WO2020035556A1

WO2020035556A1 - Novel heteroaromatic modulators of the retinoid-related orphan receptor gamma

Info

Publication number: WO2020035556A1
Application number: PCT/EP2019/071908
Authority: WO
Inventors: Kristoffer Maansson; Krister Henriksson
Original assignee: Leo Pharma A/S
Priority date: 2018-08-17
Filing date: 2019-08-15
Publication date: 2020-02-20

Abstract

The present invention relates to a compound according to general formula (I). The invention further relates to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds and to intermediates for preparation of said compounds.

Description

NOVEL HETEROAROMATIC MODULATORS OF THE RETINOID-RELATED ORPHAN RECEPTOR GAMMA

FIELD OF THE INVENTION

This invention relates to compounds which are ROR-gamma (RORy) modulators, to intermediates for the preparation thereof, to said compounds for use in therapy and to pharmaceutical compositions comprising said compounds and to methods of treating diseases with said compounds.

BACKGROUND OF THE INVENTION

The Retinoic acid-related orphan receptor (ROR) gene family is part of the nuclear hormone receptor super-family and consists of three members ROR alpha, ROR beta and ROR gamma (RORa, RORp and RORy). Each ROR gene is expressed in different isoforms; the isoforms differ in their pattern of tissue-specific expression and can regulate distinct physiological processes and target genes. More specifically two isoforms of RORy have been identified; RORyl and RORy2 (known as RORyt). RORyl is expressed in multiple tissues, such as heart, brain, kidney, lung, liver and muscle; whereas RORyt is restricted to the cells of the immune system and is expressed in lymphoid organs, such as the thymus (Jetten, A. M.; Adv. Dev. Biol. (2006), 16, 313-355).

RORyt has been shown to be crucial for the development of T helper 17 cells (T_H17 cells) (Ivanov et.a I., Cell (2006), 126, 1121-1133). T_H17 cells, which produce IL-17, IL-21 and IL-22, have an essential role in the development of many autoimmune and inflammatory disorders, such as multiple sclerosis, psoriasis and rheumatoid arthritis. (Betelli, E. et al., Nature Immunol. (2007), 8, 345-350; Fouser, L. et al. Immunol. Rev. (2008), 226, 87-102); suggesting that development of RORy modulators may be beneficial for treatment of autoimmune and inflammatory diseases (Kojetin, D. et al.; Nature Rev Drug Discovery (2014) 13, 197-215).

Recently, Proof-of-Concept was shown with an oral RORyt inhibitor (VTP 43742) in a Phase 2a clinical trial in psoriatic patients.

Several other compounds modulating RORyt have been reported, for example;

WO2015/159233 discloses 'Aryl and heteroaryl ether compounds as ROR gamma modulators';

W02016/020295 and W02016/020288 disclose Optionally fused heterocyclyl- substituted derivatives of pyrimidine useful for the treatment of diseases';

WO2017/ 102784 discloses 'Isoindoles';

W02018/030550 discloses 'Heterocyclic compounds with an ROR(gamma)T modulating activity'. Thus it is desirable to provide compounds that modulate the activity of RORy for use in the treatment of autoimmune and inflammatory disorders.

SUMMARY OF THE INVENTION

The inventors have surprisingly found that novel compounds of the present invention exhibit modulating effect on ROR-gamma, such as inverse agonist effect, and may be useful as therapeutic agents for diseases mediated by ROR-gamma, including

autoimmune or inflammatory diseases such as psoriasis, psoriatic arthritis, multiple sclerosis, rheumatoid arthritis, Crohns disease, ulcerative colitis, alopecia areata, contact dermatitis, including irritative contact dermatitis and allergic contact dermatitis, spondyloarthritis; and cancers, including prostate cancer and non-small cell lung cancer.

Compounds of the present invention may have favorable pharmacokinetic and pharmacodynamic properties such as favorable oral bioavailability, solubility, absorption and metabolic stability or a favorable toxicity profile.

Compounds of the present invention may have low clearance in human liver microsomes thus making them suitable for oral use; or compounds of the present invention may have high clearance in human liver microsomes thus making them suitable for topical use as they may have reduced systemic side-effects while retaining the topical anti- inflammatory efficacy.

Accordingly, the present invention relates to a compound according to general formula

(I)

wherein

Ri is selected from the group consisting of (Ci-C4)alkyl, (C3-C5)cycloalkyl, halo(Ci- C4)alkyl, halo(C3-C5)cycloalkyl and -NR_aR_b, wherein R_a and R_b each independently represents hydrogen, (Ci-C4)alkyl, (C3-C5)cycloalkyl, halo(Ci-C4)alkyl or halo(C₃- C5)cycloalkyl; R₂ is selected from the group consisting of HC(O)-, (Ci-C₄)alkyl-C(0)-, (C3-C5)cycloalkyl- C(O)-, (Ci-C₄)alkoxy-(Ci-C₄)alkyl-C(0)- and (C₃-C₅)cycloalkyl(Ci-C₄)alkyl-C(0)-, wherein said (Ci-C₄)alkyl-C(0)-, (C₃-C₅)cycloalkyl-C(0)-, (Ci-C₄)alkoxy-(Ci-C₄)alkyl-C(0)- and (C₃-C₅)cycloalkyl(Ci-C₄)alkyl-C(0)- are optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano;

R3 is selected from the group consisting of (Ci-C4)alkyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkyl(Ci-C4)alkyl and (Ci-C4)alkyl(C3-C7)cycloalkyl, wherein said (Ci-C4)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(Ci-C4)alkyl and (Ci-C4)alkyl(C3-C7)cycloalkyl are optionally substituted with one or more halogen; and

R4 is selected from the group consisting of halogen, cyano, (Ci-C4)alkyl, (Ci- C4)alkoxy(Ci-C4)alkyl, (C3-C7)cycloalkyl and (Ci-C4)alkoxy, wherein said (Ci-C4)alkyl, (Ci-C4)alkoxy(Ci-C4)alkyl, (C3-C7)cycloalkyl and (Ci-C4)alkoxy is optionally substituted with one or more halogen;

Xi, X₂, X₃ and X₄ each independently represents CH or N, with the proviso that at least one of Xi, X₂, X₃ or X₄ represents N;

Yi and Y₂ each independently represents CH or N; or pharmaceutically acceptable salts, solvates or hydrates thereof.

In another aspect, the invention relates to a compound of general formula (I) for use as a medicament.

In yet another aspect, the invention relates to a compound of general formula (I) for use in treatment of autoimmune or inflammatory diseases.

In yet another aspect, the invention relates to a pharmaceutical composition comprising a compound according to general formula (I) together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s).

In yet another aspect, the invention relates to a method of preventing, treating or ameliorating psoriasis, the method comprising administering to a person suffering from psoriasis an effective amount of one or more compounds according to general formula (I), optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds. DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term "hydrocarbon radical" is intended to indicate a radical containing only hydrogen and carbon atoms, and it may comprise cyclic moieties, branched or linear moieties or combinations thereof. The term includes alkyl and cycloalkyl, as indicated herein. The number of carbon atoms in a hydrocarbon radical is indicated by the prefix "(C_a-C_b)", wherein a is the minimum number and b is the maximum number of carbons in the hydrocarbon radical. The number of carbon atoms in a hydrocarbon radical may also be indicated by the prefix "(C_c-C_d)", wherein c is the minimum number and d is the maximum number of carbons in the hydrocarbon radical. Thus, for example, (Ci- C₄)alkyl is intended to indicate an alkyl radical comprising from 1 to 4 carbon atoms and (C3-C7)cycloalkyl is intended to indicate a cycloalkyl radical comprising from 3 to 7 carbon ring atoms.

The terms "(C_a-C_b)alkyl" or "(C_c-C_d)alkyl" is intended to indicate a radical obtained when one hydrogen atom is removed from a branched or linear hydrocarbon. Said (C_a-C_b)alkyl or "(C_c-C_d)alkyl" comprises (Ci-C₄)alkyl, (Ci-C3)alkyl such as (C2-C3)alkyl or such as (Ci-C2)alkyl. The term includes the subclasses normal alkyl (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert. -butyl.

The term " (C_a-C_b)alkyl-(C_c-C_d)cycloalkyl" is intended to indicate a (C_a-C_b)alkyl radical appended to the parent molecular moiety through a (C_c-C_d)cycloalkyl group, as defined herein. The term comprises for example methylcyclopropyl and methylcyclobutyl.

The terms "(C_a-C_b)alkyloxy" and "(C_a-C_b)alkoxy" are intended to indicate a radical of the formula -OR, wherein R is (C_a-C_b)alkyl as indicated herein, wherein the (C_a-C_b)alkyl group is appended to the parent molecular moiety through an oxygen atom, e.g.

methoxy (-OCH₃), ethoxy (-OCH₂CH₃), n-propoxy, isopropoxy, butoxy, tert- butoxy, and the like.

The term "(C_a-C_b)alkyloxy(C_c-C_d)alkyl" " is intended to indicate a (C_a-C_b)alkyloxy radical appended to the parent molecular moiety through an (C_c-C_d)alkyl group, as defined herein, e.g. methoxymethyl.

The term "cyano" is intended to indicate a -CN group attached to the parent molecular moiety through the carbon atom. The term "(C_a-C_b)cycloalkyl" or "(C_c-C_d)cycloalkyl" is intended to indicate a saturated cycloalkane hydrocarbon radical, comprising from a to b carbon atoms or from c to d carbon atoms, such as (C3-C7)cycloalkyl, (C3-C6)cycloalkyl, (C3-C5)cycloalkyl, (C3- C4)cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

The term "(C_a-C_b)cycloalkyl(C_c-C_d)alkyl" is intended to indicate a (C_a-C_b)cycloalkyl radical appended to the parent molecular moiety through an (C_c-C_d)alkyl group, as defined herein; e.g. cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl or cyclopentylmethyl.

The term "halo(C_a-C_b)alkyl" is intended to indicate a (C_a-C_b)alkyl group as defined herein substituted with one or more independently selected halogen atoms as defined herein, , e.g. fluoro or chloro, such as difluoromethyl or trifluoromethyl.

The term "halo(C_a-C_b)cycloalkyl" is intended to indicate a (C_a-C_b)cycloalkyl group as defined herein substituted with one or more independently selected halogen atoms as defined herein, e.g. fluoro or chloro, such as difluorocyclopropyl and difluorocyclobutyl.

The term "halogen" is intended to indicate a substituent from the 7^th main group of the periodic table, such as fluoro, chloro and bromo.

The term "oxo" is intended to indicate an oxygen atom which is connected to the parent molecular moiety via a double bond (=0).

When two or more of the above defined terms are used in combination, such as cycloalkylalkyl and the like, it is to be understood that the first mentioned radical is a substituent on the latter mentioned radical, where the point of attachment to the parent molecular moiety is on the latter radical.

