WO2021255085A1 - Small molecule modulators of il-17 - Google Patents

Abstract

The present invention relates to a compound according to formula (I) and pharmaceutically acceptable salts, hydrates, or solvates thereof. The invention further relates to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases, e.g. dermal diseases, with said compounds, and to the use of said compounds in the manufacture of medicaments.

Description

SMALL MOLECULE MODULATORS OF IL-17

FIELD OF THE INVENTION

This invention relates to novel amino-acid anilides and derivatives thereof, to said compounds for use in therapy and to pharmaceutical compositions comprising said compounds.

BACKGROUND OF THE INVENTION

IL-17 (also known as IL-17A or CTLA8) is a pro-inflammatory cytokine involved in anti microbial defense at epithelial surfaces. IL-17 is comprised of two covalently joined IL-17A subunits (IL-17AA) with an approximate mass of 32 kDa, and signals through a receptor comprising IL17RA and IL17RC subunits. This receptor is predominantly expressed in epithelial and mesenchymal cells. The IL17RA/IL17RC receptor is also used by IL-17 variants IL-17AF and IL-17FF, which both are successively weaker, partial agonists on this receptor (Monin, L., Gaffen, S.L.; 2018, Cold Spring Harb. Perspect. Biol. 10. doi: 10. 1101/cshperspect.a028522). Crucial for signaling is the assembly of signaling complexes containing the multifunctional protein ACT1/CIKS, which in turn can recruit TRAF and other proteins.

Via these signaling complexes IL-17 induces cytokines, chemokines, antimicrobial peptides and growth factors via activation of transcription factor NFkB or via MAP kinase-dependent pathways (e.g. IL-6, IL-8, CXCL1, CXCL2, CXCL5, CCL20, G-CSF, BD4) and stabilizes the mRNAs of certain inflammatory cytokines, such as CXCL1. This leads to amplification of their effects. Further, IL-17 acts in concert with IL-lbeta, IL-22 and IFNgamma (Amatya, N. et a/., Trends in Immunology, 2017, 38, 310-322. doi: 10.1016/j.it.2017.01.006; Onishi, R.M.,

Gaffen, S.L. Immunology, 2010, 129, 311-321. doi: 10. 1111/j.1365-2567.2009.03240.x).

IL-17 is secreted by a variety of immune cells, such as Thl7 helper cells, Tcl7 cytotoxic cells, ILC3 innate cells, NKT cells, TCRbeta+ natural T cells and gamma-deltaT-cells (Monin, L., Gaffen, S.L.; 2018, Cold Spring Harb. Perspect. Biol. 10. doi: 10. 1101/cshperspect.a028522). Increased, disease-provoking levels of IL-17 are observed in several autoimmune diseases, such as psoriasis, ankylosing spondylitis, spondyloarthritis and psoriatic arthritis. Other diseases where deregulation of IL-17 is observed are rheumatoid arthritis, systemic lupus erythematosus, asthma, inflammatory bowel disease, autoimmune uveitis, multiple sclerosis and certain cancers (Gaffen, S.L. et a/., Nat Rev Immunol., 2014, 14, 585-600. doi: 10. 1038/nri3707; Monin, L., Gaffen, S.L. ; 2018, Cold Spring Harb. Perspect. Biol. 10. doi: 10.1101/cshperspect.a028522). Hence, IL-17 is a significant therapeutic target. Therapeutic, neutralizing antibodies against IL-17A (Secukinumab, Ixekizumab) or receptor IL17RA (Brodalumab) have shown high efficacy in the treatment of psoriasis, ankylosing spondylitis and psoriatic arthritis. These antibodies have long half-lives in the body.

Although various antibodies against IL-17A or IL-17RA are approved, there are currently no approved, orally available modulators of IL-17. The following small molecule modulators are known.

WO2013116682 discloses Macrocyclic Compounds for Modulating IL-17;

WO2014066726 discloses Compounds for Modulating IL-17;

WO2018229079 discloses Compounds for Modulating IL-17;

WO2019223718 discloses Compounds for Modulating IL-17;

W02019138017 discloses Compound for Modulating IL-17;

W02020011731 discloses Compound for Modulating IL-17;

W02020120140 discloses Compounds for Modulating IL-17;

W02020120141 discloses Compounds for Modulating IL-17;

W02020260426 discloses Compounds for Modulating IL-17;

W02020260425 discloses Compounds for Modulating IL-17;

W02020261141 discloses Compounds for Modulating IL-17;

WO2020146194 discloses IL-17A inhibitors.

Chinese patent applications CN112341429A, CN 112341435A, CN 112341439A, CN112341440A, CN112341441A, CN112341442A, CN112341446A, CN112341450A, CN112341451A and CN112341519A disclose Compounds for Modulating IL-17.

Scientific Reports (2016) 6, 30859 discloses Macrocyclic IL-17A Antagonists.

Leslie Dakin, 12^th Swiss Course on Medicinal Chemistry, Leysin, October 09-14, 2016 discloses 'Hit Identification, binding site elucidation and structure guided design of novel macrocyclic IL- 17A antagonists'.

Orally available, highly efficacious small molecule IL-17 modulators which bind to IL-17 to decrease its functional ability to activate the IL-17 receptor complex may have a number of advantages compared to monoclonal antibodies. Oral administration and flexible treatment regimen may be two significant aspects in favor of patient convenience and the compounds may exhibit improved safety due to the possibility of faster withdrawal of the drug should adverse events occur.

Therefore, there is a continuous need to develop small molecule modulators of IL-17, particularly small molecules suitable for oral administration.

In addition, some patients may be treated by topical application of small molecule modulators of IL-17. This can be particularly suitable for patients with skin lesions that are readily accessible and limited in body surface area. Topical treatment may also be prescribed for certain patients who could benefit from avoiding systemic modulation of the IL-17 pathway, for example when undergoing treatment for infections or gastrointestinal problems.

SUMMARY OF THE INVENTION

The inventors have surprisingly found that novel compounds of the present invention exhibit modulating effect on the IL-17 signalling pathway.

Thus, the invention relates to compounds of formula (I)

wherein

Ri is selected from the group consisting of (Ci-C6)alkyl, (C3-C7)cycloalkyl, (Ci-C6)alkoxy, (C3- C7)cycloalkoxy, phenyl, phenyl-(Ci-C₄)alkyl, 4-6-membered heterocycloalkyl, 9- or 10- membered bicyclic heteroaryl, 5-or 6-membered heteroaryl, and -NR_cRd, wherein said (Ci- C₆)alkyl, (C₃-C7)cycloalkyl, (Ci-C₆)alkoxy, (C₃-C7)cycloalkoxy, phenyl, phenyl-(Ci-C₄)alkyl, 4-6- membered heterocycloalkyl, 9- or 10-membered bicyclic heteroaryl, and 5-or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from Raj

R_a is deuterium, halogen, hydroxy, -NR_cRd, (Ci-C6)alkyl, (Ci-C6)alkylcarbonyl, (C3- C7)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-6-membered heterocycloalkyl, wherein said (Ci-C₆)alkyl, (Ci-C₆)alkylcarbonyl, (C₃-C7)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-6-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, (Ci-C4)alkyl, (C3-C7)cycloalkyl, (Ci-C4)alkoxy, (Ci-C4)alkyl-S-,(Ci-C4)alkyl-SO-, (Ci-C4)alkyl-SC>2- and -NRcRd;

R_åa and R_åb each independently are selected from (C3-C7)cycloalkyl and (C3-C7)cycloalkyl(Ci- C₆)alkyl wherein said (C₃-C7)cycloalkyl and (C₃-C7)cycloalkyl(Ci-C₆)alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano and (Ci-C₄)alkyl;

R3 is hydrogen, halogen, (Ci-C6)alkyl, or (Ci-C6)alkoxy, wherein said (Ci-C6)alkyl and (Ci- C6)alkoxy may optionally be substituted with one of more substituents selected from halogen;

X is CH, or N;

Rcand Rd each independently are selected from the group consisting of hydrogen and (Ci- C₆)alkyl, or R_cand R_d together form azetidinyl, pyrrolidinyl or piperidinyl, wherein said (Ci- C6)alkyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy; or pharmaceutically acceptable salts, hydrates and solvates thereof.

In a specific embodiment the invention relates to compounds of formula (la)

wherein Ri, R2a, R2t_>, R3 and X are as defined above.

Compounds of the present invention may have advantageous properties such as high metabolic stability and/or membrane permeability properties that make them suitable for oral administration. Other compounds of the present invention may have advantageous properties for local topical therapy, such as high skin permeability and high metabolic instability.

Compounds of the present invention may be beneficial in preventing, treating or ameliorating a variety of diseases which involve up-regulation or de-regulation of IL-17, such as for example psoriasis, ankylosing spondylitis and psoriatic arthritis. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of general formula (I) as defined herein together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s), optionally together with one or more other therapeutically active compound(s).

In yet another aspect, the invention relates to the use of a compound according to formula I as defined herein for use in therapy, for example for use in treatment of a disease, disorder or condition, which disease, disorder or condition is responsive of modulation of IL-17, for example for use in treatment of autoimmune diseases.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term "(Ca-Cb)alkyl" is intended to indicate a hydrocarbon radical obtained when one hydrogen atom is removed from a branched or linear hydrocarbon. Said alkyl comprises (a-b) carbon atoms, such as 1-6, such as 1-4, such as 1-3, such as 2-3 or such as 1-2 carbon atoms. 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, tert. -butyl, n- pentyl, isopentyl, neopentyl, n-hexyl and isohexyl.

The term "(Ca-Cb)alkoxy" is intended to indicate a radical of the formula -OR', wherein R' is (Ca-Cb)alkyl as indicated herein, wherein the (Ca-Cb)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 "cyano" is intended to indicate a -CN group attached to the parent molecular moiety through the carbon atom.

The term "(Ca-Cb)cycloalkyl" is intended to indicate a saturated (Ca-Cb)cycloalkane hydrocarbon radical, including polycyclic radicals such as bicyclic or tricyclic radicals, including spirocyclic radicals, comprising a-b carbon atoms, such as 3-10 carbon atoms, such as 3-8 carbon atoms, such as 3-7 carbon atoms, such as 3-6 carbon atoms, such as 3-5 carbon atoms or such as 3-4 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, adamantyl, spiro[2.5]octanyl, spiro[2.3]hexanyl, bicyclo[3,l,0]hexanyl, bicyclo[4,l,0]heptanyl and bicyclo[2,2,2]octanyl. The term "(Ca-Cb)cycloalkoxy" is intended to indicate a radical of the formula -OR', wherein R' is (Ca-C_b)cycloalkyl as indicated herein, wherein the (Ca-C_b)cycloalkyl group is appended to the parent molecular moiety through an oxygen atom, e.g. cyclopentyloxy or cyclobutyloxy.

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

The term "(Ca-Cb)cycloalkyl(Ca-Cb)alkyl" is intended to indicate an (Ca-Cb)alkyl group as defined herein substituted with one or more (Ca-Cb)cycloalkyl as defined herein, suitably the (Ca-Cb)alkyl group is substituted with one (Ca-Cb)cycloalkyl group.

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 "5- or 6-membered heteroaryl" is intended to indicate radicals of monocyclic heteroaromatic rings comprising 5- or 6-membered ring which contains from 1-5 carbon atoms and from 1-4 heteroatoms selected from oxygen, sulphur and nitrogen; such as 2-5 carbon atoms and 1-3 heteroatoms, such as 3-5 carbon atoms and 1-2 heteroatoms, such as 4-5 carbon atoms and 1-2 heteroatoms selected from oxygen, sulphur and nitrogen, such as furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl and triazolyl. The term "5- or 6-membered heteroaryl" includes compounds wherein a ring member is a C(O) or carbonyl group.

The term "5-membered heteroaryl" is intended to indicate radicals of 5-membered monocyclic heteroaromatic ring which contains from 1-4 carbon atoms and from 1-4 heteroatoms selected from oxygen, sulphur and nitrogen; such as 2-4 carbon atoms and 1-3 heteroatoms, such as 3-4 carbon atoms and 1-2 heteroatoms, such as 4 carbon atoms and 1 heteroatom selected from oxygen, sulphur and nitrogen; such as furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl and triazolyl. The term "5-membered heteroaryl" includes compounds wherein a ring member is a C(O) or carbonyl group.

The term "9- or 10-membered bicyclic heteroaryl" is intended to indicate fused bicyclic heteroaromatic radicals comprising 9- or 10- carbon or heteroatoms, which for example contain from 3-9 carbon atoms and 1-7 heteroatoms selected from oxygen, sulphur and nitrogen, such as 1-5 heteroatoms and 5-9 carbon atoms, such as 1-3 heteroatoms and 7-9 carbon atoms, such as 1-2 heteroatoms and 8-9 carbon atoms, such as 1 heteroatom and 8 carbon atoms, such as 1 heteroatom and 9 carbon atoms, such as 2 heteroatom and 7 carbon atoms, such as 2 heteroatom and 8 carbon atoms. Said bicyclic heteroaromatic radicals comprise a 5- or 6-membered heteroaromatic ring fused to phenyl and a 5- or 6-membered heteroaromatic ring fused to another 5- or 6-membered heteroaromatic ring, as defined herein. The heteroaryl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heteroaryl group. Representative examples of 9- or 10-membered bicyclic heteroaryl include, but are not limited to azaindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzothienyl, cinnolyl, imidazopyridinyl, imidazopyrimidinyl, indazolyl, indolyl, isobenzofuranyl, isoquinolyl, quinolyl, pyrrolopyrimidinyl, thienopyridinyl, pyrrolo[2,3]pyridinyl, pyrrolo[2,3]pyridinyl, pyrazolo[l,5]pyridinyl, pyrazolo[l,5]pyridazinyl, imidazo[l,2]pyrimidinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[l,5- ajpyridinyl, pyrazolo[l,5-b]pyridazinyl, imidazo[l,2-a]pyrimidinyl, and imidazo[l,2]pyridazinyl.

