, (C_rC₆)hydroxyaikyl and (CrCeJhaloalkyl.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R³ is aryl, optionaîly substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (C_rC₄)alkyl, (C_rC₄)haloalkyl, hydroxyl, hydroxy(C_rC₄)alkyl, (C_rC₄)alkoxy, (CrC₄)alkoxy(CrC₄)alkyl, (C_rC₄)haloalkoxy, -NR₂, (R₂N)(C_rC₄)alkyl-, (Ci-C₄)afkyithio, (Ci-C₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OG(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)_aNR₂, -N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R³ is heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (C_rC₄)alkyl, (C_rC₄)haloalkyl, hydroxyl, hydroxy(C_rC₄)alkyl, (Ci-C₄)alkoxy, (C₁-C₄)alkoxy(Ci-C₄)alkyl, (C_rC₄)haloalkoxy, -NR₂, (RüNX^-CUJalkyl-, (Ci-C₄)a|kylthio, (Ci-C₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR_2i -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂ and -N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R³ is pyrazoyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alkyl, (C_rC₄)haJoalkyl, hydroxyl, hydroxy(C_rC₄)alkyl, (C_rC₄)aIkoxy, (CrC₄)alkoxy(CrC₄)alkyl, (C_rC₄)haloalkoxy, -NR₂, (R₂N)(CrC₄)alkyl·, (Ci-C₄)alkylthio, (C_rC₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂₁ -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂, -N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R³ is pyrimidinyl optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alkyl, (Ci-C₄)haloalkyl, hydroxyl, hydroxyfCrC^alkyl, (C_rC₄)alkoxy, (CrCUJalkoxyiCrC^alkyl, (CrC^haloaikoxy, -NR₂, (R₂N)(C_rC₄)alkyl·. (C_rC₄)alkylthio, (CrC₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR_2i -N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R³ is -C(=O)R⁴. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R³ is -C(=O)OR⁴. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R³ is -S(=O)₂R⁴.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R³ is -C(=O)N(R⁵)2; and R⁵ is independently selected for each occurrence from the group consisting of hydrogen, (CpOeJalkyl, (C3-C_a)cycloalkyl, (C₃C_a)heterocycloalkyl, (C₃-C_a)cycloalkyl)(Ci-C₆)alkyl and (Cs-CeJheterocycloalkyOiCr C₅)alkyl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (C₄ -C₄)alkyl, (CiC₄)haloalkyl, hydroxyl, (Ci-C₄)hydroxyalkyl, (Ct-C₄)alkoxy, (C_rC₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)haloalkoxy, -NR₂, (R₂N)(Ci-C₄)alkyl-, (C_rC₄)alkylthio, (CrC₄)haloalkyIthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=0)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C{=O)NR₂₁ -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂, -N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein wherein R³ is -C(=O)N(R⁵)2; and R^s is independently selected for each occurrence from the group consisting of hydrogen, aryl and heteroaryl, optionally substituted with one, two, three, four or five substitutents Independently selected for each occurrence from the group consisting of halo, cyano, (CrC^alkyl, (C1-C₄)haloalkyl, hydroxyl, (C_rC₄)hydroxyalkyl, (C_rC₄)alkoxy, (C.i-C₄)alkoxy(Ci-C₄)alkyl, (C_rC₄)haloalkoxy, -NR₂, (R₂N)(CrC₄)alkyl-, (CrC^alkylthio, (C₁-C₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂₁ -N(R)C(=O)R, -CH₂C(=O)R, 'CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O), -N(R)S(=O)₂R, -a and -CH₂A.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R³ is -C(=O)N(R⁵)2; and the two R⁵ groups are taken together with the nitrogen atom to which they are attached to form a 4~, 5-, 6- or 7-membered saturated C3. aheterocycloalkyl which is substituted with one, two or three substituents independently selected from the group consisting of (C_rC₄)alkyl, halo, hydroxyl, (C₁-C₄)hydroxyalkyl, (C_rC₄)haloalkyl and =O.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R⁴ is (C_rC₆)alkyl, (C₃-C₈)cycloalkyl, (C₃-C_a)heterocycloalkyl, (C₃

Ca)cycloalkyi(Ci-Ce)aikyl or (C₃-Ca)heterocycloalkyl(CrC6)alkyl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alkyl, (C_rC₄)haloalkyl, hydroxyl, (C_rC₄)hydroxyalkyl, (C]-C₄)alkoxy, (Ci-C₄)alkoxy(Ci-C₄)alkyl, (Ci-C₄)haloalkoxy, -NR₂₁(R2N)(Ci-C₄)aikyl-, (CrC^alkylthio, (CrC^haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=0)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R_t -S(=O)₂R, -S(=O)₂NR₂, -N(R)S(=O)₂R, -A and -CH₂A. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R⁴ is (Ci-C₆)alkyl, (C₃-Ce)cycloalkyi, (C₃-C_a)heterocycloalkyl, (C₃-C_e)cycloalkyi(Cr C₆)alkyl or (Ca-CaJheterocycloalkyKCi-CeJalkyl, substituted with cyano and further optionally substituted with an additional one, two, three or four substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alky(, (Cr C₄)haloalkyl, hydroxyl, (CrC^hydroxyalkyl, (CrC^alkoxy, (C_rC₄)alkoxy(C_rC₄)alkyl, (C_rC₄)haloalkoxy, -NR₂, (R₂N)(C_rC₄)alkyl-, (C_rC₄)alkylthio, (Ci-C₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR_2| -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR_2i -CH₂N(R)C(=O)R, -S(=O)₂R,-S(=O)₂NR_a> -N(R)S(=O)₂R, -A and -CH₂A.

In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R⁴ is aryl or heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C4)alkyl, (CrC4)haloalkyl, hydroxyi, (CrC4)hydroxyalkyl, (CiC4)alkoxy, (Ci-C4)alkoxy(Ci-C4)alkyl, (Ci-C4)haioalkoxy, -NR21 (R2N)(Ci-C4)alky|-, (C·,C4)alkylthio, (CrC4)haloalkylthio, -C(=O)R, -C(=O)OR, OC(=0)R, -C(=O)NR2l -N(R)C(=O)R, -CH2C(=O)R, -CH2C(=O)OR, -CH2OC(=O)R, -CH2C(=O)NR21 -CH2N(R)C(=O)R, -S(=O)2R, -S(=O)2NR2, -N(R)S(=O)2R, -A and -CH2A. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R⁴ is aryl or heteroaryl, substituted with cyano and optionally further substituted with one, two, three or four substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C4)alkyl, (C_rC₄)hafoalkyl, hydroxyl, (C_rC₄)hydroxyalkyl, (Ci-C₄)alkoxy, (Ci-C₄)alkoxy(Ci-C₄)alkyl, (CrC₄)haloalkoxy, -NR₂, (R₂N)(C₁-C₄)alkyl-, (CrC^alkyithio, (CrC^haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R,

-C(=O)NR_2i -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂₁-CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR_2j -N(R)S(=O)₂R, -a and -CH₂A.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R⁴ is phenyl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (CrC4)alkyl, (CpC^haloaikyl, hydroxyl, (CrC^hydroxyalkyl, (CrC4)alkoxy, (Cr C4)alkoxy(CrC4)alkyl, (CrC4)haloalkoxy, -NR2, (R2N)(CrC4)a[kyl·, (CvC^alkylthio, (Cr C4)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR2, -N(R)C(=O)R, -CH2C(=O)R, -CH2C(=O)OR, -CH2OC(=O)R, -CH2C(=O)NR2, -CH2N(R)C(=O)R, -S(=O)2R, -S(=O)2NR2 and -N(R)S(=O)2R. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R⁴ is phenyl, substituted with cyano and optionally further substituted with an additional one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Cr C₄)alkyl, (CrC^haloalkyl, hydroxyl, (C₁-C₄)hydroxyalkyi, (C_rC₄)alkoxy, (C_rC₄)alkoxy(C_rC₄)alkyl, (C_rC₄)haloalkoxy, -NR₂₁ (R₂N)(Ci-C₄)alkyi-, (C_rC₄)alkylthio, (C_rC₄)haloalkylthio_t-C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR_2i -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂ and -N(R)S(=O)₂R.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R⁴ is pyridyl, optionally substituted with one, two, three, four or five substitutents Independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C4)alkyl, (Ci-C4)haloalkyl, hydroxyl, (CrC4)hydroxyalkyl, (CrC4)alkoxy. (Giclai koxy(CrC4)alkyl, (CrC4)haloalkoxy, -NR2, (R2N)(Ci-C4)alky|-, (CrC4)alkylthiot (CiC4)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR2, -N(R)C(=O)R, -CH2C(=O)R, -CH2C(=O)OR, -CH2OC(=O)R, -CH2C(=O)NR2, -CH2N(R)C(=O)R, -S(=O)2R, -S(=O)2NR2 and -N(R)S(=O)2R. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R⁴ is pyridyl, substituted with phenyl and further optionally substituted with an additional one, two, three or four substitutents independently selected for each occurrence from the group consisting of halo, cyano, (C4-C₄)alkyi, (C_rC₄)haloalkyi, hydroxyl, (C_rC₄)hydroxyalkyl, (C₁-C₄)alkoxy, (CrC^alkoxyfCrC^alkyl, (C_rC₄)haloalkoxy, -NR₂₁ (R₂N)(C₁-C₄)alkyl-, (Ci-C₄)alkylthio, (Ci-C₄)haloalkylthîo, -C(=O)R,

-C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂ and -N(R)S(=O)₂R.

In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R is independently selected for each occurrence from the group consisting of hydrogen, (C_rC₄)alkyl, (C_rC₄)haloalkyl, (CrC^cyanoalkyl, (CiC₄)hydroxyalkyl, (C₃-C₈)cycloalkyl and (C₃-C₈)heterocycloalkyl. In certain embodiments, the présent invention relates to any of the aforementioned compounds, wherein R is independently selected for each occurrence from the group consisting of hydrogen and (CrC₄)alkyl.

Another embodiment of the invention is a compound selected from the group consisting of the compounds of Examples 1-95 and pharmaceutically acceptable salts thereof.

Therapeutic Applications

It is contemplated that the compounds of Formulae i, II, III, IV, V, VI and VII provide therapeutic benefits to subjects suffering from an immune disorder or inflammatory disorder. Accordingly, one aspect of the invention provides a method of treating a disorder selected from the group consisting of an immune disorder or inflammatory disorder. The method comprises administering a therapeutically effective amount of a compound of Formulae I, II, III, IV, V, VI and VII, to a subject in need thereof to ameliorate a symptom of the disorder, wherein Formulae I, II, III, IV, V, VI and VII are as described above. In certain embodiments, the particular compound of Formulae I, II, III, IV, V, VI and VII is a compound defined by one of the embodiments described above.

In certain embodiments, the disorder an immune disorder. In certain other embodiments, the disorder is an inflammatory disorder. In certain other embodiments, the disorder is an autoimmune disorder. In certain other embodiments, the disorder is 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, or epidermal hyperplasia.

In certain other embodiments, the disorder is cartilage inflammation, bone dégradation, arthritis, juvénile arthritis, juvénile rheumatoid arthritis, pauciarticular juvénile rheumatoid arthritis, polyarticular juvénile rheumatoid arthritis, systemic onset juvénile rheumatoid arthritis, juvénile ankylosing spondylitis, juvénile enteropathic arthritis, juvénile reactive arthritis, juvénile Reter's Syndrome, SEA Syndrome, juvénile dermatomyositis, juvénile psoriatic arthritis, juvénile scleroderma, juvénile systemic lupus erythematosus, juvénile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, dermatomyositis, psoriatic arthritis, vasculitis, myolitis, polymyolitis, dermatomyolitis, osteoarthritis, polyarteritis nodossa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopie dermatitis, atherosclerosis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Type I diabètes mellitus, Graves* disease, Addison’s disease, Raynaud's phenomenon, autoimmune hepatitis, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, érythrodermie psoriasis, or an immune disorder associated with or arising from activity of pathogenic lymphocytes. In certain embodiments, the psoriasis is plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, or érythrodermie psoriasis.

In certain other embodiments, the disorder is noninfectious uveitis, Behcet's disease or Vogt-Koyanagi-Harada syndrome.

Another aspect of the invention provides for the use of a compound of Formulae I, II, III, IV, V, VI and VII in the manufacture of a médicament. In certain embodiments, the médicament is for treating a disorder described herein.

Another aspect of the invention provides for the use of a compound of Formulae I, II, III, IV, V, VI and VII for treating a medical disorder, such a medical disorder described herein.

Further, it is contemplated that compounds of Formulae I, II, III, IV, V, VI and VII, can inhibit the activity of RORy. Accordingly, another aspect of the invention provides a method of inhibiting the activity of RORy. The method comprises exposing a RORy to an effective amount of a compound of Formulae I, II, III, IV, V, VI and VII, to inhibit said RORy, wherein Formulae I, II, [il, IV, V, VI and VII are as described above. In certain embodiments, the particular compounds of Formulae I, II, III, IV, V, VI and Vil is the compound defined by one of the embodiments described herein.

Further, it is contemplated that compounds of Formulae I, II, III, IV, V, VI and VII, can reduce the amount of interleukin-17 (IL-17) in a subject. IL-17 is a cytokine that affects numerous biological fonctions, including înduclng and mediating pro-inflammatory responses. Accordingly, another aspect of the invention provides a method of reducing the amount of IL-17 In a subject. The method comprises administering to a subject an effective amount of a compound of I to reduce the amount of IL-17 in the subject, wherein Formulae I, II, III, IV, V, VI and VII are as described above. In certain embodiments, the particular compounds of Formulae I, II, III, IV, V, VI and VII is the compound defined by one of the embodiments described herein.

In certain embodiments, the subject is a human. In certain embodiments, administering the compound reduces the amount of IL-17 produced by Th-17 cells in the subject. A change in the amount of IL-17 produced by, for example, Th-17 cells can be measured using procedures described in the literature, such as an ELISA assay or intracellular stainîng assay.

Further, it is contemplated that compounds of Formulae I, II, III, IV, V, VI and Vil, may inhibit the synthesis of IL-17 in a subject. Accordingly, another aspect of the invention provides a method of inhibiting the synthesis IL-17 in a subject. The method comprises administering to a subject an effective amount of a compound of Formulae l, II, III, IV, V, VI and VII, to inhibit the synthesis IL-17 in the subject, wherein Formulae I, II, III, IV, V, VI and VII are as described above. In certain embodiments, the particular compounds of Formulae I, II, III, IV, V, VI and VII is the compound defined by one of the embodiments described herein.

The description above describes multiple embodiments providing définitions for variables used herein. The application specifically contemplâtes ail combinations of such variables.

Combination Therapy

Another aspect of the invention provides for combination therapy. For example, the compounds of Formulae I, II, III, IV, V, VI and VII ortheir pharmaceutically acceptable salts may be used in combination with additional therapeutic agents to treat medical disorders, such as medical disorders associated with inappropriate IL-17 pathway activity. Exemplary additional therapeutic agents include, for example, (1) a TNF-a inhibitor; (2) a non-selective COX-l/COX-2 inhibitor; (3) a sélective COX-2 inhibitor, such as celecoxib and rofecoxib; (4) other agents for treating inflammatory disease and autoimmune disease including, for example, methotrexate, leflunomide, sulfasalazine, azathioprine, peniclllamine, bucillamine, actarit, mizoribine, lobenzarit, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin, parentéral gold, oral gold, cyclophosphamide, Lymphostat-B, a BAFF/ APRIL inhibitor, CTLA-4-lg, or a mimetic of CTLA-44g; (5) a leukotriene biosynthesis inhibitor, such as a 5-lipoxygenase (5-LO) inhibitor, or a 5-lipoxygenase activating protein (FLAP) antagonist; (6) a LTD4 receptor antagonist; (7) a phosphodiesterase type IV (PDE-IV) inhibitor, such as cilomilast (ariflo) or roflumilast; (8) an antihistamine HI receptor antagonist; (9) an od- and oc2-adrenoceptor agonist; (10) an anticholinergic agent; (11) a β-adrenoceptor agonist; (12) an insulin-like growth factor type I (IGF-1 ) mimetic; (13) a glucocorticosoid; (14) a kinase inhibitor such as an Inhibitor of a Janus Kinase (e.g., JAK 1 and/or JAK2 and/or JAK 3 and/or TYK2), p38 MAPK, Syk or IKK2; (15) a B-cell target biologie such as rituximab; (16) a sélective co-stimulation modulator such as abatacept; (17) an interleukin inhibitor or interieukin receptor inhibitor, such as the IL-1 inhibitor anakinra, IL-6 inhibitor tocilizumab, and IL12/IL-23 inhibitor ustekimumab; (18) an anti-IL17 antibody, anti-IL21 antibody, or anti-IL22 antibody (19) a S1P1 agonist, such as fingolimod; (20) an interferon, such as interferon beta 1; (21) an integrîn inhibitor such as natalizumab; (22) a mTOR inhibitor such as rapamycin, cyclosporin and tacrolimus; (23) a non-steroidal antiinflammatory agent (NSAID), such as propionic acid dérivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprafen, suprofen, tiaprofenre acid, and tioxaprofen), acetic acid dérivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxptnac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid dérivatives (flufenamic acid, meelofenamie acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxyiic acid dérivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (24) a NRF2 pathway activator, such as the fumaric acid dérivative, BG-12; and (25) a chemokine or chemokine receptor inhibitor, such as a CCR9 antagonist.

In certain embodiments, the additional therapeutic agent is selected from the group consisting of Corticosteroids, Vitamin D3, Anthralin and Retinoids. In certain embodiments, the additional therapeutic agent is a Corticosteroid. In certain embodiments, the additional therapeutic agent is Vitamin D3. In certain embodiments, the additional therapeutic agent is Anthralin. In certain embodiments, the additional therapeutic agent is a Retinoids.

The amount of the compounds of Formulae i, II, III, IV, V, VI and VII and additional therapeutic agent and the relative timing of administration may be selected in order to achieve a desired combined therapeutic effect. For example, when administering a combination therapy to a patient în need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be adminîstered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. Further, for example, a compound of any one of Formulae I, II, III, IV, V, VI and VII may be adminîstered during a time when the additional therapeutic agent(s) exerts its prophylactic or therapeutic effect, or vice versa.

The doses and dosage regimen of the active ingrédients used in the combination therapy may be determined by an attending clînician. In certain embodiments, the compound of any one of Formulae I, II, III, IV, V, VI and Vil and the additional therapeutic agent(s) are adminîstered in doses commonly employed when such agents are used as monotherapy for treating the disorder. In other embodiments, the compound of any one of Formulae I, II, III, IV, V, VI and VII and the additional therapeutic agent(s) are adminîstered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder. In certain embodiments, a compound of any one of Formulae I, 11, III, IV, V, VI and VII and the additional therapeutic agent(s) are présent in the same composition, which is suitable for oral administration.

In certain embodiments, the compound of any one of Formulae I, II, III, IV, V, VI and VII and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.

Another aspect of this invention is a kit comprising a therapeutically effective amount of a compound of any one of Formulae I, II, III, IV, V, VI and VII, a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.

Pharmaceutîcal 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 pharmaceutîcal composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the 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 phamnaceutical 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 pharmaceutîcal 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 longue; (2) parentéral administration, for example, by subcutaneous, intramuscular, intravenous or épidural injection as, for example, a stérile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-reiease 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, materiaîs, 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 lauryl sulfate and magnésium stéarate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

Exemples 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, tartaric acid, phosphoric acid, and the like.

Formulations of the present 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 particular 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 fineiy 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-acceptabîe carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as 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 polyethyiene 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-Iinked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, 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 mtcrospheres. 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 incoiporating 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 micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable émulsions, microemulsîons, 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, sotubilizing agents and emuisifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohoi, 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 suspendlng agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendlng agents as, for exampîe, ethoxylated isostearyl alcohols, polyoxyethylene sorbitot and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room 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 transdermai 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, paraffins, 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 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.

Transdermai patches hâve the added advarrtage of providing controlled delivery of a compound of the présent Invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dîssolved 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 suitable for ocular and aurai administration include 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 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 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, 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 blood of the intended récipient or suspending or thlckening 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, chlorobutanoi, 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. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In 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. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the subject compounds in 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 oraily, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For exampfe, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, olntment, 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, 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 s 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 10 any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceuticai 15 compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

Actual dosage levels of the active ingrédients in the pharmaceutîcal 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, 20 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 present 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, 25 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 determine and 30 prescribe the effective amount of the pharmaceutîcal 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 iowest 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.

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 Formulae I, II, III, IV, V, VI and VII or a spécifie compound described herein, or pharmaceutically acceptable salts thereof, in a therapeutically effective amount for the treatment of an immune or inflammatory disorder, such as one of the particular immune disorders or inflammatory disorders described herein.

General Synthetic Schemes and Procedures

The compounds of Formulae I, ll, III, IV, V, VI and Vil may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familtar to those of ordinary skill in the art. The starting matériels used herein are commercially available or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol.

l-VI (published by Wiley-lnterscience)). Preferred methods include, but are not limited to, those described below.

During any of the following synthetic sequences it may be necessary and/or désirable to protect sensitive or réactivé groups on any of the molécules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.

Compounds of Formulae I, 11, III, IV, V, VI and VII, or their pharmaceutically acceptable salts, can be prepared according to the reaction Schemes dtscussed herein below. Unless otherwise indicated, the substituents in the Schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.

It will be understood by one skilled in the art that the various symbols, superscripts and subscripts used in the schemes, methods and examples are used for conventence of représentation and/or to reflect the order in which they are introduced in the schemes, and are not intended to necessarily correspond to the symbols, superscripts or subscripts in the appended daims. The schemes are représentative of methods useful in synthesizing the compounds of the present invention. They are not to constrain the scope of the invention in any way.

Compounds of Formulae I, II, III, IV, V, VI and VII may be prepared as single enantiomer or as a mixture of individual enantiomers which Includes racemic mixtures. Methods to obtain preferentially a single enantiomer from a mixture of individual enantiomers or a racemic mixture are well known to those ordinarily skilled in the art of organic chemistry. Such methods include but are not limited to preferential crystallization of diastereomeric salts (e.g. tartrate or camphor sulfonate), covalent derivatization by a chiral, non-racemic reagent followed by 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 the invention or on any intermediates to compounds of the invention which bear a stereogenic center. Also, to facilitate séparation by any of the methods described above, the compounds of the invention or any intermediates to the compounds of the invention 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. Condensation of 5-nîtro-1H-indole (A-1, Y = H) with tert-butyl 4-oxopiperidine-1-carboxylate affords A-2. The indole nitrogen is then alkylated with alkyl halides of the formula R¹I or R¹ Br in the presence of base to provide A-3. Hydrogénation of A-3 provides compounds of the formula A-4. The resulting amine A-4 may be transfomned to amides by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents or A-4 may be transformed to ureas by the reaction with a phosgene équivalent followed by an amine. Following deprotection of the nitrogen protecting group, intermediate A-6 may be transformed into compounds of the formula A-7 (Formula I) through common amine transformations including amide formation, sulphonamide formation, urea formation and reductive amination. Similarly, beginning with 4-methyl-5nitro-1 H-indole (A-1, Y = Me) and following similar steps provides compounds of the formula A-7 (Y = Me).

SCHEME A

R = C(O)Ot-Bu

R = H —i

R = R³ —I

Alternative^, compounds of formula (I) may be prepared as described in Scheme B. Intermediate A-4 can be transformed to sulphonamides of the formula B-1 by reacting with sulfonyl chlorides in the presence of a base. Following deprotection of the nitrogen protecting group, intermediate B-2 may be transformed into compounds of the formula B-3 (Formula I) through common amine transformations including amide formation, sulphonamide formation, urea formation and reductive amination.

A-4

SCHEME B

f— B-1 R = C(O)0t-Bu

L* B-2 R = H -η

B-3 R = R3 -J

Alternatively, compounds of formula (I) may be prepared as described in Scheme C. Deprotection of the nitrogen protecting group in A-3 affords amine C-1 which is then 5 transformed in to amides by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents to provide compounds of the formula C2. Hydrogénation of intermediate C-2 affords compounds of the formula C-3. The resulting amine C-3 may be transformed to compounds of formula (I) through common procedures for sulphonamide formation, amide formation or urea formation.

1° SCHEMEC

Alternatively, compounds of formula (I) may be prepared as described in Scheme D. Condensation of 5-nitro-1 H-indole (A-1) with tert-butyf 3-oxopiperidine-1-carboxyfate affords D-1. The indole nitrogen is then alkylated with alkyl halides of the formula R¹! or R¹ Br in the presence of base to provide D-2. Hydrogénation of D-2 provides compounds of the formula D-3. The resulting amine D-3 may be transformed to amides (Z = CO) by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents or D-3 may be transformée! to ureas (Z = CO) by the reaction with a phosgene équivalent followed by an amine or D-3 may be transformed to sulfonamides (Z = SO₂) by the reaction with sulfonyl chlorides in the presence of a base. Following deprotection of the nitrogen protecting group, intermediate D-5 may be transformed into compounds of the formula D-6 (Formula I) through common amine transformations including amide formation, sulphonamide formation, urea formation and reductive amination.

