Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Abstract

The present invention discloses compounds according to Formula (I), wherein R1, R2, R3, R4, R5, R6a, R6b, R6c, R6d, R7, R8, R9 and R10 are as defined herein. The present invention relates to compounds having α4β7 integrin inhibitory action, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and / or treatment of a disease, disorder or condition that is mediated by α4β7 integrin, by administering the compound of the invention.

Description

NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS.FIELD OF THE INVENTION

[0001] The present invention relates to novel compounds that have a4[37 integrin inhibitory action, and prodrugs thereof. The present invention also provides methods for the manufacture of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and / or treatment of autoimmune and inflammatory diseases by administering the compounds of the invention.BACKGROUND OF THE INVENTION

[0002] Integrins are heterodimeric proteins consisting of an alpha and a beta subunit. In mammals, integrins are assembled from eighteen alpha and eight beta subunits.

[0003] Inhibiting the interactions of integrins with their respective ligands has been proposed as an effective method for treating a variety of diseases, including fibrotic, autoimmune, and inflammatory diseases.

[0004] a4[37 integrin is expressed on the surface of lymphocytes and recognizes the extracellular ligand mucosal addressing cell adhesion molecule- 1 (MAdCAM-1). a4[37 integrin governs lymphocyte trafficking to and retention in gut tissues through its interaction with MAdCAM-1, which is expressed on venules in the intestinal mucosa and high endothelial venules (HEV) in the gut-associated lymphoid tissues (GALT) . Blocking the a4[37 -MAdCAM- 1 interaction has shown therapeutic benefit in inflammatory bowel disease. Vedolizumab is a monoclonal antibody medication developed for the treatment of ulcerative colitis and Crohn's disease, which binds to integrin a4[37, resulting in a gut-selective anti-inflammatory activity.

[0005] There is a need for new a4[37 integrin antagonist molecules with improved properties for the treatment of autoimmune and inflammatory diseases, including inflammatory bowel disease (in particular, Crohn’s disease and ulcerative colitis).SUMMARY OF THE INVENTION

[0006] The present invention provides compounds that are a4[37 integrin inhibitors. The invention also provides compositions comprising the compounds, in particular pharmaceutical compositions, and methods of using / administering and making the compounds and compositions. The compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by a4[37 integrin. The invention also provides compounds for use in therapy. The invention further provides compounds for use in a method of treating a disease, disorder, or condition that is mediated by a4[37 integrin. Moreover, the invention provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by a4[37 integrin.

[0007] Accordingly, in a first aspect, the present invention provides compounds of Formula (I):whereinR1is a hydrogen atom; orCi-6 alkyl unsubstituted or substituted with one or more independently selected R8; orC2-6 alkenyl unsubstituted or substituted with one or more independently selected R8; orC2-6 alkynyl unsubstituted or substituted with one or more independently selected R8; orC3-7 cycloalkyl unsubstituted or substituted with one or more substituents independently selected R6a; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6a; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6a; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6a; or aryl, preferably phenyl, which is unsubstituted or substituted with one or more independently selected R6a;R2is a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6b; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6b; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6b; or-N(C=O)CI-6 alkoxy; or- -NH-C(=O)NH2; or- -NH-C(=0)NH(CI-6) alkyl); or- -NH-C(=0)N(CI.6) alkyl)2;R3is hydroxyl, Ci-6 alkyl, Ci-6 alkoxy, cyano, nitro, halogen, Ci-6 haloalkyl, Ci-6 haloalkoxy, -SO2(Ci- e)alkyl, -SO2(Ci.6)haloalkyl, -SO2(C3-6)cycloalkyl, -CHO, -CO2(Ci.6)alkyl, -C(O)NH2, -C(O)NH(CI.4alkyl), -C(O)N(CI-4 alkyl)2, -NRnR12, where R11and R12are each independently hydrogen or C1-C3 alkyl or R11and R12together with the nitrogen atom form a 4- to 6-membered heterocyclic ring, which ring is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, Ci- 4 haloalkyl and C3-7 cycloalkyl; orR3is C2alkenyl, which alkenyl is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, C1-4 haloalkyl and C3-7 cycloalkyl; orR3is C4-8 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkenyl, which cycloalkenyl is unsubstituted or substituted with one or more substituents independently selected from halogen, C1-4 alkyl and C1-4 haloalkyl; orR3is C2alkynyl, which alkynyl is unsubstituted or substituted with one or more substituents independently selected from C1-3 alkyl and C1-3 haloalkyl; orR3is C2alkynyl, which alkynyl is substituted with a C3-6 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one or more independently selected R6c; or a 3-6 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl containing at least one heteroatom selected from O, N, and S, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;R4is a hydrogen atom or C1-6 alkyl;R5is: aryl, preferably phenyl, which is unsubstituted or substituted with one or more independently selected R6c; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6c; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6c; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6c; or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one or more independently selected R6c; each R6ais independently selected from: cyano; hydroxy; halogen;Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen; andCi -e alkyl unsubstituted or substituted with one or more independently selected halogen; each R6bis independently selected from: cyano; hydroxy; halogen;Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen and (Ci-4 alkyl)2amino;Ci-4 alkylamino, which is unsubstituted or the alkyl group of which is substituted with a (Ci-4 alkyl)2amino;(Ci-4 alkyl)2amino, which is unsubstituted or an alkyl group of which is substituted with a (Ci-4 alkyl)2amino;-NHSChheterocycloalkyl, which heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which is unsubstituted or substituted with a Ci-4 alkyl;Ci -e alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, Ci-4 alkoxy, Ci-4 alkylamino, (Ci-4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6d;- -NHSO2(Ci-4)alkyl;-NHSO2(Ci-4)haloalkyl;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more independently selected - CN, -OH, C1-4 alkoxy, halo, (C1-4 alkyl)2amino or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; and4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which heterocycloalkyl is unsubstituted or substituted with a C1-4 alkyl; or an oxo group; each R6cis independently selected from: cyano; hydroxy; halogen;Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen;Ci -e alkyl unsubstituted or substituted with one or more or more substituents independently selected from halogen;C2-6 alkenyl unsubstituted or substituted with one or more independently selected halogen;C2-6 alkynyl unsubstituted or substituted with one or more independently selected halogen;- -NHSO2(Ci-4)alkyl;-NHSO2(Ci-4)haloalkyl;-P(O)(Ci-4 alkyl)2, or -P(O)(R13)(R14) wherein R13and R14together with the phosphorous atom form a 3-6 membered monocyclic heterocycloalkyl;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more independently selected - CN, -OH, C1-4 alkoxy, halo, or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; and4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which heterocycloalkyl is unsubstituted or substituted with a C1-4 alkyl; each R6dis independently selected from: cyano; hydroxy; halogen; andCi -e alkyl unsubstituted or substituted with one or more independently selected cyano, hydroxy, halogen;R7is hydrogen or C1-6 alkyl; each R8is independently selected from: cyano; hydroxy; halogen;- -NH(CI.6 alkyl);- -N(CI.6 alkyl)( C1.6 alkyl);Ci -4 alkoxy unsubstituted or substituted with one or more independently selected halogen;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more substituents independently selected from halogen, C1-4 haloalkyl, cyano and hydroxy; a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6d; and R9and R10are each independently selected from: hydrogen; cyano; halogen;C1-6 alkyl;C1-6 haloalkyl; andC3-6 cycloalkyl;or a pharmaceutically acceptable salt and / or solvate thereof.

[0008] In a second aspect, the invention provides compositions comprising the compounds, in particular pharmaceutical compositions comprising a compound of the invention and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of inflammatory bowel disease (in particular, Crohn’s disease and ulcerative colitis).

[0009] In a further aspect, the invention provides use of the compounds, or a pharmaceutical composition comprising them, in medicine, in particular in the prophylaxis and / or treatment of a disease, disorder or condition that is mediated by a4[37 integrin, including, in particular, inflammatory bowel disease (in particular, Crohn’s disease and ulcerative colitis).

[0010] In another aspect, the invention provides the compounds, or a pharmaceutical composition comprising them, for use in a method of treating a disease, disorder, or condition that is mediated by a4[37 integrin, including inflammatory bowel disease (in particular, Crohn’s disease and ulcerative colitis).

[0011] In a yet further aspect, the invention provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by a4[37 integrin, including inflammatory bowel disease (in particular, Crohn’s disease and ulcerative colitis).

[0012] In another aspect, the invention provides methods of using / administering the compounds or a pharmaceutical composition comprising them.

[0013] In an additional aspect, the invention provides methods of making the compounds and compositions comprising them.

[0014] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0015] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0016] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0017] Furthermore, it has been unexpectedly demonstrated that the compounds of the invention exhibit advantageous properties for their use treating diseases, disorders, or conditions that are mediated by a4[37 integrin.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0018] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0019] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms,if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0020] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.

[0021] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.

[0022] A wavy line drawn through a line in a structure indicates a point of attachment of a group.Similarly, a squiggly line on a chemical group as shown, for example, indicates a point of attachment, i.e., it shows the broken bond by which the group is connected to another described group.

[0023] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-8 alkyl” indicates that the alkyl group has from 1 to 8 carbon atoms.

[0024] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0025] Unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0026] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (- CH2-CH2-CH2-CH3), isobutyl (-CH2CH(CH3)2), tert-butyl (-CFF-C CFbjs), sec-butyl (-CH2-CH( dUfr)- n- pentyl (-CH2-CH2-CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCFFj-C CFhjFb-CFb-CFF). Particular alkyl groups have between 1 and 4 carbon atoms.

[0027] ‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2) and the like.

[0028] ‘Alkylene’ refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.

[0029] ‘Alkynylene’ refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -C=C-, -CH2- C=C-, and -C(CH3)H-C=CH-.

[0030] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-Ci e alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0031] ‘ Amino’ refers to the radical -NH2.

[0032] ‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0033] ‘Cycloalkyl’ refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0034] ‘Cyano’ refers to the radical -CN.

[0035] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0036] ‘Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

[0037] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0038] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0039] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0040] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0041] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0042] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0043] Examples of representative heteroaryls include the following:wherein each Y is selected from >C=O, NH, O and S.

[0044] ‘Heterocycloalkyl’ means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. Examples of heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), tetrahydrofuranyl (e.g. 1 -tetrahydrofuranyl, 2-tetrahydrofuranyl and 3 -tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1 -tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4- tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0045] As used herein, the term ‘heterocycloalkenyl’ means a ‘heterocycloalkyl’, which comprises at least one double bond. Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples:wherein each W is selected from CEE, NH, O and S; each Y is selected from NH, O, C(=O), SO2, and S; and each Z is selected from N or CH.