The term (5- or 6-membered heteroaryl)-(Ca-Ct_>)alkyl is intended to indicate a 5- or 6- membered heteroaryl appended to the parent molecular moiety through a (Ca-Cb)alkyl group, as defined herein.

The term "(a-b) membered heterocycloalkyl" is intended to indicate a cycloalkane radical as described herein, including polycyclic radicals such as bicyclic or tricyclic radicals, including spirocyclic radicals, wherein one or more carbon atoms of said cycloalkane radical are replaced by heteroatoms, i.e. the a-b membered heterocycloalkyl comprise from a to b carbon- or hetero-atoms. Such a-b membered heterocycloalkyl could comprise for example 2-9 carbon atoms and 1-6 heteroatoms selected from 0, N, or S, such as 3-8 carbon atoms and 1-4 heteroatoms, such as 3-7 carbon atoms and 1-3 heteroatoms, such as 3-6 carbon atoms and 1-2 heteroatom. The heterocycloalkyl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heterocycloalkyl group. Representative examples of heterocycloalkyl groups include, but are not limited to azepanyl, azetidinyl, aziridinyl, dioxolanyl, dioxolyl, imidazolidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thietanyl, 2,6- diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa-5-aza-[2.2.1]heptanyl, 2-oxa-8-azaspiro[3.5]nonanyl, 2- oxa-7-azaspiro[3.5]nonanyl, 2-oxa-8-azaspiro[3.5]nonanyl, 6-oxa-2-azaspiro[3.3]heptanyl, 2- oxa-7-azaspiro[3,4]octanyl, and 1, 3, 3a, 4, 6, 6a-hexahydrofuro[3,4-c]pyrrolyl. The term includes compounds wherein a ring member of said "(a-b) membered heterocycloalkyl" is a C(O) or carbonyl group and S(O) group. The term "(a-b membered heterocycloalkyl)-(C -Cd)alkyl" is intended to indicate a a-b membered heterocycloalkyl radical appended to the parent molecular moiety through an (C - Cd)alkyl group, as defined herein.

The term "hydrocarbon radical" is intended to indicate a radical containing only hydrogen and carbon atoms, it may contain one or more double and/or triple carbon-carbon bonds, and it may comprise cyclic moieties in combination with branched or linear moieties. Said hydrocarbon comprises 1-6 carbon atoms, e.g. 1-5, e.g. 1-4, e.g. 1-3, e.g. 1-2 carbon atoms. The term includes alkyl and cycloalkyl as indicated herein.

The term "hydroxy(Ca-Ct_>)alkyl" is intended to indicate an (Ca-Cb)alkyl group as defined above substituted with one or more hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl.

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

The term "phenyl-(Ca-Ct_>)alkyl" is intended to indicate a phenyl group appended to appended to the parent molecular moiety through an (Ca-Cb)alkyl group, as defined herein.

When two or more of the above defined or similar terms are used in combination, such as cycloalkylalkyl or phenyl-(C_a-Cb)alkyl 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 independent 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).

As used herein whenever a molecular drawing of a substituent contains an arrow - the arrow indicates the bond attaching the substituent to the rest of the molecule.

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-hydroxyethanesulfonic acid, toluenesulfonic, sulfamic or fumaric 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, zinc hydroxide, barium hydroxide, ammonia or the like, or suitable non-toxic amines, such as lower alkylamines (such as diethylamine, tetraalkylammonium hydroxide), hydroxy-lower alkylamines (such as diethanolamine, 2-(diethylamino)-ethanol, ethanolamine, triethanolamine, tromethamine, deanol), cycloalkylamines, ethylene diamine, or benzylamines, (such as benethamine and benzathine), betaine, choline hydroxide, N-methyl-glucamine, hydrabamine, lH-imidazole, 4-(2-hydroxyethyl)-morpholine, piperazine, l-(2-hydroxyethyl)- pyrrolidine, 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, and Stahl, P.H. and in Wermuth,

C.G, Handbook of Pharmaceutical Salts, Properties, Selection and Use, 2^nd Edition, Wiley-VCH, 2011 both of which are incorporated herein by reference.

The term 'monovalent cation' is intended to indicate monovalent cations such as alkali metal ions, such as for example sodium (Na⁺), potassium (K⁺) or lithium (Li⁺), or ammonium ions, such as for example NH4⁺, dialkylammonium (NH2((Ci-C4)alkyl)2)⁺, trialkylammonium (NH((Ci- C4)alkyl)3)⁺, or tetraalkylammonium (N((Ci-C4)alkyl)4)⁺, alkylammonium (H3N(Ci-C4)alkyl)⁺ or hydroxyalkylammonium (H₃N-hydroxy(Ci-C₄)alkyl)⁺, the protonated forms of L-arginine, L- lysine or the protonated forms of any pharmaceutically acceptable bases such as those mentioned above.

The term 'divalent cation' is intended to indicate divalent cations such as alkaline earth metal ions such as calcium (Ca²⁺), Magnesium (Mg²⁺), barium (Ba²⁺), or Zinc (Zn²⁺).

The term 'prodrug' is intended to indicate compounds which are drug-precursors which, upon administration, are converted to the parent drug in vivo by enzymatic and/or chemical reactions. Generally, the pro-drug is less biologically active than its parent drug. The prodrug may have improved physical-chemical properties compared to the parent drug, such as improved aqueous solubility, thereby facilitating the absorption and consequently the bioavailability of the parent compound upon administration.

The term 'parent drug' or 'parent compound' is intended to indicate the biologically active compound which is released from the prodrug via enzymatic and/or chemical processes following administration of the prodrug. The parent drug is frequently the starting material for the preparation of the corresponding prodrug. Examples of prodrugs according to the invention are prodrugs that are attached to a nitrogen or oxygen of the parent molecule.

For example when the parent molecule contains a 5- membered heteroaryl containing nitrogen substituted with hydrogen as a ring atom said hydrogen may be replaced with a substituent selected from -L-PO(OH)2, wherein L is selected from the group consisting of a bond or -CHRgO- and R_g is selected from hydrogen and (Ci-C6)alkyl to form a prodrug.

5-membered heteroaryls such as pyrrole, imidazole, pyrazole, triazole and tetrazole when attached to the reminder of the molecule via a carbon ring atom are moieties that may contain a nitrogen ring atom substituted by hydrogen.

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 a crystalline form. When water is the solvent, said species is referred to as a hydrate.

The term "or pharmaceutically acceptable salts, hydrates and solvates thereof" includes compound of formula (I) and hydrates or solvates thereof, and pharmaceutically acceptable salts of the compounds of formula(I) as well as hydrates or solvates thereof.

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 may also include 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.

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.

According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein Ri is selected from pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl, wherein the pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl is optionally substituted with one or more substituents independently selected from R_a. According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein R_a is selected from one or more (Ci-C6)alkyl, and said one or more (Ci-C6)alkyl is optionally substituted with halogen, hydroxy, (Ci-C4)alkoxy, (Ci-C4)alkyl-S-, (Ci-C4)alkyl-SO-, and (Ci-C4)alkyl-SC>2-.

According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein said pyrazolyl is optionally substituted with one or more substituents independently selected from (Ci-C6)alkyl wherein said one or more (Ci-Ce)alkyl is optionally substituted with halogen, hydroxy, (Ci-C4)alkoxy, (Ci-C4)alkyl-S-, (Ci-C4)alkyl-SO-, and (Ci-C4)alkyl-SC>2-.

According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein Ri is 2-(Ci-C3)alkyl)-pyrazol-3-yl.

According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein Ri is selected from (C3-C7)cycloalkyl and (C3-C7)cycloalkoxy, wherein said (C3- C7)cycloalkyl and (C3-C7)cycloalkoxy is optionally substituted with a substituent independently selected from R_a.

According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein Ri is 1-fluoro-cyclopropyl.

According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein R_åa and R2b are each independently selected from (C3-C7)cycloalkyl wherein said (C3- C7)cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, cyano and (Ci-C4)alkyl.

According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein R_åa and R2b are each independently selected from (C3-C4)cycloalkyl.

According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein each of R_åa and R_åb is cyclopropyl.

According to one embodiment, the invention relates to a compound of formula (I) or (la), wherein each of R_åa and R_åb is cyclobutyl.

In one or more embodiments of the present invention, the compounds of general formula I have an (EC50) value in an IL-8 release assay of less than 1 micromolar, or of less than 100 nanomolar.

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 co-solvent 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 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 amines, or 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.

Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. Any geometric isomer, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention.

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 includes all suitable isotopic variations of the compounds of general Formula I. For example, different isotopic forms of hydrogen include

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.

Some compounds have lower aqueous solubility which may affect the absorption and consequently the bioavailability of the compounds. Such compounds may advantageously be administered in the form of prodrugs improving the aqueous solubility of the parent compound. Such prodrugs which, upon administration, are converted to their parent compounds may be less active in vitro compared to their parent compounds, but because of the improved aqueous solubility, facilitating the absorption and consequently the bioavailability of the parent compounds upon administration, such prodrugs have improved in vivo activity compared to their parent compounds.

Prodrugs of the compounds of formula (I) form part of the invention claimed.

Solvates and hydrates form part of the invention claimed.

The compounds of the present invention may be useful for preventing, treating or ameliorating any of the following diseases: psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis, lichen planus, lupus nephritis, Sjogren's syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE (besides LN and DLE), multiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, pityriasis rubra pilaris, pyoderma gangrenosum, hidradenitis suppurativa, discoid lupus erythematosus, Papulopustolar rosacea, atopic dermatitis, Ichthyosis, bullous pemphigoid, scleroderma, tendinopathy, chronic wounds and cancer.

In an embodiment the invention relates to the use of a compound of general formula (I) as defined above, in the manufacture of a medicament for the prophylaxis, treatment or amelioration of any of the following diseases: psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis, lichen planus, lupus nephritis, Sjogren's syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE (besides LN and DLE), multiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, pityriasis rubra pilaris, pyoderma gangrenosum, hidradenitis suppurativa, discoid lupus erythematosus, Papulopustolar rosacea, atopic dermatitis, Ichthyosis, bullous pemphigoid, scleroderma, tendinopathy, chronic wounds and cancer.

In an embodiment the invention relates to the use of a compound of general formula (I) as defined above, in the manufacture of a medicament for the prophylaxis, treatment or amelioration of autoimmune diseases, such as psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis. In an embodiment the invention relates to a method of preventing, treating or ameliorating autoimmune diseases, such as psoriatic arthritis, lichen planus, lupus nephritis, Sjogren's syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE (besides LN and DLE), multiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, pityriasis rubra pilaris, pyoderma gangrenosum, hidradenitis suppurativa, discoid lupus erythematosus, Papulopustolar rosacea, atopic dermatitis, Ichthyosis, bullous pemphigoid, scleroderma, tendinopathy, chronic wounds and cancer, 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 general formula (I), optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

In an embodiment the invention relates to a method of preventing, treating or ameliorating autoimmune diseases, such as psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis, 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 general formula (I) or (la), 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 Compositions 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 0.0001-99.9% 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 300 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 intradermally and 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.

If the treatment involves administration of another therapeutically active compound it is recommended to consult Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9^th Ed., J.G. Hardman and L.E. Limbird (Eds.), McGraw-Hill 1995, 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 transdermal, intradermal, ophthalmic, topical, nasal, sublingual or buccal administration.

The formulations may conveniently be presented in dosage unit form and may be prepared 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, 21ed ed., 2005. 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 formulations 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.

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; for example with 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. Freeze dried tablets may be formed in a freeze-dryer from a solution of the drug substance. 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. Liposomal formulations are also suitable for parenteral administration.

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 aqueous preparation of the active ingredients. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for ophthalmic administration.

Formulations suitable for topical, such as dermal, intradermal or ophthalmic administration include liquid or semi-solid preparations, solutions or suspensions.

Formulations suitable for nasal or buccal administration include powder, self-propelling and spray formulations, such as aerosols and atomisers.

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 the invention could 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 could 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 or commercially available compounds, or may be prepared by routine synthetic methods well known to a person skilled in the art.

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. The organic solvents used were usually anhydrous. The solvent ratios indicated refer to vokvol unless otherwise noted. Thin layer chromatography was performed using Merck 60F254 silica-gel TLC plates. Visualisation of TLC plates was performed using UV light (254 nm) or by an appropriate staining technique.

Proton nuclear magnetic resonance spectra were obtained at the stated frequencies in the solvents indicated. Tetramethylsilane was used as an internal standard for proton spectra. The value of a multiplet, either defined doublet (d), triplet (t), quartet (q) or (m) at the approximate midpoint is given unless a range is quoted, (br) indicates a broad peak, whilst (s) indicates a singlet.

Mass spectra were obtained using the following methods. LCMS Method 1 was used, unless otherwise stated.

LCMS Method 1 :

Column: Acquity UPLC HSS T3 1.8pm; 2.1 x 50mm Flow: 0.7mL/min Column temp: 30°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: 1 pi

Gradient:

UPLC (inlet method): XEV Metode 1 CM MS - method : Pos_50_1000 or Neg_50_1000

Instruments: Waters Acquity UPLC, Waters XEVO G2-XS QTof, Waters PDA (Photodiode Array)

LCMS Method 2:

Column: Waters Acquity UPLC HSS T3 1.8pm, 2. 1 x 50 mm.