SCHEME D

D-2

¹⁰ Altematively, compounds of formula (I) may be prepared as described in Scheme E.

5-Nitro-1H-indole (A-1) is halogenated to afford bromide E-1. Palladium mediated coupling of E-1 with tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1carboxylate provides E-2. The indole nitrogen is then alkylated with alkyl halides of the formula R¹I or R¹ Br in the presence of base to provide compounds of the formula E-3.

Hydrogénation of E-3 provides compounds of the formula E-4. The resulting amine E-4 may be transformed to amides (Z = CO) by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents or E-4 may be transformed to ureas (Z = CO) by the reaction with a phosgene équivalent followed by an amine or E-4 may be transformed to sulfonamides (Z = SO₂) by the reaction with sulfonyf chlorides in the presence of a base. Following deprotection of the nitrogen protecting group, intermediate E-6 may be transformed into compounds of the formula E-7 (Formula I) through common amine transformations including amide formation, sulphonamide formation, urea formation and reductive amination.

SCHEME E

E-4 E-5 R = C(O)Ot-Bu ί* E-6 R = H —i

E-7 R = R³ -J

Compounds of formula (II) may be prepared as described in Scheme F. lodination of 510 nîtro-1 H-pyrrolo[2,3-b]pyridine (F-1 ) followed by alkylation of the nitrogen by alkyl halides of the formula R¹1 or R¹Br in the presence of base provides compounds of the formula F-2. Palladium mediated coupling of F-2 with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2dîoxaborolan-2-yl)-5,6-dihydropyridîne-1(2H)-carboxylate provides compounds of the formula F-3. Hydrogénation of F-3 provides compounds of the formula F-4. The resulting amine F-4 may be transformed to amides (Z = CO) by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents or F-4 may be transformed to ureas (Z = CO) by the réaction with a phosgene équivalent followed by an amine or F-4 may be transformed to sulfonamides (Z = SO₂) by the reaction with sulfonyl chlorides in the presence of a base. Following deprotectîon of the nitrogen protecting group, intermediate F-6 may be transformed into compounds of the formula F-7 through common amine transformations including amide formation, suiphonamide formation, urea formation and reductive amination.

SCHEME F

F-3

F-6 R = H —i

F-7 R = R³

Compounds of formula (III) or formula (IV) may be prepared as described in Scheme G. Amine protection of intermediate G-1 (wherein X=N, Y=CH or X=CH, Y=N) followed by io hydrogénation and ring closure-elimination provides compounds of the formula G-3. lodination of G-3 provides compounds of the formula G-4 which are then alkylated by alkyl halides of the formula R¹l or R¹ Br in the presence of base provides compounds of the formula G-5. Palladium mediated coupling of G-5 with 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-5_l6-dihydropyridïne-1(2H)-carboxylate amides provide compounds of the formula G-6. Hydrogénation of G-6 provîdes compounds of the formula G-7. The resulting amine G-7 may be transformed to amides (Z = CO) by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents or G-7 may be transformed to ureas (Z = CO) by the reaction with a phosgene équivalent followed by an amine or G-7 may be transformed to sulfonamides (Z = SO2) by the reaction with sulfonyl chlorides in the presence of a base to provide compounds of the formula G-8.

SCHEME G

Compounds of formula (V) may be prepared as described in Scheme H. Reductive dehalogenation of 2,4-dichloro-5H-pyrrolo[3_r2-d]pyrirriidine (H-1) provides H-2 which is then iodinated to afford compound H-3. Alkylation of the nitrogen by alkyl halides of the formula R¹l or R¹Br in the presence of base provides compounds of the formula H-4. Palladium mediated coupling of H-4 with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)10 5,6-dihydropyridine-1 (2H)-carboxylate amides provide compounds of the formula H-5. Hydrogénation of H-5 provides compounds of the formula H-6. The resulting amine H-6 may be transformed to amides (Z = CO) by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents or H-6 may be transformed to ureas (Z = CO) by the reaction with a phosgene équivalent followed by an amine or H-6 may be transformed to sulfonamides (Z = SO₂) by the reaction with sulfonyl chlorides in the presence of a base to provide compounds of the formula H-7.

SCHEME H

Compounds of formula (VI) may be prepared as described in Scheme I. The addition of lithiated 1-bromo-4-fluorobenzene to intermediate 1-1 provides the ketone I-2.

Condensation of I-2 with hydroxylamine provides hydroxyl imîne I-3 which undergoes ring closure in the presence of base to provide isoxazole I-4. Palladium mediated amination of I-4 with an amine surrogate followed by deprotection of the nitrogen protecting group affords intermediate I-5. The resulting amine I-5 may be transformed to amides (Z = CO) by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate io coupling agents or 1-5 may be transformed to ureas (Z = CO) by the reaction with a phosgene équivalent followed by an amine or 1-5 may be transformed to sulfonamides (Z = SO₂) by the reaction with sulfonyl chlorides in the presence of a base. Following deprotection of the nitrogen protecting group, intermediate 1-7 may be transformed into compounds of the formula 1-8 through common amine transformations including amide formation, sulphonamide formation, urea formation and reductive amination.

SCHEME I

Compounds of formula (VII) may be prepared as described in Scheme J. Compounds such as 6-nitro-1H-indazole (J-1 wherein R¹ is H) may be alkylated with tert-butyl 45 ((methylsulfonyl)oxy)piperidine-1-carboxylate in the presence of an inorganic base to provide compounds of the formula J-2. Hydrogénation of J-2 provides compounds of the formula J-3. The resulting amine J-3 may be transformed to amides (Z = CO) by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents or J-3 may be transformed to ureas (Z = CO) by the reaction with a phosgene équivalent followed by an amine or J-3 may be transformed to sulfonamides (Z = SO₂) by the reaction with sulfonyl chlorides in the presence of a base. Following deprotection of the nitrogen protecting group, intermediate J-5 may be transformed into compounds of the formula J-6 through common amine transformations including amide formation, sulphonamide formation, urea formation and reductive amination.

SCHEME J

J-3 r— J-4 R = C(O)Ot-Bu

L* J-5 R = H —i

J-6 R = R³ -J

Compounds of formula (I) may be prepared as described in Scheme K. Hologenation of Indoles such as 4-methyl-5-nitro-1 H-indole (K-1, Y = Me) with iodine in the presence of an 5 inorganic base followed by alkylation of the indole nitrogen with an alkylhalide of the formula R¹I or R'Br in the presence of base provides compounds of the formula K-2. Coupling of K-2 with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6dihydropyridine-1(2H)-carboxylate in the presence of a palladium catalyst provides compounds of the formula K-3. Following deprotection of the nitrogen protecting group, intermediate K-4 may be transformed into compounds of the formula K-5 through common amine transformations including amide formation, sulphonamide formation, urea formation and reductive amination. Compounds of the formula K-5 may be treated with reducing conditions to provide K-6. The resulting amine may be transformed to amides by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents or K-6 may be transformed to ureas by tFie reaction with a phosgene équivalent followed by an amine.

SCHEME K

Compounds of formula (II) may be prepared as described in Scheme L. Nitration of L-1 provides compound L-2 which is then converted to L-3 by the treatment with trimethylaluminum in the presence of a palladium catalyst. Deprotection of the indole nitrogen followed by iodination provided compound L-5. Alkylation of the indole nitrogen by alkylhalides such as iodomethane provided compound L-6. Coupling of L-6 with tert-butyl o 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate in the presence of a palladium catalyst provides compound L-7. Compound L-7 may be treated with reducing conditions to provide L-8. The resulting amine may be transformed to amides by the reaction with acid chlorides in the presence of base or carboxylic acids with appropriate coupling agents or L-8 may be transformed to ureas by the reaction with a phosgene équivalent followed by an amine. Following deprotection of the nitrogen protecting group, intermediate L-10 may be transformed into compounds of the formula L11 through common amine transformations including amîde formation, sulphonamide formation, urea formation and reductive amination.

SCHEME L

<— L-1 R = H *-*· L-2 R = NO₂ i— L-4 R = H L* L-5 R = I

Compounds of formula (I) may be prepared as described in Scheme M. Condensation of 2-oxooxazolidine-3-suIfonyl chloride with compounds of the formula M-1 in the presence of pyridine provide compounds of the formula M-2. Reaction of M-2 with primary or secondary amines provides compounds of the formula M-3.

SCHEME Μ

M-2

M-3

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 present 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.

Expérimente were generally carried out under inert atmosphère (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or întermediates 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, Ô) 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).

The following abbreviations are used herein: DCM: dichloromethane; DMF: dimethylformamide; NMP: N-Methylpyrrolidone; BINAP: 2,2'-bis(diphenylphosphino)-1,1’binaphthyl; MeOH: methanol; TEA: triethylamine; and THF: tetrahydrofuran.

Example 1

Préparation of 3-cyano-N-(3-(1-(cyciopentylcarbonyl)piperidin-4-y[)-1-methyl-1Hindol-5-yl)benzamide

Step 1: tert-Butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Int1). To freshly prepared sodium methoxide (5.0 g, 92.59 mmol) in MeOH (100 mL) was added 5-nitroindole (5.0 g, 30.87 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (18.56 g, 19.52 mmol). The reaction mixture was heated to reflux for 24 h. The progress of reaction was monitored by TLC (40% ethyl acetate in hexane). After most of the starting material consumed (By TLC), reaction mixture was cooled to room température and concentrated under vacuum. The residue obtained was diluted with water (100 mL), extracted by using ethyl acetate (3x100 mL), dried (NaaSCti), filtered and concentrated to obtain crude material. The crude compound was purified by using column chromatography (silica gel, 100-200 mesh) to afford the title compound (9.0 g, 87%) as a yellow solid. ¹H NMR (400 MHz, CDCI3): δ 11.93 (s, 1H), 8.72 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 8.71 (s, 1 H), 7.56 (d, J = 8.8 Hz, 1 H), 6.20 (s, 1 H), 4.18 (m, 2H), 3.64 (m, 2H), 2.58 (m, 2H), 1.45 (s, 9H); LCMS: m/e 243.95 [M-100]+ Boc deprotected

Step 2: tert-Butyl 4-(1-methyI-5-nitro-1H-indol-3-yl)-5,6-dîhydropyridine-1(2H)carboxylate (lnt-2). To a solution of tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine1 (2H)-carboxylate (lnt-1 ; 4.5 g, 13.12 mmol) in 80 mL of THF was added NaH (2.1 g, 52.48 mmol, 60% w/w in minerai oil) at 0 °C. The reaction mixture was stirred at room température for 1 h and then Mel (3.3 mL, 52.48 mmol) was added dropwise at 0 °C. The reaction mixture was then allowed to stir at room température for overnight. The progress of reaction was monitored by TLC (40% ethyl acetate in hexane). After completion, reaction mixture was quenched by addition of ice-water and then extracted by using ethyl acetate (2x100 mL). The combined organic phases were dried (Na₂SO₄), filtered and concentrated to obtain the title compound (4.6 g, 98%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1 H), 8.07 (d, J = 9.2 Hz, 1 H), 7.71 (s, 1 H), 7.66 (d, J = 9.2 Hz, 1 H), 6.21 (s, 1 H), 4.08 (brs, 2H), 3.86-3.84 (m, 3H), 3.58-3.57 (m, 2H), 2.54 (m, 2H, Merged), 1.44 (s, 9H); LCMS: m/e 258.95 [M-100]+ Boc deprotected

Step 3. tert-Butyl 4-(5-amino-1-methyl-1H-indol-3-yl) piperidine-1-carboxylate. To a solution of tert-butyl 4-(1-methyl-5-nitro-1 H-indol-3-yl)-5,6-dihydropyridine-1(2H)carboxylate (4.5 g, 12.61 mmol) in 50 mLof methanol was added Pd/C (0.1g) and the reaction mixture was heated at 40 °C under H₂ atmosphère (Balloon pressure) for 7 h. The progress of reaction was monitored by TLC (50% ethyl acetate in hexane). After completion, the reaction mixture was filtered through Celite, washed with methanol and the combined filtrate was concentrated in vacuum to obtain the title compound (3.4 g, 82%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.04 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.69 (s, 1H), 6.51 (dd, J = 1.6, 8.4 Hz, 1H), 4.47 (s, 2H), 4.06-4.03 (m, 2H), 3.60 (s, 3H), 3.09-2.75 (m, 5H), 1.87 (d, J = 12.4 Hz, 2H), 1.41 (s, 9H). LCMS: m/e 352.10 [M+Na]+

Step 4: 3-Cyanobenzoyl chloride. To a solution of 3-cyanobenzoic acid (7 g, 47.61 mmol) in toluene (100 mL) was added SOCI₂ (17.38 mL, 238.09 mmol) and DMF (2-3 drops, catalytic). The reaction mixture was allowed to heat at 95 °C for 4 h. The progress of reaction was monitored by TLC (30% Ethyl acetate in hexane, the reaction mass was quenched with dry methanol for TLC). After compietion, reaction mixture was concentrated in vacuo to give a crude 3-cyanobenzoyl chloride (7.84 g, 99%) which is used In the next reaction wîthout further purification.

Step 5: tert-Butyl 4-(5-(3-cyanobenzamido)-1-methyl-1 H-indol-3-yl)piperidine-1carboxylate. To a solution of tert-butyl 4-(5-amino-1 -methyl-1 H-indol-3-yl)piperidine-1carboxylate (lnt-2; 5 g, 15.19 mmol) in DCM ( 70 mL) was added TEA (6.4 mL, 45.59 mmol) followed by addition of 3-cyanobenzoyl chloride (3 g, 18.23 mmol) in DCM (10 mL) at 0 °C. The progress of reaction was monitored by TLC (50% ethyl acetate in hexane). After compietion, reaction mixture was quenched with water and extracted by using DCM. The combined extracts were dried (Na₂SO₄), filtered and concentrated in vacuo to give a crude compound which was subjected to column chromatography (Silica gel, 100-200 mesh) to afford the title compound (4.32 g, 62%) as a light brown solid. ’H NMR (400 MHz, CDCl₃): δ 8.21 (s, 1H), 8.14 (d, J=7.6 Hz, 1H), 8.00-7.93 (m, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.63 (t. J= 7.6 Hz, 1 H), 7.33 (d, J= 8.8 Hz, 1 H), 7.28 (d, J= 8.8 Hz, 1 H), 6.83 (s, 1 H), 4.204.13 (m, 2H), 3.75 (s, 3H), 2.98-2.84 (m, 3H), 2.04-1.99 (m, 2H), 1.67-1.56 (m, 2H), 1.48 (s, 9H). LCMS: m/e 358.95 [M-100] + (De-Boc compound observed as a base peak).

Step 6: 3-cyano-N-(1-methyl-3-(piperidin-4-yl)-1H-indol-5-yl)benzamide. To a solution of tert-butyl 4-(5-(4-cyanopyridinθ-2-carboxamido)-1-methyI-1H-indol·3yl)piperidine-1-carboxylate (3 g, 9.43 mmol) in 20 mL of methanol was added 4M HCl rn dioxane (30 mL) at 0 ^DC. The reaction mixture was allowed to warm up to room température and stirred ovemight. The progress of reaction was monitored by TLC (10% methanol in DCM). After compietion, reaction mixture was concentrated in vacuo to give a crude compound which was neutralized with sat. NaHCO3 solution and then extracted with 10% methanol in DCM. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuum to give the title compound (1.5 g, 44.64%) as a brown solid. ¹H NMR (400 MHZ, CDC13): δ 8.21 (s, 1H), 8.15 (d, J=8.0 Hz, 1 H), 8.04-7.99 (m, 2H), 7.81 (d, J=8.4 Hz, 1 H), 7.63 (t, J= 8.0 Hz, 1 H), 7.36 (d, J= 8.0 Hz, 1 H), 7.28 (d, J= 8.0 Hz, 1 H), 6.85 (s, 1H), 3.75 (s, 3H), 3.19-2.76 (m, 6H), 2.04-1.65 (m, 4H). LCMS: m/e 358.95 [M+1 ] +

Step 7: 3-cyano-N-(3-(1 -(cyclopentylcarbonyï)piperidin-4-yl)-1 -methyl-1 H-indol-5yl)benzamide. Cyclopentanecarboxylic acid (128 mg, 1.114 mmol) and TBTU (430 mg, 1.337 mmol) were dissolved in DMF (15 mL) and DI PEA (720 mg, 5.57mmol) was added.

After stirring at 40 °C for 1 hr, 3-cyano-N-(1-methyl-3-(piperidin-4-yl)-1H-indol-5yl)benzamide (400 mg, 1.114 mmol) was added and the mixture was stirred at 40 °C ovemight. The crude product was purified by préparative TLC to give the title compound (21 mg, 4.1%) as a yellow solid. ’H NMR (400 MHZ,CDCI₃): δ 8.21 (br.s, 1 H), 8.17 (d,

J=7.6 Hz, 1 H), 8.01 (br.s, 1H), 7.92 (br.s, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.29-7.33 (m, 2H), 6.84 (s, 1H), 4.78 (d, J= 13.2 Hz, 1 H), 4.10 (d, J= 13.2 Hz,1H), 3.76 (s, 3H), 3.05-3.23 (m, 2H), 2.91-2.98 (m,1H), 2.69-2.76 (m,1H), 2.04-2.16 (m, 2H), 1.69-1.48 (m, 6H), 1.55-1.66 (m, 4H). LCMS: m/e 455.10 [M+1J+.

The following examples were prepared analogous to Example 1.

Example	Structure	Name	MS (M+H)
2	f I [f	y° ¹ Ί h t⁷ o XX/ \	3-cyano-N-(1-methyl-3-(1-(3methylbutanoy[)piperidin-4-yI)-1Hindol-5-yl)benzamide	442.2
3	f I [Γ	j ^H°X ¹ Ί H V⁷ ° UQ \	3-cyano-N-(3-(1-((2S,3S)-2-hydroxy- 3-methylpentanoyl)piperidin-4-y])-1methyl-1 H-indol-5-yl)benzamide	472.2

Example	Structure	' Name	MS (M+H)
4	F I	J ^H0 ¹ λ^ν Ί h V⁷ o XX/ \	3 -cyan ο- N -(3-( 1 - ((2 S) -2 -hy droxy-4methylpentanoyl)piperidin-4-yl)-1methyl-1 H-indol-5-yl)benzamide	472.2
5	F I if	HO 1 ^-N Ί h ο XX/ \	3-cyano-N-(3-{1 -[(cis-4hydroxycyclohexyl)carbonyl]piperidin4-yl }-1 -methyl-1 H-indol-5yl)benzamide	484.2

Example 6

Préparation of 4-cyano-N-(3-(1-(cyclopentylcarbonyi)piperidin-4-yI)-1-methyI-1 Hindol-5-yl)pyridine-2-carboxamide

Step 1: tert-Butyl 4-(5-(4-cyanopyridine-2-carboxamido)-1-methyl-1H-indol-3yl)piperidine-1-carboxylate (lnt-2). To a solution of tert-butyl 4-(5-(4-cyanopicolinamido)-1methyl-1H-indol-3-yl) piperidine-1-carboxylate (prepared in Example 1,3.3 g, 10.03 mmol) in DCM ( 20 mL) was added TEA (4.2 mL, 30.09 mmol) followed by addition of 4cyanopicolinoyl chloride (2.1 g, 12.53 mmol) in DCM (10 mL) at 0 °C. The progress of réaction was monitored by TLC (50% ethyl acetate in hexane). After completion, reaction mixture was quenched with water and extracted by using DCM. The combined extracts were dried (Na₂SO₄), filtered and concentrated in vacuo to give a crude compound which was subjected to column chromatography (Silica gel, 100-200 mesh) to afford the title compound (3.7 g, 80%) as a light brown solid. ¹H NMR (400 MHz, CDCI3): δ 9.88 (s, 1 H), 8.82 (d, J = 4.8 Hz, 1 H), 8.55 (s, 1 H), 8.13 (s, 1 H), 7.71 (dd, J = 1.2, 4.8 Hz, 1 H), 7.47 (dd, J =2.0, 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.84 (s, 1H), 4.23-4.18 (m, 2H), 3.76 (s, 3H), 3.15-2.88 (m, 3H), 2.03 (d, J = 12.8 Hz, 2H), 1.65-1.54 (m, 2H), 1.49 (s, 9H); LCMS: m/e 359.90 [M-100]+ Boc deprotected.

Step 2: 4-Cyano-N-(1-methyï-3-(piperïdin-4-yl)-1H-indoI-5-yl) picolinamide. To a solution of tert-butyl 4-(5-(4-cyanopyridine-2-carboxamido)-1-methyl-lH-indol-3yl)piperidine-1-carboxylate (lnt-2; 3.7 g, 8.04 mmol) in 15 mLof methanol was added 4M HCl in dioxane (30 mL) at 0 °C. The réaction mixture was allowed to warm up to room température and stirred overnight. The progress of the reaction was monitored by TLC (10% methanol in DCM). After completion, reaction mixture was concentrated in vacuo to give a crude compound which was neutralîzed with sat. NaHCOa solution and then extracted with 10% methanol in DCM. The combined extracts were dried (Na₂SO4), filtered and concentrated in vacuum to give the title compound (2.2 g, 78%) as a brown solid. ¹H NMR (400 MHz, CDCI₃): δ 10.03 (s, 1H), 8.79-8.77 (m, 2H), 8.15 (s, 1H), 8.03 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.86 (s, 1H), 5.78 (brs, 1H), 3.75 (s, 3H), 3.22-2.79 (m, 5H), 2.03 (d, J = 10.4 Hz, 2H), 1.78-1.68 (m, 2H). LCMS: m/e 377. 90 [M+H₂O]+

Step 3: 4-cyano-N-(3-(1-(cyclopentylcarbonyl)piperidin-4-yl)-1-methyl-1 H-indol-5yl)pyridine-2-carboxamide. A solution of cyclopentylcarboxylic acid (105 mg, 0.92 mmol), DIPEA (0.75 mL, 4.2 mmol) and EDCI.HCI (531 mg, 2.77 mmol) and HOBT (340 mg, 2.52 mmol) in DMF (1 mL) was stirred at room température for 1h. KB 4-Cyano-N-(1-methyl-3(piperidin-4-yl)-1 H-indol-5-yl) picolinamide (300 mg, 0.84 mmol) was added to the above mixture and stirred at room température. The progress of reaction was monitored by TLC (5% methanol in DCM) and LCMS. After completion of the reaction (overnight), the reaction was diluted with water and extracted with DCM. The combined organic layers were dried (NasSOi»), filtered, concentrated and the crude material was purified by column chromatography (silica gel, 230-400 mesh) to give the title compound (2Θ0 mg, 74%) as a yellow solid. ¹H NMR (400 MHZ, CDCI3): δ 9.Θ8 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.55 (s,

1 H), 8.18 (s, 1 H), 7.71 (dd, J= 1.2, 4.8, Hz, 1H), 7.44 (dd, J= 1.6, 8.8 Hz, 1 H), 7.29 (d, J=

8.8, Hz, 1H), 6.84 (s, 1H), 4.78 (d, J= 12.8 Hz, 1 H), 4.15-4.08 (m, 1H), 3.76 (s, 3H), 3.23 (t, J= 12.8 Hz, 1H), 3.14-2.94 (m, 2H), 2.75 (t, J= 12.8 Hz, 1H), 2.18-2.10 (m, 2H), 1.87-1.59 (m, 10H). LCMS: m/e 456.00 [M+H]+

The following examples were prepared analogous to Example 6.