The group -C(O)- is intended to represent a carbonyl group (C=0).

If substituents are described as being independently selected from a group, each substituent is selected independently of the other. Each substituent may therefore be identical or different from the other substituent(s).

The term "optionally substituted" means "unsubstituted or substituted", and therefore the general formulas described herein encompasses compounds containing the specified optional substituent(s) as well as compounds that do not contain the optional

substituent(s). The term "pharmaceutically acceptable salt" is intended to indicate salts prepared by reacting a compound of formula I, which comprise a basic moiety, with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, 2,2-dichloroacetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D-glucuronic, methanesulfonic, salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane-1, 2-disulfonic, 2-hydroxy ethanesulfonic acid, toluenesulfonic, sulfamic, fumaric and ethylenediaminetetraacetic acid. Pharmaceutically acceptable salts of compounds of formula I comprising an acidic moiety may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, ammonia or the like, or suitable non-toxic amines, such as lower alkylamines, hydroxy-lower alkylamines, cycloalkylamines, or benzylamines, or L- arginine or L-lysine. Further examples of pharmaceutical acceptable salts are listed in Berge, S.M.; J. Pharm. Sci.; (1977), 66(1), 1-19, which is incorporated herein by reference.

The terms "ROR gamma" and "RORy" are used to describe RORyl and/or RORyt

The term "solvate" is intended to indicate a species formed by interaction between a compound, e.g. a compound of formula I, and a solvent, e.g. alcohol, glycerol or water, wherein said species are in an amorphous or in a crystalline form. When water is the solvent, said species is referred to as a hydrate.

The term "treatment" as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the amelioration, alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition. The term includes prevention of the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects.

Unless otherwise indicated, all exact values provided herein are representative of corresponding approximate values, e.g. exact exemplary values provided with respect to a particular measurement can be considered to also provide a corresponding

approximate measurement, modified by "about" where appropriate. All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference, regardless of any separately provided incorporation of particular documents made elsewhere herein.

Embodiments of the invention

The compounds of formula I may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a cosolvent that may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline forms, such as polymorphs and pseudopolymorphs, and also mixtures thereof.

Compounds of formula I may comprise asymmetrically substituted (chiral) carbon atoms which give rise to the existence of isomeric forms, e.g. enantiomers and possibly diastereomers. The present invention relates to all such isomers, either in optically pure form or as mixtures thereof (e.g. racemic mixtures or partially purified optical mixtures). Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of procedures known in the art. The various isomeric forms may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. high pressure liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts which may be formed with optically active acids. Optically purified compounds may subsequently be liberated from said purified diastereomeric salts. Enantiomers may also be resolved by the formation of

diastereomeric derivatives. Alternatively, enantiomers may be separated by

chromatographic techniques using chiral stationary phases. Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the

appropriate starting materials, provided that the reaction occur stereoselectively or stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chiral pure starting materials.

In the compounds of general Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of general Formula I. For example, different isotopic forms of hydrogen include *H, ²H and ³H, different isotopic forms of carbon include ¹²C, ¹³C and ¹⁴C and different isotopic forms of nitrogen include ¹⁴N and ¹⁵N. Enriching for deuterium (²H) may for example increase in-vivo half-life or reduce dosage regiments, or may provide a compound useful as a standard for characterization of biological samples. Isotopically enriched compounds within general formula (I) can be prepared by conventional techniques well known to a person skilled in the art or by processes analogous to those described in the general procedures and examples herein using appropriate isotopically enriched reagents and/or intermediates.

In one or more embodiments of the present invention, the compounds of general formula (I) as defined above are useful in therapy and in particular for use in the treatment of psoriasis.

In one or more embodiments of the present invention, the compounds of general formula (I) as defined above are useful in treatment of a disease, disorder or condition, which disease, disorder or condition is responsive of modulation of ROR-gamma.

In one or more embodiments of present invention provides a pharmaceutical

composition comprising a compound according to general formula (I) together with one or more other therapeutically active compound(s) together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s).

In one or more embodiments of the present invention, the compounds of general formula (I) are useful in the manufacture of a medicament for the prophylaxis, treatment or amelioration of autoimmune or inflammatory diseases.

In one or more embodiments of the present invention, the compounds of general formula (I) are useful in the manufacture of a medicament for the prophylaxis, treatment or amelioration of psoriasis.

In one or more embodiments of the present invention, the compounds of general formula (I) are useful in a method of preventing, treating or ameliorating autoimmune or inflammatory diseases or conditions, the method comprising administering to a person suffering from at least one of said diseases an effective amount of one or more compounds according to according to general formula (I), optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

Besides being useful for human treatment, the compounds of the present invention may also be useful for veterinary treatment of animals including mammals such as horses, cattle, sheep, pigs, dogs, and cats.

Pharmaceutical

of the Invention

For use in therapy, compounds of the present invention are typically in the form of a pharmaceutical composition. The invention therefore relates to a pharmaceutical composition comprising a compound of formula I, optionally together with one or more other therapeutically active compound(s), together with a pharmaceutically acceptable excipient, vehicle or carrier(s). The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Conveniently, the active ingredient comprises from 0.0001-50 % by weight of the formulation.

In the form of a dosage unit, the compound may be administered one or more times a day at appropriate intervals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner. Conveniently, a dosage unit of a formulation contain between 0.001 mg and 1000 mg, preferably between 0.01 mg and 250 mg, such as 50-200 mg of a compound of formula I.

A suitable dosage of the compound of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician. The compound may be administered either orally, parenterally, topically, transdermally or interdermally + other routes according to different dosing schedules, e.g. daily, weekly or with monthly intervals. In general a single dose will be in the range from 0.001 to 400 mg/kg body weight. The compound may be administered as a bolus (i.e. the entire daily dose is administered at once) or in divided doses two or more times a day.

In the context of topical treatment it may be more appropriate to refer to a "usage unit", which denotes a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid, semisolid or liquid pharmaceutical diluents or carriers.

The term "usage unit" in connection with topical use means a unitary, i.e. a single dose, capable of being administered topically to a patient in an application per square centimetre of the treatment area of from 0.001 microgram to 1 mg and preferably from 0.05 microgram to 0.5 mg of the active ingredient in question.

It is also envisaged that in certain treatment regimes, administration with longer intervals, e.g. every other day, every week, or even with longer intervals may be beneficial.

If the treatment involves administration of another therapeutically active compound it is recommended to consult Goodman & Gilman's The Pharmacological Basis of

Therapeutics, 12^th Ed., L. L. Brunton (Ed.), McGraw-Hill 2010, for useful dosages of said compounds.

The administration of a compound of the present invention with one or more other active compounds may be either concomitantly or sequentially.

The formulations include e.g. those in a form suitable for oral, rectal, parenteral

(including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous), transdermal, intradermal, ophthalmic, topical, nasal, sublingual or buccal administration.

The formulations may conveniently be presented in dosage unit form and may be pre- pared by but not restricted to any of the methods well known in the art of pharmacy, e.g. as disclosed in Remington, The Science and Practice of Pharmacy, 22nd ed., 2013. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the formula- tions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier, semisolid carrier or a finely divided solid carrier or combinations of these, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral and buccal administration may be in the form of discrete units as capsules, sachets, tablets, chewing gum or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder, granules or pellets; in the form of a solution or a suspension; or in the form of a gel, a nano- or microemulsion, an oil-in-water emulsion, a water-in-oil emulsion or other dispensing systems. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural surfactants and viscosifying agents. The active ingredients may also be administered in the form of a bolus, electuary or paste.

A tablet may be made by compressing, moulding or freeze drying the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient(s) in a free-flowing form such as a powder or granules, optionally mixed by a binder and/or filler; a lubricant; a disintegrating agent or a dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent. Freeze dried tablets may be formed in a freeze- dryer from a solution of the drug substance. Suitable filler can be included.

Formulations for rectal administration may be in the form of suppositories in which the compound of the present invention is admixed with low melting point, water soluble or insoluble solids.

Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic with the blood of the recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution. Furthermore, the formulation may contain cosolvent, solubilising agent and/or complexation agents. Liposomal formulations as disclosed in e.g. Encyclopedia of Pharmaceutical Technology, vol.9, 1994, are also suitable for parenteral administration.

Alternatively, the compounds of formula I may be presented as a sterile, solid

preparation, e.g. a freeze-dried powder, which is readily dissolved in a sterile solvent immediately prior to use.

Transdermal formulations may be in the form of a plaster, patch, microneedles, liposomal or nanoparticulate delivery systems or other cutaneous formulations applied to the skin.

Formulations suitable for ophthalmic administration may be in the form of a sterile aque- ous preparation of the active ingredients, which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems e.g. as disclosed in Encyclopedia of Pharmaceutical Technology, vol.2, 1989, may also be used to present the active ingredient for ophthal- mic administration.

Formulations suitable for topical, such as dermal, intradermal or ophthalmic admi- nistration include liquid or semi-solid preparations such as liniments, lotions, gels, applicants, sprays, foams, film forming systems, microneedles, micro- or nano- emulsions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.

For topical administration, the compound of formula I may typically be present in an amount of from 0.001 to 20% by weight of the composition, such as 0.01% to about 10 %, but may also be present in an amount of up to about 100% of the composition.

Formulations suitable for nasal or buccal administration include powder, self-propelling and spray formulations, such as aerosols and atomisers. Such formulations are disclosed in greater detail in e.g. Modern Pharmaceutics, 2^nd ed., G.S. Banker and C.T. Rhodes (Eds.), page 427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3^th ed., G.S. Banker and C.T. Rhodes (Eds.), page 618-619 and 718-721, Marcel Dekker, New York and Encyclopedia of Pharmaceutical Technology, vol. 10, J. Swarbrick and J.C. Boylan (Eds), page 191-221, Marcel Dekker, New York.

In addition to the aforementioned ingredients, the formulations of a compound of formula I may include one or more additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, penetration enhancing agents, solubility enhancing agents preservatives, e.g. methyl hydroxybenzoate (in- cluding anti-oxidants), emulsifying agents and the like.

The pharmaceutical composition may additionally comprise one or more other active components conventionally used in the treatment of autoimmune or inflammatory diseases such as psoriasis, psoriatic arthritis, multiple sclerosis, rheumatoid arthritis, crohns disease, alopecia areata, contact dermatitis, spondyloarthritis; and cancers.

METHODS OF PREPARATION

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of synthesis. The compounds of formula I may for example be prepared using the reactions and techniques outlined below together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art. Not all compounds falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used. The compounds of the present invention or any intermediate may be purified if required using standard methods well known to a synthetic organist chemist, e.g. methods described in "Purification of Laboratory Chemicals", 6^th ed. 2009, W. Amarego and C. Chai, Butterworth-Heinemann. Starting materials are either known compounds, commercially available, or they may be prepared by routine synthetic methods well known to a person skilled in the art.