Column temperature: 60°C.

UV: PDA 210-400 nm.

Injection volume: 2 pi.

Eluents: A: 10 mM Ammonium acetate with 0.1% formic acid, B: 100% Acetonitrile with 0.1% formic acid.

Gradient:

MS: Electrospray switching between positive and negative ionisation.

Instruments: Waters ACQUITY UPLC, Waters SQD, Waters PDA (Photodiode array)

Basic preparative HPLC conditions:

Column: XBridge Prep C18 5pm OBD, 19x150 mm

Eluents: Ammonium formate (50 mM)/acetonitrile, 10-100% acetonitrile

Flow: 30 mL/min

Acidic preparative HPLC conditions:

Column: XTerra^® RP-18 5pm OBD, 19x150 mm

Eluents: 0.1% formic acid in water/acetonitrile, 10-100% acetonitrile

Flow: 30 mL/min

The following abbreviations have been used throughout: AcOH acetic acid

ALK alkyl

Boc tert-butoxycarbonyl

BOP (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

BuLi butyllithium

CBz benzyloxycarbonyl

CDI carbonyldiimidazole

CPME cyclopentyl methyl ether

DCC dicyclohexylcarbodiimide

DCM dichloro methane

DIPEA diisopropylethylamine

DMF L/,/V-dimethylformamide

DMSO dimethylsulfoxide dppf l,l'-bis(diphenylphosphino)ferrocene

EDC /V-(3-Dimethylaminopropyl)-/V'-ethylcarbodiimide

EtOAc ethyl acetate

EtOH ethanol

FMOC fluorenylmethoxycarbonyl

HATU 1- [bis(d imethyla mino) methylene]- lH-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

HBTU /V_//V_//V^, _//V^,-Tetramethyl-0-(l/-/-benzotriazol-l-yl)uronium hexafluorophosphate

HPLC high-performance liquid chromatography

I PA isopropyl alcohol

LAH lithium aluminium hydride

LCMS liquid chromatography-mass spectrometry

LHMDS lithium bis(trimethylsilyl)amide

Me methyl

MeCN acetontitrile

MeOH methanol

MHz megahertz

NBS N-bromosuccinimide

NMR nuclear magnetic resonance ppm parts per million

Prep. Preparation

Prep. HPLC preparative HPLC

PyBOP (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate

RT retention time SEM 2-(trimethylsilyl)ethoxymethyl

SFC supercritical fluid chromatography

SM starting material

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

Ts tosyl

T3P propanephosphonic acid anhydride

General Methods

Compounds of the invention may be prepared according to the following non-limiting general methods and examples:

Scheme 1

Synthesis of a compound of general formula (I), wherein Ri, R2a, R_åb, R3 and X are as previously defined and PG represents a suitable protecting group:

Ri

Int 4 Int 5 (I)

Compounds of general formula (I) can be prepared, as shown in Scheme 1. Compounds of general formula (Int 1), which are either commercially available or are synthesised in a racemic form or an enantiomerically pure form, are coupled with amines of general formula (Int 2), which are synthesised (for preparations see: WO2018229079A1), in the presence of a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC and in most of the cases in the presence of a base, such as DIPEA or TEA, in a suitable solvent, such as DMF or MeCN to form compounds of formula (Int 3). Protecting groups (PG), such as Boc, Cbz or FMOC, on compounds of general formula (Int 3) can be removed or selectively removed by methods known to those skilled in the art. Compounds of general formula (Int 4) are coupled with compounds of general formula (Int 5), which are either commercially available or synthesised, in the presence of a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC and in most of the cases in the presence of a base, such as DIPEA or TEA, in a suitable solvents, such as DMF or MeCN to form compounds of general formula (I). Racemic compounds of general formula (Int 3), (Int 4) or (I) can be separated by chiral SFC, to give the S-enantiomers of compounds of general formula (Int 3), (Int 4) or (I).

Scheme 2

Alternative preparation of a compound of general formula (I), wherein Ri, R2a, R_åb, R3 and X are as previously defined and PG and PGi represent suitable protecting groups.

Int 8 Int 5 Int 9 (I)

Compounds of general formula (I) can be prepared, as shown in Scheme 2. Compounds of general formula (Int 1), which are either commercially available or are synthesised in a racemic form or an enantiomerically pure form, are coupled with compounds of general formula (Int 6), which are synthesised with a suitable orthogonal protecting group (PGi), such as SEM, (for preparations see: WO2018229079A1), in the presence of a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC and in most of the cases in the presence of a base, such as DIPEA or TEA, in a suitable solvent, such as DMF or MeCN to form compounds of formula (Int 7). Protecting groups (PG), such as Boc, Cbz or FMOC, on compounds of general formula (Int 7) can be selectively removed by methods known to those skilled in the art. Compounds of general formula (Int 8) are coupled with compounds of general formula (Int 5), which are either commercially available or synthesised, in the presence of a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC and in most of the cases in the presence of a base, such as DIPEA or TEA, in a suitable solvents, such as DMF or MeCN to form compounds of general formula (Int 9). Protecting groups (PGi) on compounds of general formula (Int 9) can be removed or selectively removed by methods known to those skilled in the art to give compounds of general formula (I).

Scheme 3

Preparation of a compound of formula (Int 1), wherein Råa and Råb are as previously defined and PG represents a suitable protecting group:

Int 10 Int 11 Int 12 Int 1

Compounds of formula (Int 13) can be prepared as shown in Scheme 3. Compounds of general formula (Int 10) which are either commercially available or are synthesised can be reacted with ammonium carbonate and potassium cyanide in water and methanol to form compounds of general formula (Int 11) (For Bucherer Bergs reaction, see: Chemical Reviews 2017 117 (23), 13757-13809). Compounds of general formula (Int 12) can be prepared by treatment of compounds of formula (Int 11) with alkali hydroxides such as potassium hydroxide in water. The amines of general formula (Int 12) can be protected by methods known to those skilled in the art, to give compounds of general formula (Int 1), where a suitable PG can be Boc or Cbz.

Scheme 4

Preparation of a compound of general formula (Int 5) as previously defined.

Int 14 Int 15 reduction carboxylation

~

Int 16 Int 17

Compounds of formula (Int 17) can be prepared as shown in Scheme 4. Pyrazole can be reacted with compounds of general formula (Int 14) where LG is a suitable leaving group such as Br, Cl or OTs, in the presence of a base such as K2CO3 or CS2CO3 in a suitable solvent such as MeCN or DMF, to give compounds of general formula (Int 15). Reduction of compounds of formula (Int 15) to give compounds of formula (Int 16) can be achieved with a strong reducing agent such as LAH in a suitable solvent such as THF or Et20. Compounds of general formula (Int 17) can be prepared by treatment of compounds of formula (Int 16) with a strong base such as n-BuLi in the presence of TMEDA and gaseous CO_å in a suitable solvent such as THF.

Scheme 5

Preparation of a compound of general formula (Int 23), wherein R3 is Cl, PGi represents a suitable protecting group and Q is a halogen such as Br or I.

Int 21 Int 23

Compounds of general formula (Int 22) can be prepared as shown in Scheme 5. Compounds of formula (Int 18) can be protected with a suitable orthogonal protecting group, such as SEM, using methods known to those skilled in the art. Compounds of general formula (Int 19) can be reacted with Br_å in aqueous tert-BuOH or 1,4-dioxane, or pyridinium tribromide in 1,4- dioxane to give compounds of formula (Int 20). Compounds of formula (Int 21) can be accessed by reacting compounds of formula (Int 19) with zinc dust in a suitable solvent mix such as THF and saturated aqueous NH4CI. Compounds of formula (Int 21) can be reacted with compounds of formula (Int 22) in the presence of a suitable base such as LHMDS, n-BuLi or CS2CO3 in a suitable solvent such as THF or DMF to give compounds of formula (Int 23).

Scheme 6

Synthesis of a compound of general formula (Int 33), wherein R3 = F, PGi represents a suitable protecting group and Q is a halogen such as Br or I.

Compounds of formula (Int 33) can be prepared as shown in Scheme 6. Compounds of formula (Int 24) can be reacted with iodine monochloride in a suitable solvent such as AcOH, to afford compounds of formula (Int 25). Compounds of formula (Int 25) can be reacted with alkoxyvinylborylates under standard Suzuki coupling conditions using a catalyst such as Pd(dppf)Cl2 or Pd(OAc)2 and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, in the presence of a base such as K2CO3 or K3PO4 in a suitable solvent such as DMF, MeCN, THF or 1,4-dioxane and water to give compounds of formula (Int 26). Cyclisation to compounds of formula (Int 27) can be effected by the treatment of compounds of formula (Int 26) with concentrated hydrogen chloride in a suitable solvent such as MeOH or EtOH. Compounds of formula (Int 27) can be protected with a suitable orthogonal protecting group, such as SEM, using methods known to those skilled in the art. Compounds of general formula (Int 28) can be reacted with BG2 in aqueous tert-BuOH or 1,4-dioxane, or pyridinium tribromide in 1,4-dioxane to give compounds of formula (Int 29). Compounds of formula (Int 30) can be accessed by reacting compounds of formula (Int 29) with zinc dust in a suitable solvent mix such as THF and saturated aqueous NH4CI. Compounds of formula (Int 30) can be reacted with compounds of formula (Int 22) in the presence of a suitable base such as LHMDS, n-BuLi or CS2CO3 in a suitable solvent such as THF or DMF to give compounds of formula (Int 31). Compounds of formula (Int 31) can be reacted with (4-methoxyphenyl)methanamine in a suitable solvent such as MeCN , with or without a suitable base such as DIPEA or TEA, at ambient or elevated temperature to give compounds of formula (Int 32). The removal of the benzyl group from compounds of formula (Int 32) can be effected under standard hydrogenation conditions, known to those skilled in the art, to afford compounds of formula (Int 33). Scheme 7

Alternative preparation of a compound of general formula (Int 7), wherein Ri, R2a, R_åb R3 and X are as previously defined and PG and PGi represent suitable protecting groups.

Int 23

Buchwald/Hartwig

conditions

Int 1 Int 34 solvent Int 7

Compounds of general formula (Int 7) can be prepared as shown in Scheme 7. Compounds of general formula (Int 1), which are either commercially available or are synthesised in a racemic form or an enantiomerically pure form, are reacted with ammonium chloride in the presence of a coupling reagent such as T3P, CDI, DCC, HATU, HBTU and EDC and in the majority of cases, in the presence of a base, such as DIPEA or TEA, in a suitable solvent, such as DMF or acetonitrile or reacted with ammonium bicarbonate in the presence of tert- butoxycarbonyl tert-butyl carbonate and pyridine in a solvent such as 1,4-dioxane to form compounds of formula (Int 34). Compounds of formula (Int 34) can be reacted with compounds of formula (Int 23) in the presence of tetrakis(triphenylphosphine)palladium(0) or palladium(II) acetate and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and a base such as K2CO3 OR CS2CO3 in a solvent such as THF or DMF, to form compounds of formula (Int 7).

Scheme 8

Alternative preparation of a compound of general formula (Int 7), wherein Ri, R2a, R_åb R3 and X are as previously defined, Q represents halogen and PG and PGi represent suitable protecting groups.

Int 1 Int 35 Int 7

Compounds of general formula (Int 7) can be prepared as shown in Scheme 8. Compounds of general formula (Int 1), which are either commercially available or are synthesised in a racemic form or an enantiomerically pure form, are reacted to form activated esters of general formula (Int 35). Typically this could be a reaction of compound of general formula (Int 1) with 2,3,4,5,6-pentafluorophenol, with a coupling reagent such as DCC, EDC or DIC, in the presence of a suitable base such as DMAP, in a solvent such as MeCN or DCM. Compounds of general formula (Int 35) can be reacted with compounds of general formula (Int 33) in the presence of suitable alkylmagnesium halides such as ^lBuMgCI or ^lBuMgBr, in a suitable solvent such as THF, to give the compounds of general formula (Int 7).

PREPARATIONS AND EXAMPLES

PREPARATIONS

Preparation 1 : (l-cyclopropyl-2-methoxy-vinyl)cyclopropane

n-BuLi (2.5 M solution in heptanes, 26 mL, 65.6 mmol) was added slowly to a suspension of methoxymethyl(triphenyl)phosphonium chloride (22.5 g, 65.6 mmol) in dry THF (130 mL) at 5°C under argon. The resulting deep red solution was stirred for 20 min, then dicyclopropyl- methanone (5 mL, 4.82 g, 43.8 mmol) was added and the reaction mixture was stirred overnight at 60°C under argon. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo and the residue was purified by dry-flash chromatography (silica gel, eluting with hexane). Crude title compound (5.69 g, 94%) was isolated as a clear oil which was used without further purification. 1H NMR (300 MHz, Chloroform-d) d 5.86 (dd, J = 1.6, 0.7 Hz, 1H), 3.57 (s, 3H), 1.87 - 1.74 (m, 1H), 0.89 - 0.78 (m, 1H), 0.76 - 0.67 (m, 2H),

0.64 - 0.57 (m, 2H), 0.51 - 0.41 (m, 2H), 0.27 - 0.19 (m, 2H).