[0046] Particular examples of monocyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.

[0047] Particular examples of fused bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.

[0048] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S- and each Z is selected from N or CH.

[0049] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected from -CH2-, -NH-, -O- and -S-.

[0050] ‘Hydroxyl’ refers to the radical -OH.

[0051] ‘ Oxo’ refers to the radical =0.

[0052] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0053] ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as -SO3H.

[0054] ‘ Thiol’ refers to the group -SH.

[0055] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.

[0056] ‘Thioalkoxy’ refers to the group -S-alkyl where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -S-C1-6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy, n- thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0057] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0058] ‘Pharmaceutically acceptable ’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0059] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid,citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0060] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0061] ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0062] ‘ Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0063] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0064] ‘ Effective amount’ means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0065] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[0066] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0067] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0068] As used herein the term “diseases, disorders, or conditions that are mediated by a4[37 integrin” refers to, without limitation, acne, acid- induced lung injury, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, adult-onset Still's disease, adult respiratory distress syndrome (ARDS), age- related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergies, allergic encephalomyelitis, allergic neuritis, allograft rejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, angiofibroma, anhidrotic ectodermal dysplasia-ill, anti -glomerular basement membrane disease, antigen-antibody complex mediated diseases, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polyendocrinopathies, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoinflammatory diseases, back pain, Bacillus anthracis infection, Bechet's disease, bee sting-induced inflammation, Behcet’s syndrome, Bell’s palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis, bullous pemphigoid (BP) asthma, bums, bursitis, cardiac hypertrophy, carpal tunnel syndrome, Castleman's disease, catabolic disorders, cataracts, Celiac disease, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, complications oforgan transplantation, conjunctivitis, connective tissue disease, contact dermatitis, comeal graft neovascularization, comeal ulcer, Crohn's disease, cryopyrin-associated periodic syndromes, cutaneous lupus erythematosus (CLE), cryptococcosis, cystic fibrosis, deficiency of the interleukin- 1 receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme, erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy, familial cold urticarial, familial Mediterranean fever, fetal growth retardation, fibromyalgia, Crohn’s disease, fistulizing Crohn’s disease, food allergies, giant cell arteritis, glaucoma, glioblastoma, glomerular disease, glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy, gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatous hepatitis, Graves' disease, growth plate injuries, Guillain-Barre syndrome, gut diseases, hair loss, Hashimoto's thyroiditis, head injury, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilic joints, Henoch-Scholein purpura, hepatitis, hepatic steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hereditary periodic fever syndrome, heritable disorders of connective tissue, herpes zoster and simplex, hidradenitis suppurativa (HS), hip replacement, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperactive inflammatory response, hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivity pneumonitis, hypertropic bone formation, hypoplastic and other anemias, hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, Idiopathic inflammatory myopathies (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin nephropathies, immune complex nephritis, immune thrombocytopenic purpura (ITP), incontinentia pigmenti (IP, Bloch- Siemens syndrome), infectious mononucleosis, infectious diseases including viral diseases such as AIDS (HIV infection), hepatitis A, B, C, D, and E, herpes; inflammation, inflammation of the CNS, inflammatory bowel disease (IBD), inflammatory disease of the lower respiratory tract including bronchitis or chronic obstructive pulmonary diseases, inflammatory disease of the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis, inflammatory diseases of the respiratory tract, inflammatory ischemic event such as stroke or cardiac arrest, inflammatory lung disease, inflammatory myopathy such as myocarditis, inflammatory liver disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, interstitial cystitis, interstitial lung disease, iritis, irritant-induced inflammation, ischemia / reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidney injury caused by parasitic infections, kidney transplant rejection, leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), Lambert- Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupus nephritis, Lyme disease, Marfan syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), mucositis, multiple organ injury syndrome, multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onsetmultisystem inflammatory disease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis, neuropathological diseases, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, Osier-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, pachyonychia congenita, Paget’s disease, Paget’s disease of bone, pancreatitis, Parkinson's disease, pediatric rheumatology, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pernicious anemia (Addison's disease), pertussis, PFAPA (periodic fever aphthous pharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumocystis infection, pneumonia, pneumonitis, poison ivy / urushiol oil- induced inflammation, polyarthritis nodosa, polychondritis, polycystic kidney disease, polymyalgia rheumatic, giant cell arteritis, polymyositis, pouchitis, reperfusion injury and transplant rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary sclerosing cholangitis (PSC), proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriatic epidermis, psychosocial stress diseases, pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenic granuloma retrolental fibroplasias, pyogenic sterile arthritis, Raynaud’s syndrome, Reiter's disease, reactive arthritis, renal disease, renal graft rejection, reperfusion injury, respiratory distress syndrome, retinal disease, retrolental fibroplasia, Reynaud's syndrome, rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoid arthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis, Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, Sezary syndrome, sickle cell anemia, silica-induced disease (Silicosis), Sjogren's syndrome, skin diseases, skin irritation, skin rash, skin sensitization (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathies, sports injuries, sprains and strains, Stevens- Johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunbum, synovial inflammation, systemic inflammatory response syndrome (SIRS), systemic lupus erythematosus (SLE), systemic mast cell disease (SMCD), systemic vasculitis, systemic-onset juvenile idiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroditis, thyroiditis, tissue transplant, toxoplasmosis, trachoma, transplantation rejection, traumatic brain injury, tuberculosis, tubulointerstitial nephritis, tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS), type 1 diabetes, type 2 diabetes, complications from type 1 or type 2 diabetes, ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis, vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis, and Whipple's disease.

[0069] As used herein the term “inflammatory bowel disease” or “IBD” is a collective term describing inflammatory disorders of the gastrointestinal tract, the most common forms of which are ulcerative colitis and Crohn’s disease. Other forms of IBD include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behcet' s disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn’s (granulomatous) colitis, irritable bowelsyndrome, mucositis, radiation induced enteritis, short bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, and chronic diarrhea.

[0070] ‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0071] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.

[0072] The terms “inhibit” and “inhibition” indicate a decrease in the baseline activity of a biological activity or process. “Inhibition of activity of a4[37 integrin” or variants thereof refers to a decrease in activity of a4[37 integrin as a direct or indirect response to the presence of a compound of the present application relative to the activity of a4[37 integrin in the absence of the compound of the present application. “Inhibition of a4[37” refers to a decrease in a4[37 integrin activity as a direct or indirect response to the presence of a compound described herein relative to the activity of a4[37 integrin in the absence of the compound described herein. In some embodiments, the inhibition of a4[37 integrin activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.

[0073] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.

[0074] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature ( referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latterembodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0075] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (nC), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36C1), chlorine-37 (37C1), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0076] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such asnC,18F,150 and13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0077] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.

[0078] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.

[0079] ‘ Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7i electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.

[0080] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0081] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0082] An optical isomer with unknown absolute configuration may be depicted with an asterix (*) at the chiral center, e.g.,Likewise, when a chemical structure possessing one or more asymmetric centers is described using its chemical name, stereocenters with unknown absolute configuration may be depicted with an asterix (*), e.g. R* and / or S*.

[0083] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0084] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.THE INVENTION

[0085] The present invention relates to compounds that may be useful in the prophylaxis and / or treatment of diseases, disorders, or conditions that are mediated by a4[37 integrin. The present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and / or treatment of diseases, disorders, or conditions that are mediated by a4[37 integrin by administering a compound of the invention.

[0086] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula (I):whereinR1is a hydrogen atom; orCi-6 alkyl unsubstituted or substituted with one or more independently selected R8; orC2-6 alkenyl unsubstituted or substituted with one or more independently selected R8; orC2-6 alkynyl unsubstituted or substituted with one or more independently selected R8; orC3-7 cycloalkyl unsubstituted or substituted with one or more substituents independently selected R6a; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6a; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6a; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6a; or aryl, preferably phenyl, which is unsubstituted or substituted with one or more independently selected R6a;R2is a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6b; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6b; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6b; or-N(C=O)CI-6 alkoxy; or- -NH-C(=O)NH2; or- -NH-C(=0)NH(CI-6) alkyl); or- -NH-C(=0)N(CI.6) alkyl)2;R3is hydroxyl, Ci-6 alkyl, Ci-6 alkoxy, cyano, nitro, halogen, Ci-6 haloalkyl, Ci-6 haloalkoxy, -SO2(Ci- e)alkyl, -SO2(Ci.6)haloalkyl, -SO2(C3-6)cycloalkyl, -CHO, -CO2(Ci.6)alkyl, -C(O)NH2, -C(O)NH(CI.4alkyl), -C(O)N(CI-4 alkyl)2, -NRnR12, where R11and R12are each independently hydrogen or C1-C3 alkyl or R11and R12together with the nitrogen atom form a 4- to 6-membered heterocyclic ring, which ring is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, Ci- 4 haloalkyl and C3-7 cycloalkyl; orR3is C2alkenyl, which alkenyl is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, C1-4 haloalkyl and C3-7 cycloalkyl; orR3is C4-8 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkenyl, which cycloalkenyl is unsubstituted or substituted with one or more substituents independently selected from halogen, C1-4 alkyl and C1-4 haloalkyl; orR3is C2 alkynyl, which alkynyl is unsubstituted or substituted with one or more substituents independently selected from C1-3 alkyl and C1-3 haloalkyl; orR3is C2 alkynyl, which alkynyl is substituted with a C3-6 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one or more independently selected R6c; or a 3-6 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl containing at least one heteroatom selected from O, N, and S, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;R4is a hydrogen atom or C1-6 alkyl;R5is: aryl, preferably phenyl, which is unsubstituted or substituted with one or more independently selected R6c; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6c; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6c; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6c; or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one or more independently selected R6c; each R6ais independently selected from: cyano; hydroxy; halogen;Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen; andCi -e alkyl unsubstituted or substituted with one or more independently selected halogen; each R6bis independently selected from: cyano; hydroxy; halogen;Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen and (C1-4 alkyl)2amino;C1-4 alkylamino, which is unsubstituted or the alkyl group of which is substituted with a (Ci-4 alkyl)2amino;(Ci-4 alkyl)2amino, which is unsubstituted or an alkyl group of which is substituted with a (Ci-4 alkyl)2amino;-NHSChheterocycloalkyl, which heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which is unsubstituted or substituted with a C1-4 alkyl;Ci -e alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6d;- -NHSO2(Ci-4)alkyl;-NHSO2(Ci-4)haloalkyl;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more independently selected - CN, -OH, C1-4 alkoxy, halo, (C1-4 alkyl)2amino or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; and4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which heterocycloalkyl is unsubstituted or substituted with a C1-4 alkyl; or an oxo group; each R6cis independently selected from: cyano; hydroxy; halogen;Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen;Ci -e alkyl unsubstituted or substituted with one or more or more substituents independently selected from halogen;C2-6 alkenyl unsubstituted or substituted with one or more independently selected halogen;C2-6 alkynyl unsubstituted or substituted with one or more independently selected halogen;- -NHSO2(Ci-4)alkyl;-NHSO2(Ci-4)haloalkyl;-P(O)(Ci-4 alkyl)2, or -P(O)(R13)(R14) wherein R13and R14together with the phosphorous atom form a 3-6 membered monocyclic heterocycloalkyl;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more independently selected - CN, -OH, C1-4 alkoxy, halo, or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; and4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which heterocycloalkyl is unsubstituted or substituted with a C1-4 alkyl;each R6dis independently selected from: cyano; hydroxy; halogen; andCi -e alkyl unsubstituted or substituted with one or more independently selected cyano, hydroxy, halogen;R7is hydrogen or Ci-6 alkyl; each R8is independently selected from: cyano; hydroxy; halogen;- -NH(CI.6 alkyl);- -N(CI.6 alkyl)( Ci-6 alkyl);Ci -4 alkoxy unsubstituted or substituted with one or more independently selected halogen;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more substituents independently selected from halogen, C1-4 haloalkyl, cyano and hydroxy; a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6d; andR9and R10are each independently selected from: hydrogen; cyano; halogen;C1-6 alkyl;C1-6 haloalkyl; andC3-6 cycloalkyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0087] Certain compounds according to the invention may exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and / or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drug-drug interaction (DDI) or CYP-interaction characteristics, etc), improved selectivity for one or more disease-associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.