GENERAL PROCEDURES, PREPARATIONS AND EXAMPLES

The following schemes illustrate the preparation of compounds of the formula I, throughout which Ri - R₄, Xi - X₄, Yi - Y₂, are as described above:

Exemplified heterocyclic compounds can be accessed through either one of the two general routes described below (Scheme 1, Scheme 1.1)

General preparation of intermediates is described in schemes 2-6 below.

Scheme 1

Step a, amide coupling.

Scheme 1.1

Step b, protecting group deprotection; Pg represents a nitrogen protecting group. Step c, isoindoline amine substitution.

Scheme 2

Step d, Reductive amination

Step e, SNAr coupling; X represents C or N

Step f, Nitro reduction. Scheme 3

Step g, amide coupling Scheme 4

Step h, amide coupling.

Step i, protecting group deprotection; Pg represents a nitrogen protecting group.

Scheme 5

Step j, SNAr coupling.

Step k, Nitro reduction.

Scheme 6

XIX

Step I, SNAr coupling.

Step m, hydrolysis.

Step n, Curtius rearrangement.

Step o, Boc deprotection.

Detailed processes to the compounds of the specification are further described in the examples below.

*H nuclear magnetic resonance (NMR) spectra were recorded at 300 MHz or 600 MHz instruments. Chemical shift values (5, in ppm) are quoted relative to internal

tetramethylsilane (5 = 0.00) standards. The value of a multiplet, either defined doublet (d), triplet (t), quartet (q) or not (m) at the approximate midpoint is given unless a range is quoted, (br s or bs) indicates a broad singlet, whilst (s) indicates a singlet and (2s) indicates a singlet split up in to rotamers. Mixture of rotamers (X* : l) is the ratio in which a particular compound is shown to exist as amide rotamers by NMR spectroscopy. All NMR spectra are recorded in DMSO-d₆ unless another solvent is stated.

The organic solvents used were usually anhydrous. The solvent ratios indicated refer to vohvol unless otherwise noted.

LCMS Method :

Column: Acquity UPLC HSS T3 1.8pm; 2.1 x 50mm

Flow: 0.7ml/min

Column temp: 40°C

Mobile phases: A: 10 mM Ammonium acetate + 0.1% formic acid

B: 100% Acetonitrile + 0.1% formic acid

UV: 240-400 nm Injection volume: 2pl

Gradient: Time A% B%

0.0 99% A 1% B

0.5 94% A 6% B

1.0 94% A 6% B

2.6 5% A 95% B

3.8 5% A 95% B

3.81 99% A 1% B

4.8 99% A 1% B

UPLC (inlet method): XE Metode 7 CM

MS - method : PosNeg_50_1000

Instruments: Waters Acquity UPLC, Waters LCT Premier XE

List of Abbreviations

AcOH acetic acid

AcCI acetyl chloride

BOC tert-butyloxycarbonyl n-BuOH normal butanol

CAN Ceric ammonium nitrate

CDI l,l'^_carbonyldiimidazole

DCM dichloromethane

DMF dimethylformamide

DMSO dimethylsulfoxide

DPPA diphenylphosphoryl azide

EtOAc ethyl acetate

EtOH ethanol

FA Formic acid

HCI hydrogen chloride

Hunig's base diisopropylethylamine I PA propan-2-ol

K₂C0₃ potassium carbonate KI potassium iodide

UAIH4 lithium aluminium hydride

LiOH lithium hydroxide

UOH.H2O lithium hydroxide hydrate MeCN acetonitrile

MeOH methanol

Na₂C03 sodium carbonate

Pd palladium

SFC Supercritical fluid chromatography

SNAr nucleophilic aromatic substitution

T3P 2,4,6-Tripropyl-l,3,5,2,4,6- trioxatriphosphorinane-2, 4, 6-trioxide solution >50 wt. % in ethyl acetate

TEA triethylamine

TFA trifluoro acetic acid

THF tetrahydrofuran

The compounds described in this specification are further illustrated in the following Examples. Chemical names are preferable IUPAC names which were generated using Accelrys draw 4.0.

PREPARATIONS AND EXAMPLES

Preparation 1: [2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5- yl]azinate

2-Chloro-5-Nitropyrimidine (0.978 g, 6.13 mmol) was added to a solution of N- Cyclopropylamine-4-(Trifluoromethyl)-Benzylamine (1.20 g, 5.58 mmol) in

tetrahydrofuran (100 mL). To this mixture was added diisopropylethylamine (3.84 mL, 27.6 mmol). The resulting reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated to dryness under reduced pressure. The crude product dissolved in small amount of acetonitrile was added water dropwise until crystallisation occurs. The formed crystals was collected by filtration to give the title compound as a colorless solid. (1.57 g, 83.0%).

1H NMR (600 MHz, DMSO-d6) d 9.25 (s, 1H), 9.14 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H),

7.43 (d, J = 8.0 Hz, 2H), 5.06 (s, 2H), 3.02 - 2.98 (m, 1H), 0.95 - 0.85 (m, 2H), 0.80 - 0.74 (m, 2H). Preparation 2: N2-cyclopropyl-N2-[[4-(trifluoromethyl)phenyl] methyl] pyrimidine-2, 5- diamine

Iron powder (4.67 g, 83.6 mmol) was added to a solution of nitro compound from Preparation 1 (1.57 g, 4.63 mmol) in acetic acid (30 ml_). The reaction mixture was stirred for 15 min at 50° C, then filtered through a pad of Celite^® and washed with acetic acid. The acetic acid solution was diluted with methanol to app. Cone, of 2M. This was loaded to an Isolute™ SCX catridge (4xl0g). The SCX was flushed with methanol and the product eluted with 2M ammonia in methanol. The methanolic ammonia was evaporated under reduced pressure to afford title compound as brown solid. (1.19 g, 69.0%).

1H NMR (600 MHz, DMSO-d6) d 7.91 (s, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.82 (s, 2H), 4.60 (s, 2H), 2.63 - 2.58 (m, 1H), 0.77 - 0.69 (m, 2H), 0.57 - 0.51 (m, 2H). LCMS: m/z 309.2 [M + H⁺].

Preparation 3: N-cyclopropyl-5-nitro-N-[[4-(trifluoromethyl)phenyl]methyl]pyridin-2- amine

2-Chloro-5-Nitropyridine (307 mg, 1.94 mmol) was added to a solution of N- Cyclopropylamine-4-(Trifluoromethyl)-Benzylamine (416 mg, 1.94 mmol)

diisopropylethylamine (0.675 ml_). The resulting reaction mixture was stirred at 75°C for 2 h. The mixture was concentrated to dryness under reduced pressure. The crude product dissolved in small amount of acetonitrile was added water dropwise until crystallisation occurs. The formed crystals was collected by filtration to give the title compound as a yellow solid, (1.57 g, 83.0%).

1-H NMR (600 MHz, DMSO-d6) d 8.97 (d, J = 2.8 Hz, 1H), 8.37 (dd, J = 9.5, 2.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 9.5 Hz, 1H), 5.07 (s, 2H), 2.83 -2.77 (m, 1H), 1.01 - 0.92 (m, 2H), 0.80 - 0.74 (m, 2H). Preparation 4: N2-cyclopropyl-N2-[[4-(trifluoromethyl)phenyl] methyl] pyridine-2, 5- diamine

Iron powder (1.62 g, 29.1 mmol) was added to a solution of nitro compound from Preparation 3 (560 mg, 1.66 mmol) in acetic acid (15 ml_). The reaction mixture was stirred for 30 min at 50° C, then filtered through a pad of Celite^® and washed with acetic acid. The acetic acid solution was diluted with MeOH to app. Cone, of 2M. This was loaded to an Isolute™ SCX cartridge (4xl0g). The SCX was flushed with methanol and the product eluted with 2M ammonia in methanol. The methanolic ammonia was evaporated under reduced pressure. The obtained residue was purified by silica gel (100-200 mesh) column chromatography eluting with a gradient of 10-100% ethyl acetate with 4%(2M NH^/MeOH) in heptane. Clean fractions were evaporated under reduced pressure to give the title compound as a purple oil. (1.19 g, 69.0%).

1H NMR (600 MHz, DMSO-d6) d 7.60 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 2.7 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 6.96 (dd, J = 8.8, 2.9 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.79 (s, 2H), 4.49 (s, 2H), 2.38 - 2.33 (m, 1H), 0.81 - 0.75 (m, 2H), 0.57 - 0.51 (m, 2H).

Preparation 5: 2-acetyl-5-methylsulfonyl-isoindoline-l-carboxylic acid

To solution of 5-methylsulfonylisoindoline-l-carboxylic acid hydrochloride (6.2 g, 22.38 mmol) in dichloromethane (100 ml_), triethyl amine (9.4 ml_, 67.14 mmol) and acetic anhydride (2.1 ml_, 22.38 ml.) was added at 0°C. Resulting reaction mass was stirred at 0°C for 30 mins. On completion, diluted with water (150 ml.) and washed with dichloromethane (2 x 100 mL). Aqueous layer was concentrated under reduced pressure. The crude product was washed with 10% MeOH/CH₂Cl2, and solid was dried under vacuum to afford the title compound (3.0 g, 47%) as an off white solid.

^JH NMR (400 MHz, DMSO -d₆) d ppm 13.5 (bs,l H) 7.98 - 7.94 (d, J=8.10 Hz, 1 H) 7.91 (d, J=8.14 Hz, 1 H) 7.71 - 7.62 (m, 1 H) 5.87-5.54 (s, 1 H) 5.03-4.83 (m, 2 H) 3.20 (s, 3 H) 1.96 - 2.13 (s, 3 H); LCMS (ESI): m/z 284 [M + H⁺], Preparation 6: (lR)-2-acetyl-5-methylsulfonyl-isoindoline-l-carboxylic acid

(3.0g, 10.6 mmol) of Preparation 5 was purified by preparative SFC as follows:

Column/dimensions Lux Amylose-2 (30x250 mm), 5m

Mobile phase 0.2% TFA in n-HEXANE: Ethanol (45: 55)

Flow 42.0 ml/min

Temperature Ambient

Wave length 280nm

Run time 20 mins

Load/Inj 43.4 mg

Solubility Ethanol+CAN

On SFC purification afforded (1.4g, 47%) of the title compound (peak-1 as first eluting peak) as Brown solid.

NMR (400 MHz, DMSO -cfe) d ppm 7.94 - 7.98 (d, J=8.10 Hz, 1 H) 7.91 (d, J=8.14 Hz, 1 H) 7.62 - 7.71 (m, 1 H) 5.54-5.87 (m, 1 H) 4.83-5.03 (m, 2 H) 3.20 (s, 3 H) 1.96 - 2.13 (s, 3 H). LCMS (ESI): m/z 284 [M + H⁺]; 93%; RT = 2.34 min; (AQUITY UPLC BEH C18 column, 0.05% TFA in water with MeCN) and Chiral

HPLC~89.5% SFC METHOD: Column : Lux Amylose-2 (30x250 mm), 5m, Mobile phase-A: 0.2% TFA in n-HEXANE, Mobile phase-B: Ethanol Isocratic of (A: B): 50: 50, flow rate : 1.0 mL/min, Diluent : Ethanol, RT: 9.70 min.