Preparation 2: 2,2-dicyclopropylacetaldehyde

The compound of Preparation 1 (5.6 g, 41 mmol) was dissolved in THF (20 mL) and 6M HCI (20 mL) was added. The mixture was stirred vigorously for 1 week at room temperature. The reaction mixture was extracted with ether (2 x 50 mL), dried (NazSCU) and carefully evaporated. Crude 2,2-dicyclopropylacetaldehyde (2.80 g, 56%) was isolated as a pale yellow oil which was used directly in the following step without any further purification. Preparation 3: 2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid

The compound of Preparation 2 (2.80 g, 22.5 mmol) was placed in a 20 mL microwave vial with KCN (2.20 g, 33.8 mmol) and ammonium carbonate (6.50 g, 67.6 mmol) in MeOH:water (8 mL:8 mL). The vial was capped and stirred at 60°C (conventional heating) for 2 days to give a brown mixture with some precipitation. 4M HCI was added until the pH was less than 5. After cooling to room temperature the brown solid was filtered off, washed with water (3 mL) and dried to give crude hydantoin (4.38 g, 22.6 mmol) that was used without further purification.

The crude hydantoin (4.38 g, 22.6 mmol) was heated at reflux in 5M NaOH (30 mL) overnight, then cooled in an ice bath and 5M HCI (20 mL) was added slowly. THF (30 mL) was added followed by Boc anhydride (4.93 g, 22.6 mmol). The mixture was stirred at room temperature for 1 hour then 5M HCI was added carefully until the pH was between 3 and 4. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were dried (NazSCU) and evaporated. Purification by column chromatography (silica gel, eluting with EtOAc: heptane) gave the title compound (1.32 g, 22%) as a pale yellow oil. 1H NMR (300 MHz, Chloroform-d) Mixture of rotamers d 7.90 (br s, 1H), 5.78 (br, 0.15H), 5.26 (d, J = 9.2 Hz, 0.85H), 4.55 (d, J = 9.2 Hz, 0.85H), 4.37 (br, 0.15H), 1.46 (s, 9H), 1.33 - 1.21 (m, 1H), 0.85 - 0.64 (m, 2H), 0.61 - 0.36 (m, 4H), 0.32 - 0.13 (m, 4H); LCMS (METHOD 2) (ES) : m/z 268.4 [M-H]-, RT = 0.70 min.

Preparation 4: (4-methoxyphenyl)methyl (2R)-2-(tert-butoxycarbonylamino)-3,3- dicyclopropyl-propanoate and (4-methoxyphenyl)methyl (2S)-2-(tert-butoxycarbonylamino)- 3,3-dicyclopropyl-propanoate

EDC (7.77 g, 40.5 mmol) was added to a mixture of the acid of Preparation 3 (7.28 g, 27.0 mmol), 4-methoxybenzylalcohol (4.48 g, 32.4 mmol) and DMAP (3.3 g, 27.0 mmol) in DCM (100 mL) and stirred overnight at room temperature. The reaction mixture was washed with 0.25M HCI (15 mL), dried (Na2S04) and evaporated. Purification by column chromatography (silica, eluting with EtOAc: heptane) gave the racemic title compound (9.30 g, 88%) as a white solid. 1H NMR (300 MHz, Chloroform-d) d 7.38 - 7.18 (m, 2H), 6.98 - 6.79 (m, 2H), 5.24 (d, J = 9.3 Hz, 1H), 5.09 (s, 2H), 4.53 (d, J = 9.3 Hz, 1H), 3.81 (s, 3H), 1.44 (s, 9H), 0.80 - 0.55 (m, 3H), 0.55 - 0.26 (m, 4H), 0.25 - 0.10 (m, 3H), 0.07 - -0.05 (m, 1H); LCMS (METHOD 2) (ES) : m/z 390.3 [M + H]⁺, RT = 0.95 min.

The two enantiomers were separated by preparative chiral SFC giving (4- methoxyphenyl)methyl (2R)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoate (Preparation 4a) (Column: Lux A2 (4.6mm x 250mm, 5pm), Eluent: 20:80 IPA:C02 (0.2% v/v NH3), Temp: 40°C, Flow rate: 4 mL/min, BPR: 125 Bar, retention time: 1.4 min) and (4- methoxyphenyl)methyl (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoate (Preparation 4b) (Column: Lux A2 (4.6mm x 250mm, 5pm), Eluent: 20:80 IPA:C0₂ (0.2% v/v NH3), Temp: 40°C, Flow rate: 4 mL/min, BPR: 125 Bar, retention time: 1.9 min).

Preparation 5: (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid

A solution of (4-methoxyphenyl)methyl (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl- propanoate (Preparation 4b) (5.30 g, 13.6 mmol) in MeOH (25 mL) was hydrogenated over 10% Pd/C (250 mg) using a hydrogen balloon. After 2Vi hours the reaction mixture was filtered and evaporated. Purification by column chromatography (silica, eluting with EtOAc: heptane) gave the title compound (3.50 g, 96%) as a clear syrup. 1H NMR (400 MHz, DMSO-d6) Mixture of rotamers d 12.41 (s, 1H), 6.81 (d, J = 9.0 Hz, 0.82H), 6.48 (d, J = 8.2 Hz, 0.18H), 4.12 (dd, J = 9.0, 4.4 Hz, 0.82H), 4.05 (s, 0.18H), 1.39 (s, 7.4H), 1.25 (s, 1.6H), 1.02 - 0.88 (m, 1H), 0.83 - 0.72 (m, 1H), 0.56 - 0.42 (m, 2H), 0.41 - 0.20 (m, 4H), 0.19 - 0.01 (m, 3H); LCMS (METHOD 2) (ES) : m/z 268.4 [M-H] , RT = 0.71 min.

Preparation 6: tert-butyl N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[indoline-3,4'- tetrahydropyran]-6-yl)amino]ethyl]carbamate.

HATU (40.8 mg, 0.107 mmol) was added to a solution of the compound of Preparation 5 (26.7 mg, 0.099 mmol), 6-aminospiro[indoline-3,4'-tetrahydropyran]-2-one (synthesis described in WO2018229079, 18.0 mg, 0.083 mmol) and DIPEA (0.042 mL, 0.247 mmol) in DMF (0.25 mL) at room temperature. The reaction mixture was stirred for 2 h, before it was quenched with 10% aq. sodium bicarbonate solution (2.5 mL). The aqueous mixture was extracted with EtOAc (2 x 1.5 mL). The combined organic extracts were washed with sat. brine solution (1.0 mL), dried over NazSCU, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with 30-50% EtOAc in heptane, to afford the title compound as a pale yellow solid. (28.2 mg, 69% yield). LCMS (METHOD 2) (ES) : m/z 470.4 [M + H]⁺, RT = 0.74 min.

Preparation 7: (2S)-2-amino-3,3-dicyclopropyl-N-(2-oxospiro[indoline-3,4'-tetrahydropyran]- 6-yl)propenamide hydrochloride.

Hydrogen chloride (4M solution in dioxane, 0.3 mL, 1.2 mmol) was added to a solution of the compound of Preparation 6 (28.2 mg, 0.06 mmol) in MeOH (0.3 mL) at room temperature and the mixture was stirred for 45 min. The reaction mixture was concentrated in vacuo, then azeotroped with DCM (2 x 2 mL) to afford the title compound as a pale orange solid. (26.0 mg, assume 100% yield). LCMS (METHOD 2) (ES) : m/z 370.3 [M + H]⁺, RT = 0.46 min.

Preparation 8: tert-butyl N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[[2-oxo-l-(2- trimethylsilylethoxymethy spirotpyrrolotS^-clpyridine-S^'-tetrahydropyranJ-e- yl]amino]ethyl]carbamate

HBTU (236 mg, 0.622 mmol) was added to a solution of the compound of Preparation 5 (134.1 mg, 0.498 mmol), 6-amino-l-(2-trimethylsilylethoxymethyl)spiro[pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-2-one (synthesis described in WO2018229079, 145 mg, 0.415 mmol) and TEA (0.104 mL, 0.747 mmol) in DMF (0.5 mL) at room temperature. The reaction mixture was stirred for 48 h. LCMS indicated little product but mainly unreacted starting materials. DIPEA (0.145 mL, 0.83 mmol) and HATU (220.8 mg, 0.581 mmol) were added and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with MeCN (10 mL) and purified by basic prep. HPLC to afford the title compound. (106 mg, 40% yield). LCMS (METHOD 2) (ES) : m/z 601.6 [M + H]⁺, RT = 0.97 min.

Preparation 9: (2S)-2-amino-3,3-dicyclopropyl-N-[2-oxo-l-(2- trimethylsilylethoxymethy spirotpyrrolotS^-clpyridine-S^'-tetrahydropyranJ-e- yljpropenamide hydrochloride

According to the method of Preparation 7 the compound of Preparation 8 (106 mg, 0.168 mmol) was reacted to give the title compound as an off-white solid (90 mg, assume 100% yield). LCMS (METHOD 2) (ES) : m/z 501.4 [M + H]⁺, RT = 0.73 min.

Preparation 10: ethyl 2-pyrazol-l-ylpropanoate

K2CO3 (9.74 g, 70.5 mmol) was added to a solution of pyrazole (4.0 g, 58.9 mmol) and ethyl 2-bromopropanoate (9.41 mL, 64.6 mmol) in MeCN (80 mL) and the reaction mixture was stirred at 85°C for 4 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with Etå0 (3 x 50 ml). The combined organic layer was dried over Na2S04, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a clear oil (4.48 g, 45% yield). 1H NMR (400 MHz, Chloroform-d) d 7.54 (d, J = 2.2 Hz, 1H), 6.32 (t, J = 2.1 Hz, 1H), 5.11 (q, J = 7.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 1H), 1.79 (d, J = 7.4 Hz, 1H), 1.25 (t, J = 7.1 Hz, 2H); LCMS (METHOD 2) (ES) : m/z 169.1 [M + H]⁺, RT = 0.51 min.

Preparation 11 : 2-pyrazol-l-ylpropan-l-ol

LAH (1M solution in THF, 14.6 mL, 14.6 mmol) was added slowly to a solution of the compound of Preparation 10 (4.48 g, 26.6 mmol) in anhydrous Et20 (50 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with citric acid (5% aqueous solution, 15 mL) and extracted with Et20 (50 ml). The combined organic layer was dried over NazSCU, filtered and concentrated in vacuo to afford the title compound as a clear oil (4.48 g, 45% yield). 1H NMR (400 MHz, Chloroform-d) d 7.52 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 6.27 (t, J = 2.1 Hz, 1H), 4.41 (pd, J = 6.8, 4.1 Hz, 1H), 4.06 - 3.76 (m, 2H), 3.30 (s, 1H), 1.51 (d, J = 6.9 Hz, 3H).

Preparation 12: 2-(2-hydroxy-l-methyl-ethyl)pyrazole-3-carboxylic acid

n-BuLi (2.5 M solution in heptanes, 15.0 mL, 37.7 mmol) was added dropwise to a solution of the compound of Preparation 11 (1.90 g, 15.1 mmol) in anhydrous THF (50 mL) at 0°C. The resulting suspension was stirred at 0°C for 30 minutes. The reaction mixture was purged with carbon dioxide gas for 10 minutes. The reaction mixture was concentrated in vacuo and the pH was adjusted to 3-4 with hydrogen chloride (4M aq. solution). The aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude solid was triturated with Et20: hexane (1 : 1, 20 mL) and dried to afford the title compound as an off-white solid (1.60 g, 62% yield). 1H NMR (300 MHz, DMSO-d6) d 13.18 (s, 1H), 7.54 (dd, J = 1.9, 0.5 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 5.59 - 5.16 (m, 1H), 3.74 - 3.54 (m, 2H), 1.34 (d, J = 6.7 Hz, 3H).

Preparation 13: 2-[(4,6-dichloropyrrolo[3,2-c]pyridin-l-yl)methoxy]ethyl-trimethyl-silane.

Sodium hydride (1.19 g, 29.7 mmol) was added to a solution of 4,6-dichloro-lH-pyrrolo[3,2- cjpyridine (5.05 g, 27.0 mmol) in dry DMF (50 mL) under nitrogen at 5°C. The mixture was stirred for 15 min, then SEM chloride (5.73 mL, 5.40 g, 32.4 mmol) was added slowly. The dark mixture was stirred for 1 hour at 5°C then poured into water (300 mL) and extracted with Etå0 (3 x 120 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a colourless solid (7.4 g, 86% yield). LCMS (METHOD 2) (ES) : m/z 317.1 [M + H]⁺, RT = 0.99 min.

Preparation 14: 3,3-dibromo-4,6-dichloro-l-(2-trimethylsilylethoxymethyl)pyrrolo[3,2- c]pyridin-2-one. NBS (18.6 g, 104 mmol) was added in small portions to a solution the compound of Preparation 13 (9.45 g, 29.8 mmol) in dioxane:THF:water (50 mL: 50 mL:30 mL) at room temperature and stirred for 18 hours. The reaction mixture was diluted with water (400 mL) and extracted with EtOAc (2 x 150 mL). The combined organic phase was dried over NazSCU, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a yellow oil (11.2 g, 77% yield). 1H NMR (400 MHz, Chloroform-d) d 7.05 (s, 1H), 5.19 (s, 2H), 3.63 - 3.56 (m, 2H), 0.98 - 0.84 (m, 2H), -0.02 (s, 9H).

Preparation 15: 4,6-dichloro-l-(2-trimethylsilylethoxymethyl)-3H-pyrrolo[3,2-c]pyridin-2-one.

Zinc dust (7.21 g, 110 mmol) was added to a biphasic mixture of the compound of Preparation 14 (6.77 g, 13.8 mmol) in THF: saturated aq. NH4CI (80 mL:30 mL) cooled by an ice water bath and stirred for 1 hour. The reaction mixture was diluted with water (200 mL) and filtered. The filtrate was extracted with diethyl ether (200 mL), dried over NazSCU and concentrated in vacuo. The crude title compound was isolated as a pale yellow solid which was used without further purification (4.50 g, 98% yield). 1H NMR (400 MHz, Chloroform-d) d 1H NMR (400 MHz, Chloroform-d) d 6.97 (s, 1H), 5.09 (s, 2H), 3.61 - 3.52 (m, 4H), 0.96 - 0.87 (m, 2H), - 0.01 (s, 9H); LCMS (METHOD 2) (ES) : m/z 331.2 [M + H]⁺, RT = 0.93 min.