Example	Structure	Name	MS (M+H)
7	N III --N o w \	4-cyano-N-{3-[1(cyclohexylcarbonyl)piperidin-4-yl]-1methyl-1 H-indol-5-yl]pyridine-2carboxamide	470.2
8	F. fA—/ N Il —-N θ W \	4-cyano-N-(3-{1 -[(3,3difluorocyclopentyl)carbonyl]piperidin4-y l}-1 -methyl-1 H-indoI-5-yl)pyridine2-carboxamide	490.1

Example		Structure	Name	MS (M+H)
9	I f T	yj ^a=\ \__/ Π l L l-- O	4-cyano-N-(3-{1 -[(3,3difluorocyclobutyl)carbonyl]piperidin4-yl}-1 -methyl-1 H-indol-5-yl)pyridine2-carboxamide	477.2
10	Γ I T	J )*O 1 /-N 1 H o kA/ \	4-cyano-N-(1 -methyi-3-{1 -[(5methylisoxazol-3yl)carbonyl]piperidin-4-yl}-1H-indal-5yl)pyridine-2-carboxamide	469.15
11	F I ζ	O 7^><'z y \=°	4-cyano-N-(1-methyl-3-{1-[(1-methyl- 1H-pyrazol-5-yl)carbonyl]pïperidin-4- yl}-1H-Îndol-5-yl)pyridine-2carboxamide	468.15
12	^o=\ ZI u \ o o	4-cyano-N-{1 -methyl-3-[1 -(tetrahydro- 2H-pyran-4-ylacetyl)piperidin-4-yl]-1H- indol-5-yl}pyridine'2-carboxamide	486.20

Example	Structure	Name	MS (M+H)
13	r I (.	o ( l Pz'-'r^z' M X / \ ^xz _v	4-cyano-N-[3-(1-{[(1 S,2R)-2hydroxycyclopentyl]carbonyl}piperidin4-yl)-1-methy[-1H-indol-5-y[]pyridine2-carboxamide	472.20
14	r I ζ	O \__/-z Λ /⁼⁼\ P xz po	4-ον3ηο-Ν-(1-ηθίΗνΙ-3-{1-[(4-ΠΊθΙήν1- 1,3-οχ3ΖθΙ-5-νΙ)σ3Η3θΓψΓ\|ρίρβπάΐη-4- yl}-1 H4ndol-5-yl)pyridine-2carboxamide	469.10
15	r I T	Γ°\ J ^>=0 ¹ r-N -Vrri 0 w \	4-cyano-N-{1 -methyl-3-[1 -(tetrahydro2H-pyran-3-ylcarbonyi)piperidin-4-yl]IH-indol-S-yllpyridine^-carboxamide	472.20
16	h I ζ	xz^Z ° xz p° /“C	4-cyano-N-[1-methyl-3-(1 -{[2(methylamino)pyridin-3yl]carbonyl}piperidin-4-yl)-1H4ndol-5yl]pyridine-2-carboxamide	494.15

Example	Structure	Name	MS (M+H)
17	I [f	Cr < yo I ί h i y⁷ 0 υζ/ \	4-cyano-N-(1-methyl-3-{1-[(5-methyl- 1,3-oxazol-4-yl)carbonyl]piperidin-4- yl]-1H-indol-5-yl)pyridine-2carboxamide	469.15
18	r I i.	p/ ^o=\ \ z^y^ o	4-cyano-N-{1 -methyl-3-[1 -(1,3-thiazol4-ylcarbonyl)piperidin-4-yl]-lH-indol5-yl}pyridine-2-carboxamide	471.00
19	I* I i.	‘W — o=\ ZI o	4-cyano-N-{1 -methyI-3-[ 1 -(tetrahydro2H-pyran-4-ylcarbonyl)piperidin-4-yl]1H-indol-5-yl}pyridine-2-carboxamide	472.20
20	t I	yj _oy ZI Jyy w \ z-y^ o	4-cyano-N-{1 -methyl-3-[1 -(pyrimidin- 4-ylcarbonyI)piperidin-4-yl]-1H-indol- 5-yl}pyridîne-2-carboxamide	466.15

Example		Structure	Name	MS (M+H)
21	fs I	OH l'N νΛ /^^N Ί H ¹ if o W \	4-cyano-N-(3-{1-[(6-hydroxypyridin-2yl )carbonyl ]pipe ridi n-4-y I }-1 -methyl1H4ndol-5-yl)pyridine-2-carboxamide	481.15
22	b I h	HO zÇo I 1 H o M-V \	4-cyano-N-{3-[1 -(3-hydroxy-2,2dimethylpropanoyl)piperidin-4-yl]-1methyl-1 H-indol-5-yl}pyridine-2carboxamide	460.15
23	r I ( r	\\ // ^o=\ ZI 7=( ¹ <? \ H / “Π o	4-cyano-N-{1 -methyl-3-[1 -(3,3,3trifluoro-2-hydroxypropanoyl)piperidin4-yl]-1 H-indol-5-yl}pyridine-2carboxamide	486.20
24		o O IZ 5=0	4-cyano-N-{1 -methyl-3-[1 -(pyrimidin2-ylcarbonyl)piperÎdin-4-yl]-1 H-ïndol5-yl)pyridine-2-carboxamide	466.15

Example		Structure	Name	MS (M+H)
25	ί I	^o=\ ZI f) \ ζ^Λο °	4-cyano-N-{ 1 -methyl-3-[1 (tetrahydrofuran-2ylcarbonyl)piperidin-4-yl]-1H-indol-5yl}pyridine-2-carboxamide	458.15
26	I (	o ”‘^CÔ XZ y=o	4-cyano-N-{1 -methyl-3-[ 1 -(pyrazin-2ylcarbonyl)piperidin-4-yl]-1H-indo[-5yl}pyridine-2-carboxamide	466.20
27	r I (	o ^λζ-γ /\ x n xz \=O	4-cyano-N-(3-{1 -[(trans-4hydroxycyclohexyl)carbonyl]piperidin4-yi)-1 -methyl-1 H-indol-5-yl)pyridîne2-carboxamîde	486.30
28	h	^HO y_o N Ί h r⁷ VrrÇ ° M-/ \	4-cyano-N-{3-[1 -(2-hydroxy-3methylbutanoyl)piperidin-4-yl]-1methyl-lH-indol-5-yl}pyridine-2carboxamide	460.25

Example	Structure	N a me	MS (M+H)
29	I ζ	HO I f-N W o W \	4-cyano-N-(3-{1 -[(cls-4hydroxycyclohexyt)carbonyl]piperidin4-yl}-1 -methyl-1 H-lndol-5-yl)pyridine2-carboxamide	486.25
30	h I %	Ma O	4-cyano-N-{1 -methyl-3-[1 -{4,4,4trifluorobutanoyl)piperidin-4-yl]-1Hindol-5-yl}pyridine-2-carboxamîde	484.1
31	h I f h	o ~~Z^Z ( vS k/y'z-' IZ y°	N-{3-[1 -(bicyclo[1.1.1]pent-1ylcarbonyl)piperidin-4-yl]-1 -methyl-1 Hindol-5-yl)-4-cyanopyridine-2carboxamîde	454.2
32	N f\=O l\|l fil ^H r⁷ Wm o AA/ \	4-cyano-N-(3-{1 -[(2,2difluorocyclopropyl)carbonyl]piperidin4-yl}-1 -methyl-1 H-indol-5-yl)pyridine2-carboxamide	464.2

Example		Structure	Name	MS (M+H)
33	r I i	^o=\ ZI o	4-cyano-N-{3-[1 · (cyclopropylacetyl)piperidin-4-yl]-1methyl-lH-indol-5-yl)pyridine-2carboxamide	442.3
34	r I (.	M ^o=\ ZI _ / I ___£j	4-cyano-N-{3-[1 - (m ethoxyacetyl)piperidi n-4-y ]]-1 methyl-1H-indol-5-yl}pyridine-2carboxamide	432.2
35	r I	F F / ^Fj >° I ^-N Αγβ θ W \	4-cyano-N-{1 -methyl-3-[1 -(3,3,3trifluoropropanoyl)piperidin-4-yl]-1Hindol-5-yl}pyridine-2-carboxamide	470.2

Example 36

Préparation of 4-cyano-N-(3-(1 -(cyc!opentanecarbonyl)piperidin-4-yl)-1 -ethyl-1 Hindol-5-yl)picolinamide

Step 1: préparation of tert-butyl 4-(5-amino-1H-indol-3-yl)piperidine-1-carboxylate. A high pressure flask was charged with éthanol (140 mL), tert-butyl 4-(5-nitro-1H-indol-3yl)-5,6-dihydropyridine-1(2H)-carboxylate (prepared In Example 1,7 g, 0.02 mol), acetic acid (1.2 g, 0.02 mol) and 20% Pd/C (50% wet, 0.7 g). The mixture was agitated under a hydrogen atmosphère for 16 h. The reaction was filtered through a pad of Celite® and the solvent removed under reduced pressure. The resulting solid was partitioned between saturated potassium carbonate and EtOAc. The organic phase was extracted and evaporated to afford the titïe compound which was carried further in the sequence without any further purification or characterization.

Step 2: préparation of tert-butyl 4-(5-(4-cyanopicolinamido)-lH-indol-3-yl)piperidine1-carboxytate. To a slurry of tert-butyl 4-(5-amino-1H-indol-3-yl)piperidine-1-carboxylate (8.25 g, 26.2 mmol) in dichloromethane (120 mL) was added Et₃N and the mixture was cooled to 0 °C, whereupon 4-cyanopicolinoyl chloride (4.49 g, 26,9 mmol) in DCM (60 mL) was added slowly. The cooling bath was removed after one hour and the mixture was stirred at room température for 20 hours. Saturated aqueous sodium chloride was added, and the phases were separated. The aqueous phase was extracted with DCM and ethyl acetate, and the combined organic extracts were evaporated. The crude was concentrated in vacuo and was then triturated in éthanol (150 ml, 99.7%), filtered and washed with 50 ml éthanol. The product was dissolved in acetone and DCM, filtered, evaporated and dried in vacuo to provide 12.16 g (95%) the title compound as a yellow solid. LC/MS (20-100% CH₃CN:0.05%HCOOH(aq) gradient over 5 min): 3.20 min. 447 M+H.

Step 3: préparation of tert-butyl 4-(5-(4-cyanopicolinamido)-1-ethyl-1H-indol-3yl)piperidine-1-carboxyiate. Tert-butyl 4-{5-(4-cyanopicolinamido)-1 H-indol·3-yl)piperidine1-carboxylate (200 mg, 0.45 mmol) was dissolved in DCM. NaOH (6.3 ml, 2.5M), a few drops of phase transfer catalyst Aliquat 336 and ethyl iodide (1.1 ml, 13.5 mmol) were added and the mixture was stirred at room température for 24 h. The phases were partitioned. The aqueous phase was extracted with DCM and the combined organic phase was evaporated. The residue was purified by prep-HPLC to provide 110 mg (52%) of the title compound as a yellow solid. LC/MS (20-100% CH₃CN:0.05%HCOOH(aq) gradient over 5 min): 3.80 min. 474 M+H.

Step 4: préparation of 4-cyano-N-(1-ethyl-3-(piperidin-4-yl)-1 H-indol-5yljpicolinamide. To tert-butyl 4-(5-(4-ον3ηορΐοοΙΐη3π^ο)-1-θ^ψΙ-1Η-^οΙ-3-νΙ)ρίρ6πΰΐηβ-1carboxylate (110 mg, 0.23 mmol) was added HCl (0.9 ml, 4 M in Dioxane) and the mixture was stirred at room température for 12 h. Saturated aqueous NaHCO₃ and DCM were added, the phases were separated and the organic phase was evaporated to obtain 86 mg (87%) of the title compound. The crude was used without further purification in the subséquent step. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 3.87 mtn. 374 M+H.

Step 5: préparation of 4-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-ethyl1 H-indol-5-yl)picolinamide. 4-Cyano-N-(1-ethyl-3-(piperidin-4-yl)-1H-indoI-5yljpicolinamide (HCl salt)(82 mg, 0.20 mmol), triethylamine (32 μΙ, 0.23 mmol) and cyclopentanecarbonyl chloride (28 μΙ, 0.23 mmol) were stirred in dry DCM (5 ml) at room température for 1h. 1M HCl (20 ml) and DCM (50 ml) were added, the phases were separated, and the solvents were evaporated. The residue was purified by prep-HPLC to provide 60 mg (64%) of the title compound as a white powder. LC/MS (20-100% CH₃CN:0.05%HCOOH(aq) gradient over 5 min): 3.12 min. 470 M+H. ’H NMR (500 MHz, CD₃OD) δ ppm 8.89 (d, J=4.82, 1H), 8.41 (d, J=2.0. 1 H), 8.11 (d, J= 2.0, 1H), 7.88 (dd, 4=4.94, 1.61, 1H), 7.44 (dd, J=8.64, 2.0,1 H), 7.36 (d, J=8.64, 1H), 7.07 (s, 1H); 4.67 (m, 1H), 4.17 (m, 3H), 3.26 (m, 1H), 3.11 (m, 2H), 2.80 (m, 1H), 2.13 (m, 2H), 1.75 (m, 10H), 1.40 (t, J=7.23, 3H).

Exampie 37

Préparation of 4-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1 H-indol-5yl)picolinamide

Step 1: (4-(5-amino-1H-indol-3-yl)piperidin-1-yl)(cyclopentyl)methanone. Toa solution of tert-butyl 4-(5-amino-1H-indol-3-yl)piperidine-1-carboxyIate (prepared in Example 36, 5.0 g, 16.0 mmol) in 100 mL of dichloromethane was added (9H-fluoren-9yl)methyl-2,5-dioxopyrrolidin-1-yl carbonate (5.9 g, 17.4 mmol), and A/-ethyl-/Visopropylpropan-2-amine (2.3 g, 17.4 mmol). The mixture was then stirred at room température for 18 hours then was washed with water and saturated sodium chloride. The organic layer was then collected and was dried over magnésium sulfate, fiitered and evaporated under reduced pressure to give 6.7 g of a crude solid which was immediately diluted with 120 mLof methanol and treated with 30 mL of 4N hydrochloric acid in dioxane. This mixture was then stirred for 3 hours at room température and then concentrated under reduced pressure to give 5.5 g of a crude solid which was immediately treated with 30 mL of dimethylformamide. To this stirring solution was then added cyclopentyl carboxylic acid (1-72 g, 15.10 mmol), O-fBenzotriazol-l-ylJ-N.N.N'.N'-tetramethyluronîum tetrafluoroborate (4.99 g, 15.10 mmol), and /V-ethyl-Af-isopropylpropan^-amine (4.59 g, 34.80 mmol). The mixture was then stirred at room température for 1 hour then concentrated under reduced pressure and added to 300 mL of ethyl acetate. The mixture was then washed with water, saturated sodium chloride, dried with magnésium sulphate and then concentrated under reduced pressure to give 6.4 g of a crude solid which was immediately dissolved in ethyl acetate (120 mL) and the resulting solution was cooled to 0 °C. To this chilled solution was added piperidine (2.0 g, 23.0 mmol) and the resulting mixture was allowed to warm to room température while stirring over the course of 18 hours. The mixture was then concentrated under reduced pressure, then triturated with heptane and dried under vacuum to give 1.4 g (60%) of the titled compound as an off-white solid: ’H NMR (400 MHz, Methanol-d4): Ô: 7.22 (d, 1H, J = 8.4 Hz), 7.14 (s, 1H), 7.00 (s, 1H), 6.78 (d, 1H, J = 7.2 Hz), 4.65 (m, 1H),

4.20 (m, 1H), 3.31 (m, 1H), 3.10 (m,2H), 2.80 (t, 1H),2.11 (m, 2H), 1.87 (m, 2H), 1.74 (m, 4H), 1.63 (m,4H).

Step 2: 4-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1 H-indol-5yl)picolinamide. To a solution of 4-cyanopicolinic acid (21,3 mg, 0.14 mmol) in 1 mL of toluene was added (4-(5-amino-1 H-indol-3-yl)piperidin-1 -yl)(cyclopentyl)methanone (30.0 mg, 0.09 mmol), O-(Benzotriazol-1-yl)-W_l/V,/V',/V'-tetramethyluronium tetrafiuoroborate (47.7 mg, 0.14 mmol), and diisopropylethylamine (38.0 mg, 0.29 mmol). The mixture was then stirred at room température for 30 minutes then was washed with saturated aqueous sodium chloride. The organic layer was then collected and was dried over sodium sulfate, filtered and evaporated to give the title compound. LC/MS (10%-90% CH₃CN:H₂O gradient over 10 min): 5.35 min. 442.1 M+H. ¹H NMR (500 MHz, DMSO-cfe) δ ppm 10.82 (br. s„ 1 H), 10.56 (s, 1 H), 8.97 (d, J=4.88 Hz, 1 H), 8.47 (s, 1 H), 8.07 - 8.20 (m, 2 H), 7.50 - 7.59 (m, 1 H), 7.31 (d, J=8.79 Hz, 1 H), 7.12 (s, 1 H), 4.54 (d, J=12.70 Hz, 1 H), 4.09 (d, ^=13.18 Hz. 1 H), 3.18 (t. J=12.45 Hz, 1 H), 2.95 - 3.06 (m, 2 H), 2.69 (t, JL11.96 Hz, 1 H),

1.92 - 2.10 (m, 2 H), 1.41 -1.85(m, 10 H).

The following examples were prepared analogous to Example 37.

Example	Structure	Name	MS (M+H)
38	n—y y O=\ 21 \___/ O	N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1H-indol-5-yl}-2fluorobenzamide	433.2

Example	Structure	Name	MS (M+H)
39	c/xg¹ IZ	3-cyano-N-{3-[1(cyclopentylcarbonyljpiperidin4-ylj-1 H-indol-5-yl)benzamide	440.2
40	—-^ O=( ZI ⁼^~cA O	5-cyano-N-{3-[1 (cyclopentylcarbonyl)piperidin4-yl]-1 H-indol-5-y[}-2methoxybenzamide	470.2
41	N 111 ^-N A h V⁷ VV-Nx/xJ H XX? H	5-cyano-N-{3-[1(cyclopentylcarbonyi)piperidin4-yl]-1 H-indol-5-yl}-2fluorobenzamide	458.2
42	^Xo \=z O=\ ZI ^oA O	N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 H-indol-5-yl}-5methoxypyridine-2carboxamide	446.2 _

Example	Structure	Name	MS (M+H)
43	Z^Cfl ZI O	N-{3-[1(cyctopentylcarbonyl)piperidin4-yl]-1 H-indol-5-yl}-1,3be nzothiazole-5-carboxamide	472.2
44	^o=\ ZI IZ \_/ O	2-chloro-N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 H-indol-5-yl}benzamide	449.2
45	I O ZI ^c-T²°	N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 H-indol-5-yi}-4(hydroxymethyl)benzamide	455.2
46	I O op ZI ^C-J²O	N-{3-[1- (cyclopentylcarbonyl)piperidin- 4-yl]-1 H-indo!-5-yl}-3hydroxybenzamide	431.2

Example	Structure	Name	MS (M+H)
47	\ 7— ZI ⁼^~c-P o	3-(3-cyanophenyl)-N-{3-[1 (cyclopentylcarbonyl)piperidin4-yl]-1 H-indol-5yljpropanamide	468.3
48	xz \=° ^=o O r	3-({3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 H'indol-5yl}carbamoyl)benzoic acid	459.2
49	a H h V·⁷ n / π η TA ’Ù—s o U JL / ^b Aÿ^-N H	(cyclopentylcarbonyl)piperidin4-yl]-1 H-indol-5-yl}-1,3benzothîazole-7-carboxamide	473.0
50	O AT TZ /=° Z <Ί X	N-{3-[1(cyclopentylcarbonyl)piperidîn' 4-yl]-1H-indol-5yljisophthalamide	459.1

Example	Structure	Name	MS (M+H)
51	r-^N H / ) «•XX H J ° ΈJT' H	(cyclopentylcarbonyl)piperidin4~yl]-1 H-indol-5-yl}-1 Hbenzimidazole-5-carboxamide	456.1
52	z^z- A ZI ιζ \__/ V o	N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 H-i ndol-5-y I}-1 -methyl1 H-benzimidazole-5carboxamide	470.1
53	n ¹¹ Λ^νν ⁰ x JXv H	5-cyano-N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 H-îndol-5-yl}-6methylnicotinamide	456.2

Example 54

Préparation of 3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-1 H5 pyrrolo[2,3-b]pyridin-5-yl)benzamide

Step 1 : préparation of 3-iodo-1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine. To a suspension of 5-nitro-lH-pyrrolo[2,3-b]pyridine (500 mg, 3.06 mmol) in DMF (15 ml) was added KOH (241 mg, 4.29 mmol, pellets). The mixture was stirred at room température for 10 min. A clear orange solution was obtained. lodine (856 mg, 3.37 mmol) was then added, and stirring was continued for 90 min. To the mixture was added K₂CO₃ (974 mg, 7.05 mmol) followed by iodomethane (1.14 ml, 18.4 mmol), and stirring was continued at room température for 2.5 hours. The mixture was diluted with water (50 ml), treated with NaHSO3 until yellow, and was then stirred for 30 min. The precipitate was collected by filtration, washed with plenty of water, and dried in vacuo to provide 845 mg (91%) of the title compound as a yellow solid. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 2.40 min. 288 M+H.

Step 2: préparation of tert-butyl 4-(1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)5,6-dihydropyridine-1 (2H)-carboxylate. 3-iodo-1 -methyl-5-nitro-1 H-pyrrolo[2,3-b]pyridine (500 mg, 1.65 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6dihydropyridine-1(2H)-cartioxylate (612 mg, 1.98 mmol), Pd EnCat TPP30 (palladium acetate / PPh3, encapsulated, Aldrich 644706,110 mg), K₂CO₃ (456 mg, 3.30 mmol), DME (8 ml), EtOH (2 ml) and H₂O (2 ml) were mixed in a réaction vessel, and the mixture was degassed with nitrogen for 10 min. The tube was then sealed, and the mixture was heated at 60 C for 18 h. CHCI₃ and water were added and the phases were separated. The aqueous layer was extracted three times with CHCI3 and the combined organics were dried over Na₂SO₄. Evaporation of the solvents gave a solid yellow residue. The crude was purified by flash chromatography to provide 410 mg (69%) of the title compound as a bright yellow solid. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 3.42 min. 359 M+H.

Step 3: préparation of tert-butyl 4-(5-amino-1-methyl-1 H-pyrrolo[2,3-b]pyridin-3yl)piperidine-1-carboxy!ate. A mixture of tert-butyl 4-(1 -methyl-5-nitro-1 H-pyrrolo[2,3b]pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxyiate (102 mg, 0.28 mmol), 5% Pd/C (30 mg), ammonium formate (215 mg, 3.42 mmol) in 96% EtOH (5 ml) was flushed with nitrogen, and the mixture was heated at 80 °C for 1 hour in a sealed vessel. The mixture was fïltered through a plug of Celite, and the filtrate was concentrated in vacou. The residue was partitioned between CHCI3 and water. The layers were separated, and the aqueous layer was extracted twice with CHCI3. The combîned extracts were evaporated. The crude was dissolved in EtOH (10 ml), and treated with 2 M NaOH (10 ml) and the mixture was stirred at 60 °C for 1 hour. The mixture was concentrated in vacuo until most of the EtOH was removed, and was then extracted four times with chloroform. The combîned extracts were evaporated in vacuo, leaving 77 mg (82%) of the title compound as a light-tan foam. No further purification was performed. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 1.35 min. 331 M+H.

Step 4: préparation of tert-butyl 4-(5-(3-cyanobenzamido)-1-methyl-1 H-pyrrolo[2,3b]pyridin-3-yl)piperidine-1-carboxylate. To an ice-cold solution of tert-butyl 4-(5-amino-1methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate (100 mg, 0.30 mmol) and 3cyanobenzoyl chlorrde (55 mg, 0.33 mmol) in DCM (5 ml) was added triethylamine (169 pl, 1.21 mmol). The température was allowed to room température and the mixture was stirred for 90 min. The solvents were evaporated and the residue was purified by flash chromatography to provide 105 mg (76%) of the title compound. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 2.85 min. 460 M+H.

Step 5: préparation of 3-cyano-N-(1-methyl-3-(piperrdin-4-yl)-1 H-pyrrolo[2,3b]pyridin-5-yl)benzamide (HCl sait). To 4-(5-(3-cyanobenzamido)-1-methy|-1H-pyrrolo[2,3b]pyridin-3-yl)piperidine-1-carboxylate (105 mg, 0.23 mmol) was added a solution of HCl in dioxane (2.3 ml, 4M). The mixture was stirred at room température for 1h. The solvents were evaporated to provide 78 mg (86%) of the title compound. The crude product was used without further purification in the next step. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 1.22 min. 360 M+H.

Step 6: préparation of 3-cyano-N-(3-(1-(cyc!opentanecarbonyl)piperidin-4-yl)-1methyi-1 H-pyrrolo[2,3-b]pyridin-5-yl)benzamide. To an ice-cold solution of 3-cyano-N-(1 methyl-3-(piperidÎn-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (HCl salt)(78 mg, 0.2 mmol) and cycfopentanecarbonyl chloride (29 μΙ, 0.24 mmol) in DCM (4 ml) was added triethylamine (121 μΐ, 0.87 mmol). The température was allowed to room température and the mixture was stirred at room température for 16 hours. The solvents were evaporated and the residue was purified by flash chromatography to provide 68 mg (75%) of the title compound as a white powder. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 2.47 min. 456 M+H. ¹H NMR (500 MHz, CD3OD) ô ppm 8.56 (m, 2H), 8.39 (m, 2H), Θ.00 (m, 1 H). 7.79 (t, 1H), 7.26 (s, 1H), 4.70 (m, 1 H), 4.20 (m, 1H), 3.83 (s, 3H), 3.26 (m, 1H), 3.16-3.03 (m, 3H), 2.85-2.70 (m, 3H), 2.12 (m, 1H), 1.81 (m, 4H)_t 1.67 (m, 3H), 1.57 (m, 3H).

Example 55

Préparation of 4-ον3πο-Ν-(3-(1-(ονα1ορεηί3η6ϋ3Γ5οηγΙ)ρΐρ6ΓΪόΐη-4-γΙ)-1-Γηε1ΚγΙ-ΐΗpyrrolo[3,2-b]pyridin-5-yl)picolinamide

Step 1 : préparation of (E)-N^,-(6-((E)-2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)-N,Ndimethylformimidamide. To a stirred solution of 6-methyl-5-nitropyridin-2-amine (1.0 g, 6.5 mmol) in DMF (5 ml) was added 1,1-dimethoxy-N,N-dimethylmethanamine (4.3 ml, 33 mmol) and the mixture was heated to 110 °C for 24 h. Evaporation of the solvents in vacuo provided 1.7 g (100%) of the title compound. The crude product was used in the next step without further purification.

