Heteroaryl carboxylic acid derivatives as GPR84 agonists

Abstract

The present invention relates to heteroaryl carboxylic acid derivatives, especially compounds of formula (I), which are useful as agonists of G-Protein Coupled Receptor 84 (GPR84) activity, in particular for the treatment of proliferative conditions such as cancers. (I)

Description

HETEROARYL CARBOXYLIC ACID DERIVATIVES AS GPR84 AGONISTS FIELD OF INVENTION

[0001] The present invention relates to heteroaryl carboxylic acid derivatives, especially compounds of formula (I) as detailed hereafter, which are useful as agonists of G-Protein Coupled Receptor 84 (GPR84) activity, in particular for the treatment of proliferative conditions such as cancers.BACKGROUND OF INVENTION

[0002] GPR84 is a Gi-coupled G-Protein Coupled Receptor that has been suggested to recognize endogenous medium-chain fatty acids (MCFAs). Among native fatty acids, capric acid with a 10-carbon atom chain length showed the highest potency for activating GPR84 (Wang et al., J. Biol. Chem, 281, pp34457-34464 (2006)).

[0003] GPR84 was found to be predominantly expressed by immune cells, and its expression can be strongly upregulated under inflammatory conditions to augment inflammatory responses and enhance phagocytosis (Wang et al., J. Biol. Chem, 281, pp34457-34464 (2006); Suzuki et al., J. Biol. Chem, 288, ppl0684-10691 (2013); Luscombe et al., DNA Cell Biol 39, ppl926-1937 (2020)).

[0004] One of the immunological functions of GPR84 signalling is to promote inflammation and phagocytosis in macrophages (Recio et al., Front Immunol, 9, 1419 (2018)). This has been indicated in a recent study for cancer cells (Kamber et al., Nature 597, pp549-554 (2021)). This study identified an enzyme expressed in cancer cells named APMAP (Adipocyte Plasma Membrane Associated Protein) that functions as an antiphagocytic factor to impede antibody-dependent cellular phagocytosis (ADCP) of cancer cells induced by blocking CD20. Loss of the APMAP gene can significantly enhance the macrophage phagocytosis of cancer cells, which is dependent upon GPR84. Zang et al., (Nature Communications, (2023) 14:5706) have also shown that activation of GPR84 cansynergize with blockade of CD47 to drive the phagocytosis of cancer cells. More recently it has been showed from analysis of single-cell transcriptome data arising from multiple tumor models that tumor-associated macrophages (TAMs) uniquely express elevated levels of GPR84. Genetic ablation of GPR84 in mice leads to impaired pro-inflammatory polarization of macrophages, while enhancing their anti-inflammatory phenotype. By contrast, GPR84 activation by a synthetic agonist, 6-n-octylaminouracil (6-OAU), potentiates a pro-inflammatory phenotype via the enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly slows tumor growth and increases the anti-tumor efficacy of anti-PD-1 therapy (Li et al., Cancer Immunology, Immunotherapy (2024) 73:52). Together these data suggested a critical role of the GPR84-Gi signalling axis in mediating pro-inflammatory and phagocytosis activities of macrophages, especially TAMs, against cancer cells.

[0005] Therefore, GPR84 agonists may provide a promising and powerful therapeutic opportunity to develop new anti-cancer drugs.

[0006] GPR84 activity is also implicated in conditions such as autoimmune diseases, infectious diseases, atherosclerosis, and neurological or neurodegenerative diseases.

[0007] The present invention thereby describes new GPR84 agonists, which can be useful in the treatment of GPR84-related diseases, for example cancers, autoimmune diseases, infectious diseases, atherosclerosis, and neurological or neurodegenerative diseases, especially cancers.SUMMARY

[0008] This invention thus relates to a compound of formula (I):O (I)or a pharmaceutically acceptable salt and / or solvate thereof, wherein Ar1, Y, Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, Rd’, m, n, p, R4, and - are as defined in in the claims and hereafter.

[0009] The invention also relates to a pharmaceutical composition comprising a compound according to the invention, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier.

[0010] Another aspect of the invention is directed to a compound according to the invention, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament.

[0011] The invention is also directed to a compound according to the invention, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of cancers, autoimmune diseases, infectious diseases, atherosclerosis, and neurological or neurodegenerative disease. In one embodiment, cancers are selected from bladder cancer, bile duct and gall blabber cancers, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal / upper aerodigestive cancer, eye cancer, glioblastoma, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, non- small cell lung cancer (NSCLC), neuroendocrine cancer, head and neck cancer, oral cancer, oral squamous cell carcinoma, melanoma, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, sebaceous gland carcinoma, skin cancer, stomach cancer, and testicular cancer, thyroid cancer, urinary tract cancer, and uterine cancer.

[0012] The invention is further directed to a compound according to the invention, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of diseases or disorders which are responsive to GPR84 agonism.DEFINITIONS

[0013] The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims. When describing thecompounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

[0014] In the present invention, the following terms have the following meanings:

[0015] “Alkyl”, by itself or as part of another substituent, refers to a hydrocarbyl radical of formula CnH2n+1 wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Suitable alkyl groups include for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, and i-propyl.

[0016] “Alkoxy” as used herein refers to any group -O-alkyl, wherein alkyl is as defined above. Suitable alkoxy groups include for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, s-butoxy, and n-pentoxy.

[0017] “Aryl”, by itself or as part of another substituent, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.

[0018] “Cx-y” preceding the name of a group means that the group comprises from x to y carbon atoms, in accordance to common terminology in the chemistry field.

[0019] “Cycloalkyl”, by itself or as part of another substituent, refers to a cyclic alkyl group, that is to say, a fully saturated or partially unsaturated hydrocarbyl group having 1 or 2 cyclic structures, preferably 1 cyclic structure. When being partially unsaturated, cycloalkyl groups may comprise for example 1, 2 or 3 double bonds, preferably 1 double bond. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. When being bicyclic hydrocarbyl groups, cycloalkyl groups may be under the form of fused cycles (cycles linked on two adjacent carbon atoms) or bridged cycles (cycles linked on two non-adjacent carbon atoms). Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, preferably from 3 to 8 carbon atoms and more preferably from 3 to 6 carbon atoms. Suitable cycloalkyl groups include for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Suitable cycloalkyl groups mays also include bridged cycloalkyl such as for example bicyclo[l.l.l]pentanyl, and fused cycloalkyl such as for example bicyclo[2.2.1]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, or bicyclo[3.2.0]hept-2-enyl, hexahydropentalenyl.

[0020] “Spiro-bicycloalkyl”, by itself or as part of another substituent, refers to a carbocyclic group made of two cycloalkyl rings sharing one common carbon atom (spiro atom). Suitable examples of spiro-bicycloalkyl groups include for example spiro[3.3]heptanyl, spiro[2.3]hexanyl, spiro[2.2]pentanyl, spiro[3.4]octanyl, spiro [2.5 ] octanyl, spiro [2.4] heptanyl.

[0021] “Spiro-(cycloalkyl)(heterocyclyl)”, by itself or as part of another substituent, refers to a carbocyclic group made of one cycloalkyl ring and one heterocyclyl ring sharing one common carbon atom (spiro atom). Suitable examples of spiro-(cycloalkyl)(heterocyclyl) groups include for example thiaspiro[3.3]heptanyl.

[0022] “Halo” or “halogen” refer to fluoro, chloro, bromo, or iodo. Generally, halo groups of this invention are fluoro, chloro or bromo.

[0023] “Haloalkyl”, by itself or as part of another substituent, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals includechloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1 -trifluoroethyl and the like.

[0024] “Heteroaryl”, by itself or as part of another substituent, refers to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3]thiazolyl, thieno[3,2-b]furanyl, thieno [3, 2-b] thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

[0025] “Heterocyclyl", by itself or as part of another substituent, refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-member monocyclic, 7- to 11-member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring orring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and / or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, isoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 377-indolyl, indolinyl, isoindolinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin- 1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl sulfoxide, thiomorpholin-4-ylsulfone, 1, 3-dioxolanyl, 1,4-oxathianyl, 1H-pyrrolizinyl, tetrahydro- 1,1 -dioxothiophenyl, and morpholin-4-yl.

[0026] “Oxo”, refers to the substituent =0.

[0027] “Pharmaceutically acceptable” means that the component not deleterious to the subject to which it is administered and is compatible with each other component administered together.

[0028] “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse, allergic, or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA.

[0029] “Prodrug” as used herein means the pharmacologically acceptable derivatives of the compounds of the invention, whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters.

[0030] “Solvate” is used herein to describe a molecular complex comprising a compound of the invention and contains stoichiometric or sub- stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol. The term “hydrate” refers to when said solvent is water.

[0031] “Administration”, or a variant thereof (e.g., “administering"), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the subject in need thereof.

[0032] “Subject” refers to a mammal, preferably a human. According to the present invention, a subject is a mammal, preferably a human, suffering from the targeted disease and / or prone to develop the targeted disease. In one embodiment, the subject is a “patient”, i.e., a mammal, preferably a human, who / which is awaiting the receipt of, or is receiving medical care or was / is / will be the object of a medical procedure or is monitored for the development of the targeted disease.

[0033] “Therapeutically effective amount” (or more simply an “effective amount”) as used herein refers to the amount of active agent or active ingredient that is aimed at, without causing significant negative or adverse side effects to the subject in need of treatment, preventing, reducing, alleviating, or slowing down (lessening) one or more of the symptoms of the targeted disease.

[0034] “Treating” or “treatment” refers to a therapeutic treatment, to a prophylactic (or preventative) treatment, or to both a therapeutic treatment and a prophylactic (or preventative) treatment, wherein the object is to prevent, reduce, alleviate, and / or slow down (lessen) one or more of the symptoms the targeted disease, in a subject in need thereof. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.DETAILED DESCRIPTIONCompounds

[0035] This invention relates to a compound of formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;Ar1is a 5- or 6-membered heteroaryl selected from (Ar1a), (Ar1b), and (Ar1c):wherein:R1is H or halo;R2is H, Ci-3-alkyl, or Ci-3-alkoxy;R3is H, or R3is linked with Raand / or Ra’ as detailed below;A1is selected from CH and S; A2and A3are each independently selected from CH, S, N, NH, and O; provided that at least one of A1, A2and A3is S, N, NH or O;- represents a single or double bond, depending on A1, A2and A3; * represents the point of attachment to the carboxylic acid moiety; and ** represents the point of attachment to Y; andm, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor’w eny is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl; orRaand / or Ra’, with R3present on Ar1aor Ar1bform together with the carbon atoms and Y to which they are linked a fused 5 -membered ring selected from heterocyclyl, heteroaryl, cycloalkyl and aryl; provided that the heterocyclyl or heteroaryl comprise a single heteroatom being S;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; andwhen Ar1is Ar1a:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, and heterocyclyl; and / orwherein the C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl substituents are optionally substituted by one or more hydroxyl; and / orwherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;;when Ar1is Ar1b:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy,C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl; or when R2is not H, R4can also alternatively be a C2-8-alkyl optionally substituted by one or more group selected from halo and C1-3-alkoxy, andwhen the bonds on either side of CRaRa’ are single bonds, then Y is S; andwhen Ar1is Ar1c:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl; and Ra -^-Y— C— -|-Y=lz1, the compound of formula (I) does not comprise«?or Ra', wherein Raand Ra’ represent each independently H, halo, Ci-3-alkyl, or Ci-3-alkoxy, and represents the points of attachment to the rest of the compound.

[0036] In one embodiment, in the compound of formula (I):when Ar1is Ar1a:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy;when Ar1is Ar1b:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents areoptionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy; or when R2is not H, R4can also alternatively be a C2-8-alkyl optionally substituted by one or more group selected from halo and C1-3-alkoxy, andwhen the bonds on either side of CRaRa’ are single bonds, then Y is S; andwhen Ar1is Ar1c:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy; andRa -^-Y— C— -|-Y=lz1, the compound of formula (I) does not comprise«?or Ra', wherein Raand Ra’ represent each independently H, halo, Ci-3-alkyl, or Ci-3-alkoxy, and represents the points of attachment to the rest of the compound.

[0037] In one embodiment the compound of formula (I) is not:5 -butyl-2-pyrimidinecarboxylic acid,5 -pentyl-2-pyrimidinec arboxylic acid,5 -hexyl-2-pyrimidinec arboxylic acid,5 -heptyl-2-pyrimidinec arboxylic acid,5 -butyl-4-methoxy-2-pyrimidinecarboxylic acid,6-ethyl-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-propyl-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(1H-pyrrol-2-ylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(3-methylbutyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2,2-dimethylpropyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(cyclopropylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,5 - [(cyclopentylmethyl)thio] -2-pyridinecarboxylic acid,5-[2-(l,6-dihydro-6-oxo-4-propyl-2-pyrimidinyl)-l-buten-l-yl]-2- pyridinecarboxylic acid,5 - [2-(4-bromo-2-thiazolyl)ethenyl] -2-pyridinecarboxylic acid,5 - [2- (5 -bromo-2-pyrimidinyl)ethenyl] -2-pyridinecarboxylic acid,5-[2-(3,4,5,6,7,8-hexahydro-4-oxo-2-quinazolinyl)ethenyl]-2-pyridinecarboxylic acid,5-(2-cyclopropylvinyl)picolinic acid,2-( 1 -methyl- 1 H-pyrazol-4-yl)thieno [3,2-b]pyridine-5-carboxylic acid,2-cyclopropylthieno [3,2-b]pyridine-5-carboxylic acid,2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridine-5-carboxylic acid,5 - [2- (5 -chloro-2-thiazolyl)ethenyl] -2-pyridinecarboxylic acid,5-(2'-methyl-[l,l'-bi(cyclopropane)]-2-carbonyl)furan-3-carboxylic acid,4-(2'-methyl-[l, T-bi(cyclopropane)]-2-carbonyl)-lH-pyrrole-2-carboxylic acid, 4-([ 1, 1 '-bi(cyclopropane)]-2-carbonyl)- 1 -methyl- lH-pyrrole-2-carboxylic acid, 5-([ 1, 1 '-bi(cyclopropan)] -2-ylmethyl)- 1,3,4-thiadiazole-2-carboxylic acid, 5-([l,l'-bi(cyclopropan)]-2-ylmethyl)furan-3-carboxylic acid,4-([ 1, 1 '-bi(cyclopropan)] -2-ylmethyl)- lH-pyrrole-2-carboxylic acid,5-[2-(2,2,6-trimethylcyclohexyl)ethyl]-lH-pyrazole-3-carboxylic acid,4-[[(2-ethylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid,4-[[(2,2-dimethylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid,5-(2-([l,l'-bi(cyclopropan)]-2-yl)acetyl)furan-3-carboxylic acid,4-(2-([l,l'-bi(cyclopropan)]-2-yl)acetyl)-lH-pyrrole-2-carboxylic acid,4-[[(2-methylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid, or5-[2-(2,2-dimethylcyclopropyl)ethyl]-l,3,4-thiadiazole-2-carboxylic acid.

[0038] The above disclaimed specific compounds were disclosed in the prior art either as substances without any related use or with a use different from the one of the compounds of the present invention, i.e. as agonist of GPR84.Ar1

[0039] According to one embodiment, the compounds of formula (I) comprise a 5- or 6-mebered heteroaryl selected from a pyrimidine, a pyridine or a 5-membered heteroaryl of formula (Arla), (Arlb) and (Arlc) respectively:wherein R1, R2, R3, A1, A2, A3, -, * and ** are as defined above.

[0040] Preferably, Ar1is selected from a pyrimidine (Arla) and a pyridine (Arlb). More preferably, Ar1is a pyrimidine (Arla).

[0041] In one embodiment, the compounds of the invention are of formula (la), (lb) or (Ic):wherein R1, R2, R3, A1, A2, A3, Y, Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, Rd’, m, n, p, R4, and - are as defined in formula (I).

[0042] In one embodiment, the compounds of the invention are of formula (la) or (lb).

[0043] In a preferred embodiment, Ar1is a pyrimidine of formula (Arla). In a preferred embodiment, the compounds of the invention are pyrimidine derivatives; preferably of formula (la).

[0044] In one embodiment, in formula (I) or in subformulae thereof, R1is H or halo; preferably R1is H or F.

[0045] In one embodiment, in formula (I) or in subformulae thereof, R2is H, Ci-3-alkyl, or Ci-3-alkoxy; preferably R2is H, methyl or methoxy; more preferably R2is methyl.

[0046] In one embodiment, in formula (I) or in subformulae thereof, R3is H, or R3is linked with Raand / or Ra’ and forms together with the carbon atoms and Y to which they are linked a fused 5-membered ring selected from heterocyclyl, heteroaryl, cycloalkyl and aryl; provided that the heterocyclyl or heteroaryl comprise a single heteroatom being S.

[0047] In a preferred embodiment, in formula (I) or in subformulae thereof, R3is H.

[0048] When R3is linked with Raand / or Ra’ and forms together with the carbon atoms and Y to which they are linked a fused 5-membered ring as defined above, the compound of the invention can be of formula (la- 1) or (Ib-1):wherein R1, R2, Y, Ra, Rb, Rb’, Rc, Rc’, Rd, Rd’, m, n, p, R4, and - are as defined in formula (I); andZ is S or CRfRf, wherein Rfand Rf’ are each independently either absent; or represent H, halo, Ci-3-alkyl, or Ci-3-alkoxy;provided that Y and Z are not simultaneously S.

[0049] According to one embodiment, the fused ring in the compound of formula (la- 1 ) is selected from:wherein* represents the point of attachment to the carboxylic acid moiety; and*** represents the point of attachment to CRbRb.

[0050] According to one embodiment, Ar1is selected from:wherein* represents the point of attachment to the carboxylic acid moiety;** represents the point of attachment to Y.

[0051] According to one embodiment, Arlais selected from:wherein* represents the point of attachment to the carboxylic acid moiety; and** represents the point of attachment to Y.

[0052] According to a preferred embodiment, in Arla, R2is methyl and R3is H.

[0053] According to one embodiment, Arlbis selected from:wherein* represents the point of attachment to the carboxylic acid moiety; and** represents the point of attachment to Y.

[0054] According to a preferred embodiment, in Arlb, R1is H, R2is methyl and R3is H.

[0055] According to one embodiment, Arlcis selected from:wherein* represents the point of attachment to the carboxylic acid moiety; and** represents the point of attachment to Y.

[0056] In one embodiment, Y is S.

[0057] In another embodiment, Y is CReRewherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group. In an embodiment, Y is CH, CH2 or CF2. In a preferred embodiment, Y is CH2.

[0058] In another embodiment, Y is CReRewherein Reor Re’ is linked with Raor Ra’ and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl.

[0059] In one embodiment, the compound of the invention is of formula (II- 1):O (II-l)wherein Ar1, Re’, Ra’, Rb, Rb’, Rc, Rc’, Rd, Rd’, m, n, p, R4, and - are as defined in formula (I); and q is 1, 2, 3 or 4.

[0060] When the compounds of the invention are of formula (lb), i.e. when Ar1is Ar1b, and when the bonds on either side of CRaRa’ are single bonds, then Y is S.

[0061] In a preferred embodiment, the compounds of the invention are of formula (la) and Y is S or CH2; more preferably Y is S.m, n,p

[0062] In one embodiment, m, n, and p are 0; or m is 1, and n and p are 0; or m and n are 1, and p is 0; or m, n, and p are 1.

[0063] In one embodiment, m, n, and p are 0. In one embodiment, m is 1, and n and p are 0. In one embodiment, m and n are 1, and p is 0. In one embodiment, m, n, and p are 1.

[0064] In a preferred embodiment, m is 1, and n and p are 0; or m and n are 1, and p is 0.Ra, RaRb, Rb, Rc, Rc, Rd, andRd’

[0065] In one embodiment, Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independently either absent; or represent H, halo, Ci-3-alkyl, Ci-3-alkoxy; preferably H, Cl, F, methyl, methoxy; more preferably, H, F, methyl.

[0066] In a preferred embodiment, Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independently either absent or represent H.

[0067] In one embodiment, Raand Rb, or Rband Rc, or Rcand Rd, form together with the carbon atoms to which they are attached a C3-6-cycloalkyl.

[0068] In one embodiment, the compound of the invention is of formula (II-2), (II-3) or (II-4):o (11-2)O (11-3)O (11-4)wherein Ar1, Y, Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, Rd’, m, n, p, R4, and - are as defined in formula (I); and q is 1, 2, 3 or 4.Linker (i)

[0069] In the compounds of the invention, the moiety starting from Y to the point of attachment of R4, i.e. corresponding to Y(CRaRa)(CRbRb)m(CRcRc)n(CRdRd)p, is herein referred to as “linker (i)”. Linker (i) thus corresponds to:whereinY, Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, Rd’, m, n, p, and - are as defined in formula (I), ** represents the point of attachment to Ar1; and■~w represents the point of attachment to R4.

[0070] In one embodiment, linker (i) comprises 0, 1 or 2 double bonds. This embodiment refers to the bonds present in backbone of the linker and does not refer to the points of attachment of the linker. When linker (i) comprises 2 double bonds, the double bonds areeither spaced by one or more single bond, or are adjacent and form an allene group. In a preferred embodiment, linker (i) comprises 1 or 2 double bonds.

[0071] The bond attaching linker (i) to R4can be a single bond or double bond. In a preferred embodiment, the bond attaching linker (i) to R4is a single bond.

[0072] In one embodiment, linker (i) comprises from 0 to 10 lateral groups selected from Re, Re’, Ra, Rb, Rb’, Rc, Rc’, Rd, and Rd’; preferably from 0 to 4 lateral groups; more preferably 0, 1 or 2 lateral groups. By “lateral group”, it is referred to substituents being present and other than H. In one embodiment, when linker (i) comprises one or more lateral groups, the lateral groups are selected from halo, Ci-3-alkyl, Ci-3-alkoxy; preferably from F, Cl, methyl, and methoxy; more preferably from F and methyl.

[0073] In one embodiment, linker (i) comprises 0 or 1 C3-6-cycloalkyl moiety in the linker backbone. In one embodiment, linker (i) does not comprise a C3-6-cycloalkyl moiety.

[0074] According to one embodiment, linker (i) is selected from:wherein** represents the point of attachment to Ar1; andrepresents the point of attachment to R4.

[0075] According to one embodiment, linker (i) is selected from:Fwherein** represents the point of attachment to Ar1; andrepresents the point of attachment to R4.

[0076] When the compounds of the invention are of formula (lb), i.e. when Ar1is Ar1b, then in the linker (i), when the bonds on either side of CRaRa’ are single bonds, then Y is S.

[0077] When the compounds of the invention are of formula (Ic), i.e. when Ar1is Ar1c,Ra-^-Y— C—-|-v=L1,the compound and thus linker (i) do not comprise «?orRa', wherein Raand Ra’ represent each independently H, halo, Ci-3-alkyl, or Ci-3-alkoxy, and represents the points of attachment to the rest of the compound.R4

[0078] In one embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl (with the exception that when R4is a C2-8-alkyl, it cannot be substituted by an hydroxyl); and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl (preferably a C3-6-cycloalkyl). In one embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, and hydroxyl (with the exception that when R4is a C2-8-alkyl, it cannot be substituted by an hydroxyl); and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl. In a preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In another preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl (with the exception that when R4is a C2-8-alkyl, it cannot besubstituted by an hydroxyl); and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In another preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), C2-8-alkyl, or 3- to 6-membered heterocyclyl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl (with the exception that when R4is a C2-8-alkyl, it cannot be substituted by an hydroxyl); and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In a more preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In another more preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), or 3- to 6-membered heterocyclyl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl.

[0079] In one embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy. In a preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), 3- to 6-membered heterocyclyl, phenyl, or 5-or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy. In another preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents areoptionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy. In another preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), C2-8-alkyl, or 3- to 6-membered heterocyclyl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy. In a more preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy. In another more preferred embodiment, R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), or 3- to 6-membered heterocyclyl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy.

[0080] In a preferred embodiment, R4is a C3-8-cycloalkyl or a spiro-bi(C3-6-cycloalkyl), optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; preferably selected from F, methyl, butyl, -CF3, -CH2-CF3, cyclopropyl, cyclobutyl, and hydroxyl; and / or the spiro-bi(C3-6-cycloalkyl) is optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl, preferably spiro-fused to cyclopropyl.

[0081] In a preferred embodiment, R4is C3-8-cycloalkyl, optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy; preferably selected from halo, and Ci-3-alkyl; more preferably selected from F and methyl.

[0082] According to one embodiment, R4is selected from:FBr

[0084] According to one embodiment, R4is selected from:wherein represents the point of attachment to the rest of the compound.

[0085] According to a specific embodiment, R4is selected from:wherein -~w represents the point of attachment to the rest of the compound.

[0086] In one embodiment, the compounds of the invention are of formula (la), i.e. Ar1is Ar1a, wherein R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted byone or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl (with the exception that when R4is a C2-8-alkyl, it cannot be substituted by an hydroxyl); and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl.

[0087] In one embodiment, the compounds of the invention are of formula (la), i.e. Ar1is Ar1a, wherein R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, and Ci-3-alkoxy.

[0088] In a preferred embodiment, in formula (la), R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In another preferred embodiment, in formula (la), R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl (with the exception that when R4is a C2-8-alkyl, it cannot be substituted by an hydroxyl); and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In another preferred embodiment, in formula (la), R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), C2-8-alkyl, or 3- to 6-membered heterocyclyl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl (with the exception that when R4is a C2-8-alkyl, it cannot be substituted by an hydroxyl); and / or wherein thespiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In a more preferred embodiment, in formula (la), R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In another more preferred embodiment, in formula (la), R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), or 3- to 6-membered heterocyclyl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl.

[0089] In a preferred embodiment, in formula (la), R4is a C3-8-cycloalkyl or a spiro-bi(C3-6-cycloalkyl), optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; preferably selected from F, methyl, butyl, -CF3, -CH2-CF3, cyclopropyl, cyclobutyl, and hydroxyl; and / or the spiro-bi(C3-6-cycloalkyl) is optionally further spiro-fused to a C3-6-cycloalkyl, preferably spiro-fused to cyclopropyl.

[0090] In one embodiment, the compounds of the invention are of formula (lb), i.e. Ar1is Ar1b, wherein:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;or when R2is not H, R4can also alternatively be a C2-8-alkyl optionally substituted by one or more group selected from halo and C1-3-alkoxy.

[0091] Preferably, in formula (lb), R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In another embodiment, in formula (lb), R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), or 3- to 6-membered heterocyclyl,; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl.

[0092] In one embodiment, the compounds of the invention are of formula (Ic), i.e. Ar1is Ar1c, wherein R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl. In one embodiment, in formula (Ic), R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), ), spiro-(C3-6-cycloalkyl)(heterocyclyl), or 3- to 6-membered heterocyclyl,; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl.

[0093] In one embodiment, the compounds of the invention are of formula (la):0(la) or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;R2is H, Ci-3-alkyl, or Ci-3-alkoxy;R3is H, or R3is linked with Raand / or Ra’ as detailed below;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor Ra’, when Y is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl; orRaand / or Ra’ with R3form together with the carbon atoms and Y to which they are linked a fused 5-membered ring selected from heterocyclyl, heteroaryl, cycloalkyl and aryl; provided that the heterocyclyl or heteroaryl comprise a single heteroatom being S;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; andR4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, C1-3-alkyl, C1-3-haloalkyl, C1-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl (with the exception that when R4is a C2-8-alkyl, it cannot be substituted by an hydroxyl);and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;and provided that the compound of formula (la) is not:5 -butyl-2-pyrimidinecarboxylic acid,5 -pentyl-2-pyrimidinec arboxylic acid,5 -hexyl-2-pyrimidinec arboxylic acid,5 -heptyl-2-pyrimidinec arboxylic acid,5 -butyl-4-methoxy-2-pyrimidinecarboxylic acid,6-ethyl-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-propyl-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(1H-pyrrol-2-ylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(3-methylbutyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2,2-dimethylpropyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(cyclopropylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid.

[0094] In one embodiment, the compounds of the invention are of formula (la) or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;R2is H, Ci-3-alkyl, or Ci-3-alkoxy;R3is H, or R3is linked with Raand / or Ra’ as detailed below;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor’w eny is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl; orRaand / or Ra’ with R3form together with the carbon atoms and Y to which they are linked a fused 5-membered ring selected from heterocyclyl, heteroaryl, cycloalkyl and aryl; provided that the heterocyclyl or heteroaryl comprise a single heteroatom being S;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; andR4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;and provided that the compound of formula (la) is not:6-(1H-pyrrol-2-ylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(cyclopropylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid.

[0095] In one embodiment, the compounds of the invention are of formula (la) or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;R2is H, Ci-3-alkyl, or Ci-3-alkoxy;R3is H;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor’w eny is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; andR4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl.

[0096] In one embodiment, the compounds of the invention are of formula (lb):0(lb) or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;R1is H or halo;R2is H, Ci-3-alkyl, or Ci-3-alkoxy;R3is H, or R3is linked with Raand / or Ra’ as detailed below;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor’w eny is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl; orRaand / or Ra’ with R3form together with the carbon atoms and Y to which they are linked a fused 5-membered ring selected from heterocyclyl, heteroaryl, cycloalkyl and aryl; provided that the heterocyclyl or heteroaryl comprise a single heteroatom being S;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; and with the condition that when the bonds on either side of CRaRa’ are single bonds, then Y is S;R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl; or when R2is not H, R4can also alternatively be a C2-8-alkyl optionally substituted by one or more group selected from halo and C1-3-alkoxy;and provided that the compound of formula (lb) is not:5 - [(cyclopentylmethyl)thio] -2-pyridinecarboxylic acid,5-[2-(l,6-dihydro-6-oxo-4-propyl-2-pyrimidinyl)-l-buten-l-yl]-2-pyridinecarboxylic acid,5 - [2-(4-bromo-2-thiazolyl)ethenyl] -2-pyridinecarboxylic acid,5 - [2- (5 -bromo-2-pyrimidinyl)ethenyl] -2-pyridinecarboxylic acid,5-[2-(3,4,5,6,7,8-hexahydro-4-oxo-2-quinazolinyl)ethenyl]-2-pyridinecarboxylic acid,5-(2-cyclopropylvinyl)picolinic acid,2-( 1 -methyl- 1 H-pyrazol-4-yl)thieno [3,2-b]pyridine-5-carboxylic acid,2-cyclopropylthieno [3,2-b]pyridine-5-carboxylic acid,2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridine-5-carboxylic acid,5 - [2- (5 -chloro-2-thiazolyl)ethenyl] -2-pyridinecarboxylic acid.

[0097] In one embodiment, the compounds of the invention are of formula (lb) or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;R1is H or halo;R2is H, Ci-3-alkyl, or Ci-3-alkoxy;R3is H;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor Ra’, when Y is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; and with the condition that when the bonds on either side of CRaRa’ are single bonds, then Y is S;R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), or spiro-(C3-6- cycloalkyl)(heterocyclyl),; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;and provided that the compound of formula (lb) is not:5 - [(cyclopentylmethyl)thio] -2-pyridinecarboxylic acid,5-(2-cyclopropylvinyl)picolinic acid.

[0098] In one embodiment, the compounds of the invention are of formula (Ic):Ra / Rb\ / Rc\ / Rd\0V (IC) or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;A1is selected from CH and S; A2and A3are each independently selected from CH, S, N, NH, and O; provided that at least one of A1, A2and A3is S, N, NH or O; - represents a single or double bond, depending on A1, A2and A3;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor Ra’, when Y is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; andR4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein thespiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;and the compound of formula (Ic) does not comprise<?or Ra1, wherein Raand Ra’ represent each independently H, halo, Ci-3-alkyl, or Ci-3-alkoxy, and represents the points of attachment to the rest of the compound;and provided that the compound of formula (Ic) is not:5-(2'-methyl-[l,l'-bi(cyclopropane)]-2-carbonyl)furan-3-carboxylic acid,4-(2'-methyl-[l,l'-bi(cyclopropane)]-2-carbonyl)-lH-pyrrole-2-carboxylic acid, 4-([ 1, 1 '-bi(cyclopropane)]-2-carbonyl)- 1 -methyl- lH-pyrrole-2-carboxylic acid, 5-([ 1, 1 '-bi(cyclopropan)] -2-ylmethyl)- 1,3,4-thiadiazole-2-carboxylic acid, 5-([l,l'-bi(cyclopropan)]-2-ylmethyl)furan-3-carboxylic acid,4-([ 1, 1 '-bi(cyclopropan)] -2-ylmethyl)- lH-pyrrole-2-carboxylic acid,5-[2-(2,2,6-trimethylcyclohexyl)ethyl]-lH-pyrazole-3-carboxylic acid,4-[[(2-ethylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid,4-[[(2,2-dimethylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid,5-(2-([l,l'-bi(cyclopropan)]-2-yl)acetyl)furan-3-carboxylic acid,4- (2- ( [ 1, 1 '-bi(cyclopropan) ] -2-yl) acetyl) - 1 H-pyrrole-2-c arboxylic acid,4- [[(2-methylcyclopropyl)methyl]thio] -2-thiophenecarboxylic acid, or5 - [2-(2,2-dimethylcyclopropyl)ethyl] - 1,3,4-thiadiazole-2-carboxylic acid.

[0099] In one embodiment, the compounds of the invention are of formula (Ic) or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;A1is selected from CH and S; A2and A3are each independently selected from CH, S, N, NH, and O; provided that at least one of A1, A2and A3is S, N, NH or O; - represents a single or double bond, depending on A1, A2and A3;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; andR4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6-cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;and the compound of formula (Ic) does not comprise<?or Ra1, wherein Raand Ra’ represent each independently H, halo, Ci-3-alkyl, or Ci-3-alkoxy, and represents the points of attachment to the rest of the compound;and provided that the compound of formula (Ic) is not:5-[2-(2,2,6-trimethylcyclohexyl)ethyl]-lH-pyrazole-3-carboxylic acid,4- [[(2-ethylcyclopropyl)methyl]thio] -2-thiophenecarboxylic acid,4-[[(2,2-dimethylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid,4- [[(2-methylcyclopropyl)methyl]thio] -2-thiophenecarboxylic acid, or5 - [2-(2,2-dimethylcyclopropyl)ethyl] - 1,3,4-thiadiazole-2-carboxylic acid.

[0100] Unless otherwise specified, when it is referred to compounds according to the invention, it encompasses compounds of formula (I) and any of above subformulae thereof. Unless otherwise specified, when it is referred to compounds of formula (I), it also encompasses any of above subformulae thereof.List of compounds