Preparation 16: 4,6-dichloro-l-(2-trimethylsilylethoxymethyl)spiro[pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-2-one.

Cesium carbonate (2.40 g, 7.37 mmol) was added to a solution of the compound of Preparation 15 (1.23 g, 3.68 mmol) in degassed dry DMF (45 mL) at room temperature under nitrogen. The mixture was stirred for 10 min, then l-bromo-2-(2-bromoethoxy)ethane (0.509 mL, 940 mg, 4.05 mmol) was added and stirred at 70°C for 2 hours. The reaction mixture was diluted with saturated aq. NaHCCb (50 mL) and water (300 mL), then extracted with Et20 (4 x 70 mL). The combined organic phase was dried over NazSCU, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a pale orange solid (846 mg, 57% yield). 1H NMR (400 MHz, Chloroform-d) d 1H NMR (400 MHz, Chloroform-d) d 6.99 (s, 1H), 5.10 (s, 2H), 4.35 - 4.22 (m, 2H), 3.98 - 3.86 (m, 2H), 3.59 - 3.49 (m, 2H), 2.78 (ddd, J = 14.1, 12.6, 5.2 Hz, 2H), 1.46 (br d, J = 13.3 Hz, 2H), 0.95 - 0.88 (m, 2H), -0.02 (s, 9H); LCMS (METHOD 2) (ES): m/z 403.2 [M + H]⁺, RT = 0.97 min.

Preparation 17: tert-butyl N-[(lS)-l-carbamoyl-2,2-dicyclopropyl-ethyl]carbamate.

Ammonium bicarbonate (1.00 g, 13.0 mmol) was added to a solution of the compound of Preparation 5 (2.69 g, 10.0 mmol), tert-butoxycarbonyl tert-butyl carbonate (2.84 g, 13.0 mmol) and pyridine (0.50 mL, 0.49 g, 6.2 mmol) in dioxane (30 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to low volume then water (30 mL) was added and the mixture was stirred for 10 minutes. The title compound precipitated as a white solid and was filtered off and air dried and used without further purification. 1H NMR (600 MHz, DMSO-d6) d 7.21 (s, 1H), 6.96 (s, 1H), 6.45 (d, J = 9.5 Hz, 1H), 4.08 (dd, J = 9.6, 5.0 Hz, 1H), 1.39 (s, 9H), 0.88 - 0.63 (m, 2H), 0.52 - 0.39 (m, 2H), 0.38 - 0.22 (m, 3H), 0.21 - 0.08 (m, 4H).

Preparation 18: tert-butyl N-[(lS)-l-[[4-chloro-2-oxo-l-(2- trimethylsilylethoxymethy spirotpyrrolotS^-clpyridine-S^'-tetrahydropyranJ-e- yl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate.

Palladium(II)acetate (44 mg, 0.19 mmol) and Xantphos (224 mg, 0.388 mmol) were added to a mixture of the compound of Preparation 17 (286 mg, 1.07 mmol), the compound of Preparation 16 (391 mg, 0.969 mmol) and potassium carbonate (268 mg, 1.94 mmol) in THF (8 mL) in a microwave vial under nitrogen. The reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was concentrated in vacuo. Water (5 mL) and saturated brine (5 mL) were added and the mixture was extracted with EtOAc (2 x 15 mL). The combined organic phase was dried over NazSCU, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a colourless solid (500 mg, 81% yield). 1H NMR (600 MHz, Chloroform-d) d 8.54 (s, 1H), 7.98 (s, 1H), 5.28 (s, 1H), 5.11 (s, 2H), 4.43 (s, 1H), 4.37 - 4.24 (m, 2H), 3.91 (dd, J = 11.6, 5.1 Hz, 2H), 3.62 - 3.51 (m, 2H), 2.76 (dddd, J = 13.9, 12.6, 5.3, 3.3 Hz, 2H), 1.47 (s, 11H),

0.94 - 0.89 (m, 3H), 0.80 - 0.64 (m, 2H), 0.60 - 0.51 (m, 2H), 0.51 - 0.38 (m, 2H), 0.32 - 0.16 (m, 4H), -0.04 (s, 9H); LCMS (METHOD 2) (ES) : m/z 635.5 [M + H]⁺, RT = 1.06 min.

Preparation 19: (2S)-2-amino-N-(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)-3,3-dicyclopropyl-pro panamide.

A mixture of the compound of Preparation 18 (500 mg, 0.79 mmol) and TFA (3 mL) in DCM (5 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo then dissolved in MeOH (3 mL). Ethylenediamine (0.5 mL) was added and the mixture was stirred at room temperature for 1 hour before it was diluted with water (10 mL). The solid precipitate was filtered off and dried in vacuo. The title compound was isolated as a colourless solid (290 mg, 91%). LCMS (METHOD 2) (ES) : m/z 405.3 [M + H]⁺, RT = 0.63 min.

Preparation 20: 2,6-difluoro-3-iodo-pyridin-4-amine.

Iodine monochloride (3.23 mL, 10.0 g, 61.7 mmol) was added to a solution of 2,6- difluoropyridin-4-amine (8.03 g, 61.7 mmol) in AcOH (80 mL) at room temperature, then stirred at 50°C for 2 hours. The orange suspension was cooled to room temperature and then concentrated in vacuo. Water (200 mL) was added and the pH adjusted to 7-8 with solid K2CO3. The mixture was extracted with EtOAc (2 x 150 mL), dried over NazSCU, filtered and concentrated in vacuo to give the crude title compound as a colourless solid which was used without any further purification (15.3 g, 97% yield). 1H NMR (400 MHz, DMSO-d6) d 6.95 (br s, 2H), 6.15 (s, 1H); LCMS (METHOD 2) (ES) : m/z 257.0 [M + H]⁺, RT = 0.60 min.

Preparation 21 : 3-[(E)-2-butoxyvinyl]-2,6-difluoro-pyridin-4-amine.

Pd(dppf)Cl2 (1.2 g, 1.7 mmol) was added to a mixture of the compound of Preparation 20 (8.6 g, 34 mmol), 2-[(E)-2-butoxyvinyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (11 g, 50 mmol) and potassium carbonate (7.0 g, 50 mmol) in dioxane (80 mL) and water (20 mL) under nitrogen and stirred at 80°C for 18 hours. The dark brown mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with saturated brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a colourless solid (4.66 g, 61% yield). LCMS (METHOD 2) (ES) : m/z 229.1 [M + H]⁺, RT = 0.74 min and 0.77 min.

Preparation 22: 4,6-difluoro-lH-pyrrolo[3,2-c]pyridine.

Concentrated hydrogen chloride (3 mL, 36 mmol) was added to a solution of the compound of Preparation 21 (4.66 g, 20.4 mmol) in MeOH (40 mL) and stirred at 50°C for 3 hours. The reaction mixture was concentrated in vacuo until the product started to precipitate, then the mixture was neutralised with K2CO3 (10% aq. solution) and the crude title product was filtered off. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a pale yellow solid (2.22 g, 71% yield). 1H NMR (400 MHz, DMSO-d6) d 11.97 (br s, 1H), 7.51 (ddd, J = 3.0, 2.3, 0.6 Hz, 1H), 7.03 (dt, J = 1.9, 0.9 Hz, 1H), 6.60 (ddd, J = 3.2, 2.0, 1.0 Hz, 1H); LCMS (METHOD 2) (ES) : m/z 155.1 [M + H]⁺, RT = 0.55 min. Preparation 23: 2-[(4,6-difluoropyrrolo[3,2-c]pyridin-l-yl)methoxy]ethyl-trimethyl-silane.

Sodium hydride (60%, 630 mg, 16 mmol) was added to a solution of the compound of Preparation 22 (2.20 g, 14 mmol) in dry DMF (20 mL) at 5°C under nitrogen. After 10 minutes SEM chloride (2.8 mL, 2.6 g, 16 mmol) was added and the reaction mixture was stirred for 1 hour at 5°C. The reaction mixture was quenched with saturated NhUCI (aq. solution, 50 mL) and extracted with EtzO (2 x 50 mL). The combined organic phase was dried over NazSCU, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a clear oil (3.66 g, 90%). 1H NMR (400 MHz, Chloroform-d) d 7.16 (dd, J = 3.5, 0.7 Hz, 1H), 6.83 (dd, J = 1.7, 0.9 Hz, 1H), 6.62 (dd, J = 3.5, 0.9 Hz, 1H), 5.42 (s, 2H), 3.53 - 3.42 (m, 2H), 0.95 - 0.85 (m, 2H), -0.06 (s, 9H); LCMS (METHOD 2) (ES): m/z 285.2 [M + H]⁺, RT = 0.93 min.

Preparation 24: 3,3-dibromo-4,6-difluoro-l-(2-trimethylsilylethoxymethyl)pyrrolo[3,2- c]pyridin-2-one.

NBS (7.09 g, 39.8 mmol) was added in small portions to a solution of the product of Preparation 23 (3.66 g, 12.9 mmol) in dioxane:water (60 mL:20 mL) at room temperature for 18 hours. No work-up was performed and the crude reaction mixture was used directly in the next reaction. LCMS (METHOD 2) (ES): m/z 455.0 [M]-, RT = 0.98 min.

Preparation 25: 4,6-difluoro-l-(2-trimethylsilylethoxymethyl)-3H-pyrrolo[3,2-c]pyridin-2-one.

Saturated NH4CI (aq. solution, 40 mL) was added to the reaction mixture from Preparation 24, followed by THF (25 mL). Zinc dust (6.73 g, 102.8 mmol) was added in small portions to the biphasic mixture under vigorous stirring at room temperature. The mixture was stirred for 1 hour, then the zinc residues were filtered off. The filtrate was diluted with saturated brine (100 mL) and extracted with diethyl ether (2 x 100 mL). The combined organic phase was dried over Na2SC>4, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a clear oil (2.86 g, 74% yield). 1H NMR (400 MHz, Chloroform-d) d 6.52 (br s, 1H), 5.12 (s, 2H), 3.67 - 3.42 (m, 4H), 0.95 - 0.89 (m, 2H), -0.01 (s, 9H); LCMS (METHOD 2) (ES) : m/z 301.2 [M + H]⁺, RT = 0.86 min.

Preparation 26: 4,6-difluoro-l-(2-trimethylsilylethoxymethyl)spiro[pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-2-one.

Cesium carbonate (6.20 g, 19.0 mmol) was added to a solution of the compound of Preparation 25 (2.86 g, 9.52 mmol) in dry DMF (10 mL) at room temperature under nitrogen. The mixture was stirred for 10 min, then l-bromo-2-(2-bromoethoxy)ethane (1.32 mL, 2.43 g, 10.5 mmol) was added and the reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was diluted with water (300 mL) and saturated NH4CI (50 mL) and extracted with Etå0 (2 x 100 mL). The combined organic phase was dried over NazSCU, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a clear oil (2.75 g, 78% yield). 1H NMR (400 MHz, Chloroform-d) d 6.53 (dd, J = 2.0, 1.1 Hz, 1H), 5.11 (s, 2H), 4.23 (dddd, J = 12.1, 10.9, 2.8, 1.3 Hz, 2H), 3.93 (dt, J = 12.0, 4.0 Hz, 2H), 3.59 - 3.50 (m, 2H), 2.28 (ddd, J = 14.0, 10.8, 4.6 Hz, 2H), 1.78 - 1.67 (m, 2H), 0.94 - 0.88 (m, 2H), -0,02 (s, 9H); LCMS (METHOD 2) (ES) : m/z 371.3 [M + H]⁺, RT = 0.92 min.

Preparation 27: 4-fluoro-6-[(4-methoxyphenyl)methylamino]-l-(2- trimethylsilylethoxymethyl)spiro[pyrrolo[3,2-c]pyridine-3,4^l-tetrahydropyran]-2-one.

A mixture of the compound of Preparation 26 (405 mg, 1.09 mmol) and (4- methoxyphenyl)methanamine (0.714 mL, 750 mg, 5.47 mmol) in MeCN (2.5 mL) was heated in the microwave at 135°C for 2 hours. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in saturated NaHC03 (20 mL) and extracted with Etå0 (2 x 25 mL). The combined organic phase was dried over Na2S04, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a pale yellow solid (440 mg, 83% yield). 1H NMR (400 MHz, Chloroform- d) d 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.93 (d, J = 2.2 Hz, 1H), 5.14 - 5.07

(m, 1H), 5.03 (s, 2H), 4.40 (d, J = 5.2 Hz, 2H), 4.18 (dddd, J = 11.7, 10.4, 3.0, 1.2 Hz, 2H),

3.90 (dt, J = 11.8, 4.3 Hz, 2H), 3.79 (s, 3H), 3.56 - 3.45 (m, 2H), 2.17 (ddd, J = 14.4, 10.3, 4.4 Hz, 2H), 1.71 (dt, J = 14.1, 3.5 Hz, 2H), 0.90 - 0.85 (m, 2H), -0.04 (s, 9H); LCMS (METHOD 2) (ES) : m/z 488.4 [M + H]⁺, RT = 0.95 min.

Preparation 28: 6-amino-4-fluoro-l-(2-trimethylsilylethoxymethyl)spiro[pyrrolo[3,2- c]pyridine-3,4'-tetrahydropyran]-2-one.