[0088] Preferred values of R1, R2, R3, R4, R5, R6a, R6b, R6c, R6d, R7, R8, R9and R10are, in any combination thereof, as set out below:

[0089] Preferably R1is: a hydrogen atom; orCi-6 alkyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-6 alkenyl unsubstituted or substituted with one, two, three or four independently selected R8; or C2-6 alkynyl unsubstituted or substituted with one, two, three or four independently selected R8; or C3-7 cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected R6a; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6a; or phenyl, which is unsubstituted or substituted with one, two, three or four independently selected R6a.

[0090] More preferably R1is:C2-5 alkyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-5 alkenyl unsubstituted or substituted with one, two, three or four independently selected R8; or C2-5 alkynyl unsubstituted or substituted with one, two, three or four independently selected R8; or C3-6 cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected R6a.

[0091] Even more preferably R1is selected from ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tertbutyl and neopentyl, each of which is unsubstituted or substituted with one, two or three fluorine atoms; orR1is allyl or propargyl;

[0092] More preferably still R1is selected from propyl, butyl, iso-butyl, sec-butyl, tert-butyl, neopentyl

[0093] Most preferably R1is selected from propyl, butyl, iso-butyl, sec-butyl, tert-butyl, neopentyl and propargyl; or R1is. Especially most preferred, R1is iso-butyl.

[0094] Preferably R2is a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6b; ora 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one, two, three or four independently selected R6b; or heteroaryl, which heteroaryl is unsubstituted or substituted with one, two, three or four independently selected R6b; or-N(C=O)CI-6 alkoxy; or- -NH-C(=O)NH2; or- -NH-C(=0)NH(CI-6) alkyl); or- -NH-C(=0)N(CI.6) alkyl)2.

[0098] Preferably R3is C1-4 alkoxy, cyano, nitro, halogen, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(Ci-4)alkyl, -SO2(Ci.4)haloalkyl, -SO2(C3-5)cycloalkyl, -C(O)NH2, -C(O)NH(CI.2alkyl), -C(O)N(CI.2alkyl)2, -NRnR12, where R11and R12are each independently hydrogen or C1-C3 alkyl or R11and R12together with the nitrogen atom form a 4- to 6-membered heterocyclic ring, which ring is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, C1-4 haloalkyl and C3-7 cycloalkyl; orR3is C2alkenyl, which alkenyl is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, C1-2 haloalkyl and C3-6 cycloalkyl; orR3is C4-7 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkenyl, which cycloalkenyl is unsubstituted or substituted with one or more substituents independently selected from halogen, C1-2 alkyl and C1-2 haloalkyl; orR3is C2alkynyl, which alkynyl is unsubstituted or substituted with one or more substituents independently selected from C1-3 alkyl and C1-3 haloalkyl; orR3is C2alkynyl, which alkynyl is substituted with a C3-6 cycloalkyl or a 3-6 membered monocyclic heterocycloalkyl containing one heteroatom selected from O, N, and S, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy.

[0099] More preferably R3is C1-2 alkoxy, cyano, fluoro, chloro, bromo, C1-2 haloalkyl, C1-2 haloalkoxy, - SO2(Ci.2)alkyl, -SO2(Ci.2)haloalkyl, -C(O)NH2, -C(O)NH(CH3), or C2alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; or R3is C2alkynyl, which alkynyl is substituted with a C3-6 cycloalkyl or a 3-6 membered monocyclic heterocycloalkyl containing one heteroatom selected from O and N, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, Ci-4haloalkyl or C 1.4 alkoxy.

[0100] More preferably still R3is difluoromethyl, trifluoromethyl, chloro, fluoro, cyano, -SO2CH3, - CH2CF3, -CF2CF3, CF2CH3 or C2alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; or R3is C2alkynyl, which alkynyl is substituted with a C3-5 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from fluorine, hydroxyl, methyl, trifluoromethyl or methoxy;

[0101] Most preferably R3is difluoromethyl, trifluoromethyl, chloro, cyano, or C2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; or R3is a C2 alkynyl selected from

[0102] Preferably R4is a hydrogen atom or C1-4 alkyl.

[0103] Most preferably R4is a hydrogen atom.

[0104] Preferably R5is: phenyl, which is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one, two, three or four independently selected R6c; or heteroaryl, which heteroaryl is unsubstituted or substituted with one, two, three or four independently selected R6c; ora 5-9 membered monocyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one, two, three or four independently selected R6c.

[0107] Preferably each R6ais independently selected from: cyano; hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one, two, three or four substituents independently selected from halogen; andCi-6 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen.

[0108] More preferably each R6ais independently selected from: cyano; hydroxy; halogen; andCi-2 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen.

[0109] Most preferably each R6ais independently selected from: fluoro; andchloro.

[0110] Preferably each R6bis independently selected from: cyano; hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one, two, three or four substituents independently selected from halogen and (C1.4 alkyl)2amino;C1.4 alkylamino, which is unsubstituted or the alkyl group of which is substituted with a (Ci-4 alkyl)2amino;(C1-4 alkyl)2amino, which is unsubstituted or an alkyl group of which is substituted with a (Ci-4 alkyl)2amino;C1-6 alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, C1.4 alkoxy, C1-4 alkylamino, (C1.4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d;- -NHSO2(Ci.4)alkyl;-NHSO2(Ci-4)haloalkyl; and an oxo group.[OlH] Most preferably each R6bis independently selected from: an oxo group fluoro; chloro; andC1.4 alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, C1.4 alkoxy, C1-4 alkylamino, (C1.4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d.

[0112] Preferably each R6cis independently selected from:C1.4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen;C1-6 alkyl unsubstituted or substituted with one or more or more substituents independently selected from halogen; cyano;-NHSC>2(Ci.4)alkyl; and-NHSO2(Ci-4)haloalkyl; andC3-6 monocyclic cycloalkyl.

[0113] Most preferably each R6cis independently selected from: cyano;Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from fluoro and chloro; andCi -4 alkyl unsubstituted or substituted with one or more or more substituents independently selected from fluoro and chloro.

[0114] Preferably each R6dis independently selected from halogen; and Ci-6 alkyl unsubstituted or substituted with one or more independently selected cyano, hydroxy, halogen.

[0115] Most preferably each R6dis independently selected from fluoro; chloro; and C1-2 alkyl unsubstituted or substituted with one, two, three or four substituents independently selected from fluoro and chloro.

[0116] Preferably R7is hydrogen or C1-4 alkyl.

[0117] More preferably R7is hydrogen or C1-2 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen.

[0118] Most preferably R7is a hydrogen atom.

[0119] Preferably each R8is independently selected from: cyano; hydroxy; halogen;- -NH(CI.6 alkyl);-N(CI-6 alkyl)2;C1.4 alkoxy unsubstituted or substituted with one, two, three or four independently selected halogen;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected from halogen, C1-2 haloalkyl, cyano and hydroxy; and a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d.

[0120] Most preferably each R8is independently selected from: cyano; hydroxy; fluoro; and chloro.

[0121] Preferably R9and R10are each independently selected from: hydrogen cyano; fluoro;chloro;- Ci-3 alkyl;Ci-s haloalkyl; andC3-6 cycloalkyl.

[0122] More preferably R9and R10are each independently selected from: hydrogen; fluoro; chloro;Ci-2haloalkyl;C3-4 cycloalkyl; and methyl.

[0123] Even more preferably R9and R10are each independently selected from hydrogen, fluoro and trifluoromethyl.

[0124] Yet more preferably R9and R10are each independently selected from hydrogen and fluoro.

[0125] Most preferably R9is hydrogen and R10is fluoro; or R9is fluoro and R10is hydrogen; or both of R9and R10are hydrogen.