[0101] According to one embodiment, the compound according to the invention is selected from those listed in Table 1:z p — / / Table 1CD1 5-((2-cyclohexylethyl)thio)-4- methylpicolinic acid2 5-((2-cyclohexylethyl)thio)-4- methylpyrimidine-2-carboxylic acidHOyV O03 5-((2-cyclohexylethyl)thio)-4- wmethoxypyrimidine-2-carboxylic t> / HOacid2°=o4 ZE (E’)-5-(3-cyclohexylprop- 1 -en- 1 - yl)-4-methylpyrimidine-2- carboxylic acid05 (E)-5-(3-cyclohexylallyl)-4-methylpyrimidine-2-carboxylic acidHOyV O06 (E’)-5-(3-cyclopentylallyl)-4- methylpyrimidine-2-carboxylic acid HO. JLnNo7 4-methyl-5-(((tetrahydro-2H-pyran- 2-yl)methyl)thio)pyrimidine-2- carboxylic acid05-((3-cyclopentylpropyl)thio)-4- ZE I I ZE I methylpyrimidine-2-carboxylic acid o o o O o / / / / / o o o o O=====0 \ \ \ \ \zzzzz=====) ) ))>)) z 2) Z — / — / — — / / / / / / / / / / \\ \ \ 5-((2-cyclohexylpropyl)thio)-4-N\s CD CD u> methylpyrimidine-2-carboxylic acid " W w04-methyl-5-((2-(2- methylcyclopentyl)ethyl)thio)pyrim idine-2-carboxylic acid5-((2-cyclopentylpropyl)thio)-4- methylpyrimidine-2-carboxylic acid4-methyl-5-((2-( 1 - methylcyclopentyl)ethyl)thio)pyrim idine-2-carboxylic acid(E)-5-(3- cyclopentylallyl)pyrimidine-2- carboxylic acid5-((2- cyclopentylcyclopropyl)methyl)-4- methylpyrimidine-2-carboxylic acid(E’)-5-((2-cyclopentylvinyl)thio)-4- methylpyrimidine-2-carboxylic acidHOYM0M(E)-5-(3-cyclopentylallyl)-3-fluoropicolinic acido O o / ^ o oo71==(=V \zz=) z ~Z 6-(2-cyclopentylethyl)thieno [3,2- > — z / . / / / / / s / / \s \d]pyrimidine-2-carboxylic acid W(E)-5-(3-cyclopentylallyl)-4-methoxypyrimidine-2-carboxylic acidfE)-5-(3-cyclopcntyl-2- methylallyl)-4-methylpyrimidine-2- HO^V Mcarboxylic acid0 Z\z—zZ Az= / =( Z)-5-(3-cyclopentyl-2-fluoroallyl)- 2 / °°=o o 4-methylpyrimidine-2-carboxylic I THOyVF Macid0(E)-5-(3-cycloheptylallyl)-4-methylpyrimidine-2-carboxylic acid(E’)-5-(4-cyclobutylbut-2-en-l-yl)-NA / YXYJ4-methylpyrimidine-2-carboxylic acid0(E)-4-methyl-5-(3-(1-methylcyclopentyl)allyl)pyrimidine-2-carboxylic acid(E)-5-((2-cyclobutylvinyl)thio)-4-methylpyrimidine-2-carboxylic acid / O=) z / — / / W (E)-5-(3-cyclopentylbut-2-en-1-yl)-4-methylpyrimidine-2-carboxylic acid“V ~J J06-(2-cyclopentylethyl)-6,7- dihydrothieno [3,2-d] pyrimidine-2- carboxylic acido(Z)-5-(3-cyclopentyl-3-fluoroallyl)-4-methylpyrimidine-2-carboxylic acid0Md(E’)-5-(3-cyclopentyl-3-fluoroallyl)- 4-methylpyrimidine-2-carboxylic acidHO. JI JJlN0(E) -5 - (4-cy clobutylbut-2-en- 1 - yl)pyrimidine-2-carboxylic acid “V -J0(E’)-5-((2-cyclohexylvinyl)thio)-4- methylpyrimidine-2-carboxylic acid n^ J04-methyl-5 - (2- ( spiro [3.3 ] heptan-2- I ylidene)ethyl)pyrimidine-2- o / o= carboxylic acidHOy \Vz=0 ) z — / / / (E)-5-(4-cyclopentylbut-2-en-1-yl)-4-methylpyrimidine-2-carboxylic acid(E’)-5-(3-cyclopentyl- 1,1- difluoroallyl)pyrimidine-2- carboxylic acid5-(3-cyclopentylpropyl)-4- methylpyrimidine-2-carboxylic acidzHOy zZV=L' / )° o=o(E)-5-(5-cyclobutylpent-2-en-1-yl)-4-methylpyrimidine-2-carboxylic acid0(£’)-4-methyl-5-(5-methylhex-2-en- l-yl)pyrimidine-2-carboxylic acidH0- / V0(E’)-5-((3-cyclobutylprop-l-en-l- yl)thio)-4-methylpyrimidine-2-HOcarboxylic acidYM0fEj-4- mcthyl-5 -(4-( 1 - T I I methylcyclopropyl)but-2-en- 1 - o o o o / / ^4 o o o o=== yl)pyrimidine-2-carboxylic acid 0 \ \ \ Vzzz==z=) )) z z z — / / — —) / / / / z / / \ w — / / \\ \ ( E)-4-methyl-5 -(4-phenylbut-2-en- l-yl)pyrimidine-2-carboxylic acid(E)-4-methyl-5 -(3- (spiro [3.3]heptan-2- HO. A <2 ^ \ \Y^Nyl)allyl)pyrimidine-2-carboxylic 0acid(E)-5-(4-( 1 -fluorocyclobutyl)but-2-NAYX^X / } en- 1 -yl)-4-methylpyrimidine-2-HOyV carboxylic acid0(E)-4-methyl-5 -(4-( 1 - methylcyclobutyl)but-2-en- 1 - yl)pyrimidine-2-carboxylic acid(E)-5-(4-cyclopropylbut-2-en-l-yl)- 4-methylpyrimidine-2-carboxylic acid(E)-5-((3-cyclobutylprop-l-en-l-N-ys^Ayl)thio)pyrimidine-2-carboxylicHOYV acid0(E)-4-methyl-5 -(3- (spiro[2.3]hexan-l- yl)allyl)pyrimidine-2-carboxylic acid( Z)-5 -(4-c yclobut yl -3 -fl uorobut-2- iFr~7I I en- 1 -yl)-4-methylpyrimidine-2- o o / / o o== carboxylic acid0 \ yzz==- ) z) / — z / / - z / / w 5-(4-cyclobutylbuta- 1,2-dien- 1 -yl)- 4-methylpyrimidine-2-carboxylic OacidfEj-4- mcthyl-5 -(4- (2- Jmethylcyclopropyl)but-2-en- 1 - yl)pyrimidine-2-carboxylic acid “W0(E’)-5-(3-(2,2-NAy / \ / \ / dimethylcyclopropyl)allyl)-4- methylpyrimidine-2-carboxylic acid " V -'J0(E) -5 - (4-cy clobutylidenebut-2-en- N'''V / 'xAs;^M1 -yl)-4-methylpyrimidine-2-HOYV carboxylic acid0( £’)-5-(5-cyclopropylpent-2-en- 1 - yl)-4-methylpyrimidine-2- carboxylic acid(E’)-5-(4-cyclobutylbut-2-en-l-yl)- 4-methylpicolinic acid0(E’)-5-(4-cyclobutylbut-2-en-l-yl)- H / \7lH-pyrazole-3-carboxylic acid II 7^ - 0(E)-5-(4-cyclobutylpent-2-en-l-yl)- “ T T 4-methylpyrimidine-2-carboxylic o o / / Y o o==M1acid0 \z=) z / — / / \ \ (Z)-5-(4-cyclobutylbut-2-en-1-yl)-4-methylpyrimidine-2-carboxylic acid(E) -5 - (4-cy clobutylbut-2-en- 1 - yl)thiazole-2-carboxylic acid5-(4-cyclobutylbutyl) -4- methylpyrimidine-2-carboxylic acid “W Zz=0O \=oT (E’)-5-(4-cyclobutylbut- 1 -en- 1 -yl)- 4-methylpyrimidine-2-carboxylic acid“W04-methyl-5-(phenethylthio)pyrimidine-2-carboxylic acidO(E)-4-methyl-5-((4-methylpent-1-en-1-yl)thio)pyrimidine-2-carboxylic acid(Z) -4-methyl- 5 - ((4-methylpent- 1 - en- 1 -yl)thio)pyrimidine-2- carboxylic acid0(E)-5-((3-(l-fluorocyclobutyl)prop- X s^x l-en-l-yl)thio)-4-HOyV methylpyrimidine-2-carboxylic acid 0F> O (Z)-5-((3 -( 1 -fluorocyclobutyl)prop- l-en-l-yl)thio)-4-smethylpyrimidine-2-carboxylic acidHVV0(E)-4-methyl-5-((3-(l- X s^x methylcyclobutyl)prop- 1 -en- 1 - x xvzyl)thio)pyrimidine-2-carboxylic x° 0I o acid(Z)-4-methyl-5-((3-(l- methylcyclobutyl)prop- 1 -en- 1 - yl)thio)pyrimidine-2-carboxylic acid(E’)-5-((3-cyclobutylallyl)thio)-4- X Xmethylpyrimidine-2-carboxylic acidHOyX0(Z)-5-((3 -cyclobutylallyl)thio)-4- AySx^.methylpyrimidine-2-carboxylic acidHOYV A0 'S(E)-5-((3-cyclobutyl-l-fluoroprop- X^Xl-en-l-yl)thio)-4- “Xf0 methylpyrimidine-2-carboxylic acid(Z)-5-((3 -cyclobutyl- 1 -fluoroprop- l-en-l-yl)thio)-4- methylpyrimidine-2-carboxylic acidHOYXNJ) F05-((cyclohexylidenemethyl)thio)-4- methylpyrimidine-2-carboxylic acid(Z)-5-((3 -cyclobutylprop- 1 -en- 1 - yl)thio)-4-methylpyrimidine-2- X Ucarboxylic acidHO. U-?nN0( Ej-4- methyl -5 -((2- (spiro[2.3]hexan-l- M2 20°== yl)vinyl)thio)pyrimidine-2- o oX X carboxylic acid(Z) -4-methyl- 5 - ((2- (spiro[2.3]hexan-l- X U yl)vinyl)thio)pyrimidine-2-HX carboxylic acid0X"'s5-(((2-thiaspiro[3.3]heptan-6- N^ysylidene)methyl)thio)-4-HOyU methylpyrimidine-2-carboxylic acid o4-methyl-5 - (( spiro [2.3 ] hexan- 5 - n x ylidenemethyl)thio)pyrimidine-2- U o N-" carboxylic acid(E)-5-((3-cyclobutyl-2-methylprop- I i T l-en-l-yl)thio)-4- o o OHO / / / y o o O=== V methylpyrimidine-2-carboxylic acid 0(Z)-5-((3 -cyclobutyl-2-methylprop- C CDDz c> l-en-l-yl)thio)-4- X sA7methylpyrimidine-2-carboxylic acidHoyV0(E)-4-methyl-5-((2-(spiro[3.3]heptan-2-HOyV ^3 yl)vinyl)thio)pyrimidine-2- 0carboxylic acid(Z) -4-methyl- 5 - ((2- (spiro [3.3]heptan-2- yl)vinyl)thio)pyrimidine-2- carboxylic acid(E)-4-methyl-5-((2-(spiro[2.2]pentan-1- yl)vinyl)thio)pyrimidine-2- carboxylic acid(Z) -4-methyl- 5 - ((2- (spiro[2.2]pentan-l- XsJ^ yl)vinyl)thio)pyrimidine-2-HOyV carboxylic acid04-methyl-5 - (( spiro [3.3 ] heptan-2- ylidenemethyl)thio)pyrimidine-2- carboxylic acid6E>5-((3-(3- fluorobicyclo [1.1.1 ]pentan- 1 -HVV yl)prop- 1 -en- 1 -yl)thio)-4- 0 methylpyrimidine-2-carboxylic acid (Z)-5-((3-(3- fluorobicyclo [1.1.1 ]pentan- 1 - yl)prop- 1 -en- 1 -yl)thio)-4- N^VSHoyv methylpyrimidine-2-carboxylic acid 0F 5 -(((6, 6-difluoro spiro [3.3 ] heptan-2- r-y-Fylidene)methyl)thio)-4- methylpyrimidine-2-carboxylic acidHOyV0(£’)-4-methyl-5-((3-(2- methylcyclopropyl)prop- 1 -en- 1 -HOy *N^ yl)thio)pyrimidine-2-carboxylic 0acid(Z)-4-methyl-5-((3-(2- methylcyclopropyl)prop- 1 -en- 1 - yl)thio)pyrimidine-2-carboxylicHyV acid05-((3-(4-bromophenyl)prop- 1-en- 1- yl)thio)-4-methylpyrimidine-2- TAcarboxylic acidHY¥05-((cyclopentylidenemethyl)thio)- 4-methylpyrimidine-2-carboxylic acid0(E)-5-((3-cyclobutyl-2-fluoroprop- I l-en-l-yl)thio)-4- o / o= methylpyrimidine-2-carboxylic acidHOyV0& (E)-4-methyl-5-((3-(l- LS^ )Amethylcyclopropyl)prop- 1 -en- 1 -HOySJ yl)thio)pyrimidine-2-carboxylic 0acid(Z)-4-methyl-5-((3-(l- methylcyclopropyl)prop- 1 -en- 1 - x -u^yl)thio)pyrimidine-2-carboxylicHOyX acid0( Z)-5-((2-cyclopentylvinyl)thio)-4- methylpyrimidine-2-carboxylic acid(E)-4-methyl-5-(styrylthio)pyrimidine-2-carboxylicacid0(Z)-4-methyl-5- 0 (styrylthio)pyrimidine-2-carboxylic acidN^VSH°Y^N^05-(((3,3- X s^X dimethylcyclobutylidene)methyl)thiHOyV o)-4-methylpyrimidine-2- 0 carboxylic acid(E)-5-((3-cyclopentylprop-l-en-l-Nlfs^X>I yl)thio)-4-methylpyrimidine-2- oV / o= V carboxylic acid0(Z)-5-((3 -cyclopentylprop- 1 -en- 1 - cnyl)thio)-4-methylpyrimidine-2- carboxylic acid4-methyl-5 - (( spiro [3.3 ] heptan-2- LX ylmethyl)thio)pyrimidine-2-HOyV carboxylic acido} (E’)-5-((3-cyclobutylbut- 1 -en- 1 - yl)thio)-4-methylpyrimidine-2-HYX1x carboxylic acid2° 0=zo(Z)-5-((3-cyclobutylbut-1-en-1- yl)thio)-4-methylpyrimidine-2- carboxylic acid(E)-5-((4,4-dimethylpent-1-en-1- yl)thio)-4-methylpyrimidine-2- carboxylic acid0(Z)-5-((4,4-dimethylpent-l-en-l- yl)thio)-4-methylpyrimidine-2-Hcarboxylic acid°X0(E)-5-((3-cyclopropylprop- 1 -en- 1 - I X XHyl)thio)-4-methylpyrimidine-2- o° / y o=V carboxylic acid0X^Z(Z)-5-((3 -cyclopropylprop- 1 -en- 1 - yl)thio)-4-methylpyrimidine-2- X Ucarboxylic acidHO. X- >nN0(E)-4-methyl-5-((2-(spiro[2.3]hexan-5- yl)vinyl)thio)pyrimidine-2- 0carboxylic acid(Z) -4-methyl- 5-((2- (spiro[2.3]hexan-5- X U yl)vinyl)thio)pyrimidine-2- carboxylic acidHYv04-methyl-5-((spiro [3.4] octan-2- x x ° ylidenemethyl)thio)pyrimidine-2- carboxylic acidHOyV01F / '"7 (Z)-5-((3 -cyclobutyl-2-fluoroprop- l-en-l-yl)thio)-4-HjxfX?smethylpyrimidine-2-carboxylic acid 0(Z)-5-(((2- cyclopropylcyclobutylidene)methyl )thio)-4-methylpyrimidine-2- carboxylic acid(E)-5-(((2- cyclopropylcyclobutylidene)methyl )thio)-4-methylpyrimidine-2- 0carboxylic acidr^ / F 5-(((6-fluorospiro[3.3]heptan-2- ylidene)methyl)thio)-4- XsXXmethylpyrimidine-2-carboxylic acid 0(E)-5-(((3,3- b X dimethylcyclopentylidene)methyl)t X hio)-4-methylpyrimidine-2- 0 carboxylic acid3 C / fZ>-5-(((3,3- dimethylcyclopentylidene)methyl)t x x fx>hio)-4-methylpyrimidine-2-o carboxylic acidX 04-methyl-5-(((3- V(trifluoromethyl)cyclobutylidene)m b JjfX ethyl)thio)pyrimidine-2-carboxylicHOXJacid0(Z)-5-((4-fluoro-4-methylpent-1-en-1-yl)thio)-4-methylpyrimidine-2- N^VScarboxylic acidHOX0(E)-5-((4-fluoro-4-methylpent-1-en-1-yl)thio)-4-methylpyrimidine-2-carboxylic acid(E)-4-methyl-5-((5,5,5-trifluoro-4- methylpent- 1 -en- 1 - -yVTfyl)thio)pyrimidine-2-carboxylic 0acid(Z)-4-methyl-5-((5,5,5-trifluoro-4- methylpent- 1 -en- 1 - yl)thio)pyrimidine-2-carboxylicHOyV acid05-(((3-(tert- butyl)cyclobutylidene)methyl)thio)- 4-methylpyrimidine-2-carboxylic ”°yVacid0(Z)-5-((cis-bicyclo[3.2.0]hept-2-en- 6-ylidenemethyl)thio)-4- X s^9methylpyrimidine-2-carboxylic acidHOyV0(E’)-5-((cz‘5-bicyclo[3.2.0]hept-2-en- i if 6-ylidenemethyl)thio)-4-H°Y^N^ methylpyrimidine-2-carboxylic acid 0\^F 4-methyl-5-(((6- (trifluoromethyl) spiro [3.3 ] heptan- i rVZjF2-ylidene)methyl)thio)pyrimidine- f YsHYY 2-carboxylic acid0(E)-5-(((1-fluorospiro[3.3]heptan-2-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid(Z)-5-(((1-fluorospiro[3.3]heptan-2- ylidene)methyl)thio)-4- N^YSmethylpyrimidine-2-carboxylic acid 05-(((3- cyclopropylcyclobutylidene)methylHOYV )thio)-4-methylpyrimidine-2- carboxylic acid05-(( [ 1, 1 '-bi(cyclobutan)] -3- ylidenemethyl)thio)-4- methylpyrimidine-2-carboxylic acidw / 4-methyl-5-(((l- methylspiro[3.3]heptan-2- M2°= ylidene)methyl)thio)pyrimidine-2- oX carboxylic acid 0(one of 128 and 129 is (Z)-, the other is (E)-) / HO rx 5-((( 1 -hydroxy spiro [3.3]heptan-2- ylidene)methyl)thio)-4- methylpyrimidine-2-carboxylic acid (one of 130 and 131 is (Z)-, the other 0is (E)-)4-methyl-5-(((2- methylcyclohexylidene)methyl)thio AS^9 )pyrimidine-2-carboxylic acidHOYM104-methyl-5-(((3- methylcyclohexylidene)methyl)thioHOYV )pyrimidine-2-carboxylic acid 0(Z)-5-((bicyclo[2.2.1]heptan-2- ylidenemethyl)thio)-4-HOY¥ methylpyrimidine-2-carboxylic acid 0(E) -5 - ((bicyclo [2.2.1 ] heptan-2- X sX D ylidenemethyl)thio)-4-HOyV methylpyrimidine-2-carboxylic acid 04-methyl-5-(((5- methylspiro[3.3]heptan-2- ylidene)methyl)thio)pyrimidine-2-HOyV carboxylic acid0F 5-(((4,4- i XV-F difluorocyclohexylidene)methyl)thi o)-4-methylpyrimidine-2-HQT J / 'N; scarboxylic acid0F 4-methyl-5-(((3-(2,2,2- trifluoroethyl)cyclobutylidene)methH°X yl)thio)pyrimidine-2-carboxylic 0 acid4-methyl-5 - (( spiro [2.5 ] octan- 6- X sX r ylidenemethyl)thio)pyrimidine-2- carboxylic acidH<VV0F\ / ^7 (Z)-5-((2-(2,2-fA— AJdifluoro spiro [2.3 ] hexan- 1 - yl)vinyl)thio)-4-methylpyrimidine- 2-carboxylic acid0(E)-5-((2-(2,2- difluoro spiro [2.3 ] hexan- 1 -H°YV FXF yl)vinyl)thio)-4-methylpyrimidine- 02-carboxylic acid(Z)-5-((2-(l-fluorospiro[2.3]hexan- FA l-yl)vinyl)thio)-4- methylpyrimidine-2-carboxylic acid? jfs0(E)-5-((2-(1-fluorospiro[2.3]hexan- l-yl)vinyl)thio)-4- / o=oX methylpyrimidine-2-carboxylic acid 05-(((*trans*-3,4- dimethylcyclopentylidene)methyl)t.hio)-4-methylpyrimidine-2-H°Y *N^carboxylic acid05-((cis-bicyclo[3.1.0]hexan-2- X =^Q ylidenemethyl)thio)-4-HOyV methylpyrimidine-2-carboxylic acid 0 (one of 145 and 146 is (Z)-, the other is (E)-) / 4-methyl-5-(((3- methylcyclopentylidene)methyl)thi o)pyrimidine-2-carboxylic acid(147 being a racemic mixture of (Z)- or (E)-, and 148 being both pure enantiomers of either single regioisomer (Z)- or (E))5 -(((5, 5 -difluoro spiro [3.3 ] heptan-2- ylidene)methyl)thio)-4- methylpyrimidine-2-carboxylic acidsHCVV0(E)-4-methyl-5-((2-(spiro[2.4]heptan-1-yl)vinyl)thio)pyrimidine-2-carboxylic acidcarboxylic acidJJ w '- (Z) -4-methyl- 5-((2- (spiro[2.4]heptan-1- ) / o °= yl)vinyl)thio)pyrimidine-2- o oT T carboxylic acid5-(((trans-hexahydropentalen- XSXP 2( 1 H)-ylidene)methyl)thio)-4- "'X methylpyrimidine-2-carboxylic acid o(E)-4-methyl-5-((2- (spiro[2.4]heptan-5- yl)vinyl)thio)pyrimidine-2- carboxylic acid(Z) -4-methyl- 5 - ((2- (spiro[2.4]heptan-5- Xsj yl)vinyl)thio)pyrimidine-2- carboxylic acidHO. X JJnN0155 5-((dispiro[2.0.3.2]nonan-6- ylidenemethyl)thio)-4- O / O= methylpyrimidine-2-carboxylic acid156 5-(((cis-bicyclo[3.2.0]heptan-3- X X X ylidene)methyl)thio)-4-HO / N;methylpyrimidine-2-carboxylic acid 0157 5-(((trans-bicyclo[3.2.0]heptan-3- X XX ylidene)methyl)thio)-4- methylpyrimidine-2-carboxylic acid 0158 5-(((cis-bicyclo[3.1.0]hexan-3- ylidene)methyl)thio)-4- methylpyrimidine-2-carboxylic acid 0and stereoisomers thereof, and pharmaceutically acceptable salts and / or solvates thereof.

[0102] The compounds of Table 1 were named using ChemDraw 22®.

[0103] All references to compounds of formula (I) include references to salts, solvates, multi-component complexes and / or liquid crystals thereof. All references to compounds of formula (I) include references to polymorphs and / or crystal habits thereof. All references to compounds of formula (I) include references to pharmaceutically acceptable prodrugs thereof.

[0104] The compounds of formula (I) and subformulae thereof may contain asymmetric centres and thus may exist as different stereoisomeric forms. Accordingly, all references to compounds of formula (I) include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and diastereomers andtheir non-racemic mixtures as well. Mixtures of diastereomers are also included. When a compound is desired as a single stereo-isomer, such single stereo-isomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art.

[0105] Bonds from an asymmetric carbon in compounds are generally depicted using a solid line ( ), a solid wedgea dotted wedge ( 1), a bold unwedged bond ( ), or a dotted unwedged bondThe use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included. The use of a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. The use of two unwedged bonds (bold and / or dotted) to depict the bonds from two asymmetric carbon atoms is meant to represent the relative stereochemistry of the two attached moieties (cis or trans), including the two possible absolute configurations, as represented for example on the structures below (considering that RAand RBmoieties are different):i) trans configurationii) cis configuration

[0106] Double bonds are generally depicted as ^=, enabling to represent the Z or E configurations without any special marking. If the configuration is not known, the double bond is replaced with a crossed double bond (»-=), corresponding to either Z or E or a mixture of the two.Z stereoisomer E stereoisomer unknown / unspecified stereoisomer(s)

[0107] All references to compounds of formula (I) include references to isotopically-labelled compounds of formula (I), including deuterated compounds of formula (I).

[0108] The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

[0109] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, ammonium, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, bitartrate / tartrate, borate, bromide, calcium edetate, camsylate, chloride, citrate, clavulanate, cyclamate, dihydrochloride, edetate, edisylate, estolate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hibenzate, hydrochloride / chloride, hydrabamine, hydrobromide / bromide, hydroiodide / iodide, hydroxynaphthoate, isethionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, methylbromide, N-methylglucamine, methylnitrate, methylsulphate, mucate, naphthylate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate, pantothenate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, pyroglutamate, saccharate, salicylate, stearate, succinate, sulfate, subacetate, tannate, teoclate, tosylate, triethiodide, trifluoroacetate, valerate, and xinofoate salts.

[0110] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, ammonia, arginine, benzathine, N-benzylphenethylamine, calcium, choline, chloroprocaine, N,N´-dibenzylethylenediamine, diethanolamine, diethylamine, 2-(diethylamino)ethanol, diolamine, ethylenediamine, ethanolamine, glycine, 4-(2-hydroxyethyl)morpholine, lithium, lysine, magnesium, meglumine, N-methyl-glutamine, morpholine, olamine, ornithine, potassium, piperazine, procaine, sodium, tetramethylammonium hydroxide, tris(hydroxymethyl)aminomethane, tromethamine and zinc salts.

[0111] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

[0112] When the compounds of formula (I) contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g., NH), the invention also covers salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

[0113] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of these methods:(i) by reacting the compound of formula (I) with the desired acid;(ii) by reacting the compound of formula (I) with the desired base;(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and / or(iv) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

[0114] All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0115] Although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and / or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to formdiastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of formula (I) above.Process of manufacturing

[0116] The compound of invention can be synthesized by methods known in the art. Especially, the compound of invention can be synthesized by the methods detailed in the experimental part below.Pharmaceutical composition

[0117] This invention also relates to a pharmaceutical composition comprising a compound according to the invention, as described hereinabove, and at least one pharmaceutically acceptable carrier.

[0118] According to a first embodiment, the pharmaceutical composition comprises the compound according to the invention as sole therapeutic agent.

[0119] According to a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent. In one embodiment, the other therapeutic agent is selected from therapeutic agents detailed hereafter with regard to combination therapy.

[0120] The pharmaceutical composition of the invention may further comprise therapeutically active compounds other than those listed herein, which are usually applied in the treatment of the targeted pathological conditions.Medical use and methods of treatment

[0121] This invention also relates to a compound according to the invention, as described hereinabove, for use as a medicament.

[0122] This invention also relates to a compound according to the invention, as described hereinabove, for use as agonist of GPR84 activity. Especially, this invention also relates to a compound according to the invention, as described hereinabove, for pharmacologicalactivation of GPR84 receptor. This comprises a biochemical interaction of GPR84 with an effective amount of a compound according to the invention, to activate GPR84 whereby the compound acts as a specific agonist of this receptor.

[0123] This invention also relates to a compound according to the invention, as described hereinabove, for use in the treatment of a disease or disorder in which GPR84 activity is implicated. Examples of diseases or disorders in which GPR84 activity is implicated include proliferative conditions such as cancers. GPR84 activity is also implicated in conditions such as autoimmune diseases, infectious diseases, atherosclerosis, and neurological or neurodegenerative diseases.

[0124] In preferred embodiments, the diseases or disorders in which GPR84 activity is implicated are responsive to GPR84 agonism.

[0125] In one embodiment, the invention thus provides a compound as described hereinabove for use in the treatment of cancers, autoimmune diseases, infectious diseases, atherosclerosis, and neurological or neurodegenerative diseases.

[0126] In one embodiment, the invention provides a compound according to the invention, as described hereinabove, for use in the treatment of a proliferative condition.

[0127] The terms “proliferative condition” and “proliferative disorder” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic, or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, and cancers.

[0128] In one embodiment, the proliferative condition is cancer. The invention thus provides a compound according to the invention, as described hereinabove, for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer. In an embodiment the cancer is a solid cancer.

[0129] In one embodiment, the cancer is a solid tumor. In certain embodiments, the cancer is a carcinoma or a sarcoma.

[0130] Examples of cancers include, without being limited to bladder cancer, bile duct and gall blabber cancers, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal / upper aerodigestive cancer, eye cancer, glioblastoma, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, non-small cell lung cancer (NSCLC), neuroendocrine cancer, head and neck cancer, oral cancer, oral squamous cell carcinoma, melanoma, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, sebaceous gland carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, urinary tract cancer, and uterine cancer.

[0131] The invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of an autoimmune disease. “Autoimmune diseases” refer to conditions in a subject characterized by cellular, tissue and / or organ injury caused by an immunologic reaction of the subject to its own cells, tissues and / or organs. Examples of autoimmune diseases include, without being limited to, Crohn’s disease, multiple sclerosis, rheumatoid arthritis, lupus, and dermatitis.

[0132] The invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of infectious diseases. Infectious diseases include bacterial or viral infections. Examples of infectious diseases include human anaplasmosis, brucellosis, ehrlichiosis, melioidosis, pneumonia, bronchitis, meningitis, salmonellosis, tuberculosis and HIV infection.

[0133] The invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of neurological or neurodegenerative diseases. Examples of neurological or neurodegenerative diseases include Alzheimer’s disease, multiple sclerosis, Huntington’s disease and Parkinson’s disease.

[0134] The invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of atherosclerosis. " Atherosclerosis” comprises any disease or disorder characterized by the deposition of fats, cholesterol, and othersubstances in and on the walls of an artery causing the arteries to narrow thereby blocking blood flow or leading to a blood clot.

[0135] This invention also relates to the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament that is an agonist of GPR84 activity.

[0136] This invention also relates to the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for pharmacological activation of GPR84 receptor.

[0137] This invention also relates to the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of a disease or disorder in which GPR84 activity is implicated, as defined above.

[0138] In one embodiment, the invention provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of a proliferative condition, as defined above.

[0139] The invention thus provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of cancer, as defined above.

[0140] The invention also provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of an autoimmune disease, as defined above.

[0141] The present invention also provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of an infectious disease as defined above.

[0142] The present invention also provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of a neurological or neurodegenerative disease, as defined above.

[0143] The present invention also provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of atherosclerosis.

[0144] This invention also relates to a method of pharmacological activation of GPR84 receptor in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0145] This invention also relates to a method for the treatment of a disease or disorder in which GPR84 activity is implicated, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0146] This invention also relates to a method for the treatment of a proliferative condition, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0147] This invention also relates to a method for the treatment of a cancer, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0148] This invention also relates to a method for the treatment of an autoimmune disease, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0149] This invention also relates to a method for the treatment of an infectious disease, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0150] This invention also relates to a method for the treatment of a neurological or neurodegenerative disease, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention.

[0151] This invention also relates to a method for the treatment of atherosclerosis, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention.Combination therapies

[0152] According to one embodiment, the compound according to the invention is administrated to the subject as sole therapeutic agent.

[0153] According to another embodiment, the compound according to the invention is administrated to the subject in combination with at least another therapeutic agent.

[0154] In one embodiment, the other therapeutic agent may be selected from a second anti-cancer therapy, such as chemotherapy, immunotherapy, cell therapy and / or any anticancer agent currently in clinical use or in clinical trials.

[0155] According to one embodiment, the compound according to the invention may be administered in combination with conventional surgery, radiotherapy, or transplantation, and / or with at least another therapeutic agent as mentioned above.

[0156] Such conjoint treatments may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. Such combination products employ the compounds of the invention within the dosage range described herein and the other therapeutic agent within its approved dosage range.

[0157] In the context of the present invention the term “combination” preferably means a combined occurrence of the compound according to the invention and an additional therapeutic agent. Therefore, the combination may occur either as one composition, comprising all the components in one and the same mixture (e.g. a pharmaceutical composition), or may occur as a kit of parts, wherein the different components formdifferent parts of such a kit of parts. The administration of the compound according to the invention and of the additional therapeutic agent may occur either simultaneously or timely staggered, with similar or different timing of administration (i.e. similar or different numbers of administration of each component), either at the same site of administration or at different sites of administration, under similar of different dosage forms.Methods of administration

[0158] The compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular, intracistemal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0159] The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. 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 pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active ingredient is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0160] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrupsor elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U. S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0161] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0162] The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0163] For topical use, creams, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the present invention are employed.

[0164] In the treatment or prevention of GPR84-related diseases, an appropriate dosage level will generally be about 0.01 to 250 mg per kg patient body weight per day (mg / kg per day) which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 100 mg / kg per day, such as between 0.1 and 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered as a single daily dose, divided over one or more daily doses, for example on a regimen of 1 to 4 times per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.EXAMPLES

[0165] The present invention is further illustrated by the following examples.I. CHEMISTRY EXAMPLESMaterials and Methods

[0166] All reported temperatures are expressed in degrees Celsius (°C); all reactions were carried out at rt (rt) unless otherwise stated.Analytical methods

[0167] Analytical thin layer chromatography (TLC) was used to monitor reactions, establish flash chromatography conditions and verify purity of intermediates or final products. TLC plates used were Merck TLC aluminium sheet silica gel 60 F254. TLC plates were revealed using ultraviolet irradiation (wavelength = 254 nm) at rt or KMnCL, or vanillin, or PMA or bromocresol or ninhydrin staining upon heating at 160°C. The KMnCL TLC stain was prepared by dissolving 1.5 g of KMnCU, 10 g K2CO3, and 1.25 mL 10% NaOH in 200 mL of water. The vanillin TLC stain was prepared by dissolving, 15 g vanillin, 2.5 mL concentrated sulfuric acid in 250 mL of 96% ethanol. The phosphomolybdic acid stain was prepared by dissolving 10 g of phosphomolybdic acid in 100 mL of 96% ethanol. The bromocresol solution was prepared by adding 0.04 g of bromocresol green to 100 ml of absolute ethanol and a 0.1 M solution of aqueous NaOH until a blue color just appears in solution. Ninhydrin solution was prepared by dissolving 1.5 g ninhydrin in 100 mL of n-butanol and then add 3.0mL acetic acid.

[0168] ’H and13C NMR spectra were recorded on a Bruker ARX 300MHz. Chemical shifts are expressed in parts per million (ppm, 5 units). Coupling constants are expressed in Hertz (Hz). Splitting patterns describe apparent multiplicities and are described as s (singlet), d (doublet), t (triplet), q (quartet), p (pentaplet), h (hexaplet), hept (heptaplet), m (multiplet), or br (broad).

[0169] HPLC-MS spectra were obtained:• Gradient A: on Agilent LCMS using Electrospray ionization (ESI). The instrument includes an autosampler 1200, a binary pump 1100, a multiwavelength detector 1100 and a 6100 single quadrupole mass spectrometric detector. The column used was an Sunfire C18 3.5pm 3.0x50mm. Eluent was a mixture of solution “A” (0.1% TFA in H2O) and solution “B” (0.1% TFA in MeCN). Gradient used is as follows: held the initial conditions of 5% solution “B” for 0.2min, increased linearly to 95% solution “B” over 1.8 min, held at 95% for 1.75 min, returned to initial conditions over 0.25 min. Flow: 1.0 mL / min.• Gradient B: on Agilent LCMS using Electrospray ionization (ESI). The instrument includes an autosampler 1200, a binary pump 1100, a multiwavelength detector 1100 and a 6100 single quadrupole mass spectrometric detector. The column used was an Sunfire C18 3.5pm 3.0x50mm. Eluent was a mixture of solution “A” (0.1% TFA in H2O) and solution “B” (0.1% TFA in MeCN). Gradient used is as follows: held the initial conditions of 5% solution B for 0.2 min, increased linearly to 95% over 5.3 min, held at 95% for 2.25 min, returned to initial conditions over 0.25 min. Flow: 1.0 mL / min.• Gradient C: on Agilent LCMS using Electrospray ionization (ESI). The instrument includes an autosampler 1200, a binary pump 1100, a multiwavelength detector 1100 and a 6100 single quadrupole mass spectrometric detector. The column used was an Sunfire C18 3.5pm 3.0x50mm. Eluent was a mixture of solution “A” (0.1% TFA in H2O) and solution “B” (0.1% TFA in MeCN). Gradient used is as follows: held the initial conditions of 5% solution B for 0.2 min, increased linearly to 50% over 0.3 min, increased linearly to 95% over 1.5 min, held at 95% for 1.75 min, returned to initial conditions over 0.25 min. Flow: 1.0 mL / min• Gradient D: on Agilent LCMS using Electrospray ionization (ESI). The instrument includes an autosampler 1200, a binary pump 1100, a multiwavelength detector 1100 and a 6100 single quadrupole mass spectrometric detector. The column used was an Sunfire C18 3.5pm 3.0x50mm. Eluent was a mixture of solution “A” (0.1% TFA in H2O) and solution “B” (0.1% TFA in MeCN). Gradient used is as follows: held the initial conditions of 5% solution B for 0.2 min, increased linearly to 50% over 0.3 min, increased linearly to 95% over 1.5 min, held at 95% for 2.75 min, returned to initial conditions over 0.25 min. Flow: 1.0 mL / min

[0170] Determination of chiral purity was performed on an Agilent 1100 HPLC instrument. The instrument includes an autosampler 1100, a binary pump 1100 and a multiwavelength detector 1100. The columns used were Chiralpak IA, Chiralpak IB,Chiralpak ID and Chiralpak IE, each of said columns were filled with 5 pm particles, 4.6 x 250 mm in dimensions. Mixtures of eluents were selected individually depending on the separation obtained of enantiomers or diastereomers.

[0171] Preparative HPLC purifications were carried out on Agilent 1200 preparative HPLC instrument. This instrument consists of gradient pump 1200, a multiwavelength detector 1200 and Rheodyne manual injector.

[0172] For reverse phase preparative HPLC purifications the columns used were a Waters XBridge C18 5 pm 19 x 100 mm or Phenomenex Luna C18(2) 5 pm 21.2 x 100 mm. The gradient was adapted depending on nature of the purified compound and impurities, to allow sufficient separation between impurities and target compound. Unless noted otherwise, eluent was a mixture of solution “A” (ammonium bicarbonate 0.02 M) and solution “B” (MeCN).

[0173] For chiral preparative HPLC purifications the columns used were Chiralpak IA, Chiralpak IB, Chiralpak ID and Chiralpak IE, each of said columns were filled with 5 pm particles, 10 or 20 x 250 mm in dimensions. Mixtures of eluents were selected depending on the separation of enantiomers or diastereomers obtained with the analytical method. Usually, eluent mixtures were the same as those used for the determination of ee or de. Unless otherwise specified, wavelength used was 280 nm.

[0174] Solvents, reagents and starting materials were purchased and used as received from commercial vendors unless otherwise specified.Abbreviations

[0175] The following abbreviations are used:ACN or MeCN: Acetonitrile,Ar: Argon,br: Broad,d: Doublet,DABCO: l,4-diazabicyclo[2.2. 2]octane,DAST: Diethylamino sulfur trifluoride,DCM: Dichloromethane,de. Diasteromeric excess,DIBAL(-H): Di-isobutyl Aluminium hydride,DIEA: A, A-diisopropylethylamine,DIPA: Diisopropylamine,DMA: A, A-dimethylacetamide,DME: Dimethoxyethane,DMF: A, A-dimethylformamide,DMSO: Dimethylsulfoxide,dppf: l,l’-bis(diphenylphosphino) ferrocene,EDC: l-Ethyl-3- (3-Dimethylamino propyl)carbodiimide, ee Enantiomeric excess,eq: Equivalent,EtOAc: Ethyl acetate,EtOH: Ethanol,ES: Electrospray,ESI: Electrospray ionization,g: Grams,h: Hours,h: HexapletHz: HertzHept: HeptapletHex: Hexane,HPLC: High performance liquid chromatography, IPA: Isopropyl AlcoholLAH: Lithium aluminium hydrides,LCMS: Liquid chromatography mass Spectrometer, LDA: Lithium diisopropylamide,LED: Light emitting diode,LiHMDS: Lithium bis(trimethylsilyl)amide,m: Multiplet,MCPBA: 3-Chloroperbenzoic acid,MeCN: Acetonitrile,MeOH: Methanol,min: Minutes,mg: Milligrams,MHz: Megahertz,mL: Milliliter(s),mmol: Millimole(s),MS: Mass spectrometry,NMR: Nuclear Magnetic Resonance,p: Pentaplet,q: Quartet,RBF: Round bottom flask,Ry: Relative front,rt: Room temparature,s: Singulet,t: Triplet,TBME: Tert-butylmethylether,TEA: Triethylamine,TFA: Trifluoroacetic acid,THF: Tetrahydrofuran,TLC: Thin layer chromatography,Ts: Tosyl,Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene,pL: Microliters.

[0176] All compounds were named using ChemDraw 22® purchased from CambridgeSoft (Cambridge, MA, USA).General proceduresGeneral procedure Al: Hydrolysis

[0177] To a solution of ester (1.0 eq) in a 1 / 1 mixture of THF and water (between 0.03 to 0.11 M, typically 0.07 M) was added LiOH (between 2.07 to 5.88 eq, typically 4.0 eq) and stirred at rt between 5 min to 2 h (typically 30 min) unless otherwise noted. The reaction was concentrated to remove the THF. Water was added and the reaction mixture was acidified with HC1 (1 M) to pH 1 to 3, typically 2.0 (monitored by a pH meter) and extracted with EtOAc or DCM. The combined organic layers were dried over MgSCE, filtered, and concentrated under reduced pressure to dryness affording the crude carboxylic acid.General procedure A2: Hydrolysis (with organic solvent wash)

[0178] Same procedure than Al but prior to acidification the reaction mixture was diluted with water or a mixture of saturated aqueous solution of NaHCO3and water (1 / 9) and washed with Et2O. Then aqueous layer was acidified with HC1 (1 M) to pH ~ 2 to 3 (monitored by a pH meter) and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to dryness affording the crude carboxylic acid.General procedure Bl: Reduction with DIBAL (Rochelle’s salt work-up)

[0179] To a colorless solution of unsaturated ester (1.0 eq) in anhydrous DCM (0.25 to 0.49 M) under Ar atmosphere was added DIBAL in DCM or hexanes solution (2.00 to 2.49 eq) dropwise at -78 °C to afford a colorless solution. After 30 min to 2 h at -78 °C, the reaction mixture was treated with a saturated solution of Rochelle's salt and resulting gel was vigorously stirred at rt for 16 h to give a biphasic solution. The phases were separated and the aqueous phase was extracted with Et2O then combined organic phases were washed with brine then dried over MgSO4, filtered and concentrated to dryness under reduced pressure to afford a crude oil which was purified by flash chromatography on silica gel.General procedure B2: Reduction with DIBAL (Fieser’s work-up)

[0180] A 1.0 M solution of diisobutylaluminium hydride (1.3 eq of DIBAL in toluene was used for Weinreb amide, or 2.16 to 2.56 eq DIBAL in hexanes for unsaturated ester) was added dropwise to a solution of amide (1.0 eq) in anhydrous THF (0.65 M) or a solution of unsaturated ester in anhydrous DCM (0.39 to 0.46 M) at -78 °C under Ar atmosphere unless otherwise noted. The mixture was stirred at -78 °C for 1 to 3 h. H₂O [0.04 x (mmol of DIBAL) mL] was added slowly, followed by a 15% aqueous solution of NaOH [0.04 x (mmol of DIBAL) mL] and then H₂O [0.1 x (mmol of DIBAL) mL]. The bath was removed, and the reaction mixture was stirred at rt for 15 min. Then MgSO₄ was added, and stirred for 15 min. The solids were removed by filtration through fritted funnel, and the filtrate was concentrated under reduced pressure to afford the desired product in solution or neat and purified by flash chromatography on silica gel if needed.General procedure C: Allylic boronic esters synthesis from allylic alcohols

[0181] In a RBF under Ar atmosphere was added bis(pinacolato)diboron (1.83 to 2.27 eq) and TsOH monohydrate (5.0 to 8.8 mol%) followed by anhydrous DMSO (0.55 M -based on alcohol) at rt then a solution of alcohol (1.0 eq) in anhydrous methanol (0.55 M - based on alcohol) to give a colorless solution which was degassed by Ar bubbling under stirring at rt for 20 min. Then, palladium trifluoroacetate (5.0 to 5.9 mol%) was added to instantaneously give a red solution which was stirred at 50 °C (pre-heated oil bath) for 18 to 23 h. The resulting mixture was filtered through a short pad of celite which was then rinsed with Et₂O. Filtrate was washed with water and brine then dried over MgSO₄, filtered and filtrate concentrated to dryness under reduced pressure to give a crude oil which was purified by flash chromatography on silica gel.General procedure D: Potassium trifluoroborate synthesis

[0182] To a solution of dioxaborolane (1.0 eq) in MeCN (1.20 M - based on dioxaborolane) under Ar atmosphere at rt was added a solution of potassium hydrogen fluoride (5.0 eq) in water (6.21 M - based on potassium hydrogen fluoride) dropwise to give a white suspension after few minutes at rt unless otherwise noted. Evolution of thereaction was monitored by TLC. The white suspension was concentrated under reduced pressure to dryness to give an oily solid. Acetone was added to the residue and the mixture was concentrated again under reduced pressure to dryness to give a white solid. Acetone was added at rt to the solid and mixture was sonicated for ~30 sec, heated to boiling point and hot filtered. Since some white solid was still stuck on the flask, acetone was added and the same procedure was repeated twice. Combined filtrates were concentrated under reduced pressure to dryness and residue was slurried in Et₂O then filtered and obtained solid was rinsed and dried under vacuum to give a white solid.General procedure E: Suzuki coupling (with potassium trifluoroborate)

[0183] In a sealable tube, a mixture of bromoaryl derivative (1.0 eq), potassium trifluoroborate (1.22 to 1.55 eq) and cesium carbonate (3.00 to 3.66 eq) in a mixture of water and DME (1 / 4, 0.18 to 0.21 M) was degassed by Ar bubbling under stirring at rt for 5 min to give an orange suspension. Tetrakis(triphenylphosphine)palladium(0) (5.0 to 10.3 mol%) was added at rt. The tube was sealed and the mixture was stirred at 120 °C for 1.5 to 6 h. The suspension was cooled to rt and diluted with EtOAc and water. The organic phase was washed with brine then dried over MgSO₄, filtered and filtrate was concentrated under reduced pressure to dryness to afford a brown oil which was purified by flash chromatography on silica gel or preparative HPLC.General procedure F: Acidic ethanolysis of cyano to ester (Pinner reaction)

[0184] In a sealable tube, a solution of carbonitrile derivative (1.0 eq) in 1.25 M HC1 in EtOH (5.0 to 20.0 eq, typically 10.0 eq) was heated under stirring at 70 to 90 °C for 1.5 to 8.5 h (typically 3 h) unless otherwise noted. The reaction was cooled to rt and concentrated under reduced pressure. A saturated aqueous solution of NaHCO₃ was added and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown oil which was purified by flash chromatography on silica gel.General procedure G: Thiol formation

[0185] A solution of 5-bromo-4-methyl-pyrimidine-2-carbonitrile (1.0 eq) in anhydrous DMF (0.91 to 0.96 M) was degassed by Ar bubbling for 10 min. Then Na₂S (1.02 eq) was added and the reaction mixture was stirred at 40 °C for 40 min. Alkyl methanesulfonate (1.01 eq) was added, and heating was continued at 60 °C for 16 h. The reaction mixture was cooled to rt and diluted with EtOAc and washed with NaHCO₃. The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to dryness affording a crude oil.General procedure H: Mesylate formation

[0186] Methanesulfonyl chloride (1.05 to 1.5 eq) was slowly added to a solution of alcohol derivative (1.0 eq) in pyridine (10.5 eq) at -15 °C under stirring. Then, the mixture was slowly warmed to rt over 20 to 30 min and the reaction progress monitored by TLC. The white suspension was diluted with EtOAc and 1.0 M HC1 was slowly added under stirring. The aqueous phase was extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated to dryness under reduced pressure to afford a colorless oil which was purified by flash chromatography on silica gel if needed.General procedure I1: Reduction to alcohol from carboxylic acid (with borane)

[0187] A solution of borane-THF complex (1.0 M in THF) (2.0 eq) was added in a solution of carboxylic acid derivative (1.0 eq) in anhydrous THF (0.26 to 0.43 M) at 0 °C. After the addition, the reaction mixture was allowed to warm to rt and stirred for 16 h. The mixture was quenched cautiously with water then diluted with EtOAc and washed with 1.0 M NaOH. The organic layer was separated, dried over MgSO4, filtered and concentrated to dryness under reduced pressure to afford a crude colorless oil.General procedure I2: Reduction to alcohol from carboxylic acid or ester (with LAH)

[0188] To a suspension of LAH (1.0 to 1.81 eq) in anhydrous Et₂O (0.33 M - based on LAH) at 0 °C was added aliphatic carboxylic acid or ester derivative (1.0 eq) neat or in solution in anhydrous Et₂O (0.5 to 0.8 M - based on carboxylic acid or ester) dropwiseover 5 min. The reaction mixture was allowed to stir at rt for 2 to 4 h unless otherwise noted.

[0189] Work-up by default: The reaction was cooled to 0 °C and carefully quenched with a NaOH 10% aqueous solution. The mixture was filtered over fritted. The resulting white paste was rinsed with Et₂O. The filtrate was washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the corresponding aliphatic alcohol.