Preparation 7: (lS)-2-acetyl-5-methylsulfonyl-isoindoline-l-carboxylic acid

(3.0g, 10.6 mmol) of Preparation 5 was purified by preparative SFC as follows:

Column/dimensions Lux Amylose-2 (30x250 mm), 5m

Mobile phase 0.2% TFA in n-HEXANE: Ethanol (45: 55)

Flow 42.0 ml/min

Temperature Ambient

Wave length 280nm

Run time 20 mins

Load/Inj 43.4 mg

Solubility Ethanol+CAN On SFC purification afforded (1.4g, 47%) of the title compound (peak-2 as second eluting peak) as Brown solid. ¹ NMR (400 MHz, DMSO -de) d ppm 7.94 - 7.98 (d, J=8.10 Hz, 1 H) 7.91 (d, J=8.14 Hz, 1 H) 7.62 - 7.71 (m, 1 H) 5.54-5.87 (s, 1 H) 4.83-5.03 (m, 2 H) 3.20 (s, 3 H) 1.96 - 2.13 (s, 3 H). LCMS (ESI): m/z 284 [M + H + ]; 91%; RT = 2.34 min; (AQUITY UPLC BEH C18 column, 0.05% TFA in water with MeCN) and Chiral HPLC~86% SFC METHOD: Column : Lux Amylose-2 (30x250 mm), 5m, Mobile phase-A: 0.2% TFA in n-HEXANE, Mobile phase-B: Ethanol Isocratic of (A: B): 50: 50, flow rate :

1.0 mL/min, Diluent : Ethanol, RT: 21.2 min.

Preparation 8: [5-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]-2- pyridyl]azinate

To a stirred solution of 5-fluoro-2-nitropyridine (1.5 g, 1.056 mmol) in Ethanol (30 mL) was added DIPEA (3.8 mL, 31.69 mmol) and Cyclopropylamine-4-(Trifluoromethyl)- Benzylamine (3.4 g, 15.84 mmol) at room temperature. Resulting reaction mass was stirred at 100°C for 16 h in a sealed tube. On completion, Reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). Combined organic layer was dried over Na₂S0₄ and concentrated under reduced pressure to afford the titled compound (1.2 g, 34%) as a yellow solid.

LCMS (ESI): m/z 338 [M + H⁺].

Preparation 9: N5-cyclopropyl-N5-[[4-(trifluoromethyl)phenyl] methyl] pyridine-2, 5- diamine

To a stirred solution of Compound from Preparation 8 (1.2 g, 3.26 mmol) and 10% Pd/C (200 mg) in methanol (35 mL) was stirred under H₂ atm (balloon pressure) at RT for 16 h. On completion, the reaction mixture was filtered through Celite pad and washed with methanol. Then filtrate was concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (0-5% MeOH in CH2CI2 as eluent) to afford the titled compound (700 mg, 64%) as a brown gummy.

1H NMR (400 MHz, DMSO-d6) d 7.65-7.62 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 7.15 (dd, J = 8.8 Hz, 2.8 Hz 1H) 6.37 (d, 8.8 Hz 1H), 5.21 (s, 2H), 4.50 (s, 1H) 0.77 - 0.73 (m,

2H), 0.52 - 0.48 (m, 2H). LCMS (ESI): m/z 308 [M + H⁺].

Preparation 10: tert-butyl (lR)-l-[[5-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]-2-pyridyl]carbamoyl]-5-methylsulfonyl- isoindoline-2-carboxylate

(lR)-2-tert-butoxycarbonyl-5-methylsulfonyl-isoindoline-l-carboxylic acid (15 mg, 0.0439 mmol) was added to a solution of the amine from Preparation 9 (14.9mg, 0.048mmol) in ethyl acetate (0.15 ml_). Temperature was lowered to 10° C and pyridine (0.0391 ml_, 0.048 mmol) followed by 2,4,6-Tripropyl-l,3,5,2,4,6- trioxatriphosphorinane-2, 4, 6-trioxide solution >50 wt. % in ethyl acetate ( 0.039 ml_, 0.066 mmol). The resulting reaction mixture was stirred for lh letting temperature increase to room temperature. The mixture was diluted with ethyl acetate, washed with citric acid. The combined organic layers was concentrated under reduced pressure. The obtained residue was purified by basic preparative HPLC. Clean fractions were

concentrated under reduced pressure to give the title compound as a white solid. (5 mg, 19.6%). LCMS: m/z 631.2 [M + H⁺].

Preparation 11: (lR)-N-[5-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]-2- pyridyl]-5-methylsulfonyl-isoindoline-l-carboxamide

Trifluoroacetic acid (1 mL) was added to a solution of product from Preparation 10 (5 mg, 0.009 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. Trifluoroacetic acid was azeotroped using toluene to afford the title compound as an off white solid. (4 mg, 100%). LCMS: m/z 531.2 [M + H⁺]. Preparation 12: methyl 5-[cyclopropyl-[[4- (trifluoromethyl)phenyl]methyl]amino]pyrazine-2-carboxylate

To solution of methyl 5-chloropyrazine-2-carboxylate (5 g, 28.96 mmol) in n-Butanol (50 ml.) was added diisopropylamine (16 ml_, 86.9 mmol) and N-[[4- (trifluoromethyl)phenyl]methyl]cyclopropanamine (6.2 g, 28.96 mmol) at room temperature. Resulting reaction mixture was stirred at 80°C for 16 h. On completion, n- Butanol was concentrated under reduced pressure, diluted with water (150 ml.) and extracted with ethyl acetate (2 x 150 mL). Combined organic layer was dried over Na₂S04 and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (20-50% EtOAc in Hexane as eluent) to afford the title compound (4.6 g, 45%) as a brown solid.

^NMR (DMSO-d6, 300 MHz): d (ppm) 8.68 (d, J = 1.10 Hz, 1 H) 8.58 (d, J = 1.10 Hz, 1 H) 7.66 (d, J = 7.70 Hz, 2 H) 7.41 (d, J = 8.07 Hz, 2 H) 4.99 (s, 2 H) 3.83 (s, 3 H) 2.88 - 2.84 (m,l H) 1.03- 0.95 (m, 2 H) 0.83 - 0.75 (m, 2 H); LCMS (ESI): m/z 351 [M⁺].

Preparation 13: 5-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrazine-2- carboxylic acid

To a solution of Preparation 12 (4.6 g, 13.09 mmol) in tetrahydrofuran (65 mL) and water (65 mL) was added. Lithiumhydroxide hydrate (2.74 g, 65.48 mmol) was added portion wise at room temperature. The reaction mixture was stirred at ambient temperature for lh. On completion, the reaction mixture was concentrated under reduced pressure. The residue obtained was acidified (pH~5-6) with citric acid solution and extracted with ethyl acetate (2 x 150 mL). Combined organic layer was dried over Na₂S04 and concentrated under reduced pressure to afford the title compound (4.5 g; crude) as an off-white solid. ^NMR (DMSO-d6, 300 MHz): d (ppm) 12.68 (bs, 1 H) 8.66 (s, 1 H) 8.57 (s, 1 H) 7.66 (d, J = 8.07 Hz, 2 H) 7.41 (d, J = 8.07 Hz, 2 H) 4.99 (s, 2 H) 2.83-2.86 (m, 1 H) 0.99 (d, J = 5.14 Hz, 2 H) 0.72 - 0.82 (m, 2 H); LCMS (ESI): m/z 338 [M + H⁺].

Preparation 14: tert-butyl N-[5-[cyclopropyl-[[4- (trifluoromethyl)phenyl]methyl]amino]pyrazin-2-yl]carbamate

To a solution of Preparation 13 (3 g, 8.902 mmol) in t-Butanol (30 ml.) at room temperature was added drop wise Diphenylphosphoryl azide (1.9 ml_, 8.902 mmol) and triethylamine (2.43 ml_, 17.804 mmol) at room temperature. Resulting reaction mass was stirred at 100°C for 16 h. On completion, the crude reaction mass was diluted with water (50 ml.) and extracted with ethyl acetate (2 x 50 ml_), then combined organic layer was washed with brine (50 ml_) respectively. Resulting organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (20-50% EtOAc in Hexane as eluent) to afford the title compound (300 mg, 8%) as an brown gummy.

^JH NMR (CDCL3, 400 MHz): d (ppm) 8.70 (br s, 1 H) 8.09 (d, J = 1.55 Hz, 1 H) 7.51 (d,

J = 8.11 Hz, 2 H) 7.32 (d, J = 7.99 Hz, 2 H) 6.84 (d, J = 1.07 Hz, 1 H) 4.89 (s, 2 H) 2.49 - 2.54 (m, 1 H) 1.52 (s, 9 H) 0.90 - 0.95 (m, 2 H) 0.70-0.75 (m, 2 H); LCMS (ESI): m/z 409 [M + H⁺].

Preparation 15: N5-cyclopropyl-N5-[[4-(trifluoromethyl)phenyl]methyl]pyrazine-2,5- diamine

To a stirred solution of Preparation 14 (150 mg, 0.367 mmol) in dichloromethane (3 mL) at 0°C was added trifluoroacetic acid (83.7 mg, 0.734 mmol). Resulting reaction mixture was stirred at room temperature for 2h. On completion, trifluoroacetic acid was concentrated under reduced pressure, diluted with water (30 mL), basified with NaHC0₃ (5 mL, 10%) and extracted with dichloromethane (2 x 50 mL). Combined organic layer was dried over Na₂S04 and concentrated under reduced pressure to afford the title compound (80 mg, 71%) as off-white solid.

^NMR (DMSO-d6, 400 MHz): d (ppm) 7.84 (d, J = 1.53 Hz, 1 H) 7.62 (d, J = 8.11 Hz, 2 H) 7.54 (d, J = 1.32 Hz, 1 H) 7.36 (d, J = 7.89 Hz, 2 H) 5.45 (s, 2 H) 4.75 (s, 2 H) 2.40 - 2.45(m, 1 H) 0.80 - 0.85 (m, 2 H) 0.55 - 0.61 (m, 2 H); LCMS (ESI): m/z 309 [M + H⁺].

Preparation 16: tert-butyl (lR)-l-[[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]carbamoyl]-5-methylsulfonyl- isoindoline-2-carboxylate

Using a procedure similar to that described for Preparation 10, but using (lR)-2-tert- butoxycarbonyl-5-methylsulfonyl-isoindoline-l-carboxylic acid (300 mg, 0.879 mmol) the title compound was prepared as a white solid. (370 mg, 67%).