[0126] A preferred group of compounds according to the invention are those of formula I- la, which are compounds of formula I wherein:R1is a hydrogen atom; orC1-6 alkyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-6 alkenyl unsubstituted or substituted with one, two, three or four independently selected R8; or C2-6 alkynyl unsubstituted or substituted with one, two, three or four independently selected R8; or C3-7 cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected R6a; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6a; or phenyl, which is unsubstituted or substituted with one, two, three or four independently selected R6a;R2is a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6b; ora 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one, two, three or four independently selected R6b; or heteroaryl, which heteroaryl is unsubstituted or substituted with one, two, three or four independently selected R6b; or -N(C=O)CI-6 alkoxy; or- -NH-C(=O)NH2; or- -NH-C(=0)NH(CI-6) alkyl); or- -NH-C(=0)N(CI.6) alkyl)2;R3is Ci-4 alkoxy, cyano, nitro, halogen, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(Ci-4)alkyl, -SO2(Ci-4)haloalkyl, -SO2(C3-5)cycloalkyl, -C(O)NH2, -C(O)NH(CI.2alkyl), -C(O)N(CI.2alkyl)2, or C2alkynyl, which alkynyl is unsubstituted or substituted with C1-2 alkyl, C1-2 haloalkyl or C3-6 cycloalkyl;R4is a hydrogen atom or C1-4 alkyl;R5is: phenyl, which is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one, two, three or four independently selected R6c; or heteroaryl, which heteroaryl is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 5-9 membered monocyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one, two, three or four independently selected R6c; each R6ais independently selected from: cyano; hydroxy; halogen;C1-4 alkoxy unsubstituted or substituted with one, two, three or four substituents independently selected from halogen; andC1-6 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen; each R6bis independently selected from: cyano;hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one, two, three or four substituents independently selected from halogen and (C1-4 alkyl)2amino;C1-4 alkylamino, which is unsubstituted or the alkyl group of which is substituted with a (Ci-4 alkyl)2amino;(C1-4 alkyl)2amino, which is unsubstituted or an alkyl group of which is substituted with a (Ci-4 alkyl)2amino;Ci -e alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d;- -NHSO2(Ci-4)alkyl;-NHSO2(Ci-4)haloalkyl; and an oxo group; each R6cis independently selected from:Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen;Ci -e alkyl unsubstituted or substituted with one or more or more substituents independently selected from halogen;- -NHSO2(Ci-4)alkyl;-NHSO2(Ci-4)haloalkyl; andC3-6 monocyclic cycloalkyl; each R6dis independently selected from: halogen; andCi -e alkyl unsubstituted or substituted with one or more independently selected cyano, hydroxy, halogen;R7is hydrogen or C1-4 alkyl; each R8is independently selected from: cyano; hydroxy; halogen;- -NH(CI.6 alkyl);-N(CI-6 alkyl)2;C1-4 alkoxy unsubstituted or substituted with one, two, three or four independently selected halogen;Cs-e monocyclic cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected from halogen, C1-2 haloalkyl, cyano and hydroxy; and a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d; andR9and R10are each independently selected from: hydrogen cyano; fluoro; chloro;- C1.3 alkyl;C1-3 haloalkyl; andC3-6 cycloalkyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0127] A preferred group of compounds according to the invention are those of formula I- lb, which are compounds of formula I wherein:R1is: a hydrogen atom; orC1-6 alkyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-6 alkenyl unsubstituted or substituted with one, two, three or four independently selected R8; or C2-6 alkynyl unsubstituted or substituted with one, two, three or four independently selected R8; or C3-7 cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected R6a; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6a; or phenyl, which is unsubstituted or substituted with one, two, three or four independently selected R6a;R2is a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6b; ora 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one, two, three or four independently selected R6b; or heteroaryl, which heteroaryl is unsubstituted or substituted with one, two, three or four independently selected R6b; or -N(C=O)CI-6 alkoxy; or- -NH-C(=O)NH2; or- -NH-C(=0)NH(CI-6) alkyl); or- -NH-C(=0)N(CI.6) alkyl)2;R3is Ci-4 alkoxy, cyano, nitro, halogen, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(Ci-4)alkyl, -SO2(Ci-4)haloalkyl, -SO2(C3-5)cycloalkyl, -C(O)NH2, -C(O)NH(CI.2alkyl), -C(O)N(CI.2alkyl)2, -NRnR12, where R11and R12are each independently hydrogen or C1-C3 alkyl or R11and R12together with the nitrogen atom form a 4- to 6-membered heterocyclic ring, which ring is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, C1-4 haloalkyl and C3-7 cycloalkyl; orR3is C2alkenyl, which alkenyl is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, C1-2 haloalkyl and C3-6 cycloalkyl; orR3is C2alkynyl, which alkynyl is unsubstituted or substituted with one or more substituents independently selected from C1-3 alkyl and C1-3 haloalkyl; orR3is C2alkynyl, which alkynyl is substituted with a C3-6 cycloalkyl or a 3-6 membered monocyclic heterocycloalkyl containing one heteroatom selected from O, N, and S, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;R4is a hydrogen atom or C1-4 alkyl;R5is: phenyl, which is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one, two, three or four independently selected R6c; or heteroaryl, which heteroaryl is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 5-9 membered monocyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one, two, three or four independently selected R6c;each R6ais independently selected from: cyano; hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one, two, three or four substituents independently selected from halogen; andCi-6 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen; each R6bis independently selected from: cyano; hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one, two, three or four substituents independently selected from halogen and (C1-4 alkyl)2amino;C1-4 alkylamino, which is unsubstituted or the alkyl group of which is substituted with a (Ci-4 alkyl)2amino;(C1-4 alkyl)2amino, which is unsubstituted or an alkyl group of which is substituted with a (Ci-4 alkyl)2amino;Ci -e alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d;- -NHSO2(Ci-4)alkyl;-NHSO2(Ci-4)haloalkyl; and an oxo group; each R6cis independently selected from:Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen;Ci -e alkyl unsubstituted or substituted with one or more or more substituents independently selected from halogen; cyano;-NHSC>2(Ci.4)alkyl; and-NHSO2(Ci-4)haloalkyl; andC3-6 monocyclic cycloalkyl; each R6dis independently selected from halogen; and Ci-e alkyl unsubstituted or substituted with one or more independently selected cyano, hydroxy, halogen;R7is hydrogen or C1-4 alkyl;

[0128] each R8is independently selected from: cyano; hydroxy; halogen;- -NH(CI.6 alkyl);-N(CI-6 alkyl)2;C1-4 alkoxy unsubstituted or substituted with one, two, three or four independently selected halogen;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected from halogen, C1-2 haloalkyl, cyano and hydroxy; and a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d; andR9and R10are each independently selected from: hydrogen cyano; fluoro; chloro;- C1.3 alkyl;C1-3 haloalkyl; andC3-6 cycloalkyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0129] Another preferred group of compounds according to the invention are those of formula I-2a, which are compounds of formula I wherein:R1isC2-5 alkyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-5 alkenyl unsubstituted or substituted with one, two, three or four independently selected R8; or C2-5 alkynyl unsubstituted or substituted with one, two, three or four independently selected R8; or C3-6 cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected R6a;R3is Ci-2 alkoxy, cyano, fluoro, chloro, bromo, C1-2 haloalkyl, C1-2 haloalkoxy, -SC>2(Ci.2)alkyl, -SC>2(Ci. 2)haloalkyl, -C(0)NH2, -C(0)NH(CH3), or C2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, trifluoromethyl or C3-4 cycloalkyl;R4is a hydrogen atom;each R6ais independently selected from cyano; hydroxy; halogen; andCi-2 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen;R7is hydrogen or C1-2 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen; each R8is independently selected from: cyano; hydroxy; fluoro; and chloro; andR9and R10are each independently selected from: hydrogen;C3-4 cycloalkyl; fluoro; chloro;Ci-2haloalkyl; and methyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0130] Another preferred group of compounds according to the invention are those of formula I-2b, which are compounds of formula I wherein:R1is:C2-5 alkyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-5 alkenyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-5 alkynyl unsubstituted or substituted with one, two, three or four independently selected R8; orCs-e cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected R6a;R3is Ci-2 alkoxy, cyano, fluoro, chloro, bromo, C1-2 haloalkyl, C1-2 haloalkoxy, -SC>2(Ci.2)alkyl, -SC>2(Ci. 2)haloalkyl, -C(0)NH2, -C(0)NH(CH3), or C2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; orR3is C2 alkynyl, which alkynyl is substituted with a C3-6 cycloalkyl or a 3-6 membered monocyclic heterocycloalkyl containing one heteroatom selected from O and N, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;R3is C1-2 alkoxy, cyano, fluoro, chloro, bromo, C1-2 haloalkyl, C1-2 haloalkoxy, -SC>2(Ci.2)alkyl, -SC>2(Ci. 2)haloalkyl, -C(0)NH2, -C(0)NH(CH3), or C2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; orR3is C2 alkynyl, which alkynyl is substituted with a C3-6 cycloalkyl or a 3-6 membered monocyclic heterocycloalkyl containing one heteroatom selected from O and N, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy.R4is a hydrogen atom;each R6ais independently selected from cyano; hydroxy; halogen; andC1-2 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen;R7is hydrogen or C1-2 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen; each R8is independently selected from: cyano; hydroxy; fluoro; and chloro; andR9and R10are each independently selected from:hydrogen;C3-4 cycloalkyl; fluoro; chloro;Ci-2haloalkyl; and methyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0131] Another preferred group of compounds according to the invention are those of formula I-3a, which are compounds of formula I wherein:R1is selected from ethyl, propyl, isopropyl, butyl, iso-butyl, sec -butyl, tert-butyl and neopentyl, each of which is unsubstituted or substituted with one, two or three fluorine atoms; orR1is allyl or propargyl; orR3is difluoromethyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, ethoxy, trifluoromethoxy, -SO2CH3, hydroxyl, -CH2CF3 , -CF2CF3, or CF2CH3;R4is a hydrogen atom;R7is hydrogen; andR9and R10are each independently selected from hydrogen, fluoro and trifluoromethyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0132] Another preferred group of compounds according to the invention are those of formula I-3b, which are compounds of formula I wherein:R1is selected from ethyl, propyl, isopropyl, butyl, iso-butyl, sec -butyl, tert-butyl and neopentyl, each of which is unsubstituted or substituted with one, two or three fluorine atoms; orR1is allyl or propargyl;R3is difluoromethyl, trifluoromethyl, chloro, fluoro, cyano, -SO2CH3, -CH2CF3, -CF2CF3, CF2CH3 orC2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl;or R3is C2 alkynyl, which alkynyl is substituted with a C3-5 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from fluorine, hydroxyl, methyl, trifluoromethyl or methoxy;R7is hydrogen; andR9and R10are each independently selected from hydrogen, fluoro and trifluoromethyl; or a pharmaceutically acceptable salt and / or solvate thereof

[0133] Another preferred group of compounds according to the invention are those of formula I-4a, which are compounds of formula I wherein:R1is selected from propyl, butyl, iso-butyl, sec-butyl, tert-butyl, neopentyl and propargyl; orR3is difluoromethyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, ethoxy, trifluoromethoxy, -SO2CH3, -CH2CF3, -CF2CF3, CF2CH3 or hydroxyl;R4is a hydrogen atom;R7is hydrogen; andR9and R10are each independently selected from hydrogen and fluoro, wherein preferably R9is hydrogen and R10is fluoro, or R9is fluoro and R10is hydrogen, or both of R9and R10are hydrogen; or a pharmaceutically acceptable salt and / or solvate thereof.