[0190] Or Fieser work-up was applied: The reaction mixture was diluted with Et₂O and cooled to 0 °C, H₂O [(g of LAH) mL] was added slowly, followed by a 15% aqueous solution of NaOH [(g of LAH) mL] and then H₂O [3 x (g of LAH) mL]. The bath was removed, and the reaction mixture was stirred at rt for 15 min. Then MgSO4was added, and stirred for 15 min. The solids were removed by filtration through fritted funnel, and the filtrate was concentrated under reduced pressure to afford the desired product.General procedure J: Tosyl hydrazone synthesis

[0191] To a solution of carbaldehyde derivative (1.0 eq) in anhydrous methanol (0.51 to 0.77 M) under Ar atmosphere was added 4-methylbenzene-sulfonhydrazide (1.01 to 1.05 eq) at rt. The reaction mixture was stirred at rt for 4 to 4.5 h. The reaction solution was concentrated under reduced pressure to dryness to afford a white solid with >95% purity.General procedure K: Barluenga cross-coupling

[0192] A mixture of potassium carbonate (1.50 to 2.25 eq, typically 2.20 eq), hydrazone derivative (1.0 eq) and boronic acid (1.20 to 1.94 eq, typically 1.50 eq) in anhydrous 1,4-dioxane (0.18 to 0.26 M) was stirred at 110 °C (pre-heated bath) under Ar atmosphere between 40 min and 2 h unless otherwise noted (gas releases after 1 min). The reaction mixture was cooled to rt, diluted with EtOAc, filtered through a short pad of Celite, and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to dryness to afford a crude material which was purified by flash chromatography on silica gel.General procedure L1: Oxidation to sulfone (with MCPBA)

[0193] To a solution of thioether derivative (1.0 eq) in DCM (0.1 M) at 0 °C was added MCPBA (2.36 to 2.60 eq) portion wise over 2 min. The reaction was stirred at 0 °C for 2 to 6.5 h. The reaction was quenched with a saturated aqueous solution of NaHCO₃. The mixture was stirred 2 min and layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure to afford a crude material which was purified by flash chromatography on silica gel.General procedure L2: Oxidation to sulfone (with molybdenum complex)

[0194] To a solution of thioether derivative (1.0 eq) in ethanol (0.16 to 0.20 M) was added ammonium molybdate tetrahydrate (0.15 to 0.17 eq) and then hydrogen peroxide solution (8.0 eq) at rt over 1 min. The mixture was stirred at rt for 1 to 3 h. The reaction mixture was diluted with EtOAc and water. The layers were separated and aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford a crude material.General procedure M: Cyanation

[0195] To a solution of 2-methylsulfonyl-pyrimidine derivative (1.0 eq) in anhydrous DMF (0.2 M) under Ar atmosphere was added potassium cyanide (between 1.2 eq and 2.2 eq) in one portion. The reaction was stirred at rt or at 40 °C over 24 to 32 h unless otherwise noted. The reaction mixture was diluted with cold (<10 °C) water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to dryness to afford the crude material.General procedure N: Boronic acid pinacol ester hydrolysis

[0196] To the solution of boronic acid pinacol ester (1.0 eq) in mixture of acetone / H₂O (1 / 1, 0.07 to 0.20 M) was added sodium periodate (5.0 eq) and ammonium acetate (5.0 eq). The reaction mixture was stirred at rt for 40 min to 2 h unless otherwise noted. The reaction mixture was concentrated under reduced pressure to remove acetone. Then water and ethyl acetate were added, the phases were separated and the aqueous phase extractedwith EtOAc. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated under reduced pressure to afford a crude mixture.General procedure O: Photoredox deoxygenative cross-coupling

[0197] Vial was charged with deoxazole (1.60 to 2.20 eq, typically 1.60 eq) and a magnetic stir bar. The vial was vacuumed and refilled with Ar (3x). TBME (0.8 M - based on deoxazole) was added. Alcohol derivative (1.1 to 2.25 eq, typically 2.0 eq) in TBME (0.55 M - based on alcohol derivative) was added dropwise over 1 min and the reaction stirred at rt for 5 min. Then, pyridine (1.60 to 2.12 eq, typically 2.0 eq) in TBME (0.8 M - based on pyridine) was added dropwise at rt over 2 min. The resulting solution was stirred at rt for 10 min. A white solid precipitated out during this time. Another vial was charged with [Ir(dtbbpy)(ppy)₂]PF₆ (1.5 to 3.3 mol%, typically 2.0 mol%), (dtbpy)NiBr₂ (5.0 to 7.1 mol%, typically 5 mol%), quinuclidine (1.74 to 2.20 eq, typically 1.75 eq), 5-bromopyrimidine derivative (1.0 eq) and a magnetic stir bar unless otherwise noted. The vial was evacuated and backfilled with Ar (3x). DMA (0.1 M - based on 5-bromopyrimidine derivative) was added to this vial under an atmosphere of Ar. The TBME suspension was transferred to a syringe. Then a syringe filter and new needle were installed on the syringe, before the TBME solution was injected through the syringe filter into the DMA solution. The reaction mixture was sparged with Ar for 15 min before sealing with parafilm. The vial was stirred vigorously and irradiated under 450 nm LED and air flow for 2 to 4 h. The volatiles were concentrated under reduced pressure. Water and Et2O were added and the phases were separated. The aqueous layer was further extracted with Et₂O. The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to afford the crude product which was purified by flash chromatography on silica gel and / or reverse phase preparative HPLC.General procedure P: Synthesis of alkenylboronate pinacol ester

[0198] To a solution of 2,2,6,6-tetramethylpiperidine (1.20 to 1.50 eq, typically 1.20 eq) in anhydrous THF (0.55 to 1.60 M - based on TMP) under Ar atmosphere at 0 °C was added 1.6 M n-butyl lithium in hexane (1.17 to 1.26 eq typically 1.20 eq) over 5 min.After 10 min at 0 °C, a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (1.15 to 1.22 eq, typically 1.15 eq) in anhydrous THF [1.0 to 1.1 M - based on bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane] was added over 5 min and the reaction mixture was stirred for 5-10 min resulting in a light yellow suspension unless otherwise noted. Then, the reaction was cooled to -78 °C, and a solution of aldehyde or ketone (1.0 eq) in anhydrous THF (0.9 to 1.2 M - based on aldehyde or ketone) was added over 5 min. The reaction was allowed to stir at -78 °C for an additional 5 min to 1 h and then at rt for 1 to 4 h. The reaction was directly concentrated under reduced pressure to give the crude product. The crude material was purified by flash chromatography on silica gel to afford the desired alkenylboronate pinacol ester.General procedure Q1: HWE olefination (with NaH)

[0199] To a solution of triethylphosphonoacetate (1.10 eq) in anhydrous THF (0.34 to 0.43 M - based on phosphonoacetate) was added NaH (60 % dispersion in mineral oil) (1.20 to 1.50 eq) at 0 °C under Ar atmosphere. The reaction mixture was stirred at rt for 1 h and cooled to 0 °C. Aldehyde or ketone (1.0 eq) was added neat or in solution in anhydrous THF (3.40 to 3.85 M - based on aldehyde or ketone) dropwise at 0 °C. The reaction mixture was stirred at rt for 1 to 3.5 h unless otherwise noted. Reaction mixture was quenched by the addition of HC1 1.0 N. The mixture was extracted with EtOAc and the combined organic layers were dried over MgSO₄ and filtered. The filtrate was concentrated under reduced pressure to afford the crude product and purified by flash chromatography on silica gel if needed.General procedure Q2: HWE olefination (with n-BuLi)

[0200] A solution of trimethylphosphonoacetate (1.20 to 1.60 eq) in anhydrous THF (0.85 to 1.11 M - based on phosphonoacetate) was cooled to 0 °C under Ar atmosphere. Then, n-butyl lithium (1.10 to 1.50 eq, 1.6 M in hexane) was added over 2 min. After 15 min, aldehyde derivative (1.0 eq) in anhydrous THF (1.55 to 1.70 M - based on aldehyde) was added via a canula over 5 min and was stirred at 0 °C for 35 min. A saturated aqueous solution of NH4CI was added at 0 °C and extracted with Et₂O. The combined organic layers were washed with brine, dried over MgSO₄, filtered through cotton wool andconcentrated under reduced pressure to afford the crude product which may be purified by flash chromatography on silica gel to afford the desired olefine.General procedure R: Vinyl sulfide synthesis

[0201] In a sealable tube, was added 1,10-phenanthroline (15 to 25 mol%), triphenylphosphine (10 to 18 mol%), sodium thiolate (1.0 eq), copper(I) iodide (10 to 19 mol%), potassium phosphate tribasic (1.53 to 3.0 eq), and a solution of iodovinyl derivative (1.35 to 2.95 eq) in anhydrous and degassed toluene (0.10 to 0.19 M). Resulting mixture was heated to 110 °C for 3.5 to 65 h. The reaction mixture was cooled to rt and filtered over Celite. The Celite was rinsed with EtOAc and the filtrate washed with water, brine dried over MgSO₄, filtered and concentrated under reduced pressure to afford the crude product as an oil which was purified by flash chromatography on silica gel to afford the desired vinyl sulfide.General procedure S: Alcohol oxidation to aldehyde or ketone with DMP

[0202] To a solution of alcohol derivative (1.0 eq) in DCM (0.21 to 0.23 M) was added NaHCO₃ (6.0 eq) and Dess-Martin periodinane (1.25 eq). The reaction mixture was allowed to stir at rt for 1 to 3 h. An 5% w / w aqueous solution of NaHCO₃ was added (strong evolution of gas) followed by a 10% w / w aqueous solution of Na₂S₂O₃. The mixture was vigorously stirred at rt for 1.5 h (until organic phase was clear). The phases were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with a 10% w / w aqueous solution of Na₂S₂O₃, dried over MgSO₄, filtered and concentrated under reduced pressure to afford crude aldehyde or ketone.General procedure T1: vinyl sulfide synthesis via HWE (with LDA)

[0203] To a solution of diisopropylamine (1.25 eq) in anhydrous THF (0.54 M - based on DIPA) under Ar atmosphere at 0 °C was added n-BuLi (1.25 eq - 1.6 M in hexane) over 20 sec. After 15 minutes at 0 °C, this solution was added to a solution of ethyl 5-(((diethoxyphosphoryl)methyl)thio)-4-methylpyrimidine-2-carboxylate (1.0 eq) in anhydrous THF (0.4 M - based on ethyl 5-(((diethoxyphosphoryl)methyl)thio)-4-methylpyrimidine-2-carboxylate) at -78 °C under Ar. After 20 min at -78 °C, a solutionof carbonyl (between 1.35 and 2.60 eq of aldehyde or ketone) in anhydrous THF (0.77 M - based on carbonyl) was added over 1 min. The reaction was stirred at this temperature for 5 min and then at 0 °C for 50 min. The reaction was quenched with a saturated aqueous solution of NH4CI and warmed to rt. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel and / or reverse phase preparative HPLC.General procedure T2: vinyl sulfide synthesis via HWE (with LiHMDS)

[0204] To a solution of ethyl 5-(((diethoxyphosphoryl)methyl)thio)-4-methylpyrimidine-2-carboxylate (1.0 eq) in anhydrous THF (0.36 M - based on ethyl 5-(((diethoxyphosphoryl)methyl)thio)-4-methylpyrimidine-2-carboxylate) at -78 °C under Ar atmosphere was added a solution of LiHMDS (between 1.0 and 1.2 eq - 1.0 M in THF). After 15 min, a solution of carbonyl (between 0.75 and 2.0 eq of aldehyde or ketone) anhydrous THF (0.36 M - based on carbonyl) was added dropwise over 30 sec. The mixture was stirred 5 min at -78 °C and then was allowed to warm to 0 °C and stir for 35 min. The reaction was quenched with a saturated aqueous solution of NH4CI and warmed to rt. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel and / or reverse phase preparative HPLC.Synthesis of the compounds of the inventionSynthesis of compound 1:Scheme 1: Synthesis of compound 1

[0205] Stage 1: Synthesis of 1.1: methyl 5-((2-cyclohexylethyl)thio)-4-methylpicolinate. To a solution of S-(2-cyclohexylethyl) ethanethioate (160 mg, 0.86 mmol, 1.98 eq) in anhydrous methanol (1.0 mL) (previously degassed with Ar for 10 min) was added K2CO3 (130 mg, 0.94 mmol, 2.16 eq) at rt under Ar. After 30 min, the reaction mixture was concentrated under reduced pressure. To the resulting solid was added a solution of methyl 5-bromo-4-methylpicolinate (100 mg, 0.43 mmol) in anhydrous DMF (2.0 mL - previously degassed with Ar for 10 min). The reaction mixture was stirred at rt under Ar for 20 min and diluted with EtOAc (25 mL) and washed with a saturated aqueous solution of NaHCO3(2 x 15 mL). Organic layer was washed with brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure to dryness to afford oil which was purified by silica gel flash chromatography (petroleum ether / EtOAc: 95 / 5 to 9 / 1) to afford 1.1 (125 mg, 93% yield, 95% purity, retention time = 3.3 min (method A)) as a white solid. Rf~ 0.3 (heptane / EtOAc: 8 / 1). m / z (ES+): [M+H]+= 294.

[0206] Stage 2: Synthesis of 1: 5-((2-cyclohexylethyl)thio)-4-methyl >icolinic acid. General Procedure Al was used with 1.1 (120 mg, 0.41 mmol) to afford 1 (100 mg, 88% yield, 100% purity, retention time = 5.0 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 58.32 (s, 1H), 7.96 (s, 1H), 3.04 (s, 2H), 2.39 (s, 3H), 1.84 - 1.60 (m, 8H), 1.38 (s, 1H), 1.16 (q, J = 10.7 Hz, 3H), 0.92 (d, J = 11.9 Hz, 2H). 1H exchanged with solvent, m / z (ES+): [M+H]+= 280.Synthesis of compound 2:2, R4= c-Hex59, R4= Ph Scheme 2: Synthesis of compounds 2 and 59

[0207] Stage 1: Synthesis of 2.1: methyl 5-((2-cyclohexylethyl)thio)-4-methylpyrimidine-2-carboxylate. To a solution of methyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (40 mg, 0.17 mmol) in anhydrous DMF (3.8 mL) under Ar atmosphere,was added 2-cyclohexylethanethiol (75 mg, 0.52 mmol, 3.0 eq) followed by K2CO3(41 mg, 0.30 mmol, 1.7 eq) at rt and the reaction mixture was stirred for 72 h. The reaction mixture was diluted with EtOAc (25 mL), washed with a saturated aqueous solution of NaHCO3(15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure to dryness to afford an oil which was purified by silica gel flash chromatography (petroleum ether / EtOAc: 8 / 2) to afford 2.1 (36 mg, 70% yield, 99% purity, retention time = 3.2 min (method A)) as a solid. Rf~ 0.6 (petroleum ether / EtOAc: 1 / 1). m / z (ES+): [M+H]+= 295.

[0208] Stage 2: Synthesis of 2: 5-((2-cyclohexylethyl)thio)-4-methylpyrimidine-2-carboxylic acid. General Procedure Al was used with 2.1 (36 mg, 0.12 mmol) to afford 2 as a white solid (24 mg, 66% yield, 94% purity, retention time = 5.1 min (method B)). ’H NMR (300 MHz, CDCl3) 58.53 (s, 1H), 3.17 - 3.04 (m, 2H), 2.61 (s, 3H), 1.88 - 1.57 (m, 8H), 1.46 (s, 1H), 1.36 - 1.12 (m, 3H), 1.07 - 0.87 (m, 2H). 1H exchanged with solvent, m!z (ES+): [M+H]+= 281.Synthesis of compound 3:3.1 7.2 (via 7.1)Scheme 3: Synthesis of compounds 3 and 7a

[0209] Stage 1: Synthesis of 3.1: 5-((2-cyclohexylethyl)thio)-4-methoxypyrimidine-2-carbonitrile. To a solution of 5-bromo-4-methoxy-pyrimidine-2-carbonitrile (456 mg, 1.28 mmol) in anhydrous degassed (with Ar bubbling for 15 min) DMF (3 mL) was added Na2S (174 mg, 2.23 mmol, 1.7 eq). The reaction mixture was stirred at rt. After 15 min, l-bromo-2-cyclohexylethane (0.30 mL, 1.9 mmol, 1.5 eq) was added and the reaction mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with EtOAc (25 mL),washed with brine (30 mL) and water (30 mL). The organic layer was dried over MgSO4, filtered, concentrated under reduced pressure to dryness to afford a crude material which was purified by silica gel flash chromatography (petroleum ether / EtOAc: 95 / 5) to afford 3.1 (102 mg, 27% yield, 95% purity, retention time = 3.5 min (method A)) as an off-white solid. Rf~ 0.4 (petroleum ether / EtOAc: 9 / 1). m / z (ES+): [M+H]+= 278.

[0210] Stage 2: Synthesis of 3.2: ethyl 5-((2-cyclohexylethyl)thio)-4-methoxy >yrimidine-2-carboxylate. In a sealed tube charged with 3.1 (102 mg, 0.37 mmol) was added a solution of 1.25 M HC1 in EtOH (0.15 mL, 3.68 mmol, 10 eq) and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to rt and concentrated to dryness. The residue was taken up with EtOAc (40 mL) and washed with NaHCO3(30 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to dryness to afford a crude material which was purified by silica gel flash chromatography (DCM / MeCN: 1 / 0 to 9 / 1) to afford a mixture of 3.2 (56 mg, 31% yield, 65% purity (method A), retention time = 3.3 min) and ethyl 5-(2-cyclohexylethylsulfanyl)-4-ethoxy-pyrimidine-2-carboxylate (35% purity (method A), retention time = 3.5 min) as a yellow oil. Rf~ 0.8 (DCM). m / z (ES+): [M+H]+= 325.

[0211] Stage 3: Synthesis of 3: 5-((2-cyclohexylethyl)thio)-4-methoxypyrimidine-2-carboxylic acid. General Procedure Al was used with 3.2 (56 mg, 0.11 mmol, 65% purity) to afford 3 (36 mg) as a crude white solid which was purified by reverse phase preparative HPLC (SunFire C18 5pm 20x100 mm, mobile phase: “A” = 0.1% TFA in water; “B” = MeCN, gradient used: increased linearly from 20 to 70% of “B” over 8 min, then increased linearly from 70 to 80% of “B” over 2 min, then increased linearly from 80 to 90% of “B” over 1 min, held at 90% during 1 min and returned to initial conditions over 1 min, 15 mL / min) to afford 3 (19.6 mg, 54% yield, 96% purity, retention time = 5.2 min (method B)) as a white solid.1H NMR (300 MHz, CDCE) 8 8.29 (s, 1H), 4.19 (s, 3H), 3.03 (t, J = 6.0 Hz, 2H), 1.74 - 0.93 (m, 13H), 1H exchanged with solvent, m / z (ES+):[M+H]+= 297.Synthesis of compound 4:Scheme 4: Synthesis of compounds 4 and 5

[0212] Stage 1: Synthesis of 4.1: ethyl (£’')-5-(3-cvclohexylprop-l-en-l-yl')-4-methylpyrimidine-2-carboxylate. A glass pressure tube was charged with ethyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (500 mg, 2.04 mmol), allylcyclohexane (294 mg, 2.27 mmol, 1.1 eq), palladium acetate (52 mg, 0.23 mmol, 10 mol%), tri-o-tolylphosphine (30 mg, 0.10 mmol, 5 mol%), TEA (735 pL, 5.27 mmol, 2.6 eq) and anhydrous MeCN (2 mL). The tube was flushed with Ar, sealed and heated to 110 °C for 2.5 h. The brown mixture was concentrated to dryness under reduced pressure and the residue was diluted with water (50 mL) and extracted with DCM (3 x 75 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to dryness afford a yellow oil which was purified by silica gel flash chromatography (petroleum ether / EtOAc: 80 / 20 to 75 / 25) to afford 4.1 (300 mg, 51% yield, 100% purity, retention time = 5.8 min (method B)) as a yellow oil. Rf~ 0.6 (petroleum ether / EtOAc: 1 / 1). m / z (ES+): [M+H]+= 289.

[0213] Stage 2: Synthesis of 4: (£)-5-(3-cyclohexyhJro >-l-en-l-yl)-4-methylpyrimidine-2-carboxylic acid. General Procedure A2 (carried out for 14 h) was used with 4.1 (36 mg, 0.12 mmol) to afford 4 (36 mg) as a crude white solid which was purified by reverse phase preparative HPLC (SunLire Cl 8 5pm 20x100 mm, mobile phase: “A” = 0.1% TLA in water; “B” = MeCN, gradient used: increased linearly from 35 to 70% of “B” over 10 min, then increased linearly from 70 to 90% of “B” over 1 min, held at 90% during 1 min and returned to initial conditions over 1 min, 15 mL / min) to afford 4 (12 mg, 42% yield, 100% purity, retention time = 4.9 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 5 8.81 (s, 1H), 6.36 (d, J= 9.8 Hz, 2H), 2.66 (s, 3H), 2.22 (t, J = 6.5 Hz, 2H), 1.74 (s, 5H), 1.56 - 0.90 (m, 6H), 1H exchanged with solvent. m / z (ES+): [M+H]+= 261.Synthesis of compound 5 (see Scheme 4):

[0214] Stage 1: Synthesis of 5.1: ethyl (£)-5A3-cyclohexylallyl)-4-methylpyrimidine-2-carboxylate A glass pressure tube was charged with ethyl 5-bromo-4-methyl-pyrimidine- 2-carboxylate (1.00 g, 4.08 mmol, 1.0 eq), allylcyclohexane (586 mg, 4.53 mmol, 1.1 eq), palladium acetate (100 mg, 0.44 mmol, 11 mol%), tri-o-tolylphosphine (60 mg, 0.20 mmol, 5 mol%), TEA (1.5 mL, 10.76 mmol, 2.6 eq) and anhydrous MeCN (4 mL). The tube was flushed with Ar, sealed and heated to 110 °C for 6 h. The brown mixture was concentrated to dryness under reduced pressure and the residue was diluted with water (100 mL) and extracted with DCM (3 x 150 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to dryness afford a yellow oil which was purified by silica gel flash chromatography (petroleum ether / EtOAc: 85 / 15 to 75 / 25) to afford 5.1 (416 mg, 19% yield, 58% purity, retention time = 5.6 min (method B)) as a yellow oil. Rf~ 0.45 (petroleum ether / EtOAc: 1 / 1). mlz (ES+): [M+H]+= 289.

[0215] Stage 2: Synthesis of 5: (E)-5-(3-cyclohexylallyl)-4-methyhJVrimidine-2-carboxylic acid. General Procedure Al was used with 5.1 (416 mg, 0.76 mmol, 53% purity (method B)) to afford 5 (247 mg) as a crude yellow oil which was purified by reverse phase preparative HPLC (SunLire C18 5pm 20x100 mm, mobile phase: “A” = 0.1% TLA in water; “B” = MeCN, gradient used: increased linearly from 20 to 90% of “B” over 14 min, held at 90% during 1 min and returned to initial conditions over 1 min, 15 mL / min) to afford 5 (125 mg, 51% yield, 99% purity, retention time = 4.1 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 5 12.08 (s, 1H), 8.75 (s, 1H), 5.46 (s, 2H), 3.44 (s, 2H), 2.67 (s, 3H), 1.97 (s, 1H), 1.70 (d, J = 9.6 Hz, 5H), 1.13 (dd, J = 50.8, 12.5 Hz, 5H). m / z (ES+): [M+H]+= 261.Synthesis of compound 6:RBpin RBF3K 6.2 6.3 55.3 (E isomer) 55.4 (E isomer)6 4 R2 >Me6.5, R2= Me 13.1, R2= H 13.2, R2= H 18.2, R2= OMe 55.6, R2= MeR2I _ 18^Et2_=_OMe _!Scheme 5: Synthesis of compounds 6, 13, 18 and 55

[0216] Stage 1: Synthesis of 6.1: (E)-3-CYclopcntylprop-2-cn- l-ol. General procedure B 1 (reaction carried out for 2 h at -78 °C, and MeOH (10 mL) was added prior to Rochelle’s salt work-up) was used with methyl (E)-3-cyclopcntylacrylatc (14.1) (3.00 g, 19.5 mmol) to afford 6.1 (2.3 g, 89% yield, 95% purity by1H NMR) as a colorless oil. ‘H NMR (300 MHz, CDCl3) 55.74 - 5.54 (m, 2H), 4.13 - 4.05 (m, 2H), 2.53 - 2.36 (m, 1H), 1.82 - 1.72 (m, 2H), 1.73 - 1.52 (m, 3H), 1.38 - 1.21 (m, 5H). Rf~ 0.5 (heptane / Et2O: 1 / 1).

[0217] Stage 2: Synthesis of 6.2: (E)-2-(3-cyclopentylallyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane. General procedure C was used with 6.1 (6.97 g, 55.2 mmol) to afford 6.2 (9.35 g, 72% yield) as a colorless oil. ’H NMR (300 MHz, CDCl3) 55.51 - 5.29 (m, 2H), 2.37 (h, J = 7.6 Hz, 1H), 1.81 - 1.43 (m, 10H), 1.24 (s, 9H). Rf~ 0.25 (heptane / Et2O: 99 / 1).

[0218] Stage 3: Synthesis of 6.3: potassium (E)-(3-cvclopentylallyl)trifluoroborate. General procedure D was used with 6.2 (9.35 g, 39.6 mmol) to afford 6.3 (8.02 g, 94% yield) as a white solid. ’H NMR (300 MHz, DMSO) 5 5.39 (dtd, J = 15.2, 7.7, 1.1 Hz, 1H), 4.94 (dd, J= 15.2, 7.4 Hz, 1H), 2.26 (h, J = 8.0 Hz, 1H), 1.72 - 1.35 (m, 6H), 1.24 - 1.11 (m, 2H), 0.80 (s, 2H).

[0219] Stage 4: Synthesis of 6.4: (E)-5-(3-cyclopentylallyl)-4-methylpyrimidine-2-carbonitrile General procedure E was used between 5-bromo-4-methylpyrimidine-2-carbonitrile (1.40 g, 6.72 mmol) and 6.3 (1.88 g, 8.70 mmol) to afford 6.4 (750 mg, 49% yield, 100% purity, 84 / 16 E / Z ratio by1H NMR, retention time = 5.9 min, (method B)) as a colorless oil.

[0220] Stage 5: Synthesis of 6.5: ethyl (E)-5-(3-cyclopentylallyl)-4-methylpyrimidine- 2-carboxylate General procedure F was used with 6.4 (750 mg, 2.77 mmol, 84% purity, 16% of Z isomer) to afford a mixture of EIZ (84 / 16) isomers (706 mg) which was purified by chiral preparative HPLC (Chiralpak ID 5 m 10x250mm, mobile phase: hexane / EtOH / DCM / DEA 90 / 5 / 5 / 0.1, 7 mL / min) to afford 6.5 (first peak collected at 4.6 min, 549 mg, 60% yield, 98% purity, retention time = 5.4 min (method B)) as a single E isomer and as a light-yellow oil (chiral HPLC (ID) purity = 98.3%). ’H NMR (300 MHz, CDCl3) 5 8.56 (s, 1H), 5.50 - 5.37 (m, 2H), 4.53 (q, J= 7.1 Hz, 2H), 3.37 (d, J = 4.5 Hz, 2H), 2.60 (s, 3H), 2.48 - 2.35 (m, 1H), 1.81 - 1.68 (m, 2H), 1.64 - 1.49 (m, 4H), 1.46 (t, 7= 7.1 Hz, 3H), 1.30- 1.16 (m, 2H). m / z (ES+): [M+H]+= 275.

[0221] Stage 6: Synthesis of 6: (E)-5-(3-cyclopentylallyl)-4-methyhJVrimidine-2-carboxylic acid. General Procedure Al was used with 6.5 (785 mg, 0.76 mmol) to afford 6 (692 mg, 94% yield, 96% purity, retention time = 4.6 min (method B)) as an off-white solid. ’H NMR (300 MHz, CDCI3) 5 8.60 (d, 7= 0.7 Hz, 1H), 5.57 - 5.40 (m, 2H), 3.46 - 3.35 (m, 2H), 2.63 (s, 3H), 2.44 (q, 7= 6.8 Hz, 1H), 1.85 - 1.70 (m, 2H), 1.70 - 1.46 (m, 4H), 1.33 - 1.17 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 247.Synthesis of compound 7a (see Scheme 3):

[0222] Stage 1: Synthesis of 7.1: sodium 2-cyano-4-methyl )yrimidine-5-thiolate. A solution of 5-bromo-4-methylpyrimidine-2-carbonitrile (1.50 g, 7.57 mmol, 1.0 eq) in anhydrous DMF (15 mL) was further degassed by Ar bubbling for 5 min. Then Na2S (625 mg, 8.01 mmol, 1.1 eq) was added in one portion. The reaction mixture was stirred at 40 °C for 23 h then concentrated under reduced pressure to dryness, co-evaporated with heptane (5 x 50 mL) and DCM (3 x 50 mL) to afford a brown crude solid which wassuspended into DCM (10 mL) and TBME (150 mL). The resulting suspension was stirred at rt for 1 h, filtered and rinsed with TBME (2 x 10 mL). The crude solid was collected, dried under reduced pressure to afford 7.1 (1.54 g, 81% yield, 69% purity, retention time = 2.4 min (method A)) as a brown solid.

[0223] Stage 2: Synthesis of 7.2: 4-methyl-5-(((tetrahydro-2H-pyran-2-yl)methyl)thio)pyrimidine-2-carbonitrile. To a solution of 7.1 (300 mg, 1.2 mmol, 1.0 eq) and K2CO3(240 mg, 1.72 mmol, 1.4 eq) in anhydrous degassed DMF (1.5 mL) was added 2-(bromomethyl)tetrahydro-2H-pyran (0.16 mL, 1.22 mmol, 1.02 eq) in one portion under Ar atmosphere. The reaction mixture was stirred at 60 °C for 2 h, then cooled to rt, diluted with EtOAc (15 mL) and washed with NaHCO3(15 mL). The aqueous layer was further extracted with EtOAc (10 mL). The combined organic layers were washed with brine (3 x 15 mL), dried over MgSO4, filtered and concentrated to dryness affording a brown oil which was purified by silica gel flash chromatography (heptane / EtOAc: 100 / 0 to 70 / 30) to afford 7.2 (52 mg, 17% yield, 100% purity, retention time = 2.9 min (method A)) as a white solid. Rf~ 0.7 (heptane / EtOAc: 1 / 1). m / z (ES+): [M+H]+= 250.

[0224] Stage 3: Synthesis of 7.3a: ethyl 4-methyl-5-(((tetrahydro-2H-r>yran-2-yl)methyl)thio)pyrimidyl)thio)pyrimidine-2-carboxylate. General procedure F was used with 7.2 (243 mg, 0.97 mmol) to afford a mixture of enantiomers (330 mg) which was purified by chiral preparative HPLC (Chiralpak ID 5µm 20x150mm, mobile phase: hexane / EtOAc / DEA 40 / 60 / 0.1, 7 mL / min) to afford enantiomer 7.3a (first peak collected at 11.2 min, 120 mg, 42% yield, 98% purity, retention time = 2.6 min (method A)) as a white solid (chiral HPLC (ID) purity = 99.7%, ee = 99.5%) H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.04 - 3.94 (m, 1H), 3.60 - 3.48 (m, 1H), 3.42 (td, J= 11.4, 3.4 Hz, 1H), 3.20 - 3.00 (m, 2H), 2.62 (s, 3H), 1.92 - 1.85 (m, 1H), 1.76 -1.69 (m, 1H), 1.63 - 1.47 (m, 4H), 1.44 (t, J = 7.1 Hz, 3H). m / z (ES+): [M+H]+= 297.

[0225] Stage 4: Synthesis of 7a: 4-methyl-5-(((tetrahydro-2H-pyran-2-yl)methyl)thio) )yrimidine-2-carboxylic acid. General Procedure Al was used with enantiomer 7.3a (120 mg, 0.40 mmol) to afford enantiomer 7a (105 mg, 96% yield, 97% purity, retention time = 3.3 min (method B)) as a white solid.1H NMR (300 MHz, CDCI3) 5 8.70 (s, 1H), 4.01 (d, J= 11.4 Hz, 1H), 3.59 (s, 1H), 3.44 (t, J= 10.2 Hz, 1H), 3.16 (t,J= 5.1 Hz, 2H), 2.64 (s, 3H), 1.90 (s, 1H), 1.74 (d, J= 10.0 Hz, 1H), 1.53 (d, J= 9.9 Hz, 4H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 269.Synthesis of compound 8:SCH2R2HetAr-Br RCO H — ► RCH2OH RCH2OMS - ■ >9.1 8.1 NC 10.1 9.2 11.1 10.2 8.2 8.3 12.1 11.2 9.3 9.4, 9.4b 12.2 10.3 10.4, 10.4a, 10.4d 11.3 11.3b 12.3 12.4Scheme 6: Synthesis of compounds 8, 9, 9b, 10, 10a, lOd, 11b and 12

[0226] Stage 1: Synthesis of 8.1: 3 -cyclopentylpropyl methanesulfonate. General Procedure H (reaction carried out with 2.45 eq of MsCl, 3.54 eq of pyridine at 0 °C to rt over 1 h, Et2O was used for work-up instead of EtOAc) was used with 8.1 3-cyclopentylpropan-l-ol (478 mg, 3.5 mmol, 1.0 eq) to afford 8.1 (989 mg, 50% purity by1H NMR) as a crude colorless oil.

[0227] Stage 2: Synthesis of 8.2: 5-((3-cyclopcntylpropyl )thio)-4-mcthylpyrimidinc-2-carbonitrile. A solution of 5-bromo-4-methyl-pyrimidine-2-carbonitrile (200 mg, 0.89 mmol) in anhydrous DMF (1.5 mL, 0.6 M) was degassed by Ar bubbling for 10 min. Na2S (70 mg, 0.90 mmol, 1.0 eq) was added and the reaction mixture was stirred at 60 °C for 16 h. 8.1 (400 mg, 0.97 mmol, 50% purity) was added and the reaction mixture was stirred at 60 °C for 30 min. The reaction mixture was allowed to reach rt then 1.0 M triethylphosphine solution in THF (850.uL, 0.85 mmol, 0.95 eq) was added at rt and the reaction mixture was stirred at rt for 3.5 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (5 x 10 mL). Organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to dryness affording 8.2 as a crude brown oil (331 mg, 14% purity, retention time = 3.4 min (method A)).

[0228] Stage 3: Synthesis of 8.3: ethyl 5-((3-cyclopentylpropyl)thio)-4-methylpyrimidine-2-carboxylate General procedure F (reaction carried out with 35.0 eq of HC1 at 80 °C for 18 h) was used with 8.2 (331 mg, 14% purity) to afford 8.3 (57 mg, 100%, retention time = 3.3 min (method A)) as a yellow oil. Rf~ 0.25 (petroleum ether / EtOAc: 8 / 2). m / z (ES+): [M+H]+= 309.

[0229] Stage 4: Synthesis of 8: 5-((3-cyclopentylpropyl)thio)-4-methylpyrimidine-2-carboxylic acid. General Procedure A2 (reaction carried out for 3 min) was used with 8.3 (57 mg, 0.18 mmol) to afford 8 (105 mg, 39% yield, 96% purity (method B), retention time = 5.1 min) as a white solid. ’H NMR (300 MHz, CDCl3) 88.54 (s, 1H), 3.08 (t, J = 7.3 Hz, 2H), 2.62 (s, 3H), 1.85 - 1.72 (m, 5H), 1.63 - 1.46 (m, 6H), 1.15 -0.97 (m, 2H), 1H exchanged with solvent. m / z (ES+): [M+H]+= 281.Synthesis of compound 9 (see Scheme 6):

[0230] Stage 1: Synthesis of 9.1: 2-cyclohexylpropan-l-ol. General Procedure II was used with 2-cyclohexylpropanoic acid (100 mg, 0.61 mmol) to afford 9.1 (200 mg, 81 % yield, 35% purity by1H NMR, retention time = 2.8 min (method A)) as a crude colorless oil. m / z (ES+): [M+H-H2O]+= 125.

[0231] Stage 2: Synthesis of 9.2: 2-cyclohexylpropyl methanesulfonate. General Procedure H was used with 9.1 (200 mg, 0.6 mmol, 43% purity) to afford 9.2 (120 mg, 80% yield, 90% purity by1H NMR) as a colorless oil.1H NMR (300 MHz, CDCl3) 84.26 (dd, J= 9.5, 5.6 Hz, 1H), 4.12 (dd, J= 9.4, 7.0 Hz, 1H), 3.00 (s, 3H), 1.87 - 1.70 (m, 6H), 1.41 - 1.05 (m, 6H), 1.02 (s, 3H). Rf~ 0.8 (petroleum ether / EtOAc: 7 / 3).

[0232] Stage 3: Synthesis of 9.3: 5-((2-cyclohexyhJrotwl)thio)-4-methyhJVrimidine-2-carbonitrile General Procedure G was used with 9.2 (120 mg, 0.46 mmol, 1.01 eq) to afford 9.3 (250 mg, 52% purity, retention time = 3.5 min (method A)) as a crude orange oil. m / z (ES+): [M+H]+= 276.

[0233] Stage 4: Synthesis of 9.4: ethyl 5-((2-cyclohexyhJro >yl)thio)-4-methylpyrimidine-2-carboxylate General Procedure F was used with 9.3 (250 mg,0.47 mmol, 52% purity) to afford 9.4 (115 mg, 74% yield, 98% purity, retention time = 3.4 min (method A)) as a yellow oil. m / z (ES+): [M+H]+= 323.

[0234] Stage 5: Synthesis of 9: 5-((2-cyclohexy Jropyl)thio)-4-methy JVrimidine-2-carboxylic acid. General Procedure A2 was used with 9.4 (15 mg, 0.05 mmol) to afford racemic compound 9 (10 mg, 70% yield, 100% purity, retention time = 5.3 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 5 8.55 (s, 1H), 3.23 - 3.13 (m, 1H), 2.93 - 2.84 (m, 1H), 2.63 (s, 3H), 1.82- 1.61 (m, 7H), 1.26 - 1.01 (m, 8H), 1H exchanged with solvent, mlz (ES+): [M+H]+= 295.Synthesis of compound 9b (see Scheme 6):

[0235] Stage 1: Synthesis of 9.4b: ethyl 5-((2-cyclohexyhJropyl)thio)-4-methylpyrimidine-2-carboxylate 9.4 (97 mg, 0.31 mmol, 100% purity (method A)) was purified by chiral preparative HPLC (Chiralpak ID 5µm 10x250mm, mobile phase: hexane / EtOAc / DEA 80 / 20 / 0.1, 7 mL / min) to afford enantiomer 9.4b (second peak collected at 8.7 min, 36 mg, 98% purity, retention time = 5.5 min (method B)) as a single enantiomer and as white solid (chiral HPLC (ID) purity = 96.9%, ee = 93.2%). mlz (ES+):[M+H]+= 323.

[0236] Stage 2: Synthesis of 9b: 5-((2-cyclohexylpropyl)thio)-4-methylpyrimidine-2-carboxylic acid. General Procedure A2 was used with enantiomer 9.4b (35 mg, 0.11 mmol) to afford enantiomer 9b (20 mg, 63% yield, 100% purity, retention time = 5.3 min (method B)) as a white solid.1H NMR (300 MHz, CDCl3) 88.55 (s, 1H), 3.23 - 3.13 (m, 1H), 2.93 - 2.84 (m, 1H), 2.63 (s, 3H), 1.82 - 1.61 (m, 7H), 1.26 - 1.01 (m, 8H), 1H exchanged with solvent, mlz (ES+): [M+H]+= 295.Synthesis of compound 10 (see Scheme 6):

[0237] Stage 1: Synthesis of 10.1: 2-(2-methylcyclopentyl)ethan-l-ol. General Procedure II was used with (2-methylcyclopentyl)acetic acid (100 mg, 0.67 mmol) toafford 10.1 (170 mg, 99 % yield, 50% purity by1H NMR) as a mixture of stereoisomers and as a crude colorless oil. m / z (ES+): [M+H-H2O]+= 111.

[0238] Stage 2: Synthesis of 10.2: 2-(2-mcthylcyclopcntyl)cthyl methanesulfonate. General Procedure H was used with 10.1 (170 mg, 0.66 mmol, 50% purity) to afford 10.2 (95 mg, 69% yield) as a mixture of stereoisomers (75 / 25) and a colorless oil. ’H NMR (300 MHz, CDCl3) 54.35 - 4.07 (m, 2H), 3.01 (s, 3H), 2.04 - 1.11 (m, 10H), 0.98 (d, J = 6.4 Hz, 2H), 0.81 (d, J = 7.0 Hz, 0.65H). Rf~ 0.8 (petroleum ether / EtOAc: 7 / 3).

[0239] Stage 3j Synthesis of 10.3: 4-methyl-5-((2-(2-methylcyclopentyl)ethyl)thio)pyrimidine-2-carbonitrile. General Procedure G was used with 10.2 (90 mg, 0.45 mmol) to afford 10.3 (275 mg, 97% yield, 42% purity, retention time = 3.4 min (method A)) as a mixture of stereoisomers and as an orange oil. mlz (ES+):[M+H]+= 262.

[0240] Stage 4: Synthesis of 10.4: ethyl 4-methyl-5-((2-(2-:-2-carboxylate. General Procedure F was used with 10.3 (275 mg, 0.47 mmol, 42% purity) to afford 10.4 (97 mg, 71% yield, 100% purity, retention time = 3.3 min (method A)) as a mixture of stereoisomers and as a yellow oil. m / z (ES+): [M+H]+= 309.

[0241] Stage 5: Synthesis of 10: 4-methyl-5-((2-(2-:-2-carboxylic acid. General Procedure A2 was used with 10.4 (10 mg, 0.03 mmol) to afford racemic compound 10 (9 mg, 96% yield, 97% purity, retention time = 5.0 min (method B)) as a mixture of stereoisomers and as a white solid.1H NMR (300 MHz, CDCl3) 58.56 (s, 1H), 3.20 - 2.95 (m, 2H), 2.62 (s, 3H), 2.03 - 1.11 (m, 10H), 0.98 (d, J = 5.8 Hz, 2H), 0.81 (d, J= 7.0 Hz, 1H). 1H exchanged with solvent, m / z (ES+): [M+H]+= 281.Synthesis of compounds 10a and lOd (see Scheme 6):

[0242] Stage 1: Synthesis of 10.4a, 10.4.d: ethyl 4-methyl-5-((2-(2-:-2-carboxylate. Mixture of isomers 10.4(117 mg, 0.38 mmol, 90% purity (method A)) was purified by chiral preparative HPLC (Chiralpak IB 5pm 10x250mm, mobile phase: hexane / EtOH / DCM / DEA 98 / 2 / 3 / 0.1, 6 mL / min) to afford enantiomer 10.4a (first peak collected at 6.8 min, 31 mg, 98% purity, retention time = 5.3 min (method B)) as a single trans enantiomer and as a white solid (chiral HPLC (IB) purity = 99.6%, de = 99.6%, ee >99.9%), and enantiomer 10.4d (fourth peak collected at 8.9 min, 16 mg, 100% purity, retention time = 5.2 min (method B)) as a single cis enantiomer and as a white solid (chiral HPLC (IB) purity = 93.4%, de = 93.2%, ee > 99.9%). m / z (ES+): [M+H]+= 309.

[0243] Stage 2: Synthesis of 10a, and IQd: 4-methyl-5-((2-(2-methylcyclopentyl)ethyl)thio)pyrimidine-2-carboxylic acid.

[0244] General Procedure A2 was used with enantiomer 10.4a (31 mg, 0.10 mmol) to afford enantiomer 10a (21 mg, 75% yield, 97% purity, retention time = 4.9 min (method B)) as a yellow solid.

[0245] General Procedure A2 was used with enantiomer 10.4d (16 mg, 0.05 mmol) to afford enantiomer lOd (5 mg, 34% yield, 98% purity, retention time = 4.8 min (method B)) as a yellow solid.1H NMR (300 MHz, MeOH) 5 8.21 (s, 1H), 3.00 - 2.74 (m, 2H), 2.46 (s, 2H), 1.99 - 1.06 (m, 12H), 0.65 (d, J = 6.9 Hz, 2H), 1H exchanged with solvent. m / z (ES+): [M+H]+= 281.Synthesis of compound 11b (see Scheme 6):

[0246] Stage 1: Synthesis of 11.1: 2-cyclopentylpropan-l-ol. General Procedure I1 was used with cyclopentylpropionic acid (100 mg, 0.67 mmol) to afford 11.1 (210 mg, 86 % yield, 35% purity by1H NMR) as a mixture of enantiomers and as a crude colorless oil.

[0247] Stage 2: Synthesis of 11.2: 2-cvclopentylpro >yl methanesulfonate. General Procedure H was used with 11.1 (210 mg, 0.66 mmol, 40% purity) to afford 11.2 (95 mg, 70% yield, 100% purity) as a mixture of enantiomers and a colorless oil. ’H NMR (300 MHz, CDCl3) 54.26 - 4.18 (m, 1H), 4.02 (dd, J= 9.4, 6.6 Hz, 1H), 3.01 (d, J= 1.5Hz, 3H), 1.84 - 1.50 (m, 8H), 1.19 (d, J= 6.3 Hz, 2H), 1.02 (s, 3H). Rf~ 0.8 (petroleum ether / EtOAc: 7 / 3).

[0248] Stage 3: Synthesis of 11.3: 5-((2-cyclopentylpropyl)thio)-4-methylpyrimidine-2-carbonitrile General Procedure G was used with 11.2 (95 mg, 0.46 mmol) to afford 11.3 (280 mg, 99% yield, 42% purity, retention time = 3.4 min (method A)) as a mixture of enantiomers and as an orange oil. m / z (ES+): [M+H]+= 262.

[0249] Stage 4: Synthesis of 11.3b: ethyl 5-((2-cyclopentyhJropyl)thio)-4-methylpyrimidine-2-carboxylate General Procedure F was used with 11.3 (280 mg, 0.45 mmol, 42% purity) to afford a mixture of enantiomers which was purified by chiral preparative HPLC (Chiralpak ID 5µm 10x250mm, mobile phase: hexane / EtOAc / DEA 80 / 20 / 0.1, 7 mL / min) to afford enantiomer 11.3b (second peak collected at 19.8 min, 36 mg, 98% purity, retention time = 5.2 min (method B)) as a single enantiomer and as a white solid (chiral HPLC (ID) purity = 97.7%, ee = 95.5%). m / z (ES+): [M+H]+= 309.