LCMS: m/z 632.2 [M + H⁺].

Preparation 17: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-5-methylsulfonyl-isoindoline-l- carboxamide dihydrochloride

Preparation 16 (370 mg, 0.586 mmol) was dissolved in hydrochloric acid (7 mL, 4M dioxane) and stirred at room temperature for 1 h.. Hydrochloric acid was azeotroped using toluene to afford the title compound as a salt. (370 mg, 100%).

1H NMR (600 MHz, DMSO-d6) d 11.72 (s, 1H), 10.99 (bs, 1H), 9.66 (bs, 1H), 8.69 (s, 2H), 8.08 - 8.04 (m, 1H), 8.03 - 7.96 (m, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 5.87 (s, 1H), 4.92 (s, 2H), 4.78 (d, J = 15.0 Hz, 1H), 4.71 (d, J = 15.0 Hz, 1H), 3.25 (s, 3H), 2.81 - 2.74 (m, 1H), 0.85 - 0.79 (m, 2H), 0.66 - 0.61 (m, 2H). LCMS: m/z 432.2 [M + H⁺]. Preparation 18: [2-[methyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5- yl]azinate

Using a procedure similar to that described for Preparation 1, but using N-methyl-l-[4- (trifluoromethyl)phenyl]methanamine the title compound was prepared.

Preparation 19: N2-methyl-N2-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-2,5- diamine

Using a procedure similar to that described for Preparation 2, but using Preparation 18 the title compound was prepared.

Preparation 20: tert-butyl (lR)-5-methylsulfonyl-l-[[2-[methyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]carbamoyl]isoindoline-2- carboxylate

Using a procedure similar to that described for Preparation 10, but using Preparation 19 the title compound was prepared.

LCMS: m/z 606.2 [M + H⁺]

Preparation 21: N-[[5-(trifluoromethyl)-2-pyridyl]methyl]cyclopropanamine

To a solution of 5-(trifluoromethyl)pyridine-2-carbaldehyde (265 mg, 1.51 mmol) in dichloromethane was added cyclopropanamine (130 mg, 2.27 mmol) and acetic acid (0.173 mL, 3.03 mmol). After 30 min of stirring at room temperature the mixture was cooled to -10° C and added sodium triacetoxyborohydride (417 mg, 1.97 mmol). On completion, the reaction mixture was quenched with sodium hydroxide (1.51 mL, 1M in water). The product was extracted with dichloromethane. The combined organic layers was washed with brine respectively. The resulting organic layer was dried over anhydrous Na₂S04 and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (0-60% EtOAc in Hexane as eluent) to afford the title compound (242 mg, 74 %) as a colorless oil.

Preparation 22: [2-[methyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5- yl]azinate

Using a procedure similar to that described for Preparation 1, but using Preparation 21 the title compound was prepared.

Preparation 23: N2-cyclopropyl-N2-[[5-(trifluoromethyl)-2-pyridyl]methyl]pyrimidine- 2, 5-diamine

Using a procedure similar to that described for Preparation 2, but using Preparation 22 the title compound was prepared.

Preparation 24: tert-butyl (lR)-l-[[2-[cyclopropyl-[[5-(trifluoromethyl)-2- pyridyl]methyl]amino]pyrimidin-5-yl]carbamoyl]-5-methylsulfonyl-isoindoline-2- carboxylate

Using a procedure similar to that described for Preparation 10, but using Preparation 23 the title compound was prepared.

LCMS: m/z 633.2 [M + H⁺]

Preparation 25: N-[[6-(trifluoromethyl)-3-pyridyl]methyl]cyclopropanamine

Using a procedure similar to that described for Preparation 21, but using

6-(trifluoromethyl)pyridine-3-carbaldehyde, the title compound was prepared.

Preparation 26: [2-[cyclopropyl-[[6-(trifluoromethyl)-3- pyridyl]methyl]amino]pyrimidin-5-yl]azinate

Using a procedure similar to that described for Preparation 1, but using Preparation 25 the title compound was prepared.

Preparation 27: N2-cyclopropyl-N2-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrimidine- 2, 5-diamine

Using a procedure similar to that described for Preparation 2, but using Preparation 26 the title compound was prepared. Preparation 28: tert-butyl (lR)-l-[[2-[cyclopropyl-[[6-(trifluoromethyl)-3- pyridyl]methyl]amino]pyrimidin-5-yl]carbamoyl]-5-methylsulfonyl-isoindoline-2- carboxylate

Using a procedure similar to that described for Preparation 10, but using Preparation 27 the title compound was prepared.

LCMS: m/z 633.2 [M + H⁺]

Preparation 29: N-[[4-(l,l-difluoroethyl)phenyl]methyl]cyclopropanamine

Using a procedure similar to that described for Preparation 21, but using

4-(l,l-difluoroethyl)benzaldehyde, the title compound was prepared.

Preparation 30: [2-[cyclopropyl-[[4-(l,l-difluoroethyl)phenyl]methyl]amino]pyrimidin-

5-yl]azinate

Using a procedure similar to that described for Preparation 1, but using Preparation 29 the title compound was prepared.

Preparation 31: N2-cyclopropyl-N2-[[4-( l,l-difluoroethyl)phenyl] methyl] pyrimidine- 2, 5-diamine

Using a procedure similar to that described for Preparation 2, but using Preparation 30 the title compound was prepared.

Preparation 32: tert-butyl (lR)-l-[[2-[cyclopropyl-[[4-(l,l- difluoroethyl)phenyl]methyl]amino]pyrimidin-5-yl]carbamoyl]-5-methylsulfonyl- isoindoline-2-carboxylate

Using a procedure similar to that described for Preparation 10, but using Preparation 31 the title compound was prepared.

LCMS: m/z 633.2 [M + H⁺]

Preparation 33: [6-[cyclopropyl-[[5-(trifluoromethyl)-2-pyridyl]methyl]amino]-3- pyridyl]azinate

Using a procedure similar to that described for Preparation 3, but using Preparation 21 the title compound was prepared.

Preparation 34: N2-cyclopropyl-N2-[[5-(trifluoromethyl)-2-pyridyl]methyl]pyridine- 2, 5-diamine

Using a procedure similar to that described for Preparation 4, but using Preparation 33 the title compound was prepared.

Preparation 35: [6-[cyclopropyl-[[6-(trifluoromethyl)-3-pyridyl]methyl]amino]-3- pyridyl]azinate

Using a procedure similar to that described for Preparation 3, but using Preparation 25 the title compound was prepared.

Preparation 36: N2-cyclopropyl-N2-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyridine- 2, 5-diamine

Using a procedure similar to that described for Preparation 4, but using Preparation 35 the title compound was prepared.

EXAMPLES

Example 1: (lR)-2-acetyl-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-5-methylsulfonyl-isoindoline-l- carboxamide

(lR)-2-acetyl-5-methylsulfonyl-isoindoline-l-carboxylic acid (62.0 mg, 0.219 mmol) was added to a solution of the amine from Preparation 2 (67.5 mg, 0.219 mmol) in ethyl acetate (0.713 ml_). Temperature was lowered to 10° C and pyridine (0.195 ml_, 0.2407 mmol) followed by 2,4,6-Tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide solution >50 wt. % in ethyl acetate ( 0.193 ml_, 0.328 mmol). The resulting reaction mixture was stirred for lh letting temperature increase to room temperature. The mixture was diluted with ethyl acetate, washed with citric acid. The combined organic layers was concentrated under reduced pressure. The obtained residue was purified by basic preparative HPLC, (10% to 100% acetonitrile in 50mM ammonium bicarbonate /aq on a XBridge

^BD Prep Column, 13qA, 5 pm, 30 x250 mm). Clean fractions were concentrated under reduced pressure to give title compound as a white solid. (61 mg, 48.6%).

1H NMR (600 MHz, DMSO-d6, mixture of rotamers, 3.5* : 1) 10.60*, 10.41 (2s, 1H), 8.59, 8.58* (2s, 2H), 8.02, 7.99* (2s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.78, 7.71* (2d, J = 8.0 Hz, 1H) 7.64 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.90, 5.68* (2s, 1H), 5.08 - 4.75 (m, 4H), 3.23*, 3.23 (2s, 3H), 2.78 - 2.71 (m, 1H), 2.15*, 2.01 (2s, 3H), 0.84 - 0.77 (m, 2H), 0.64 - 0.58 (m, 2H). LCMS : m/z 574.2 [M + H⁺] ; RT = 2.29 min.

Example 2: (lS)-2-acetyl-N-[2-[cyclopropyl-[[4-

Using a procedure similar to that described for Example 1, but using (ls)-2-acetyl-5- methylsulfonyl-isoindoline-l-carboxylic acid (62.0 mg, 0.219 mmol) the title compound was prepared as a solid. (3.2 mg, 13%).

1H NMR (600 MHz, DMSO-d6, mixture of rotamers, 3.5* : 1) 10.60, 10.41* (2s, 1H), 8.59, 8.58* (2s, 2H), 8.02, 7.99* (2s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.78, 7.71* (2d, J = 8.0 Hz, 1H) 7.64 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.90, 5.68* (2s, 1H), 5.07 - 4.75 (m, 4H), 3.23*, 3.23 (2s, 3H), 2.78 - 2.71 (m, 1H), 2.15*, 2.01 (2s, 3H), 0.84 - 0.77 (m, 2H), 0.64 - 0.58 (m, 2H). LCMS : m/z 574.2 [M + H⁺] ; RT = 2.29 min.

Example 3: (lR)-2-acetyl-N-[6-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]-3-pyridyl]-5-methylsulfonyl-isoindoline-l- carboxamide

Using a procedure similar to that described for Example 1, but using the compound described in Preparation 4 (12 mg, 0.040 mmol), the title compound was prepared as a solid. (9.3 mg, 48%). 1H NMR (600 MHz, DMSO-d6, mixture of rotamers, 3.3* : 1) 10.51, 10.28* (2s, 1H),

8.27 (d, J = 2.7 1H), 8.02, 7.99* (2s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 - 7.78, (m,

1H) 7.76, 7.70* (2d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H),

7.07 - 7.01 (m, 1H), 5.87, 5.67* (2s, 1H), 5.08 - 4.75 (m, 4H), 3.23*, 3.22 (2s, 3H),

2.75 - 2.48 (m, 1H), 2.15*, 2.00 (2s, 3H), 0.90 - 0.81 (m, 2H), 0.65 - 0.58 (m, 2H).

LCMS: m/z 573.2 [M + H⁺] ; RT = 2.28 min.