[0134] Another preferred group of compounds according to the invention are those of formula I-4b, which are compounds of formula I wherein:R1is selected from propyl, butyl, iso-butyl, sec-butyl, tert-butyl, neopentyl and propargyl; orR1is -CH2CF(CH3)2, -CF2CH(CH3)2, -CH2CF2CH3or -CH2CH2CF3; orR3is difluoromethyl, trifluoromethyl, chloro, fluoro, cyano, -SO2CH3, -CFbCF,. -CF2CF3, CF2CH3or C2alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; or R3is C2alkynyl, which alkynyl is substituted with a C3.s cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from fluorine, hydroxyl, methyl, trifluoromethyl or methoxy;R7is hydrogen; andR9and R10are each independently selected from hydrogen and fluoro, wherein preferably R9is hydrogen and R10is fluoro, or R9is fluoro and R10is hydrogen, or both of R9and R10are hydrogen; or a pharmaceutically acceptable salt and / or solvate thereof.

[0135] Another preferred group of compounds according to the invention are those of formula 1-5, which are compounds of formula I wherein:R1is iso-butyl;R3is difluoromethyl, trifluoromethyl, chloro, cyano, or C2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; or R3is a C2 alkynyl selected fromR4is a hydrogen atom;R5isR7is a hydrogen atom; andR9is hydrogen and R10is fluoro, or R9is fluoro and R10is hydrogen, or both of R9and R10are hydrogen; or a pharmaceutically acceptable salt and / or solvate thereof.

[0136] In one embodiment, the compound of the invention according to Formula I is selected from:

[0137] In one embodiment, the compounds of the invention are provided in a natural isotopic form.

[0138] In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e.2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of theinvention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0139] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0140] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.

[0141] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0142] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.

[0143] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0144] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.

[0145] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.

[0146] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above and below. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0147] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.

[0148] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0149] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.EMBODIMENTS

[0150] Further embodiments according to the invention are provided as set out below.

[0151] Embodiment 1 provides a compound of Formula (I):whereinR1is a hydrogen atom; orC1-6 alkyl unsubstituted or substituted with one or more independently selected R8; orC2-6 alkenyl unsubstituted or substituted with one or more independently selected R8; orC2-6 alkynyl unsubstituted or substituted with one or more independently selected R8; orC3-7 cycloalkyl unsubstituted or substituted with one or more substituents independently selected R6a; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6a; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6a; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6a; or aryl, preferably phenyl, which is unsubstituted or substituted with one or more independently selected R6a;R2is a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6b; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6b; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6b; or-N(C=O)CI-6 alkoxy; or- -NH-C(=O)NH2; or- -NH-C(=0)NH(CI-6) alkyl); or- -NH-C(=0)N(CI.6) alkyl)2;R3is hydroxyl, Ci-6 alkyl, Ci-6 alkoxy, cyano, nitro, halogen, Ci-6 haloalkyl, Ci-6 haloalkoxy, -SO2(Ci- e)alkyl, -SO2(Ci.6)haloalkyl, -SO2(C3-6)cycloalkyl, -CHO, -CO2(Ci.6)alkyl, -C(O)NH2, -C(O)NH(CI.4alkyl), -C(O)N(CI-4 alkyl)2, -NRnR12, where R11and R12are each independently hydrogen or C1-C3 alkyl or R11and R12together with the nitrogen atom form a 4- to 6-membered heterocyclic ring, which ring is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, Ci- 4 haloalkyl and C3-7 cycloalkyl; orR3is C2alkenyl, which alkenyl is unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, C1-4 haloalkyl and C3-7 cycloalkyl; orR3is C4-8 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkenyl, which cycloalkenyl is unsubstituted or substituted with one or more substituents independently selected from halogen, C1-4 alkyl and C1-4 haloalkyl; orR3is C2alkynyl, which alkynyl is unsubstituted or substituted with one or more substituents independently selected from C1-3 alkyl and C1-3 haloalkyl; orR3is C2alkynyl, which alkynyl is substituted with a C3-6 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one or more independently selected R6c; or a 3-6 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl containing at least one heteroatom selected from O, N, and S, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;R4is a hydrogen atom or C1-6 alkyl;R5is: aryl, preferably phenyl, which is unsubstituted or substituted with one or more independently selected R6c; ora 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6c; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6c; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6c; or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one or more independently selected R6c; each R6ais independently selected from: cyano; hydroxy; halogen;Ci .4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen; andCi -e alkyl unsubstituted or substituted with one or more independently selected halogen; each R6bis independently selected from: cyano; hydroxy; halogen;Ci .4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen and (Ci-4 alkyl)2amino;Ci-4 alkylamino, which is unsubstituted or the alkyl group of which is substituted with a (Ci-4 alkyl)2amino;(Ci-4 alkyl)2amino, which is unsubstituted or an alkyl group of which is substituted with a (Ci-4 alkyl)2amino;-NHSChheterocycloalkyl, which heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which is unsubstituted or substituted with a Ci-4 alkyl;Ci -e alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, Ci-4 alkoxy, Ci-4 alkylamino, (Ci-4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6d;- -NHSO2(Ci-4)alkyl;-NHSO2(Ci-4)haloalkyl;Cs-e monocyclic cycloalkyl unsubstituted or substituted with one or more independently selected - CN, -OH, Ci-4 alkoxy, halo, (C1-4 alkyl)2amino or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; and4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which heterocycloalkyl is unsubstituted or substituted with a C1-4 alkyl; or an oxo group; each R6cis independently selected from: cyano; hydroxy; halogen;Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen;Ci -e alkyl unsubstituted or substituted with one or more or more substituents independently selected from halogen;C2-6 alkenyl unsubstituted or substituted with one or more independently selected halogen;C2-6 alkynyl unsubstituted or substituted with one or more independently selected halogen;- -NHSO2(Ci-4)alkyl;-NHSO2(Ci-4)haloalkyl;-P(O)(Ci-4 alkyl)2, or -P(O)(R13)(R14) wherein R13and R14together with the phosphorous atom form a 3-6 membered monocyclic heterocycloalkyl;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more independently selected - CN, -OH, C1-4 alkoxy, halo, or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; and4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which heterocycloalkyl is unsubstituted or substituted with a C1-4 alkyl; each R6dis independently selected from: cyano; hydroxy; halogen; andCi -e alkyl unsubstituted or substituted with one or more independently selected cyano, hydroxy, halogen;R7is hydrogen or C1-6 alkyl; each R8is independently selected from: cyano; hydroxy; halogen;- -NH(CI.6 alkyl);- -N(CI.6 alkyl)( Ci-6 alkyl);Ci -4 alkoxy unsubstituted or substituted with one or more independently selected halogen;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more substituents independently selected from halogen, C1-4 haloalkyl, cyano and hydroxy; a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6d; and R9and R10are each independently selected from: hydrogen; cyano; halogen;C1-6 alkyl;C1-6 haloalkyl; andC3-6 cycloalkyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0152] Embodiment 2 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, wherein R1is: a hydrogen atom; orC1-6 alkyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-6 alkenyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-6 alkynyl unsubstituted or substituted with one, two, three or four independently selected R8; or C3-7 cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected R6a; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6a; or phenyl, which is unsubstituted or substituted with one, two, three or four independently selected R6a.

[0153] Embodiment 3 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1 or 2, wherein R2is: a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6b; ora 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one, two, three or four independently selected R6b; or heteroaryl, which heteroaryl is unsubstituted or substituted with one, two, three or four independently selected R6b; or -N(C=O)CI-6 alkoxy; or- -NH-C(=O)NH2; or- -NH-C(=0)NH(CI-6) alkyl); or- -NH-C(=0)N(CI.6) alkyl)2.

[0154] Embodiment 4 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2 or 3, wherein R3is Ci-4 alkoxy, cyano, nitro, halogen, Ci-4 haloalkyl, Ci-4haloalkoxy, -SO2(Ci.4)alkyl, -SO2(Ci.4)haloalkyl, -SO2(C3-5)cycloalkyl, -C(O)NH2, -C(O)NH(CI.2alkyl), -C(O)N(CI-2alkyl)2, or C2alkynyl, which alkynyl is unsubstituted or substituted with Ci-2alkyl, Ci-2haloalkyl or C3-6 cycloalkyl.

[0155] Embodiment 5 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3 or 4, wherein R4is a hydrogen atom or Ci.4alkyl.

[0156] Embodiment 6 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4 or 5, wherein R5is: phenyl, which is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one, two, three or four independently selected R6c; or heteroaryl, which heteroaryl is unsubstituted or substituted with one, two, three or four independently selected R6c; or a 5-9 membered monocyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one, two, three or four independently selected R6c.

[0157] Embodiment 7 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5 or 6, wherein each R6ais independently selected from: cyano; hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one, two, three or four substituents independently selected from halogen; andCi-6 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen.

[0158] Embodiment 8 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6 or 7, wherein each R6bis independently selected from: cyano; hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one, two, three or four substituents independently selected from halogen and (C1.4 alkyl)2amino;C1.4 alkylamino, which is unsubstituted or the alkyl group of which is substituted with a (Ci-4 alkyl)2amino;(C1-4 alkyl)2amino, which is unsubstituted or an alkyl group of which is substituted with a (Ci-4 alkyl)2amino;C1-6 alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, C1.4 alkoxy, C1-4 alkylamino, (C1.4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d;- -NHSO2(Ci.4)alkyl;-NHSO2(Ci-4)haloalkyl; and an oxo group.

[0159] Embodiment 9 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7 or 8, wherein each R6cis independently selected from:C1.4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen;C1-6 alkyl unsubstituted or substituted with one or more or more substituents independently selected from halogen;-NHSC>2(Ci.4)alkyl; and-NHSO2(Ci-4)haloalkyl; andC3-6 monocyclic cycloalkyl.

[0160] Embodiment 10 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein each R6dis independently selected from halogen; and C1-6 alkyl unsubstituted or substituted with one or more independently selected cyano, hydroxy, halogen.

[0161] Embodiment 11 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein R7is hydrogen or Ci-4 alkyl.

[0162] Embodiment 12 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein each R8is independently selected from: cyano; hydroxy; halogen;- -NH(CI.6 alkyl);-N(CI-6 alkyl)2;Ci-4 alkoxy unsubstituted or substituted with one, two, three or four independently selected halogen;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected from halogen, C1-2 haloalkyl, cyano and hydroxy; a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d.

[0163] Embodiment 13 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein R9and R10are each independently selected from: hydrogen cyano; fluoro; chloro;- C1.3 alkyl;C1-3 haloalkyl; andC3-6 cycloalkyl.

[0164] Embodiment 14 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein R1is:C2-5 alkyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-5 alkenyl unsubstituted or substituted with one, two, three or four independently selected R8; or C2-5 alkynyl unsubstituted or substituted with one, two, three or four independently selected R8; or C3-6 cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected R6a.