The compound of Preparation 27 (1.80 g, 3.69 mmol) was dissolved in MeOH (50 mL) and 10% Pd/C (1 g) was added under nitrogen. The reaction mixture was then flushed with hydrogen and stirred at room temperature for 30 min under balloon pressure. The reaction mixture was flushed with nitrogen and the catalyst was filtered off. All the volatiles were evaporated and the resulting mixture was triturated with heptane (10 mL). The solid material was filtered off and dried to give the crude title compound as a pale brown solid which was used without further purification (1.21 g, 89% yield). 1H NMR (600 MHz, DMSO-d6) d 6.42 (s, 2H), 6.05 (d, J = 2.2 Hz, 1H), 4.99 (s, 2H), 4.01 (td, J = 11.8, 11.1, 2.9 Hz, 2H), 3.77 (dt, J = 11.6, 4.3 Hz, 2H), 3.48 (dd, J = 8.5, 7.5 Hz, 2H), 1.95 (ddd, J = 14.3, 10.2, 4.4 Hz, 2H), 1.66 (dt, J = 14.2, 3.7 Hz, 2H), 0.90 - 0.77 (m, 2H), -0.06 (s, 9H); LCMS (METHOD 2) (ES) : m/z 367.3 [M + H]⁺, RT = 0.77 min.

Preparation 29: (2,3,4,5,6-pentafluorophenyl) (2S)-2-(tert-butoxycarbonylamino)-3,3- dicyclopropyl-propanoate.

A solution of the compound of Preparation 5 (1.08 g, 4.01 mmol), (2,3,4,5,6- pentafluorophenyl) 2,2,2-trifluoroacetate (1.24 g, 4.41 mmol) and pyridine (0.484 mL, 6.01 mmol) in DCM (20 mL) was stirred at room temperature for 2 hours. The solution was washed successively with HCI (1M, 10 mL) and saturated NaHCCb (10 mL). The organic phase was dried over MgSCU, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a colourless oil (1.04 g, 60% yield). 1H NMR (400 MHz, Chloroform-d) d 5.33 (d, J = 9.3 Hz, 1H), 4.87 (d, J = 9.3 Hz, 1H), 1.47 (s, 9H), 0.72 - 0.19 (m, 11H).

Preparation 30: tert-butyl N-[(lS)-l-(dicyclopropylmethyl)-2-[[4-fluoro-2-oxo-l-(2- trimethylsilylethoxymethy spirotpyrrolotS^-clpyridine-S^'-tetrahydropyranJ-S-yllaminol- - oxo-ethyl ]ca rba mate .

To a solution of the compound of Preparation 29 (107 mg, 0.245 mmol) and the compound of Preparation 28 (90 mg, 0.245 mmol) in THF (5 mL) was added tert- butyl magnesium chloride (1M in THF, 0.98 mL, 0.98 mmol) at 5°C under nitrogen and stirred for 1 hour. The reaction mixture was quenched with saturated NH4CI (5 mL) and extracted with Et_å0 (2 x 20 mL). The combined organic phase was dried over NazSCU, filtered and concentrated in vacuo.

Purification by column chromatography (silica gel, eluting with EtOAc in heptane) gave the title compound as a colourless foam (90.0 mg, 59% yield). LCMS (METHOD 2) (ES): m/z 619.5 [M + H]⁺, RT = 1.03 min.

Preparation 31: [(lS)-l-(dicyclopropylmethyl)-2-[[4-fluoro-2-oxo-l-(2- trimethylsilylethoxymethyl)spiro[pyrrolo[3,2-c]pyridine-3,4^l-tetrahydropyran]-6-yl]amino]-2- oxo-ethyl]ammonium;chloride.

Hydrogen chloride (3M in CPME, 0.5 mL, 2 mmol) was added to a solution of the compound of Preparation 30 (90.0 mg, 0.145 mmol) in MeOH (2 mL) and was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the crude title compound as a colourless solid (81 g, 100% yield). LCMS (METHOD 2) (ES) : m/z 519.3 [M + H]⁺, RT = 0.91 min.

EXAMPLES

Example 1 : N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[indoline-3,4'- tetrahydropyran]-6-yl)amino]ethyl]-2-methyl-pyrazole-3-carboxamide.

HATU (14.8 mg, 0.039 mmol) was added to a solution of the product of Preparation 7 (13.0 mg, 0.03 mmol), 2-methylpyrazole-3-carboxylic acid (4.54 mg, 0.036 mmol) and DIPEA (0.03 mL, 0.18 mmol) in DMF (0.2 mL) at room temperature. The reaction mixture was stirred for 2.5 h, before it was diluted with DMF (0.75 mL) and purified by acidic prep. HPLC to afford the title compound as an off-white solid. (10.3 mg, 72% yield). 1H NMR (600 MHz, DMSO-d6) d 10.39 (s, 1H), 10.17 (s, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 8.2, 2.0 Hz, 1H), 7.05 (d, J = 2.1 Hz, 1H), 4.80 (t, J = 8.3 Hz, 1H), 4.04 (s, 3H), 4.01 (ddd, J = 11.2, 7.2, 3.7 Hz, 2H), 3.85 - 3.76 (m,

2H), 1.68 (dddd, J = 66.3, 13.5, 7.2, 3.6 Hz, 4H), 0.93 - 0.83 (m, 1H), 0.83 - 0.70 (m, 2H), 0.45 (ddt, J = 9.3, 7.9, 5.2 Hz, 1H), 0.36 (tdd, J = 9.2, 5.8, 3.2 Hz, 2H), 0.33 - 0.26 (m, 1H),

0.21 (dddt, J = 15.9, 10.7, 7.7, 5.5 Hz, 3H), 0.14 - 0.06 (m, 1H); LCMS (ES) : m/z 478.246 [M + H]⁺, RT = 2.10 min

Example 2: N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[indoline-3,4'- tetrahydropyran]-6-yl)amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide.

According to the method of Example 1, the compound of Preparation 7 (13.0 mg, 0.03 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (5.55 mg, 0.036 mmol) to afford the title compound as an off-white solid after acidic prep. HPLC. (9.8 mg, 58% yield). 1H NMR (600 MHz, DMSO-d6) d 10.39 (s, 1H), 10.15 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 8.1, 1.9 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.78 (t, J = 8.4 Hz, 1H), 4.01 (ddd, J = 11.2, 7.2, 3.7 Hz, 2H), 3.80 (dddd, J = 16.5, 8.8, 4.1, 2.2 Hz, 2H), 1.74 (ddt, J = 13.3, 6.6, 3.1 Hz, 2H), 1.63 (ddd, J = 13.4, 7.2, 3.8 Hz, 2H), 1.41 - 1.31 (m, 6H), 0.88 (qt, J = 8.3, 5.1 Hz, 1H), 0.79 (ddd, J = 10.3, 5.1, 2.3 Hz, 1H), 0.78 - 0.71 (m, 1H), 0.50 - 0.41 (m, 1H),

0.41 - 0.32 (m, 2H), 0.32 - 0.26 (m, 1H), 0.26 - 0.15 (m, 3H), 0.15 - 0.08 (m, 1H); LCMS (ES) : m/z 506.28 [M + H]⁺, RT = 2.23 min

Example 3: N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[indoline-3,4'- tetrahydropyran]-6-yl)amino]ethyl]-5-methyl-l-tetrahydropyran-4-yl-pyrazole-4-carboxamide.

According to the method of Example 1, the compound of Preparation 7 (18.0 mg, 0.044 mmol) was reacted with 5-methyl-l-tetrahydropyran-4-yl-pyrazole-4-carboxylic acid (12.3 mg, 0.059 mmol) to afford the title compound as an off-white solid after acidic prep. HPLC. (7.0 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) d 10.38 (s, 1H), 10.08 (s, 1H), 8.08 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.10 (dd, J = 8.1, 1.9 Hz, 1H), 4.76 (t, J = 8.1 Hz, 1H), 4.42 (tt, J = 11.3, 4.2 Hz, 1H), 4.11 - 3.90 (m, 4H), 3.80 (ddd, J = 11.2, 7.0, 3.8 Hz, 2H), 3.48 (td, J = 12.1, 2.1 Hz, 2H), 2.53 (s, 3H), 2.02 (dtd, J = 16.9, 12.4, 4.6 Hz, 2H), 1.74 (td, J = 12.1, 11.1, 4.8 Hz, 4H), 1.67 - 1.57 (m, 2H), 0.74 (dp, J = 17.7, 9.1, 8.1 Hz, 2H), 0.44 (td, J = 7.5, 6.4, 3.6 Hz, 1H), 0.35 (q, J = 6.3, 5.7 Hz, 2H), 0.32 - 0.26 (m, 1H), 0.25 - 0.15 (m, 3H), 0.15 - 0.06 (m, 1H); LCMS (ES) : m/z 562.2 [M + H]\ RT = 0.63 min.

Example 4: N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[lH-pyrrolo[3,2-c]pyridine-

3,4'-tetrahydropyran]-6-yl)amino]ethyl]-2-(2-hydroxy-l-methyl-ethyl)pyrazole-3- carboxamide. DIPEA (0.015 mL, 0.084 mmol) was added to a solution of the compound of Preparation 9 (15.0 mg, 0.028 mmol), 2-(2-hydroxy-l-methyl-ethyl)pyrazole-3-carboxylic acid (7.1 mg, 0.042 mmol) (from Preparation 12) and HATU (11.7 mg, 0.03 mmol) in DMF (0.5 mL). The reaction mixture was shaken at room temperature for 18 h. The reaction mixture was concentrated in vacuo and re-dissolved in DCM (0.5 mL). TFA (0.5 mL) was added and the reaction mixture was shaken at room temperature for 2 h. The mixture was concentrated in vacuo and purified firstly by basic prep. HPLC, then acidic prep. HPLC to afford the title compound as a mixture of diastereomers. (3.5 mg, 24%). 1H NMR (400 MHz, DMSO-d6) d 10.65 (s, 1H), 10.38 (d, J = 3.3 Hz, 1H), 8.33 - 8.14 (m, 3H), 7.50 (d, J = 4.5 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 6.66 (dd, J = 16.4, 2.0 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.67 (q, J = 7.9 Hz, 1H), 3.77 (dt, J = 10.3, 4.6 Hz, 2H), 3.65 - 3.31 (m, 4H), 1.61 (ddd, J = 13.0, 8.5, 4.0 Hz, 2H), 1.42 (d, J = 11.5 Hz, 2H), 1.11 (dd, J = 12.0, 6.7 Hz, 3H), 0.72 (tp, J = 8.3, 4.4, 3.9 Hz, 1H), 0.66 - 0.58 (m, 1H), 0.57 - 0.48 (m, 1H), 0.30 - 0.20 (m, 1H), 0.11 (ddd, J = 29.3, 8.3, 4.2 Hz, 6H); LCMS (ES) : m/z 523.267 [M + H]⁺, RT = 1.94 min

Example 5: N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[lH-pyrrolo[3,2-c]pyridine- 3,4'-tetrahydropyran]-6-yl)amino]ethyl]-2-ethyl-pyrazole-3-carboxamide.

According to the method of Example 4, the compound of Preparation 9 (15.0 mg, 0.028 mmol) was reacted with 2-ethylpyrazole-3-carboxylic acid (5.9 mg, 0.042 mmol) to afford the title compound as an off-white solid after basic prep. HPLC then acidic prep. HPLC. (6.5 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6) d 10.84 (s, 1H), 10.60 (s, 1H), 8.41 (m, 2H), 7.71 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 4.89 (t, J = 8.0 Hz, 1H), 4.46 (qd, J = 6.7, 4.2 Hz, 2H), 3.99 (dt, J = 10.5, 4.7 Hz, 2H), 3.81 (t, J = 9.1 Hz, 2H), 1.82 (ddd, J = 12.8, 8.5, 4.1 Hz, 2H), 1.63 (d, J = 14.4 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.99 - 0.90 (m, 1H), 0.89 - 0-80 (m, 1H), 0.74 (q, J = 9.0 Hz, 1H), 0.36 (dd, J = 10.0, 5.1 Hz, 1H), 0.32 - 0.13 (m, 7H); LCMS (ES): m/z 493.256 [M + H]⁺, RT = 2.06 min

Example 6: N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[lH-pyrrolo[3,2-c]pyridine- 3,4'-tetrahydropyran]-6-yl)amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide

According to the method of Example 4, the compound of Preparation 9 (15.0 mg, 0.028 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (6.5 mg, 0.042 mmol) to afford the title compound as an off-white solid after basic prep. HPLC then acidic prep. HPLC. (7.0 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6) d 10.64 (s, 1H), 10.39 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H) overlapping 8.19 (s, 1H), 7.50 (s, 1H), 7.30 (d, J = 1.9 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 5.16 (hept, J = 6.7 Hz, 1H), 4.67 (t, J = 8.0 Hz, 1H), 3.78 (dt, J = 10.4, 4.6 Hz, 2H), 3.60 (ddd, J = 11.7, 8.4, 3.2 Hz, 2H), 1.61 (ddd, J = 12.9, 8.4, 4.0 Hz, 2H), 1.47 - 1.37 (m, 2H), 1.15 (dd, J = 16.1, 6.6 Hz, 6H), 0.74 (tq, J = 8.1, 5.2, 4.3 Hz, 1H), 0.62 (dd, J = 10.0, 4.2 Hz, 1H), 0.58 - 0.47 (m, 1H), 0.30 - 0.20 (m, 1H), 0.20 - 0.12 (m, 1H), 0.12 - -0.10 (m, 6H); LCMS (ES) : m/z 507.272 [M + H]⁺, RT = 2.14 min.

Example 8: N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'-tetrahydropyran]- 6-yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-2-ethyl-pyrazole-3-carboxamide.