Example 4: (lR)-2-acetyl-N-[5-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]-2-pyridyl]-5-methylsulfonyl-isoindoline-l- carboxamide

Acetic anhydride (0.002 ml_, 0.023 mmol) was added to a solution of the amine from Preparation 8 (6 mg, 0.011 mmol) in dichloromethane (1 ml_). The mixture was added diisopropylethylamine (0.020 ml_, 0.113 mmol) and stirred at room temperature for lh. Reaction was quenched with water, extracted with dichloromethane, washed with brine, dried with Magnesium Sulfate and concentrated in vacue. The residue was purified by basic preparative HPLC, (35% to 80% acetonitrile in 50mM ammonium bicarbonate /aq on a XBridge

OBD Prep Column, 13qA, 5 pm, 30 x250 mm). Clean fractions were evaporated under reduced pressure to give the title compound as a solid. (5 mg, 77.2%) 1H NMR (600 MHz, DMSO-d6, mixture of rotamers, 3.3* : 1) 11.04, 10.72* (2s, 1H),

8.08 - 7.93 (m, 2H), 7.90 (d, J = 8.1 Hz, 1H), 7.80 - 7.61 (m, 4H), 7.39 (d, J = 8.1 Hz, 2H), 7.36 - 7.27 (m, 1H), 5.99, 5.82* (2s, 1H), 5.09 - 4.76 (m, 2H), 4.71 (s, 2H), 3.22 - 3.18 (m, 3H), 2.70 - 2.55 (m, 1H), 2.13*, 1.96 (2s, 3H), 0.95 - 0.80 (m, 2H), 0.68 - 0.54 (m, 2H). LCMS : m/z 573.2 [M + H⁺] ; RT = 2.37 min.

Example 5: (lR)-2-acetyl-N-[5-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrazin-2-yl]-5-methylsulfonyl-isoindoline-l- carboxamide

Using a procedure similar to that described for Example 1, but using the compound described in Preparation 15 (14.5 mg, 0.047mmol), together with (lR)-2-acetyl-5- methylsulfonyl-isoindoline-l-carboxylic acid (11.1 mg, 0.039 mmol), the title compound was prepared (5.1 mg, 22.5%).

1H NMR (300 MHz, DMSO-d6, mixture of rotamers, 4.3* : 1) 11.24, 10.95* (2s, 1H), 8.66*, 8.64 (2d, J = 1.5 1H), 8.29, 8.29* (2d, 1H), 8.04 - 7.95 (m, 1H), 7.83 - 7.78, (m, 1H) 7.91 (d, J = 8.0 Hz, 1H), 7.74, 7.68* (2d, J = 8.1 Hz 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 6.02, 5.87* (2s, 1H), 5.12 - 4.70 (m, 4H), 3.25 - 3.18 (m, 3H), 2.75 - 2.60 (m, 1H), 2.14*, 1.98 (2s, 3H), 0.99 - 0.88 (m, 2H), 0.75 - 0.66 (m, 2H). LCMS: m/z 574.2 [M + H⁺], RT = 2.28 min.

Example 6: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-[(lS)-2,2- difluorocyclopropanecarbonyl]-5-methylsulfonyl-isoindoline-l-carboxamide

(lS)-2,2-difluorocyclopropanecarboxylic acid (0.100 ml_, 0.3M DMSO) was mixed with the isoindoline from Preparation 17 (0.0833 ml_, 0.3M DMSO) together with HATU (0.125 ml_, 0.3M DMSO) and diisopropylethylamine (0.0212 ml_, 0.125 mmol). The mixture was vortexed at room temperature for lhr. Purification was performed using basic preparative HPLC, (15% to 90% acetonitrile in 50mM ammonium bicarbonate /aq on a XBridge OBD Prep Column, 13qA, 5 pm, 19x100 mm). Clean fraction were evaporated under reduced pressure to give the title compound.

LCMS: m/z 636.2 [M + H⁺], RT = 2.43 min.

Example 7: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-[(lR)-2,2- difluorocyclopropanecarbonyl]-5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using (lR)-2,2- difluorocyclopropanecarboxylic acid, the title compound was prepared.

LCMS: m/z 636.2 [M + H⁺], RT = 2.43 min. Example 8: ((lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(l-fluorocyclopropanecarbonyl)-

5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using 1- fluorocyclopropanecarboxylic acid, the title compound was prepared.

LCMS: m/z 618.2 [M + H⁺], RT = 2.44 min.

Example 9: (lR)-2-(2-cyanoacetyl)-N-[2-[cyclopropyl-[[4-

Using a procedure similar to that described for Example 6, but using 2-cyanoacetic acid, the title compound was prepared.

LCMS: m/z 599.2 [M + H⁺], RT = 2.34 min.

Example 10: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2-hydroxy-2-methyl- propanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using 2-hydroxy-2- methyl-propanoic acid, the title compound was prepared.

LCMS: m/z 618.2 [M + H⁺], RT = 2.32 min. Example 11: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2,2-difluoropropanoyl)-5- methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using 2,2- difluoropropanoic acid, the title compound was prepared.

LCMS: m/z 624.2 [M + H⁺], RT = 2.47 min

Example 12: (lR)-N-[2-[cyclopropyl-[[4- (trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(l- hydroxycyclopropanecarbonyl)-5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using

1-hydroxycyclopropanecarboxylic acid, the title compound was prepared.

LCMS: m/z 616.2 [M + H⁺], RT = 2.31 min

Example 13: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(3,3- difluorocyclobutanecarbonyl)-5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using 3,3-difluorocyclobutanecarboxylic acid, the title compound was prepared.

LCMS: m/z 650.2 [M + H⁺], RT = 2.46 min

Example 14: (lR)-2-(cyclopropanecarbonyl)-N-[2-[cyclopropyl-[[4-

Using a procedure similar to that described for Example 6, but using

cyclopropanecarboxylic acid, the title compound was prepared. LCMS: m/z 600.2 [M + H⁺], RT = 2.38 min

Example 15: (lR)-2-(l-cyanocyclopropanecarbonyl)-N-[2-[cyclopropyl-[[4-

Using a procedure similar to that described for Example 6, but using

1-cyanocyclopropanecarboxylic acid, the title compound was prepared.

LCMS: m/z 625.2 [M + H⁺], RT = 2.42 min

Example 16: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2,2-difluorobutanoyl)-5- methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using 2,2-difluorobutanoic acid, the title compound was prepared.

LCMS: m/z 638.2 [M + H⁺], RT = 2.52 min

Example 17: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(3,3-difluoro-2, 2-dimethyl- propanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using

3, 3-difluoro-2, 2-dimethyl-propanoic acid, the title compound was prepared.

LCMS: m/z 652.2 [M + H⁺], RT = 2.50 min

Example 18: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2,2-difluoroacetyl)-5- methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using 2,2-difluoroacetic acid, the title compound was prepared.

LCMS: m/z 610.2 [M + H⁺], RT = 2.41 min

Example 19: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2-fluoroacetyl)-5- methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using 2-fluoroacetic acid, the title compound was prepared. LCMS: m/z 592.2 [M + H÷], RT = 2.33 min

Example 20: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2-methoxyacetyl)-5- methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using 2-methoxyacetic acid, the title compound was prepared.

LCMS: m/z 604.2 [M + H÷], RT = 2.30 min

Example 21: (lR)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2-fluoropropanoyl)-5- methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 6, but using 2-fluoropropanoic acid, the title compound was prepared.

LCMS: m/z 606.2 [M + H÷], RT = 2.38 min

Example 22: (lR)-2-acetyl-5-methylsulfonyl-N-[2-[methyl-[[4- (trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]isoindoline-l-carboxamide

Trifluoroacetic acid (0.5 mL) was added to a solution of product from Preparation 20 (16.1 mg, 0.027 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The mixture was concentrated and remaining trifluoroacetic acid was azeotroped using dichloromethane. The residue was re-dissolved in dichloromethane (0.3 mL) and added diisopropylethylamine (0.102 mL, 0.586 mmol) followed by acetic anhydride (0.293 mL, 5M in dichloromethane). The mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated till dryness and the residue was purified by acidic prep HPLC. Clean fractions were evaporated under reduced pressure to give the title compound as a solid. (5.4 mg, 17%).

1H NMR (300 MHz, DMSO-d6, mixture of rotamers, 3.6* : 1) 10.62*, 10.37 (2s, 1H), 8.55, 8.54* (2s, 2H), 8.02 - 7.97 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.78, 7.71* (2d, J = 8.0 Hz, 1H) 7.67 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.91, 5.67* (2s, 1H), 5.09 - 4.72 (m, 4H), 3.23*, 3.22 (2s, 3H), 3.12*, 3.11 (2s, 3H), 2.15*, 2.01 (2s, 3H). LCMS: m/z 548.2 [M + H⁺]; RT = 2.24 min.

Example 23: (lR)-2-acetyl-N-[2-[cyclopropyl-[[5-(trifluoromethyl)-2- pyridyl]methyl]amino]pyrimidin-5-yl]-5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 22, but using the compound described in Preparation 24, the title compound was prepared.

1H NMR (300 MHz, DMSO-d6, mixture of rotamers, 3.5* : 1) 10.61*, 10.40 (2s, 1H),

8.87 - 8.83 (m, 1H), 8.55, 8.54* (2s, 2H), 8.11 - 8.04 (m, 1H), 8.02 - 7.97 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.76, 7.70* (2d, J = 8.0 Hz, 1H) 7.37 - 7.30 (m, 1H), 5.89, 5.67* (2s, 1H), 5.09 - 4.71 (m, 4H), 3.22*, 3.22 (2s, 3H), 2.96 - 2.85 (m, 1H), 2.14*, 2.00 (2s, 3H), 0.86 - 0.73 (m, 2H), 0.68 - 0.60 (m, 2H). LCMS: m/z 575.2 [M + H⁺]; RT = 2.12 min.

Example 24: (lR)-2-acetyl-N-[2-[cyclopropyl-[[6-(trifluoromethyl)-3- pyridyl]methyl]amino]pyrimidin-5-yl]-5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 22, but using the compound described in Preparation 28, the title compound was prepared. 1H NMR (300 MHz, DMSO-d6, mixture of rotamers, 3.5* : 1) 10.66*, 10.44 (2s, 1H),

8.64 - 8.61 (m, 1H), 8.60, 8.59* (2s, 2H), 8.04 - 7.98 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 - 7.79 (m, 1H), 7.77, 7.71* (2d, J = 8.0 Hz, 1H), 5.90, 5.68* (2s, 1H), 5.07 - 4.73 (m, 4H), 3.23*, 3.22 (2s, 3H), 2.83 - 2.71 (m, 1H), 2.15*, 2.01 (2s, 3H), 0.88 - 0.78 (m, 2H), 0.68 - 0.60 (m, 2H). LCMS : m/z 575.2 [M + H⁺] ; RT = 2.12 min.

Example 25: (lR)-2-acetyl-N-[2-[cyclopropyl-[[4-(l,l- difluoroethyl)phenyl]methyl]amino]pyrimidin-5-yl]-5-methylsulfonyl-isoindoline-l- carboxamide

Using a procedure similar to that described for Example 22, but using the compound described in Preparation 32, the title compound was prepared.