[0165] Embodiment 15 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein R2is:

[0166] Embodiment 16 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein R3is C1-2 alkoxy, cyano, fluoro, chloro, bromo, C1-2 haloalkyl, C1-2 haloalkoxy, -SO2(Ci-2)alkyl, -SO2(Ci-2)haloalkyl, -C(O)NH2, - C(O)NH(CH3), or C2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, trifluoromethyl or C3-4 cycloalkyl.

[0167] Embodiment 17 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein R4is a hydrogen atom.

[0168] Embodiment 18 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, wherein R5is:

[0169] Embodiment 19 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein each R6ais independently selected from: cyano; hydroxy; halogen; andCi-2 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen.

[0170] Embodiment 20 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, wherein each R6bis independently selected from: an oxo group fluoro; chloro; andCi-4 alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, Ci-4 alkoxy, Ci-4 alkylamino, (Ci-4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d.

[0171] Embodiment 21 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein each R6cis independently selected from:Ci -4 alkoxy unsubstituted or substituted with one or more substituents independently selected from fluoro and chloro; andCi -4 alkyl unsubstituted or substituted with one or more or more substituents independently selected from fluoro and chloro.

[0172] Embodiment 22 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21, wherein each R6dis independently selected from fluoro; chloro; and C1-2 alkyl unsubstituted or substituted with one, two, three or four substituents independently selected from fluoro and chloro.

[0173] Embodiment 23 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, wherein R7is hydrogen or C1-2 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen.

[0174] Embodiment 24 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, wherein each R8is independently selected from: cyano; hydroxy; fluoro; and chloro.

[0175] Embodiment 25 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, wherein R9and R10are each independently selected from: hydrogen;C3-4 cycloalkyl; fluoro; chloro;Ci-2haloalkyl; and methyl.

[0176] Embodiment 26 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25, wherein R1is selected from ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl and neopentyl, each of which is unsubstituted or substituted with one, two or three fluorine atoms; or R1is allyl or propargyl;

[0177] Embodiment 27 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein R2is:

[0178] Embodiment 28 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27, wherein R3is difluoromethyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, ethoxy, trifluoromethoxy, -SO2CH3, -CH2CF3, -CF2CF3, CF2CH3 or hydroxyl.

[0179] Embodiment 29 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, wherein R5is:

[0180] Embodiment 30 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29, wherein each R6ais independently selected from:fluoro; and chloro.

[0181] Embodiment 31 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, wherein R7is a hydrogen atom.

[0182] Embodiment 32 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31, wherein R9and R10are each independently selected from hydrogen, fluoro and trifluoromethyl.

[0183] Embodiment 33 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31, wherein R9and R10are each independently selected from hydrogen and fluoro.

[0184] Embodiment 34 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31, wherein R9is hydrogen and R10is fluoro; or R9is fluoro and R10is hydrogen; or both of R9and R10are hydrogen.

[0185] Embodiment 35 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, wherein the compound is selected from:

[0186] Embodiment 36 provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of embodiments 1-35.

[0187] Embodiment 37 provides a compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of embodiments 1-35, or a pharmaceutical composition according to embodiment 36, for use in medicine.

[0188] Embodiment 38 provides a compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of embodiments 1-35, or a pharmaceutical composition according to embodiment 36,for use in the prophylaxis and / or treatment of a disease, disorder or condition that is mediated by a4p7 integrin.

[0189] Embodiment 38 provides a compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of embodiments 1-35, or a pharmaceutical composition according to embodiment 36, for use in the prophylaxis and / or treatment of inflammatory bowel disease, in particular Crohn’s disease and / or ulcerative colitis.

[0190] Specific examples of compounds of Formula (I) are illustrated below:PHARMACEUTICAL COMPOSITIONS

[0191] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0192] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0193] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0. 1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0194] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.

[0195] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0196] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and morepreferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.

[0197] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0198] The above -de scribed components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17thedition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0199] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0200] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.Formulation 1 - Tablets

[0201] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.Formulation 2 - Capsules

[0202] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0203] A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.Formulation 4 - Tablets

[0204] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.Formulation 5 - Injection

[0205] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL.Formulation 6 - Topical

[0206] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of A compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.METHODS OF TREATMENT

[0207] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of a disease, disorder, or condition that is mediated by a4[37 integrin.

[0208] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of a disease, disorder, or condition that is mediated by a4[37 integrin.

[0209] In another embodiment, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with a disease, disorder, or condition that is mediated by a4[37 integrin, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition.

[0210] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a treatment agent directed to a disease, disorder, or condition that is mediated by a4[37 integrin.

[0211] In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of a disease selected from: acne, acid- induced lung injury, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, adult-onset Still's disease, adult respiratory distress syndrome (ARDS), age-related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen- induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergies,allergic encephalomyelitis, allergic neuritis, allograft rejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, angiofibroma, anhidrotic ectodermal dysplasia-ill, anti -glomerular basement membrane disease, antigen-antibody complex mediated diseases, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polyendocrinopathies, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoinflammatory diseases, back pain, Bacillus anthracis infection, Bechet's disease, bee sting-induced inflammation, Behcet’s syndrome, Bell’s palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis, bullous pemphigoid (BP) asthma, bums, bursitis, cardiac hypertrophy, carpal tunnel syndrome, Castleman's disease, catabolic disorders, cataracts, Celiac disease, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, complications of organ transplantation, conjunctivitis, connective tissue disease, contact dermatitis, comeal graft neovascularization, comeal ulcer, Crohn's disease, cryopyrin-associated periodic syndromes, cutaneous lupus erythematosus (CLE), cryptococcosis, cystic fibrosis, deficiency of the interleukin- 1 receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme, erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy, familial cold urticarial, familial Mediterranean fever, fetal growth retardation, fibromyalgia, fistulizing Crohn’s disease, food allergies, giant cell arteritis, glaucoma, glioblastoma, glomerular disease, glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy, gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatous hepatitis, Graves' disease, growth plate injuries, Guillain-Barre syndrome, gut diseases, hair loss, Hashimoto's thyroiditis, head injury, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilic joints, Henoch-Scholein purpura, hepatitis, hepatic steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hereditary periodic fever syndrome, heritable disorders of connective tissue, herpes zoster and simplex, hidradenitis suppurativa (HS), hip replacement, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperactive inflammatory response, hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivity pneumonitis, hypertropic bone formation, hypoplastic and other anemias, hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, Idiopathic inflammatory myopathies (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin nephropathies, immune complex nephritis, immune thrombocytopenic purpura (ITP),incontinentia pigmenti (IP, Bloch-Siemens syndrome), infectious mononucleosis, infectious diseases including viral diseases such as AIDS (HIV infection), hepatitis A, B, C, D, and E, herpes; inflammation, inflammation of the CNS, inflammatory bowel disease (IBD), inflammatory disease of the lower respiratory tract including bronchitis or chronic obstructive pulmonary diseases, inflammatory disease of the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis, inflammatory diseases of the respiratory tract, inflammatory ischemic event such as stroke or cardiac arrest, inflammatory lung disease, inflammatory myopathy such as myocarditis, inflammatory liver disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, interstitial cystitis, interstitial lung disease, iritis, irritant-induced inflammation, ischemia / reperfiision, joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidney injury caused by parasitic infections, kidney transplant rejection, leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), Lambert-Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupus nephritis, Lyme disease, Marfan syndrome (MPS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Muckle- Wells syndrome (urticaria deafness amyloidosis), mucositis, multiple organ injury syndrome, multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis, neuropathological diseases, nonallergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, Osier-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, pachyonychia congenita, Paget’s disease, Paget’s disease of bone, pancreatitis, Parkinson's disease, pediatric rheumatology, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pernicious anemia (Addison's disease), pertussis, PLAPA (periodic fever aphthous pharyngitis and cervical adenopathy), pharyngitis and adenitis (PLAPA syndrome), plant irritant-induced inflammation, pneumocystis infection, pneumonia, pneumonitis, poison ivy / urushiol oil- induced inflammation, polyarthritis nodosa, polychondritis, polycystic kidney disease, polymyalgia rheumatic, giant cell arteritis, polymyositis, pouchitis, reperfusion injury and transplant rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary sclerosing cholangitis (PSC), proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriatic epidermis, psychosocial stress diseases, pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenic granuloma retrolental fibroplasias, pyogenic sterile arthritis, Raynaud’s syndrome, Reiter's disease, reactive arthritis, renal disease, renal graft rejection, reperfusion injury, respiratory distress syndrome, retinal disease, retrolental fibroplasia, Reynaud's syndrome, rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoid arthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis, Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, Sezary syndrome, sickle cell anemia, silica-induced disease (Silicosis), Sjogren's syndrome, skin diseases, skin irritation, skin rash, skin sensitization (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathies, sports injuries,sprains and strains, Stevens- Johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovial inflammation, systemic inflammatory response syndrome (SIRS), systemic lupus erythematosus, systemic mast cell disease (SMCD), systemic vasculitis, systemic-onset juvenile idiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroditis, thyroiditis, tissue transplant, toxoplasmosis, trachoma, transplantation rejection, traumatic brain injury, tuberculosis, tubulointerstitial nephritis, tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS), type 1 diabetes, type 2 diabetes, complications from type 1 or type 2 diabetes, ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis, vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis, and Whipple's disease.

[0212] In another embodiment, a method is provided for alleviating a symptom of a disease or disorder mediated, at least in part, by a4[37 integrin. In a particular embodiment, the method includes identifying a mammal having a symptom of a disease or disorder mediated, at least in part, by a4[37 integrin, and providing to the mammal an amount of a compound as described herein effective to ameliorate (i.e., lessen the severity of) the symptom.

[0213] In another embodiment, the disease or condition mediated, at least in part, by a4[37 integrin is an inflammatory disease or LPS induced endotoxin shock. In a particular embodiment, the disease is an autoimmune disease. In another particular embodiment, the autoimmune disease is systemic lupus erythematosus (SLE), myasthenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis, Sjoegren’s syndrome, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD), ankylosing spondylitis, acute gout and ankylosing spondylitis, reactive arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile onset rheumatoid arthritis, juvenile rheumatoid arthritis or psoriatic arthritis. In other embodiments, the disease is inflammation. In yet other embodiments, the disease is excessive or destructive immune reactions, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.