Step 2: préparation of (E)-N,N-dimethyl-N'-(1H-pyrrolo[3,2-b]pyridin-5yl)formimidamide. (E)-N’-(6-((E)-2-(dimethylamino)vinyI)-5-nitropyridin-2-yl)-N,Ndimethylformimidamide (1.7 g, 6.6 mmol) was dissolved in EtOH (12 ml) and Pd/C (27 mg, 10%) was added. The mixture was hydrogenated in a hydrogénation apparatus for four hours at 30 psi. The mixture was passed through a plug of celite and the fitrate was evaporated. The residue was purified by chromatography on neutral alumina to provide 1.24 g (100%) of the title compound. LC/MS (5-50% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 189 M+H.

Step 3: préparation of (E)-N'-(3-iodo-1 H-pyrrolo[3,2-b]pyridin-5-yl)-N,Ndimethylformimidamide. To a stirred solution of (EJ-N.N-dimethyl-N'-ÎIH-pyrroloia^b]pyridin-5-yl)formimidamide (470 mg, 2.50 mmol) in DMF at 0 °C was added Niodosucclnimide (590 mg, 2.62 mmol), and the mixture was stirred for 18 hours at room température. The solvent was evaporated in vacuo and the residue was purified by neutral alumina chromatography to provide 785 mg (100%) of the title compound. LC/MS (5-50% CH₃CN:0.05%NH4Ac(aq) gradient over 5 min): 2.32 min. 315 M+H.

Step 4: préparation of (E)-N’-(3-iodo-1-methyl-1 H-pyrrolofa^-bJpyridin-S-yO-N.Ndimethylformimidamide. To a stirred solution of (E)-N‘-(3-iodo-1H-pyrrolo[3,2-b]pyridin-5yl)-N_rN-dimethylformimidamide (785 mg, 2.5 mmol) in DCM (22 ml), tetrabutylammonium bromide (80 mg, 0.25 mmol), NaOH (4 ml, 2M) and Mel (200 μΙ, 3.25 mmol) were added and the mixture was stirred for 16 hours at room température. Water, DCM and EtOAc were added and the phases were separated. The solvents were evaporated and the residue was purified by neutral alumina chromatography to provide 686mg (84%) of the title compound. LC/MS (5-50% CH₃CN:0.05% NH4Ac(aq) gradient over 5 min): 3.05 min. 329 M+H.

Step 5: préparation of (4-(5-amino-1-methyl-1 H-pyrrolo[3,2-b]pyridin-3-yl)-5,6dihydropyridin-1 (2H)-yl)(cyclopentyl)methanone. A mixture of (E)-N'-(3-iodo-1 -methyl-1 Hpyrrolo[3,2-b]pyridin-5-yl)-N,N-dimethylformimidamide (40 mg, 0.12 mmol), cyclopentyl(4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1 (2H)-yl)methanone (89 mg, 0.29 mmol), tetrakis(triphenylphosphine)Pd(0)(14 mg, 0.01 mmol) and K₂CO₃ (50 mg, 0.37 mmol) in a mixture of DMF/water 8:1 (1.5 mi) was degassed and flushed with nitrogen gas. The reaction mixture was stirred at 100 °C for 16 hours. Water and DCM were added and the phases were separated. The solvents were evaporated and the residue was purified by préparative HPLC to provide I5mg (35%) of the title compound. LC/MS (20100% CH₃CN:0.05%NH4Ac(aq) gradient over 5 min): 1.20 min. 325 M+H.

Step 6: préparation of (4-(5-amino-1-methyl-1 H-pyrrolo[3,2-b]pyridin-3-yl)piperidin-1yl)(cyclopentyl)methanone. (4-(5-amino-1 -methyl-1 H-pyrrolo[3,2-b]pyridin-3-yl)-5,6 dihydropyridin-1(2H)-yl)(cyclopentyl)methanone (12 mg, 0.04 mmol), ammonium formate (47 mg, 0.74 mmol) and palladium black (2.0 mg, 0.02 mmol) were mixed in DMF/NMP 5:1 (1 ml). The reaction mixture was heated under microwave irradiation at 150 °C for 60 minutes. The mixture was filtered through a plug of celite, the solvents were evaporated (except NMP) to provide the crude title compound. Yield not calculated. LC/MS (20-100% CH₃CN:0.05%NH4Ac(aq) gradient over 5 min): 2.69 min. 327 M+H.

Step 7: préparation of 4-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1methyl-1 H-pyrrolo[3,2-b]pyridin-5-y()picolinamide. To the crude (4-(5-amino-1-methyl-1Hpyrrolo[3,2-b]pyridin-3-yl)piperidin-1-yl)(cyclopentyl)methanone from step 6 was added

DCM (0.5mL), Et₃N (30μΙ_, 0.22 mmol) and 4-cyanopicolinoyl chloride (11 mg, 0.07 mmol). The mixture was stirred at room température for 30 minutes, whereupon the solvents were evaporated. The residue was purified by préparative HPLC to providelO mg (59%) of the title compound. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 2,63 min. 357 M+H. ¹H NMR (500 MHz, CD3OD) δ ppm 8.96 (dd, J=5.0,1.0, 1 H) 8.54 (s, 1 H),

8.25 (d, J=9.0,1 H), 7.98 (dd, J=5.0, 1.56, 1 H), 7.89 (d, J= 9.0, 1 H), 7.31 (s, 1 H). 4.69 (m, 1H), 4.23 (m, 1H), 3.82 (s, 3H), 3.13 (m, 1H), 2.84 (m, 1H), 2.25-2.11 (m, 2H), 1.94-1.60 (m, 12H).

Example 56

Préparation of 4-cyano-N-(7-(1-(cyclopentanecarbonyl)piperidin-4-yl)-5-methyl-5H20 pyrrolo[3,2-d]pyrimidin-2-yl)picolinamide

N

Step 1: préparation of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine. 2,4-dichloro-5Hpyrrolo[3,2-d]pyrimidine (134 mg, 0.71 mmol), NaHCO₃ (66 mg, 0.78 mmol) and Pd/C (1.52 mg, 10/o) were mixed in EtOH (4 ml). Hydrogen (3psi) was applied and the mixture was stirred for 2.5 hours at room température, The mixture was passed through a plug of celite and the filtrate was evaporated. The residue was purified by flash chromatography to afford 90mg (88%) of the title compound. LC/MS ¢20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 1.58 min. 154 M+H.

Step 2: préparation of 2-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidîne. To a stirred solution of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (90 mg, 0.59 mmol) in DMF (1 ml) at 0 °C was added N-iodosuccinimide (138 mg, 0.62 mmol). The température was allowed to room température and the mixture was stirred for 17 hours. The solvent was evaporated and the residue was purified by flash chromatography to provide 110 mg (67%) of the title compound. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 2.75 min. 279 M+H.

Step 3: préparation of 2-chloro-7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimldine. To a stirred solution of 2-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (110 mg, 0.39 mmol) in DCM (5 ml) was added tetrabutylammonium bromide (19 mg, 0.06 mmol), NaOH (1 ml, 2M) and Mel (47 μΙ, 0.47 mmol) were added and the mixture was stirred for 16 hours at room température. Water, DCM and EtOAc were added and the phases were separated. Concentration by évaporation followed by trituration using Et20 gave 110mg (94%) of the title compound. LC/MS (20-100% CH_aCN:0.05% HCOOH(aq) gradient over 5 min): 3.07 min. 294 M+H.

Step 4: préparation of (4-(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5,6dihydropyridin-1(2H)-yl)(cyclopentyl)methanone. 2-chloro-7-iodo-5-methyl-5H-pyrrolo[3,2d]pyrimidine (25 mg, 0.09 mmol), cyclopentyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5,6-dihydropyridln-1(2H)-yl)methanone (34 mg, 0.11 mmol), Dichlorobis(triphenylphosphine)-palladium(ll)(6 mg, 0.01 mmol) and K₂CO₃ (26 mg, 0.19 mmol) were mixed in DME/EtOH/H₂O 4:1:1 (1 ml) under an atmosphère of nitrogen. The reaction was run at 120 °C for 20 minutes in a microwave reactor. DCM/EtOAc and water were added, the phases were separated and the solvents were evaporated. The residue was purified by prep HPLC to afford 10mg (34%) of the title compound. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 2.48 min. 345 M+H.

Step 5: préparation of cyclopentyl(4-(2-(diphenylmethyleneamino)-5-methyl-5Hpyrrolo[3,2-d]pyrimidin-7-yI)-5,6-dihydropyridin-1(2H)-yl)methanone. Pd(OAc)2 (1 mg, 0.15 mmol) and BINAP (4 mg, 0.22 mmol) were dissolved in degassed dioxane (0.5 ml) and stirred for 5 min. This solution was added to a mixture of (4-(2-chloro-5-methyl-5H18716 pyrro|o[3,2-d]pyrimidin-7-yl)-5,6-dihydropyridin-1 (2H)-yl)(cyclopenty|)methanone (10 mg, 0.03 mmol), diphenylmethanimine (16 mg, 0.09 mmol) and sodium tert-butoxide (6 mg, 0.06 mmol) in degassed dioxane (0.5 ml). The mixture was heated under microwave irradiation for 30 min at 140 °C. DCM/EtOAc and a small amount of water was added and s the phases were separated. The solvents were evaporated and the crude product was purified by préparative HPLC to afford 10 mg (71%) of the title compound. LC/MS (20100% CH₃CN:0.05% HCOOH(aq) gradient over 2 min): 0.97 min. 490 M+H.

Step 6: préparation of (4-(2-amino-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-7yl)piperidin-1-yl)(cyclopentyl)methanone. Cyclopentyl(4-(2-(diphenylmethyleneamino)-51 o methyl-5H-pyrrolo[3,2-d]pyrimidin-7-y|)-5,6-dihydropyridin-1 (2H)-yl)methanone (10 mg, 0.02 mmol), ammonium formate (52 mg, 0.82 mmol) and Pd black (1 mg, 0.01 mmol) were mixed In THF/NMP 5:1 (0.5 ml). The mixture was heated under microwave irradiation at 150 °C for 60 minutes. The mixture was filtered through a plug of celite, the solvents were evaporated (except NMP). The crude mixture was directly used ίπ the subséquent step 15 without further purification. Yield not calculated. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 1.48 min. 328 M+H.

Step 7: préparation of 4-cyano-N-(7-(1-(cyclopentanecarbonyl)pÎperidin-4-yl)-5methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)picolinamide. To the crude (4-(2-amino-5-methyl5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)(cyclopentyl)methanone from the previous 20 step was added DCM (0.5 ml), Et₃N (30 pl) and 4-cyanopicolinoyl chloride (12mg, 0.07).

The reaction mixture was stirred at room température for 30 min, whereupon the solvents were evaporated. The residue was purified by préparative HPLC to pravide 0.4 mg (4% over two steps) of the title compound. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 1.98 min. 458 M+H. Ή NMR (500 MHz, (CD3)2CO) δ ppm 9.02 (d, 25 J=5.0,1H), 8.86 (s, 1H), 8.54 (s, 1H), 8.11 (dd, J=5.0, 1.8,1H), 7.58 (s, 1H), 4.68 (m, 1H),

4.18 (m, 1H), 3.96 (s, 3H), 3.23 (m, 2H), 3.07 (m, 1H), 2.24, m, 1H), 1.90-1.50 (m, 12H).

Example 57

Préparation of 4-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-1Hpyrrolo[2,3-c]pyridin-5-yl)picolinamide

Step 1: préparation of (E)-N‘-(4-((E)-2-(dimethylamino)vinyl)-5-nitropyridin-2-y|)-N,Ndimethylformimidamide. To a stirred solution of 4-methyl-5-nitropyridin-2-amine (500 mg, 3.26 mmol) in DMF (5 ml) was added 1,1-dimethoxy-N.N-dimethylmethanamine (4.3 ml, 33 mmol) and the mixture was heated to 110 °C for 24 h. Evaporation of the solvents in vacuo provided 850 mg (99%) of the title compound. The crude product was used in the next step without further purification.

Step 2: préparation of (E)-N,N-dimethyl-N‘-(1 H-pyrrolo[2,3-c]pyridîn-5yl)fomnimidamide. The crude (E)-N'-(4-((E)-2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)Ν,Ν-dimethylformimidamide (850 mg g, 3.23 mmol) was dissolved in EtOH (9 ml) and Pd/C (22 mg, 10%) was added. The mixture was hydrogenated in a hydrogénation apparatus for four hours at 40 psi. The mixture was passed through a plug of celite and the fitrate was evaporated. The residue was purified by chromatography on neutral alumina to provide 582 mg (96% over two steps) of the title compound. LC/MS (20-100% CH3CN:0.05% HCOOH(aq) gradient over 5 min): 1.37 min, 189 M+H.

Step 3: préparation of (E)-N'-(3-iodo-1H-pyrrolo[2,3-c]pyridin-5-yl)-N,Ndimethylformimidamide. To a stirred solution of (EJ-N.N-dimethyl-N'-fl H-pyrrolo[2,3c]pyridin-5-yl)formimidamide (470 mg, 2.50 mmol) in DMF at 0 °C was added Niodosuccinimide (590 mg, 2.62 mmol), and the mixture was stirred for 18 hours at room température. The solvent was evaporated in vacuo and the residue was purified by neutral alumina chromatography to provide 407 mg (52%) of the title compound. LC/MS (20-100% CH3CN:0.05% HCOOH(aq) gradient over 5 min): 2.62 min. 315 M+H.

Step 4: (E)-N'-(3-iodo-1-methyl-1 H-pyrrolo[2,3-c]pyrîdin-5-yl)-N,Ndimethylformimidamide. To a stirred solution of (E)-N'-(3-iodo-1 H-pyrrolo(2,3-c]pyridin-5yl)-N,N-dimethylformimidamide (407 mg, 1.30 mmol) in DCM (22 ml), tetrabutylammonium bromide (80 mg, 0.25 mmol), NaOH (4 ml, 2M) and Mel (200 μΙ, 3.25 mmol) were added and the mixture was stirred for 16 hours at room température. Water, DCM and EtOAc were added and the phases were separated. The solvents were evaporated and the residue was purified by neutral aiumina chromatography to provide 131 mg (31%) of the title compound. LC/MS (20-100% CH3CN:0.05% HCOOH(aq) gradient over 5 min): 1.48 min. 329 M+H.

Step 5, préparation of N-(3-(1-(cyclopentanecarbonyl)-1,2,3,6-tetrahydropyridin-4yl)-1 -methyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)formamide. A mixture of (E)-N'-(3-iodo-1 -methyl1H-pyrrolo[2,3-c]pyridin-5-yl)-N,N-dimethylformimidamide (31 mg, 0.09 mmol), cyclopentyl(4-(4_l4,5,5-tetramethyl-1,3₁2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)yl)methanone (38 mg, 0.12 mmol), tetrakis(triphenylphosphine)Pd(0)(7 mg, 0.01 mmol) and K2CO3 (29 mg, 0.21 mmol) in a mixture of DMF/water 8:1 (1 ml) was degassed and flushed with nitrogen gas. The reaction mixture was heated under microwave irradiation at 120 °C for 20 minutes. Water and DCM were added and the phases were separated. The solvents were evaporated and the residue was purified by préparative HPLC to provide 12 mg (36%) of the title compound. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 2.90 min. 353 M+H.

Step 6: préparation of (4-(5-amino-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1yl)(cyclopentyl)methanone. N-(3-(1-(cyclopentanecarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)1-methyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)formamlde (6.0 mg, 0.02 mmol), ammonium formate (43 mg, 0.68 mmol) and palladium black (1.0 mg, 0.01 mmol) were mixed in DMF/NMP 5:1 (1 ml). The reaction mixture was heated under microwave irradiation at 150 °C for 60 minutes. The mixture was filtered through a plug of celite, the solvents were evaporated (except NMP) to provide the crude title compound. To the residue was added HCl (1 ml, 2M) and MeOH (1 ml) and the mixture was stirred for 1 hour, whereupon EtOAc was added. The aqueous phase was basified with 2M NaOH and again extracted. The phases were separated and the solvents were evaporated to provide the title compound which was used directly in the subséquent step without further purification. Yield not calculated. LC/MS (5-50% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 2.20 min. 327 M+H.

Step 7: préparation of 4-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1methyl-1 H-pyrrolo[3,2-b]pyridin-5-yl)picolinamide. To the crude (4-(5-amino-1 -methyl-1 Hpyrrolo[3,2-b]pyridin-3-yl)piperidin-1-yl)(cyclopentyl)methanone from step 6 was added

DCM (0.5mL), EfcN (30μ!_, 0.22 mmol) and 4-cyanopicolînoyl chloride (11mg, 0.07 mmol). The mixture was stirred at room température for 30 minutes, whereupon the solvents were evaporated. The residue was purified by préparative HPLC to provide 0.7 mg (9% over two steps) of the title compound. LC/MS (5-50% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 3.75 min. 457 M+H. ¹H NMR (500 MHz, (CD₃)₂CO) δ ppm 9.02 (d, J=5.0, 1H), 8.62 (s, 1H), 8.57 (d, J=10, 2H), 8.10 (dd, J=5.0, 1.70, 1H), 7.34 (s, 1H), 4.73 (m, 1H), 4.22 (m, 1H), 3.93 (s, 3H), 3.31 (m, 1H), 3.19 (m, 1H), 3.08 (m, 1 H), 2.16 (m, 1H), 1.94-1.52 (m, 12H).

Example 58

Préparation of 3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidîn-4-yl)-1-methyl-1Hindol-5-yl)piperidine-1-carboxamide

Step 1 : préparation of cyclopentyl(4-(5-isocyanato-1-methyl-1 H-indol-3-yl)piperidin1-yl)methanone. Triphosgene (7.3 mg, 0.02 mmol) was added to a stirred solution of (4-(5amino-1-methyl-1H-indol-3-yl)piperidin-1-yl)(cyclopentyl)methanone (20 mg, 0.06 mmol) and triethylamine (28 μιΙ, 0.22 mmol) in DCM (1 ml) at room température. The mixture was heated at reflux for 16 hours. The solvents were evaporated, whereupon the residue was resuspended in diethylether (5 ml) and stirred at room température for 5 min. The ensuing crystals were removed by filtration and the filtrate was concentrated in vacuo to afford the crude title compound which was employed for the next step without further purification.

Step 2: préparation of 3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1methyl-1H-indol-5-yl)piperidine-1-carboxamide. To the crude cyclopentyl(4-(5-isocyanato1-methyl-1H-indol-3-yl)piperidin-1-yl)methanone in THF (1 ml) was added triethylamine (28 pl, 0.22 mmol) and piperidine-3-carbonitrile (14 mg, 0.12 mmol). The mixture was stirred at room température for one hour, whereupon the reaction mixture was filtered through a syringe filter and then purified by préparative HPLC to afford 5.27mg (19% over two steps) of the title compound. LC/MS (20-100% CH₃CN:0.05% HCOOH(aq) gradient over 5 min): 2.40 min. 462 M+H. ¹H NMR (500 MHz, (CD3)2CO δ ppm 7.93 (s, 1 H), 7.76 (d, J=2.0, 1H), 7.25 (dd, J=8.71,2.0, 1H), 7.21 (d, J=8.71,1H), 6.97 (s, 1H), 4.68 (m, 1H), 4.17 (m,

1H), 3.90 (dd, J=13.5, 3.80,1H), 4.17 (m, 1H), 3.90 (m, 1H), 3.73 (s, 3H), 3.70-3.60 (m,

2H), 3.47 (m, 1H), 3.23 (m, 1 H), 3.05 (m, 2H), 2.70 (m, 1H), 1.90 (m, 1H), 1.94-1.49 (m, 14 H).

The following examples were prepared analogous to Example 58.

Example	Structure	Name	MS (M+H)
59	z. Z— °=< ZI À ° i	1 -(2-cyanoethyl)-3-{3-[1 (cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5-yl)-1 methylurea	436.3
60	xz ? Z	(3S)-3-cyano-N-{3-[1 (cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5yl)pyrrolidine-1 -carboxamide	448.3
61	N I¹ /Ά o LA? \	3- (cyanomethyl)-N-{3-[1 (cyclopentylcarbonyl)piperidin- 4- yl]-1-methyl-1 H-indol-5yl)azetidine-1 -carboxamide	448.3

Example	Structure	Name	MS (M+H)
62	o -/zλ / J YY^Y^Z^ >=o O—'	2-cyano-N-(3-[1 (cyclopentylcarbonyljpiperidin4-y[]-1 -methyl-1 H-indol-5yl}morpholine-4-carboxamide	464.4
63	h Y ΥΎΛ ° w ___	3-cyano-N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5yl}azetidi ne-1 -carboxam ide	434.4 _

Example 64

Préparation of N-(3-(1-(cyclopentylcarbonyl)piperidin-4-yl)-1-methyl-1 H-indol-5-y|)-4fluorobenzenesulfonamide

Step 1: Methyl-5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (lnt-1). To a solution of tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (prepared in Example 1,2.0g, 5.60 mmol) in 10 mL of methanol was added 4M HCl in dioxane (10 mL) at 0 °C. The reaction mixture was allowed to warm up to room io température and stirred for overnight. The progress of reaction was monitored TLC (10% methanol tn DCM). After completion, reaction mixture was concentrated in vacuo to give a crude compound which was neutralized with sat. NaHCO₃ solution and then extracted with 10% methanol in DCM. The combined extracts were dried over (Na₂SO4), filtered and concentrated in vacuum to give the title compound (1.2 g, 85.7%) as a brown solid. ¹H NMR (400 MHz, CDCI₃): Ô 8.84 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1 H), 7.14 (s, 1H), 6.27 (s, 1H), 3.83 (s, 3H), 3.62 (br.s, 2H), 3.16 (t. J = 5.2 Hz, 2H), 2.47 (br.s, 2H). LCMS: m/e 257.95 [M+H]+

Step 2: Cyclopentyl (4-(1-methyl-5-nitro-1 H-indol-3-yl)-5,6-dihydropyridin-1(2H)yl)methanone (lnt-2). To a solution of methyl-5-nîtro-3-(1,2,3,6-tetrahydrapyridin-4-yl)-1 Hindole (lnt-1 ; 1.2 g, 4.66 mmol) in DCM (20 mL) was added TEA (2 mL, 14 mmol) followed by addition of cyclopentanecarbonyl chloride (0.810 g) in DCM (5 mL) at 0 °C. The progress of réaction was monitored TLC (5% methanol in DCM). After completion, reaction mixture was quenched with water and extracted by using DCM. The combined extracts were dried ( Na₂SO4), filtered and concentrated in vacuum to give a crude compound which was washed with diethyl ether and hexane to afford the title compound (1.7 g, 97.7%) as a light yellow colored solid. ^jH NMR (400 MHz, CDCI₃): Ô D8.79 (d, J = 14.0 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1 H), 7.35-7.32 (m, 1H), 7.15 (d, J = 14.4 Hz, 1 H), 6.21 (s, 1H), 4.31 (d, J = 9.2 Hz, 2H), 3.90-3.78 (m, 5H), 3.12-2.96 (m, 2H), 2.61-2.55 (m, 2H), 1.89-1.60 (m, 6H), 1.40 (t, J = 7.6 Hz, 1H); LCMS: m/e 353.90 [M+H]+

Step 3:4-(5-Amino-1-methyl-1 H-indol-3-yl)piperidin-1-yl)(cyclopentyl)methanone (lnt-3). To a solution of cyclopentyl (4-(1-methyl-5-nitro-1H-indol-3-yl)-5,6-dihydropyridin1(2H)-yl)methanone (lnt-2; 4.5 g, 12.74 mmol) in 50 mL of methanol was added Pd/C (400mg) and reaction mixture was stirred under 50 psi of H2 at 40 °C overnight. The progress of reaction was monitored by TLC (50% ethyl acetate in hexane). The mixture was filtered through Celite and the filtrate was concentrated in vacuum to give the title compound. ¹H NMR (400 MHz, CDCI₃): δ 7.14-7.12 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.04 (d, J = 12.8 Hz, 1H), 3.68 (s, 3H), 3.49 (q, J = 7.2 Hz, 1H), 3.19-2.67 (m, 4H), 2.09-1.56 (m, 10H), 1.21 (t, J = 7.2 Hz, 2H); LCMS: m/e 325.10 [M+H]+

Step 4: N-(3-(1-(cyclopentylcarbonyl)piperidrn-4-yl)-1 -methyl-1 H-indol-5-yl)-4fluorobenzenesulfonamide. To a stirred solution of of (4-(5-amino-1-methyl-1 H-indol-3 yl)piperidin-1-yl)(cyclopentyl)methanone (lnt-3; 100 mg, 1 eq.) in DCM (3 mL) were added pyridine (5 eq.), DMAP (0.1 eq.) and sulphonyl chloride ( 1.2-2 eq.) and the reaction mixture was stirred at room température for 1-5 h. LC/MS after 1 h showed almost full conversion to the desired product. The conversions were in the range of 70-30% by LCMS (Starting material was 85% pure by LCMS). After compietion, reaction mixture was diluted with water and extracted with DCM. The combined organic layer was dried (Na₂SO₄), filtered and concentrated to give crude material which was purified by column chromatography followed by triturating with ether to provide 19 mg of the title compound.