HATU (35.1 mg, 0.092 mmol) was added to a solution of the compound of Preparation 19 (34.0 mg, 0.084 mmol), 2-ethylpyrazole-3-carboxylic acid (12.9 mg, 0.092 mmol) and DIPEA (0.03 mL, 0.19 mmol) in MeCN (1.0 mL) at room temperature. The reaction mixture was stirred for 30 minutes, before it was purified by prep, basic HPLC to afford the title compound as a colourless solid. (27 mg, 61% yield). 1H NMR (600 MHz, DMSO-d6) d 11.15 - 10.84 (s, 2H), 8.41 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 4.85 (t, J = 8.0 Hz, 1H), 4.53 - 4.34 (m, 2H), 4.11 (ddt, J = 13.4, 11.4, 2.3 Hz, 2H), 3.76 (dd, J = 11.2 Hz, J = 5.2 Hz, 2H), 2.44 (td, J = 13.5, 5.4 Hz, 2H), 1.56 (ddd, J = 10.5, 8.2,

4.5 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 0.99 - 0.93 (m, 1H), 0.87 - 0.81 (m, , 1H), 0.75 - 0.70 (m, 1H), 0.53 - 0.42 (m, 1H), 0.39 - 0.35 (m, 1H), 0.31 - 0.10 (m, 6H); LCMS (METHOD 1) (ES) : m/z 527.218 [M + H]⁺, RT = 2.32 min.

Example 9: N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'-tetrahydropyran]- 6-yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-2-isopropyl-pyrazole-3-carboxamide.

According to the method of Example 8, the compound of Preparation 19 (34.0 mg, 0.084 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (14.2 mg, 0.092 mmol) to afford the title compound as a colourless solid after prep, basic HPLC (19 mg, 42% yield). 1H NMR (400 MHz, DMSO-d6) d 10.89 (s, 2H), 8.41 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 5.36 (sept, J = 6.6 Hz, 1H), 4.84 (t, J = 7.9 Hz, 1H), 4.11 (t, J = 12.1 Hz, 2H), 3.76 (dd, J = 11.2, 5.0 Hz, 2H), 2.44 (dt, J = 13.2, 6.8 Hz, 2H),

1.56 (dd, J = 13.2, 5.7 Hz, 2H), 1.35 (dd, J = 16.0, 6.6 Hz, 6H), 1.04 - 0.78 (m, 2H), 0.76 - 0.68 (m, 1H), 0.54 - 0.06 (m, 8H); LCMS (METHOD 1) (ES) : m/z 541.233 [M + H]⁺, RT = 2.40 min.

Example 10: N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-3-isopropyl-triazole-4- carboxamide.

According to the method of Example 8, the compound of Preparation 19 (26.0 mg, 0.064 mmol) was reacted with 3-isopropyltriazole-4-carboxylic acid (11.0 mg, 0.071 mmol) to afford the title compound as a colourless solid after prep, basic HPLC (17 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6) d 11.04 (br s, 1H), 10.97 (s, 1H), 8.80 (d, J = 8.5 Hz, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 5.36 (sept, J = 6.7 Hz, 1H), 4.90 (t, J = 7.8 Hz, 1H), 4.11 (t, J = 11.9 Hz, 2H), 3.76 (dd, J = 11.4, 5.0 Hz, 2H), 2.45 (dt, J = 13.3, 5.2 Hz, 2H), 1.57 (dd, J = 13.4, 7.8 Hz, 2H), 1.49 (dd, J = 13.6, 6.7 Hz, 6H), 1.03 - 0.80 (m, 2H), 0.76 - 0.65 (m, 1H), 0.53 - 0.33 (m, 2H), 0.32 - 0.13 (m, 6H); LCMS (METHOD 1) (ES) : m/z 542.228 [M + H]⁺, RT = 2.32 min.

Example 11: N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-3-isopropyl-isoxazole-4- carboxamide.

According to the method of Example 8, the compound of Preparation 19 (34.0 mg, 0.084 mmol) was reacted with 3-isopropylisoxazole-4-carboxylic acid (14.3 mg, 0.092 mmol) to afford the title compound as a colourless solid after prep, basic HPLC (21 mg, 46% yield). 1H NMR (400 MHz, DMSO-d6) d 11.02 (s, 1H), 10.89 (s, 1H), 9.33 (s, 1H), 8.41 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 4.85 (t, J = 7.5 Hz, 1H), 4.11 (t, J = 12.4 Hz, 2H), 3.76 (dd, J = 11.1, 5.0 Hz, 2H), 3.42 (sept, J = 6.9 Hz, 1H), 2.44 (dt, J = 13.2, 6.7 Hz, 2H), 1.56 (dd, J = 13.0, 5.8 Hz, 2H), 1.23 (dd, J = 14.2, 6.9 Hz, 6H), 1.01 - 0.81 (m, 2H), 0.70 - 0.61 (m, J = 9.6, 6.7 Hz, 1H), 0.52 - 0.09 (m, 8H); LCMS (METHOD 1) (ES): m/z 542.217 [M + H]⁺, RT = 2.43 min.

Example 12: N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-2-(3-hydroxypropyl)pyrazole-3- carboxamide.

According to the method of Example 8, the compound of Preparation 19 (26.0 mg, 0.064 mmol) was reacted with 2-(3-hydroxypropyl)pyrazole-3-carboxylic acid (29.9 mg, 0.176 mmol) to afford the title compound as a colourless solid after prep, basic HPLC (15 mg, 42% yield). 1H NMR (400 MHz, DMS0-d6) d 11.04 (s, 1H), 10.91 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 4.85 (t, J = 7.9 Hz, 1H), 4.47 (tt, J = 8.4, 4.1 Hz, 3H), 4.11 (t, J = 12.1 Hz, 2H), 3.76 (dd, J = 11.1, 5.0 Hz, 2H), 3.41 - 3.32 (m, 2H), 2.44 (dt, J = 13.1, 6.7 Hz, 2H), 1.85 (p, J = 6.8 Hz, 2H), 1.56 (br d, J = 15.0 Hz, 2H), 1.00 - 0.78 (m, 2H), 0.77 - 0.67 (m, 1H), 0.51 - 0.11 (m, 8H); LCMS (METHOD 1) (ES) : m/z 557.228 [M + H]⁺, RT = 2.18 min.

Example 13: N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2- c]pyridine-3,4 -tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3- carboxamide.

HATU (10.7 mg, 0.028 mmol) was added to a solution of the product of Preparation 31 (12.0 mg, 0.022 mmol), 2-isopropylpyrazole-3-carboxylic acid (4.3 mg, 0.028 mmol) and DIPEA (0.011 mL, 0.065 mmol) in MeCN (0.5 mL) at room temperature. The reaction mixture was stirred for 1 hour, then concentrated in vacuo. TFA (1 mL) was added and the reaction mixture was stirred at 50°C for 30 minutes. The reaction mixture was concentrated in vacuo and the residual material was dissolved in MeOH (0.5 mL). Concentrated ammonia (aq., 0.50 mL) was added and stirred for 10 minutes at room temperature. The mixture was then purified by prep, basic HPLC to afford the title compound as a colourless solid. (8.4 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6) d 11.04 (br s, 1H), 10.81 (s, 1H), 8.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 5.36 (sept, J = 6.7 Hz, 1H), 4.84 (t, J = 7.9 Hz, 1H), 4.03 (t, J = 10.0 Hz, 2H), 3.76 (dt, J = 11.9, 4.5 Hz, 2H), 1.95 (ddd, J = 13.9, 9.7, 4.3 Hz, 2H), 1.76 (dd, J = 14.2, 3.7 Hz, 2H), 1.35 (dd, J = 15.9, 6.6 Hz, 6H), 1.02 - 0.64 (m, 3H), 0.53 - 0.07 (m, 8H); LCMS (METHOD 1) (ES) : m/z 525.263 [M + H]⁺, RT = 2.33 min.

Example 14: N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2- c]pyridine-3,4 -tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-2-ethyl-pyrazole-3-carboxamide. According to the method of Example 13, the compound of Preparation 31 (16.5 mg, 0.030 mmol) was reacted with 2-ethylpyrazole-3-carboxylic acid (8.3 mg, 0.059 mmol) to afford the title compound as a colourless solid after prep, basic HPLC (5.8 mg, 38% yield). 1H NMR (600 MHz, DMSO-d6) d 11.02 (s, 1H), 10.81 (s, 1H), 8.41 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 4.85 (t, J = 8.0 Hz, 1H), 4.56 - 4.37 (m, 2H), 4.03 (dt, J = 12.5, 3.0 Hz, 2H), 3.77 (dt, J = 11.5, 4.4 Hz, 2H), 1.95 (ddd, J = 13.9, 9.8, 4.4 Hz, 2H), 1.78 - 1.73 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.98 - 0.92 (m , 1H), 0.88 - 0.80 (m, 1H), 0.73 (td, J = 9.4, 7.4 Hz, 1H), 0.51 - 0.42 (m, 1H), 0.39 - 0.35 (m , 1H), 0.31 - 0.07 (m, 6H); LCMS (METHOD 1) (ES) : m/z 511.247 [M + H]⁺, RT = 2.26 min.

Example 15: N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2- c]pyridine-3,4'-tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-3-isopropyl-triazole-4- carboxamide.

According to the method of Example 13, the compound of Preparation 31 (16.5 mg, 0.030 mmol) was reacted with 3-isopropyltriazole-4-carboxylic acid (9.2 mg, 0.059 mmol) to afford the title compound as a colourless solid after prep, basic HPLC (6.8 mg, 44% yield). 1H NMR (600 MHz, DMSO-d6) d 11.02 (s, 1H), 10.88 (s, 1H), 8.81 (d, J = 8.5 Hz, 1H), 8.29 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 5.38 (sept, J = 6.7 Hz, 1H), 4.89 (t, J = 7.8 Hz, 1H), 4.08 - 3.97 (m, 2H), 3.77 (dt, J = 11.6, 4.4 Hz, 2H), 1.95 (ddd, J = 14.1, 9.7, 4.4 Hz, 2H), 1.80 - 1.71 (m, 2H), 1.49 (dd, J = 20.1, 6.7 Hz, 6H), 1.02 - 0.92 (m, 1H), 0.89 - 0.83 (m, 1H), 0.70 (td, J = 9.6, 7.2 Hz, 1H), 0.54 - 0.44 (m, 1H), 0.44 - 0.32 (m, 1H), 0.32 - 0.09 (m, 6H); LCMS (METHOD 1) (ES) : m/z 526.258 [M + H]⁺, RT = 2.26 min.

Example 16: N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2- c]pyridine-3,4'-tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-3-ethyl-isoxazole-4-carboxamide. According to the method of Example 13, the compound of Preparation 31 (16.5 mg, 0.030 mmol) was reacted with 3-ethylisoxazole-4-carboxylic acid (8.4 mg, 0.059 mmol) to afford the title compound as a colourless solid after prep, basic HPLC (4.8 mg, 32% yield). 1H NMR (600 MHz, DMSO-d6) d 10.99 (d, J = 47.5 Hz, 1H), 10.81 (s, 1H), 9.40 (s, 1H), 8.39 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 4.86 (t, J = 7.7 Hz, 1H), 4.10 - 3.96 (m, 2H), 3.77 (dt, J =

11.7, 4.5 Hz, 2H), 2.83 (q, J = 7.3 Hz, 2H), 1.95 (ddd, J = 13.9, 9.8, 4.4 Hz, 2H), 1.76 (dq, J = 13.4, 4.1 Hz, 2H), 1.17 (t, J = 7.5 Hz, 3H), 0.99 - 0.93 (m , 1H), 0.88 - 0.82 (m, 1H), 0.65 (td, J = 9.7, 6.9 Hz, 1H), 0.51 - 0.42 (m, 1H), 0.40 - 0.36 (m, 1H), 0.33 - 0.13 (m, 6H); LCMS (METHOD 1) (ES) : m/z 512.230 [M + H]⁺, RT = 2.31 min.

Example 17: N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2- c]pyridine-3,4 -tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-4-ethyl-l,2,5-oxadiazole-3- carboxamide.