1H NMR (300 MHz, DMSO-d6, mixture of rotamers, 3.5* : 1) 10.60*, 10.39 (2s, 1H), 8.58, 8.57* (2s, 2H), 8.03, 7.97* (2s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.77, 7.71* (2d, J = 8.0 Hz, 1H) 7.46 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.90, 5.68* (2s, 1H), 5.09 - 4.74 (m, 4H), 3.23*, 3.22 (2s, 3H), 2.78 - 2.67 (m, 1H), 2.15*, 2.01 (2s, 3H), 1.92 (d, J = 18.0 Hz, 1H), 0.86 - 0.76 (m, 2H), 0.65 - 0.57 (m, 2H). LCMS : m/z 570.2 [M + H⁺] ; RT = 2.25 min.

Example 26: (lR)-2-acetyl-N-[6-[cyclopropyl-[[5-(trifluoromethyl)-2- pyridyl]methyl]amino]-3-pyridyl]-5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 1, but using the compound described in Preparation 34, the title compound was prepared.

1H NMR (300 MHz, DMSO-d6, mixture of rotamers, 3.2* : 1) 10.55*, 10.27 (2s, 1H),

8.88 - 8.81 (m, 1H), 8.22 -8.15 (m, 1H), 8.09 - 7.95 (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.85 - 7.77 (m, 1H), 7.75, 7.68* (2d, J = 8.0 Hz, 1H), 7.31 - 7.23 (m, 1H), 7.13 - 7.06 (m, 1H), 5.87, 5.66* (2s, 1H), 5.08 - 4.71 (m, 4H), 3.22 (bs, 3H), 2.77 - 2.67 (m, 1H), 2.14*, 1.99 (2s, 3H), 0.92 - 0.80 (m, 2H), 0.69 - 0.59 (m, 2H). LCMS : m/z 574.2

[M + H⁺] ; RT = 2.12 min. Example 27: (lR)-2-acetyl-N-[6-[cyclopropyl-[[6-(trifluoromethyl)-3- pyridyl]methyl]amino]-3-pyridyl]-5-methylsulfonyl-isoindoline-l-carboxamide

Using a procedure similar to that described for Example 1, but using the compound described in Preparation 36, the title compound was prepared.

1H NMR (300 MHz, DMSO-d6, mixture of rotamers, 3.2* : 1) 10.52*, 10.28 (2s, 1H),

8.61 (bs, 1H), 8.32 - 8.24 (m, 1H), 8.55, 8.54* (2s, 2H), 7.86 - 7.66 (m, 4H), 7.09 - 7.02 (m, 1H), 5.87, 5.67* (2s, 1H), 5.09 - 4.73 (m, 4H), 3.22 (bs, 3H), 2.61 - 2.52 (m, 1H), 2.15*, 2.00 (2s, 3H), 0.95 - 0.82 (m, 2H), 0.69 - 0.60 (m, 2H). LCMS: m/z 574.2 [M + H⁺]; RT = 2.14 min.

ROR-gamma binding assay

This assay is used to evaluate the binding affinity of compounds to the ligand-binding pocket of the human RORgt nuclear receptor based on displacement of a radio-ligand. The EC50 values are calculated using a four parameter fit. Compounds binding with high affinity to RORgt will have low EC50 values.

The assay is a Scintillation Proximity Assay (SPA) that involves competition between an unlabeled test compound and tritium-labeled 25-hydroxycholesterol for binding to RORgT ligand binding domain (LBD) protein immobilized on the surface of SPA beads. These beads contain a scintillant that emits light if excited by a radioactive particle, and this light is detected using a scintillation counter. In this assay, tritium-labelled 25- hydroxycholesterol is used as radiotracer.

400 nl_ of titrated test and reference compounds in DMSO were transferred by the Echo liquid handling system to a 384-well assay plate followed by addition of 5 pL [3H]-25- Hydroxycholesterol (Perkin Elmer) and 35 pl_ diluted RORgT LBD protein (Swiss Prot ID P51449, Purchased from Proteros Biostructures GmbH).

After 30 min of preincubation, 40 pL of HIS-TAG PVT SPA beads (Perkin Elmer) were added. The plates were then incubated for minimum 4 hours at room temperature in darkness before measuring the SPA signal using a MicroBeta plate scintillation counter. Final assay conditions were: 50 mM HEPES pH 7.4, 150 mM NaCI, 5 mM MgCI2, 0.1% BSA, 4 pg/well HIS-TAG PVT SPA Beads, 30 ng/well RORgT LBD (equal to a final concentration of 12 nM), 15 nM [³H]-25-Hydroxycholesterol, 0.5 % DMSO and varying concentrations of test compound in a total volume of 80 pL/well. ECso values were calculated using a 4-parameter non-linear regression curve-fitting model.

The exemplified compounds were tested in the ROR-gamma binding assay.

Results are shown in Table 2.

Human PBMC IL-17A assay

This assay measures the IL-17A inhibitory potential of test compounds in Human peripheral mononuclear cells.

Peripheral blood mononuclear cells (PBMC) were isolated from human buffy coats using density grade centrifugation (Lymphoprep, Medinor), washed twice in PBS and frozen at -150°C for later use.

Test compounds were diluted in DMSO and 70 nl_ of titrated test and reference compounds were transferred by the Echo liquid handling system to a 384-well assay plate in to give a final concentration of 0.1% DMSO in the wells.

The PBMC were thawed, washed and suspended in RPMI-1640 supplemented with pen/strep, glutamax, 10 % bovine calf serum and 20 ng/ml_ of IL-23 (R&D systems).

The cells were mixed with antiCD3/antiCD28-coated beads (1 cells pr one bead)

(Milteney T-cell expansion kit), and immediately thereafter the cells were pipetted to the plate at 130,000c/well. The plate was incubated for 3 days in humidified air/C0₂ (95%/5%) On day 3 the level of IL-17A in the culture supernatant is measured using alpha-LISA kit (Perkin Elmer). Cell viability was measured by adding 6 uL pr well Prestoblue© (Life Technologies) and incubating for 2 hours followed by fluorescent measurement (Ex535/Em615). ECso values were calculated using a 4-parameter non- linear regression curve-fitting model.

Donors may be pre-screened in order to select PBMC with a high secretion of IL-17A.

The exemplified compounds were tested in the Human PBMC IL-17A assay.

Human whole blood IL-17A assay

The EC50 value reported from this assay is a measure of the potency of the tested compound in inhibiting IL-17A levels in the blood after three days of incubation.

Test compounds were diluted in DMSO and 80 nl_ of titrated compound is transferred by the Echo liquid handling system to a 384-well assay plate to give a final concentration of 0.1% DMSO in the wells. Freshly drawn human peripheral blood stabilized with heparin was diluted 1 : 1 with X- vivo 15 medium (Lonza) added pen/strep and glutamax. Staphylococcus enterotoxin B (Sigma) at 300 ng/mL was added to the diluted blood just prior to pipetting into wells,

80 uL per well. The plates were incubated for 3 days at 37°C in humidified air/C0₂ (95%/5%). After 3 days of incubation, the level of IL-17A was measured using an alpha- LISA kit (Perkin Elmer).

EC50 values were calculated using a 4-parameter non-linear regression curve-fitting model.

The exemplified compounds were tested in the Human whole blood IL-17A assay.

Human liver microsomes (HLM) assay

Compounds of the invention were tested in the Human liver microsomes (HLM) assay. Incubations of test compounds in DMSO, diluted with phosphate buffer, pH 7.4, at 0.5 mM were carried out with human liver microsomes (0.5 mg/mL). The percentage of organic solvent in the incubations was 1%. The human liver microsomal suspension in phosphate buffer was mixed with NADPH (1 mM) and preheated to 37 °C before test compound was added. Aliquots were taken at 0, 5, 10, 20, 30 and 40 minutes, and reactions were terminated by addition of cold acetonitrile containing analytical internal standard (IS).

The results were expressed as apparent clearance (Cl_app) (mL/min/kg) and hepatic extraction ratio (E_h) (%) calculated from the elimination rate constant (k) (min^-1) of test compound depletion. Apparent clearance is a measure of compound elimination from the liver.

Table 1

Further embodiments of the invention

Embodiment 1. A compound according to general formula (I)

wherein Ri is selected from the group consisting of (Ci-C₄)alkyl, (C₃-C₅)cycloalkyl, halo(Ci- C₄)alkyl, halo(C₃-C₅)cycloalkyl and -NR_aR_b, wherein R_a and R_b each independently represents hydrogen, (Ci-C₄)alkyl, (C₃-C₅)cycloalkyl, halo(Ci-C₄)alkyl or halo(C₃- C₅)cycloalkyl;

R₂ is selected from the group consisting of HC(O)-, (Ci-C₄)alkyl-C(0)-, (C₃-C₅)cycloalkyl- C(O)-, (Ci-C₄)alkoxy-(Ci-C₄)alkyl-C(0)- and (C₃-C₅)cycloalkyl(Ci-C₄)alkyl-C(0)-, wherein said (Ci-C₄)alkyl-C(0)-, (C₃-C₅)cycloalkyl-C(0)-, (Ci-C₄)alkoxy-(Ci-C₄)alkyl- C(O)- and (C₃-C₅)cycloalkyl(Ci-C₄)alkyl-C(0)- are optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano;

R₃ is selected from the group consisting of (Ci-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₃- C₇)cycloalkyl(Ci-C₄)alkyl and (Ci-C₄)alkyl(C₃-C₇)cycloalkyl, wherein said (Ci-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(Ci-C₄)alkyl and (Ci-C₄)alkyl(C₃-C₇)cycloalkyl are optionally substituted with one or more halogen; and

R₄ is selected from the group consisting of halogen, cyano, (Ci-C₄)alkyl, (Ci- C₄)alkoxy(Ci-C₄)alkyl, (C₃-C₇)cycloalkyl and (Ci-C₄)alkoxy, wherein said (Ci-C₄)alkyl, (Ci-C₄)alkoxy(Ci-C₄)alkyl, (C₃-C₇)cycloalkyl and (Ci-C₄)alkoxy is optionally substituted with one or more halogen;

Embodiment 2. The compound according to embodiment 1 wherein Xi and X₄ each represent N and wherein X₂ and X₃ each represent CH.

Embodiment 3. The compound according to embodiment 1 wherein and X₄ represents N and wherein Xi, X₂ and X₃ each represent CH.

Embodiment 4. The compound according to embodiment 1 wherein and X₂ represents N and wherein Xi, X₃ and X₄ each represent CH. Embodiment 5. The compound according to embodiment 1 wherein X₂ and X₄ each represent N and wherein Xi and X3 each represent CH.

Embodiment 6. The compound according to any one of embodiments 1-5 wherein Yi and Y₂ each represent CH.