[0250] Stage 5: Synthesis of 11b: 5-((2-cyclopentylpropyl)thio)-4-methylpyrimidine-2-carboxylic acid. General Procedure A2 was used with enantiomer 11.3b (38 mg, 0.1 mmol) to afford enantiomer 11b (25 mg, 72% yield, 100% purity, retention time = 2.9 min (method A)) as a white solid.1H NMR (300 MHz, CDCl3) 8 8.59 (s, 1H), 3.25 (dd, J= 11.9, 3.4 Hz, 1H), 2.86 (dd, J= 11.9, 8.0 Hz, 1H), 2.63 (s, 3H), 1.91 - 1.51 (m, 8H), 1.19 (s, 2H), 1.10 (d, J= 6.0 Hz, 3H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 281.Synthesis of compound 12 (see Scheme 6):

[0251] Stage 1: Synthesis of 12.1: 2-(l-methylcyclo >entyl)ethan-l-ol. General Procedure I1 was used with (1-methylcyclopentyl)acetic acid (83 mg, 0.55 mmol) to afford 12.1 (71 mg, 100% yield) as a colorless oil. ’H NMR (300 MHz, CDCl3) 83.78 -3.58 (m, 2H), 1.70- 1.51 (m, 6H), 1.51 - 1.21 (m, 5H), 0.93 (s, 3H).

[0252] Stage 2: Synthesis of 12.2: 2-(l-methylcyclopentyl)ethyl methanesulfonate. General Procedure H (reaction carried out for 2.5 h) was used with 12.1 (71 mg, 0.55 mmol) to afford 12.2 (53 mg, 46% yield) as a colorless oil.

[0253] Stage 3j Synthesis of 12.3: 4-methyl-5-((2-(l--2-carbonitrile To a solution of 12.2 (53 mg, 0.26 mmol, 1.0 eq) in anhydrous and degassed DMF (1.0 mL) was added a 0.44 M solution in DMF of 7.1 (600 pL, 0.26 mmol, 1.03 eq) in one portion under Ar atmosphere. The reaction mixture was stirred at 60 °C for 3 h, then cooled to rt, diluted with EtOAc (20 mL) and washed with NaHCO3(25 mL). The aqueous layer was further extracted with EtOAc (20 mL)The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated to dryness affording 12.3 (92 mg, 100% yield, 73% purity, retention time = 3.4 min (method A)) as a dark yellow oil. m / z (ES+): [M+H]+= 262.

[0254] Stage 4: Synthesis of 12.4: ethyl 4-methyl-5-((2-(l-:-2-carboxylate General procedure F was used with 12.3 (92 mg, 0.26 mmol, 73% purity) to afford 12.4 (47 mg, 59% yield, 95% purity, retention time = 3.3 min (method A)) as a pale yellow oil. m / z (ES+): [M+H]+= 309.

[0255] Stage 5: Synthesis of 12: 4-methyl-5-((2-(l-:-2-carboxylic acid. General Procedure A2 was used with 12.4 (47 mg, 0.15 mmol) to afford 12 (25 mg, 75% yield, 98% purity, retention time = 4.8 min (method B)) as a white solid.1H NMR (300 MHz, CDCl3) 88.55 (s, 1H), 3.13 - 2.96 (m, 2H), 2.61 (s, 3H), 1.72 (dd, 7= 20.0, 11.6 Hz, 7H), 1.42 (s, 5H), 1.03 (s, 3H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 281.Synthesis of compound 13 (see Scheme 5):

[0256] Stage 1: Synthesis of 13.1: (E)-5-(3-cyclopentylallyl)pyrimidine-2-carbonitrile. General procedure E was used between 5-bromo-pyrimidine-2-carbonitrile (0.50 g, 2.69 mmol) and 6.3 (709 mg, 3.28 mmol) to afford 13.1 (174 mg, 28% yield, 94% purity,86 / 14 E / Z ratio by ’H NMR, retention time = 5.4 min (method B)) as a yellow oil.1H NMR (300 MHz, CDCl3) 8 8.66 (d, J = 2.3 Hz, 2H), 5.59 (dd, J = 15.2, 7.2 Hz, 1H), 5.47 (dt, J= 15.2, 6.3 Hz, 1H), 5.41 - 5.33 (m, 0.14H from Z isomer), 3.50 (d, J = 7.5 Hz, 0.32H from Z isomer), 3.40 (d, J = 6.3 Hz, 2H), 2.82 - 2.67 (m, 0.20H from Z isomer), 2.55 - 2.35 (m, 1H), 1.85 - 1.71 (m, 2H), 1.71 - 1.49 (m, 4H), 1.36 - 1.20 (m, 2H). Rf~ 0.2 (heptane / Et2O: 8 / 2). m / z (ES+): [M+H]+= 214.

[0257] Stage 2: Synthesis of 13.2: ethyl (E)-5-(3-cvclopcntylallyl)pyrimidinc-2-carboxylate. General procedure F was used with 13.1 (174 mg, 0.77 mmol, 94% purity, 14% of Z isomer) to afford a mixture of E / Z (86 / 14) isomers (160 mg) which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 45 to 50% of “B” over 7.5 min, then increased linearly from 50 to 80% of “B” over 1 min, returned to initial conditions over 0.5 min, 15 mL / min) affording 13.2 (110 mg, 55% yield, 100% purity (method A)) as a colorless oil. ’H NMR (300 MHz, CDCl3) 88.74 (s, 2H), 5.62 - 5.41 (m, 2H), 4.54 (q, J = 7.2 Hz, 2H), 3.40 (d, J = 5.2 Hz, 2H), 2.50 - 2.34 (m, 1H), 1.80 - 1.72 (m, 2H), 1.67 - 1.55 (m, 4H), 1.47 (t, J= 7.1 Hz, 3H), 1.26 (s, 2H). m / z (ES+): [M+H]+= 261.

[0258] Stage 3: Synthesis of 13: (E)-5-(3-cyclopentylallyl)pyrimidine-2-carboxylic acid. General Procedure Al was used with 13.2 (110 mg, 0.42 mmol) to afford 13 (95 mg, 97% yield, 98% purity, retention time = 4.1 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 88.89 - 8.80 (m, 2H), 5.67 - 5.44 (m, 2H), 3.46 (d, J = 5.8 Hz, 2H), 2.54 - 2.35 (m, 1H), 1.86 - 1.72 (m, 2H), 1.70 - 1.48 (m, 4H), 1.35 - 1.21 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 233.Synthesis of compounds 14a / b and 14b (trans isomers):19.7, 21.7 I 14a / b: mixture 14c:"; of trans isomers single cis i 14b: singlelsomeri trans isomerRCO2Et 19.1RCH2OH 19.2RB(OH)2RCH2Bpin 14.6, 14.15, 21.3 19.3Scheme 7: Synthesis of compounds 14a / b, 14b, 14c, 19 and 21

[0259] Stage 1: Synthesis of 14.1: methyl (£)-3-cvclor>entylacrylate. To a stirred solution of ( ^-S-cyclopentylacrylic acid (8.0 g, 57.07 mmol, 1.0 eq, ratio E / Z 67 / 33) in anhydrous methanol (30 mL, 2.0 M) was slowly added sulfuric acid (320 pL, 5.7 mmol, 0.10 eq) at rt. The solution was stirred at reflux under Ar for 17 h. The reaction was cooledto rt and the solvent was removed by concentration under vacuo. The resulting residue was diluted in Et2O (180 mL) and a saturated aqueous solution of NaHCO3(60 mL). The layers were separated and the aqueous layer was extracted with Et2O (50 mL). Organic layers were merged, washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 14.1 (8.38 g, 50.54 mmol, 89% yield, 93% purity by1H NMR) as a mixture of EIZ isomers (ratio 68 / 32) and as a light-yellow liquid.1H NMR (300 MHz, CDCl3) 5 6.95 (dd, J = 15.6, 8.0 Hz, 1H (E isomer)), 6.12 (t, J = 10.7 Hz, 0.45H (Z isomer)), 5.79 (dd, J= 15.6, 1.3 Hz, 1H (E isomer)), 5.68 (d, J= 11.4 Hz, 0.45H (Z isomer)), 3.72 (s, 3.45H (E isomer)), 3.70 (s, 1.35H (Z isomer)), 2.59 (h, J = 8.1 Hz, 1H (E isomer)), 1.85 (dd, J= 11.6, 6.8 Hz, 3H), 1.75 - 1.58 (m, 7H), 1.47 - 1.35 (m, 2H).

[0260] Stage 2: Synthesis of 14.2: methyl 2-cyclopentylcvclor>ro )ane-l -carboxylate. To an ice cold solution of methyl 3-cyclopentylprop-2-enoate (2.05 g, 12.36 mmol, 1.0 eq) and palladium(II) acetate (143 mg, 0.62 mmol, 5 mol%) in mixture of anhydrous DCM / Et2O (61 mL, 1 / 2.4), was added slowly a solution of 0.72 M diazomethane in Et2O (70 mL, 50.4 mmol, 4.1 eq) (Caution: diazomethane is explosive and toxic). The reaction mixture was stirred at 0 °C for 1 h and then at rt for 2 h. The brownish suspension was cooled to 0 °C and acetic acid (2.8 mL, 49.32 mmol, 4.0 eq) was added dropwise and the reaction was stirred for 5 min at rt. The reaction mixture was filtered over Celite and rinsed with Et2O (100 mL). To the filtrate was added a saturated aqueous solution of NaHCO3(150 mL). The mixture was stirred 5 min and the layers were separated. The aqueous layer was extracted with Et2O (100 mL) and the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated to afford 14.2 (2.1 g, 10.85 mmol, 88% yield, 89% purity by ’H NMR) as a brownish liquid. ’H NMR (300 MHz, CDCl3) 53.66 (s, 3H), 2.06 - 0.93 (m, 12H), 0.82 - 0.70 (m, 1H).

[0261] Stage 3: Synthesis of 14.3: 2-cyclopentylcyclopropane- 1 -carboxylic acid. KOH (5.0 g, 87.54 mmol, 8.07 eq) was added to a solution of 14.2 (2.05 g, 10.85 mmol, 1.0 eq) in a mixture of MeOH / H2O (21 mL, 2 / 1) and stirred at rt for 17 h. Reaction mixture was concentrated under reduced pressure to remove MeOH. To the resulting solution was added HCl 6.0 N to get acidic pH (~1). The mixture was extracted with DCM (3 x 50 mL). The organics layers were merged, dried over MgSO4, filtered and concentrated underreduced pressure to dryness to afford 14.3 (1.82 g, 10.74 mmol, 99% yield, 91% purity by1H NMR, retention time = 2.57 and 2.60 min (method A)) as a dark green oil.1H NMR (300 MHz, CDCl3) 5 1.95 - 0.97 (m, 12H), 0.88 - 0.78 (m, 1H), 1H exchanged with solvent, mlz (ES+): [M+H]+= 155.

[0262] Stage 4: Synthesis of 14.4: 2 -(((2-cyclopentylcyclopropane-l-carbonyl)oxy)carbonyl)benzoic acid. To a solution of 14.3 (1 82 g, 10.74 mmol, 1.0 eq), 4-dimethylaminopyridine (132 mg, 1.07 mmol, 0.1 eq) and A-hydroxyphthal imide (1.97 g, 11.83 mmol, 1.1 eq) in anhydrous DCM (18 mL, 0.6 M) under Ar at 0 °C was drop wise added N,N-diisopropylcarbodiimide (1.87 mL, 11.8 mmol, 1.1 eq). After the addition, the reaction is allowed to be stirred at rt for 21 h. Water (50 mL) and DCM (30 mL) were added. The layers were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were merged, washed with brine (20 mL), dried over MgSO4, filtered and concentrated to afford a crude material which was purified by silica gel flash chromatography (heptane / EtOAc: 100 / 0 to 90 / 10) to afford 17.4 (2.07 g, 64% yield, 96% purity, retention time = 3.2 min (method A)) as a colorless oil. Rf~ 0.25 (heptane / EtOAc: 8 / 2). ’H NMR (300 MHz, CDCl3) 57.92 - 7.82 (m, 2H), 7.83 - 7.75 (m, 2H), 2.16 - 1.16 (m, 12H), 1.16 - 1.03 (m, 1H). mlz (ES+):[M+Na]+= 322.

[0263] Stage 5: Synthesis of 14.5: 2-(2-cyclopentylcyclopropyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane To a RBF, equipped with a stir bar, were added, 14.4 (2.07 g, 6.64 mmol, 1.0 eq), bis(pinacolato)diboron (5.20 g, 20.07 mmol, 3.0 eq), lithium hydroxide (2.50 g, 100.18 mmol, 15.09 eq), cupric acetylacetonate (552 mg, 2.0 mmol, 0.3 eq) and magnesium chloride (966 mg, 9.94 mmol, 1.5 eq). The RBF was evacuated and backfilled with Ar (3x). A mixture of degassed TBME / DME (46.8 mL, 5.9 / 1, 0.14 M) were added and the resulting mixture was vigourusly stirred at rt for 40 min. EtOAc (250 mL) and water (250 mL) were added. The mixture was stirred 10 min and then vigorously shaken (to get limpid layers). The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to afford a crude material which was purified by silica gel flash chromatography (heptane / Et2O: 100 / 0 to 95 / 5) to afford 14.5 (518 mg, 33% yield, 100% purity by ’H NMR) as a colorless oil. Rf~ 0.4(heptane / Et2O: 95 / 5). ‘H NMR (300 MHz, CDCl3) 5 1.80 - 1.22 (m, 9H), 1.21 (s, 11H), 0.93 - 0.83 (m, 1H), 0.69 - 0.57 (m, 1H), 0.50 - 0.38 (m, 1H), -0.29 - -0.42 (m, 1H).

[0264] Stage 6: Synthesis of 14.6: (2-cyclopcntylcyclopropyl )boronic acid. To a solution of 14.5 (518 mg, 2.19 mmol, 1.0 eq) in a mixture of THF / H2O (19.3 mL, 4.1 / 1, 0.11 M) at rt was added NaICU (1.43 g, 6.65 mmol, 3.0 eq). The reaction was stirred for 30 min, and then 2.0 M HClaq(1.10 mL, 2.2 mmol, 1.0 eq) was added. The mixture was stirred for 24 h. The reaction was diluted with water (75 mL). The aqueous layer was extracted with EtOAc (2 x 150 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 14.6 (338 mg, 2.13 mmol, 97% yield, 97% purity by1H NMR) as a red solid / oil.1H NMR (300 MHz, CDCl3) 5 1.89 - 1.40 (m, 7H), 1.36 - 1.19 (m, 4H), 1.02 - 0.79 (m, 1H), 0.75 - 0.57 (m, 1H), 0.57 - 0.44 (m, 1H), -0.26 - -0.49 (m, 1H).

[0265] Stage 7: Synthesis of 14.7: 4-methyl-2- (methylthio)pyrimidine- 5 -c arbaldehyde. To a solution of 5-bromo-4-methyl-2-methylsulfanyl-pyrimidine (2 g, 9.13 mmol, 1.0 eq) in anhydrous THF (30 mL, 0.3 M) at 0 °C under Ar, was added isopropylmagnesium chloride - lithium chloride (1.3 M solution in THF) (7.7 mL, 10.01 mmol, 1.1 eq) dropwise. The solution was stirred at rt for 0.5 h. Then anhydrous N, N-dimethylformamide (1.4 mL, 18.08 mmol, 2.0 eq) was added dropwise and the reaction was stirred at rt for 30 min. The reaction was quenched with saturated aqueous NH4CI solution (15 mL) and water was added (15 mL). The mixture was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford a crude yellow solid which was purified by silica gel flash chromatography (heptane / EtOAc: 100 / 0 to 80 / 20) to afford 14.7 (870 mg, 55% yield, 97% purity, retention time = 2.5 min (method A)) as a yellow solid. Rf~ 0.3 (heptane / : 8 / 2). ’H NMR (300 MHz, CDCl3) 8 10.15 (s, 1H), 8.77 (s, 1H), 2.78 (s, 3H), 2.62 (s, 3H). m / z (ES+): [M+H2O+H]+= 187.

[0266] Stage 8: Synthesis of 14.8: (£’)-4-methyl-N'-((4-methyl-2- -5-yl)methylene)benzenesulfonohydrazide General procedure J was used with 14.7 (974 mg, 5.62 mmol) to afford 14.8 (1.95 g, 99% yield, 96% purity, retention time = 2.8 min (method A)) as a white solid. ’H NMR (300 MHz, CDCl3) 811.63 (s, 1H), 8.60 (s, 1H), 7.98 (s, 1H), 7.76 (d, J= 8.1 Hz, 2H), 7.42 (d, J= 7.8 Hz, 2H), 2.50 (s, 3H), 2.44 (s, 3H), 2.36 (s, 3H). m / z (ES+): [M+H]+= 337.

[0267] Stage 9: Synthesis of 14.9: 5-((2-cyclopentylcyclo )ror)yl)methyl)-4-methyl-2-(methylthio)pyrimidine. General procedure K was used with between 14.8 (595 mg, 1.77 mmol) and 14.6 (338 mg, 2.13 mmol) to afford 14.9 (234 mg, 50% yield, 99% purity, retention time = 3.5 min (method A)) as a yellowish oil. ’H NMR (300 MHz, CDCl3) 8 8.32 (s, 1H), 2.56 (s, 3H), 2.54 - 2.35 (m, 5H), 1.79 - 1.11 (m, 9H), 0.80 - 0.67 (m, 1H), 0.58 - 0.45 (m, 1H), 0.45 - 0.35 (m, 1H), 0.35 - 0.24 (m, 1H). m / z (ES+): [M+H]+= 263.

[0268] Stage 10: Synthesis of 14.10: 5-((2-cyclopentylcyclopropyl)methyl)-4-methyl-2-(methylsulfonyl)pyrimidine. General procedure LI was used with 14.9 (234 mg, 0.88 mmol) to afford 14.10 (210 mg, 78% yield, 96% purity, retention time = 2.9 min (method A)) as a colorless oil. ’H NMR (300 MHz, CDCl3) 8 8.71 (s, 1H), 3.34 (s, 3H), 2.74 - 2.51 (m, 5H), 1.80 - 1.07 (m, 9H), 0.87 - 0.73 (m, 1H), 0.65 - 0.52 (m, 1H), 0.52 - 0.42 (m, 1H), 0.41 - 0.30 (m, 1H). Rf~ 0.2 (heptane / EtOAc: 1 / 1). m / z (ES+): [M+H]+= 295.

[0269] Stage 11: Synthesis of 14.11: 5-((2-cyclopentylcyclopropyl)methyl)-4- -2-carbonitrile General procedure M (reaction carried out with 2.0 eq of KCN for 4 h at rt, then extra 2.0 eq of KCN for 17 h at rt, then extra 2.0 eq of KCN for 23 h at rt) was used with 14.10 (210 mg, 0.68 mmol) to afford 14.11 (169 mg, 97% yield, 95% purity, retention time = 3.3 min (method A)) as a yellow oil. ’H NMR (300 MHz, CDCl3) 8 8.64 (s, 1H), 2.70 - 2.48 (m, 5H), 1.77 - 1.03 (m, 9H), 0.85 - 0.72 (m, 1H), 0.62 - 0.43 (m, 2H), 0.43 - 0.31 (m, 1H). m / z (ES+): [M+H]+= 242.

[0270] Stage 12: Synthesis of 14.12b: ethyl 5-((2-cyclopentylcyclopropyl)methyl)-4-methylpyrimidine-2-carboxylate General procedure F (reaction carried out at 70 °C for 22 h) was used with 14.11 (169 mg, 0.67 mmol) to afford 14.12 (140 mg, 72% yield, 99% purity, retention time = 3.1 min (method A)) as a mixture of trans enantiomers which was purified by chiral preparative HPLC (Chiralpak ID 5µm 20x250mm, mobile phase: TBME / MeOH / DEA 98 / 2 / 0.1, 6 mL / min) to afford enantiomer 14.12b (second peak collected at 6.8 min, 68 mg, 48% yield, 100% purity, retention time = 3.0 min (methodIllB)) as a single trans enantiomer and as a colorless oil (chiral HPLC (IB) purity = 99.6%, ee > 99.9%).1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 4.54 - 4.40 (m, 2H), 2.63 (dd, J = 15.4, 6.2 Hz, 1H), 2.57 (d, J= 1.3 Hz, 3H), 2.47 (dd, J= 15.6, 7.2 Hz, 1H), 1.73 -1.34 (m, 9H), 1.34 - 0.99 (m, 3H), 0.81 - 0.65 (m, 1H), 0.56 - 0.23 (m, 3H). m / z (ES+):[M+H]+= 289.

[0271] Stage 13: Synthesis of 14a / b: 5-((2-cyclopentylcyclopropyl)methyl)-4-methylpyrimidine-2-carboxylic acid. General Procedure Al (carried out with for 1 h) was used with the mixture of trans enantiomers 14.12 (14 mg, 0.05 mmol) to afford the mixture of trans enantiomers 14a / b (9 mg, 69% yield, 95% purity, retention time = 2.7 min (method B)) as a white solid.

[0272] Stage 13: Synthesis of 14b: 5-((2-cvclopcntylcvclopropyl)mcthyl)-4-methylpyrimidine-2-carboxylic acid. General Procedure Al (carried out with for 16 h) was used with trans enantiomer 14.12b (68 mg, 0.24 mmol) to afford trans enantiomer 14b (60 mg, 98% yield, 100% purity, retention time = 4.4 min (method B)) as a white solid, (chiral HPLC (ID) purity = 100%, ee > 99.9%).1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 2.77 - 2.51 (m, 5H), 1.77 - 1.40 (m, 7H), 1.40 - 1.06 (m, 4H), 0.91 - 0.73 (m, 1H), 0.64 - 0.54 (m, 1H), 0.53 - 0.44 (m, 1H), 0.43 - 0.33 (m, 1H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 261.Synthesis of compound 14c (cis isomer) (see Scheme 7):

[0273] Stage 1: Synthesis of 14.13: (Z)-2-(2-cyclopentylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Zinc (3.14 g, 47.07 mmol, 3.0 eq) was charged into a flask under Ar atmosphere. Anhydrous DMA (31 mL) and iodo trimethyl silane (60 pL, 0.41 mmol, 3 mol%) were added followed by iron(II) trifluoromethanesulfonate (1.30 g, 3.63 mmol, 0.2 eq), 2-ethynyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.50 g, 15.63 mmol, 1.0 eq) and iodocyclopentane (5.60 mL, 46.97 mmol, 3.0 eq). The reaction mixture was stirred at 50 °C for 21 h. The reaction was cooled to rt, and water (150 mL) was added. The suspension was filtered on a pad of Celite, which was rinsed with Et2O (3 x 200 mL). Layers were separated. The organic layer was washed with water (2 x 100 mL). Thecombined aqueous layers were extracted with Et2O (3 x 50 mL). All the organic layers were combined, washed with brine (3 x 30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford a crude brown oil which was purified by silica gel flash chromatography (heptane / Et2O: 100 / 0 to 98 / 2) to afford 14.13 (1.06 g, 31% yield) as a mixture of ZIE isomers (ratio 69 / 31) and as a brown oil. Rf~ 0.7 (heptane / Et2O: 9 / 1).1H NMR (300 MHz, CDCl3) δ 6.60 (dd, J = 17.9, 7.3 Hz, 0.44H, E isomer), 6.31 (dd, J= 13.4, 9.6 Hz, 1H, Z isomer), 5.39 (dd, J= 17.9, 1.2 Hz, 0.44H, E isomer), 5.22 (dd, J = 13.4, 0.8 Hz, 1H, Z isomer), 3.16 (h, J = 8.5 Hz, 1H, Z isomer), 2.55 - 2.44 (m, 1H, E isomer), 1.87 - 1.45 (m, 12H), 1.29 - 1.18 (m, 17H).

[0274] Stage 2: Synthesis of 14.14: 2-(2-cyclopentylcyclopropyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane A solution of diethylzinc (10.60 mL, 9.54 mmol, 2.0 eq 0.9 M in hexane) in anhydrous DCM (11.5 mL) was cooled to -40 °C and treated dropwise with trifluoroacetic acid (750 p L, 9.64 mmol, 2.0 eq) over 5 min. After 25 min, diiodomethane (800 pL, 9.83 mmol, 2.1 eq) was added dropwise over 5 min. After 25 min, a solution of 14.13 (1.06 g, 4.77 mmol, 1.0 eq) in anhydrous DCM (1.1 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to rt and stirred for 24 h. The reaction mixture was diluted with Et2O (20 mL) and quenched with water (1 mL) and brine (5 mL). The layers were separated, and the aqueous layer was extracted with Et2O (2 x 20 mL). The combined organics layers were merged, dried over MgSO4, filtered and concentrated under reduced pressure to dryness to afford a crude brown oil which was purified by silica gel flash chromatography (heptane / Et2O: 100 / 0 to 97 / 3) to afford 14.14 (725 mg, 45% yield, 70% purity by1H NMR) as a mixture of cisltrans isomers (ratio 70 / 30) and as a colorless oil. Rf~ 0.8 (heptane / Et2O: 9 / 1). ’H NMR (300 MHz, CDCl3) δ 1.82 - 1.13 (m, 30H), 0.94 - 0.82 (m, 3H), 0.75 (td, J = 8.5, 3.4 Hz, 1H, Z isomer), 0.67 - 0.61 (m, 0.44H, E isomer), 0.47 - 0.38 (m, 1.42H), -0.10 (td, J = 9.2, 6.8 Hz, 1H, Z isomer), -0.36 (dt, J = 9.5, 5.7 Hz, 0.42H, E isomer).

[0275] Stage 3: Synthesis of 14.15: (2-cyclopentylcvclor>ro )yl)boronic acid. NaIO4(2.0 g, 9.31 mmol, 3.0 eq) was added to a rt solution of 14.14 (725 mg, 3.07 mmol, 1.0 eq) in THF (22 mL) and water (5.5 mL). The reaction mixture was stirred for 30 min, and then 1.0 M HCl (1.60 mL, 3.2 mmol, 1.0 eq) was added. The mixture was stirred for 76h under Ar atmosphere. The reaction was diluted with water (25 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were then dried with MgSO4, filtered, and concentrated under reduced pressure to provide a red solid / oil. Et2O was added, and solid was filtered. Filtrate was concentrated under reduced pressure to afford 14.15 (491 mg) as a mixture of cis I trans isomers (ratio 70 / 30) and as a crude red oil.

[0276] Stage 4: Synthesis of 14.16: 5-((2-cyclopentylcyclopropyl)methyl)-4-methyl-2-(methylthio)pyrimidine. General procedure K was used between 14.8 (900 mg, 2.57 mmol) and 14.15 (491 mg, 3.19 mmol) to afford 14.16 (158 mg, 23% yield, 96% purity, retention time = 3.4 min (method A)) as a mixture of cis! trans isomers (ratio 60 / 40) and as a yellow oil. Rf~ 0.3 (heptane / EtOAc: 9 / 1). m / z (ES+): [M+H]+= 263.

[0277] Stage 5: Synthesis of 14.17: 5-((2-cyclopentylcyclopropyl)methyl)-4-methyl-2-(methylsulfonyl)pyrimidine. General procedure L2 was used with 14.16 (168 mg, 0.61 mmol) to afford 14.17 (158 mg, 77% yield, 88% purity, retention time = 3.0 min (method A)) as a mixture of cis / trans isomers (ratio 63 / 37) and as a yellow oil. m / z (ES+):[M+H]+= 295.

[0278] Stage 6: Synthesis of 14.18: 5-((2-cyclopentylcyclopropyl)methyl)-4-methylpyrimidine-2-carbonitrile. General procedure M was adapted: To a solution of 14.17 (158 mg, 0.47 mmol, 1.0 eq) in anhydrous DMF (2.4 mL) under Ar was added KCN (60 mg, 0.92 mmol, 1.95 eq). The reaction mixture was stirred at rt under Ar for 1 h. A 2ndaddition of KCN (122 mg, 1.8 mmol, 3.81 eq) was added to the reaction mixture and stirred at rt for 16 h. Then, a 3rdaddition of KCN (235 mg, 3.46 mmol, 7.34 eq) was added to the reaction mixture and stirred for 112 h. The reaction mixture was diluted with with EtOAc (30 mL), and washed with NaHCO3saturated solution (2 x lOmL). The organic layer was washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to dryness to afford 14.18 (105 mg, 72% yield, 78% purity, retention time = 3.3 min (method A)) as a mixture of cis / trans isomers (ratio 63 / 37) and as a brown oil. m / z (ES+): [M+H]+= 242.

[0279] Stage 7: Synthesis of 14.19c: ethyl 5-((2-cyclopentylcyclopropyl)methyl)-4-methylpyrimidine-2-carboxylate General procedure F was used with 14.18 (105 mg, 0.33 mmol) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 45 to 50% of “B” over 5 min, then increased linearly from 50 to 90% of “B” over 2 min, returned to initial conditions over 1 min, 15 mL / min) affording a mixture of cA-stereoisomers. The mixture of isomers was purified by chiral preparative HPLC (Chiralpak ID 5µm 20x150mm, mobile phase: TBME / MeOH / DEA 98 / 2 / 0.1, 7 mL / min). First peak collected at 5.4 min was purified by chiral preparative HPLC (Chiralpak IA 5µm 20x150mm, mobile phase: n-Hexane / IPA / DEA 95 / 5 / 0.1, 7 mL / min) to afford enantiomer 14.19c (second peak collected at 6.9 min, 20 mg, 40% yield, 100% purity, retention time = 3.0 min (method B)) as a single cis enantiomer and as a white solid (chiral HPLC (IA) purity = 99.4%, de > 98.9%, ee > 99.9%), ’H NMR (300 MHz, CDCl3) 5 8.76 (s, 1H), 4.51 (q, J= 7.1 Hz, 2H), 2.87 (dd, J= 16.2, 5.9 Hz, 1H), 2.62 (s, 3H), 2.53 (dd, J= 16.1, 8.3 Hz, 1H), 1.86 - 1.75 (m, 1H), 1.70 - 1.61 (m, 3H), 1.57 - 1.36 (m, 7H), 1.33 - 1.22 (m, 1H), 1.11 - 0.93 (m, 1H), 0.89 - 0.70 (m, 2H), 0.03 - -0.12 (m, 1H). m / z (ES+): [M+H]+= 289.

[0280] Stage 8: Synthesis of 14c: 5- (( 2-cyclopentylcyclopropyl)methyl) -4-methylpyrimidine-2-carboxylic acid. General Procedure Al was used with single cis enantiomer 14.19c (21 mg, 0.07 mmol) to afford single cis enantiomer 14c (8 mg, 42% yield, 99% purity, retention time = 4.4 min (method B)) as a white solid, (chiral HPLC (ID) purity = 98.9%, ee = 98.9%).1H NMR (300 MHz, CDCl3) δ 8.82 (s, 1H), 2.92 (dd, J= 16.2, 5.9 Hz, 1H), 2.66 (s, 3H), 2.58 (dd, J= 16.4, 8.5 Hz, 1H), 1.90 - 0.98 (m, 10H), 0.88 - 0.80 (m, 2H), 0.05 - -0.01 (m, 1H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 261.Synthesis of compound 15:I R =15, R' = Me 24, R' = Me 37, R' = Me 90, R' = Me109’R' =MeScheme 8: Synthesis of compounds 15, 24, 30, 37, 44, 90 and 109

[0281] Stage 1: Synthesis of 15.1: (E)-(2-iodovinyl)cyclopcntanc.Bis(cyclopentadienyl)zirconium(IV) chloride hydride (1.05 g, 3.87 mmol, 1.5 eq) was added to a solution of cyclopentylacetylene (0.25 g, 2.58 mmol, 1.0 eq) in anhydrous DCM (10 mL, 0.26 M) (flask covered by aluminium foil). The reaction was stirred at rt for 45 min and / V-iodo succinimide (965 mg, 4.07 mmol, 1.6 eq) was added.The reaction mixture was diluted with Et2O (20 mL), and filtered on Celite pad and rinsed with Et2O (3 x 10 mL). Filtrate was washed with an aqueous saturated solution of NaHCO3(10 mL). Organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to dryness to afford a yellow oil with solid which was purified by silica gel flash chromatography (heptane / Et2O: 100 / 0 to 99 / 1) to afford 15.1 (386 mg, 67% yield) as a colorless oil. Rf~ 0.8 (heptane / Et2O: 9 / 1).

[0282] Stage 2: Synthesis of 15.2: (E)-5-((2-cyclopentylvinyl)thio)-4-methylpyrimidine-2-carbonitrile. General procedure R was used with 15.1 (386 mg, 1.78 mmol) to afford 15.2 (165 mg, 39% yield, 71% purity by ’H NMR, retention time = 3.2 min (method A)) as a yellow oil. ’H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 6.34 (dd, J= 14.8, 8.0 Hz, 1H), 6.03 (dd, 7= 14.8, 1.0 Hz, 1H), 2.76 - 2.59 (m, 1H), 2.52 (s,3H), 1.94 - 1.83 (m, 2H), 1.75 - 1.60 (m, 4H), 1.46 - 1.36 (m, 2H). Rf~ 0.4 (heptane / EtOAc: 9 / 1). m / z. (ES+): [M+H]+= 246.

[0283] Stage 3: Synthesis of 15.3: ethyl (E)-5-((2-cvclopentylvinyl)thio)-4- carboxylate General procedure F was used with 15.2 (165 mg, 0.48 mmol, 71% purity) to afford 15.3 (108 mg, 68% yield, 88% purity by ’H NMR, retention time = 5.3 min (method B)) as a yellow solid. ’H NMR (300 MHz, CDCE) 8 8.56 (s, 1H), 6.27 (dd, J= 14.8, 7.9 Hz, 1H), 6.04 (dd, J= 14.9, 1.0 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 2.71 - 2.61 (m, 1H), 2.60 (s, 3H), 1.92 - 1.79 (m, 2H), 1.76 - 1.55 (m, 3H), 1.49 - 1.31 (m, 6H). Rf~ 0.45 (heptane / EtOAc: 1 / 1). m / z (ES+): [M+H]+= 293.

[0284] Stage 4: Synthesis of 15: (E)-5-((2-cyclopentylvinyl)thio)-4-methylpyrimidine- 2-carboxylic acid. General Procedure Al was used with 15.3 (108 mg, 0.33 mmol) to afford 15 (81 mg, 92% yield, 98% purity, retention time = 4.4 min (method B)) as a yellow solid. ’H NMR (300 MHz, CDCl3) 88.56 (s, 1H), 6.34 (dd, J= 14.8, 8.0 Hz, 1H), 6.07 (d, J = 14.8 Hz, 1H), 2.74 - 2.63 (m, 1H), 2.61 (s, 3H), 1.98 - 1.30 (m, 8H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 265.Synthesis of compound 16:16.1 16 Scheme 9: Synthesis of compound 16

[0285] Stage 1: Synthesis of 16.1: methyl (£)-5-(3-cyclopentylallyl)-3-fluoropicolinate. General procedure E was used between methyl 5-bromo-3-fluoropicolinate (101 mg, 0.39 mmol, 90% purity) and 6.3 (105 mg, 0.49 mmol, 1.25 eq) to afford a crude mixture of isomers which was purified by reverse phase preparative HPLC (Waters XB ridge OBD C185 pm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 40 to 55% of “B” over 10.0 min, then increased linearly from 55 to 90% of “B” over 2 min, returned to initial conditions over 2 min, 15 mL / min) affording 16.1 (19 mg, 18% yield, 99% purity, retention time = 3.1 min (methodA)) as a colorless oil. ’H NMR (300 MHz, CDCl3) δ 8.36 (t, J= 1.9 Hz, 1H), 7.35 (dd, J = 11.1, 1.7 Hz, 1H), 5.59 - 5.40 (m, 2H), 4.00 (s, 3H), 3.40 (d, J= 5.8 Hz, 2H), 2.53 -2.34 (m, 1H), 1.85 - 1.46 (m, 6H), 1.36 - 1.18 (m, 2H).19F NMR (282 MHz, CDCl3) δ -115.13 (d, J= 12.2 Hz), m / z (ES+): [M+H]+= 264.

[0286] Stage 2: Synthesis of 16: (E)-5-(3-cyclopentylallyl)-3-fhioropicolinic acid. General Procedure Al (carried out with 8.60 eq of LiOH) was used with 16.1 (18 mg, 0.07 mmol) to afford 16 (11 mg, 65% yield, 100% purity, retention time = 4.7 min (method B)) as a white solid.1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.46 (d, J = 10.6 Hz, 1H), 5.60 (dd, J= 15.3, 7.1 Hz, 1H), 5.48 (dt, J= 15.2, 6.3 Hz, 1H), 3.45 (d, J = 6.3 Hz, 2H), 2.54 - 2.35 (m, 1H), 1.86 - 1.49 (m, 6H), 1.37 - 1.20 (m, 2H), 1H exchanged with solvent.19F NMR (282 MHz, CDCl3) 5 -113.91 (d, J = 10.7 Hz), m / z (ES+): [M+H]+= 250.Synthesis of compound 17:Scheme 10: Synthesis of compound 17

[0287] Stage 1: Synthesis of 17.1: 2,4-dichloro-6-(cyclopentylethynyl)thieno[3,2-d]pyrimidine. To a mixture of 6-bromo-2,4-dichloro-thieno[3,2-d]pyrimidine (750 mg, 2.56 mmol, 1.0 eq), copper(I) iodide (10 mg, 0.05 mmol, 20 mol%) and bis(triphenylphosphine)palladium(II) chloride (92 mg, 0.13 mmol, 5 mol%) under Ar atmosphere was added anhydrous and degassed MeCN (5 mL, 0.5 M) at rt followed by degassed triethylamine (5.20 mL, 36.93 mmol, 14.4 eq) and cyclopentylacetylene (350 pL, 2.93 mmol, 1.1 eq) to afford a white suspension. The reaction mixture was stirred atrt for 1.5 h then at 45 °C for 4 to afford a brown suspension which was purified by silica gel flash chromatography (heptane / EtOAc: 100 / 0 to 95 / 5) to afford 17.1 (481 mg, 63% yield, 100% purity by1H NMR, retention time = 6.5 min (method B)) as a yellow solid. Rf~ 0.4 (heptane / EtOAc: 9 / 1). ’H NMR (300 MHz, CDCl3) δ 7.40 (d, J= 0.4 Hz, 1H), 3.01 - 2.85 (m, 1H), 2.12 - 1.98 (m, 2H), 1.88 - 1.59 (m, 6H). m / z (ES+): [M+H]+= 297, 299.

[0288] Stage 2: Synthesis of 17.2: 2-chloro-6-(2-cyclopentylethyl)thieno[3,2-d]pyrimidine. To a mixture of 17.1 (381 mg, 1.28 mmol, 1.0 eq) in anhydrous and degassed ethyl acetate (14 mL, 0.1 M) under Ar atmosphere was added DIEA (450 pL, 2.56 mmol, 2.0 eq) followed by 10% palladium on activated carbon (140 mg, 0.13 mmol, 0.1 eq). The system was purged with hydrogen and stirred under hydrogen atmosphere with a balloon (2-3 bars) at rt for 24 h. The reaction mixture was purged with Ar then filtered through a short pad of Celite then concentrated under reduced pressure to dryness to afford a crude material which was purified by silica gel flash chromatography (heptane / EtOAc: 100 / 0 to 90 / 10) to afford 17.2 (275 mg, 79% yield, 98% purity by ’H NMR, retention time = 3.4 min (method A)) as a white solid. Rf~ 0.4 (heptane / EtOAc: 8 / 2). ’H NMR (300 MHz, CDCl3) δ 8.95 (d, J = 0.7 Hz, 1H), 7.18 (q, J = 0.9 Hz, 1H), 3.08 - 2.97 (m, 2H), 1.93 - 1.73 (m, 5H), 1.72 - 1.44 (m, 4H), 1.27 - 1.04 (m, 2H). m / z (ES+): [M+H]+= 267, 269.

[0289] Stage 3: Synthesis of 17.3: 6-(2-cyclopentylethyl)thieno[3,2-d]pyrimidine-2-carbonitrile. A mixture of 17.2 (355 mg, 1.3 mmol, 1.0 eq), DABCO (80 mg, 0.71 mmol, 0.5 eq) and KCN (290 mg, 4.45 mmol, 3.4 eq) in anhydrous DMSO (2.6 mL, 0.5 M) under Ar atmosphere was stirred at 50 °C for 17.5 h to afford a dark purple solution. The reaction mixture was cooled to rt and diluted with EtOAc (30 mL), washed with brine (5 x 50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to dryness to afford a crude material which was purified by silica gel flash chromatography (heptane / EtOAc: 100 / 0 to 90 / 10) to afford 17.3 (202 mg, 60% yield, 100% purity, retention time = 3.3 min (method A)) as an orange oil. Rf~ 0.4 (heptane / EtOAc: 8 / 2). ’H NMR (300 MHz, CDCl3) δ 9.15 (d, J= 0.7 Hz, 1H), 7.32 (q, J= 0.9 Hz, 1H), 3.07 (t, J =7.2 Hz, 2H), 1.91 - 1.76 (m, 5H), 1.73 - 1.46 (m, 4H), 1.23 - 1.08 (m, 2H). mlz (ES+):[M+H]+= 258.

[0290] Stage 4: Synthesis of 17.4: ethyl 6-(2-cyclopentylethyl)thieno[3,2-d]pyrimidine-2-carboxylate General procedure F was used with 17.3 (202 mg, 0.78 mmol) to afford 17.4 (188 mg, 76% yield, 96% purity by ’H NMR, retention time = 3.1 min (method A)) as a white solid. Rf~ 0.45 (heptane / EtOAc: 4 / 6). ’H NMR (300 MHz, CDCl3) δ 9.25 (d, J = 0.8 Hz, 1H), 7.41 (q, J = 0.9 Hz, 1H), 4.58 (q, J = 7.1 Hz, 2H), 3.05 (t, J = 7.1 Hz, 2H), 1.86 - 1.76 (m, 5H), 1.72- 1.43 (m, 7H), 1.22 - 1.12 (m, 2H). m / z (ES+): [M+H]+= 305.

[0291] Stage 5: Synthesis of 17: 6-(2-cyclopentylethyl)thieno[3,2-d]pyrimidine-2-carboxylic acid. General Procedure Al was used with 17.4 (15 mg, 0.05 mmol) to afford 17 (11 mg, 84% yield, 92% purity, retention time = 4.3 min (method B)) as a white solid.1H exchanged with solvent. ’H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 7.45 (s, 1H), 3.09 (t, J = 7.2 Hz, 2H), 1.94 - 1.77 (m, 5H), 1.73 - 1.44 (m, 4H), 1.17 (s, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 277.Synthesis of compound 18 (see Scheme 5):

[0292] Stage 1: Synthesis of 18.1: (E)-5-(3-cyclopentylallyl)-4-methoxypyrimidine-2-carbonitrile General procedure E was used between 5-bromo-4-methoxypyrimidine-2-carbonitrile (126 mg, 0.59 mmol) and 6.3 (160 mg, 0.74 mmol, 1.3 eq) to afford crude 18.1 (120 mg, 73% yield, 87% purity, retention time = 5.8 min (method B)) as a mixture of E / Z (ratio 87 / 13) colorless oil. m / z (ES+): [M+H]+= 244.