NMR (400 MHZ, CDCI₃): δ 7.69-7.65 (m, 2H), 7.28-7.04 (m, 4H), 6.82-6.81 (m, 2H),

6.31 (s, 1H), 4.76 (d, J=12.0 Hz, 1H), 4.05 (d, J=12.0 Hz, 1H), 3.71 (s, 3H), 3.17 (t, J=12.4

Hz, 1H), 2.96-2.92 (m, 2H), 2.70 (t, J=12.4 Hz, 1H), 2.04-1.54 (m, 12H). LCMS: m/e 484.20 [M+H]+

The following examples were prepared analogous to Example 64.

Example	Structure	Name	MS (M+H)
65	H₂N N / / il Ί H )— A O O kl/ VT	2-amino-N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1-methyl-1 H-indoI-5yl}pyrimidine-5-sulfonamide	483.25
66	f Π ^H Γ 'T \| \|\| v ⁰⁰ kJV _________J	N-{3-[1- (cyclopentylcarbonyl)pîperidin- 4-yl]-1-methyl-1 H-indol-5-yl}-3- fluorobenzenesulfonamide	484.20

Example	Structure	Name	MS (M+H)
67	N V¹⁰ i 1 ^-N T II v ^oo W	3-cyano-N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5yQbenzenesuifonamide	491.15
68	<^N ίΓ^Ί h V⁷ T \|j ⁰⁰ kA/ \	N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5yljbenzenesulfonamide	466.20
69	A *o w; / O ti	N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5-yl}-1 methyl-1 H-imidazo!e-4sulfonamide	470.20
70	CX»^Jr <& w \	N-{3-[1- (cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5yljcyclohexanesulfonamide	472.20

Example	Structure	Name	MS (M+H)
71	z Λ CK / / ° ΖΣ o	4-cyano-N-{3-[1(cyclopentylcarbonyl)piperidin4-y I ]-1 -methyl-1 H-indo\|-5yljbenzenesulfonamide	491.15
72	ck P* 'en ° ZZ o	N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5yljcyclopropanesulfonamide	430.15
73	N °-'o w \	N-{3-[1- (cyclopentylcarbonyl)prperidin4-yl]-1 -methyl-1 H-indol-5yl}propane-1 -sulfonamide	432.2
74	Os / ;ω ° 'zz o _	N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5-yi}-3methoxypropane-1 -sulfonamide	462.25

100

Example	Structure	Name	MS (M+H)
75	N il η h ^{0 0} W	N-{3-[1(cyclopentyicarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5-yI}-4methoxybenzenesulfonamide)	496.20
76	<ⁿ\ n / j Q_sv 8 °*°W	N-{3-[1(cyclopentylcarbonyl)pîperidin4-yl]-1 -methyl-1 H-indol-5yl}pyridine-3-sulfonamide	467.20
77	8 °'zi o	N-{3-[1(cyclopentylcarbonyl)piperidin4-yl]-1 -methyl-1 H-indol-5-yl}-1 phenylmethanesulfonamide	480.20

Example 78

Préparation of N-(3-(1*(1H-Pyrazole-4-carbonyl)piperidin-3-yl)-1-methyl-1H-indol-5yl)-4-cyanopicolinamide

101

Step 1: tert-Butyl 5-(5-nitro-1 H-indol-3-yl)-3,4-dihydropyridine-1(2H)-carboxylate. To freshly prepared sodium methoxide (5 g, 30.9 mmol) in MeOH (100 mL) were added 5nitroindole (5 g, 15.4 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (11 g, 55.55 mmol). The reaction mixture was heated to reflux for 24 h. The progress of reaction was monitored by TLC (40% ethyl acetate in hexane). After most of the starting material was consumed (By TLC), reaction mixture was cooled to room température and concentrated under vacuum. The residue obtained was diluted with water (50 mL), extracted by using ethyl acetate (3x100 mL), dried (NasSOi), filtered and concentrated to obtain crude material. The crude compound was purified by using column chromatography (sîlrca gel, 100-200 mesh) to afford the title compound (3.39 g, 32%; 1.7 g 5-nitroindole was recovered) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.85 (s, 1H), 8.69-8.65 (m, 1H), 8.02 (dd, J = 2.4, 9.2 Hz, 1H), 7.63-7.41 (m, 3H), 3.60-3.50 (m, 2H), 2.45-2.40 (m, 2H), 1.96-1.90 (m, 2H), 1.55 (s, 5H), 1.50 (s, 4H); LCMS: m/e 244 [M-Boc]+

Step 2: tert-Butyl 5-(1-methyl-5-nitro-1 H-indol-3-yl)-3,4-dihydropyridine-1 (2H)carboxylate. To a solution of tert-butyi 5-(5-nitro-1H-indol-3-yl)-3,4-dihydropyridine-1(2H)carboxylate (1 g, 2.92 mmol) in 15 mL of THF was added NaH (466 mg, 11,66 mmol, 60% w/w in minerai oil) at 0 °C. The reaction mixture was stirred at room température for 1 h and Mel (0.73 mL, 11.66 mmol) was added drop wise at 0 ^qC. The reaction mixture was then allowed to stir at room température for overnight. The progress of reaction was monitored by TLC (40% ethyl acetate in hexane). After completion, reaction mixture was quenched by addition of ice-water and then extracted by using ethyl acetate (2x50 mL). The combined organic phases were dried (Na₂SO4), filtered and concentrated to obtain the title compound (725 mg, 70%) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 1H), 8.08-8.12 (m, 1H), 7.70-7.65 (m, 2H), 7.45 (s, 1H), 3.84 (s, 3H), 3.58-3.51 (m, 2H), 2.42-2.33 (m, 2H), 1.94-1.91 (m, 2H), 1.52-1.38 (s, 9H); LCMS: m/e 258 [M-Boc]+

102

Step 3: tert-Butyl 3-{5-amino-1-methyl-1 H-indol-3-yl)piperidine-1-carboxylate. To a solution of tert-butyl 5-(1-methyl-5-nîtro-1H-indol-3*yl)-3,4-dihydropyridine-1(2H)carboxylate (700 mg, 1.96 mmol) in 20 mL of methanol was added Pd/C (100mg) and the reaction mixture was heated at 40 °C under H2 atmosphère (Balloon pressure) for 7 h. The progress of reaction was monitored by TLC (50% ethyl acetate in hexane). After completion, the reaction mixture was filtered through Celite, washed with methanol and the combined filtrate was concentrated in vacuum to obtain the title compound (480 mg, 74%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.05 (d, J = 8.8 Hz, 1 H), 6.92 (s, 1H), 6.70 (s, 1H), 6.52 (d, J = 8.8 Hz, 1H), 4.51-3.94 (m, 3H), 3.61 (s, 3H), 2.76-2.67 (m, 3H), 1.99 (d, J = 11.6 Hz, 1 H), 1.73-1.46 (m, 4H), 1.42 (s, 9H). LCMS: m/e 352.10 [M+Na]+

Step 4: tert-Butyl 3-(5-(4-cyanopicolinamido)-1-methyl-1 H-indol-3-yl)piperidine-1carboxylate. To a solution of tert-butyl 3-(5-amino-1-methyl-1H-indol-3-yl)piperidine-1carboxyiate (475 mg, 1.44 mmol) in DCM ( 10 mL) was added TEA (0.9 mL, 6.49 mmol) followed by addition of 4-cyanopicolinoyl chloride (217 mg, 1.29 mmol) in DCM (5 mL) at 0 °C. The progress of reaction was monitored TLC (50% ethyiacetate in hexane). After completion, reaction mixture was quenched with water and extracted by using DCM. The combined extracts were dried (NaaSC^), filtered and concentrated in vacuo to give a crude compound which was subjected to column chromatography (Silica gel, 100-200 mesh) to afford the title compound (444 mg, 67%) as a light brown colored solid. ’H NMR (400 MHz, CDCIa): ô 9,89 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.55 (s, 1H), 8.05 (s, 1H), 7.72 (d, J = 4.8 Hz, 1 H), 7.61 (d, J = 8.8 Hz, 1 H). 7.29 (d, J = 8.8 Hz, 1 H), 6.89 (s, 1 H). 4.44-4.06 (m, 2H), 3.76 (s, 3H), 3.04-2.86 (m, 3H), 2.19-1.59 (m, 4H), 1.49 (s, 9H); LCMS: m/e 365.05 [M-Boc]+

Step 5: 4-Cyano-N-(1-methyl-3-(piperidin-3-yl)-1H-indol-5-yl) picolinamide. To a solution of tert-Butyl 3-(5-(4-cyanopicolinamido)-1-methyl-1H-indol-3-yl)piperidine-1carboxylate (430 mg, 0.93 mmol) in 10 mL of methanol was added 4M HCl in dioxane (8 mL) at 0 °C. The reaction mixture was allowed to warm up to room température and stirred ovemight. The progress of reaction was monitored TLC (10% methanol in DCM). After completion, reaction mixture was concentrated in vacuo to give a crude compound which was neutralized with sat. NaHCOa solution and then extracted with 10% methanol in DCM. The combined extracts were dried (NaaSCti), filtered and concentrated in vacuo to give the

103 title compound (275 mg, 88%) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): ô 10.60 (s, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.47 (s, 1 H). 8.09-8.08 (m, 1H), 8.04 (d, J = 4.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.03 (s, 1H), 3.89 (s, 3H), 3.11-2.43 (m, 6H, merged), 2.10-1.97 (m, 1H), 1.63-1.51 (m, 3H); LCMS: m/e 360 [M+H]+

Step 6: N-(3-(1 -(1 H-Pyrazole-4-carbonyl)piperidin-3-yl)-1 -methyl-1 H-indol-5-yl)-4cyanopicolinamide. A solution of 1 H-pyrazole-3-carboxylic acid (1.1 eq.), DIPEA (3 eq.) and HATU (3.3 eq.) in DMF (1 mL) was stirred at room température for 1h. 4-Cyano-N-(1methyl-3-(piperidin-3-yl)-1H-indol-5-yl) picolinamide (1eq.) was then added to the reaction mixture and stirred at room température for 24 hr. The crude product was purified by reverse phase HPLC to afford the title compound. ¹H NMR (400 MHZ, CDCI₃): δ 10.02 (s, 1H), 8.93 (s, 1H), 8.85 (d, J=4.4 Hz, 1 H), 8.59 (s, 1H), 7.75 (d, J=4.4 Hz, 1H), 7.62 (d, J= 2.4 Hz, 1 H), 7.27 (d, J= 8.8 Hz, 1 H), 7.07 (d, J= 8.8 Hz, 1 H), 6.94 (s, 1 H), 677 (s, 1 H), 5.19 (d, J= 12.4 Hz, 1H), 4.87 (d, J= 12.4 Hz, 1H), 3.76 (s, 3H), 3.50-3.48 (m, 1H), 2.782.68 (m, 2H), 2.22 (d, J= 9.2 Hz, 1H), 1.94-1.79 (m, 4H). LCMS: m/e 454.20 (M+H]+.

Example 79

Préparation of 3-cyano-N-(3-(1-(cyclopentylcarbonyl)pyrrolidin-3-yl)-1 -methyl-1 Hindol-5-yl)benzamide

Step 1: préparation of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboroian-2-yl)-1Hpyrrole-1-carboxylate. A mixture of the compound N-Boc-pyrrole (6 g, 35.9 mmol) and Bis (pinacolato)diboron (53 mg, 5.3 mmol) in THF (50 mL) was degassed for 3 times and then [lr(OMe)cod]_z (714 mg, 1.1 mmol) and 4,4-di-tert-butyl-2,2-bipyridine (48 mg, 0.018 mmol) was added to the above mixture. The mixture was degassed for another 3 times and heated to reflux 5 h. The progress of reaction was monitored by TLC (10% ethyl acetate in hexane). After completîon, reaction mixture was concentrated in vacuum to give a crude

104 compound which was purified by column chromatography on silica gel (100-200 mesh) to afford the title compound (6.5 g, 61.90 %). ’H NMR (400 MHz, CDCI3): δ 7.65 (s, 2H), 6.47 (s, 1 H), 1.58 (s, 9H), 1.32 (12H). LCMS: m/e 294.0 (M+HJ+

Step 2: 3-Bromo-5-nitro-1H-indole. To a solution of 5-nitro-indole (200 mg, 1.2 mmol) in pyridine (5 mL) was added Py.HBr₃ (474 mg, 1.4 mmol) at -10 °C and mixture was stirred for 10 min. Then reaction mixture was quenched by addition of water at 0 °C and then the reaction mixture was extracted with diethyl ether. The organic layer was washed successively with 6N HCl (20 mL), 5% NaHCO₃ (20 mL) followed by brine. The combined organic layers were dried (Na₂SO₄), filtered and concentrated to obtain the title compound (200 mg, 67%) as yellow colored solid. ¹H NMR (400 MHz, CDCI₃): δ 8.58-8.57 (m, 2H), 8.16 (dd, J = 2.0, 8.8 Hz, 1 H), 7.44 (d, J = 8.8 Hz, 1 H), 7.41 (d, J = 2.8 Hz, 1 H). LCMS: m/e 240.80 [M+H]+

Step 3: tert-Butyl 3-(5-nitro-1H-indol-3-yl)-1H-pyrrole-1-carboxylate. To a solution of the 3-bromo-5-nitro-1H-indole (200 mg, 0.83 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (267 mg, 0.91 mmol) in THF (10 mL) was added Na₂CO₃ (175 mg, 1.7 mmol) in H₂O (3 mL). The mixture was degassed and refilled with nitrogen for 3 times. Then Pd (PPh₃)₂CI₂ (47 mg, 0.065 mmol) was added to the above mixture and the mixture was degassed for another 3 times. The mixture was heated to reflux for ovemight. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The combined organic layer was dried (Na₂SO₄), and concentrated to get crude product, which was purified by column chromatography on 100-200 mesh silica gel to afford the title compound (100 mg, 37%) as yellow solid. ¹H NMR (400 MHz, CDCI3): δ 08.81 (d, J =1.2 Hz, 1H), 8.50 (br.s, 1H), 8.14-8.17 (dd, J =2.0, 8.8 Hz, 1H), 7.56 (s, 1H), 7.36-7.46 (m, 3H), 6.53-6.52 (m, 1H), 1.65 (s, 9H). LCMS: m/e 327.85 [M+H]+

Step 4: tert-Butyl 3-(1-methyl-5-nîtro-lH-indol-3-yl)-1H-pyrrole-1-carboxylate. To a solution of tert-butyl 3-(5-nitro-1 H-indol-3-yl)-1 H-pyrrole-1-carboxylate (650 mg, 1.98 mmol) in THF (10 mL) was added NaH (190 mg, 7.9 mmol, 60% w/w in minerai oil) at 0°C and reaction mixture was stirred ai same the same température for 1h. To this was added methyl iodide (1.12 g, 7.9 mmol) and then reaction mixture was stirred at room température for 3h. The progress of reaction was monitored by TLC. After completion, reaction mixture

105 was concentrated in vacuum, diluted with water and extracted with ethyl acetate. The combined organic layer was dried (Na₂SO₄), filtered and concentrated to give crude product which was purified by column chromatography on 100-200 mesh silica gel to afford the title compound (400 mg, 59%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.78 (d, J = 1.6 Hz, 1H), 8.15-8.18 (dd, J = 1.6, 9.2 Hz, 1 H), 7.53 (br.s, 1H), 7.26-7.53 (m, 3H), 6.51 (s, 1H), 3.88 (s, 3H), 1.65 (s, 9H); LCMS: m/e 341.85 [M+H]

Step 5: tert-Butyl 3-(5-amino-1 -methyl-1 H-indol-3-yl)pyrrolidine-1 -carboxylate. To a solution of tert-Butyl 3-(1-methyl-5-nitro-1H-indol-3-yl)-1H-pyrrole-1-carboxylate (500 mg,

1.15 mmol) in 20 mL of methanol was added Pd/C (100 mg) and the reaction mixture was heated under 50 psi of H₂ atmosphère at 40°C for 12 h. The progress of réaction was monitored by TLC (5% methanol in DCM). After 12 h, LCMS showed only réduction of nitro group and pyrrole ring intact. Then reaction was further continued with excess Pd/C (400 mg) at 45 °C under 100 psi for 12 hrs, when LCMS shows 49% formation of product. Reaction was cooled and filtered through Celîte and concentrated to give 220 mg of the title compound which was directly used for next reaction. ¹H NMR (400 MHz, MeOD): δ

7.15 (d, J = 8.4 Hz, 1 H), 6.99 (s, 1 H), 6.91 (s, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 3.75-3.83 (m, 1H), 3.68 (s, 3H), 3.51-3.55 (m, 4H), 3.31-3.43 (m, 2H), 2.08-2.29 (m, 2H), 1.48 (s, 9H). LCMS: m/e 315.41 [M+H]

Step 6: tert-Butyl 3-(5-(3-cyanobenzamido)-1-methyl-1 H-indol-3-yl)pyrrolidine-1carboxylate. To a solution of tert-butyl 3-(5-amino-1 -methyl-1 H-indol-3-yl)pyrrolidine-1carboxylate (47.5 mg, 0.15 mmol) in DCM ( 5 mL) was added TEA (61 mg,0.60 mmol) followed by addition of 3-cyanobenzoyl chloride (50 mg, 0.3 mmol) in DCM (5 mL) at 0 °C. The progress of reaction was monitored TLC (5% methanol in Chloroform). After completion, reaction mixture was diluted with water and extracted by using DCM. The combined extracts were dried (Na₂SO₄), filtered and concentrated in vacuum to give a crude compound which was subjected to column chromatography (Silica gel, 100-200 mesh) to afford the title compound (30 mg, 36%) as a brown colored solid. ¹H NMR (400 MHz,CDCI₃): δ 8.31 (s, 1 H). 8.26 (d, J = 7.6 Hz, 1H) 7.92-7.95 (m, 3H), 7.71 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H ), 7.06 (s, 1H), 3.81-3.87 (m, 1H), 3.78 (s, 3H), 3.55-3.63 (m, 2H), 3.35-3.45 (m, 2H), 2.11-2.35 (m, 2H), 1.48 (s, 9H). LCMS: m/e 345.05 [M-Boc]

106

Step 7: S-Cyano-N-il-methylHHpyrrolidin-S-ylJ-IH-indoi-S-yObenzarnide. To a solution of lnt-5 (1eq) in methanol was added 4M HCl solution in dioxane at 0°C and then reaction was stirred at room température for 4-5 hrs. The progress of reaction was monitored TLC (20% methanol in DCM), after completion, reaction mixture was concentrated and diluted with water and extracted by using chloroform. Aqueous layer was separated and basified with sat. solution of NaHCO₃ and extracted with 10% solution of methanol in chloroform, The combined extracts were dried (Na₂SO₄), filtered and concentrated in vacuum to give the title compound as a brown colored solid. ¹H NMR (400 MHz, MeOD): δ 8.32 (s, 1H), 8.26 (d, J = 8 Hz, 1H), 7.92-7.96 (m, 2H), 7.69-7.73 (m, 1H), 7.42 (d, J = 1.6 Hz 1 H), 7.40 (d, J=1.6 Hz, 1H), 7.35 (d, J = 8 Hz 1 H), 7.05 (s, 1H), 3.76 (s, 3H), 3.35-3.38 (m, 2H), 2.98-3.16 (m, 2H), 2.87-2.91 (m, 1H), 2.26-2.34 (m, 1 H), 1.8Θ-2.03 (m, 2H). LCMS: m/e 345.2 [M+H]

Step 8: S-cyano-N-tSOTcyciopentylcarbonyOpyrrolidin-S-yO-l-methyl-IH-indol-Syl)benzamide. A solution of cyclopentanecarboxylic acid (1.1 eq.), DIPEA (3 eq. mmol) and EDCI.HCI (2.2eq) and HOBT (1.2 eq.) in DMF (2mL) was stirred at room température for 1hr. 3-Cyano-N-(1-methyl-3-(pyrrolidin-3-yl)-1H-indol-5-yl)benzamide (1 eq.) was added to the above mixture and stirred at room température for 24 hr. The crude product was purified by reverse phase HPLC to afford the title compound. ¹H NMR (400 MHZ, CDCl₃): δ 8.23-8.21 (m, 2H), 8.17 (d, J=7.6 Hz, 1H), 7.99 (s, 0.5H), 7.89 (s, 0.5H), 7.81 (d, J=7.6 Hz, 1H), 7.64-7.60 (m, 1 H), 7.44-7.29 (m, 2H), 6.90 (s, 0.5H), 6.87 (s, 0.5H), 4.02-3.49 (m, 8H), 2.86-2.75 (m, 1 H), 2.45-1.54 (m, 10H). LCMS: m/e 441.20 [M+H]

Example 80

Préparation of N-(3-cyanophenyl)-3-(1-(5-isopropylpyriniidin-2-yl) piperidin-4-yl)-1methyl-1 H-indole-5-carboxamide

107

A solution of 3-cyano)-N-(1-methyl-3(piperidin-4-yl)-1H-indol-5-yl)benzamide (prepared in Example 1, 1eq.), TEA (6eq.) in IPA (3 mL) was stirred at room température for 15min. 2-Chloro-5-isopropylpyrimidine (1eq.) was added to the above reaction mixture and stirred at 05 °C for 6-1 Oh. The progress of reaction was monitored by TLC (5% methanol in DCM) and LCMS. After completion of the reaction, the mixture was concentrated, water was added to it, the mixture was extracted with DCM, dried (Na₂SO4) and concentrated. The crude material was purified by column chromatography (Silica gel100-200mesh, 1-2% MeOH in DCM) and then triturated with ether to provide the title compound. ¹H NMR (400 MHZ, CDCfe): δ 10.29 (s, 1H), 8.44 (s, 1H), 08.23-8.03 (m, 5H),

7.75 (t, J= 8 Hz, 1H), 7.50 (m, J= 8.8 Hz, 1H), 7.36 (d, J= 9.2 Hz, 1H), 7.11 (s, 1H), 4.79-

4.76 (m, 2H), 3.72 (s, 3H), 3.05-2.73 (m, 4H), 2.04-1.55 (m, 4H), 1.19 (s, 3H) 1.17 (s, 3H). LCMS: m/e 479.30 [M+1]+.

The following examples were prepared analogous to Example 80.

Example	Structure	Name	MS (M+H)
81	N ! n r^N I î .—-N ΙΪΊ H V⁷ O XXn \	3- cyano-N-(1 -methyl-3-(1 -(5methytpyrimidîn-2-yl)piperidin- 4- yl)-1 H-indol-5-yl)benzamide	451.25

108

Example	Structure	Name	MS (M+H)
82	N / n Il N ΙΪΊ ^H O W \	3-cyano-N-(3-[1-(5isopropylpyrimidin-2yl)piperidin-4-yl]-1 -methyl-1Hindol-5-yl)benzamide	479.30

Example 83

Préparation of 3-cyano-N-(3-{1-(cyclopentanecarbonyl)piperidin-4“

Step 1: tert-butyl 4-(5-bromo-2-fluorobenzoyl)piperidine-1-carboxylate. To a mixture of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (24 g, 240 mmol) in anhydrous tetrahydrofuran (500 mL) at -70 °C was added butyllithium (100 mL, 2.5 N) 10 dropwise and then the mixture was stirred for 1 h. Then 1 -bromo-4-fluorobenzene (35 g, 200 mmol) in anhydrous THF (50 mL) was added to the solution dropwise at -70 °C and stirred for 1 h. After that, 1 -bromo-4-fluorobenzene (54.4 g, 200 mmoi) in anhydrous tetrahydrofuran (20 mL) was added to the solution dropwise at -70 °C and stirred for another 30 minutes. Saturated ammonium chloride (200 mL) was added to the solution and 15 the mixture was stirred for 10 minutes. Then the mixture was poured into water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried

109 over sodium sulfate, filtered, and concentrated in vacuum under reduced pressure to afford the titled compound as an off-white solid (48 g, 62%): ¹H NMR (400 MHz, DMSO-d6): δ: 7.86-7.84 (s, 1H), 7.60-7.57 (s, 1H), 7.02 (t, 1H), 4.09 (s, 2H), 3.20 (t, 1H), 2.83 (d, 2H), 1.86 (d, 2H), 1.62-1.54 (m, 2H), 1.42 (s, 9H).

Step 2: (Z)-tert-butyl 4-((5-bromo-2-fluorophenyl)(hydroxyimino)methyl)piperidine-1carboxylate. To a solution of tert-butyl 4-(5-bromo-2-fluorobenzoyl)piperidine-1-carboxylate (19.3 g, 50 mmol), hydroxylamine hydrochloride (8.75 g, 125 mmol) in 1:1 isopropanol/water (300 mL) was added potassium hydroxide (28 g, 500 mmol). The mixture was refluxed for 16 hours. And then was poured into water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were concentrated under reduced pressure to afford the titled compound (12 g, 60 %) as a white solid which was carried on in the synthetic sequence without further purification: ¹H NMR (400 MHz, CDCI3): δ 9.12 (s, 1H), 7.48-7.44 (m, 1H), 7.32-7.30 (m, 1H), 6.98 (t, 1H), 4.13 (t, 2H), 3.35 (t, 1H), 2.72 (s, 2H),1.76 (d, 2H)_t 1.428 (s, 9H).