[0214] In another embodiment, the disease or condition mediated, at least in part, by a4[37 integrin is inflammatory bowel disease (IBD). In a particular embodiment, the inflammatory bowel disease is ulcerative colitis or Crohn’s disease. In another particular embodiment, the inflammatory bowel disease is diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn’s (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation induced enteritis, short bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, or chronic diarrhea.

[0215] In another embodiment, treating or preventing IBD also includes ameliorating or reducing one or more symptoms of IBD. In a particular embodiment, the method includes ameliorating or reducing symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and othermore serious complications, such as dehydration, anemia and malnutrition. A number of such symptoms are subject to quantitative analysis (e.g. weight loss, fever, anemia, etc.). Some symptoms are readily determined from a blood test (e.g. anemia) or a test that detects the presence of blood (e.g. rectal bleeding). The diagnosis is typically determined by way of an endoscopic observation of the mucosa, and pathologic examination of endoscopic biopsy specimens.

[0216] In another embodiment, the disease or condition treated by the administration of a compound or composition described herein includes acute gout and ankylosing spondylitis, allergic disorders, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis and multiple sclerosis, atherosclerosis, bacterial infections, bone cancer pain and pain due to endometriosis, BRAF resistant melanoma, brain stem glioma or pituitary adenomas, bums, bursitis, cancer of the anal region, cancer of the endocrine system, cancer of the kidney or ureter (e.g. renal cell carcinoma, and carcinoma of the renal pelvis), cancer of the penis, cancer of the small intestine, cancer of the thyroid, cancer of the urethra, cancers of the blood such as acute myeloid leukemia, cancers of the tongue, carcinoma of the cervix, carcinoma of the endometrium, carcinoma of the fallopian tubes, carcinoma of the renal pelvis, carcinoma of the vagina or carcinoma of the vulva, chronic myeloid leukemia, chronic or acute leukemia, chronic pain, classic Bartter syndrome, common cold conjunctivitis, coronary heart disease, cutaneous or intraocular melanoma, dermatitis, dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis, fibromyalgia, fungal infections, gout, gynecologic tumors, uterine sarcomas, carcinoma of the fallopian tubes, headache, hemophilic arthropathy, Parkinson's disease, AIDS, herpes zoster, Hodgkin's disease, Huntington's, hyperprostaglandin E syndrome, influenza, iritis, juvenile arthritis juvenile onset rheumatoid arthritis, juvenile rheumatoid arthritis, low back and neck pain, lymphocytic lymphomas, myofascial disorders, myositis, neuralgia, neurodegenerative disorders such as Alzheimer's disease, neuroinflammatory disorders, neuropathic pain, carcinoma of the vulva, Parkinson's disease, pediatric malignancy, pulmonary fibrosis rectal cancer, rhinitis, sarcoidosis, sarcomas of soft tissues, scleritis, skin cancer, solid tumors of childhood, spinal axis tumors, sprains and strains, stomach cancer, stroke, subacute and chronic musculoskeletal pain syndromes such as bursitis, surgical or dental procedures, symptoms associated with influenza or other viral infections, synovitis, toothache, ulcers, uterine cancer, uterine sarcomas, uveitis, vasculitis, viral infections, viral infections {e.g. influenza) and / or wound healing.

[0217] In another embodiment, the methods are applied to a subject having IBD during a time period of remission (i.e., inactive disease). In such embodiment, the method provides benefit by extending the time period of remission (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In another embodiment, the method may be applied to a subject having IBD during a period of active disease. Such method provides benefit by reducing the duration of the period of active disease, reducing or ameliorating one or more symptoms of IBD, or treating IBD.

[0218] In another embodiment, the disease or condition is immune-mediated liver injury, disease or condition.

[0219] In another embodiment, the disease or condition mediated, at least in part, by a4[37 integrin is alcoholic hepatitis. In a particular embodiment, the compounds of the invention are administered in combination with the current treatments for alcoholic hepatitis.

[0220] In another embodiment, the disease or condition mediated, at least in part, by a4[37 integrin is fatty liver disease. In a particular embodiment, the disease is hepatic steatosis, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). In a particular embodiment, the compounds of the invention are administered in combination with the current treatments for fatty liver diseases.

[0221] In another embodiment, the present invention provides methods of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0222] In another embodiment, the disease or condition mediated, at least in part, by a4[37 integrin is systemic lupus erythematosus (SLE), lupus nephritis, lupus-related, or other autoimmune disorders or a symptom of SLE. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, mouth sores, swollen lymph nodes, sensitivity to sunlight, skin rash, headaches, numbness, tingling, seizures, vision problems, personality changes, abdominal pain, nausea, vomiting, abnormal heart rhythms, coughing up blood and difficulty breathing, patchy skin color and Raynaud's phenomenon.

[0223] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g / day for a 40 to 80 kg human patient.

[0224] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0225] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.

[0226] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0227] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0228] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0229] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.

[0230] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of a disease involving inflammation, particular agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, my cophenolate, mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0231] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept).

[0232] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of proliferative disorders, particular agents include but are not limited to: methotrexate, leukovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5 -fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. Herceptin™), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. Iressa®, Tarceva™, Erbitux™), VEGF inhibitors (e.g. Avastin™), proteasome inhibitors (e.g. Velcade™), Glivec® and hsp90 inhibitors (e.g. 17-AAG). Additionally, the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease or leukaemia.

[0233] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of autoimmune diseases, particular agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g.methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3 (0TK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-J3), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fingolimod and myriocin..

[0234] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of transplant rejection, particular agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Ra receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)).

[0235] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of asthma and / or rhinitis and / or COPD, particular agents include but are not limited to: beta2 -adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled). Long-acting [32 -agonists (e.g. salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. ceterizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline).

[0236] Additionally, a compound of the invention may be administered in combination with emergency therapies for asthma and / or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g. epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamiphylline), inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.

[0237] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of inflammatory bowel disease (IBD), particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).

[0238] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of SLE, particular agents include but are not limited to: human monoclonal antibodies (belimumab (Benlysta)), Disease-modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.

[0239] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of psoriasis, particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort™), fluocinonide, vitamin D3 analogues (for example, calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologies such as Amevive™, Enbrel™, Humira™, Remicade™, Raptiva™ and ustekinumab (a IL- 12 and IL-23 blocker). Additionally, a compound of the invention may be administered in combination with other therapies including, but not limited to phototherapy, or photochemotherapy (e.g. psoralen and ultraviolet A phototherapy (PUVA)).

[0240] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of allergic reaction, particular agents include but are not limited to: antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g. prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or antileukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.

[0241] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.CHEMICAL SYNTHETIC PROCEDURESGeneral

[0242] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0243] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Wuts & Greene 2006).

[0244] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0245] All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 pm) or with Interchim® PuriFlash® Si HC flash chromatography cartridges. Thin layer chromatography is carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Biotage® ISOLUTE® phase separators (e.g., Cat# 120-1907-E) are used for aqueous phase separation. Biotage® ISOLUTE® SCX-3 cation exchange sorbent (e.g., Cat# 533-0100-C) is used to extract basic analytes. ’H NMR spectra are recorded on a Bruker Avance 400 NMR spectrometer (400 MHz). Chemical shifts (5) for ’H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (50.00) or the appropriate residual solvent peak, i.e. CHCL (57.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m) and broad (br). Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a to a Waters QDA Mass detector spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7pm, 2.1mm ID x 50mm L, or Waters Acquity UPLC CSH C18 1.7pm, 2.1mm ID x 50mm L. The methods are using 5-95 % MeCN / H2O gradients in either 2 or 8 minute runs. H2O contains either 0.1% formic acid (when used with CSH column) , or 15 mM NH3 (when used with BEH column). Final compounds were analyzed on 8 minute runs, using either acidic conditions (analytical method A) or basic conditions (analytical method B). Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XBRIDGE BEH C18 OBD 19 mm ID * 100 mm L columns and ACN / H2O gradients with either 0.1% formic acid in H2O or 0.5% NH3 in H2O. Reversed phase column chromatography is performed using a Buchi® Pure C850 FlashPrep using the same columns as for preparative HPLC. Microwave heating is performed with a Biotage® Initiator-l-.Table I. List of abbreviations used in the experimental section:SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTIONExample 1. Synthetic methods

[0246] Generally, the compounds disclosed herein are constructed via amide coupling of a beta-amino ester with an amine, using a peptide coupling reagent like HATU (method 1), followed by basic ester hydrolysis to the corresponding carboxylic acid using a base like LiOH (method 2).Method 1: amide coupling

[0247] Acid (1-1.5 eq.) and beta-amino ester (1 eq.) are dissolved in N,N-dimethylformamide , N,N- diisopropylethylamine (2-4 eq.) is added, followed by l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1.5-2 eq.). The reaction mixture is stirred at room temperature for l-16h. The crude mixture is purified by preparative HPLC or normal phase chromatography, or used as such to afford the title compound.Representative example for Method 1: Int 7Example 2. methyl (3S)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)-3-(4-methyl- 2-(2-oxopyridin-l(2H)-yl)pentanamido)propanoate

[0248] (S)-4-methyl-2-(2-oxopyridin-l(2H)-yl)pentanoic acid (Int 6, 0.61 mmol, 135 mg, 1.2 eq.) and methyl (S)-3-amino-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoate hydrochloride (Int 5, 0.51 mmol, 200 mg, 1.0 eq.) were dissolved in N,N-dimethylformamide (4 mL) after which N,N- diisopropylethylamine (1.33 mmol, 0.23 mL, 2.6 eq.) was added, followed by 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.80 mmol, 305 mg, 1.6 eq.). The resulting mixture was stirred overnight at room temperature, after which full consumption of the starting material was obtained. The crude mixture was purified via reversed phase column chromatography. The product containing fractions were concentrated and freeze-dried to obtain a mix of two diastereomers as white powder (Int 7, 127 mg, 44% yield). LCMS (ESI, m / z): 544.3 [M+H]+Representative example for Method 1: Int 20Example 3. methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(4-methyl-2-(2- oxopyridin-l(2H)-yl)pentanamido)propanoate

[0249] 4-methyl-2-(2-oxopyridin-l(2H)-yl)pentanoic acid (Int 19, 0.74 mmol, 154 mg, 1.2 eq.) and methyl (S)-3-amino-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)propanoate hydrochloride (Int 18, 0.64 mmol, 250 mg, 1.0 eq.) were dissolved in N,N-dimethylformamide (5 mL) after which N,N- diisopropylethylamine (2.24 mmol, 0.39 mL, 3.5 eq.) was added, followed by HATU (0.96 mmol, 365 mg, 1.5 eq.) was added and stirred at room temperature for Ih. The crude mixture was purified via reversed phase column chromatography to obtain the title compound Int 20 as a mix of two diastereomers. LCMS (ESI, m / z): 510.2 [M+H]+Representative example for Method 1: Int 14Example 4. methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyri din-2- yl)propanoate