[0293] Stage 2: Synthesis of 18.2: ethyl (E)-5-(3-cyclopentylallyl)-4-methylpyrimidine-2-carboxylate General procedure F was used with 18.1 (120 mg, 0.42 mmol, 87% purity, E / Z (ratio 87 / 13) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 250 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 40 to 50% of “B” over 10 min, then increased linearly from 50 to 80% of“B” over 7 min, returned to initial conditions over 1 min, 15 mL / min) affording 18.2 (27 mg, 21% yield, 100% purity, retention time = 3.1 min (method A)) as a colorless oil. ’H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 5.58 - 5.39 (m, 2H), 4.48 (q, J= 7.2 Hz, 2H), 4.10 (s, 3H), 3.26 (d, 7= 5.2 Hz, 2H), 2.50 - 2.31 (m, 1H), 1.81 - 1.47 (m, 6H), 1.44 (t, 7= 7.2 Hz, 3H), 1.33 - 1.15 (m, 2H). m / z (ES+): [M+H]+= 291.

[0294] Stage 3: Synthesis of 18: (D-5-(3-cyclopentylallyl)-4-methoxypyrimidine-2-carboxvlic acid. General Procedure Al was used with 18.2 (27 mg, 0.09 mmol) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XB ridge OBD Cl 85 pm, 19 x 250 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 40 to 50% of “B” over 10 min, then increased linearly from 50 to 80% of “B” over 7 min, returned to initial conditions over 1 min, 15 mL / min) affording 18 (16 mg, 66% yield, 100% purity, retention time = 4.2 min (method B) as a white solid. ’H NMR (300 MHz, CDCl3) δ 11.37 (s, 1H), 8.52 (s, 1H), 5.61 - 5.40 (m, 2H), 4.15 (s, 3H), 3.30 (d, 7= 5.4 Hz, 2H), 2.51 - 2.32 (m, 1H), 1.86 -1.43 (m, 6H), 1.36 - 1.15 (m, 2H). m / z (ES+): [M+H]+= 263.Synthesis of compound 19 (see Scheme 7):

[0295] Stage 1: Synthesis of 19.1: ethyl (E)-3-cyclopentyl-2-methylacrylate. General procedure Q was used between ethyl 2-(diethoxyphosphoryl)propanoate (6.40 mL, 29.25 mmol, 1.0 eq) and cyclopentanecarboxaldehyde (3.30 mL, 29.36 mmol, 1.0 eq) to afford 19.1 (4.26 g, 80% yield, 100% purity, retention time = 3.3 min (method A)) as a mixture of E / Z isomers (ratio 42 / 58) and as colorless oil. Rf~ 0.6 (heptane / EtOAc: 9 / 1).1H NMR (300 MHz, CDCl3) δ 6.67 (d, 7 = 9.6 Hz, 1H, E isomer), 5.80 (d, 7 = 9.6 Hz, 1H, Z isomer), 4.18 (tdd, 7= 8.8, 6.3, 2.0 Hz, 5H), 3.29 (p, 7= 8.2 Hz, 1H, E isomer), 2.71 (p, 7= 8.4 Hz, lH, Zisomer), 1.91 - 1.82 (m, 11H), 1.70- 1.55 (m, 9H), 1.39- 1.20 (m, 19H), 0.87 (q, 7 = 4.3 Hz, 5H).

[0296] Stage 2: Synthesis of 19.2: (E)-3-cvclopentvL2-methvhJror>-2-en-l-ol. To a colorless mixture of 19.1 (4.24 g, 23.26 mmol, 1.0 eq) in anhydrous DCM (58 mL) under Ar atmosphere was added DIBAL in DCM solution (98 mL, 98 mmol, 4.2 eq) dropwiseat -78 °C to afford a colorless solution. The reaction mixture was stirred at -78 °C for 1.5 h. The reaction was allowed to reach rt and stirred for 16 h. The reaction mixture was cooled to 0 °C, and MeOH (100 mL) was added slowly then Rochelle's salt solution (100 mL) was added to the jelly. After addition, mixture became stirrable, water (100 mL) and DCM (150 mL) were added. The heterogenous mixture was stirred for 45 min and layers were separated. The aqueous layer was extracted with DCM (3 x 150 mL), the combined organic layers were merged, dried over MgSO4, filtered and concentrated under reduced pressure to afford pinkish oil was purified by silica gel flash chromatography (heptane / EtOAc: 100 / 0 to 75 / 25) to afford 19.2 (2.42 g, 74% yield, 100% purity, retention time = 2.7 min (method A)) as a mixture of E / Z isomers (ratio 44 / 56) and as a colorless oil. R / ~ 0.1 (heptane / EtOAc: 9 / 1). ’H NMR (300 MHz, CDCl3) 5 5.38 - 5.28 (m, 1H, E isomer), 5.22 (d, J= 9.5 Hz, 1H, Z isomer), 4.15 (d, J= 5.5 Hz, 2H, Z isomer), 3.99 (d, J= 5.8 Hz, 2H, E isomer), 2.73 - 2.56 (m, 2H), 1.86 - 1.49 (m, 18H), 1.34 - 1.12 (m, 6H). m / z (ES+): [M-H2O]+= 123.

[0297] Stage 3: Synthesis of 19.3: (E)-2-(3-cyclopentyl-2-methylallyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane. In RBF under Ar atmosphere, to solution of 4-methylbenzenesulfonic acid monohydrate (505 mg, 2.61 mmol, 15 mol%) and 19.2 (2.42 g, 17.26 mmol, 1.0 eq, E / Z isomers (ratio 44 / 56)) in anhydrous DMSO (30 mL) at rt was added a solution of bis(pinacolato)diboron (18.36 g, 70.87 mmol, 4.11 eq) in anhydrous methanol (30 mL). The resulting colorless solution was degassed by Ar bubbling under stirring at rt for 20 min. Palladium trifluoroacetate (659 mg, 1.97 mmol, 11 mol%) was added to instantaneously give a red solution which was stirred at 50 °C (pre-heated oil bath) for 16 h. The resulting mixture was filtered through a short pad of Celite which was then rinsed with Et2O (4 x 100 mL). The filtrate was washed with water (4 x 100 mL), brine (2 x 100 mL), dried over MgSO4, filtered and concentrated to dryness under reduced pressure to give a crude white solid which was purified by silica gel flash chromatography (heptane / Et2O: 100 / 0 to 97.5 / 2.5) to afford 19.3 (787 mg, 15% yield, 84% purity, retention time = 3.6 min (method A)) as a mixture of E / Z isomers (ratio 92 / 8) and as a colorless oil. Rf~ 0.4 (heptane / Et2O: 9 / 1). m / z (ES+): [M+H]+= 251.

[0298] Stage 4: Synthesis of 19.4: (£’)-5-(3-cyclopentyl-2-methylallyl)-4-methyl-2- (methylthio)pyrimidine. To a flask, were added 19.3 (600 mg, 2.01 mmol, 1.10 eq), 5-bromo-4-methyl-2-methylsulfanyl-pyrimidine (400 mg, 1.83 mmol, 1.0 eq), K2CO3 (760.00 mg, 5.44 mmol, 2.98 eq), Pd(PPh3)4 (220 mg, 0.19 mmol, 0.10 eq). The flask was evacuated and backfilled with argon (3x), then anhydrous and degassed THF / H2O (9 / 1, 10 mL) was added. The mixture was bubbling with argon for 30 s and stirred at 80 °C for 72 h. After the reaction mixture was cooled to rt, and reaction mixture was diluted with EtOAc (50 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were merged, washed with brine (2 x 10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford orange oil which was purified by silica gel flash chromatography (DCM / MeOH: 100 / 0 to 99 / 1) to afford 23.4 (290 mg, 60% yield, 99% purity, retention time = 3.5 min (method A)) as a mixture of ElZIbranched (ratio 33 / 34 / 32) and as yellow oil. m / z (ES+): [M+H]+= 263.

[0299] Stage 5: Synthesis of 19.5: (E)-5-(3-cvclopentyl-2-methylallyl)-4-methyl-2- (methylsulfonyl)pyrimidine. General procedure L1 was used with 19.4 (290 mg, 1.11 mmol, 99% purity, ElZIbranched (ratio 33 / 34 / 32)) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 40 to 55% of “B” over 10 min, then increased linearly from 55 to 90% of “B” over 2 min, returned to initial conditions over 2 min, 15 mL / min) affording 23.5 (64 mg, 20% yield, 100% purity, retention time = 5.0 min (method B)) as a mixture of E / Z (ratio 39 / 61) and as a colorless oil. m / z (ES+): [M+H]+= 295.

[0300] Stage 6: Synthesis of 19.6: (E)-5-(3-cvclopentyl-2-methylallyl)-4--2-carbonitrile General procedure M (reaction carried out for 24 h at rt) was used with 19.5 (64 mg, 0.22 mmol, 99% purity, E / Z (ratio 39 / 61)) to afford 19.6 (34 mg, 56% yield, 87% purity, retention time = 3.3 min (method A)) as a mixture of E / Z (ratio 38 / 62) and as a pink oil. m / z (ES+): [M+H]+= 242.

[0301] Stage 7: Synthesis of 19.7: ethyl (E)-5-(3-cyclopentyl-2-methylallyl)-4-:-2-carboxylate General procedure F was used with 19.6 (42 mg,0.15 mmol, 87% purity, E / Z (ratio 42 / 58)) to afford a crude material which was purified by chiral preparative HPLC (Chiralpak ID 5µm 20x150mm, mobile phase: TBME / MeOH / DEA 98 / 2 / 0.1, 6 mL / min) to afford 19.7 (second peak collected at 8.1 min, 10 mg, 20% yield, 100% purity, retention time = 3.1 min (method A)) as a colorless oil. m / z (ES+): [M+H]+= 289.

[0302] Stage 8: Synthesis of 19: (E)-5-(3-cyclopentyl-2-methylallyl)-4-methylpyrimidine-2-carboxylic acid. General Procedure Al was used with 23.7 (10 mg, 0.03 mmol) to afford 23 (4 mg, 43% yield, 96% purity, retention time = 4.1 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 58.58 (s, 1H), 4.99 (d, J= 9.0 Hz, 1H), 3.36 (s, 2H), 2.61 (s, 4H), 1.82 - 1.70 (m, 2H), 1.70 - 1.48 (m, 7H), 1.19 - 1.06 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 261.Synthesis of compound 20:20.2 22.3 23.2 43.1 45.2 48.5 49.1 50.2 51.1 54.4 20.3 22.4 23.3 43.2 45.3 48.6 49.2 45.4, 48.7a, 48.7b, 49.3b, 50.3 50.4, 51.3, 54.6a, 54.6b 51.254.523, R' = H 43, R' = H 49b, R' = H;45a,45b R' = H 50, R' = H 51 R' = H48a(trans).R' =H54a, 54b, R' = H i 48b (cis), R' = H IScheme 11: Synthesis of compounds 20, 22, 23, 43, 45a, 45b, 48a, 48b, 49b, 50, 5154a, 54b and 57

[0303] Stage 1: Synthesis of 20.1: [(£)-2-bromo-2-fhioro-vinyl]cyclopentane. To a solution of triphenylphosphine (4.34 g, 16.55 mmol, 1.2 eq), tribromofluoromethane (1.70 mL, 17.22 mmol, 1.25 eq) and cyclopentanecarboxaldehyde (1.55 mL, 13.79 mmol, 1.0 eq) in anhydrous THF (200 mL, 0.07 M) was added a solution of diethylzinc solution (18.40 mL, 16.56 mmol, 1.2 eq) in hexanes dropwise over 30 min at rt under Ar. The mixture was stirred at rt for Ih, then quenched with methanol (13 mL), stirred for 30 min, and concentrated under reduced pressure (360 mbar, 40°C) to afford a yellow oil which was stored at rt. After 1 h, the formed white precipitate was filtered and washed with pentane (100 mL). The filtrate was stored for 20 min and the precipitate was filtered. The filtrate was concentrated under reduced pressure (360 mbar, 40 °C) to afford a yellow oil which was taken up in pentane (20 mL) and was washed with a 10 wt. % aqueous solution of metabisulfite (2 x 25 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure (360 mbar, 40 °C) to afford 20.1 ( 1.85 g, 51 % yield, 74% purity, retention time = 3.6 min (method A)) as a mixture of EIZ isomers (ratio 55 / 45) and as a yellow oil.

[0304] Stage 2: Synthesis of 20.2: (Z)-2-(2-cyclopentyl-l-fluorovinyl -4,4,5,5-tetramethyl- 1,3,2-dioxaborolane A mixture of 20.1 (1.85 g, 7.09 mmol, 74% purity, 1.0 eq, EIZ (ratio 55 / 45)) and potassium acetate (2.30 g, 22.97 mmol, 3.24 eq) in anhydrous and degassed (Ar bubbling) 1,4-dioxane (67 mL) was added over 30 min to a mixture of Pd(dppf)Ch. DCM (630 mg, 0.77 mmol, 0.11 eq) and bis(pinacolato)diboron (7.95 g, 30.68 mmol, 4.33 eq) in anhydrous and degassed (Ar bubbling) 1,4-dioxane (188 mL) in a sealable tube. The vial was sealed and the mixture was stirred at 95 °C for 5 h then at rt for 16 h. The reaction was filtered on Celite and the Celite was rinsed with heptane (70 mL). The filtrate was concentrated to dryness and the obtained solid was slurried in heptane (70 mL) for 10 min then filtered. The solid was washed with heptane (25 mL). The filtrate was concentrated under reduced pressure to dryness to afford a crude colorless oil which was purified by silica gel flash chromatography (heptane) to afford 20.2 (970 mg, 57% yield, 100% purity) as a mixture of E / Z isomers (ratio 42 / 58) and as a yellow oil. Rf~ 0.4 (heptane / DCM: 2 / 1).

[0305] Stage 3: Synthesis of 20.3: (Z)-(2-cyclopentyl-l -fluoro vinyl)boronic acid. General Procedure N was used with 20.2 (720 mg, 3.00 mmol) to afford 20.3 (500 mg, 91% yield, 86% purity) as mixture of EIZ isomers (ratio 42 / 58) and as a yellow oily solid.

[0306] Stage 4: Synthesis of 20.4: ethyl 4-methyl-5-vinyl >yrimidine-2-carboxylate. A suspension of ethyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (525 mg, 2.14 mmol, 1.0 eq) and potassium vinyltrifluoroborate (365 mg, 2.67 mmol, 1.25 eq) in commercial anhydrous ethanol (2.1 mL) was degassed in a sealed tube under Ar bubbling for ~5 min. TEA (350 pL, 2.51 mmol) was added and the resulting mixture was heated to 70 °C to afford a solution, which was further degassed at rt by Ar bubbling for ~ 5 min. Then Pd(dppf)Ch. DCM (99 mg, 0.12 mmol, 6 mol%) was added at once at rt and mixture was heated at 100 °C for 2 h. The reaction mixture was concentrated to dryness under reduced pressure to dryness to afford a crude colorless oil which was purified by silica gel flash chromatography (heptane / EtOAc 80 / 20 to 30 / 70) to afford 20.4 (374 mg, 91% yield, 100% purity) as a red oil. Rf~ 0.2 (heptane / EtOAc: 1 / 1). ’H NMR (300 MHz, CDCl3) 8 8.83 (s, 1H), 6.84 (dd, 7= 17.6, 11.2 Hz, 1H), 5.86 (d, 7= 17.5 Hz, 1H), 5.63 (d, 7= 11.2 Hz, 1H), 4.53 (q, 7=7.1 Hz, 2H), 2.67 (s, 3H), 1.46 (t, 7=7.1 Hz, 3H). m / z (ES+): [M+H]+= 193.

[0307] Stage 5: Synthesis of 20.5: ethyl 5-formyl-4-methylpyrimidine-2-carboxylate. To a solution of 20.4 (374 mg, 1.95 mmol, 1.0 eq) in THF (2.4 mL) and water (2.4 mL) were added NaICU (1.16 g, 5.42 mmol, 2.79 eq) and a 4 wt. % solution of osmium tetroxide in water (1.30 mL, 0.19 mmol, 0.10 eq) dropwise at 0 °C. The reaction mixture was allowed to stir at rt for 20 min. A Na2SiCh saturated aqueous solution (20 mL) was added and reaction mixture was stirred at rt for 1 h then mixture was extracted with EtOAc (3 x 25 mL) then combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to dryness affording 20.5 (189 mg, 0.97 mmol, 50% yield, 100% purity by ’H NMR) as a brown solid. ’H NMR (300 MHz, CDCl3) 8 10.39 (s, 1H), 9.19 (s, 1H), 4.57 (q, 7= 7.2 Hz, 2H), 2.98 (s, 3H), 1.48 (t, 7= 7.1 Hz, 4H). m / z (ES+): [M+H]+= 195.

[0308] Stage 6: Synthesis of 20.6: ethyl (D-4-methyl-5-((2-:-2-carboxylate General procedure J was usedwith 20.5 (3.50 g, 16.76 mmol) to afford 20.6 (5.64 g, 93% yield, 100% purity) as a white solid. Rf~ 0.47 (EtOAc). ’H NMR (300 MHz, CDCl3) 5 8.99 (s, 1H), 7.93 (s, 1H), 7.86 (d, J= 8.3 Hz, 2H), 7.34 (d, J= 8.1 Hz, 2H), 4.53 (q, J= 7.2 Hz, 2H), 2.71 (s, 3H), 2.43 (s, 3H), 1.46 (t, J = 7.1 Hz, 4H). m / z (ES+): [M+H]+= 363.

[0309] Stage 7: Synthesis of 20.7: ethyl (Z)-5-(3-cyclopentyl-2-fluoroallyl)-4-methylpyrimidine-2-carboxylate General Procedure K was used between 20.6 (190 mg, 0.52 mmol) and 20.3 (250 mg, 1.36 mmol, 86% purity, 2.60 eq) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 30 to 40% of “B” over 10 min, then increased linearly from 40 to 95% of “B” over 2 min, held for 4 min, returned to initial conditions over 1 min, 15 mL / min) affording 20.5 (10 mg, 6% yield, 100% purity, retention time = 3.0 min (method B)) as a colorless oil. m / z (ES+): [M+H]+= 293.

[0310] Stage 8: Synthesis of 20: (Z)-5-(3-cyclopentyl-2-fluoroallyl)-4-methylpyrimidine-2-carboxylic acid. General Procedure Al was used with 20.7 (10 mg, 0.03 mmol) to afford 20 (4 mg, 71% yield, 96% purity, retention time = 4.2 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 58.67 (s, 1H), 4.57 (dd, J = 37.1, 9.2 Hz, 1H), 3.57 (d, J= 15.3 Hz, 2H), 2.81 (p, J= 8.4 Hz, 1H), 2.67 (s, 3H), 1.88 - 1.74 (m, 2H), 1.60 (ddt, J = 19.5, 11.9, 8.1 Hz, 4H), 1.33 - 1.08 (m, 2H), 1H exchanged with solvent. m / z (ES+): [M+H]+= 265.Synthesis of compound 21 (see Scheme 7):

[0311] Stage 1: Synthesis of 21.1: ethynylcycloheptane. To a solution of cycloheptanecarbaldehyde (1.30 g, 6.9 mmol, 1.0 eq) and K2CO3 (1.98 g, 14.18 mmol, 2.06 eq) in anhydrous methanol (40 mL) under Ar are added dimethyl (l-diazo-2-oxopropyl)phosphonate (1.76 g, 8.34 mmol, 1.21 eq) and stirring was continued for 18 h. The reaction mixture is diluted with Et2O (50 mL), washed with an aqueous solution of NaHCO3(5%) (50 mL), dried over MgSO4and concentrated under reduced pressure to afford a crude material which was purified by silica gel flash chromatography(pentane / Et2O 100 / 0 to 80 / 20) to afford 21.1 (230 mg, 65% yield, 88% purity by ’H NMR) as a colorless oil. Rf~ 0.88 (pentane / Et2O). ’H NMR (300 MHz, CDCl3) 5 8.99 (s, 1H), 7.93 (s, 1H), 7.86 (d, J= 8.3 Hz, 2H), 7.34 (d, J= 8.1 Hz, 2H), 4.53 (q, J= 7.2 Hz, 2H), 2.71 (s, 3H), 2.43 (s, 3H), 1.46 (t, 7 = 7.1 Hz, 4H).

[0312] Stage 2: Synthesis of 21.2: (E)-2T2-cycloheptylvinyl)-4, 4,5, 5-tetramethyl- 1,3,2-dioxaborolane To a mixture of 21.1 (539 mg, 3.88 mmol, 1.0 eq) and pinacolborane (615 pL, 4.1 mmol, 1.06 eq) was added bis(cyclopentadienyl)zirconium(IV) chloride hydride (105 mg, 0.39 mmol, 0.10 eq) and triethylamine (55 pL, 0.39 mmol, 0.10 eq) under Ar. The reaction mixture was heated at 60 °C for 18 h. The reaction mixture was cooled to rt and diluted with hexane (10 mL) and the precipitate was removed by filtering over a short pad of silica and washed with hexane (85 mL). The filtrate was concentrated under reduced pressure to afford 21.2 (587 mg, 2.21 mmol, 57% yield, 94% purity by1H NMR, retention time = 3.8 min (method A)) as a colorless oil.

[0313] Stage 3: Synthesis of 21.3: (E)-(2-cycloheptylvinyl)boronic acid. General Procedure N (reaction as carried out for 20 h) was used with 21.2 (583 mg, 2.19 mmol) to afford 21.3 (326 mg, 86% yield, 97% purity by1H NMR) as a white solid.

[0314] Stage 6: Synthesis of 21.4: (E)-5-(3-cycloheptylallyl)-4-methyl-2-(methylthio)pyrimidine. General procedure K (reaction carried out for 10 min) was used between 14.8 (608 mg, 1.81 mmol) and 21.3 (313 mg, 1.81 mmol, 1.0 eq) to afford 21.4 (350 mg, 67% yield, 95% purity, retention time = 3.8 min (method A)) as a mixture of E / Z (ratio 95 / 5) and as a colorless oil. m / z (ES+): [M+H]+= 277.

[0315] Stage 7: Synthesis of 21.5: (E)-5-(3-cycloheptylallyl)-4-methyl-2-. General procedure L2 was used with 21.4 (290 mg, 1.00 mmol) to afford 21.5 (327 mg, 100% yield, 94% purity, retention time = 3.1 min (method A)) as a mixture of E / Z (ratio 95 / 5) and as a colorless oil. m / z (ES+): [M+H]+= 309.

[0316] Stage 8: Synthesis of 21.6: (E)-5-(3-cycloheptylallyl)-4-methylpyrimidine-2-carbonitrile General procedure M (reaction carried out 19 h at rt then 13 h at 40 °C) wasused with 21.5 (385 mg, 1.17 mmol) to afford 21.6 (82 mg, 24% yield, 89% purity, retention time = 5.9 min (method B)) as a colorless oil. m / z (ES+): [M+H]+= 256.

[0317] Stage 9: Synthesis of 21.7: ethyl (E)-5-(3-cyclohcptylallyl )-4-mcthylpyrimidinc- 2-carboxylate General procedure E was used with 21.6 (82 mg, 0.29 mmol, 89% purity) to afford 21.7 (62 mg, 70% yield, 98% purity, retention time = 3.2 min (method A)) as a colorless oil. m / z (ES+): [M+H]+= 256.

[0318] Stage 10: Synthesis of 21: (D-5-(3-cycloheptylallyl)-4-methylpyrimidine-2-carboxylic acid. General procedure A2 was used with 21.7 (62 mg, 0.20 mmol) to afford 21 (52 mg, 93% yield, 99% purity, retention time = 4.7 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 5 10.22 (s, 1H), 8.67 (s, 1H), 5.55 - 5.31 (m, 2H), 3.39 (d, J = 5.5 Hz, 2H), 2.63 (s, 3H), 2.22 - 2.07 (m, 1H), 1.78 - 1.21 (m, 12H). m / z (ES+):[M+H]+= 275.Synthesis of compound 22 (see Scheme 11):

[0319] Stage 1: Synthesis of 22.1: 2-cyclobutyl-A-methoxy-A-methylacetamide. To a solution of cyclobutylacetic acid (1.30 g, 11.39 mmol, 1.0 eq) in anhydrous DCM (10 mL) were added N,O-dimethylhydroxylamine hydrochloride (1.70 g, 17.08 mmol, 1.50 eq), EDC hydrochloride (3.35 g, 17.13 mmol, 1.50 eq), DIEA (3.90 mL, 22.93 mmol, 2.01 eq) and 4-dimethylaminopyridine (0.14 g, 1.13 mmol, 0.10 eq) at rt under Ar atmosphere. The reaction mixture was stirred at rt for 16 h, diluted with water (30 mL) and extracted with DCM (2 x 20 mL). The organic layers were merged, dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown oil which was purified by silica gel flash chromatography (heptane / EtOAc 100 / 0 to 75 / 25) to afford 22.1 (1.38 g, 75% yield, 97% purity, retention time = 2.5 min (method A)) as a colorless oil. Rf~ 0.55 (heptane / EtOAc). ’H NMR (300 MHz, CDCl3) 53.68 (s, 3H), 3.15 (s, 3H), 2.73 (hept, J = 7.8 Hz, 1H), 2.53 (d, J= 7.4 Hz, 2H), 2.22 - 2.06 (m, 2H), 2.00 - 1.65 (m, 4H). m / z (ES+): [M+H]+= 158.

[0320] Stage 2: Synthesis of 22.2: 2-cyclobutylacetaldehyde. General procedure B2 (The reaction mixture was warmed to 0 °C and diluted with Et2O (10 mL) prior to Fieser work-up) was used with 22.1 (1.38 g, 8.51 mmol) to afford 22.2 (1.30 g, 23% yield, 15% purity by1H NMR) as a colorless liquid.

[0321] Stage 3: Synthesis of 22.3: (E)-2-(3-cyclobutylprop-l-en-l-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane General procedure P (reaction carried out at •78 °C for 2.5 h and at 0 °C for 2 h) was used with 22.2 (1.30 g, 1.99 mmol, 15% purity) to afford 22.3 (286 mg, 58% yield, 90% purity, retention time = 3.4 min (method A)) as a yellow oil. mlz (ES+): [M+H]+= 223.

[0322] Stage 4: Synthesis of 22.4: (E)-(3-cyclobutylprop-l-en-l-yl)boronic acid. General procedure N was used with 22.3 (286 mg, 1.16 mmol, 90% purity) to afford 22.4 (189 mg, 78% yield, 67% purity) as yellow crystals.

[0323] Stage 5: Synthesis of 22.5: ethyl (E)-5-(4-cyclobutylbut-2-en-l-yl)-4-methylpyrimidine-2-carboxylate General procedure K was used between 22.4 (189 mg, 0.90 mmol, 67% purity, 1.50 eq) and 20.6 (215 mg, 0.59 mmol) to afford 22.5 (64 mg, 33% yield, 84% purity, retention time = 3.0 (method A)) as a colorless oil. mlz (ES+):[M+H]+= 275.

[0324] Stage 6: Synthesis of 22: (E)-5-(4-cyclobutylbut-2-en-l-yl)-4-methylpyrimidine- 2-carboxylic acid. General procedure Al was used with 22.5 (64 mg, 0.20 mmol, 84% purity) to afford 22 (42 mg, 83% yield, 95% purity, retention time = 4.2 (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 5 8.61 (s, 1H), 5.55 - 5.44 (m, 1H), 5.44 - 5.33 (m, 1H), 3.41 (d, J = 4.7 Hz, 2H), 2.62 (s, 3H), 2.31 (hept, J = 7.6 Hz, 1H), 2.16 -2.08 (m, 2H), 2.08 - 1.95 (m, 2H), 1.89 - 1.74 (m, 2H), 1.68 - 1.52 (m, 2H), 1H exchanged with solvent, mlz (ES+): [M+H]+= 247.Synthesis of compound 23 (see Scheme 11):

[0325] Stage 1: Synthesis of 23.1: 1 -methylcyclopentane- 1-carbaldehy de. To a solution of cyclopentanecarboxaldehyde (0.54 mL, 4.84 mmol, 1.0 eq) in anhydrous DCM(24.2 mL) cooled to 0 °C was added potassium tert-butoxide (0.72 g, 6.29 mmol, 1.30 eq) and iodomethane (0.92 mL, 14.55 mmol, 3.01 eq). After 30 min at this temperature, the mixture was allowed to warm to rt and stir for 16 h. The reaction mixture was then poured into brine (50 mL) and extracted with DCM (3 x 20 mL). The organic layer was dried over MgSO4, filtered and the solvent was then removed carefully in vacuo (150 mbar, rt) to afford 23.1 (520 mg, 4.64 mmol, 96% yield, <80% purity by ’H NMR) as a white syrup.

[0326] Stage 2: Synthesis of 23.2: (£’)-4,4,5,5-tetramethyl-2-(2-(l-i- 1,3,2-dioxaborolane General procedure P (reaction carried out at -78 °C for 2.5 h and at 0 °C for 2 h) was used with 23.1 (520 mg, 4.64 mmol, <80% purity) to afford 23.2 (359 mg, 30% yield, 92% purity, retention time = 3.5 min (method A)) as a colorless oil. m / z (ES+): [M+H]+= 237.

[0327] Stage 3: Synthesis of 23.3: (£’)-(2-(l-methylcyclopentyl)vinyl)boronic acid. General procedure N was used with 23.2 (359 mg, 1.40 mmol) to afford 23.3 (210 mg, 97% yield, <87%) as colorless oil.

[0328] Stage 4: Synthesis of 23.4: ethyl (E)-4-methyl-5-(3-(l- carboxylate General procedure K was used between 23.3 (214 mg, 1.39 mmol, <87% purity, 1.39 eq) and 20.6 (330 mg, 0.89 mmol) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 40 to 50% of “B” over 5.5 min, then increased linearly from 50 to 95% of “B” over 1.5 min, returned to initial conditions over 1 min, 15 mL / min) affording 23.4 (132 mg, 62% yield, 99% purity, retention time = 2.8 min (method A)) as a yellow oil. mlz (ES+): [M+H]+= 289.

[0329] Stage 5: Synthesis of 23: (E)-4-methyl-5-(3-(l-:-2-carboxylic acid. General procedure Al was used with 23.4 (132 mg, 0.45 mmol) to afford 23 (108 mg, 89% yield, 97% purity, retention time = 4.2 (method B)) as a white solid.)1H NMR (300 MHz, CDCl3) 88.61 (s, 1H), 5.58 (d, J= 15.7 Hz, 1H), 5.39 (dt, J= 15.6, 6.2 Hz, 1H), 3.44 (s, 1H), 3.42 (s, 1H), 2.62 (s,3H), 1.72 - 1.27 (m, 8H), 1.04 (s, 3H), 1H exchanged with solvent, mlz (ES+): [M+H]+= 261.Synthesis of compound 24 (see Scheme 8):

[0330] Stage 1: Synthesis of 24.1: (£’)-5-((2-cyclobutylvinyl)thio)-4-methylpyrimidine- 2-carbonitrile General procedure R was used between 7.1 (300 mg, 1.37 mmol, 79% purity) and [(£’)-2-iodo vinyl] cyclobutane (387 mg, 1.84 mmol) to afford 24.1 (60 mg, 19% yield, retention time = 3.1 (method A)) as a colorless solid. Rf~ 0.3 (heptane / EtOAc 9 / 1). mlz (ES+): [M+H]+= 232.

[0331] Stage 2: Synthesis of 24.2: ethyl (E)-5-((2-cyclobutylvinyl)thio)-4-methylpyrimidine-2-carboxylate General procedure F was used with 24.1 (60 mg, 0.29 mmol) to afford 24.2 (36 mg, 48% yield, 97% purity, retention time = 3.2 min (method A)) as a colorless oil. Rf~ 0.2 (heptane / EtOAc 7 / 3). mlz (ES+): [M+H]+= 279.

[0332] Stage 3: Synthesis of 24: (E)-5-((2-cyclobutylvinyl)thio)-4-methylpyrimidine-2-carboxylic acid. General procedure Al was used with 24.2 (36 mg, 0.13 mmol) to afford 24 (20 mg, 59% yield, 93% purity, retention time = 4.2 (method B)) as a white solid.1H NMR (300 MHz, CDCl3) 58.56 (s, 1H), 6.44 (dd, J= 14.9, 7.1 Hz, 1H), 6.02 (d, J= 14.8 Hz, 1H), 3.24 - 3.10 (m, 1H), 2.62 (s, 3H), 2.27 - 2.16 (m, 2H), 2.08 - 1.82 (m, 4H), 1H exchanged with solvent, mlz (ES+): [M+H]+= 251.Synthesis of compound 25:46.3 42.1 41.3 40.1 38.1 35.3 32.2 31.3 29.1 27.2 25.1 RCO2Et / MeHetAryl-Br RCH2-OH 25.2 25.3, 27.4, 28.4, 29.3, 31.5, 32.4, 34.1, 35.5J36.1, 38.3, 39.1, 40.3, 41.5, 42.3, 46.5, 47.229 231.4 i R2= Me, R = 32.3Scheme 12: Synthesis of compounds 25, 27, 28, 29, 31, 32, 34, 35, 36, 38, 39, 40, 4142, 46 and 47b

[0333] Stage 1: Synthesis of 25.1: ethyl (E)-3-cvclopcntylbut-2-cnoatc. To a RBF containing NaH (0.53 g, 13.25 mmol, 1.49 eq - 60 % dispersion in mineral oil) and anhydrous THF (20 mL) at 0 °C, was added triethyl phosphonoacetate (2.90 mL, 14.32 mmol, 1.61 eq) dropwise over 3 min. The reaction mixture was naturally warmed to rt over 30 min, followed by a dropwise addition of 1 -cyclopentylethanone (1.02 g, 8.91 mmol, 1.0 eq) in anhydrous THF (10 mL). The reaction mixture was stirred for 7 h at rt. The reaction mixture was poured into a separating funnel containing water (60 mL). The aqueous layer was extracted with diethyl ether (3 x 60 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a colorless oil which was purified by silica gel flash chromatography (pcntanc / Et2O 100 / 0 to 80 / 20) to afford afford 25.1 (589 mg, 34% yield, 93% purity, retention time = 3.3 min (method A)) as a mixture of EIZ isomers (ratio 91 / 9) and as a colorless oil. Rf~ 0.6 (heptane / EtOAc 9 / 1). m / z (ES+): [M+H]+= 183.

[0334] Stage 2: Synthesis of 25.2: (E)-3-cyclopentylbut-2-en-l-ol. General procedure B2 (2.5 eq of DIBAL 1.0 M in hexane used) was used with 25.1 (565 mg, 2.88 mmol) to afford 25.2 (579 mg, 99% yield, 69% purity, retention time = 2.7 min (method A)) as a colorless oil. Rf~ 0.2 (heptane / EtOAc 9 / 1). m / z (ES+): [M-0H]+= 123.

[0335] Stage 3: Synthesis of 25.3: ethyl (E)-5-(3-cyclopentylbut-2-en-l-yl)-4-methylpyrimidyl)thio)pyrimidine-2-carboxylate. General procedure O was used between ethyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (70 mg, 0.29 mmol) and 25.2 (106 mg, 0.52 mmol, 69% purity, 1.8 eq) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 50 to 55% of “B” over 8.0 min, then increased linearly from 55 to 90% of “B” over 1.5 min, returned to initial conditions over 1 min, 15 mL / min) affording 25.3 (13 mg, 16% yield, 97% purity, retention time = 2.8 min (method A)) as a yellow oil. m / z (ES+): [M+H]+= 289.

[0336] Stage 4: Synthesis of 25: (E)-5-(3-cyclopentylbut-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid. General procedure Al was used with 25.3 (16 mg, 0.05 mmol) to afford 25 (12 mg, 83% yield, 94% purity, retention time = 4.4 (method B))as a light-yellow solid. ’H NMR (300 MHz, CDCl3) 5 8.61 (s, 1H), 5.20 (t, J = 7.0 Hz, 1H), 3.41 (d, J= 6.9 Hz, 2H), 2.62 (s, 3H), 2.49 - 2.34 (m, 1H), 1.81 - 1.67 (m, 5H), 1.67 - 1.49 (m, 4H), 1.45 - 1.27 (m, 2H). 1H exchanged with solvent, m / z (ES+): [M+H]+= 261.Synthesis of compound 26b:Scheme 13: Synthesis of compound 26b

[0337] Stage 1: Synthesis of 26.1: ethyl (E)-5-cvclopcntylpcnt-2-cnoatc. A mixture of 3-cyclopentylpropanal (872 mg, 6.56 mmol, 1.0 eq) and (ethoxycarbonylmethylene)triphenylphosphorane (2.46 g, 6.92 mmol, 1.05 eq) in anhydrous THF (32 mL) under Ar atmosphere was stirred under reflux for 4.5 h to afford a yellow solution. The reaction was cooled to rt and concentrated under reduced pressure to dryness to afford a pink pasty solid which was triturated in Et2O (30 mL) then filtered. The solid was rinsed with Et2O (2 x 10 mL) and the filtrate was concentrated underreduced pressure to dryness to afford a crude pink solid which was purified by silica gel flash chromatography (pentane / Et2O 100 / 0 to 95 / 5) to afford afford 26.1 (845 mg, 63% yield, 96% purity, retention time = 3.4 min (method A)) as a colorless oil. Rf~ 0.6 (heptane / Et2O 9 / 1). ’H NMR (300 MHz, CDCl3) 5 6.97 (dt, J = 15.6, 7.0 Hz, 1H), 5.81 (dt, J= 15.6, 1.6 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.28 - 2.14 (m, 2H), 1.83 - 1.70 (m, 3H), 1.68 - 1.39 (m, 6H), 1.28 (t, J = 7.1 Hz, 3H), 1.19-0.97 (m, 2H). m / z (ES+): [M+H]+= 197.

[0338] Stage 2: Synthesis of 26.2: ethyl 5-cyclopentyl-3-((2-ethoxy-2-oxoethyl)thio)pentanoate. To a mixture of 26.1 (545 mg, 2.67 mmol, 1.0 eq) and ethyl thioglycolate (380 pL, 3.36 mmol, 1.26 eq) under Ar atmosphere at 0 °C was added piperidine (14 pL, 0.14 mmol, 0.05 eq) and the reaction mixture was stirred at rt for 4.25 h. The reaction was directly purified by silica gel flash chromatography (pentane / Et2O 100 / 0 to 95 / 5) to afford afford 26.2 (864 mg, 85% yield, 83% purity, retention time = 3.4 min (method A)) as a colorless oil. Rf~ 0.3 (heptane / Et2O 8 / 2). mlz (ES+): [M+H]+= 317.

[0339] Stage 3: Synthesis of 26.3: ethyl 5-(2-cvclopentylethyl)-3-oxotetrahvdrothio >hene-2-carboxylate. To a solution of titanium tetrachloride (290 pL, 2.64 mmol, 1.19 eq) in anhydrous DCM (2.5 mL) under Ar atmosphere at -10 °C was added propan-2-ol (200 pL, 2.62 mmol, 1.18 eq) to afford a yellow solution which was stirred at -10 °C for 35 min. Then a solution of 26.2 (704 mg, 2.22 mmol, 1.0 eq) in anhydrous DCM (1.9 mL) was added over 5 min at -10 °C. The reaction mixture was stirred at -10 °C for 50 min. Then triethylamine (1.00 mL, 7.17 mmol, 3.23 eq) was added over 5 min to afford a black solution at the first drop. The reaction mixture was stirred at -10 °C for 1.75 h then at rt for 15 min. The reaction mixture was poured at 0 °C to 3.0 M HC1 (2.80 mL, 8.4 mmol, 3.78 eq) and stirred at rt for 30 min then at 30 °C for 1 h. The reaction mixture was cooled to rt, diluted with water (30 mL) and DCM (30 mL). The layers were separated and the aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were washed with water (30 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to dryness to afford a crude dark brown oil which was purified by silica gel flash chromatography (heptane / EtOAc 100 / 0 to 95 / 5) to afford afford 26.3 (531 mg, 88% yield, retention time = 3.3 min (method A))as a mixture of diasteromers (ratio 1 / 0.57) and as a yellow oil. Rf~ 0.2 (heptane / EtOAc 98 / 2). m / z (ES+): [M+H]+= 271.

[0340] Stage 4: Synthesis of 26.4: ethyl 5-hcxyl-3-urcido-4.5-dihydrothiophcnc-2-carboxylate. To a mixture of 26.3 (436 mg, 1.61 mmol, 1.0 eq) and urea (196 mg, 3.26 mmol, 2.02 eq) in methanol (400 qL) was added a 12 M HClaqsolution (27 qL, 0.32 mmol, 0.20 eq) and the rxn mixture was stirred under reflux for 10 h to afford a yellow gum. The reaction was cooled to rt, filtered and the yellow solid was triturated on the filter with water (2 x 1 mL), collected and dried under vacuum to afford 26.4 (456 mg, 1.33 mmol, 82% yield, 91% purity by ’H NMR, retention time = 3.1 min (method A)) as a crude yellow solid.

[0341] Stage 5: Synthesis of 26.5: 6-(2-cyclopentylethyl)-6,7-dihydrothieno[3,2-d1pyrimidine-2,4-diol. To 26.4 (456 mg, 1.33 mmol, 1.0 eq) was added a solution of sodium hydroxide (62 mg, 1.53 mmol, 1.16 eq) in water (1.0 mL) and the reaction mixture was stirred at 85 °C for 1.75 h to afford a thick beige suspension. The reaction was cooled to 0 °C and concentrated 12 M HClaq(140 qL, 1.68 mmol, 1.27 eq) was added. Since the reaction mixture solidified, extra water (1.0 mL) was added to improve the stirring. The suspension was filtered and the solid was rinsed with water (2 x 1 mL). The solid was collected and dried for 18 h under vacuum to afford 26.5 (387 mg, 1.32 mmol, 100% yield, 91% purity, retention time= 2.6 min (method A)) as a crude off-white solid.

[0342] Stage 6: Synthesis of 26.6: 2,4-dichloro-6-(2-cyclopentylethyl)-6,7-dihydrothieno [3,2-d] pyrimidine. To a solution of 26.5 (387 mg, 1.32 mmol, 1.0 eq) in A, A-diethylaniline (470 qL, 2.9 mmol, 2.19 eq) under Ar atmosphere at rt was added phosphorus(V) oxychloride (270 qL, 2.9 mmol, 2.19 eq). The reaction mixture was stirred at 110 °C for 6 h to afford a dark brown solution after few minutes at this temperature. The reaction was cooled to rt, diluted with DCM (5 mL) and concentrated under reduced pressure. The resulting residue was diluted EtOAc (20 mL) and a saturated aqueous solution of NaHCO3(20 mL). The mixture was stirred at rt for 30 min. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to dryness to afford a crude material which was purified by silica gelflash chromatography (heptane / EtOAc 100 / 0 to 90 / 10) to afford 26.6 (189 mg, 46% yield, 97% purity by1H NMR, retention time = 6.6 min (method B)) as an orange oil. Rf~ 0.2 (heptane / EtOAc 96 / 4). m / z (ES+): [M+H]+= 303.