Step 3: tert-butyl 4-(5-bromobenzo[d]isoxazol-3-yl)piperidine-1 -carboxylate. A mixture of (Z)-tert-butyl 4-((5-bromo-2-fluorophenyl)(hydroxyimino)methy|)piperidine-1carboxylate (4.5 g, 11.0 mmol) and potassium tert-butoxide (2.4 g, 22.0 mmol) in dimethylformamide (30 mL) was stirred at room température for 1 hour. Then the mixture was heated to 80 °C and stirred for 16 hours. The organic solvent was removed in vacuum under reduced pressure to give the crude residue, which was purified by column chromatography on silica gel (Petroleum ether/ethyl acetate (10:1)) to afford the titled compound (1.4 g, 33 %) as a white solid which was carried further in the sequence immediately without any further purification.

Step 4: tert-butyl 4-(5-(diphenylmethyleneamino)benzo[d]isoxazol-3-yl)piperidine-1carboxylate. To a mixture of tert-butyl 4-(5-bromobenzo[d]isoxazol'3-yl)piperidine-1carboxylate (1.15 g, 3 mmol), benzophenone imine (0.65 g, 3.6 mmol), sodium tertbutoxide (0.42 g, 4.2 mmol), 2,2'-bis(diphenylphosphino)-1,T-binaphthyl (0.37 g, 0.6 mmol) and palladium dibenzylidene acetone (0.275 g, 0.3 mmol) was added toluene (30 mL) was heated to 90 °C for 16 h under nitrogen atmosphère. The mixture was concentrated in vacuum under reduced pressure to give the residue, which was purified by column chromatography on silica gel (Petreum ether/EtOAc (10:1)) to afford the titled compound

110 (0.Θ9 g, 67 %) as a light yellow solid which required no further purification and was immediately carried forward in the synthetic sequence.

Step 5: tert-butyl 4-(5-aminobenzo[d]isoxazol-3-yl)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-(5-(diphenylmethyleneamino)benzo[d]lsoxazol-3-yl)piperidine1-carboxylate (7.6 g, 17.2 mmol) in tetrahydrofuran (40 mL) was added saturated citric acid (200 mL) and the resulting mixture was stirred at room température for 16 hours. Saturated sodium carbonate (500 mL) was added to the solution and then the mixture was extracted with ethyl acetate (50 mL x 5), The combined organic layers were concentrated in vacuum under reduced pressure to give the crude residue, which was purified by column chromatography on silica gel (Petroleum ether/EtOAc (2:1)) to afford the titled compound (2.39 g, 44 %) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d6): δ: 7.36 (d, 1 H), 6.92 (dd, 1H), 6.85 (s, 1H), 5.13 (s, 2H), 4.03 (d, 2H), 3.22-3.17 (m, 1H), 2.94 (s, 2H), 1.97 (d, 2H), 1.72-1.62 (m, 2H), 1.42 (s, 9H).

Step 6: tert-butyl 4-(5-(3-cyanobenzamido)benzo[d]isoxazoI-3-yl)piperidine-1carboxylate. To a mixture of tert-butyl 4-(5-aminobenzo[d]isoxazol-3-yl)piperidine-1carboxylate (0.18 g, 1.2 mmol), O-(Benzotriazol-1-yl)-N,N,N',N‘-tetramethyluronium tetrafluoroborate (0.38 g, 1.2 mmol), and diisopropylethylamine (0.38 mg, 1.2 mmol) was added dimethylformamide (10 mL) and the mixture was stirred for 1 hour at room température. To this mixture was added 3-cyanobenzoic acid (0.32 g, 1 mmol) in dimethylformamide (5 mL) and the solution was stirred overnight. Saturated sodium bicarbonate (200 mL) was added to the solution and stirred for 10 minutes. Then the mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were concentrated in vacuum under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (Petroleum ether/ethyl acetate (1:1)) to afford the titled compound (0.3 g, 67 %) as a white solid which was carried forward in the sequence immediately without further purification.

Step 7: 3-cyano-N-(3-(piperidin-4-yl)benzo[d]isoxazol-5-yl)benzamide. To a stirred suspension of tert-butyl 4-(5-(3-cyanobenzamido)benzo[d]isoxazol-3-yl)piperidlne-1carboxylate (0.30 g, 0.62 mmol) in dichloromethane (5 mL) at 0 °C was added trifluoroacetic acid (20 mL) dropwise. The mixture was allowed to warm up to room température and stirred for 6 hours. The mixture was then concentrated under reduced

111 pressure and then washed with ethyl acetate (10 mL) to give the titled compound as a white solid which was used directly in the next step without further purification.

Step 8: 3-cyano-N-(3-(1 -(cyclopentanecarbonyl)piperidin-4-yl)benzo[d]isoxazol-5yl)benzamide. A mixture of 3-cyano-N-(3-(piperidin-4-yl)benzo[d]isoxazol-5-yl)benzamide (0.092 g, 0.804 mmol), O-tBenzotriazol-l-ylJ-N.N.N'.N'-tetramethyluronîum tetrafluoroborate (0.26 g, 0.804 mmol) and diisopropylethylamine (2 mL) in dimethylformamide (10 mL) was stirred at room température for 2 hours. Then, cyclopentanecarboxylic acid (0.23 g, 0.67 mmol) was added to the solution and stirred overnight. Saturated sodium bicarbonate (5 mL) was added to the solution and stirred for 10 minutes. Then the mixture was poured into water (20 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were concentrated in vacuum under reduced pressure to give the crude product, which was purified to give the titled compound (0.112 g, 38 %) as a white solid: ¹H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.43 (s, 1 H), 8.39 (s, 1 H), 8.28 (d, 1 H), 8.14 (d, 1 H), 7.92 (dd, 1 H), 7.78-7.74 (m, 2H), 4.49 (d, 1 H), 4.12 (d, 1H), 3.49-3.44 (m, 1H), 3.26 (t, 1H), 3.03 (t, 1H), 2.83 (t, 1H), 2.12-2.05 (m, 2H), 1.78-1.52 (m, 10H). LC/MS (10%-90% CH₃CN:H₂O gradient over 8 min): 4.40 min. 443.2 M+H.

Example 84

Préparation of 3-cyano-N-(1-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1H-Îndazol-6yl)benzamide

Step 1:tert-butyl 4-(6-nitro-1H-indazol-1-yl)piperidine-1-carboxylate. To a solution of 6-nitro-1 H-indazole (8.1 g, 50.0 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1carboxylate (14.0 g, 50.0 mmol) in dimethylformamide (150 mL) was added césium carbonate (19.4 g, 100.0 mmol). The mixture was heated to 60 °C for 24 hours. The mixture was combined with water (200 mL) and extracted with ethyl acetate (100 mL x 3).

112

The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum under reduced pressure to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 5:1) to afford the titled compound (6.4 g, 37%) as a yellow solid: ¹H NMR (400 MHz, CDCI3): ô: 8.43 (s, 1H), 8.13 (s, 1H), 8.04-8.01 (m, 1H), 7.84 (d, 1H), 4.66 (s, 1H), 4.35 (s, 2H), 3.08 (s, 2H), 2.27-2.23 (m, 2H), 2.03 (d, 2H), 1.50 (s, 9H).

Step 2: tert-butyl 4-(6-amino-1H-indazol-1-yl)piperidine-1-carboxylate. To a solution of tert-butyl 4-(6-nitro-1H-indazol-1-yl)piperidine-1-carboxylate (5.0 g, 14.5 mmol) in tetrahydrofuran (100 mL) was added a catalytic amount of 5% palladium on carbon (0.5 g) at room température. The mixture was degassed and refilled with hydrogen In trîplicate. Then the mixture was then shaken at room température for 16 hours under an atmosphère of hydrogen (47 psi). The mixture was filtered and the filtrâtes were then concentrated in vacuum under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (Petroleum ether/EtOAc 2:1) to afford the titled compound (3.8 g, 83 %) as a yellow solid: ¹H NMR (400 MHz, DMSO-d6): δ: 7.72 (s, 1H), 7.35 (d, 1H), 6.54 (s, 1H), 6.49 (d, 1H), 5.30 (s, 2H), 4.47 (t, 1H), 4.06 (d, 2H), 2.95 (s, 2H), 1.86 (s, 4H), 1.42 (s, 9H).

Step 3: tert-butyl 4-(6-(3-cyanobenzamido)-1H-indazol-1-yl)piperidine-1-carboxylate. A mixture of 3-cyanobenzoic acid (0.7 g, 5.0 mmol), O-(Benzotriazol-1-yl)-/V,A/,A/',A/'tetramethyluronium tetrafluoroborate (1.7 g, 5.5 mmol) and diisopropylethylamine (0.9 mL, 5.5 mmol) in dimethylfbrmamide (15 mL) was stirred at room température for 2 hours.. Then tert-butyl 4-(6-amino-1H-indazol-1-yl)piperidine-1-carboxylate (1.6 g, 5.0 mmol) in dimethylformamide (15 mL) was added to the solution dropwise and the mixture was stirred at room température for 18 hours. Then saturated sodium bicarbonate (200 mL) was added to the solution and stirred for 10 minutes. Then the mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were concentrated in vacuum under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (Petroleum ether/ethyl acetate 1:1) to afford the titled compound (1.2 g, 54 %) as a pale solid: ¹H NMR (400 MHz, DMSO-d6): δ: 10.59 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 8.28 (d, 1H), 8.08 (d, 1H), 8.03 (s, 1H), 7.79-7.72 (m, 2H), 7.38 (d, 1H), 4.72 (s, 1H), 4.09 (d, 2H), 3.03 (s, 2H), 1.96 (d, 4H), 1.42 (s, 9H).

113

Step 4:3-cyano-N-(1-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1 H-indazol-6yl)benzamide. To a solution of tert-butyl 4-(6-(3-cyanobenzamido)-1H-indazol-1yl)piperidine-1-carboxylate (0.9 g, 2.0 mmol) in methanol (10 mL) at room température was added 4N hydrochloric acid in dioxane (10 mL) dropwise. Then, the mixture was stirred for 2.5 hours at room température. The solvent was then removed in vacuum under reduced pressure, and the crude product, 3-cyano-N-(1-(piperidin-4-yi)-1H-indazol-6yl)benzamide, was used in the next step without further purification. A mixture of 3-cyanoN-(1-(piperidîn-4-yl)-1H-indazol-6-yl)benzamide (0.23 g, 2 mmol), ), 0-(Benzotriazol-1 -yl)Λ/,Λ/,Λ/',Λ/'-tetramethyluronium tetrafluoroborate (0.71 g, 2.2 mmol) and diisopropylethylamine (2 mL) in dimethylformamide (10 mL) was stirred at room température for 1 hour. Then, the cyclopentanecarboxylic acid (0.69 g, 2 mmol) in dimethylformamide (5 mL) was added dropwise and stirred for 18 hours. Saturated sodium bicarbonate (10 mL) was added to the solution and stirred for 10 minutes. Then the mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were concentrated in vacuum under reduced pressure to give the crude product, which gave the titled compound (0.50 g, 57 %) as a pale solid: ¹H NMR (400 MHz, DMSO-d6): δ: 10.60 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.29 (d, 1H), 8.08 (d, 1H), 8.02 (s, 1H), 7.79-7.73 (m, 2H>, 7.38 (d, 1H), 4.81 (t, 1H), 4.55 (d, 1H), 4.14 (d, 1H), 3.06 (t, 1H), 2.84 (t, 1 H), 2.07-1.52 (m, 13H).

Example 85

Préparation of 4-(5-(3-cyanobenzamîdo)-1H-indol-3-yl)-N-cyclopentylpiperidine-1carboxamide

Step 1: 3-cyano-N-(3-(piperidin-4-yl)-1H-indol-5-yl)benzamide. To a suspension of tert-butyl 4-(5-amino-1H-indol-3-yl)piperidine-1-carboxylate (prepared in Example 36, 5.0 g, 16.0 mmol) in 60 mL of dimethylformamide at room température was added 3

114 cyanobenzoic acid (2.3 g, 15.9 mmol), O-fBenzotriazol-l-yn-N.N.N'.N'-tetramethyluronîum tetrafluoroborate (5.8 g, 17.4 mmol), and N-ethyl-N-isopropylpropan-2-amine (2.3 g, 17.4 mmol). The mixture was then stirred at rt for 96 hours then concentrated under reduced pressure, diluted with 30 mL of ethyl acetate, washed with water and brine, dried with magnésium sulphate, then filtered and concentrated under reduced pressure to give a crude solid which was immediately dissolved in 100 mL and treated with 20 mL of 4N hydrochloric acid in dioxane. The mixture was then stirred at room température for 4 hours then concentrated under reduced pressure to give 5.9 g (99%) of the titled compound as an off-white solid: ¹H NMR (400 MHz, Methanol-d4): δ 8.31 (s, 1H), Θ.24 (d, 1H, J = 8.0 Hz), 8.07 (s, 1H), 7.93 (d, 1H, J = 7.6 Hz), 7.71 (m, 1H), 7.36 (d, 1H, J = 7.6 Hz), 7.23 (d, 1H, J = 8.4 Hz), 7.12 (s, 1H), 3.49 (m, 2H), 3.19 (m, 3H), 2.29 (m, 2H), 1.97 (m, 2H).

Step 2:4-(5-(3-cyanobenzamido)-1 H-indol-3-yl)-N-cyciopentylpiperidine-1carboxamide. To a solution of 3-cyano-N-(3-(piperidin-4-yl)-1H-indol-5-yl)benzamide (100.0 mg, 0.26 mmol) in 1.5 mL of dimethylformamide was added is isocyanatocyclopentane (35.1 mg, 0.32 mmol), and triethylamine (53.2 mg, 0.53 mmol). The mixture was then stirred at room température for 30 minutes then was washed with saturated aqueous sodium chloride. The organic layer was then collected and was dried over sodium sulfate, filtered and evaporated to give the title compound. LC/MS (10%-90% CH₃CN:H₂O gradient over 8 min): 3.87 min. 456.1 M+H. ¹H NMR (400 MHz, DMSO-afe) δ ppm 10.81 (br. s., 1 H), 10.28 (s, 1 H), 8.44 (s, 1 H), 8.29 (d, J=7.32 Hz, 1 H), 8.05 (d, J=8.05 Hz, 1 H), 7.99 (s, 1 H), 7.75 (t, J=8.05 Hz, 1 H), 7.44 (d, J=8.79 Hz, 1 H), 7.32 (d, J=8.79 Hz, 1 H), 7.12 (d, J=1.46 Hz, 1 H), 6.21 (d, J=6.59 Hz, 1 H), 4.11 (d, J=12.45 Hz, 2 H), 3.85 - 3.97 (m, 1 H), 2.88 (t, vM2.08 Hz, 1 H), 2.78 (t, J=12.08 Hz, 2 H), 2.54 (s, 1 H), 1.91 (d, J=11.71 Hz, 2 H), 1.73-1.85 (m, 2 H), 1.33-1.69 (m, 9 H).

Example 86

Préparation of 3-cyano-N-(3-(1-(cyclopentylsulfonyl)piperidin-4-yl)-1 H-indol-5yl)benzamide

115

A mixture of 3-cyano-N-(3-(piperidin-4-yl)-1 H-indol-5-yl)benzamide (prepared in Example 85,40.0 mg, 0.11 mmol), cyclopentanesulfonyl chloride (21.2 mg, 0.13 mmol) and triethylamine (26.6 mg, 0.26 mmol) in dimethyiformamide (1 mL) was stirred at room température for 1 hour. Saturated sodium bicarbonate (1 mL) was added to the solution and stirred for 10 minutes. Then the mixture was poured into water (2 mL) and extracted with ethyl acetate (1 mL x 3). The combined organic layers were concentrated in vacuum under reduced pressure to give the crude product, which was purified to give the titled compound (0.50 g, 57 %) as a pale solid: ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (1 H, d, J=2.2 Hz), 10.26 (1 H, s), 8.40 (1 H, s), 8.25 (1 H, s), 8.08 - 7.94 (1 H, m), 7.71 (1 H, t, J=8.1 Hz), 7.47 - 7.24 (1 H, m), 7.12 (1 H, d, J=2.2 Hz), 3.81 - 3.50 (1 H, m), 3.06 - 2.80 (1 H, m), 2.46 (1 H, d, J=1.5 Hz), 2.11 - 1.45 (1 H, m).

Example 87

Préparation of 3-cyano-N-(3-(1-(cyclopentylmethyl)pîperidin-4-yl)-1 H-indol-5yl)benzamide

A mixture of 3^3ηο-Ν-(3-(ρΪρθπόΐη-4^Ι)-1Η-^οΙ-5·ή/Ι)Ρβηζ8Π^θ (prepared in Example 85, 50.0 mg, 0.13 mmol), cyclopentanecarbaldehyde (16.7 mg, 0.17 mmol), sodium triacetoxyborohydride (41.8 mg, 0.20 mmol), and triethylamine (19.9 mg, 0.20 mmol) in dichloromethane (2 mL) was stirred at room température for 1 hour. Acetic acid (0.1 mL) was then added to the reaction mixture at room température and the mixture was

116 then stirred ovemight. Saturated sodium bicarbonate (1 mL) was added to the solution and stirred for 10 minutes. Then the mixture was poured into water (2 mL) and extracted with ethyl acetate (1 mL x 3). The combîned organic layers were concentrated in vacuum under reduced pressure to give the crude product, which was purified to give the titled compound: MS (ES+) m/z 427 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.85 (br. s., 1 H), 10.31 (s, 1 H), 8.43 (s, 1 H), 8.28 (d, J=8.05 Hz, 1 H), 8.04 (d, J=8.05 Hz, 1 H), 8.00 (s, 1 H), 7.70 - 7.80 (m, 1 H), 7.47 (d, J=8.05 Hz, 1 H), 7.37 - 7.44 (m, 1 H), 7.28 - 7.35 (m, 1 H), 7.17 7.27 (m, 1 H), 7.09 (s, 1 H), 3.21 (d, J=10.98 Hz, 1 H), 2.76 - 2.88 (m, 1 H), 2.51 - 2.68 (m, 3 H), 2.15 (dt, J=15.19, 7.41 Hz, 1 H), 1.99 (d, J=12.45 Hz, 2 H), 1.68 -1.91 (m, 5 H), 1.42 -1.62 (m, 5 H), 1.13 -1.27 (m, 2 H).

Examples 88

Préparation of 3-cyano-N-(3-(1-(cyc!opentanecarbonyl)piperidin-4-yl)-1,4-dimethyl1 H-indol-5-yl)benzamide

Step 1:3-iodo-1,4-dimethyl-5-nitro-1 H-indole. To a cooled solution (ice-water bath) of 4-methyl-5-nitroindole (1.76 g, 10 mmol) in DMF (30 mL) was added KOH pellets (0.78 g, 14 mmol). The cooling bath was removed, and the mixture was stirred at rt for 10 min. lodine (2.79 g, 11 mmol) was added, and the stirring was continued for 5 h at room température. To this mixture was added potassium carbonate (3.17 g, 23 mmol) and methyl iodîde (3.1 mL, 50 mmol), and stirring was continued at room température for 16h. The mixture was diluted with water (150 mL), and treated with solid NaHSO₃ with stirring until ail excess îodine was quenched. The crude product was collected by filtration, washed with plenty of water, and dried. This crude product was suspended in 96% EtOH. After stirring for 15 min, the precipitate was collected and washed with two small portions of EtOH to provide 2.78 g (88%) of a golden-brownish solid. MS m/z 316 (M+H).

117

Step 2: tert-butyl 4-(1,4-dimethyl-5-nitro-1 H-indol-3-yl)-5,6-dihydropyridine-1(2H)carboxylate. 3-iodo-1,4-dimethyl-5-nitro-1H-indole (2.70 g, 8.5 mmol), tert-butyl 4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.17 g, 10.25 mmol), Pd EnCat® TPP30 (polymer based Pd-PPha, 337 mg), and potassium carbonate (2.36 g, 17.1 mmol) were charged in a vessel, followed by a mixture of DME/ethanoI/water (4:1:1,18 mL) and the mixture was degassed with nitrogen for 10 min. The vessel was then sealed, and the mixture was stirred at 70 °C for 18h,The mixture was filtered, diluted with water, and extracted three times with EtOAc. The combined organic layers were washed with brine, and concentrated in vacuo. The residue was subjected to flash chromatography (n-heptane - 30% EtOAc/n-heptane), to provide 2.17 g (68%) of the title compound as a yellow foam. MS m/z 372 (M+H]).

Step 3:1,4-dimethyl-5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole hydrochloride. A solution of tert-butyl 4-( 1,4-dimethyl-5-nitro-1 H-indol-3-yl)-5,6dihydropyridine-1(2H)-carboxylate (1.53 g, 4.12 mmol) in dioxane (30 mL) was treated with HCl (4 M solution in dioxane, 12 mL) over 10 min. The resulting mixture was stirred at room température for 48h. The solvents were removed in vacuo. The residue was coevaporated twice with with MeOH, followed by thorough drying in vacuo, providing 1.26g (99%) of the title compound as an orange solid. MS m/z272 (M+H).

Step 4: cyclopentyl(4-(1,4-dimethyl-5-nitro-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)yl)methanone. 1,4-dimethyl-5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-lH-indole hydrochloride (1.26 g, 4.1 mmol) was suspended in DCM (30 mL), and the mixture was cooled in an ice-water bath. Triethylamine (2.3 mL, 16.5 mmol), followed by cyclopentanecarbonyl chloride (0.65 mL, 5.35 mmol) were added. The mixture was slowly allowed to reach room température for 16h. Water was added, and the layers were separated. The aqueous layer was extracted with twice with DCM and the layers were separated. The combined organic extracts were concentrated to a yellow olly residue. The crude was subjected to flash chromatography (n-heptane - 50% EtOAc/n-heptane), to provide 1.34 g (89%) of the title compound as a yellow solid. LCMS m/z 368 (M+H).

Step 5: préparation of (4-(5-amino-1,4-dimethyl-1H-indol-3-yl)piperidin-1yl)(cyclopentyl)methanone. A mixture of the cyclopentyl(4-(1,4-dimethyl-5-nitro-1H-indol-3yl)-5,6-dihydropyridin-1(2H)-yl)methanone (1.0 g, 2.72 mmol), ammonium formate (2.1 g,

118 mmol), 5% Pd/C (150 mg), and 96% EtOH (50 mL) was heated at 85 °C for 90 min under an atmosphère of nitrogen. The mixture was filtered and concentrated in vacuo. The residue was diluted with water, and extracted four times with CHCI3. The combined organics were dried, and concentrated in vacuo, to provide 0.84 g (91%) of the title compound as an off-white foam. MS m/z 340 (M+H).

Step 6: 3-cyano-N-(3-(1 -(cyclopentanecarbonyl)piperidin-4-yl)-1,4-dimethyl-1 Hindol'5-yl)benzamide. (4-(5-amino-1,4-dimethyl-1 H-indol-3-yI)piperidin-1 yl)(cyciopentyl)methanone (0.84 g, 2.5 mmol) was dissolved in DCM (50 mL), and the mixture was cooled in an ice-water bath. Triethylamine (1.14 mL, 8.16 mmol) was added over 2 min, followed by 3-cyanobenzoyl chloride (0.68 g, 4.1 mmol) in one portion. The mixture was allowed to reach room température, and was then stirred for 20 h. Water was added and the mixture was then extracted four times with EtOAc. The combined organics were washed with brine, dried (NagSCU), and evaporated. The crude product was purified by prep-HPLC to provide 0.73 g (62%) as an off-white foamy solid. ¹H NMR (500 MHz, (CD₃)CO) δ ppm 8.38 (d, 1H, J=8.3Hz), 7.99 (d, 1H, J=8.0Hz), 7.78 (t, 1H, J=7.7Hz), 7.20 (d, 1H, J=8.5Hz), 7.16 (d, 1H, J=8.5Hz), 7.09 (s, 1H), 4.72 (d, 1H, J=12.9Hz), 4.19 (d, 1H, J=13.2Hz), 3.77 (s, 3H), 3.41 (m. 1H), 3.23 (m, 1H), 3.05 (m, 1H), 2.68 (m, 1H), 2.63 (s, 3H), 2.14 (m, 1H), 2.02 (m, 1H) and 1.83-1.45 (m, 10H). LCMS: m/e 469 [M+H].