Embodiment 7. The compound according to any one of embodiments 1- 6 wherein Ri is selected from the group consisting of (Ci-C4)alkyl.

Embodiment 8. The compound according to any one of embodiments 1- 7 wherein Ri represents methyl.

Embodiment 9. The compound according to any one of embodiments 1- 8 wherein R₂ is selected from the group consisting (Ci-C₄)alkyl-C(0)-.

Embodiment 10. The compound according to any one of embodiments 1- 9 wherein R₂ represents methyl-C(O)-.

Embodiment 11. The compound according to any one of embodiments 1- 10 wherein R₃ is selected from the group consisting of (C3-C7)cycloalkyl.

Embodiment 12. The compound according to any one of embodiments 1- 11 wherein R₃ represents cyclopropyl.

Embodiment 13. The compound according to any one of embodiments 1- 12 wherein R₄ is selected from the group consisting of (Ci-C4)alkyl; wherein said (Ci-C4)alkyl optionally substituted with one or more halogen.

Embodiment 14. The compound according to any one of embodiments 1- 13 wherein R₄ represents trifluoromethyl.

Embodiment 15. The compound according to any one of embodiments 1- 14 selected from the group consisting of

(lR)-2-acetyl-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5- yl]-5-methylsulfonyl-isoindoline- 1-carboxamide,

(lS)-2-acetyl-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5- yl]-5-methylsulfonyl-isoindoline- 1-carboxamide,

(lR)-2-acetyl-N-[6-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]-3-pyridyl]-

5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-2-acetyl-N-[5-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]-2-pyridyl]-

5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-2-acetyl-N-[5-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrazin-2- yl]-5-methylsulfonyl-isoindoline- 1-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-

[(lS)-2,2-difluorocyclopropanecarbonyl]-5-methylsulfonyl-isoindoline-l-carboxamide,

[(lR)-2,2-difluorocyclopropanecarbonyl]-5-methylsulfonyl-isoindoline-l-carboxamide,

((lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(l- fluorocyclopropanecarbonyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-2-(2-cyanoacetyl)-N-[2-[cyclopropyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pynmidin-5-yl]-5-methylsulfonyl-isoindoline-l- carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2- hydroxy-2-methyl-propanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(tnfluoromethyl)phenyl]methyl]amino]pynmidin-5-yl]-2-

(2,2-difluoropropanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(l- hydroxycyclopropanecarbonyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(3,3-difluorocyclobutanecarbonyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-2-(cyclopropanecarbonyl)-N-[2-[cyclopropyl-[[4-

(lR)-2-(l-cyanocyclopropanecarbonyl)-N-[2-[cyclopropyl-[[4-

(tnfluoromethyl)phenyl]methyl]amino]pynmidin-5-yl]-5-methylsulfonyl-isoindoline-l- carboxamide,

(2,2-difluorobutanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(3,3-difluoro-2,2-dimethyl-propanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(2,2-difluoroacetyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2- fluoroacetyl)-5-methylsulfonyl-isoindoline-l-carboxamide, (lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2- methoxyacetyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2- fluoropropanoyl)-5-methylsulfonyl-isoindoline-l-carboxannide,

(lR)-2-acetyl-5-methylsulfonyl-N-[2-[methyl-[[4-

(trifluoronnethyl)phenyl]nnethyl]annino]pyrinnidin-5-yl]isoindoline-l-carboxannide,

(lR)-2-acetyl-N-[2-[cyclopropyl-[[5-(trifluoronnethyl)-2-pyridyl]nnethyl]annino]pyrinnidin-

5-yl]-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-2-acetyl-N-[2-[cyclopropyl-[[6-(trifluoronnethyl)-3-pyridyl]nnethyl]annino]pyrinnidin-

5-yl]-5-methylsulfonyl-isoindoline-l-carboxannide,

(lR)-2-acetyl-N-[2-[cyclopropyl-[[4-(l,l-difluoroethyl)phenyl]methyl]amino]pyrimidin-

5-yl]-5-methylsulfonyl-isoindoline-l-carboxannide,

(lR)-2-acetyl-N-[6-[cyclopropyl-[[5-(trifluoromethyl)-2-pyridyl]methyl]amino]-3- pyridyl]-5-methylsulfonyl-isoindoline-l-carboxannide and

(lR)-2-acetyl-N-[6-[cyclopropyl-[[6-(trifluoromethyl)-3-pyridyl]methyl]amino]-3- pyridyl]-5-methylsulfonyl-isoindoline-l-carboxannide, or pharmaceutically acceptable salts, solvates or hydrates thereof.

Embodiment 16. A compound according to general formula (II), which may be useful as an intermediate for the preparation of compounds of general formula (I),

Wherein

R.₃ represents cyclopropyl;

R.₄ represents trifluoromethyl;

Yi and Y₂ each represent CH;

Xi and X₄ each represent N and X₂ and X3 each represent CH, or X₄ represents N and Xi, X2 and X3 each represent CH, or X₂ represents N and Xi, X3 and X4 each represent CH, or X2 and X4 each represent N and Xi and X3 each represent CH.

Claims

1. A compound according to general formula (I)

wherein

Ri is selected from the group consisting of (Ci-C₄)alkyl, (C₃-C₅)cycloalkyl, halo(Ci- C₄)alkyl, halo(C₃-C₅)cycloalkyl and -NR_aR_b, wherein R_a and R_b each independently represents hydrogen, (Ci-C₄)alkyl, (C₃-C₅)cycloalkyl, halo(Ci-C₄)alkyl or halo(C₃- C₅)cycloalkyl;

R₂ is selected from the group consisting of HC(O)-, (Ci-C₄)alkyl-C(0)-, (C₃-C₅)cycloalkyl- C(O)-, (Ci-C₄)alkoxy-(Ci-C₄)alkyl-C(0)- and (C₃-C₅)cycloalkyl(Ci-C₄)alkyl-C(0)-, wherein said (Ci-C₄)alkyl-C(0)-, (C₃-C₅)cycloalkyl-C(0)-, (Ci-C₄)alkoxy-(Ci-C₄)alkyl-C(0)- and (C₃-C₅)cycloalkyl(Ci-C₄)alkyl-C(0)- are optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano;

2. The compound according to claim 1 wherein Xi and X₄ each represent N and wherein X₂ and X₃ each represent CH.

3. The compound according to claim 1 wherein and X₄ represents N and wherein Xi, X₂ and X3 each represent CH.

4. The compound according to claim 1 wherein and X₂ represents N and wherein Xi, X₃ and X₄ each represent CH.

5. The compound according to claim 1 wherein X₂ and X₄ each represent N and wherein Xi and X3 each represent CH.

6. The compound according to any one of claims 1-5 wherein Yi and Y₂ each represent CH.

7. The compound according to any one of claims 1- 6 wherein Ri is selected from the group consisting of (Ci-C₄)alkyl.

8. The compound according to any one of claims 1- 7 wherein R₂ is selected from the group consisting (Ci-C₄)alkyl-C(0)-.

9. The compound according to any one of claims 1- 8 wherein R₃ is selected from the group consisting of (C₃-C₇)cycloalkyl.

10. The compound according to any one of claims 1- 9 wherein R₄ is selected from the group consisting of (Ci-C₄)alkyl; wherein said (Ci-C₄)alkyl optionally substituted with one or more halogen.

11. The compound according to any one of claims 1- 10 selected from the group consisting of

5-methylsulfonyl-isoindoline-l-carboxamide,

5-methylsulfonyl-isoindoline-l-carboxamide, (lR)-2-acetyl-N-[5-[cyclopropyl-[[4-(tnfluoromethyl)phenyl]methyl]amino]pyrazin-2- yl]-5-methylsulfonyl-isoindoline- 1-carboxamide,

((lR)-N-[2-[cyclopropyl-[[4-(tnfluoromethyl)phenyl]methyl]amino]pynmidin-5-yl]-2-(l- fluorocyclopropanecarbonyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-2-(2-cyanoacetyl)-N-[2-[cyclopropyl-[[4-

(lR)-N-[2-[cyclopropyl-[[4-(tnfluoromethyl)phenyl]methyl]amino]pynmidin-5-yl]-2-(2- hydroxy-2-methyl-propanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(2,2-difluoropropanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(tnfluoromethyl)phenyl]methyl]amino]pynmidin-5-yl]-2-(l- hydroxycyclopropanecarbonyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pynmidin-5-yl]-2-

(3,3-difluorocyclobutanecarbonyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-2-(cyclopropanecarbonyl)-N-[2-[cyclopropyl-[[4-

(lR)-2-(l-cyanocyclopropanecarbonyl)-N-[2-[cyclopropyl-[[4-

(2,2-difluorobutanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(2,2-difluoroacetyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2- fluoroacetyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(tnfluoromethyl)phenyl]methyl]amino]pynmidin-5-yl]-2-(2- methoxyacetyl)-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-N-[2-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]-2-(2- fluoropropanoyl)-5-methylsulfonyl-isoindoline-l-carboxamide, (lR)-2-acetyl-5-methylsulfonyl-N-[2-[methyl-[[4-

(trifluoromethyl)phenyl]methyl]amino]pyrimidin-5-yl]isoindoline-l-carboxamide,

(lR)-2-acetyl-N-[2-[cyclopropyl-[[5-(trifluoromethyl)-2-pyridyl]methyl]amino]pyrimidin-

5-yl]-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-2-acetyl-N-[2-[cyclopropyl-[[6-(trifluoromethyl)-3-pyridyl]methyl]amino]pyrimidin-

5-yl]-5-methylsulfonyl-isoindoline-l-carboxamide,

(lR)-2-acetyl-N-[6-[cyclopropyl-[[5-(trifluoromethyl)-2-pyridyl]methyl]amino]-3- pyridyl]-5-methylsulfonyl-isoindoline-l-carboxamide and

(lR)-2-acetyl-N-[6-[cyclopropyl-[[6-(trifluoromethyl)-3-pyridyl]methyl]amino]-3- pyridyl]-5-methylsulfonyl-isoindoline-l-carboxamide, or pharmaceutically acceptable salts, solvates or hydrates thereof.

12. A compound according to any one of claims 1-11 for use as a medicament.

13. A compound according to any one of claims 1-11 for use in treatment of

autoimmune or inflammatory diseases.

14. The compound according to claim 13 for use in the treatment of psoriasis.

15. A pharmaceutical composition comprising a compound according to any one of claims 1-11 together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s).

16. The pharmaceutical composition according to claim 15 together with one or more other therapeutically active compound(s).

17. A method of preventing, treating or ameliorating psoriasis, the method comprising administering to a person suffering from psoriasis an effective amount of one or more compounds according to according to any one of claims 1-11, optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

18. A compound according to any one of claims 1-11 for use in treatment of a disease, disorder or condition, which disease, disorder or condition is responsive of modulation of RORgamma.