According to the method of Example 13, the compound of Preparation 31 (16.5 mg, 0.030 mmol) was reacted with 4-ethyl-l,2,5-oxadiazole-3-carboxylic acid (8.5 mg, 0.059 mmol) to afford the title compound as a colourless solid after prep, basic HPLC (4.1 mg, 27% yield). 1H NMR (600 MHz, DMSO-d6) d 11.16 - 10.83 (m, 2H), 9.13 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 4.92 (t, J = 6.9 Hz, 1H), 4.2 (dt, J = 12.6, 3.1 Hz, 2H), 3.77 (dt, J = 11.6, 4.5 Hz, 2H), 2.90 (qd, J = 7.6, 2.4 Hz, 2H), 1.94 (ddd, J = 13.9, 9.7, 4.4 Hz, 2H), 1.76 (dq, J = 13.9, 4.1 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H), 0.96 - 0.90 (m, 1H), 0.85 - 0.79 (m, 1H), 0.74 (td, J = 9.5, 6.6 Hz, 1H), 0.52 - 0.44 (m, 1H), 0.41 - 0.34 (m, 1H), 0.31 - 0.12 (m, 6H); LCMS (METHOD 1) (ES) : m/z 513.226 [M + H]⁺, RT = 2.46 min. Example 7: IL-8 release assay in human epithelial keratinocvtes adult (HEKa~)

Keratinecytes were seeded at 3500 cells/well in 384-well ViewPlates (Perkin Elmer) in Epilife medium (Therme Fisher) centaining human keratinecyte growth supplement (HKGS) witheut hydrecertisene and incubated in a humid incubatcr at 37°C, 5% CO2, cvernight. The fcllcwing day growth medium was remcved and 25 pi fresh Epilife medium was added. 75 nL test ccmpcund in 100% DMSO was added intc each well reserved fcr test ccmpcunds, by the use pf accustic pipetting. The remaining wells received an equal vclume pf DMSO only, as vehicle control, or terfenadine in DMSO, as a positive control for any cytotoxic compounds. Subsequently, another 25 pL Epilife medium was added to each well. Finally, wells containing test compounds and wells prepared to yield maximum stimulation received 25 pL of 9 ng/mL recombinant, human embryonic kidney cell (HEK)-derived human IL-17AA + 30 ng/mL human TNF-alpha, in Epilife medium. Wells prepared to define 100% inhibition of IL-17 effects received 25 pL of 30 ng/mL human TNF-alpha alone, in Epilife medium. Final concentrations were 3 ng/mL HEK-human IL-17AA + 10 ng/mL human TNFalpha (maximum stimulation) and 10 ng/mL human TNFalpha alone (100% inhibition, Emax), respectively. Cells were incubated for 68-72 hours in the incubator. IL-8 released from the cells was measured by the use of a commercial homogenous time-resolved fluorescence (HTRF) assay (CisBio). 2 pL cell culture supernatant was transferred to a 384-well Proxiplate. 5 pL HTRF reagent was added and the plates were incubated sealed in the dark for 3-22 hours at room temperature. Time-resolved fluorescence was read at 665 vs 620 nm, with excitation at 320 nm, and IL-8 levels were calculated as percent of controls. Reduction of the amount of secreted IL-8 indicates decreased IL-17 signaling. Concentration response curves were fitted by the use of a four- para meter logistic equation. Relative IC50 and Emax were reported from curves showing acceptable fit (r²>0.9). Cytotoxicity was measured in the cell-containing Viewplates following addition of 7 pL PrestoBlue (Thermo Fisher) and incubation for 2.5-3 hours at room temperature, by measuring fluorescence at 615 nm (excitation at 535 nm). Fluorescence was directly proportional to the amount of metabolic activity. Reduction of fluorescence signal indicated cytotoxicity.

Compounds of the present invention were tested in the IL-8 release assay in human epithelial keratinocytes. The results are summarized in Table 1. Table 1

Embodiments:

Embodiment 1. A compound having the formula (I)

wherein

Ri is selected from the group consisting of (Ci-C6)alkyl, (C3-C7)cycloalkyl, (Ci-C6)alkoxy, (C3- C7)cycloalkoxy, phenyl, phenyl-(Ci-C₄)alkyl, 4-6-membered heterocycloalkyl, 9- or 10- membered bicyclic heteroaryl, 5-or 6-membered heteroaryl, and -NR_cRd, wherein said (Ci- C₆)alkyl, (C₃-C7)cycloalkyl, (Ci-C₆)alkoxy, (C₃-C7)cycloalkoxy, phenyl, phenyl-(Ci-C₄)alkyl, 4-6- membered heterocycloalkyl, 9- or 10-membered bicyclic heteroaryl, and 5-or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from Raj

R_a is deuterium, halogen, hydroxy, -NR_cRd, (Ci-C6)alkyl, (Ci-C6)alkylcarbonyl, (C3- C7)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-6-membered heterocycloalkyl, wherein said (Ci-C₆)alkyl, (Ci-C₆)alkylcarbonyl, (C₃-C7)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-6-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, (Ci-C4)alkyl, (C3-C7)cycloalkyl, (Ci-C4)alkoxy, (Ci-C4)alkyl-S-,(Ci-C4)alkyl-SO-, (Ci-C4)alkyl-SC>2- and - NRcRd ;

R_åa and R_åbeach independently are selected from (C3-C7)cycloalkyl and (C3-C7)cycloalkyl(Ci- C6)alkyl , wherein said (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(Ci-C6)alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano and (Ci-C₄)alkyl;

R3 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-C6)alkoxy, wherein said and (Ci-Ce)alkoxy may optionally be substituted with one of more substituents selected from halogen;

X is CH, or N;

R and Rd each independently are selected from the group consisting of hydrogen and (Ci- C₆)alkyl, or R_cand R_d together form azetidinyl, pyrrolidinyl or piperidinyl, wherein said (Ci- C6)alkyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy; or pharmaceutically acceptable salts, hydrates and solvates thereof.

Embodiment 2. The compound according to embodiment 1, having the formula (lb)

wherein Ri, R2a, R_åb, R3 and X are as defined in claim 1.

Embodiment 3. The compound according to embodiment 1, having the formula (la)

wherein Ri, R2a, R_åb, R3 and X are as defined in claim 1.

Embodiment 4. The compound according to any one of embodiments 1-3 wherein R_åa and R_åb are each independently selected from (C3-C7)cycloalkyl wherein said (C3-C7)cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, cyano and (Ci-C4)alkyl.

Embodiment 5. The compound according to embodiment 4, wherein R_åa and R2bare each independently selected from (C3-C4)cycloalkyl.

Embodiment 6. The compound according to embodiment 5, wherein each of R_åa and R_åb is cyclopropyl.

Embodiment 7. The compound according to embodiment 5, wherein each of R_åa and R_åb is cyclobutyl. Embodiment 8. The compound according to any one of embodiments 1-3 wherein R_åa and R_åb are each independently selected from (C3-C7)cycloalkyl(Ci-C6)alkyl, wherein said (C3- C7)cycloalkyl(Ci-C6)alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano and (Ci-C4)alkyl.

Embodiment 9. The compound according to embodiment 8 wherein R_åa and R_åb are each independently selected from (C3-C4)cycloalkyl(Ci-C2)alkyl.

Embodiment 10. The compound according to embodiment 9 wherein R_åa and R_åb are each independently selected from cyclopropylmethyl and cyclobutylmethyl.

Embodiment 11. The compound according to any one of embodiments 1-10, wherein Ri is selected from pyrazolyl, imidazolyl, thiazolyl, isoxazolyl and triazolyl, wherein the pyrazolyl, imidazolyl, thiazolyl, isoxazolyl and triazolyl is optionally substituted with one or more substituents independently selected from R_a.

Embodiment 12. The compound according to embodiment 11, wherein Ri is pyrazolyl, wherein said pyrazolyl is optionally substituted with one or more substituents independently selected from Ra.

Embodiment 13. The compound according to embodiment 12, wherein R_a is selected from one or more (Ci-C6)alkyl, and said one or more (Ci-Ce)alkyl is optionally substituted with halogen, hydroxy, (Ci-C4)alkoxy, (Ci-C4)alkyl-S-, (Ci-C4)alkyl-SO-, and (Ci-C4)alkyl-SC>2-.

Embodiment 14. The compound according to embodiment 13, wherein Ri is 2-(Ci-C3)alkyl)- pyrazol-3-yl.

Embodiment 15. The compound according to any one of embodiments 1-14 above, wherein X is CH.

Embodiment 16. The compound according to any one of embodiments 1-14 above, wherein X is N.

Embodiment 17. The compound according to embodiment 16 above wherein R3 is fluoro.

Claims

Claims l.A compound having the formula (I)

wherein

Ri is selected from the group consisting of (Ci-C6)alkyl, (C3-C7)cycloalkyl, (Ci-C6)alkoxy, (C3- C7)cycloalkoxy, phenyl, phenyl-(Ci-C₄)alkyl, 4-6-membered heterocycloalkyl, 9- or 10- membered bicyclic heteroaryl, 5-or 6-membered heteroaryl, and -NR_cRd, wherein said (Ci- C₆)alkyl, (C₃-C7)cycloalkyl, (Ci-C₆)alkoxy, (C₃-C7)cycloalkoxy, phenyl, phenyl-(Ci-C₄)alkyl, 4-6- membered heterocycloalkyl, 9- or 10-membered bicyclic heteroaryl, and 5-or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from Raj

R_a is deuterium, halogen, hydroxy, -NR_cRd, (Ci-C6)alkyl, (Ci-C6)alkylcarbonyl, (C3- C7)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-6-membered heterocycloalkyl, wherein said (Ci-C₆)alkyl, (Ci-C₆)alkylcarbonyl, (C₃-C7)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-6-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, (Ci-C4)alkyl, (C3-C7)cycloalkyl, (Ci-C4)alkoxy, (Ci-C4)alkyl-S-,(Ci-C4)alkyl-SO-, (Ci-C4)alkyl-SC>2- and - NRcRd ;

Råa and Råb each independently are selected from (C3-C7)cycloalkyl and (C3-C7)cycloalkyl(Ci- C₆)alkyl wherein said (C₃-C7)cycloalkyl and (C₃-C7)cycloalkyl(Ci-C₆)alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano and (Ci-C₄)alkyl;

R3 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-C₆)alkoxy, wherein said (Ci-Ce)alkyl and (Ci- C6)alkoxy may optionally be substituted with one of more substituents selected from halogen;

X is CH, or N; Rc and Rd each independently are selected from the group consisting of hydrogen and (Ci- C6)alkyl, or R_c and R_d together form azetidinyl, pyrrolidinyl or piperidinyl, wherein said (Ci- C6)alkyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy; or pharmaceutically acceptable salts, hydrates and solvates thereof.

2. The compound according to claim 1, having the formula (la)

wherein Ri, R2a, Råb, R3 and X are as defined in claim 1.

3. The compound according to any one of claims 1-2, wherein Ri is selected from pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl, wherein the pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl is optionally substituted with one or more substituents independently selected from R_a.

4. The compound according to claim 3, wherein R_a is selected from one or more (Ci-C6)alkyl, and said one or more (Ci-Ce)alkyl is optionally substituted with halogen, hydroxy, (Ci- C4)alkoxy, (Ci-C4)alkyl-S-, (Ci-C4)alkyl-SO-, and (Ci-C4)alkyl-SC>2-.

5. The compound according to claim 4, wherein Ri is pyrazolyl, wherein said pyrazolyl is optionally substituted with one or more substituents independently selected from (Ci-Ce)alkyl wherein said one or more (Ci-Ce)alkyl is optionally substituted with halogen, hydroxy, (Ci- C4)alkoxy, (Ci-C4)alkyl-S-, (Ci-C4)alkyl-SO-, and (Ci-C4)alkyl-SC>2-.

6. The compound according to claim 5, wherein Ri is 2-(Ci-C3)alkyl)-pyrazol-3-yl.

7. The compound according to any one of claims 1-2, wherein Ri is selected from (C3- C7)cycloalkyl and (C3-C7)cycloalkoxy, wherein said (C3-C7)cycloalkyl and (C3-C7)cycloalkoxy is optionally substituted with a substituent independently selected from R_a.

8. The compound according to claim 7, wherein Ri is 1-fluoro-cyclopropyl.

9. The compound according to any one of claims 1-8 wherein Rå_a and R2b are each independently selected from (C3-C7)cycloalkyl wherein said (C3-C7)cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, cyano and (Ci-C₄)alkyl.

10. The compound according to claim 9, wherein Råa and Råb are each independently selected from (C₃-C₄)cycloalkyl.

11. The compound according to claim 10, wherein each of Råa and Råb is cyclopropyl.

12. The compound according to embodiment 10, wherein each of Råa and Råb is cyclobutyl.

13. The compound according to claim 1 selected from

N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[indoline-3,4'-tetrahydropyran]-6- yl)amino]ethyl]-2-methyl-pyrazole-3-carboxamide;

N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[indoline-3,4'-tetrahydropyran]-6- yl)amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide;

N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)amino]ethyl]-2-(2-hydroxy-l-methyl-ethyl)pyrazole-3-carboxamide;

N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[indoline-3,4'-tetrahydropyran]-6- yl)amino]ethyl]-5-methyl-l-tetrahydropyran-4-yl-pyrazole-4-carboxamide;

N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)amino]ethyl]-2-ethyl-pyrazole-3-carboxamide;

N-[(lS)-l-(dicyclopropylmethyl)-2-oxo-2-[(2-oxospiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide;

N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'-tetrahydropyran]-6- yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-2-ethyl-pyrazole-3-carboxamide;

N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'-tetrahydropyran]-6- yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-2-isopropyl-pyrazole-3-carboxamide;

N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'-tetrahydropyran]-6- yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-3-isopropyl-triazole-4-carboxamide;

N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'-tetrahydropyran]-6- yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-3-isopropyl-isoxazole-4-carboxamide;

N-[(lS)-l-[(4-chloro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'-tetrahydropyran]-6- yl)carbamoyl]-2,2-dicyclopropyl-ethyl]-2-(3-hydroxypropyl)pyrazole-3-carboxamide;

N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide;

N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-2-ethyl-pyrazole-3-carboxamide; N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-3-isopropyl-triazole-4-carboxamide;

N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-3-ethyl-isoxazole-4-carboxamide; and

N-[(lS)-l-(dicyclopropylmethyl)-2-[(4-fluoro-2-oxo-spiro[lH-pyrrolo[3,2-c]pyridine-3,4'- tetrahydropyran]-6-yl)amino]-2-oxo-ethyl]-4-ethyl-l,2,5-oxadiazole-3-carboxamide, or pharmaceutically acceptable salts, hydrates and solvates thereof.

14. The compound according to any one of claims 1-13 for use in therapy.

15. The compound according to claim 14 for use in treatment of a disease, disorder or condition, which disease, disorder or condition is responsive of modulation of IL-17.

16. The compound according to claim 14 for use in treatment of autoimmune diseases.

17. The compound according to claim 14 for use in treatment of psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis.

18. The pharmaceutical composition comprising a compound according to any one of claims 1- 14 together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s).

19. The pharmaceutical composition according to claim 18 together with one or more other therapeutically active compound(s).