[0343] Stage 7: Synthesis of 26.7: 2-chloro-6-(2-cyclo >entylethyl)-6,7- dihydrothieno 13, 2 -<. To a mixture of 26.6 (186 mg, 0.59 mmol, 1.0 eq) in anhydrous and degassed ethyl acetate (6.5 mL, 0.09 M) under Ar atmosphere was added DIEA (210 pL, 1.19 mmol, 2.01 eq) followed by palladium on activated carbon (65 mg, 0.06 mmol, 10 mol% - 10 wt. % loading). The system was purged with hydrogen and stirred under hydrogen atmosphere (2-3 bars) at rt for 24 h. The flask was purged with Ar and extra palladium on activated carbon (65 mg, 0.06 mmol, 10 mol% - 10 wt. % loading) was added. The flask was purged with hydrogen and the reaction was stirred under hydrogen atmosphere (2-3 bars) at rt for 23 h. The reaction mixture was purged with Ar then filtered through a short pad of Celite. The Celite was rinsed with EtOAc (4 x 5 mL) and the filtrate was concentrated under reduced pressure to dryness to afford a crude dark brown solid which was purified by reverse phase preparative HPLC (Waters XB ridge OBD C185 pm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 55 to 70% of “B” over 5.0 min, then increased linearly from 70 to 90% of “B” over 1.0 min, held for 1.5 min, returned to initial conditions over 1 min, 15 mL / min) affording 26.7 (27 mg, 17% yield, 97% purity, retention time = 3.0 min (method A)) as a colorless oil. ’H NMR (300 MHz, CDCl3) 8 8.26 (s, 1H), 3.92 (tt, J = 8.3, 6.4 Hz, 1H), 3.45 (dd, J= 17.5, 8.2 Hz, 1H), 3.08 (dd, J = 17.6, 6.8 Hz, 1H), 1.90- 1.34 (m, 11H), 1.07 (tdd, J= 10.6, 6.0, 2.8 Hz, 2H). m / z (ES+):[M+H]+= 269.

[0344] Stage 8: Synthesis of 26.8: 6-(2-cvclopentylethyl)-6,7-dihydrothieno[3,2--2-carbonitrile To a mixture of 26.7 (28 mg, 0.1 mmol, 1.0 eq), Zn(CN)2(8 mg, 0.07 mmol, 0.66 eq), Pd2(dba)3(5 mg, 0 mmol, 5 mol%) and XantPhos (7 mg, 0.01 mmol, 12 mol%) under Ar atmosphere was added anhydrous and degassed DMF (480 pL). The reaction mixture was stirred at 120 °C for 7.5 h to afford a red suspension. The reaction mixture was cooled to rt and filtered through a short pad of Celite which was rinsed with EtOAc (3 x2 mL). The filtrate was diluted with EtOAc (10 mL), washed witha saturated solution of NH4CI (10 mL), brine (3 x 10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to dryness to 26.8 (35 mg, 0.1 mmol, 100% yield, 75% purity, retention time = 5.6 min (method B)) as a crude brown oil. mlz (ES+): [M+H]+= 260.

[0345] Stage 9: Synthesis of 26.9b: ethyl 6-(2-cyclopentylethyl)-6,7-dihydrothieno[3,2-:-2-carboxylate General procedure F (reaction carried out with 5.0 eq of HC1 (1.25 M in EtOH) at 80 °C for 7 h) was used with 26.8 (35 mg, 0.1 mmol, 75% purity) to afford a crude dark yellow solid which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 55 to 70% of “B” over 5.0 min, then increased linearly from 70 to 90% of “B” over 1.0 min, held for 1.5 min, returned to initial conditions over 1 min, 15 mL / min) affording a mixture of enantiomers.

[0346] The mixture of enantiomers was purified by chiral preparative HPLC (Chiralpak ID 5µm 20x150mm, mobile phase: TBME / MeOH / DEA 97 / 3 / 0.1, 7 mL / min) to afford enantiomer 26.9b (second peak collected at 13.3 min, 9 mg, 28% yield, 93% purity, retention time = 3.1 min (method A)) as a single enantiomer and as a white solid (chiral HPLC (ID) purity = 100%, ee > 99.9%). mlz (ES+): [M+H]+= 307.

[0347] Stage 10: Synthesis of 26b: 6-(2-cvclopentylethyl)-6,7-dihydrothieno[3,2-d]pyrimidine-2-carboxylic acid. General Procedure Al was used with enantiomer 26.9b (9 mg, 0.03 mmol) to afford enantiomer 26b (8 mg, 100% yield, 92% purity, retention time = 4.5 min (method B)) as a white solid.1H NMR (300 MHz, CDCl3) 88.55 (s, 1H), 4.09 - 3.93 (m, 1H), 3.61 (dd, J= 17.6, 8.3 Hz, 1H), 3.25 (dd, J= 17.8, 6.6 Hz, 1H), 1.90 - 1.37 (m, 11H), 1.16 - 0.98 (m, 2H), 1H exchanged with solvent, mlz (ES+): [M+H]+= 279.Synthesis of compound 27 (see Scheme 12):

[0348] Stage 1: Synthesis of 27.1: methyl 3-cyclopentylpropiolate. To a solution of cyclopentylacetylene (6 mL, 46.57 mmol, 1.0 eq) in anhydrous THF (60 mL) under Ar atmosphere at -78 °C was added n-butyl lithium in hexane (32 mL, 51.2 mmol, 1.10 eq) over 10 min to afford an off-white / milky suspension which was stirred at -78 °C for 1 h. Methyl chloroformate (5.40 mL, 69.19 mmol, 1.49 eq) was added over 5 min at - 78 °C to afford a yellow solution. The reaction mixture was stirred at -78 °C for 1 h then allowed to stir at rt for 1.25 h to afford a white suspension. A saturated aqueous solution of NH4CI (50 mL) was added to the reaction mixture and extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to dryness to afford a yellow oil which was purified by silica gel flash chromatography (pcntanc / Et2O 100 / 0 to 90 / 10) to afford afford 27.1 (7.37 g, 100% yield, 96% purity by1H NMR, retention time = 2.9 min (method A)) as a yellow oil. Rf~ 0.4 (pentane / Et2O 9 / 1). ’H NMR (300 MHz, CDCl3) 8 3.75 (s, 3H), 2.82 - 2.67 (m, 1H), 2.07 - 1.89 (m, 2H), 1.80 - 1.47 (m, 6H). m / z (ES+):[M+H]+= 153.

[0349] Stage 2: Synthesis of 27.2: methyl (Z)-3-cyclopentyl-3-fluoroacrylate. A mixture of 27.1 (350 mg, 2.21 mmol, 1.0 eq) and AgF (420 mg, 3.31 mmol, 1.50 eq) in MeCN (5 mL) and water (1 mL) was stirred under Ar atmosphere at 80 °C for 4.25 h. A saturated aqueous solution of NaHCO3(20 mL) and Et2O (30 mL) were added and the layers were separated. The aqueous layer was extracted with Et2O (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to dryness to afford a crude yellow oil which was purified by silica gel flash chromatography (pcntanc / Et2O 100 / 0 to 90 / 10) to afford 27.2 (321 mg, 71% yield, 84% purity by ’H NMR, retention time = 2.9 min (method A)) as a colorless oil. Rf~ 0.1 (pentane / Et2O 9 / 1). ’H NMR (300 MHz, CDCl3) 85.21 (d, J= 33.5 Hz, 1H), 3.72 (s, 3H), 2.77 - 2.55 (m, 1H), 2.00 - 1.82 (m, 2H), 1.81 - 1.51 (m, 6H).19F NMR (282 MHz, CDCl3) 8 -82.31 (dd, J= 33.5, 19.8 Hz), m / z (ES+): [M+H]+= 173.

[0350] Stage 3: Synthesis of 27.3: (Z)-3-cyclopentyl-3-fhioroprop-2-en-l-ol. General procedure Bl (2.5 eq of 1.0 M DIBAL in hexanes were used, and the reaction mixturewas stirred at -78 °C for 30 min and 2 h at rt prior to Rochelle’s salt work-up) was used with 27.2 (321 mg, 1.57 mmol, 84% purity) to afford 27.3 (229 mg, 96% yield, 95% purity by ’H NMR) as a colorless oil. ’H NMR (300 MHz, CDCl3) 54.87 (dtd, J= 37.0, 7.2, 0.7 Hz, 1H), 4.22 (ddd, J= 7.3, 5.6, 1.9 Hz, 2H), 2.70 - 2.47 (m, 1H), 1.95 - 1.47 (m, 8H), 1H exchanged with solvent.19F NMR (282 MHz, CDCl3) 8 -107.33 (dd, J = 36.8, 18.5 Hz). Rf~ 0.1 (pentane / Et2O: 7 / 3).

[0351] Stage 4: Synthesis of 27.4: ethyl (Z)-5-(3-cyclopentyl-3-fhioroallyl)-4-methylpyrimidine-2-carboxylate and 28.4: ethyl (E)-5-(3-' -3-fluoroallyl)-4-carboxylate General procedure O was used between ethyl 5-bromo- 4-methyl-pyrimidine-2-carboxylate (70 mg, 0.29 mmol) and 27.3 (87 mg, 0.50 mmol, 1.75 eq) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 55 to 60% of “B” over 6.0 min, then increased linearly from 60 to 90% of “B” over 1.5 min, held for 2 min; returned to initial conditions over 1 min, 15 mL / min) affording 27.4 (39 mg, 46% yield, 98% purity, retention time = 2.9 min (method A)) as a yellow oil.1H NMR (300 MHz, CDCl3) 8 8.55 (s, 1H), 4.58 (dt, J = 36.6, 7.4 Hz, 1H) - 4.43 (t, J = 7.1 Hz, 1H), 3.40 (d, J = 7.4 Hz, 2H), 2.58 (s, 3H), 2.65 - 2.49 (m, 1H), 1.87 - 1.46 (m, 8H), 1.41 (t, J = 7.2 Hz, 3H).19F NMR (282 MHz, CDCl3) 8 -107.25 (dd, J = 35.9, 19.1 Hz), m / z (ES+):[M+H]+= 293; and 28.4 (13 mg, 15% yield, 97% purity, retention time = 2.6 min (method A)) as a yellow oil. ’H NMR (300 MHz, CDCl3) 88.57 (s, 1H), 5.03 (dt, J = 20.3, 7.9 Hz, 1H), 4.51 (q, J= 7.2 Hz, 2H), 3.35 (d, J= 7.9 Hz, 2H), 2.90 (dt, J= 33.3, 8.1 Hz, 1H), 2.61 (s, 3H), 1.82 - 1.53 (m, 8H), 1.44 (t, J= 7.1 Hz, 3H).19F NMR (282 MHz, CDCl3) 8 -110.23 (dd, J= 33.6, 21.4 Hz), m / z (ES+): [M+H]+= 293.

[0352] Stage 5: Synthesis of 27: (Z)-5-(3-cyclopentyl-3-fluoroallyl)-4- 2- carboxylic acid. General Procedure A2 was used with 27.4 (39 mg, 0.13 mmol) to afford 27 (35 mg, 98% yield, 92% purity, retention time = 4.1 min (method B)) as a white solid.1H NMR (300 MHz, CDCl3) 88.66 (s, 1H), 4.63 (dt, J= 35.5, 7.4 Hz, 1H), 3.47 (d, J = 7.4 Hz, 2H), 2.64 (s, 4H), 1.91 - 1.44 (m, 8H), 1H exchanged withsolvent.19F NMR (282 MHz, CDCl3) 5 -106.66 (dd, J = 35.8, 19.1 Hz), m / z (ES+):[M+H]+= 265.Synthesis of compound 28 (see Scheme 12):

[0353] Stage 1: Synthesis of 28: (E)-5-(3-cyclopentyl-3-fluoroallyl)-4-methylpyrimidine-2-carboxylic acid. General Procedure A2 was used with 28.4 (13 mg, 0.13 mmol) to afford 28 (35 mg, 98% yield, 92% purity, retention time = 4.1 min (method B)) as a white solid.1H NMR (300 MHz, CDCl3) 58.63 (s, 1H), 5.05 (dt, J= 20.1, 7.9 Hz, 1H), 3.41 (d, J = 7.9 Hz, 2H), 2.92 (dt, J = 33.5, 8.0 Hz, 1H), 2.66 (s, 3H), 1.92 - 1.47 (m, 8H), 1H exchanged with solvent.19F NMR (282 MHz, CDCl3) 8 -109.36 (dd, J = 33.1, 20.2 Hz), m / z (ES+): [M+H]+= 265.Synthesis of compound 29 (see Scheme 12):

[0354] Stage 1: Synthesis of 29.1: ethyl (£’)-4-cyclobutylbut-2-enoate. General Procedure QI (reaction carried out for 16 h) was used with 22.2 (1.50 g, 2.29 mmol) to afford 29.1 (240 mg, 62% yield, 100% purity, retention time = 3.1 min (method A)) as a colorless oil. R / ~ 0.45 (heptane / Et2O 8 / 2).1H NMR (300 MHz, CDCl3) 8 6.88 (dt, J = 15.6, 6.9 Hz, 1H), 5.78 (dt, J = 15.6, 1.5 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.50 - 2.33 (m, 1H), 2.28 (td, J = 7.2, 1.5 Hz, 2H), 2.17 - 2.02 (m, 2H), 1.99 - 1.74 (m, 2H), 1.72 -1.60 (m, 2H), 1.28 (t, J= 7.1 Hz, 3H). m / z (ES+): [M+H]+= 169.

[0355] Stage 2: Synthesis of 29.2: (E)-4-cyclobutylbut-2-en-l-ol. General Procedure B2 (2.5 eq of DIBAL in hexanes were used) was used with 29.1 (240 mg, 1.43 mmol) to afford 29.2 (190 mg, 94% yield, 89% purity) as a colorless oil. ’H NMR (300 MHz, CDCl3) 85.71 - 5.52 (m, 2H), 4.12 - 4.03 (m, 2H), 2.32 (h, J = 7.7 Hz, 1H), 2.17 - 1.70 (m, 6H), 1.69 - 1.56 (m, 2H), 1H exchanged with solvent.

[0356] Stage 3: Synthesis of 29.3: ethyl (E)-5-(4-cyclobutylbut-2-en-l-yl)pyrimidine-2-carboxylate General Procedure O was used between ethyl 5-bromopyrimidine-2-carboxylate (270 mg, 1.17 mmol) and 29.2 (240 mg, 1.43 mmol, 1.1 eq) to afford a crudematerial which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 50 to 55% of “B” over 8.0 min, then increased linearly from 55 to 90% of “B” over 1.0 min, returned to initial conditions over 1 min, 15 mL / min) affording 29.3 (158 mg, 52% yield, 95% purity, retention time = 4.6 min (method B)) as a yellow oil.1H NMR (300 MHz, CDCl3) 58.73 (s, 2H), 5.62 - 5.38 (m, 2H), 4.53 (q, J= 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 2.39 - 2.25 (m, 1H), 2.16 - 1.95 (m, 4H), 1.90- 1.70 (m, 2H), 1.68- 1.52 (m, 2H), 1.46 (t, 7=7.2 Hz, 3H). m / z (ES+): [M+H]+= 261.

[0357] Stage 4: Synthesis of 29: (D-5-(4-cyclobutylbut-2-en-l-yl)pyrimidine-2-carboxvlic acid. General Procedure A2 was used with 29.3 (157 mg, 0.57 mmol) to afford 29 (118 mg, 84% yield, 95% purity, retention time = 4.1 min (method B)) as a yellow oil.1H NMR (300 MHz, CDCl3) δ 8.77 (s, 2H), 5.64 - 5.42 (m, 2H), 3.45 (d, J= 5.2 Hz, 2H), 2.42- 2.21 (m, 1H), 2.18 - 2.11 (m, 2H), 2.10 - 1.95 (m, 2H), 1.93 - 1.73 (m, 2H), 1.70 - 1.52 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 233.Synthesis of compound 30 (see Scheme 8):

[0358] Stage 1: Synthesis of 30.1: (D-(2-iodovinyl)cyclohexane. To a solution of 2,2,6,6-tetramethylpiperidine (910 pL, 5.12 mmol, 1.27 eq) in anhydrous THF (9.5 mL) under Ar atmosphere at 0 °C was added n-butyl lithium in hexane (3 mL, 4.8 mmol, 1.19 eq) over 5 min to afford a yellow solution which was stirred at 0 °C for 15 min. Then, a solution of bis [(pinacolato)boryl] methane (1.30 g, 4.85 mmol, 1.20 eq) in anhydrous THF (4.4 mL) was added over 5 min and the reaction mixture was stirred for 10 min resulting in a light yellow suspension. The reaction was cooled to -78 °C, and a solution of cyclohexanecarboxaldehyde (500 pL, 4.05 mmol, 1.0 eq) in anhydrous THF (4.4 mL) was added over 5 min. The reaction mixture was allowed to stir at -78 °C for an additional 20 min and at rt for 1.5 h to afford a yellow solution. A 3.0 N aqueous solution of sodium hydroxide (8 mL, 24 mmol, 5.93 eq) was added at rt and stirring continued for 10 min before iodine (4.10 g, 16.15 mmol, 3.99 eq) was added portion wise over 5 min (exothermic reaction) and was stirred for 19 h at rt. A saturated aqueous solution ofNa2SiCh (50 mL) was added followed by heptane (50 mL) to get a biphasic mixture. The layers were separated and the aqueous layer was extracted with heptane (2 x 25 mL). The combined organic layers were washed with a mixture of 1.0 M aqueous solution of sorbitol and a 1.0 M aqueous solution of Na2CO3(1 / 1 v / v, 3 x 50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to dryness to afford 30.1 (835 mg, 3.54 mmol, 87% yield) as a crude dark yellow liquid.1H NMR (300 MHz, CDCl3) 56.48 (dd, J= 14.4, 7.1 Hz, 1H), 5.95 (dd, J= 14.5, 1.3 Hz, 1H), 2.09 - 1.93 (m, 1H), 1.78 - 1.68 (m, 4H), 1.39 - 1.01 (m, 6H).

[0359] Stage 2: Synthesis of 30.2: (£’)-5-((2-cyclohexylvinyl)thio)-4-methylpyrimidine- 2-carbonitrile General procedure R was used between 7.1 (300 mg, 1.37 mmol, 79% purity) and [(£’)-2-iodo vinyl] cyclohexane (484 mg, 2.05 mmol, 1.50 eq) to afford 30.2 (30 mg, 8% yield, retention time = 3.4 (method A)) as a yellow oil. Rf~ 0.3 (heptane / EtOAc 9 / 1). m / z (ES+): [M+H]+= 260.

[0360] Stage 3: Synthesis of 30.3: ethyl (E)-5-((2-cyclohexylvinyl)thio)-4-:-2-carboxvlate General procedure F was used with 30.2 (30 mg, 0.12 mmol, 89% purity) to afford 30.3 (62 mg, 70% yield, 98% purity, retention time = 3.0 min (method A)) as a colorless oil. Rf~ 0.4 (heptane / EtOAc 6 / 4).1H NMR (300 MHz, CDCl3) 5 8.57 (s, 1H), 6.25 (dd, J = 15.0, 6.9 Hz, 1H), 6.02 (d, J= 15.0 Hz, 1H), 4.52 (q, J= 7.1 Hz, 2H), 2.60 (s, 3H), 2.19 (s, 1H), 1.89 - 1.69 (m, 4H), 1.45 (t, J= 7.1 Hz, 3H), 1.37 -1.08 (m, 6H). m / z (ES+): [M+H]+= 307.

[0361] Stage 4: Synthesis of 30: (E)-5-((2-cyclohexylvinyl)thio)-4-methylpyrimidine-2-carboxvlic acid. General Procedure Al was used with 30.3 (27 mg, 0.09 mmol) to afford 30 (24 mg, 98% yield, 100% purity, retention time = 4.8 min (method B)) as a yellow oil. ’H NMR (300 MHz, CDCl3) 8 8.56 (s, 1H), 6.31 (dd, J = 15.0, 7.0 Hz, 1H), 6.05 (d, J = 14.9 Hz, 1H), 2.61 (s, 3H), 2.22 (s, 1H), 1.76 (dt, J= 23.4, 11.1 Hz, 4H), 1.24 (tt, J = 23.8, 12.0 Hz, 6H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 279.Synthesis of compound 31 (see Scheme 12):

[0362] Stage 1: Synthesis of 31.1: 2-(cyclobutylidenemethyl)-4, 4,5, 5-tetramethyl- 1,3,2-dioxaborolane. General procedure P was used with cyclobutanone (1.60 g, 22.37 mmol) to afford 31.1 (3.51 g, 78% yield, 96% purity, retention time = 3.2 min (method A)) as a colorless oil. Rf~ 0.5 (heptane / Et2O 9 / 1).1H NMR (300 MHz, CDCl3) 5 5.08 (p, J = 2.4 Hz, 1H), 2.91 (td, J= 8.2, 2.3 Hz, 2H), 2.76 (td, J= 7.9, 2.0 Hz, 2H), 1.95 (p, J = 7.9 Hz, 2H), 1.24 (s, 12H). m / z (ES+): [M+H]+= 195.

[0363] Stage 2: Synthesis of 31.2: sr>iro[3.3]he >tan-2-one. A solution ofN,N-dimethylacetamide (1.90 mL, 20.44 mmol, 1.18 eq) in anhydrous 1,2-DCE (67 mL) under Ar was cooled to -15 °C. Trifluoromethanesulfonic anhydride (4.10 mL, 23.88 mmol, 1.38 eq) was added drop wise within 10 min, and the reaction mixture was stirred for additional 15 min while the temperature was kept below 0 °C. A mixture of 31.1 (3.51 g, 17.36 mmol, 1.0 eq) and 2,6-lutidine (2.80 mL, 23.8 mmol, 1.37 eq) in anhydrous 1,2-DCE (9 mL) was added at once (CAUTION: exothermic reaction!). The reaction mixture was heated up to reflux for 16 h. The reaction, mixture was cooled to rt and the solvent was removed under reduced pressure. Et2O (30 mL) and a saturated solution of NaHCO3(30 mL) were added to the remaining mixture which was stirred for 2 h. The layers were separated and the aqueous layer was extracted with Et2O (3 x 30 mL). The combined organic layers were washed with 36% HClaq(~5 mL), water (3 x 10 mL) until neutral, dried over MgSO4, filtered and concentrated under reduced pressure (bath 20 °C, 200 mBar) to afford 31.2 (8.0 g, 17.43 mmol, 100% yield, 24% purity by1H NMR) as a brown solution. ’H NMR (300 MHz, CDCl3) 5 3.03 (d, J = 0.8 Hz, 4H), 2.19 (t, J = 7.4 Hz, 4H), 2.00 - 1.88 (m, 2H).

[0364] Stage 3: Synthesis of 31.3: ethyl 2-(s >iro[3.3]he >tan-2-ylidene)acetate. General Procedure QI was used with 31.2 (8.0 g, 17.43 mmol, 24% purity) to afford 31.3 (2.10 g, 61% yield, 92% purity, retention time = 3.12min (method A)) as a yellow oil. Rf~ 0.45 (heptane / Et2O 8 / 2). ’H NMR (300 MHz, CDCl3) 85.60 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.11 - 3.03 (m, 2H), 2.78 (q, J= 2.0 Hz, 2H), 2.10 - 1.99 (m, 4H), 1.89 - 1.76 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). m / z (ES+): [M+H]+= 181.

[0365] Stage 4: Synthesis of 31.4: 2-(spiro[3.3]heptan-2-ylidene)ethan-l-ol. General Procedure B2 was used with 31.3 (1.0 g, 5.1 mmol) to afford 31.4 (751 mg, 94% yield, 88% purity) as a yellow oil. Rf~ 0.25 (heptane / Et2O 1 / 1). ’H NMR (300 MHz, CDCl3) 8 5.41 - 5.32 (m, 1H), 4.00 (t, J = 6.0 Hz, 2H), 2.71 - 2.62 (m, 4H), 2.00 (t, J = 7.0 Hz, 4H), 1.87 - 1.74 (m, 2H), ’H exchanged with solvent.

[0366] Stage 5: Synthesis of 31.5: ethyl 4-methyl-5-(2-(spiro[3.3]heptan-2-ylidene)ethyl) >yrimidyl)thio)pyrimidine-2-carboxylate. General Procedure O was used between ethyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (50 mg, 0.20 mmol) and 31.4 (49 mg, 0.31 mmol, 88% purity, 1.53 eq) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 25 to 30% of “B” over 4.0 min, then increased linearly from 30 to 35% of “B” over 0.5 min, then increased linearly from 35 to 90% of “B” over 1.5 min, and returned to initial conditions over 1 min, 15 mL / min) affording 31.5 (30 mg, 52% yield, 100% purity, retention time = 4.8 min (method B)) as a colorless oil. ’H NMR (300 MHz, CDCl3) 8 8.52 (s, 1H), 5.18 - 5.07 (m, 1H), 4.49 (q, J= 7.1 Hz, 2H), 3.22 (dd, J= 7.0, 1.5 Hz, 2H), 2.59 (d, J= 10.5 Hz, 7H), 2.03 - 1.91 (m, 4H), 1.86 - 1.70 (m, 2H), 1.42 (t, 7 = 7.1 Hz, 3H). m / z (ES+): [M+H]+= 287.

[0367] Stage 6: Synthesis of 31: 4-methyl-5-(2-(spiro[3.31he >tan-2-ylidene)ethyl) >yrimidine-2-carboxylic acid. General Procedure Al was used with 31.5 (30 mg, 0.10 mmol) to afford 31 (15 mg, 55% yield, 99% purity, retention time = 4.3 min (method B)) as a yellow oil. ’H NMR (300 MHz, CDCl3) 8 8.59 (s, 1H), 5.16 (s, 1H), 3.29 (d, J = 7.1 Hz, 2H), 2.71 - 2.58 (m, 7H), 2.08 - 1.96 (m, 4H), 1.90 - 1.76 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 259.Synthesis of compound 32 (see Scheme 12):

[0368] Stage 1: Synthesis of 32.1: 2-cvclopentylacetaldehyde. 2-cyclopentylethanol (5.0 g, 41.6 mmol, 1.0 eq) was dissolved in anhydrous MeCN (230 mL) under Ar atmosphere and 2-iodoxybenzoic acid (36.0 g, 125.99 mmol, 3.03 eq) was added to the solution andthe suspension was heated to 80 °C under stirring for 3.5 h. The reaction mixture was cooled to rt and the suspension was filtered through celite, rinsed with DCM (5 x 100 mL). The filtrate was concentrated under reduced pressure (bath at 20°C, 20 mbar) to afford 32.1 (4.16 g, 30.04 mmol, 72% yield, 81% purity by ’H NMR) as yellow oil with yellow solid.

[0369] Stage 2: Synthesis of 32.2: ethyl (£’)-4-cyclopentylbut-2-enoate. General Procedure QI was used with 32.1 (800 mg, 5.78 mmol, 81% purity) to afford 32.2 (786 mg, 75% yield, 100% purity, retention time = 3.2 min (method A)) as a yellow oil. R / ~ 0.6 (heptane / Et2O 9 / 1).1H NMR (300 MHz, CDCl3) 5 6.95 (dt, J = 15.4, 7.2 Hz, 1H), 5.80 (dt, J= 15.6, 1.6 Hz, 1H), 4.18 (q, 7= 7.1 Hz, 2H), 2.25 - 2.15 (m, 2H), 1.94 (hept, J = 7.4 Hz, 1H), 1.82- 1.70 (m, 2H), 1.65 - 1.45 (m, 4H), 1.29 (t, 7= 7.1 Hz, 3H), 1.20 - 1.07 (m, 2H). m / z (ES+): [M+H]+= 183.

[0370] Stage 3: Synthesis of 32.3: (E)-4-cyclopentylbut-2-en-l-ol. General Procedure B2 was used with 32.2 (786 mg, 4.31 mmol) to afford 32.3 (581 mg, 92% yield, 96% purity by ’H NMR) as a colorless oil. Rf~ 0.25 (heptane / Et2O 1 / 1). ’H NMR (300 MHz, CDCl3) 5 5.70 (dt, 7 = 15.4, 5.9 Hz, 1H), 5.62 (dt, 7 = 15.2, 4.9 Hz, 1H), 4.09 (t, 7 = 5.1 Hz, 2H), 2.05 (t, 7= 6.3 Hz, 2H), 1.95 - 1.77 (m, 1H), 1.78 - 1.67 (m, 2H), 1.64 -1.45 (m, 4H), 1.18 - 1.06 (m, 2H).

[0371] Stage 4: Synthesis of 32.4: ethyl (E)-5-(4-cyclopentylbut-2-en-l-yl)-4-methylpyrimidyl)thio)pyrimidine-2-carboxylate. General Procedure O was used between ethyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (50 mg, 0.20 mmol) and 32.3 (36 mg, 0.25 mmol) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 50 to 55% of “B” over 8.0 min, then increased linearly from 55 to 90% of “B” over 1.0 min, returned to initial conditions over 1 min, 15 mL / min) followed by a chiral preparative HPLC (Chiralpak IE 5µm 20x150mm, mobile phase: TBME / EtOH 98 / 2, 7 mL / min) to afford 32.4 (24 mg, 42% yield, 100% purity, retention time = 5.3 min (method B)) as a yellow oil.1H NMR (300 MHz, CDCl3) 8 8.55 (s, 1H), 5.53 - 5.35 (m, 2H), 4.51 (q, 7= 7.2 Hz, 2H), 3.42 -3.29 (m, 2H), 2.59 (s, 3H), 2.05 - 1.96 (m, 2H), 1.88 - 1.72 (m, 1H), 1.72 - 1.38 (m, 9H), 1.13 - 0.97 (m, 2H). m / z (ES+): [M+H]+= 289.

[0372] Stage 5: Synthesis of 32: (E)-5-(4-cyclopcntylbut-2-cn-l-yl)-4-methylpyrimidine-2-carboxylic acid. General Procedure Al was used with 32.4 (24 mg, 0.08 mmol) to afford 32 (10 mg, 44% yield, 96% purity, retention time = 4.5 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 5 8.62 (s, 1H), 5.56 - 5.39 (m, 2H), 3.49 - 3.33 (m, 2H), 2.63 (s, 3H), 2.10 - 2.01 (m, 2H), 1.86 - 1.76 (m, 1H), 1.75 - 1.47 (m, 6H), 1.15 - 1.03 (m, 2H), 1H exchanged with solvent. m!z (ES+): [M+H]+= 261.Synthesis of compound 33:Scheme 14: Synthesis of compound 33

[0373] Stage 1: Synthesis of 33.1: l-(4-methyl-2-(methyhhio)pyrimidin-5-yl)ethan-l-one. To a stirred solution of 5-bromo-2-(methylthio)pyrimidine (1.50 g, 7.17 mmol, 1.0 eq) and tributyl(l -ethoxy vinyl) stannane (3.0 mL, 8.44 mmol, 1.18 eq) in anhydrous and degassed 1,4-dioxane (18 mL, 0.4 M) was added bis(triphenylphosphine)palladium(II) chloride (360 mg, 0.5 mmol, 7 mol%). The reaction was stirred at 110 °C (pre-heated bath) for 16 h. The reaction mixture was cooled to rt, 4 M HC1 (25 mL, 100 mmol, 13.95 eq) was added and the mixture was stirred at rt for 1 h. The reaction mixture wasfiltered over cotton and rinsed with water (20 mL) and heptane (20 mL). To the filtrate was added heptane (20 mL), the layers were separated and the aqueous layer was basified with NaHCO3solid (until pH~9). The mixture was extracted with EtOAc (2 x 70 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give the crude product which was purified by silica gel flash chromatography (heptane / EtOAc 100 / 0 to 50 / 50) to afford 33.1 (382 mg, 31% yield, 99% purity, retention time = 2.4 min (method A)) as a white solid. Rf~ 0.3 (heptane / EtOAc 1 / 1). ’H NMR (300 MHz, CDCl3) 5 8.99 (s, 2H), 2.62 (s, 3H), 2.59 (s, 3H). m / z (ES+):[M+H]+= 169.

[0374] Stage 2: Synthesis of 33.2: (E)-3-cyclopentyl-l-(2-(methylthio)pyrimidin-5-i-2-en-l-one. To a solution of 33.1 (312 mg, 1.85 mmol, 1.0 eq) and cyclopentanecarboxaldehyde (420 pL, 3.74 mmol, 2.01 eq) in methanol (9 mL) at 0 °C under Ar was added pyrrolidine (190 pL, 2.28 mmol, 1.23 eq). After 10 min, the reaction was allowed to stir at rt for 3.5 h. The mixture diluted with water (75 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (heptane / EtOAc 100 / 0 to 88 / 12) to afford 33.2 (173 mg, 36% yield, 95% purity, retention time = 3.1 min (method A)) as an orange solid. Rf~ 0.25 (heptane / EtOAc 9 / 1). ’H NMR (300 MHz, CDCl3) 5 8.98 (s, 2H), 7.10 (dd, J= 15.3, 8.2 Hz, 1H), 6.72 (d, J= 15.2 Hz, 1H), 2.80 - 2.66 (m, 1H), 2.62 (s, 3H), 1.99 - 1.83 (m, 2H), 1.80 - 1.58 (m, 4H), 1.55 - 1.38 (m, 2H). m / z (ES+): [M+H]+= 249.

[0375] Stage 3: Synthesis of 33.3: (E)-5-(3-cyclopentyl-l,l-difluoroallyl)-2- (methvlthio)pvrimidine. 33.2 (154 mg, 0.62 mmol, 1.0 eq) was added to DAST (300 pL, 2.16 mmol, 3.48 eq) at 0 °C under Ar. To this suspension was added ethanol (5 pL, 0.09 mmol, 0.14 eq) (1 drop). Then the reaction was stirred at 60 °C for 29 h and 2ndaddition of DAST (300 pL, 2.16 mmol, 3.48 eq) was carried out. Then, after 60 h at 60 °C, a 3rdaddition of DAST (200 pL, 1.44 mmol, 2.32 eq) was carried out and the reaction was stirred at 60 °C for 72 h. The reaction was cooled to 0 °C and carrefully quenched with a saturated aqueous solution of NH4CI (10 mL). The mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (10 mL), driedover MgSO4, filtered and concentrated under vacuo to give the crude product as brown oil which was purified by flash chromatography on silica gel (heptane / EtOAc 100 / 0 to 93 / 7) to afford 33.3 (50 mg, 26% yield, 86% purity, retention time = 3.3 min (method A)) as a brown oil. Rf~ 0.5 (heptane / EtOAc 9 / 1).1H NMR (300 MHz, CDCl3) 88.61 (s, 2H), 6.07 - 5.90 (m, 1H), 5.85 - 5.65 (m, 1H), 2.59 (s, 4H), 1.82 (d, J= 5.3 Hz, 2H), 1.73 -1.55 (m, 4H), 1.38 - 0.98 (m, 2H).19F NMR (282 MHz, CDCl3) 8 -87.09 (d, J= 9.1 Hz). m / z (ES+): [M+H]+= 271.

[0376] Stage 4: Synthesis of 33.4: (E)-5-(3-cyclopentyl-l,l-difhioroallyl)-2-(methylsulfonyl)pyrimidine. General procedure L2 was used with 33.3 (50 mg, 0.16 mmol, 86% purity) to afford 33.4 (44 mg, 68% yield, 74% purity by ’H NMR, retention time = 2.9 min (method A)) as a greenish oil.1H NMR (300 MHz, CDCl3) 8 9.02 (s, 2H), 6.05 (ddt, J= 15.6, 7.6, 2.6 Hz, 1H), 5.79 (dt, J= 15.8, 9.6 Hz, 1H), 3.40 (d, J= 2.2 Hz, 3H), 2.65 - 2.44 (m, 1H), 1.93 - 1.78 (m, 2H), 1.63 (dddt, J= 15.8, 12.4, 8.4, 3.9 Hz, 4H), 1.46 - 1.19 (m, 2H).19F NMR (282 MHz, CDCl3) 8 -88.19 (d, J= 9.4 Hz). m / z (ES+): [M+H]+= 303.

[0377] Stage 5: Synthesis of 33.5: (E)-5-(3-cvclopentyl-l,l-difhioroallyl)pyrimidine-2-carbonitrile To a solution of 33.4 (44 mg, 0.11 mmol, 1.0 eq) in anhydrous MeCN (380 pL) and DMSO (80 pL) under Ar was added NaCN (25 mg, 0.5 mmol, 4.64 eq). The reaction mixture was stirred at rt under Ar for 2.5 h. Reaction mixture was diluted with EtOAc (15 mL) and quenched with NaHCO3saturated solution (lOmL). Aqueous layer was extracted with EtOAc (10 mL). Organic layers were merged, washed with water (10 mL), brine (5 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford a crude product which was purified by flash chromatography on silica gel (heptane / EtOAc 100 / 0 to 90.5 / 8.5) to afford 33.5 (11 mg, 35% yield, 85% purity, retention time = 3.1 min (method A)) as a brown oil. Rf~ 0.5 (heptane / EtOAc 9 / 1). ’H NMR (300 MHz, CDCl3) 8 8.95 (s, 2H), 6.07 (ddt, J= 15.6, 7.6, 2.6 Hz, 1H), 5.76 (dt, J = 15.5, 10.1 Hz, 1H), 2.62 -2.48 (m, 1H), 1.92- 1.76 (m, 2H), 1.74- 1.57 (m, 4H), 1.40 - 1.20 (m, 2H).19F NMR (282 MHz, CDCl3) 8 -88.82 (d, J= 9.6 Hz), m / z (ES+): [M+H]+= 250.

[0378] Stage 6: Synthesis of 33.6: ethyl (E)-5-(3-cyclopentyl-l,l-:-2-carboxylate General procedure F was used with 33.5 (11 mg, 0.04 mmol, 85% purity) to afford 33.6 (5 mg, 36% yield, 81% purity, retention time = 3.0 min (method A)) as a pale brown oil.1H NMR (300 MHz, CDCl3) 89.02 (s, 2H), 5.99 (ddt, J= 15.6, 7.6, 2.6 Hz, 1H), 5.79 (dt, J= 15.5, 10.1 Hz, 1H), 4.57 (q, J= 7.1 Hz, 2H), 2.61 - 2.47 (m, 1H), 1.89 - 1.74 (m, 2H), 1.72 - 1.52 (m, 4H), 1.48 (t, J= 7.1 Hz, 3H), 1.38 - 1.21 (m, 2H).19F NMR (282 MHz, CDCl3) 8 -88.32 (d, J = 9.3 Hz), m / z (ES+):[M+H]+= 297.

[0379] Stage 7: Synthesis of 33: (£’)-5-(3-cyclopentyl-l,l-difluoroallyl)pyrimidine-2-carboxylic acid. General Procedure Al was used with 33.6 (5 mg, 0.01 mmol) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XB ridge OBD C185 pm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 40 to 50% of “B” over 5.0 min, then increased linearly from 50 to 85% of “B” over 2.0 min, and returned to initial conditions over 1 min, 15 mL / min) affording 33 (3.8 mg, 100% yield, 98% purity, retention time = 4.3 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 89.10 (s, 2H), 6.18 - 6.00 (m, 1H), 5.90 - 5.68 (m, 1H), 2.67 - 2.52 (m, 1H), 1.93 - 1.78 (m, 2H), 1.71 - 1.50 (m, 4H), 1.38 - 1.30 (m, 2H), 1H exchanged with solvent.19F NMR (282 MHz, CDCl3) 8 -88.36 (d, J= 10.7 Hz), m / z (ES+): [M+H]+= 269.Synthesis of compound 34 (see Scheme 12):

[0380] Stage 1: Synthesis of 34.1: ethyl 5-(3-cyclopentylpropyl)-4-methylpyrimidine-2-carboxylate General Procedure O was used (2.55 eq of alcohol, 3.20 eq of deoxazole and pyridine were used) between ethyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (135 mg, 0.54 mmol) and 3-cyclopentyl-l -propanol (180 mg, 1.38 mmol, 2.55 eq) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 60 to 65% of “B” over 5.0 min, then increased linearly from 65 to 95% of “B” over 1.0 min, held for 10 min, then returned to initial conditions over 0.5 min, 15 mL / min) to afford 34.1 (98 mg, 65% yield, 99% purity,retention time = 3.0 min (method A)) as a colorless oil. ’H NMR (300 MHz, CDCl3) 8 8.55 (s, 1H), 4.52 (q, J= 7.2 Hz, 2H), 2.72 - 2.63 (m, 2H), 2.62 (s, 3H), 1.87 - 1.67 (m, 3H), 1.67 - 1.48 (m, 6H), 1.45 (t, 7= 7.1 Hz, 3H), 1.41 - 1.29 (m, 2H), 1.12 - 0.99 (m, 2H). m / z (ES+): [M+H]+= 277.

[0381] Stage 2: Synthesis of 34: 5-(3-cyclopentylpropyl)-4-methylpyrimidine-2-carboxylic acid. General Procedure Al was used with 34.1 (98 mg, 0.35 mmol) to afford 34 (67 mg, 75% yield, 99% purity, retention time = 4.3 min (method B)) as a white solid. ’H NMR (300 MHz, CDCl3) 88.63 (s, 1H), 2.70 (t, J= 7.8 Hz, 2H), 2.65 (s, 3H), 1.83 - 1.34 (m, 11H), 1.08 (d, J = 9.6 Hz, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 249.Synthesis of compound 35 (see Scheme 12):

[0382] Stage 1: Synthesis of 35.1: 3-cyclobutylpropan-l-ol. General Procedure 12 (reaction carried out for 20 h then Fieser’s work-up applied) was used with 3-cyclobutylpropanoic acid (3.71 g, 23.16 mmol, 80% purity) to afford 35.1 (2.67 g, 100% yield, 100% purity) as a colorless oil.1H NMR (300 MHz, CDCl3) 8 3.61 (t, J = 6.3 Hz, 2H), 2.26 (hept, 7= 7.5 Hz, 1H), 2.10 - 1.96 (m, 2H), 1.95 - 1.70 (m, 2H), 1.70 - 1.53 (m, 2H), 1.53 - 1.40 (m, 5H).

[0383] Stage 2: Synthesis of 35.2: 3-cyclobutylpropanal. General Procedure S was used with 35.1 (2.70 g, 21.52 mmol, 91% purity) to afford 35.2 (3.18 g, 99% yield, 75% purity by1H NMR) as a colorless oil. Rf~ 0.73 (heptane / EtOAc 1 / 1).1H NMR (300 MHz, CDCl3) 89.75 (q, 7 = 1.8 Hz, 1H), 2.37 - 2.30 (m, 2H), 2.30 - 2.17 (m, 1H), 2.11 - 1.98 (m, 2H), 1.94 - 1.83 (m, 1H), 1.75 - 1.49 (m, 5H).

[0384] Stage 3: Synthesis of 35.3: methyl (E)-5-cyclobutylpcnt-2-cnoatc. General Procedure Q2 was used with 35.2 (997 mg, 6.67 mmol, 75% purity) to afford 35.3 (1.13 g, 91% yield, 90% purity by1H NMR, retention time = 3.1 and 3.2 min) as a mixture of E / Z (ratio 82 / 18) isomers and as a light-yellow oil. Rf~ 0.57 (heptane / EtOAc 9 / 1). ’H NMR (300 MHz, CDCl3) 86.95 (dt, 7= 15.6, 7.0 Hz, 1H, E isomer), 6.22 (dt, 7 = 11.5, 7.6 Hz,0.18H, Z isomer), 5.80 (dt, J = 15.5, 1.6 Hz, 1H, E isomer), 5.77 - 5.72 (m, 0.18H, Z isomer), 3.72 (s, 3H, E isomer), 3.70 (s, 0.54H, Z isomer), 2.62 - 2.49 (m, 1H), 2.37 -2.17 (m, 2H), 2.17 - 1.95 (m, 5H), 1.95 - 1.69 (m, 5H), 1.69 - 1.47 (m, 7H).

[0385] Stage 4: Synthesis of 35.4: (E)-5-cvclobutylpent-2-en-l-ol. General Procedure B2 (reaction carried out at 1.5 h at 0 °C) was used with 35.3 (1.14 g, 6.1 mmol, 90% purity) to afford 35.4 (684 mg, 74% yield, 92% purity by1H NMR) as a mixture of E / Z (ratio 61 / 39) isomers and as a colorless oil. Rf~ 0.24 (heptane / EtOAc 9 / 1).