Example 89

Préparation of (R)-3-cyano-N-(1,4-άϊπΐθΐΙηγΙ-3-(1-(4,4₁44πΑυοΓο-3-ΙινάΓθχν6υΐ3ηονΙ)pîperidin-4-yl)-1 H-indol-5-yl)benzamide

Step 1: tert-butyl 4-(5-amino-1,4-dimethyl-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)carboxylate. A mixture of tert-butyl 4-( 1,4-dimethyl-5-nitro-1 H-indol-3-yl)-5,6dihydropyridine-1(2H)-carboxylate (180 mg, 0.48 mg), ammonium formate (367 mg, 5.8

119 mmol), 5% Pd/C (30 mg) in 96% EtOH (10 mL) was heated at 85 °C for 90 min under an atmosphère of nitrogen. The mixture was filtered through a Tefton filter and the filtrate was concentrated. The residue was then partitioned between CHCI₃ and water and the aqueous layer was extracted three more times with CHCI₃. The combined organics were concentrated in vacuo to provide the title compound. MS m/z344 [M+H],

Step 2: tert-butyl 4-(5-(3-cyanobenzamido)-1,4-dimethyl-1 H-indol-3-yl)piperidine-1carboxylate. The residue from the previous step was dissolved in pyridine (4 mL). 3Cyanobenzoyl chloride (120 mg, 0.73 mmol) was added, and the mixture was stirred at room température overnight. The pyridine was removed in vacuo. The residue was partitioned between CHCI₃ and water. The aqueous layer was extracted twice with CHCI_3>and the combined organics were concentrated in vacuo. The residue was subjected to flash chromatography (n-heptane - EtOAc/n-heptane 1:1). Further purification was done by prep-HPLC to provide 74 mg of the title compound as an off-white solid. MS: m/z473 [M+HJ.

Step 3: 3-cyano-N-(1,4-dimethyl-3-(piperidin-4-yl)-1H-indol-5-yl)benzamide hydrochloride. A solution tert-butyl 4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-indol-3yl)piperidine-1-carboxylate (74 mg, 0.16 mmol) in 1,4-dioxane (6 mL) cooled in an icewater bath was treated with HCl (0.47 mL, 4 M solution in dioxane) over 5 min. The cooling bath was removed and the resulting mixture was stirred at room température for 36h. The mixture was evaporated in vacuo, and then co-evaporated twice with MeOH to provide the title compound. The compound was used as such in the subséquent step. MS m/zZll [M+HJ.

Step 4: (R)-3-cyano-N-(1,4-dimethyl-3-(1-(4,4,4-trifluaro-3hydroxybutanoyl)piperidin-4-yl)-1 H-indol-5-yl)benzamide. 3-cyano-N-(1,4-dImethyl-3(piperidin-4-yl)-1H-lndol-5-yl)benzamide hydrochloride was suspended in DMF (3 mL). A solution of DIPEA (109 μΙ, 0.63 mmol), HATU (77 mg, 0.20 mmol), and (R)-4,4,4-trifluoro-3hydroxybutanoic acid (32 mg, 0.20 mmol) In 0.5 mL DMF) was added at room température. A yellow solution was obtained within minutes. The reaction mixture was then stirred at room température overnight. The mixture was purified directly by prep-HPLC to provide 57 mg (71% over two steps) of the title compound an off-white solid. ¹H NMR (500 MHz, (CD₃)₂CO) δ ppm 8.42 (s, 1H), 8.36 (d, 1H, J=7.8Hz), 7.97 (d, 1H, J=7.8Hz), 7.75 (t, 1H,

120

J=7.7Hz), 7.17 (m, 2H), 7.07 (s, 1H), 4.71 (m, 1H), 4.58 (m, 1 H), 4.13 (m, 1H), 3.75 (s, 3H), 3.42 (m, 1 H), 3.28 (m, 1H), 2.82-2.68 (m, 3H), 2.62 (s, 3H), 2.10 (m, 2H), 1.66 (m, 1H) and 1.52 (m, 1H). MS m/z 513 [M+H].

Example 90

Préparation of (R)-3-cyano-N-(1-methyl-3-(1-(4,4,4-trifluoro-3hydroxybutanoyl)piperidin-4-y[)-1 H-indol-5-yl)benzamide

3-cyano-N-(1-methyl-3-(piperidin-4-yl)-1H-indol-5-yl)benzamide (40 mg, 0.11 mmol), (R)-4,4,4-trifluoro-3-hydroxybutanoic acid (26 mg, 0.17 mmol), dimethylaminopropylcarbodümide (26 mg, 0.17 mmol), 1-hydroxy-benzotriazole (23 mg, 0.17 mmol) and triethylamine (39 μΙ, 0.28 mmol) were mixed with DMF (0.5 mL). The mixture was stirred at room température for 3h. The volatiles were evaporated and the residue was passed through a plug of silica (0.5g) using EtOAc as eluent. After évaporation, the residue was purified by flash chromatography with heptane/EtOAc (1:1 -4:6) to provide 30 mg (54%) of the title compound as a white solid. ¹H NMR (500 MHz, (CD₃)₂CO) δ ppm 8.41 (s, 1H), 8.35 (d, 1H, J=8.1Hz), 8.19 (d, 1H, J=11.4Hz), 7.98 (d, 1H, J=7.6Hz), 7.77 (t, 1H, J=8.0Hz), 7.54 (m, 1H), 7.35 (d, 1H, J=8.6Hz), 7.06 (d, 1H, J=2.8Hz), 4.70 (m, 1H), 4.59 (m, 1H), 4.15 (m, 1H), 3.79 (s, 3H), 3.23 (m, 1H), 3.13 (m, 1H), 2.85-2.80 (m, 4H),2.11 (m, 1H) and 1.84-1.58 (m, 2H). MS m/z 499 [M+H],

Example 91

Préparation of (R)-4-fIuoro-N-(1-methyl-3-(1-(4,4,4-trifluoro-3hydroxybutanoyl)piperidin-4-yl)-1 H-indol-5-yl)benzenesulfonamide

121

Step 1: tert-butyl 4-(5-(4-fluorophenylsulfonamido)-1 -methyl-1 H-indol-3-yl)piperidlne1-carboxylate. 4-Fluorobenzene-1-sulfonyl chloride (236 mg, 1.21 mmol) was added to a stirred solution of tert-butyl 4-(5-amino-1 -methyl-1 H-indol-3-yl)piperidine-1 -carboxylate (200 mg, 0.61 mmol) and pyridine (100 μΙ_, 1.21 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at room température overnight. Water (10 mL) was added. The phases were separated and the organic layer was concnetrated. The crude product was purified by flash chromatography (EtOAc/heptane; 2:8-3:7) to provide 250 mg (84%) of the title compound as a white/yellow solid. LCMS m/z 488 [M+H].

Step 2: 4-fluoro-N-(1-methyl-3-(piperidin-4-yl)-1H-indol-5-yl)benzenesulfonamide. A solution of HCl in 1,4-dioxane (1.7 mL, 4M) was added to a slurry of tert-butyl 4-(5-(4fluorophenylsulfonamido)-1-methyl-1 H-indol-3-yl)piperidine-1-carboxylate (210 mg, 0.44 mmol) in methanol cooled on an Ice-water bath. The température was allowed to warm to room température for 30 min, whereupon the pH was adjusted to 9 by addition of NaHCO₃(sat.), followed by extraction with dichloromethane/MeOH (9:1) four times. The extracts were dried with Na₂SO₄ and concentrated. The crude product was purified by flash chromatography with dichloromethane/EtOH/Et₃N (7.6:1.9:0.5) to provide 160 mg (97%) of the title compound as a yeîlow solid. LCMS m/z388 [M+H].

Step 3: (R)-4-fluoro-N-(1 -methy[-3-(1 -(4,4,4-trifluoro-3-hydroxybutanoyl)piperidin-4yl)-1H-indol-5-yl)benzenesulfonamide. 4-fluoro-N-(1-methyI-3-(piperidin-4-yl)-1H-indol-5yljbenzenesulfonamide (2.2 g, 5.7 mmol), {R)-4,4,4-trifluoro-3-hydroxybutanoic acid (1.1 g, 6.8 mmol), dimethylamînopropylcarbodiimide (1.1 g, 6.8 mmol) and 1-hydroxybenzotriazole (0.9 g, 6.8 mmol) were mixed. DMF (20 mL) was added, and the mixture was cooled in an ice-water bath. Triethylamine (2.0 mL, 14 mmol) was added over 5 min. The mixture was allowed to reach room température overnight. The reaction was quenched by adding water. The aqueous phase was extracted 3 times with EtOAc, and the combined organics were washed sequentially with 5% citric acid, sat. NaHCO₃, brine, and were then dried over MgS04. Evaporation of the solvents in vacuo, followed by thorough drying under vacuum provided 2.4 g (81%) of the title compound as a light-tan foamy solid. ¹H NMR (500 MHz, (CD₃)₂CO) δ ppm 7.75 (m, 2H), 7.34 (d, 1H, J=4.1), 7.27-7.22 (m, 3H), 7.03 (s, 1 H), 6.99 (d, 1 H, J=8.6Hz)_t 4.67 (d, 1 H, J=12.6Hz), 4.58 (m, 1 H), 4.11 (m, 1 H), 3.73 (s, 3H), 3.28 (m, 1H), 3.03 (m, 1 H), 2.81-2.69 (m, 4H), 1.97 (m, 1H), 1.65 (m, 1H) and 1.52 (m, 1H). MS m/z 528 [M+H].

Example 92

Préparation of 4-fluoro-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyÎ-1H-indol-5yl)benzenesulfonamide

4-Fluoro-N-(1-methyl-3-(piperidin-4-yl)-1H-indol-5-yl)benzenesulfonamide (1.8 g, 4.7 mmol) was suspended in DCM, and the mixture was cooled in an ice-water bath. Pyridine (1.1 mL, 14 mmol) was added, followed by the isobutyryl chloride (660 pl, 6.3 mmol) over 10 min. The resulting mixture was stirred on an ice-water bath for 2h. The température was allowed to room température for 2 h, whereupon water was added. The layers were separated. The aqueous layer was extracted twice with DCM, and the combined organics were concentrated. The residue was purified by prep-HPLC to provide 1.3 g (61%) as an off-white solid. ¹H NMR (500 MHz, (CD₃)₂CO) δ ppm 7.75 (m, 2H), 7.32 (d, 1H, J=1.9), 7.27-7.22 (m, 3H), 7.03 (s, 1H), 6.95 (dd, 1H, J=8.7, 1.9Hz), 4.67 (d, 1H, J=12.6Hz), 4.12 (d, 1H, J=13.6Hz), 3.73 (s, 3H), 3.23 (m, 1H), 3.02-2.90 (m. 2H), 2.67 (m, 1H), 1.96 (m, 2H), 1.52 (m, 2H) and 1.08 (s, 6H). LCMS: m/e 458 [M+H].

Experlment 93

Préparation of N-(3-(1 -(cyclopentanecarbonyl)pîperîdin-4-yl)-1-methyi-1 H-indol-5-yl)4-methylpiperïdine-1-sulfonamide

123

Step 1:2-oxooxazolidine-3-sulfonyl chloride. To solution of oxazolidin-2-one (4 g, 46 mmol), DMAP (0.56 g, 4.6 mmol) and triethylamine (7.7 mL, 55 mmol) in dichloromethane (100 mL) cooled on an ic-water bath was added sulfuryl chloride (3.7 mL, 46 mmol) drop-wise. The cooling bath was removed and the mixture was stirred at room température overnight. The mixture was washed with 0.2 M HCl (2x15 mL). The phases were separated and the solvents were evaporated. The residue was filtered through a plug of silica with dichloromethane as eluent. After évaporation of the solvents, the residue was washed with isohexane and a small amount of EtOAc to provide 5.3 g (62%) of the title compound as white powder. MS m/z 186 [M+H].

Step 2: N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1 -methyl-1 H-indol-5-yl)-2oxooxazolîdine-3-sulfonamide. A slurry of (4-(5-amino-1-methyl-1 H-indol-3-yl)piperidin-1yl)(cyclopentyl)methanone hydrochloride (30 mg, 0.08 mmol) in MeCN (1.5 mL) was added drop-wise to a solution of 2-oxooxazolidine-3-sulfonyl chloride (92 mg, 0.5 mmol) and pyridine (33 pi, 0.41 mmol) in acetonitrile (2 mL) under an atmosphère of nitrogen at room température. The mixture was stirred at room température overnight. The solvents were evaporated and the residue was purified by prep-HPLC to provide 5 mg (13%) of the title compound as a purple solid. LCMS m/z 475 [M+H].

Step 3: N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-1 H-indol-5-yl)-4methylpiperidine-1-sulfonamide. 4-methylpiperidine (8 mg, 0.08 mmol) was added to a solution of N-(3-(1 -(cyclopentanecarbonyi)piperidin-4-yl)-1-methyl-1 H-tndol-5-yl)-2oxooxazoltdine-3-sulfonamide (4 mg. 0.01 mmol) and triethylamine (12 pl, 0.08 mmol) in MeCN (1.5 mL) under an atmosphère of nitrogen at room température. The mixture was stirred at 70 °C overnight. After filtration through a syringe filter, purification was done by prep-HPLC to provide 2 mg (49%) of the title compound as a white powder. ¹H NMR (500 MHz, (CD₃OD) δ ppm 7.48 (d, 1H, J=1.9Hz), 7.25 (d, 1H, J=8.7Hz), 7.07 (dd, 1H, J=8.7,

124

1.9Hz), 6.98 (s, 1H), 4.65 (m, 1H), 4.20 (m, 1H), 3.72 (s, 3H), 3.65 (m, 2H), 3.09 (m, 2H), 2.81 (m, 1 H), 2.65 (m, 2H), 2.11 (m, 1 H), 2.04 (m, 1 H), 1.92-1.56 (m, 12H), 1.34 (m, 2H), 1.03 (m, 2H) and 0.85 (d, 3H, J=6.5Hz). LCMS m/z487 [M+H].

Example 94

Préparation of 3-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1,4-dimethyl1H-pyrrolo[2,3-b]pyridin-5-yl)benzamîde

Step 1: 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. 4-chloro-1Hpyrrolo[2,3-b]pyridine (5.25 g, 34 mmol), benzenesulfonyl chloride (6.6 mL, 52 mmol), triethylamine (5.2 mL, 38 mmol) and N.N-dimethylpyridin-4-amine (420 mg, 3.4 mmol) were mixed and stirred at room température for 2 h. The mixture was washed with 1 M HCl followed by saturated NaHCO₃ (aq), filtered through a phase separator. The organic phase was evaporated, and the residue was triturated with 2-propanol to give 7.76 g (77%) of the title product. MS m/z 293 [M+H].

Step 2: 4-chloro-5-nitro-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridine. To an ice cold solution of 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.0 g, 17 mmol) in dichloromethane (60 mL) was added dropwise under stirring a solution of tetrabutylammonium nitrate (7.8 g, 26 mmol) in dichloromethane (30 mL). When addition was complété, a solution of trifluoroacetic anhydride (3.6 mL, 26 mmol) in dichloromethane (30 mL) was added dropwise under stirring. After complété addition, the reaction mixture was stirred at 0 °C for another 30 minutes, then at room température ovemight. The mixture was washed with water, the phases were separated. The organic phase was dried, filtered, and evaporated, and the residue was recrystallized from dichloromethane methanol to provide 3.2 g (55%) of the title compound. MS m/z 338 [M+H].

125

Step 3:4-Methyl-5-nitro-1-(phenylsulfonyi)-1 H-pyrrolo[2,3-b]pyridine. To a solution of 4“Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-d]pyridine (3.45 g, 10 mmol) and tetrakis triphenylphosphine palladium (0.18 g, 0.15 mmol) in dioxane (12 mL) under nitrogen was added a solution of trimethylaluminum in toluene (2 M, 5.1 mL, 10 mmol) and the mixture was heated to 130 °C for 30 minutes in a microwave reactor. CAUTION: fast buildup of pressure when heating. The mixture should be heated at the slowest possible setting. After cooling to room température, the reaction mixture was poured on ice (200 mL). CAUTION: exothermic réaction! The mixture was extracted twice with dichloromethane, the organic phase was dried by filtration through a phase separator, the solvent was evaporated and the residue was recrystallized from dichloromethane - éthanol to give 2.54 g (78%) of the title product. LCMS: m/e 318 [M+H].

Step 4: 4-Methyl-5-nitro-1 H-pyrrolo[2,3-b]pyridine. A mixture of 4-methyl-5-nitro-1(phenylsulfonyl)-l H-pyrroIo[2,3-b]pyridine (4.89 g, 15.4 mmol), potassium carbonate (4.26 g, 30.8 mmol) and morpholine (13.4 mL, 154 mmol) in methanol (150 mL) was refluxed for 10 minutes, then quickly cooled in an ice bath. The solvent was evaporated and the residue was slurrled in chloroform (100 mL), ammonium chloride (saq, 100 mL) and water (25 mL). The mixture was magnetically stirred for 15 minutes, then left standing tn a refrigerator at 3 °C over the weekend. The mixture was then filtered through a glass Bûchner funnel (P3) and the precipitate was washed with water and chloroform, then dried under vacuum. The precipitate was the title compound (2.61 g, 96%). LCMS: m/e 178 [M+H],

Step 5: 3-lodo-1,4-dimethyl-5-nitro-1 H-pyrrolo[2,3-b]pyridine. To a stirred suspension of the 4-methyl-5-nltro-1 H-pyrrolo[2,3-b]pyridine (200 mg, 1.13 mmol) in a 2:1 mixture of 2-methyltetrahydrofuran and 99.7% EtOH (9 mL) at rt, was added KOH (pellets, 203 mg, 3.61 mmol). The mixture was stirred at rt for 10 min. lodine (573 mg, 2.26 mmol) was then added, and stirring was continued at room température for 25 min. Potassium carbonate (780 mg, 5.64 mmol) and rodomethane (0.70 mL, 11.3 mmol) were added and stirring at room température was continued for 2.5 h. 10% aqueous sodium bisulfite (10 mL) was added dropwise which led to a precipitate between the organic and the aqueous phase. After complété addition the mixture was stirred at room température for 30 minutes, then filtered through a glass Bûchner funnel and the precipitate was washed with water and

126 dried under vacuum to provide 315 mg (88%) of the pure title compound. LCMS: m/e 318 [M+H].

Step 6: tert-Butyl 4-(1,4-dimethyl-5-nitro-1 H-pyrrolo[2,3-d]pyridin-3-yl)-5,6dihydropyridine-1(2H)-carboxylate. To a mixture of 3-iodo-1,4-dimethyl-5-nitro-1HPyrrolo[2,3-i)]pyridine (145 mg, 0.46 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (184 mg, 0.59 mmol), potassium carbonate (126 mg, 0.91 mmol), and Pd EnCat™ TPP30 (palladium acetate and triphenylphosphine, microencapsuled in polyuria matrix, 0,4mmol Pd/g, 1.0/0.8 Pd/TPP; 35 mg) under nitrogen was added dimethoxyethane (2.7 mL), éthanol (0.7 mL), and water (0.7 mL) and the mixture was stirred at 60 °C overnight. The mixture was poured into water and extracted with chloroform, the phases were separated with a phase separator, the organic phase was evaporated and the residue was purified by column chromatography (mobile phase: 1% methanol in dichloromethane) to provide 150 mg (88%) ofthe title compound. LCMS: m/e 373 [M+H],

Step 7: tert-Butyl 4-(5-amino-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1carboxylate. A mixture of tert-butyl 4-(1,4-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)5,6-dihydropyridine-1 (2H)-carboxylate (200 mg, 0.54 mmol), ammonium formate (406 mg, 6.4 mmol), and 5 % Palladium on active carbon (30 mg) in éthanol (10 mL) were stirred at 85 °C over a weekend. The reaction mixture was filtered through a Teflon fil ter, the solvent was evaporated, the residue was dissolved in dichloromethane and washed with sodium bicarbonate (saq), filtered through a phase separator, the organic phase was evaporated to give the title compound, used as such in the next step (yield not determined), LCMS: m/e 345 [M+H],

Step 8: tert-Butyl 4-(5-(3-cyanobenzamido)-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-3yl)piperidine-1-carboxylate. To an ice cold solution of tert-butyl 4-(5-amino-1,4-dimethyl1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxyIate (185 mg, 0.54 mmol) was added triethylamine (225 pL, 1.61 mmol) followed by 3-cyanobenzoyl chloride (116 mg, 0.70 mmol). The ice bath was removed and the mixture was stirred at room température overnight. Water was added and the mixture was extracted with dichloromethane. After filtration through a phase separator the organic phase was evaporated and the residue was purified by préparative HPLC (sunfire column, 25 mL/min, 20 -> 100 % acetonitrile, 0.05%

127 formic acid (aq), 40 minutes gradient time) to provide 65 mg (26%) of the title compound. LCMS: m/e 474 [M+H].

Step 9: 3-Cyano-N-(1,4-dimethyl-3-(piperidin-4-yl)-1 H-pyrrolo[2,3-i)]pyridin-5yl)benzamide. To a solution of tert-butyl 4-(5-(3-cyanobenzamido)-1,4-dimethyl-1 Hpyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate(50 mg, 0.11 mmol) In dichloromethane (1.5 mL) was added trifluoroacetic acid (81 pL, 1.06 mmol) and the mixture was stirred at room température for 2 h. The solvents were evaporated to provid 39 mg (100%) of the title compound. LCMS m/z 374 [M+H].

Step 10: 3-Cyano-N-(3-(1-(cyclopentanecarbonyI)piperidin-4-yl)-1,4-dimethyl-1 Hpyrrolo[2,3-b]pyridin-5-yl)benzamide. To a solution of 3-cyano-N-(1,4-dimethyl-3-(piperidin4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (20 mg, 0.06 mmol) in dimethylformamide (0.5 mL) was added cyclopentanecarbonyl chloride (14 mg, 0.11 mmol) and triethylamine (29 pL, 0.21 mmol) and the mixture was stirred at room température overnight. The mixture was injected into a préparative HPLC (sunfire column) and eluted according to the following: 25 mL/min, 20 -> 50 % acetonitrile, 0.05% formic acid (aq), 30 minutes gradient time to provide 11.4 mg (46%) of the title compound as a white solid. ¹H NMR (500 MHz, (CD₃)₂CO) δ ppm 8.45 (s, 1H), 8.39 (d, 1H, J=7.7Hz), 8.20 (s, 1H), 8.01 (d, 1H, J=7.8Hz), 7.78 (t, 1H, J=7.8Hz), 7.24 (s, 1 H), 4.71 (d, 1 H, J=12.6Hz), 4.20 (d, 1H, J=13.1Hz), 3.80 (s, 3H), 3.34 (m, 1 H), 3.24 (m, 1 H), 3.05 (m, 1 H), 2.68 (m, 1 H), 2.64 (s, 3H), 2.12 (d, 1 H, J=12.7Hz), 2.03 (d, 1H, J=13.8Hz) and 1.84-1.44 (m, 10H). LCMS m/z470 [M+H].

Example 95

Préparation of (fî)-3-Cyano-N-(1,4-dimethyl-3-(1 -(4,4,4-trifluoro-3hydroxybutanoyl)piperidin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-5-yl)benzamide

128

To a solution of 3-cyano-N-(1,4-dimethyl-3-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-

5-yl)benzamide (20 mg, 0.06 mmol) in dimethylformamide (0.5 mL) was added (fï)-4,4,4trifluoro-3-hydroxybutanoic acid (17 mg, 0.11 mmol), 0-(7-azabenzotriazol-1-yl)-/V,N,/V,A/'tetramethyluronium hexafluorophosphate (40 mg, 0.11 mmol) and diisopropylethylamine (35 pL, 0.21 mmol) and the mixture was stirred at room température overnight. The mixture was injected into a préparative HPLC (sunfire column) and eluted according to the following: 25 mL/min, 20 -> 50 % acetonitrile, 0.05% formic acid (aq), 30 minutes gradient time to provide 13.7 mg (50%) of the title compound as a white solid. ¹H NMR (500 MHz, (CD₃)₂CO) Ô ppm 8.22 (s, 1 H), 8.05 (d, 1 H, J=7.9Hz), 7.83 (d, 1 H, J=7.9Hz), 7.62 (t, 1 H, J=7.9Hz), 6.95 (s, 1H), 4.76 (m, 1 H), 4.48 (m, 1H), 3.94 (m, 1 H), 3.81 (s, 3H), 3.24 (m, 2H), 2.77-2.69 (m, 3H), 2.58 (s, 3H), 2.09 (m, 2H) and 1.58 (m, 2H). MS m/z514 [M+H].

Exampfe 96

Assay of co-activator recruitment by TR-FRET

The activity of compound of the invention can be determined by a co-activator recruitment by TR-FRET (time-resolved fluorescence résonance energy transfer) assay. In general, the assay is based on the interaction between N-terminally Six-Histidine-taggedRORC2 ligand binding domain (6-His-RORC2 LBD), expressed in E. coli and purified by affinity chromatography, and biotin-coactivator peptide SRC1-2 (biotin-aminohexanoic acidCPSSHSSLTERHKILHRLLQEGSPS-NH2; SEQ ID NO: 1) containing the LXXLL consensus domain which is responsible for receptor binding. This interaction is detected by addition of Europium labeled-anti-His antibody (Ex. 337 nm, Em. 620 nm, which binds to 6Hîs) and Streptavidin-APC (Ex. 620 nm, Em. 665 nm, which binds to biotin). When receptor and coactivator are bound to each other, upon shining light at 337 nm on the sample, the Europium emîts fluorescence that excites APC due to close proximity (FRET) and this signal is measured at 665 nm. Due to the long lasting fluorescence émission of Europium, the non-specific, short-lived fluorescence is time-resolved (TR) from the fluorescence of interest. Inhibitors of the interaction of receptor and coactivator peptide are detected by a decrease in TR-FRET signal.

Specifically, in one embodiment the aforementioned assay was performed as outlined below. The assay was carried out in black polystyrène, 384-well plates in a total assay volume of 50.5 pL. The assay buffer contaîned 50 mM TRIS-HCL pH 7.5,1 mM

129

NaCI, 2 mM MgCl_a, 0.5 mg/mL bovine sérum albumin, and 5 mM dithiothreitol. The final concentration of reagents was 6.3 nM RORC2 LBD, 200 nM S RC 1-2, 50 nM streptavidin APC, 1 nM Europium-labeled anti-His antibody, and varying concentrations of compounds such that final concentration of DMSO is 1% (v/v). The assay steps were: (1) dispensing 5 500 pL compound at 10Ox final concentration in DMSO (test wells) or DMSO only (control wells for no inhibition); and (2) dispensing 50 pL mixture of the other assay components including receptor (test wells) or excluding receptor (control wells for maximal inhibition).

Assay mixtures were incubated are room température for 3 hours and read in EnVision 2100 Multilabel Reader (PerkinElmer Life Sciences) at Excitation Filter 320, io Emission Europium Filter 615, Emission APC Filter 665, Dîchroic Mirror D400/D630.

TR-FRET signal was determined by calculating the ratio of 665 nm by 615 nm and )C₅o values of compounds of the invention were determined by the non-linear régression analysis of dose response curves.

Référencés which relate to theabove-referenced assay include: Kallen étal.

Structure, 2002, 10,1697-1707; Stehlin étal. EMBOJ2QQA, 20, 5822-5831; and Zhou et al. Mol Endocrinol 1998, 12, 1594-1604.

Example	RORC2 FRET IC_S0(nM)
1	5.8
2	17.9
3	386.9
4	590.3
5	105.9
6	4.2
7	3.4

Table 1. RORC2 FRET Data

Example	RORC2 FRET IC₅₀(nM)
8	7.3
9	8.7
10	42.9
11	34.6
12	24.3
13	19.8
14	79.6

Example	RORC2 FRETIC₅₀(nM)
15	15.9
16	131.8
17	53.4
18	26.1
19	40.6
20	246
21	1436

130

Example	RORC2 FRET IC₅₀(nM)
22	384
23	334
24	246
25	31.6
26	87.0
27	1417
28	88.1
29	56.2
30	14.3
31	121.3
32	35.5
33	7.6
34	100
35	21.6
36	295
37	34.1
38	910
39	53.9
40	380
41	327
42	953
43	1026

Example	RORC2 fretic₅₀(nM)
44	624
45	3461
46	1447
47	3406
48	211
49	1381
50	1427
51	871
52	1108
53	124
5454	8.0
55	18.2
56	638
57m, 1H), 1.90-1.50 (m, 12H). Example 57	756
58	256
59	330
60	216
61	335
62	425
63	193

Example	RORC2 FRET IC₅₀(nM)
64	5.8
65	37.3
66	7.0
67	11.4
68	6.5
69	270
70	7.2
71	23.9
72	127.9
73	67.7
74	53.0
75	14.7
76	22.9
n	50.5
7878	1074
79	199
80	259
81	335
82	3958
8383	23.4
84	214
85	859

131

Example	RORC2 FRET IC50 (nM)
86	>20000
87Hz), 2.11 -1.45 (1 H, m). Example 87	>20000

Example	RORC2 FRET IC₅₀(nM)
88	5
89	14.2
90	13.9
91	9.8

Example	RORC2 FRET IC_S0(nM)
92	10.5
93	4.9
94	13.1
95	46.8

Example 97

Assay of Gal4-RORC2 activity by luciferase reporter

The activity of compound of the invention can be also be determined by a luciferase reporter Gal4-RORC2 activity assay. In general, Neuro2A ceils (murine neuroblastoma cell line obtained from HPACC, cat #89121404) are transiently transfected with a mammalian expression vector (pM) containing Gal4-RORC2 LBD and a Gal4-responsive reporter gene containing firefly luciferase (5xGAL4(JAS-Luc3). Gal4-RORC2 LBD is constitutively active in the transfected Neuro2a cells, resulting in a robust luciferase response in the absence of stimulation. Upon treatment with an RORC2 inhibitor the transcriptional response is decreased and the magnitude of the decrease in response is dose-dependently related to the intrinsîc efficacy of the inhibitor.

Specifically, the growth medium was composed by MEM EBS w/o L-glutamine, 10% (v/v) FBS, 2 mM L-glutamine and 1x non-essential aminoacid (NEAA); the seeding medium was composed by MEM EBS w/o L-glutamine, w/o phénol red, 4% (v/v) FBS, 2 mM Lglutamine, 1x NEAA, 1% Penicillin (10,000 U/mL)/Streptomycin (10,000 pg/mL); and the assay medium was composed by MEM EBS w/o L-glutamine, w/o phénol red, 4% (v/v) FBS, 2 mM L-glutamine, 1x NEAA, 1% Penicillin (10 000 U/mL)/Streptomycin (10 000 pg/mL). In addition, Neuro2A cells were cultured in growth medium in humidified chambers at 37°C and 5% CO2 using standard tissue culture procedures.

On day one of the assay, cells were seeded and transfected. Specifically, Neuro2A cells were suspended in seeding medium and mixed with plasmids and transfection reagent which

132 was dissolved in OptiMEM I reduced sérum medium (InVitrogen), and then seeded to 384-well plates (Corning, Black, Clear bottom) in 40 pL/well containing 12,500 cells, 17,25 ng Gal4Luc3, 5,75 ng either empty pM vector (‘no receptor control' wells) or pM-Ga!4RORgammaLBD, and 0,11 μΙ_ Lipofectamine2000.

On day two of the assay, the cells were treated with compounds of the invention. Specifically, the treatment was started 20-24 hours after seeding and transfection of the cells. Compounds of the invention were serially diluted in a 384-well polypropylene plate with assay medium containing 0.5% (v/v) DMSO at 5x final assay concentration. 10 μΙ_ of the compounds (or 0.5% DMSO in assay medium for ‘no compound control’ wells) were transferred from the dilution plate to the 384-format cell plate such that final assay volume was 50 pL and final DMSO concentration was 0.1 % (v/v), followed by incubation for 20-24 hours in humidified chambers at 37°C and 5% CO₂

On day three of the assay, luminescence was measured and the results analyzed. Specifically, 10 pL of SteadyLite Plus reagent (Perkin Elmer) was added to each well. The cell 15 plates were incubated at room température for 15 min in the dark before reading of luminescence on the MicroBeta Trilux (Wallac). IC₅₀ values of the compounds tested was determined by the non-linear régression analysis of dose response curves.

References which relate to the above-referenced assay include: Stehlin-Gaon étal. Nature Structural Biology 2003, 10, 820-825; Wang et al. J Biol Chem. 2010, 285(7), 501320 5025; Kumar et al. Mol Pharmacol. 2010, 77(2), 228-36.

Example 98

Assay of IL-17 Production from human Thl7 cells

The activity of compound of the invention can be also be determined by an IL-17 production from human Th17 cells assay. In general, this assay measures blockade of IL-17 production, the signature cytokine of T helper 17 (Th17) cells, by compounds. Purified human CD4+ T cells are stimulated with anti-CD3 + anti-CD28 and incubated with a cytokine cocktail that induce their différentiation into Th17 in the absence or presence of various concentrations

133 of compound. After 6 days, IL-17A concentration is measured in the cell culture supernatant with an ELISA kit (MSD).

Préparation of human CD4+ Tcells. CD4+ T cells were purified from buffy coats from healthy donors (obtained from Massachusetts General Hospital) by négative sélection the following procedure: Mixing 25 mL of blood with 1 mL of Rosette Sep CD4+ T cell enrichment cocktail (StemCell Technologies) followed by application of a layer of 14 mL Ficoll Paque Plus (Amersham GE Heaithcare) and subséquent centrifugation at 1200 g for 20 min at room température. The Ficoll layer was then harvested and washed with phosphate saline buffer containing 2% (v/v) fêtai bovine sérum and cells were resuspended with R PMI medium containing 10 % (v/v) fêtai bovine sérum and 10% (v/v) DMSO, frozen and kept in LN2 until used.

On the first day of the assay, a vial containing 10⁷ CD4+ T cells is thawed rapidly in 37°C water bath, immediately transferred into 20 mL X-Vivo 15 medium (Lonza), is spun for 6 min at 300xg, the supernatant is discarded, and the resulting pellet is re-suspended at 10⁶cells/mL in 50 mL fresh X-Vivo 15 medium, followed by storage ovemight in a tissue culture vessel in a humidified chamber at 37°C and 5% CO₂. Serial dilutions of compounds of the invention are prepared at 10x final concentration in X-Vivo15 medium containing 3% (v/v) DMSO.

On the second day of the assay, a 384-well tissue culture plate was coated with 10 pg/mL anti-hCD3 (eBioscience) at 50 pUwell. After 2 hours at 37°C, the supernatant is discarded and the coated plates are kept in a stérile tissue culture hood.

Cytokine plus antî-CD28 cocktail is prepared by mixing 25 ng/mL hlL-6 (Peprotech), 5 ng/mL hTGFbetal (Peprotech), 12.5 ng/mL IL-1beta (Peprotech), 25 ng/mL hlL-21,25 ng/mL hlL-23 (R&D Systems), and 1 ug/mL anti-hCD28 (eBioscience) in X-Vivo 15 medium. The cytokine plus anti-CD28 cocktail with CD4+ cells is prepared such that the cocktail is diluted 10-fold and cell density is 0.22 x 10^e/mL. The mixture is incubated 1 hour at 37°C.

|it (20,000 cells) dispensed per well in the anti-hCD3 coated plate prepared as noted above.

134

10uL 10x compound is added per well (final DMSO=0.3%) from the compound plate that was previousiy prepared, followed by 6 days of incubation in a tissue culture vessel in a humidified chamber at 37°C and 5% CO2.

On day six of the assay, production of IL-17A in 10 uL of the supernatant is determined by sandwich ELISA using 384w hiL17 MSD plates following the manufacturées protocol. Measurement is carried out in a Sector Imager 6000 by the same manufacturer. Signal units from the instrument are converted to pg/mL using a calibration curve with known amounts of IL-17A. IC50 values of test compounds are determined by the non-linear régression analysis of dose response curves.

A reference which relates to the above-referenced assay is: Yang et al. Nature 2008, 454, 350-352.

Example 99

Inhibition of Superantigen-induced Th17 cytokine production

Exotoxins called ‘‘superantigens are among the most powerful T cell activators. Superantigens bind to the cell surface of major histocompatibilty complex (MHC) molécules, without intracellular processing. They stimulate T cells via the T cell receptor, irrespective of the antigen specificitles. Therefore, bacterial superantigens are able to activate a large pool of CD4+ as well as CD8+ T cells in contrast to the low T cell frequency for conventional antigens. CD4+ T cells can be classified into various subsets (ThO, Th1, Th2, Th17) based on their respective cytokine sécrétion profiles. ThO cells are uncommitted naïve precursor cells that prîmarily produce lL-2 upon stimulation. ThO cells upon activation can differentiate into Th1, Th2, or the Th17 subset depending on the local cytokine milieu. Th1 cells mainly produce lnf-y; Th2 cells, IL-4, IL-5, and IL-13, and Th17 cells, IL-17, and IL-22. During a classical immune response, the différentiation of T helper subset occurs over days, or longer. In the superantigen in-vivo model in mice injection of superantigen triggers a rapid transcription and translation of the various cytokines (i.e. IL-2, IL-4, lnf-γ, IL-17) ofthe different Th subsets after only 6 hours. A RORyt inhibitor given to animais prior to the superantigen stimulus would impair the Th17 cytokine profile without affecting the cytokine profile of the other Th subsets (ThO, Th1, Th2). The model uses approximately 8 week old C57BU6, Balb/c, or C3H/HeJ mice which are dosed orally with compound 1 to 2 hours prior to superantigen injection on the day of

135 the experiment (Day 0) based on the pharmacokinetic (PK) profile of the compound. An optional dose may be given the day before superantigen injection (Day -1) to further inhibit the response if necessary. C57BL/6 and Balb/c mice will be sensitized 1 hour prior to supematigen injection with approximately 25 mg/mouse D-Galactosamine intraperitoneally (C3H/HeJ mice do not need to be sensitized). Based on the literature superantigen is typically given at 10 pg/mouse intraperitoneally. Mice will be sacrificed at 3 hours for RNA analysis or up to 6 hours for cytokine analysis.

A reference which relates to the above-referenced assay is: Rajagopalan, G. et. al. Physiol Genomics 2009, 37, 279.

Example 100

Imiquimod Assay

Commercially available 5% imiquimod (IMQ) cream (3M Pharmaceuticals) is applied to the back and right ear of each experimental mouse for two consecutive days. Control mice are treated similarly with a commercially available vehicle cream. The experimental mice are then administered with RORyt inhibitors, and the control mice with vehicle, for 4 days. The ear thickness is measured on ail days by digital micrometer (Mitutoyo). Tissues, such as ears and speens, are harvested on Day 5 for RNA analysis. Ear swelling and sérum measurements are also made.

References describing aspects of this assay include: Van der Fits, L. et al. J. Immunol. 2009, 182(9), 5836-45; Van Belle, A.B. étal. JImmunol. 2012, 188(1), 462-9; Cai, Y. étal. Immunity 2011, 35(4), 596-610; Fanti, P.A. et al. Int. J. Dermatol. 2006, 45(12), 1464-5; Swindell, W.R. et al. PLoS One 2011,6(4), e18266; and Roller, A. étal. J. Immunol. 2012, 189(9), 4612-20.

INCORPORATION BY REFERENCE

Ail publications, patents and patent applications mentioned in this spécification are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

Claims

We daim:

A compound of Formulae I, II, III, IV, V, VI or Vil:

or a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof, wherein,

Y is hydrogen, halo, cyano, (CrC₃)alkyl, (C_rC₃) hydroxyalkyl, (CvCsJalkenyl, (CiC₃)haloalkyl, (C_rC₃) hydroxyhaloalkyl, (C₃-C₆)cycloalkyl, (C_rC₃)alkoxy or (CrC₃)haloalkoxy;

R is hydrogen, (Ci-C₆)alkyl, (C_rC₆)hydroxyalkyI or (CvCeJhaloalkyl;

137

R² is (CrC₆)alkyl, (C₃-Ca)cycloalkyl, (C₃-C₈)heterocycloalkyl, aryl or heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Cj-C^alkyl, (Ci C₄)haloalkyl, (C_rC₄)cyanoalkyl, hydroxyl, -OR, (Ci-C₄)hydroxyalkyl, (C_rC₄)hydroxyalkoxy, (Ci-C4)hydroxyalkoxy(C_rC₄)alkyl, (C_rC₄)alkoxy, (CrCLOalkoxyfC,C₄)aikyl, (C₁-C₄)alkoxy(C_l-C₄)alkoxy, (Ci-C₄)alkoxy(C_rC₄)aJkoxy(Ci-C₄)alkyl, (C_rC4)haloalkoxy, -NR₂, (R₂N)(Ci-C₄)alkyl-, (CrC^alkylthio, (CrC^haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH_aN(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂, -N(R)S(=O)₂R, -A and -CH₂A;

R is independently selected for each occurrence from the group consisting of hydrogen, (C₁-C₄)alkyl, (CrC^haloalkyi, (C_rC₄)cyanoalkyl, (C₁-C4)hydroxya)kyl, (C₃-C₀)cycloalkyl or (C₃-C₀)heterocycloalkyl; or where a nitrogen is substituted with two R groups they may be taken together with the nitrogen atom to which they are attached to form a 4-, 5-, 6- or 7-membered saturated (C₃-C₈)heterocycloalkyl which, when so formed, may be optionally substituted with one, two or three substituents independently selected from the group consisting of (C_rC₄)alkyI, halo, hydroxyl, (C_rC₄)hydroxyalkyl, (C_rC₄)cyanoalkyl, (CrC₄)haloalkyl and =0;

A is independently selected for each occurrence from the group consisting of (C₃-C_B)cycloalkyl, (Qj-CBjheterocycloalkyl, aryl and heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (C_rC₄)alkyl, (C_rC₄)haloalkyl, (C,C₄)cyanoalkyl, hydroxyl, ((^-C^hydroxyalkyl, (C_rC₄)alkoxy, (C_rC₄)alkoxy(Ci-C₄)alkyl, (C_rC₄)haloaIkoxy, -NR₂, (RsNXCrC^alkyl-, (CvC^alkylthio, (CvC^haloalkylthio, -C(=0)R, -C(=O)OR, -OC(=O)R, -C(=0)NR₂, -N(R)C(=0)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR₂ and -N(R)S(=O)_ZR;

138

with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, (C_rC₆)alkyl, (CrCgJhydroxyalkyl and (Ο_νCejhaloalkyl;

R³ is (Ci-Cejalkyl, (C3-Cs)cycloalkyl, (C3-C0)heterocycloalkyl, aryl, heteroaryl, -C(=O)R⁴, -C(=O)OR⁴, -C(=O)N(R^s)
2 or -S(=O)₂R⁴, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alkyl, (CrC^haloalkyl, (Ci-C₄)cyanoalkyl, hydroxyl, (C_vC₄)hydroxyalkyl, (C_rC₄)alkoxy, (C_rC₄)alkoxy(Ci-C₄)alkyl, (C_rC₄)haIoalkoxy, -NR₂, (R₂N)(Ci-C₄)alky|-, (CrC₄)alkylthio, (C_rC₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R. -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR₂₁ -CH₂N(R)C(=O)R, -S(=O)₂R, -S(=O)₂NR_2i -N(R)S(=O)₂R, -a and -CH₂A;

R is hydrogen, (Ci-Cejalkyi, (C₃-C₃)cycloalkyl, (Ca-Cajheterocycloalkyl, (C₃C₀)cycloalkyl(Ci-C6)alkyl, (C₃-C₈)heterocycIoalkyl(Ci-C₆)aJkyl, aryl or heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (C_f-C₄)alkyl, (CiC₄)haloalkyl, (Ci-C₄)cyanoalkyl, hydroxyl, (CvC^hydroxyalkyl, (CrCiJalkoxy, (C_rC6)alkoxy(CrC₆)alkyl, (C_vC₆)haloalkoxy, -NR₂, (R₂N)(C₁-C₆)alkyl, (CrCeJalkylthio, (C_rC₆)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)OR, -CH₂OC(=O)R, -CH₂C(=O)NR_2i -CH₂N(R)C(=O)R, ’S(=O)₂R, -S(=O)₂NR_a, -N(R)S(=O)₂R, -A and -CH₂A; and

R⁵ is independently selected for each occurrence from the group consisting of hydrogen, (Gi-Cejalkyl, (C₃-Ce)cycloalkyl, (C₃-C8)heterocycloalkyl, (C₃-C_a)cycIoalkyl(Ci-C₆)alkyl, (C
3-C₈)heterocycloalkyl(Ci-C₆)alkyl, aryl and heteroaryl, optionally substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, cyano, (Ci-C₄)alkyl, (CiC₄)haloalkyl, (CrC^cyanoalkyl, hydroxyl, (C_rC₄)hydroxyalkyl, (CrC₄)alkoxy, (Ct

139

C₄)alkoxy(Ci-C₄)alkyl, (CrC^haloalkoxy, -NR₂, (R₂N)(C_rC₄)alkyl-, (CrC₄)alkylthio, (C_rC₄)haloalkylthio, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NR₂, -N(R)C(=O)R, -CH₂C(=O)R, -CH₂C(=O)0R, -CH₂OC(=O)R, -CH₂C(=O)NR₂, -CH₂N(R)C(=O)R, *S(=O)₂R, -S(=O)₂NR₂, -N(R)S(=O)₂R, -A and -CH₂A; or where a nitrogen is substituted with two R⁵ groups may be taken together with the nitrogen atom to which they are attached to form a
4-, 5-, 6- or 7-membered saturated C₃._aheterocycloalkyl which, when so formed, may be optionally substituted with one, two or three substituents independently selected from the group consisting of (Ci-C₄)alkyl, halo, hydroxyl, (Ci-C₄)hydroxyalkyl, (C_rC₄)haloalkyl and =O.

The compound of claim 1, wherein the compound is represented by Formula I or Formula II, or pharmaceutically acceptable salts, pharmaceutically active métabolites, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvatés thereof. The compound of claim 2, wherein R¹ is hydrogen or methyl.

The compound of claim 3, wherein Y is hydrogen or methyl.
5. The compound of any one of daims 1 -4, wherein X is
6. The compound of any one of daims 1 -4, wherein X is
7. The compound of any one of daims 1-4, wherein X is
8. The compound of any one of daims 1 -7, wherein W is substituted with one, two, three, four or five substitutents independently selected for each occurrence from the group consisting of halo, (C_rC₆)alkyl, (Ci-C₆)hydroxyalkyl and (Ci-C₆)haloalkyl.

140
9.
10.

H-( N—R³

The compoundof any one of claims 1 -7, wherein W is ? '—; and R³ is

-C(=O)R⁴.

The compound of any one of claims 1-7, wherein W is selected from the group

141
12. A pharmaceutical composition comprising a compound according to any one of daims 1-11, or a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof, admixed with a pharmaceutically acceptable carrier, excipient or dilutant.
13. Use of a compound any one of daims 1 -11, or a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof, admixed with a pharmaceutically acceptable carrier, excipient or dilutant in the manufacture of a pharmaceutical composition for inhibiting RORC2.
14. Use of a compound any one of daims 1-11, or a pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof, admixed with a pharmaceutically acceptable carrier, excipient or dilutant in the manufacture of a pharmaceutical composition for treating an immune disorder or inflammatory disorder.

142
15. The use of claim 14, wherein the disorder is an inflammatory disorder.
16. The use of claim 14, wherein the disorder is an autoimmune disorder.
17. The use of claim 14, wherein the disorder is 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, cartilage inflammation, bone dégradation, arthritis, juvénile arthritis, juvénile rheumatoid arthritis, pauciarticular juvénile rheumatoid arthritis, polyarticular juvénile rheumatoid arthritis, systemic onset juvénile rheumatoid arthritis, juvénile ankylosing spondylitis, juvénile enteropathic arthritis, juvénile Reter's Syndrome, SEA Syndrome, juvénile dermatomyositis, juvénile psoriatic arthritis, juvénile scleroderma, juvénile systemic lupus erythematosus, juvénile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, dermatomyositis, psoriatic arthritis, vasculitis, myolitis, poliomyelitis, dermatomyolitis, osteoarthritis, polyarteritis nodossa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopie dermatîtis, atherosclerosis, Still’s disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Type l diabètes mellitus, Graves' disease, Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, érythrodermie psoriasis, an immune disorder associated with or arising from activity of pathogenic lymphocytes, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, érythrodermie psoriasis, noninfectious uveitis, Behcet's disease or Vogt-KoyanagiHarada syndrome.
18. A compound or pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof according to anyone of claims 1-11 for use in medicine.
19. A compound or pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof according to anyone of claims 1-11, or a pharmaceutical composition of daim 12, for use in treating or ameliorating an immune disorder or inflammatory disorder mediated by RORC2 and/or IL-17.

143
20. The use of claim 19, wherein the disorder is an inflammatory disorder.
21. The use of claim 19, wherein the disorder is an autoimmune disorder.
22. The use of claim 19, wherein the disorder is rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple scîerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopénie thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, epidermal hyperplasia, cartilage inflammation, bone dégradation, arthritis, juvénile arthritis, juvénile rheumatoid arthritis, pauciarticular juvénile rheumatoid arthritis, polyarticular juvénile rheumatoid arthritis, systemic onset juvénile rheumatoid arthritis, juvénile ankylosing spondylitis, juvénile enteropathic arthritis, juvénile Reteris Syndrome, SEA Syndrome, juvénile dermatomyositis, juvénile psoriatic arthritis, juvénile scleroderma. juvénile systemic lupus erythematosus, juvénile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reter’s Syndrome, dermatomyositis, psoriatic arthritis, vasculitis, myolitis, polymyolitis, dermatomyolitis, osteoarthritis, polyarteritis nodossa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, scîerosis, primary biliary scîerosis, sclerosing cholangitis, dermatitis, atopie dermatitis, atherosclerosis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Type I diabètes mellitus, Graves' disease, Addison’s disease, Raynaud's phenomenon, autoimmune hepatitis, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, érythrodermie psoriasis, an immune disorder associated with or arising from activity of pathogenic lymphocytes, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, érythrodermie psoriasis, noninfectious uveitis, Behcet’s disease or Vogt-Koyanagi-Harada syndrome.
23. A compound or pharmaceutically acceptable sait, pharmaceutically active métabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof according to any one of claims 1-11 for use in combination with another pharmaceutical agent.