[0386] Stage 5: Synthesis of 35.5: ethyl (E)-5-(5-cvclobutyl >ent-2-en-l-yl)-4-methylpyrimidine-2-carboxylate General Procedure O was used between ethyl 5-bromo- 4-methyl-pyrimidine-2-carboxylate (100 mg, 0.40 mmol) and 35.4 (106 mg, 0.70 mmol, 1.74 eq) to afford a crude material which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 60 to 65% of “B” over 5.0 min, then increased linearly from 65 to 95% of “B” over 1.0 min, held for 10 min, then returned to initial conditions over 0.5 min, 15 mL / min) to afford 35.5 (17 mg, 15% yield, 100% purity, retention time = 5.4 min (method B)) as a colorless oil.1H NMR (300 MHz, CDCl3) 5 8.55 (s, 1H), 5.53 - 5.35 (m, 2H), 4.52 (q, J= 7.1 Hz, 2H), 3.43 -3.31 (m, 2H), 2.67 - 2.56 (m, 3H), 2.19 (h, J = 7.8 Hz, 1H), 2.04 - 1.86 (m, 4H), 1.86 -1.69 (m, 2H), 1.63 - 1.50 (m, 2H), 1.49 - 1.35 (m, 5H). m / z (ES+): [M+H]+= 289.

[0387] Stage 6: Synthesis of 35: (E)-5-(5-cvclobutyl >ent-2-en-l-yl)-4- -2-carboxylic acid. General Procedure Al (carried out with 8 16 eq of LiOH) was used with 35.5 (17 mg, 0.06 mmol) to afford 35 (14 mg, 88% yield, 96% purity, retention time = 4.6 min (method B)) as a white solid.1H NMR (300 MHz, CDCl3) 58.64 (s, 1H), 5.46 (t, J = 4.0 Hz, 2H), 3.40 (d, 7 = 3.6 Hz, 2H), 2.62 (s, 3H), 2.29 - 2.10 (m, 1H), 2.07 - 1.88 (m, 4H), 1.88 - 1.67 (m, 2H), 1.63 - 1.47 (m, 2H), 1.47 - 1.32 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 261.Synthesis of compound 36 (see Scheme 12):

[0388] Stage 1: Synthesis of 36.1: ethyl (E)-4-methyl-5-(5-methylhex-2-en-l-:-2-carboxylate General Procedure O was used between (E)-5-mcthylhcx- 2-en-l-ol (100 mg, 0.77 mmol) and ethyl 5-bromo-4-methyl-pyrimidine-2-carboxylate (100 mg, 0.40 mmol) to afford crude product which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 60 to 65% of “B” over 5 min, then increased linearly from 65 to 95% of “B” over 1 min, returned to initial conditions over 1.5 min, 15 mL / min) affording 36.1 (16 mg, 15% yield, 97% purity, retention time = 4.9 min (method B)) as yellow oil. ’H NMR (300 MHz, CDCl3) 5 8.56 (s, 1H), 5.56 - 5.34 (m, 2H), 4.51 (q, 2H), 3.37 (d, J= 4.5 Hz, 2H), 2.60 (s, 3H), 1.95 - 1.85 (m, 2H), 1.57 (hept, J = 6.6 Hz, 1H), 1.44 (t, J= 0.8 Hz, 3H), 0.84 (d, J= 6.6 Hz, 6H). m / z (ES+): [M+H]+= 263.

[0389] Stage 2: Synthesis of 36: (E)-4-methyl-5-(5-methylhex-2-en-l-yl)pyrimidine-2-carboxylic acid. General Procedure Al (carried out with 9.67 eq of LiOH) was used with 36.1 (16 mg, 0.06 mmol) to afford 36 (15 mg, 100% yield, 97% purity, retention time = 4.1 min (method B)) as white solid. ’H NMR (300 MHz, CDCl3) 8 8.64 (s, 1H), 5.56 - 5.37 (m, 2H), 3.42 (d, J= 3.6 Hz, 2H), 2.63 (s, 3H), 1.96 - 1.87 (m, 2H), 1.59 (hept, J = 6.7 Hz, 1H), 0.85 (d, J = 6.6 Hz, 6H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 235.Synthesis of compound 37 (see Scheme 8):

[0390] Stage 1: Synthesis of 37.1: (E)-2-(3-cyclobutyl )ro )-l-en-l-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane General procedure P was used with 22.2 (509 mg, 3.79 mmol) to afford 37.1 (447 mg, 53% yield, 100% purity by1H NMR, retention time = 3.4 min (method A)) as yellow oil. Rf~ 0.85 (pcntanc / Et2O 8 / 2). m / z (ES+): [M+H]+= 223.

[0391] Stage 2: Synthesis of 37.2: (E)-(3-iodoallyl)cyclobutane. To a solution of compound 37.1 (447 mg, 2.01 mmol, 1.0 eq) in THF (21 mL) were added a solution ofNaOHaq 3.0 M (2 mL, 6 mmol, 2.98 eq). After 30 min, iodine (1.02 g, 4.02 mmol, 2.00 eq) was added portion wise (exothermic) over 1 min to the reaction mixture and was stirred at rt for 4 h. A saturated aqueous solution of Na2SiCh (50 mL) was added followed by heptane (50 mL). The layers were separated and the aqueous layer was extracted with heptane (2 x 25 mL). The combined organic layers were washed with a mixture 1.0 M aqueous solution of sorbitol in a 1.0 M aqueous Na2CO3solution (3 x 50 mL), brine (20 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to afford 37.2 (370 mg, 83% yield, 100% purity by1H NMR, retention time = 3.4 min (method D)) as a dark orange liquid.1H NMR (300 MHz, CDCl3) 86.44 (dt, J = 14.3, 7.1 Hz, 1H), 5.95 (d, J= 14.3 Hz, 1H), 2.36 (p, J= 7.7 Hz, 1H), 2.13 (t, J= 7.3 Hz, 2H), 2.09 - 1.98 (m, 2H), 1.94 - 1.76 (m, 2H), 1.68 - 1.57 (m, 2H). m / z (ES+): [M+H]+= no signal

[0392] Stage 3: Synthesis of 37.3: ethyl 5-((3-ethoxy-3-oxopropyl)thio)-4-methylpyrimidine-2-carboxylate. To a solution of ethyl 5-bromo-4-methylpyrimidine-2-carboxylate (270 mg, 1.10 mmol, 1.0 eq) and K2CO3 (171 mg, 1.22 mmol, 1.11 eq) in anhydrous DMF (4 mL) under Ar was added ethyl 3-mercaptopropionate (145 pL, 1.11 mmol, 1.01 eq) (dropwise over 2 min). After stirring at rt for 8 h, water (40 mL) was added and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (4 x 30 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 37.3 (340 mg, 92% yield, 89% purity by1H NMR, retention time = 2.6 min (method A)) as a pale yellow solid. Rf~ 0.20 (heptane / EtOAc 1 / 1). ’H NMR (300 MHz, CDCl3) 8 8.60 (s, 1H), 4.53 (q, J = 7.1 Hz, 2H), 4.18 (q, J= 7.1 Hz, 2H), 3.31 (t, J= 7.2 Hz, 2H), 2.71 (t, J= 7.1 Hz, 2H), 2.64 (s, 3H), 1.46 (t, J= 7.1 Hz, 3H), 1.27 (t, J= 7.1 Hz, 3H). m / z (ES+): [M+H]+= 299.

[0393] Stage 4: Synthesis of 37.4: sodium 2-(ethoxycarbonyl)-4-methylpyrimidine-5-thiolate. A solution of 37.3 (340 mg, 1.01 mmol, 1.0 eq) in anhydrous THF (2 mL) was cooled to 0 °C. Sodium ethoxide (540 pL, 1.4 mmol, 1.38 eq) was added dropwise over 5 min. The resulting mixture was stirred at 0 °C for 5 min and then at rt for 45 min. The reaction was concentrated under vacuum (bath 30 °C). To the residue was added DCM (5 mL). The yellow suspension was sonicated (5 min) and filtered. The yellow solid wasrinsed with DCM (5 mL) and pentane (1 mL) dried at rt under high vacuum to afford 37.4 (205 mg, 92% yield, 55% purity, retention time = 2.6 min (method A)), m / z (ES+):[M+H]+= 199.

[0394] Stage 5: Synthesis of 37.5: ethyl (E)-5-((3-cyclobutyl )ro )-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylate General procedure R was used between 37.4 (100 mg, 0.25 mmol, 55% purity) and 37.2 (164 mg, 0.74 mmol, 2.96 eq) to afford 37.5 (24 mg, 29% yield, 100% purity (method B and1H NMR), retention time = 5.35 min (method B)) as yellow solid. Rf~ 0.26 (heptane / EtOAc 7 / 3). ’H NMR (300 MHz, CDCl3) 8 8.54 (s, 1H), 6.21 (dt, J= 14.9, 6.8 Hz, 1H), 6.02 (dt, J= 14.9, 1.2 Hz, 1H), 4.51 (q, 7= 7.1 Hz, 2H), 2.59 (s, 3H), 2.51 - 2.36 (m, 1H), 2.36 - 2.27 (m, 2H), 2.18 - 2.01 (m, 2H), 1.96 -1.76 (m, 2H), 1.74- 1.59 (m, 2H), 1.44 (t, 7= 7.2 Hz, 3H). m / z (ES+): [M+H]+= 293.

[0395] Stage 6: Synthesis of 37: (E)-5-((3-cyclobutyhJro >-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid. General Procedure Al was used with 37.5 (24 mg, 0.08 mmol) to afford 37 (19 mg, 85% yield, 97% purity, retention time = 4.5 min (method B)) as white solid. ’H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 6.27 (dt, 7= 13.9, 6.7 Hz, 1H), 6.06 (d, 7= 14.9 Hz, 1H), 2.61 (s, 3H), 2.52 - 2.41 (m, 1H), 2.40 - 2.29 (m, 2H), 2.19-2.02 (m, 2H), 2.00- 1.79 (m, 2H), 1.78 - 1.60 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 265.Synthesis of compound 38 (see Scheme 12):

[0396] Stage 1: Synthesis of 38.1: ethyl (E)-4-(l-methylcyclopropyl)but-2-enoate. General Procedure QI was used with 2-(l-methylcyclopropyl)acetaldehyde (430 mg, 3.72 mmol) to afford 38.1 (245 mg, 39% yield, 100% purity by1H NMR, retention time = 3.0 min) as colorless oil. Rf~ 0.70 (heptane / EtOAc 9 / 1). ’H NMR (300 MHz, CDCl3) 86.97 (dt, 7 = 15.7, 7.2 Hz, 1H), 5.85 (d, 7 = 15.6 Hz, 1H), 4.19 (q, 7 = 7.1 Hz, 2H), 2.11 (dd, 7 = 7.2, 1.2 Hz, 2H), 1.30 (t, 7= 7.1 Hz, 3H), 1.03 (s, 3H), 0.40 - 0.26 (m, 4H). m / z (ES+): [M+H]+= 169.

[0397] Stage 2: Synthesis of 38.2: (£’)-4-(l-methylcyclopropyl)but-2-en-l-ol. General procedure B was used with 38.1 (245 mg, 1.46 mmol) (DIBAL-H in hexanes solution (IM) was used instead of DIBAL-H in DCM solution) to afford 38.2 (170 mg, 92% yield, 100% purity by ’H NMR) as colorless oil. Rf~ 0.15 (heptane / EtOAc 9 / 1). ’H NMR (300 MHz, CDCl3) 5 5.80 - 5.58 (m, 2H), 4.11 (t, J = 5.1 Hz, 2H), 1.97 (d, J= 5.5 Hz, 2H), 1.27 (t, J= 5.8 Hz, 1H), 1.01 (s, 3H), 0.35 - 0.19 (m, 4H).

[0398] Stage 3: Synthesis of 38.3: ethyl (E)-4-methyl-5-(4-(l-methylcyclopro >yl)but-2-:-2-carboxylate General Procedure O (reaction carried out with 1.0 eq of deoxazole, alcohol and pyridine, 1.50 eq of 5-bromopyrimidine, 1.5 mol% of Iridum complex, and 5.1 mol% of nickel complex for 5 h) was used with 38.2 (60 mg, 0.48 mmol) and ethyl 5-bromo-4-methylpyrimidine-2-carboxylate (178 mg, 0.48 mmol) to give the crude product which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 60 to 65% of “B” over 5 min, then increased linearly from 65 to 95% of “B” over 1 min, returned to initial conditions over 1.5 min, 15 mL / min) affording 38.3 (12 mg, 8% yield, 97% purity, retention time = 4.9 min (method B)) as colorless oil.1H NMR (300 MHz, CDCl3) 8 8.57 (s, 1H), 5.59 - 5.38 (m, 2H), 4.52 (q, J= 7.2 Hz, 2H), 3.45 - 3.36 (m, 2H), 2.61 (s, 3H), 1.93 (d, J= 5.4 Hz, 2H), 1.45 (t, J= 7.2 Hz, 3H), 0.96 (s, 3H), 0.34 - 0.16 (m, 4H). m / z (ES+): [M+H]+= 275.

[0399] Stage 4: Synthesis of 38: (E)-4-methyl-5-(4-( l-methylcyclopropyl)but-2-en- 1-:-2-carboxylic acid. General Procedure A was used with 38.3 (12 mg, 0.04 mmol) to afford 38 (11 mg, 100% yield, 95% purity, retention time = 4.1 min (method B)) as white solid. ’H NMR (300 MHz, CDCl3) 8 8.64 (s, 1H), 5.61 - 5.42 (m, 2H), 3.55 - 3.36 (m, 2H), 2.64 (s, 3H), 1.96 (d, J = 4.5 Hz, 2H), 0.98 (s, 3H), 0.35 - 0.15 (m, 4H). m / z (ES+): [M+H]+= 247.Synthesis of compound 39 (see Scheme 12):

[0400] Stage 1: Synthesis of 39.1: ethyl (£’)-4-methyl-5-(4-phenylbut-2-en-l-yl)PVrimidinc-2-carboxylatc. General procedure O (reaction carried out with 1.0 eq of deoxazole, alcohol and pyridine, 1.50 eq of ethyl 5-bromo-4-methylpyrimidine-2-carboxylate, 1.0 mol% of Iridum complex, and 5.6 mol% of nickel complex for 68 h) was used between (£’)-4-phenylbut-2-en-l-ol (206 mg, 1.35 mmol) and ethyl 5-bromo-4-methylpyrimidine-2-carboxylate (507 mg, 2.03 mmol) to give the crude product which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 60 to 65% of “B” over 5 min, then increased linearly from 65 to 95% of “B” over 1 min, returned to initial conditions over 0.5 min, 15 mL / min) affording 39.1 (45 mg, 11% yield, 100% purity, retention time = 2.8 min (method A)) as colorless oil.1H NMR (300 MHz, CDCl3) 58.57 (s, 1H), 7.34 - 7.09 (m, 5H), 5.72 - 5.48 (m, 2H), 4.52 (q, J= 7.2 Hz, 2H), 3.39 (dd, J= 15.4, 6.0 Hz, 4H), 2.59 (s, 3H), 1.45 (t, J= 7.1 Hz, 3H). m / z (ES+): [M+H]+= 297.

[0401] Stage 2: Synthesis of 39: (E)-4-mcthyl-5-(4-phcnylbut-2-cn-l-yl)pyrimidinc-2-carboxylic acid. General Procedure A was used with 39.1 (45 mg, 0.15 mmol) to afford 39 (32 mg, 79% yield, 100% purity, retention time = 4.0 (method B)) as white solid.1H NMR (300 MHz, CDCl3) 59.06 - 8.38 (bs, 1H), 8.68 (s, 1H), 7.36 - 7.07 (m, 5H), 5.68 (td, J= 15.1, 6.5 Hz, 1H), 5.57 (td, J= 15.6, 5.9 Hz, 2H), 3.45 (d, J= 5.8 Hz, 2H), 3.37 (d, J= 6.1 Hz, 2H), 2.62 (s, 3H). m / z (ES+): [M+H]+= 269.Synthesis of compound 40 (see Scheme 12):

[0402] Stage 1: Synthesis of 40.1: Ethyl (E)-3-(spiro[3.31heptan-2-yl)acrylate. General procedure QI was used with spiro[3.3]heptane-2-carbaldehyde (566 mg, 2.05 mmol, 45% purity) to afford 40.1 (172 mg, 41% yield, 95% purity by ’H NMR, retention time = 3.3 min (method A)). Rf~ 0.50 (heptane / Et2O 8 / 2). m / z (ES+): [M+H]+= 195.

[0403] Stage 2: Synthesis of 40.2: (E)-3-(spiro|3.3|hcptan-2-yl)prop-2-cn- 1 -ol. General procedure B was used with 40.1 (172 mg, 1.15 mmol) to give 40.2 (118 mg, 56% yield, 83% purity by ’H NMR). Rf~ 0.60 (pentane / Et2O 1 / 1). ’H NMR (300 MHz, CDCl3) 5 5.75 (ddd, J= 15.3, 6.9, 1.3 Hz, 1H), 5.53 (dtd, J= 15.3, 5.9, 1.3 Hz, 1H), 4.08 (d, J = 5.9 Hz, 2H), 2.76 (h, J= 8.1 Hz, 1H), 2.16 - 2.09 (m, 2H), 2.05 - 1.99 (m, 2H), 1.87 -1.72 (m, 7H), 1H exchanged with solvent.

[0404] Stage 3: Synthesis of 40.3: Ethyl (£’)-4-methyl-5-(3-(spiro[3.3]heptan-2-:-2-carboxylate General procedure O was used between 40.2 (118 mg, 0.64 mmol, 2.20 eq) and ethyl 5-bromo-4-methylpyrimidine-2-carboxylate (70 mg, 0.29 mmol) to afford the crude product which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 50 to 55% of “B” over 5.5 min, then increased linearly from 55 to 95% of “B” over 1.5 min, returned to initial conditions over 1 min, 15 mL / min). Fraction at tR~5.10 min was collected and purified by chiral preparative HPLC (Chiralpak IB 5pm 20x150mm, mobile phase: Hex / EtOH 95 / 5, 7 mL / min) to afford 40.3 (second peak collected at 5.86 min, 21 mg, 28% yield, 100% purity, retention time = 3.2 min (method A)) as a pale yellow oil. ’H NMR (300 MHz, CDCl3) 5 8.53 (s, 1H), 5.49 (dd, J = 15.4, 6.5 Hz, 1H), 5.35 (dt, J = 15.4, 5.9 Hz, 1H), 4.51 (q, 7 = 7.1 Hz, 2H), 3.34 (d, 7= 5.9 Hz, 2H), 2.82 - 2.62 (m, 1H), 2.58 (s, 3H), 2.16 - 2.02 (m, 2H), 2.02 - 1.91 (m, 2H), 1.88 - 1.63 (m, 6H), 1.44 (t, 7 = 7.2 Hz, 3H). m / z (ES+): [M+H]+= 301.

[0405] Stage 4: Synthesis of 40: (E)-4-methyl-5-(3-(spiro[3.3]heptan-2- 2- carboxylic acid. General procedure Al was used with 40.3 (21 mg, 0.07 mmol) to afford 40 (10 mg, 0.03 mmol) as a white solid (10 mg, 49% yield, 94% purity, retention time = 4.7 min (method B)).1H NMR (300 MHz, CDCl3) 58.58 (s, 1H), 5.55 (dd, 7= 15.4, 6.8 Hz, 1H), 5.37 (dt, 7= 14.8, 6.4 Hz, 1H), 3.39 (d, 7= 6.2 Hz, 2H), 2.84 - 2.67 (m, 1H), 2.61 (s, 3H), 2.20 - 2.06 (m, 2H), 2.06 - 1.93 (m, 2H), 1.87 - 1.69 (m, 6H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 273.Synthesis of compound 41 (see Scheme 12):

[0406] Stage 1: Synthesis of 41.1: 2-(l-fluorocyclobutyl)ethan- l-ol. To a solution of ethyl 2-(l-fhiorocyclobutyl)acetate (2.64 g, 15.49 mmol, 1.0 eq) in anhydrous THF (25 mL) at 0 °C was added to a suspension of LAH (894 mg, 23.56 mmol, 1.52 eq) in anhydrous THF (50 mL). The resulting solution was stirred at rt for 2 h. The reaction mixture was diluted with Et2O (70 mL) and cooled to 0 °C. Water (0.9 mL), 15 wt. % NaOHaq (0.9 mL) and water (2.7 mL) were successively added and allowed to warm to rt and stir for 15 min. MgSCL (20 g) was added and stirred at rt for 15 min. The suspension was filtered through Celite and rinsed with Et2O (3 x 50 mL). The filtrate was concentrated under reduced pressure (lOOmbar, 40 °C) to afford 41.1 (1.78 g, 93% yield, 96% purity by ’H NMR) as a colorless liquid. Rf~ 0.21 (heptane / EtOAc 98 / 2). ’H NMR (300 MHz, CDCl3) 53.82 (q, J= 6.0 Hz, 2H), 2.45 - 2.24 (m, 2H), 2.24 - 2.10 (m, 2H), 2.02 (dt, J = 24.5, 6.3 Hz, 2H), 1.94 - 1.74 (m, 2H), 1.72 - 1.64 (m, 1H), 1.60 - 1.44 (m, 1H).19F NMR (282 MHz, CDCl3) 5 -126.93 - -127.45 (m).

[0407] Stage 2: Synthesis of 41.2: 2-(l-fhiorocyclobutyl)acetaldehyde. General procedure S was used with 41.1 (1.98 g, 16.09 mmol) to afford 41.2 (2.21 g, 85% yield, 72% purity by1H NMR) as an orange liquid.1H NMR (300 MHz, CDCl3) 89.81 (t, J = 2.6 Hz, 1H), 2.80 (dd, J = 24.1, 2.6 Hz, 2H), 2.59 - 2.35 (m, 2H), 2.32 - 2.14 (m, 2H), 1.99 - 1.79 (m, 1H), 1.66 - 1.47 (m, 1H).19F NMR (282 MHz, CDCl3) 8 -125.01 - -125.49 (m).

[0408] Stage 3: Synthesis of 41.3: Methyl (E)-4-(l-fhiorocyclobutyl)but-2-enoate. General procedure Q2 was used with 41.2 (2.2 g, 13.64 mmol, 72% purity) to afford 41.3 (2.62 g, 100% yield, 90% purity by 1-H NMR, retention time = 2.8 min (method A)) as a mixture of E / Z isomers (ratio 65 / 35) as yellow oil.1H NMR (300 MHz, CDCl3, E isomer described) 86.96 (dt, J= 15.7, 7.3 Hz, 1H), 6.02 - 5.88 (m, 1H), 3.74 (s, 3H), 2.61 (dd, J =22.9, 7.3 Hz, 2H), 2.46-2.21 (m, 2H), 2.21 - 1.99 (m, 2H), 1.93 - 1.72 (m, 1H), 1.61 - 1.35 (m, 1H).19F NMR (282 MHz, CDCl3, E isomer described) 8 -125.93 - -126.41 (m). m / z (ES+): [M+H]+= 173.

[0409] Stage 4: Synthesis of 41.4: (E)-4-(l-fluorocyclobutyl)but-2-en-l-ol. General procedure B was used with 41.3 (2.62 g, 13.69 mmol, ratio E / Z: 65 / 35) to afford 41.4 (1.63 g, 81% yield, 98% purity, retention time = 2.5 min (method A)) as a mixture of EIZ isomers (ratio 63 / 37) as colorless oil.

[0410] Stage 5: Synthesis of 41.5: Ethyl (E)-5-(4-(l-fhrorocyclobutyl)but-2-en-l-yl)-4-methylpyrimidyl)thio)pyrimidine-2-carboxylate. General procedure O (reaction carried out for 20 h) was used between 41.4 (192 mg, 1.30 mmol, ratio E7Z: 63 / 37) and ethyl 5-bromo-4-methylpyrimidine-2-carboxylate (151 mg, 0.60 mmol) to afford the crude product which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: held at 40% during 5 min, increased linearly from 40 to 95% of “B” over 1 min, held at 95% during 4 min, returned to initial conditions over 1 min, 15 mL / min). to afford 41.5 (23 mg, 13% yield, 99% purity (method A)) as colorless oil.1H NMR (300 MHz, CDCl3) 5 8.57 (s, 1H), 5.68 - 5.42 (m, 2H), 4.51 (q, J = 7.2 Hz, 2H), 3.42 (d, J = 6.3 Hz, 1H), 2.60 (s, 3H), 2.42 (dd, J= 23.5, 6.5 Hz, 2H), 2.32 - 2.16 (m, 2H), 2.11 - 1.94 (m, 2H), 1.89 - 1.67 (m, 1H), 1.55 - 1.29 (m, 4H).19F NMR (282 MHz, CDCl3) 5 -126.21 - -126.71 (m). m / z (ES+): [M+H]+= 293.

[0411] Stage 6: Synthesis of 41: (E)-5-(4-(l-fhrorocyclobutyl)but-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid. General procedure Al was used with 41.5 (17 mg, 0.40 mmol) to afford 41 (16 mg, 90% yield, 88% purity (method B)) as a white solid.1H NMR (300 MHz, CDCl3) 8 8.65 (s, 1H), 5.71 - 5.46 (m, 2H), 3.46 (d, J = 5.5 Hz, 2H), 2.62 (s, 3H), 2.44 (dd, J= 23.6, 6.2 Hz, 2H), 2.37 - 2.15 (m, 2H), 2.14 - 1.95 (m, 2H), 1.92 - 1.68 (m, 2H), 1.53 - 1.32 (m, 2H), 1H exchanged with solvent.19F NMR (282 MHz, CDCl3) 8 -126.24 - -126.78 (m). m / z (ES+): [M+H]+= 265.

[0412] Synthesis of compound 42 (see Scheme 12):

[0413] Stage 1: Synthesis of 42.1: methyl (E)-4-(l-methylcvclobutyl)but-2-enoate. General procedure Q2 was used with 2-(l-methylcyclobutyl)acetaldehyde (1.23 g, 6.25 mmol, 57% purity) to afford 42.1 (660 mg, 56% yield, 89% purity by ’H NMR,retention time = 3.1 min (method A) as a mixture of E / Z isomers (ratio 83 / 17) as light yellow oil. Rf~ 0.63 (heptane / EtOAc 1 / 1). ’H NMR (300 MHz, CDCl3, E isomer described) 56.93 (dt, J= 15.4, 7.6 Hz, 1H), 5.89 - 5.78 (m, 1H), 3.73 (s, 3H), 2.28 (dd, J = 7.6, 1.4 Hz, 2H), 1.99 - 1.59 (m, 5H), 1.37 - 1.23 (m, 1H), 1.10 (s, 3H). m / z (ES+):[M+H]+= 169.

[0414] Stage 2: Synthesis of 42.2: (E)-4-(l-methylcyclobutyl)but-2-en-l-ol. General procedure B was used with 42.1 (660 mg, 89% purity, ratio E / Z: 83 / 17) to afford 42.2 (460 mg, 84% yield, 89% purity) as a mixture of E / Z isomers (ratio 83 / 17) as colorless oil. Rf~ 0.43 (heptane / EtOAc 7 / 3).

[0415] Stage 3: Synthesis of 42.3: Ethyl (E)-4-methyl-5-(4-(l-methylcyclobutyl)but-2-en-1-:-2-carboxylate General procedure O was used with 42.2 (192 mg, 1.22 mmol, 89% purity, ratio E / Z: 83 / 17, 2.0 eq) and ethyl 5-bromo-4-methylpyrimidine- 2-carboxylate (153 mg, 0.61 mmol) to afford the crude product which was purified by chiral preparative HPLC (Chiralpak IE 5µm 20x150mm, mobile phase: TBME / EtOH 99 / 1 + 0.1% DEA, 7 mL / min) to afford 42.3 (59 mg, 32% yield, 100% purity, retention time = 3.1 min (method A)) as colorless oil. ’H NMR (300 MHz, CDCl3) 88.54 (s, 1H), 5.55 - 5.32 (m, 2H), 4.49 (q, J = 7.2 Hz, 2H), 3.37 (d, J = 5.2 Hz, 2H), 2.58 (s, 3H), 2.07 (d, J = 5.9 Hz, 2H), 1.88 - 1.52 (m, 6H), 1.42 (t, J = 7.2 Hz, 3H), 0.99 (s, 3H). m / z (ES+):[M+H]+= 289.

[0416] Stage 4: Synthesis of 42: (E)-4-methyl-5-(4-(l-methylcyclobutyl)but-2-en-l-:-2-carboxylic acid. General procedure Al was used with 42.3 (59 mg, 0.20 mmol) to afford 42 (51 mg, 95% yield, 99% purity, retention time = 4.5 min (method B)) as crystalline solid.1H NMR (300 MHz, CDCl3) 88.66 (s, 1H), 7.48 (bs, 1H), 5.59 -5.38 (m, 2H), 3.44 (d, J = 4.3 Hz, 2H), 2.63 (s, 3H), 2.10 (d, J = 5.3 Hz, 2H), 1.92 - 1.56 (m, 6H), 1.03 (s, 3H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 261.Synthesis of compound 43 (see Scheme 11):

[0417] Stage 1: Synthesis of 43.1: (E)-2-(3-cyclopropylprop-l-en-l-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane. General procedure P was used with 2-cyclopropylacetaldehyde (1.15 g, 7.11 mmol, 52% purity) to afford 43.1 (276 mg, 19% yield) as colorless liquid. Rf~ 0.60 (heptane / Et₂O 9 / 1). ’H NMR (300 MHz, CDCl3) 8 6.70 (dt, J= 18.0, 6.0 Hz, 1H), 5.60 - 5.47 (m, 1H), 2.08 - 2.02 (m, 2H), 1.27 (s, 12H), 0.82 - 0.69 (m, 1H), 0.50 - 0.39 (m, 2H), 0.10 - 0.02 (m, 2H).

[0418] Stage 2: Synthesis of 43.2: (E)-(3-cyclopropylprop-l-cn-l-yl)boronic acid. General procedure N was used with 43.1 (276 mg, 1.33 mmol) to afford 43.2 (165 mg, 99% yield) as colorless oil.

[0419] Stage 3: Synthesis of 43.3: ethyl (E)-5-(4-cyclopropylbut-2-cn- l-yl)-4-methylpyrimidine-2-carboxylate General procedure K was used with 43.2 (165 mg, 1.31 mmol, 1.52 eq) and 20.6 (325 mg, 0.86 mmol) to afford 43.3 (116 mg, 51% yield, 98% purity, retention time = 2.8 min (method A)) as colorless oil. Rf~ 0.45 (heptane / EtOAc 1 / 1). ’H NMR (300 MHz, CDCl3) 8 8.58 (s, 1H), 5.63 - 5.44 (m, 2H), 4.53 (q, J= 7.1 Hz, 2H), 3.39 (d, J= 4.2 Hz, 2H), 2.62 (s, 3H), 1.93 (dd, J= 6.5, 4.5 Hz, 2H), 1.46 (t, J= 7.1 Hz, 3H), 0.76 - 0.60 (m, 1H), 0.50 - 0.37 (m, 2H), 0.09 - -0.03 (m, 2H). m / z (ES+): [M+H]+= 261.

[0420] Stage 4: Synthesis of 43: (E)-5-(4-cyclopropylbut-2-en-l-yl)-4- 2- carboxylic acid. General procedure Al was used with 43.3 (116 mg, 0.44 mmol) to afford 43 (100 mg, 96% yield, 97% purity, retention time = 3.8 min (method B)) as yellow solid.1H NMR (300 MHz, CDCl3) 88.63 (s, 1H), 5.66 - 5.46 (m, 2H), 3.44 (d, J= 4.1 Hz, 2H), 2.64 (s, 3H), 1.99 - 1.89 (m, 2H), 0.81 - 0.58 (m, 1H), 0.52 - 0.38 (m, 2H), 0.08 - -0.04 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 233.Synthesis of compound 44 (see Scheme 8):

[0421] Stage 1: Synthesis of 44.1: methyl 5-((3-ethoxy-3-oxopropyl)thio)pyrimidine-2-carboxylate To a solution of methyl 5-bromopyrimidine-2-carboxylate (500 mg, 2.26 mmol, 1.0 eq) and K2CO3 (350 mg, 2.51 mmol, 1.11 eq) in anhydrous DMF (8 mL) under Ar was added anhydrous ethyl 3-mercaptopropionate (300 pL, 2.3 mmol, 1.02 eq) (drop wise over 2 min). After stirring at rt for 3.5 h, water (40 mL) was added and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (4 x 30 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 44.1 (483 mg, 75% yield, 95% purity, retention time = 2.4 min (method A) as a white solid.1H NMR (300 MHz, CDCl3) 88.77 (s, 2H), 4.15 (q, J =7.1 Hz, 2H), 4.04 (s, 3H), 3.31 (t, 7 = 7.1 Hz, 2H), 2.68 (t, 7 = 7.1 Hz, 2H), 1.25 (t, 7= 7.1 Hz, 3H). m / z (ES+): [M+H]+= 271.

[0422] Stage 2: Synthesis of 44.2: sodium 2-(ethoxycarbonyl)pyrimidine-5-thiolate. To solution of 44.1 (483 mg, 1.7 mmol, 1.0 eq) in anhydrous THF (3.3 mL) at 0 °C was added sodium ethoxide (900 pL, 2.33 mmol, 1.37 eq - 20% solution in EtOH) dropwise over 5 min. The resulting mixture was stirred at 0 °C for 5 min and then at rt for 45 min. The reaction was concentrated reduced pressure. To the residue was added DCM (8 mL). The resulting yellow suspension was sonicated and filtered. The solid was rinsed with DCM (8 mL), pentane (2 mL), collected and dried at rt under high vacuum to give 44.2 (370 mg, 82% yield, 78% purity, retention time = 2.1 min (method A) as yellow solid, m / z (ES+): [M+H]+= 185.

[0423] Stage 3: Synthesis of 44.3: ethyl (E)-5-((3-cyclobutylprop-l-en-l-:-2-carboxylate General procedure R was used with 44.2 (100 mg, 0.38 mmol, 78% purity) and 37.2 (134 mg, 0.60 mmol, 1.57 eq) to afford 44.3 (61 mg, 56% yield, 97% purity, retention time = 3.0 (method A)) as white solid. Rf~ 0.50 (heptane / EtOAc 1 / 1). ’H NMR (300 MHz, CDCl3) 88.71 (s, 2H), 6.24 (dt, 7= 14.8, 6.8 Hz, 1H), 6.04 (d, 7= 14.8 Hz, 1H), 4.52 (q, 7= 7.1 Hz, 2H), 2.52 - 2.37 (m, 1H), 2.35 -2.27 (m, 2H), 2.17 - 2.01 (m, 2H), 2.00 - 1.75 (m, 2H), 1.75 - 1.63 (m, 2H), 1.46 (t, 7 = 7.1 Hz, 3H). m / z (ES+): [M+H]+= 279.

[0424] Stage 4: Synthesis of 44: (E)-5-((3-cyclobutylprop- 1-en- 1 -yl)thio)pyrimidine-2-carboxylic acid. General procedure Al was used with 44.3 (61 mg, 0.21 mmol) to give 44 (52 mg, 95% yield, 97% purity, retention time = 4.3 min (method B)) as white solid. ’H NMR (300 MHz, CDCl3) 58.79 (s, 2H), 7.88 (bs, 1H), 6.29 (dt, J= 14.0, 6.7 Hz, 1H), 6.08 (d, J= 14.8 Hz, 1H), 2.56 - 2.39 (m, 1H), 2.38 - 2.31 (m, 2H), 2.16 - 2.03 (m, 2H), 1.96 - 1.79 (m, 2H), 1.74 - 1.58 (m, 2H). m / z (ES+): [M+H]+= 251.Synthesis of compounds 45a and 45b (see Scheme 11):

[0425] Stage 1: Synthesis of 45.1: spiro[2.3]hexane-l-carbaldehyde. General procedure S was used with spiro[2.3]hexan-l-ylmethanol (1.0 g, 7.49 mmol, 84% purity) to give 45.1 (1.06 g, 100% yield, 78% purity by ‘H NMR) as colorless oil. Rf~ 0.75 (heptane / EtOAc 1 / 1).1H NMR (300 MHz, CDCl3) 59.07 (d, J= 5.5 Hz, 1H), 2.39 - 2.27 (m, 2H), 2.25 - 2.03 (m, 4H), 1.80 (dt, J= 8.3, 5.3 Hz, 1H), 1.41 (t app, J= 5.1 Hz, 1H), 1.23 (dd, J = 8.3, 5.0 Hz, 1H).

[0426] Stage 2: Synthesis of 45.2: (E)-4,4,5,5-tetramethyl-2-(2-(spiro[2.31hexan-l-yl)vinyl)- 1,3,2-dioxaborolane General procedure P (reaction carried out at •78 °C for 1 h) was used with 45.1 (1.06 g, 7.51 mmol, 78% purity) to afford 45.2 (942 mg, 50% yield, 94% purity, retention time = 3.4 min (method A)) as colorless oil. Rf~ 0.85 (pentane / Et2O 8 / 2). ’H NMR (300 MHz, CDCl3) 86.09 (dd, J= 17.8, 9.4 Hz, 1H), 5.42 (d, J = 17.9 Hz, 1H), 2.31 - 1.93 (m, 6H), 1.48 - 1.36 (m, 1H), 1.25 (s, 12H), 0.93 (dd, J = 8.5, 4.8 Hz, 1H), 0.66 (t app, J = 5.0 Hz, 1H). m / z (ES+): [M+H]+= 235.

[0427] Stage 3: Synthesis of 45.3: (£’)-(2-(spiro[2.3]hexan-l-yl)vinyl)boronic acid. General procedure N was used with 45.2 (942 mg, 3.78 mmol) to afford 45.3 (540 mg, 80% yield, 85% purity, retention time = 2.4 min (method A)) as yellow oil. m / z (ES+):[M+H]+= 153.

[0428] Stage 4: Synthesis of 45.4: ethyl (E)-4-methyl-5-(3-(spiro[2.3]hexan-l- carboxylate General procedure K was used between 45.3 (540 mg, 3.02 mmol, 1.52 eq, 85% purity) and 20.6 (750 mg, 1.99 mmol) to afford the crudeproduct which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: held at 40% during 5 min, increased linearly from 40 to 95% of “B” over 1 min, held at 95% during 4 min, returned to initial conditions over 1 min, 15 mL / min) to afford 45.4 (170 mg, 30% yield, 99% purity, retention time = 3.0 (method A)) as yellow oil. ‘H NMR (300 MHz, CDCl3) 88.56 (s, 1H), 5.48 (dt, J= 15.4, 6.4 Hz, 1H), 4.91 (dd, J = 15.4, 9.0 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 3.38 (dd, J = 6.4, 1.6 Hz, 2H), 2.60 (s, 3H), 2.13 - 1.89 (m, 6H), 1.44 (t, J= 7.2 Hz, 3H), 1.35 - 1.21 (m, 1H), 0.79 (dd, J= 8.7, 5.0 Hz, 1H), 0.39 (t app, J= 5.1 Hz, 1H). m / z (ES+): [M+H]+= 287. This racemic mixture was purified by chiral preparative HPLC (Chiralpak IA 5µm 20x150mm, mobile phase: TBME / MeOH / DEA 99 / 1 / 0.1, 7 mL / min) to afford enantiomer 45.4a (first peak collected at 5.6 min, 76 mg, 100% purity, retention time = 3.0 min (method A), chiral HPLC (IA) purity = 98.4%, ee > 96.8%) and enantiomer 45.4b (second peak collected at 6.3 min, 78 mg, 100% purity, retention time = 3.0 min (method A), chiral HPLC (IA) purity = 94.4%, ee > 93.7%) as a colorless oil.

[0429] Stage 5: Synthesis of 45a and 45b: (£)-4-methyl-5-(3-(sr>iro[2.31hexan-l-yl)allyl)pyrimidine-2-carboxylic acid. General procedure Al was used with enantiomer 45.4a (76 mg, 0.26 mmol) to afford enantiomer 45a (45 mg, 65% yield, 99% purity, retention time = 4.2 min (method B)) as white solid.1H NMR (300 MHz, CDCl3) 8 8.62 (s, 1H), 5.50 (dt, J= 15.4, 6.5 Hz, 1H), 4.98 (dd, J= 15.6, 9.0 Hz, 1H), 3.44 (d, J= 6.3 Hz, 2H), 2.64 (s, 3H), 2.19 - 1.91 (m, 6H), 1.34 - 1.21 (m, 1H), 0.83 (dd, J= 8.5, 4.9 Hz, 1H), 0.44 (t app, J= 5.1 Hz, 1H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 259.

[0430] General procedure Al was used with enantiomer 45.4b (79 mg, 0.27 mmol) to afford enantiomer 45b (49 mg, 68% yield, 99% purity, retention time = 4.2 min (method B)) as white solid. ’H NMR (300 MHz, CDCl3) 88.63 (s, 1H), 5.50 (dt, J= 15.5, 6.5 Hz, 1H), 4.97 (dd, J= 15.3, 9.1 Hz, 1H), 3.43 (d, J= 6.5 Hz, 2H), 2.64 (s, 3H), 2.16 - 1.93 (m, 6H), 1.36 - 1.19 (m, 1H), 0.83 (dd, J = 8.6, 5.0 Hz, 1H), 0.43 (t app, J = 5.2 Hz, 1H).1H exchanged with solvent, m / z (ES+): [M+H]+= 259.Synthesis of compound 46 (see Scheme 12):

[0431] Stage 1: Synthesis of 46.1: prop-2-yn-l-ylcyclobutane. To a suspension lithium acetylide, ethylenediamine complex (6.70 g, 65.49 mmol, 2.21 eq) in anhydrous THF (27 mL) and anhydrous DMSO (53 mL) under Ar atmosphere at 0 °C was added (bromomethyl)cyclobutane (3.40 mL, 29.65 mmol, 1.0 eq) over ~1 min. The reaction mixture was stirred at 0 °C for 10 min then at rt for 24 h. Reaction mixture was cooled to 0 °C, diluted with Et2O (100 mL), quenched slowly with brine (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with Et2O (2 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), brine (50 mL), dried over MgSCL. filtered and the filtrate was concentrated under reduced pressure to afford 46.1 (931 mg, 28% yield, 84% purity by ’H NMR) as a crude light yellow liquid.

[0432] Stage 2: Synthesis of 46.2: methyl 4-cyclobutylbut-2-ynoate. To a solution of 46.1 (1.41 g, 12.13 mmol, 1.0 eq, 81% purity) in anhydrous THF (16 mL) under Ar atmosphere at -78 °C was added n-butyl lithium (8.40 mL, 13.44 mmol, 1.11 eq - 1.6 M in hexane) over 5 min and was stirred at -78 °C for 1.25 h. Then methyl chloroformate (1.40 mL, 17.94 mmol, 1.48 eq) was added over 5 min at - 78 °C. The reaction mixture was stirred at -78 °C for 1.75 h and then allowed to stir at rt for 1.25 h. NH4CI saturated solution (20 mL) was added to the reaction mixture and was extracted with Et2O (30 mL). The organic layer was washed with NH4CI saturated solution (2 x 30 mL), brine (2 x 30 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 to 10% Et2O in pentane) to afford 46.2 (2.29 g, 68% yield, retention time = 2.90 (method A)) of a crude oil.1H NMR (300 MHz, CDCI3) 8 3.76 (s, 3H), 2.55 (hept, J = 7.5 Hz, 1H), 2.40 (d, J= 6.8 Hz, 2H), 2.18 - 2.03 (m, 2H), 1.92 - 1.71 (m, 4H).

[0433] Stage 3: Synthesis of 46.3: methyl (Z)-4-cyclobutyl-3-fluorobut-2-enoate. A mixture of 46.2 (950 mg, 9.27 mmol, 1.0 eq) and AgF (1.21 g, 9.27 mmol, 1.49 eq) in anhydrous MeCN (14 mL) under Ar atmosphere was stirred at 80 °C for 4.25 h. The reaction mixture was cooled to rt and NaHCO3saturated solution (15 mL) was added to afford a suspension which was extracted with Et2O (3 x 20 mL). The combined organiclayers were washed with water (3 x 20 mL), brine (30 mL), dried over MgSC and filtered over a paper filter. The filtrate was concentrated under reduced pressure to afford a yellow oil. The crude product was purified by flash chromatography on silica gel (0 to 10% Et2O in pentane) to afford 46.3 (393 mg, 35% yield, 97% purity by1H NMR, retention time = 2.9 min (method A)) as a pale yellow oil. Rf~ 0.40 (heptane / Et2O 8 / 2).1H NMR (300 MHz, CDCl3) 85.11 (d, J = 33.4 Hz, 1H), 3.71 (s, 3H), 2.57 (hept, 7 = 7.7 Hz, 1H), 2.35 (dd, J = 16.7, 7.4 Hz, 2H), 2.22 - 2.05 (m, 2H), 2.00 - 1.78 (m, 2H), 1.78 - 1.62 (m, 2H).19F NMR (282 MHz, CDCl3) 5 -75.41 (dt, 7= 33.6, 16.7 Hz), m / z (ES+): [M+H]+= 173.

[0434] Stage 4: Synthesis of 46.4: (Z)-4-cyclobutyl-3-fluorobut-2-en-l-ol. General procedure B was used with 46.3 (339 mg, 1.91 mmol) to afford 46.4 (272 mg, 92% yield, 93% purity by ’H NMR) as colorless oil. Rf~ 0.25 (heptane / EtOAc 7 / 3). ’H NMR (300 MHz, CDCl3) 54.78 (dt, 7= 36.9, 7.2 Hz, 1H), 4.25 - 4.15 (m, 2H), 3.41 (t, 7= 5.6 Hz, 1H), 2.51 (hept, 7= 7.7 Hz, 1H), 2.26 (dd, 7 = 16.9, 7.4 Hz, 2H), 2.17 - 2.01 (m, 2H), 1.99 - 1.76 (m, 2H), 1.76 - 1.62 (m, 2H).19F NMR (282 MHz, CDCl3) 5 -101.28 (dt, 7 = 35.6, 17.0 Hz).

[0435] Stage 5: Synthesis of 46.5: ethyl (Z)-5-(4-cyclobutyl-3-fluorobut-2-en-l-yl)-4-methylpyrimidine-2-carboxylate General procedure O was used between 46.4 (272 mg, 1.75 mmol, 2.03 eq) and ethyl 5-bromo-4-methylpyrimidine-2-carboxylate (214 mg, 0.86 mmol) to afford a crude product which purified by flash chromatography on silica gel (0 to 60% EtOAc in heptane) to afford 46.5 (49 mg, 15% yield, 78% purity, retention time = 4.79 (method B)). This was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 50 to 55% of “B” over 5 min, then increased linearly from 55 to 95% of “B” over 1 min, held at 95% during 10 min, returned to initial conditions over 0.5 min, 15 mL / min) affording 46.5 (39 mg, 15% yield, 100% purity, retention time = 2.93 (method A)) as colorless oil. ’H NMR (300 MHz, CDCl3) 8 8.53 (s, 1H), 4.52 (dt, 7= 35.7, 7.5 Hz, 3H), 4.49 (q, 7 = 7.1 Hz, 2H), 3.38 (d, 7= 7.5 Hz, 2H), 2.56 (s, 3H), 2.46 (dt, 7= 15.1, 7.5 Hz, 1H), 2.23 (dd, 7= 17.4, 7.4 Hz, 2H), 2.12 - 1.93 (m, 2H), 1.93 - 1.51 (m, 4H), 1.40 (t, 7 = 7.2 Hz, 3H).19F NMR (282 MHz, CDCl3) 8 -101.15 (dt, 7= 35.1, 16.8 Hz), m / z (ES+): [M+H]+= 293.

[0436] Stage 6: Synthesis of 46: (Z)-5-(4-cyclobutyl-3-fluorobut-2-en-l-yl)-4-;-2- carboxylic acid. General procedure Al was used with 46.5 (43 mg, 0.15 mmol) to afford 46 (34 mg, 84% yield, 96% purity, retention time = 4.1 min (method B)) as white solid.1H NMR (300 MHz, CDCl3) 58.66 (s, 1H), 7.76 (bs, 1H), 4.57 (dt, J = 35.6, 7.5 Hz, 1H), 3.46 (d, J= 7.5 Hz, 2H), 2.64 (s, 3H), 2.57 - 2.45 (m, 1H), 2.28 (dd, J = 17.4, 7.5 Hz, 2H), 2.16 - 1.98 (m, 2H), 1.95 - 1.75 (m, 2H), 1.73 - 1.58 (m, 2H).19F NMR (282 MHz, CDCl3) 5 -100.54 (dt, J = 33.4, 17.6 Hz), m / z (ES+): [M+H]+= 265.Synthesis of compound 47b (see Scheme 12):

[0437] Stage 1: Synthesis of 47.1: 4-cyclobutylbut-2-yn-l-ol. General procedure B was used with 46.2 (300 mg, 1.97 mmol) to afford 47.1 (169 mg, 66% yield, 95% purity by ’H NMR) as colorless oil. R / ~ 0.10 (heptane / Et2O 9 / 1). ’H NMR (300 MHz, CDCl3) 5 4.26 (dt, J= 6.1, 2.2 Hz, 2H), 3.41 (t, J= 5.8 Hz, 1H), 2.47 (hept, J= 7.4 Hz, 1H), 2.28 (dt, J= 6.9, 2.2 Hz, 2H), 2.14 - 1.97 (m, 2H), 1.96 - 1.64 (m, 4H).

[0438] Stage 2: Synthesis of 47.2: ethyl 5-(4-cyclobutylbuta-l,2-dien-l-yl)-4-methylpyrimidine-2-carboxylate General procedure O was used between 47.1 (169 mg, 1.29 mmol, 2.02 eq) and ethyl 5-bromo-4-methylpyrimidine-2-carboxylate (160 mg, 0.64 mmol) to afford the crude product which was purified by flash chromatography on silica gel (0 to 50% EtOAc in heptane) to afford 47.2 (47 mg, 25% yield, 93% purity, retention time = 3.0 min (method A)). This was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: held at 55% during 6 min, increased linearly from 55 to 60% of “B” over 1 min, increased linearly from 60 to 95% of “B” over 2 min, held at 95% during 2 min, decrease linearly from 95 to 40% of “B” over 1 min, 15 mL / min) to afford 47.2 (35 mg, 20% yield, 100% purity, retention time = 3.0 min (method A)) as yellow oil. ’H NMR (300 MHz, CDCl3) 58.68 (s, 1H), 6.18 (dt, J = 6.2, 3.0 Hz, 1H), 5.59 (q, J= 6.8 Hz, 1H), 4.48 (q, J= 7.1 Hz, 2H), 2.62 (s, 3H), 2.47 - 2.31 (m, 1H), 2.29 - 2.15 (m, 2H), 2.14 - 1.93 (m, 2H), 1.89 - 1.70 (m, 2H), 1.66 - 1.54 (m, 2H), 1.42 (t, J= 7.1 Hz, 3H). m / z (ES+): [M+H]+= 273.

[0439] Stage 3: Synthesis of 47b: 5-(4-cyclobutylbuta-l,2-dien-l-yl)-4-;-2- carboxylic acid. General procedure Al was used with 47.2 (17 mg, 0.06 mmol) to afford a crude product which was was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 40 to 50% of “B” over 6 min, increased linearly from 50 to 95% of “B” over 2 min, held at 95% during 2 min, decrease linearly from 95 to 40% of “B” over 1 min, 15 mL / min) to afford 47b (2.5 mg, 44% yield, 100% purity, retention time = 4.2 (method B)) as colorless oil.1H NMR (300 MHz, CDCl3) 5 8.75 (s, 1H), 6.23 (dt, J= 6.3, 3.2 Hz, 1H), 5.66 (q, J= 6.9 Hz, 1H), 2.67 (s, 3H), 2.43 (h, J= 7.7 Hz, 1H), 2.32 - 2.22 (m, 2H), 2.17 - 1.99 (m, 2H), 1.93 - 1.79 (m, 2H), 1.73 - 1.59 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 245.Synthesis of compounds 48a and 48b (see Scheme 11):

[0440] Stage 1: Synthesis of 48.1: (2-methylcvclopro >yl)methanol. General procedure 12 (work-up by default was applied) was used with 2-methylcyclopropane- 1 -carboxylic acid (2.51 g, 24.63 mmol) to afford 48.1 (1.81 g, 70% yield, 82% purity by ’H NMR) as a mixture of cis / trans isomers (ratio 15 / 85) as limpid liquid. Rf~ 0.60 (heptane / EtOAc 1 / 1).

[0441] Stage 2: Synthesis of 48.2: l-(bromomethyl)-2-methylcvclopror>ane. 48.1 (1.81 g, 17.23 mmol, 1.0 eq), imidazole (1.83 g, 26.88 mmol, 1.56 eq) and triphenylphosphine (7.0 g, 26.69 mmol, 1.55 eq) were dissolved in anhydrous DCM (65 mL). The reaction mixture was cooled to 0 °C and bromine (1.40 mL, 27.05 mmol, 1.57 eq) was added dropwise (over 5 minutes). The mixture was allowed to stir at rt for 17 h. Na2SiOs aqueous solution (13.5 mL - 2.0 M) was added and the mixture was stirred for 20 min. Water was added (40 mL) and the layers were separated. The organic layer was washed with brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. To the resulting solid was added heptane (60 mL). The mixture was sonicated (~3 min) and vigorously stirred for 5 min. The suspension was filtered and the solid was rinsed with pentane (20 mL). The filtrate was concentrated under vacuum to give a solid-liquid mixture. Pentane (20 mL) was added and the suspension was filtered over cotton wool. Filtrate was concentrated under vacuum to give 48.2 (1.47 g, 54% yield, 94% purity by1H NMR) as a mixture of cisltrans isomers (ratio 12 / 88) as orange limpid liquid.

[0442] Stage 3: Synthesis of 48.3: 2-(2-methylcyclopropyl)acetonitrile. 48.2 (1.47 g, 9.27 mmol, 1.0 eq) was added dropwise (over 3 minutes) to a suspension of NaCN (1.05 g, 21 mmol, 2.27 eq) in anhydrous DMSO (16 mL) at 60 °C under Ar. The mixture was stirred at 70 °C for 5 h and then at rt for 13h. The reaction was carefully poured onto crushed ice (25 mL). The mixture was stirred for 30 min and extracted with Et₂O (3 x 35 mL). The combined organic layers were washed with 6.0 N HClaqsolution (35 mL), NaHCO3saturated solution (35 mL), brine (20 mL), dried over MgSO4, filtered and the solvent was concentrated under vacuum (300 mbar, 30°C) to give 48.3 (671 mg, 72% yield, 95% purity by1H NMR) as a mixture of cisltrans isomers (ratio 20 / 80) as yellowish limpid liquid.1H NMR (300 MHz, CDCl3, trans isomer described) 52.43 - 2.28 (m, 2H), 1.06 (d, J= 5.7 Hz, 3H), 0.79 - 0.66 (m, 2H), 0.51 - 0.43 (m, 1H), 0.43 - 0.34 (m, 1H).

[0443] Stage 4: Synthesis of 48.4: 2-(2-methylcyclopropyl)acetaldehyde. To a solution of 48.3 (671 mg, 6.7 mmol, 1.0 eq) in anhydrous DCM (6.7 mL) at -78 °C was added diisobutylaluminium hydride (8 mL, 8 mmol, 1.19 eq - 1.0 M in hexane) dropwise. The reaction was stirred at -78 °C for 1 h, warmed to 0° C and stirred at this temperature for 3 h. The reaction mixture was then cooled to -20 °C, carefully quenched with a NH4CI saturated solution (15 mL), and stirred at -10 °C for 30 min. The reaction was warmed to rt, HClaq solution (~10 mL - 3 N) was added to acidify the mixture at pH ~ 1-2. The layers were separated. The aqueous phase was extracted with DCM (3 x 25 mL) and the combined organic phases were washed with brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure (400 mbar, 40 °C) to afford 48.4 (535 mg, 48% yield, 59% purity by1H NMR) as a mixture of cisltrans isomers (ratio 25 / 75) as a yellow liquid.1H NMR (300 MHz, CDCl3, trans isomer described) 5 9.78 (t, J = 2.1 Hz, 1H), 2.30 (td, J= 7.2, 2.1 Hz, 2H), 1.07 (d, J= 5.9 Hz, 3H), 0.72 - 0.62 (m, 1H), 0.62 - 0.50 (m, 1H), 0.38 - 0.31 (m, 2H).

[0444] Stage 5: Synthesis of 48.5: (E)-4,4,5,5-tetramethyl-2-(3-(2-i-l-en-l-yl) 1,3,2-dioxaborolane. General procedure P was usedwith 48.4 (535 mg, 3.22 mmol, 59% purity) to afford 48.5 (308 mg, 43 % yield, 100% purity, retention time = 3.4 min (method C)) as a mixture of cisl trans isomers (ratio 22 / 77) as yellowish oil. Rf~ 0.55 (heptane / Et₂O 9 / 1). ’H NMR (300 MHz, CDCl3, trans isomer described) 5 6.69 (dt, J = 18.0, 5.9 Hz, 1H), 5.52 (d, J = 18.0 Hz, 1H), 2.09 - 2.01 (m, 2H), 1.27 (s, 12H), 1.03 (d, J= 5.5 Hz, 3H), 0.91 - 0.81 (m, 1H), 0.54 - 0.40 (m, 1H), 0.28 - 0.12 (m, 2H). m / z (ES+): [M+H]+= 223.

[0445] Stage 6: Synthesis of 48.6: (E)-(3-(2-methylcyclopropyl)prop-1-en-1-yl)boronic acid. General procedure N was used with 48.5 (308 mg, 1.39 mmol) to afford 48.6 (201 mg, 100% yield, 97% purity, retention time = 2.5 min (method A)) as cisltrans isomers (ratio 17 / 83) as yellow / orange oil.

[0446] Stage 7: Synthesis of 48.7a and 48.7b: ethyl (£’)-4-methyl-5-(4-(2-methylcvclopropyl)but-2-en- 1 -yl)pyrimidyl)thio)pyrimidine-2-carboxylate. General procedure K was used with 48.6 (201 mg, 1.39 mmol, 1.20 eq) and 20.6 (440 mg, 1.17 mmol, 1.0 eq) to afford the crude product which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: held at 50% during 5 min, increased linearly from 50 to 95% of “B” over 1 min, held at 95% during 4 min, increased linearly from 60 to 95% of “B” over 2 min, held at 95% during 4 min, returned to initial conditions over 1 min, 15 mL / min) affording 48.7 (160 mg, 50% yield, 100% purity, retention time = 2.9 min (method A)) as cisltrans isomers mixture. This mixture was separated by chiral preparative HPLC (Chiralpak IA 5µm 20x150mm, mobile phase: TBME / EtOH / DEA 99 / 1 / 0.1, 7 mL / min) to afford 48.7a as trans isomers (first peak collected at 13.05 min, 110 mg, 34% yield, 100% purity, retention time 2.9 min (method A)) and as yellow oil.1H NMR (300 MHz, CDCl3) 58.54 (s, 1H), 5.52 - 5.43 (m, 2H), 4.49 (q, 7=7.1 Hz, 2H), 3.35 (d, J = 3.8 Hz, 2H), 2.58 (s, 3H), 1.94 - 1.84 (m, 2H), 1.42 (t, 7 = 7.1 Hz, 3H), 0.95 (d, 7 = 5.8 Hz, 3H), 0.48 - 0.29 (m, 2H), 0.20 - 0.07 (m, 2H). m / z (ES+): [M+H]+= 275.48.7b (second peak collected at 15.23 min, 32 mg, 9% yield, 100% purity) as cisltrans isomers (ratio 88:12) and as yellow oil.1H NMR (300 MHz, CDCl3, cis isomer described) 5 8.56 (s, 1H), 5.54 (dq, 7= 3.2, 1.6 Hz, 2H), 4.57 - 4.43 (m, 2H), 3.43 - 3.33 (m, 2H),2.59 (d, J= 2.7 Hz, 3H), 2.01 - 1.93 (m, 2H), 1.43 (t, J= 7.2 Hz, 3H), 0.97 (d, J= 6.1 Hz, 3H), 0.86 - 0.33 (m, 3H), -0.26 - -0.39 (m, 1H). m / z (ES+): [M+H]+= 275.

[0447] Stage 8: Synthesis of 48a: (E)-4-methyl-5-(4-(2-methylcyclopropyl)but-2-en-1-yl)pyrimidine-2-carboxylic acid (as trans isomers) General procedure Al was used with 48.7a (110 mg, 0.4 mmol) to afford 48a (89 mg, 90% yield, 100% purity, retention time = 4.2 min (method B)) as trans isomers and as white solid.1H NMR (300 MHz, CDCl3) 5 8.66 (s, 1H), 5.64 - 5.44 (m, 2H), 3.43 (d, J= 4.2 Hz, 2H), 2.64 (s, 3H), 1.94 (m, 2H), 1.00 (d, J = 5.6 Hz, 3H), 0.53 - 0.32 (m, 2H), 0.25 - 0.12 (m, 2H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 247.

[0448] Stage 8: Synthesis of 48b: (E)-4-methyl-5-(4-(2-methylcyclopropyl)but-2-en-1-yl)pyrimidine-2-carboxylic acid (as cis isomers) General procedure Al was used with 48.7b (32 mg, 0.12 mmol) to afford the crude product which was purified by reverse phase preparative HPLC (Waters XBridge OBD C18 5 µm, 19 x 100 mm, mobile phase: “A” = 0.1% of formic acid in water; “B” = MeCN. Gradient used: increased linearly from 40 to 50% of “B” over 6 min, increased linearly from 50 to 95% of “B” over 2 min, held at 95% during 2 min, returned to initial conditions over 1 min, 15 mL / min) to afford 48b (23 mg, 75% yield, 98% purity, retention time = 4.1 min (method B)) as cis isomers and as white solid.1H NMR (300 MHz, CDCl3) 58.68 (s, 1H), 5.66 - 5.52 (m, 2H), 3.43 (d, J= 4.4 Hz, 2H), 2.64 (s, 3H), 2.00 (m, 2H), 0.98 (d, J= 6.1 Hz, 3H), 0.87 - 0.53 (m, 3H), -0.26 - -0.36 (m, 1H), 1H exchanged with solvent, m / z (ES+): [M+H]+= 247.Synthesis of compound 49b (see Scheme 11):

[0449] Stage 1: Synthesis of 49.1: (E)-2-(2-(2,2-dimethylcvclopropyl)vinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane. General procedure P was used with 2,2-dimethylcyclopropane-l-carbaldehyde (585 mg, 3.58 mmol, 60% purity) to...

Claims

CLAIMS1. A compound of formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;Ar1is a 5- or 6-membered heteroaryl selected from (Ar1a), (Ar1b), and (Ar1c):wherein:R1is H or halo;R2is H, Ci-3-alkyl, or Ci-3-alkoxy;R3is H, or R3is linked with Raand / or Ra’ as detailed below;A1is selected from CH and S; A2and A3are each independently selected from CH, S, N, NH, and O; provided that at least one of A1, A2and A3is S, N, NH or O;- represents a single or double bond, depending on A1, A2and A3; * represents the point of attachment to the carboxylic acid moiety; and ** represents the point of attachment to Y; andm, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor’w eny is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl; orRaand / or Ra’, with R3present on Ar1aor Ar1bform together with the carbon atoms and Y to which they are linked a fused 5 -membered ring selected from heterocyclyl, heteroaryl, cycloalkyl and aryl; provided that the heterocyclyl or heteroaryl comprise a single heteroatom being S;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; andwhen Ar1is Ar1a:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6- cycloalkyl)(heterocyclyl), C2-8-alkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, and heterocyclyl; and / orwherein the C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6- cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl substituents are optionally substituted by one or more hydroxyl; and / orwherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6- cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;when Ar1is Ar1b:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6- cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6- cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;or when R2is not H, R4can also alternatively be a C2-8-alkyl optionally substituted by one or more group selected from halo and C1-3-alkoxy, andwhen the bonds on either side of CRaRa’ are single bonds, then Y is S;when Ar1is Ar1c:R4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6- cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6- membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl and hydroxyl; and / or wherein the spiro-bi(C3-6- cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl; and the compound of formula (I) does not comprise«?orRa', wherein Raand Ra’ represent each independently H, halo, Ci-3-alkyl, or Ci-3-alkoxy, and represents the points of attachment to the rest of the compound;and provided that the compound of formula (I) is not:5 -butyl-2-pyrimidinecarboxylic acid,5 -pentyl-2-pyrimidinec arboxylic acid,5 -hexyl-2-pyrimidinec arboxylic acid,5 -heptyl-2-pyrimidinec arboxylic acid,5 -butyl-4-methoxy-2-pyrimidinecarboxylic acid,6-ethyl-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-propyl-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(1H-pyrrol-2-ylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(3-methylbutyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2,2-dimethylpropyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(cyclopropylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,5 - [(cyclopentylmethyl)thio] -2-pyridinecarboxylic acid,5-[2-(l,6-dihydro-6-oxo-4-propyl-2-pyrimidinyl)-l-buten-l-yl]-2-pyridinecarboxylic acid,5 - [2-(4-bromo-2-thiazolyl)ethenyl] -2-pyridinecarboxylic acid,5 - [2- (5 -bromo-2-pyrimidinyl)ethenyl] -2-pyridinecarboxylic acid,5-[2-(3,4,5,6,7,8-hexahydro-4-oxo-2-quinazolinyl)ethenyl]-2-pyridinecarboxylic acid,5-(2-cyclopropylvinyl)picolinic acid,2-( 1 -methyl- 1 H-pyrazol-4-yl)thieno [3,2-b]pyridine-5-carboxylic acid,2-cyclopropylthieno [3,2-b]pyridine-5-carboxylic acid,2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridine-5-carboxylic acid,5 - [2- (5 -chloro-2-thiazolyl)ethenyl] -2-pyridinecarboxylic acid,5-(2'-methyl-[l,l'-bi(cyclopropane)]-2-carbonyl)furan-3-carboxylic acid, 4-(2'-methyl-[l,l'-bi(cyclopropane)]-2-carbonyl)-lH-pyrrole-2-carboxylic acid, 4-([ 1, l'-bi(cyclopropane)]-2-carbonyl)- 1 -methyl- lH-pyrrole-2-carboxylic acid, 5-([ 1, 1 '-bi(cyclopropan)] -2-ylmethyl)- 1,3,4-thiadiazole-2-carboxylic acid, 5-([l,l'-bi(cyclopropan)]-2-ylmethyl)furan-3-carboxylic acid,4-([ 1, 1 '-bi(cyclopropan)] -2-ylmethyl)- lH-pyrrole-2-carboxylic acid,5-[2-(2,2,6-trimethylcyclohexyl)ethyl]-lH-pyrazole-3-carboxylic acid,4-[[(2-ethylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid,4-[[(2,2-dimethylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid, 5-(2-([l,l'-bi(cyclopropan)]-2-yl)acetyl)furan-3-carboxylic acid,4-(2-([l,l'-bi(cyclopropan)]-2-yl)acetyl)-lH-pyrrole-2-carboxylic acid,4-[[(2-methylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid, or5-[2-(2,2-dimethylcyclopropyl)ethyl]-l,3,4-thiadiazole-2-carboxylic acid.wherein* represents the point of attachment to the carboxylic acid moiety; and** represents the point of attachment to Y.

3. The compound according to claim 1 or claims 2, wherein m is 1, and n and p are 0;or m and n are 1, and p is 0.

4. The compound according to any one of claims 1 to 3, wherein the linker of formula (i) comprises 1 or 2 double bonds, wherein linker (i) corresponds to:whereinY, Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, Rd’, m, n, p, and - are as defined in any of the preceding claims,** represents the point of attachment to Ar1; andrepresents the point of attachment to R4.

5. The compound according to claim 4, wherein linker (i) is selected from:wherein** represents the point of attachment to Ar1; and■~vv represents the point of attachment to R4.

6. The compound according to any one of claims 1 to 5, wherein R4is selected from:wherein represents the point of attachment to the rest of the compound.

7. The compound according to any one of claims 1 to 6, of formula (la)0(la) or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;R2is H, Ci-3-alkyl, or Ci-3-alkoxy;R3is H, or R3is linked with Raand / or Ra’ as detailed below;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor Ra’, when Y is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl; orRaand / or Ra’ with R3form together with the carbon atoms and Y to which they are linked a fused 5-membered ring selected from heterocyclyl, heteroaryl, cycloalkyl and aryl; provided that the heterocyclyl or heteroaryl comprise a single heteroatom being S;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; andR4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6- cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, phenyl, or 5- or 6- membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6- cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;and provided that the compound of formula (la) is not:6-(lH-pyrrol-2-ylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(cyclopropylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid,6-(2-furanylmethyl)-thieno[2,3-d]pyrimidine-2-carboxylic acid.

8. The compound according to any one of claims 1 to 6, of formula (lb)O (lb) or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;R1is H or halo;R2is H, Ci-3-alkyl, or Ci-3-alkoxy;R3is H;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy; ortwo of them present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a C3-6-cycloalkyl; orRaor Ra’, when Y is CReRe, forms with Reor Re’, and together with the carbon atoms to which they are attached, a C3-6-cycloalkyl;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; or Reor Re’ is linked with Raor Ra’ as detailed above; and with the condition that when the bonds on either side of CRaRa’ are single bonds, then Y is S;R4is C3-8-cycloalkyl spiro-bi(C3-6-cycloalkyl), or spiro-(C3-6- cycloalkyl)(heterocyclyl); wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl, heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro-(C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;and provided that the compound of formula (lb) is not:5 - [(cyclopentylmethyl)thio] -2-pyridinecarboxylic acid,5-(2-cyclopropylvinyl)picolinic acid.

9. The compound according to any one of claims 1 to 6, of formula (Ic)or a pharmaceutically acceptable salt and / or solvate thereof, wherein:- represents a single or double bond;A1is selected from CH and S; A2and A3are each independently selected from CH, S, N, NH, and O; provided that at least one of A1, A2and A3is S, N, NH or O; - represents a single or double bond, depending on A1, A2and A3;m, n, and p are each independently 0 or 1;Ra, Ra’, Rb, Rb’, Rc, Rc’, Rd, and Rd’ are each independentlyeither absent; orrepresent H, halo, Ci-3-alkyl, Ci-3-alkoxy;Y is S or CReRe, wherein Reand Re’ are each independently either absent; or represent H or F; or Reand Re’ form together an oxo group; andR4is C3-8-cycloalkyl, spiro-bi(C3-6-cycloalkyl), spiro-(C3-6- cycloalkyl)(heterocyclyl), 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; wherein the substituents are optionally substituted by one or more group selected from halo, Ci-3-alkyl, Ci-3-haloalkyl, Ci-3-alkoxy, C3-6-cycloalkyl,heterocyclyl, and hydroxyl; and / or wherein the spiro-bi(C3-6-cycloalkyl) or spiro- (C3-6-cycloalkyl)(heterocyclyl) substituents are optionally further spiro-fused to a C3-6-cycloalkyl or heterocyclyl;and the compound of formula (Ic) does not comprise<?or Ra1, wherein Raand Ra’ represent each independently H, halo, Ci-3-alkyl, or Ci-3-alkoxy, and represents the points of attachment to the rest of the compound;and provided that the compound of formula (Ic) is not:5-[2-(2,2,6-trimethylcyclohexyl)ethyl]-lH-pyrazole-3-carboxylic acid,4- [[(2-ethylcyclopropyl)methyl]thio] -2-thiophenecarboxylic acid,4-[[(2,2-dimethylcyclopropyl)methyl]thio]-2-thiophenecarboxylic acid,4- [[(2-methylcyclopropyl)methyl]thio] -2-thiophenecarboxylic acid, or5 - [2-(2,2-dimethylcyclopropyl)ethyl] - 1,3,4-thiadiazole-2-carboxylic acid.

10. The compound according to any one of claims 1 to 9, selected from:5-((2-cyclohexylethyl)thio)-4-methylpicolinic acid;5-((2-cyclohexylethyl)thio)-4-methylpyrimidine-2-carboxylic acid;5-((2-cyclohexylethyl)thio)-4-methoxypyrimidine-2-carboxylic acid;(E’)-5-(3-cyclohexylprop-l-en-l-yl)-4-methylpyrimidine-2-carboxylic acid;(E)-5-(3-cyclohexylallyl)-4-methylpyrimidine-2-carboxylic acid;(E’)-5-(3-cyclopentylallyl)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(((tetrahydro-2H-pyran-2-yl)methyl)thio)pyrimidine-2-carboxylic acid;5-((3-cyclopentylpropyl)thio)-4-methylpyrimidine-2-carboxylic acid;5-((2-cyclohexylpropyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-((2-(2-methylcyclopentyl)ethyl)thio)pyrimidine-2-carboxylic acid; 5-((2-cyclopentylpropyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-((2-(l-methylcyclopentyl)ethyl)thio)pyrimidine-2-carboxylic acid; (E’)-5-(3-cyclopentylallyl)pyrimidine-2-carboxylic acid;5-((2-cyclopentylcyclopropyl)methyl)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-((2-cyclopentylvinyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E)-5-(3-cyclopentylallyl)-3-fluoropicolinic acid;6-(2-cyclopentylethyl)thieno[3,2-d]pyrimidine-2-carboxylic acid;(E’ -5-(3-cyclopentylallyl)-4-methoxypyrimidine-2-carboxylic acid;(E’ -5-(3-cyclopentyl-2-methylallyl)-4-methylpyrimidine-2-carboxylic acid; (Z)-5-(3-cyclopentyl-2-fluoroallyl)-4-methylpyrimidine-2-carboxylic acid; (E’ -5-(3-cycloheptylallyl)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-(4-cyclobutylbut-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid;(£’)-4-methyl-5-(3-(l-methylcyclopentyl)allyl)pyrimidine-2-carboxylic acid; (E’ -5-((2-cyclobutylvinyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-(3-cyclopentylbut-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid; 6-(2-cyclopentylethyl)-6,7-dihydrothieno[3,2-d]pyrimidine-2-carboxylic acid; (Z)-5-(3-cyclopentyl-3-fluoroallyl)-4-methylpyrimidine-2-carboxylic acid; (E)-5-(3-cyclopentyl-3-fluoroallyl)-4-methylpyrimidine-2-carboxylic acid; (E’)-5-(4-cyclobutylbut-2-en-l-yl)pyrimidine-2-carboxylic acid;(E’ -5-((2-cyclohexylvinyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(2-(spiro[3.3]heptan-2-ylidene)ethyl)pyrimidine-2-carboxylic acid; (E’ -5-(4-cyclopentylbut-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid; (E’)-5-(3-cyclopentyl-l,l-difluoroallyl)pyrimidine-2-carboxylic acid;5-(3-cyclopentylpropyl)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-(5-cyclobutylpent-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid; (E)-4-methyl-5-(5-methylhex-2-en-1-yl)pyrimidine-2-carboxylic acid;(E)-5-((3-cyclobutylprop-1-en-1-yl)thio)-4-methylpyrimidine-2-carboxylic acid; (E)-4-methyl-5-(4-(1-methylcyclopropyl)but-2-en-1-yl)pyrimidine-2-carboxylic acid;(E)-4-methyl-5-(4-phenylbut-2-en-1-yl)pyrimidine-2-carboxylic acid;(£’ -4-methyl-5-(3-(spiro[3.3]heptan-2-yl)allyl)pyrimidine-2-carboxylic acid; (E’)-5-(4-(l-fluorocyclobutyl)but-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid;(E)-4-methyl-5-(4-(1-methylcyclobutyl)but-2-en-1-yl)pyrimidine-2-carboxylic acid;(E)-5-(4-cyclopropylbut-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid;(E)-5-((3-cyclobutylprop-1-en-1-yl)thio)pyrimidine-2-carboxylic acid;(E)-4-methyl-5-(3-(spiro[2.3]hexan-l-yl)allyl)pyrimidine-2-carboxylic acid; (Z)-5-(4-cyclobutyl-3-fluorobut-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid; 5-(4-cyclobutylbuta-l,2-dien-l-yl)-4-methylpyrimidine-2-carboxylic acid;(E)-4-methyl-5-(4-(2-methylcyclopropyl)but-2-en-l-yl)pyrimidine-2-carboxylic acid;(E)-5-(3-(2,2-dimethylcyclopropyl)allyl)-4-methylpyrimidine-2-carboxylic acid; (E)-5-(4-cyclobutylidenebut-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid; (E)-5-(5-cyclopropylpent-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid;(E)-5-(4-cyclobutylbut-2-en-1-yl)-4-methylpicolinic acid;(E)-5-(4-cyclobutylbut-2-en-l-yl)-lH-pyrazole-3-carboxylic acid;(E)-5-(4-cyclobutylpent-2-en-1-yl)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-(4-cyclobutylbut-2-en-l-yl)-4-methylpyrimidine-2-carboxylic acid;(E)-5-(4-cyclobutylbut-2-en-l-yl)thiazole-2-carboxylic acid;5-(4-cyclobutylbutyl) -4-methylpyrimidine-2-carboxylic acid;(E)-5-(4-cyclobutylbut-l-en-l-yl)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(phenethylthio)pyrimidine-2-carboxylic acid;( E)-4-methyl-5 -((4-methylpent- 1 -en- 1 -yl)thio)pyrimidine-2-carboxylic acid; (Z)-4-methyl-5-((4-methylpent-l-en-l-yl)thio)pyrimidine-2-carboxylic acid; (E)-5-((3-(l-fluorocyclobutyl)prop-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z -5-((3 -( 1 -fluorocyclobutyl)prop- 1 -en- 1 -yl)thio)-4-methylpyrimidine-2-carboxylic acid;( E)-4-methyl-5 -((3 -( 1 -methylcyclobutyl)prop- 1 -en- 1 -yl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-((3-(l-methylcyclobutyl)prop-l-en-l-yl)thio)pyrimidine-2-carboxylic acid;(E)-5-((3-cyclobutylallyl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-((3-cyclobutylallyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-((3-cyclobutyl-l-fluoroprop-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-((3 -cyclobutyl- 1 -fluoroprop- 1 -en- 1 -yl)thio)-4-methylpyrimidine-2-carboxylic acid;5-((cyclohexylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-((3-cyclobutylprop- 1-en- l-yl)thio)-4-methylpyrimidine-2-carboxylic acid; (£’ -4-methyl-5-((2-(spiro[2.3]hexan-l-yl)vinyl)thio)pyrimidine-2-carboxylic acid; (Z)-4-methyl-5-((2-(spiro[2.3]hexan-l-yl)vinyl)thio)pyrimidine-2-carboxylic acid; 5-(((2-thiaspiro[3.3]heptan-6-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-((spiro[2.3]hexan-5-ylidenemethyl)thio)pyrimidine-2-carboxylic acid; (E’ -5-((3-cyclobutyl-2-methylprop-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-((3-cyclobutyl-2-methylprop-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid;(£’ -4-methyl-5-((2-(spiro[3.3]heptan-2-yl)vinyl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-((2-(spiro[3.3]heptan-2-yl)vinyl)thio)pyrimidine-2-carboxylic acid;(£’ -4-methyl-5-((2-(spiro[2.2]pentan-l-yl)vinyl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-((2-(spiro[2.2]pentan-l-yl)vinyl)thio)pyrimidine-2-carboxylic acid;4-methyl-5-((spiro[3.3]heptan-2-ylidenemethyl)thio)pyrimidine-2-carboxylic acid; ( E )-5-((3-(3-fluorobicyclo[ 1.1.1 ]pentan- 1 -yl)prop- 1 -en- 1 -yl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-((3-(3-fluorobicyclo[1.1.1]pentan-1-yl)prop-1-en-1-yl)thio)-4-methylpyrimidine-2-carboxylic acid;5-(((6,6-difluorospiro[3.3]heptan-2-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E)-4-methyl-5-((3-(2-methylcyclopropyl)prop-1-en-1-yl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-((3-(2-methylcyclopropyl)prop-l-en-l-yl)thio)pyrimidine-2-carboxylic acid;5-((3-(4-bromophenyl)prop-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid;5-((cyclopentylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-((3-cyclobutyl-2-fluoroprop-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid;(E)-4-methyl-5-((3-(1-methylcyclopropyl)prop-1-en-1-yl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-((3-(l-methylcyclopropyl)prop-l-en-l-yl)thio)pyrimidine-2-carboxylic acid;(Z)-5-((2-cyclopentylvinyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E)-4-methyl-5-(styrylthio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-(styrylthio)pyrimidine-2-carboxylic acid;5-(((3,3-dimethylcyclobutylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-((3-cyclopentylprop- 1-en- l-yl)thio)-4-methylpyrimidine-2-carboxylic acid; (Z)-5-((3-cyclopentylprop-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid; 4-methyl-5-((spiro[3.3]heptan-2-ylmethyl)thio)pyrimidine-2-carboxylic acid; (E’ -5-((3-cyclobutylbut- 1-en- l-yl)thio)-4-methylpyrimidine-2-carboxylic acid; (Z)-5-((3-cyclobutylbut-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid; (E’ -5-((4,4-dimethylpent-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid; (Z)-5-((4,4-dimethylpent-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid; (E’ -5-((3-cyclopropylprop-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid; (Z)-5-((3-cyclopropylprop- 1-en- l-yl)thio)-4-methylpyrimidine-2-carboxylic acid; (£’ -4-methyl-5-((2-(spiro[2.3]hexan-5-yl)vinyl)thio)pyrimidine-2-carboxylic acid; (Z)-4-methyl-5-((2-(spiro[2.3]hexan-5-yl)vinyl)thio)pyrimidine-2-carboxylic acid; 4-methyl-5-((spiro[3.4]octan-2-ylidenemethyl)thio)pyrimidine-2-carboxylic acid;(Z)-5-((3-cyclobutyl-2-fluoroprop-1-en-1-yl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-(((2-cyclopropylcyclobutylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-(((2-cyclopropylcyclobutylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;5-(((6-fluorospiro[3.3]heptan-2-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-(((3,3-dimethylcyclopentylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-(((3,3-dimethylcyclopentylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(((3-(trifluoromethyl)cyclobutylidene)methyl)thio)pyrimidine-2-carboxylic acid;(Z)-5-((4-fluoro-4-methylpent-l-en-l-yl)thio)-4-methylpyrimidine-2-carboxylic acid;(E)-5-((4-fluoro-4-methylpent-1-en-1-yl)thio)-4-methylpyrimidine-2-carboxylic acid;(E)-4-methyl-5-((5,5,5-trifluoro-4-methylpent-1-en-1-yl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-((5,5,5-trifluoro-4-methylpent-1-en-1-yl)thio)pyrimidine-2-carboxylic acid;5-(((3-(tert-butyl)cyclobutylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-((cis-bicyclo[3.2.0]hept-2-en-6-ylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-((cis-bicyclo[3.2.0]hept-2-en-6-ylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(((6-(trifluoromethyl)spiro[3.3]heptan-2-ylidene)methyl)thio)pyrimidine-2-carboxylic acid;(E’ -5-(((l-fluorospiro[3.3]heptan-2-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-(((l-fluorospiro[3.3]heptan-2-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;5-(((3-cyclopropylcyclobutylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;5-(([l,r-bi(cyclobutan)]-3-ylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(((l-methylspiro[3.3]heptan-2-ylidene)methyl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-(((l-methylspiro[3.3]heptan-2-ylidene)methyl)thio)pyrimidine-2-carboxylic acid;(£’ -4-methyl-5-(((l-methylspiro[3.3]heptan-2-ylidene)methyl)thio)pyrimidine-2-carboxylic acid;5-(((l-hydroxyspiro[3.3]heptan-2-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-(((1-hydroxyspiro[3.3]heptan-2-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-(((l-hydroxyspiro[3.3]heptan-2-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(((2-methylcyclohexylidene)methyl)thio)pyrimidine-2-carboxylic acid;4-methyl-5-(((3-methylcyclohexylidene)methyl)thio)pyrimidine-2-carboxylic acid;(Z)-5-((bicyclo[2.2.1]heptan-2-ylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-((bicyclo[2.2.1]heptan-2-ylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(((5-methylspiro[3.3]heptan-2-ylidene)methyl)thio)pyrimidine-2-carboxylic acid;5-(((4,4-difluorocyclohexylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(((3-(2,2,2-trifluoroethyl)cyclobutylidene)methyl)thio)pyrimidine-2-carboxylic acid;4-methyl-5-((spiro[2.5]octan-6-ylidenemethyl)thio)pyrimidine-2-carboxylic acid; (Z)-5-((2-(2,2-difluorospiro[2.3]hexan-l-yl)vinyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-((2-(2,2-difluorospiro[2.3]hexan-l-yl)vinyl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-((2-(l-fluorospiro[2.3]hexan-l-yl)vinyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-((2-( 1 -fluorospiro [2.3]hexan- 1 -yl)vinyl)thio)-4-methylpyrimidine-2-carboxylic acid;5-(((trans-3,4-dimethylcyclopentylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;5-((cis-bicyclo[3.1.0]hexan-2-ylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;(Z)-5-((cis-bicyclo[3.1.0]hexan-2-ylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;(E’ -5-((cis-bicyclo[3.1.0]hexan-2-ylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;4-methyl-5-(((3-methylcyclopentylidene)methyl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-(((3-methylcyclopentylidene)methyl)thio)pyrimidine-2-carboxylic acid;(£’ -4-methyl-5-(((3-methylcyclopentylidene)methyl)thio)pyrimidine-2-carboxylic acid;5-(((5,5-difluorospiro[3.3]heptan-2-ylidene)methyl)thio)-4-methylpyrimidine-2-carboxylic acid;(£’ -4-methyl-5-((2-(spiro[2.4]heptan-1-yl)vinyl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-((2-(spiro[2.4]heptan-1-yl)vinyl)thio)pyrimidine-2-carboxylic acid;5-(((trans-hexahydropentalen-2(lH)-ylidene)methyl)thio)-4-methylpyrimidine-2- carboxylic acid;(£’ -4-methyl-5-((2-(spiro[2.4]heptan-5-yl)vinyl)thio)pyrimidine-2-carboxylic acid;(Z)-4-methyl-5-((2-(spiro[2.4]heptan-5-yl)vinyl)thio)pyrimidine-2-carboxylic acid;5-((dispiro[2.0.3.2]nonan-6-ylidenemethyl)thio)-4-methylpyrimidine-2-carboxylic acid;5-(((cis-bicyclo[3.2.0]heptan-3-ylidene)methyl)thio)-4-methylpyrimidine-2- carboxylic acid;5-(((trans-bicyclo[3.2.0]heptan-3-ylidene)methyl)thio)-4-methylpyrimidine-2- carboxylic acid;5-(((cis-bicyclo[3.1.0]hexan-3-ylidene)methyl)thio)-4-methylpyrimidine-2- carboxylic acid.and stereoisomers thereof, and pharmaceutically acceptable salts and / or solvates thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier.

12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament.

13. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of cancers, autoimmune diseases, infectious diseases, atherosclerosis, and neurological or neurodegenerative diseases.

14. The compound for use according to claim 13, or a pharmaceutically acceptable salt and / or solvate thereof, wherein cancers are selected from bladder cancer, bile duct and gall blabber cancers, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal / upper aerodigestive cancer, eye cancer, glioblastoma, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, non- small cell lung cancer (NSCLC), neuroendocrine cancer, head and neck cancer, oral cancer, oral squamous cell carcinoma, melanoma, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, sebaceous gland carcinoma, skin cancer, stomach cancer, and testicular cancer, thyroid cancer, urinary tract cancer, and uterine cancer.

15. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of diseases or disorders which are responsive to GPR84 agonism.

Images