[0250] methyl (S)-3-amino-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoate hydrochloride (Int 5, 0.11 mmol, 40 mg, 1.0 eq.), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (Int 13, 0.12 mmol, 41 mg, 1.1 eq.) and N,N- diisopropylethylamine (0.27 mmol, 0.047 mL, 2.5 eq.) were dissolved in N,N-dimethylformamide (3 mL)after which HATU (0.16 mmol, 61 mg, 1.5 eq.) was added and the mixture was stirred at room temperature overnight. The mixture was purified by via reversed phase column to obtain methyl (3S)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6- dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoate (Int 14) as a mix of two diastereomers. LCMS (ESI, m / z): 683.4 [M+H]+Representative example for Method 1: Int 23Example 5. methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoate

[0251] lithium 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanoate (Int 22, 0.35 mmol, 130 mg, 1.2 eq.) and methyl (S)-3-amino-3-(6-chloro-4-(2,6- dimethylphenyl)pyridin-2-yl)propanoate (Int 21, 0.29 mmol, 94 mg, 1.0 eq.) were dissolved in N,N- dimethylformamide (4 m ) after which N,N-diisopropylethylamine (0.73 mmol, 0.13 mb, 2.5 eq.) and HATU (0.4379 mmol, 166.5 mg, 1.500 eq.) were subsequently added. The mixture was stirred at room temperature overnight. The crude reaction mixture was purified by reversed phase chromatography, delivering Int 23 (110 mg, 58% yield) as a mixture of diastereomers. LCMS (ESI, m / z): 649.5 [M+H]+Example 6. methyl (3S)-3-(6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoate

[0252] lithium 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanoate (Int 22, 0.14 mmol, 54 mg, 1.2 eq.), methyl (S)-3-amino-3-(6-(difluoromethyl)-4-(2,6- dimethylphenyl)pyridin-2-yl)propanoate (Int 32, 0.12 mmol, 40 mg, 1.0 eq.) and N,N- diisopropylethylamine (0.30 mmol, 0.05 mL, 2.5 eq.) were dissolved in N,N-dimethylformamide (4 mL) after which HATU (0.18 mmol, 68 mg, 1.5 eq.) was added and the resulting mixture was stirred at room temperature for 30 minutes.The crude mixture was purified via reversed phase column chromatography to obtain the title compound (Int 33, 21 mg, 34% yield) as a mix of two diastereomers. LCMS (ESI, m / z): 665.5 [M+H]+Representative example for Method 1: Int 35Example 7. methyl (3S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2- oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate

[0253] To a solution of lithium 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)-4-methylpentanoate (Int 22, 133 mg, 0.36 mmol, 1.0 eq.) and methyl (S)-3-amino-3-(4-bromo-6- chloropyridin-2-yl)propanoate (Int 34, 105 mg, 0.36 mmol, leq.) in N,N-dimethylformamide (1.4 ml) was added N,N-diisopropylethylamine (0.19 ml, 1.07 mmol, 3.0 eq.), followed by HATU (280 mg, 0.72 mmol, 2.0 eq.) and the mixture was stirred at RT for 3 days. The mixture was diluted with ethyl acetate and subsequently washed with a saturated aqueous solution of K2CO3, water and brine. The organic layer was dried and concentrated then purified on silica using a gradient ranging from 0-60% Ethyl acetate / ethanol 3 / 1 +2% NH3 in heptane. Concentration of the product containing fractions afforded the title int 35 as a mixture of diastereomers. LCMS (ESI, m / z):623.2, 625.2 [M+H]+Illustrative example of Method 1: Int 44Example 8. methyl (3S)-3-(6-chloro-4-(3-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentan amido) propanoate

[0254] To a solution of lithium 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)-4-methylpentanoate (Int 22, 126 mg, 0.33 mmol, 1.0 eq.) and methyl (S)-3-amino-3-(6-chloro-4-(3- fluoro-2,6-dimethylphenyl)pyridin-2-yl)propanoate Int 43, 129 mg, 0.33 mmol, 1 eq.) in N,N- dimethylformamide (1.3 ml) was added N,N -diisopropylethylamine (0.13 ml, 0.77 mmol, 2.5 eq.), followed by HATU (175 mg, 0.46 mmol, 1.5 eq.) and the mixture was stirred at room temperature for 3h. The crude mixture was directly injected for reversed phase purification, affording the title intermediate 48 as a mixture of two diastereomers (132 mg, 65% yield). LCMS (ESI, m / z): 667.4 [M+H]+Illustrative example of Method 1: Int 52Example 9. methyl (3S)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-((R)- 3-fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoate

[0255] To a solution of 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4- methylpentanoic acid (Int 49, 53 mg, 0.16 mmol, 1.0 eq.) and methyl (S)-3-amino-3-(6-chloro-4-(4-fluoro- 2,6-dimethylphenyl)pyridin-2-yl)propanoate (Int 51, 50 mg, 0.14 mmol, 1.00 eq.) in N,N- dimethylformamide (1 ml) was added N,N-diisopropylethylamine (0.075 ml, 0.43 mmol, 3.0 eq.), followed by HATU (112 mg, 0.29 mmol, 2.0 eq.) and the mixture was stirred at room temperature for 3h. The mixture was diluted with ethyl acetate. The organic phase was then washed subsequently with a saturated aqueous NaHCOs-solution, water and brine. The combined organic layers were dried over MgSCL and concentrated. The residue was purified using normal phase chromatography ( Si O2) using a gradient ranging from 0-10% 7N NH3 in MeOH in di chloromethane. The relevant fractions were pooled and concentrated, affording the title intermediate 56 as a mixture of two diastereomers (57 mg, 61% yield). LCMS (ESI, m / z): 657.4 [M+H]+Illustrative example for method 1: Int 61Example 10. methyl (3S)-3-(6-chloro-4-(2,6-dimethyl-4-((trifluoromethyl)sulfonamido)phenyl) pyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoate

[0256] To a solution of lithium 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)-4-methylpentanoate (Int 22, 120 mg, 0.32 mmol, 1.05 eq.) and methyl (S)-3-amino-3-(6-chloro-4-(2,6- dimethyl-4-((trifluoromethyl)sulfonamido)phenyl)pyridin-2-yl)propanoate hydrochloride (Int 60, 150 mg, 0.30 mmol, leq.) in N,N-dimethylformamide (1 ml) was added N,N -diisopropylethylamine (0.15 ml, 1.1 mmol, 2.7 eq.), followed by HATU (150 mg, 0.39 mmol, 1.3 eq.) and the mixture was stirred at room temperature. After 10 minutes, LC-MS showed full conversion. The crude mixture was purified via reversed phase column chromatography to obtain the title compound (Int 60, 84 mg, 33% yield) as a mix of two diastereomers. LCMS (ESI, m / z): 796.4 [M+H]+Illustrative example of Method 1: Int 65Example 11. methyl (3S)-3-(6-chloro-4-(2,6-dimethyl-4-((l,l,l-trifluoro-N- methylmethyl)sulfonamido)phenyl)pyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate

[0257] To a solution of methyl (S)-3-amino-3-(6-chloro-4-(2,6-dimethyl-4-((l,l,l-trifluoro-N- methylmethyl)sulfonamido)phenyl)pyridin-2-yl)propanoate (Int 64, 46 mg, 0.094 mmol, 1.0 eq.) and lithium 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (Int 22, 38 mg, 0.100 mmol, 1.1 eq.) in N,N-dimethylformamide (1 ml) was added N,N- diisopropylethylamine (0.04 ml, 0.20 mmol, 2.0 eq.), followed by HATU (50 mg, 0.13 mmol, 1.4 eq.) and the mixture was stirred at room temperature for 10 min. The mixture was directly purified by reversed phase chromatography, affording the title intermediate 65 (37 mg, 48% yield). LCMS (ESI, m / z): 810.4 [M+H]+Method 2: Ester hydrolysis

[0258] To a solution of ester (1 eq.) in tetrahydrofuran or 2-methyltetrahydrofuran and water is added lithium hydroxide monohydrate (6.0 eq.). The reaction mixture is stirred at 23°C-40°C. After completion, the crude mixture can be purified by preparative HPLC, or concentrated and used as such to afford the title compound.Representative example of method 2: Cpd 1Example 12. (S)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)-3-((S*)-4-methyl-2- (2-oxopyridin-l(2H)-yl)pentanamido)propanoic acid

[0259] To a solution of methyl (3S)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)-3-(4- methyl-2-(2-oxopyridin-l(2H)-yl)pentanamido)propanoate (Int 7, 0.222 mmol, 127 mg, 1.0 eq.) in THF (4.2 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (1.33 mmol, 34 mg, 6.0 eq.). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, redissolved in ACN / water and purified via reversed phase column chromatography). The product containing fractions were concentrated and freeze-dried to obtain (S)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2- yl)-3-((S*)-4-methyl-2-(2-oxopyridin-l(2H)-yl)pentanamido)propanoic acid (cpd 1, 25% Yield, 29 mg). LCMS (retention time, analytical method A): 5.0 min; (ESI, m / z): 530.2 [M+H]+. ’H NMR (400 MHz, DMSO) 5 12.51 (s, 1H), 9.18 (d, 1H), 7.67 (dd, 2H), 7.45 (d, 1H), 7.38 (ddd, 1H), 7.26 (dd, 1H), 7.18 (d, 2H), 6.36 (dd, 1H), 6.21 (td, 1H), 5.66 (dd, 1H), 5.29 (q, 1H), 2.92 (dd, 1H), 2.74 (dd, 1H), 1.95 (s, 6H), 1.77 - 1.64 (m, 2H), 1.19 (dq, 1H), 0.77 (dd, 6H).Example 13. (S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-4-methyl-2-(2- oxopyridin-l(2H)-yl)pentanamido)propanoic acid

[0260] methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(4-methyl-2-(2-oxopyridin- l(2H)-yl)pentanamido)propanoate (Int 20, 0.163 mmol, 85 mg, 1.0 eq.) was dissolved in tetrahydrofuran (3.1 mL) and water (0.6 mL) and treated with lithium hydroxide monohydrate (0.980 mmol, 25 mg, 6.0 eq.). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo, redissolved in acetonitrile and water and purified via reversed phase column chromatography to obtain (S)- 3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-4-methyl-2-(2-oxopyridin-l(2H)- yl)pentanamido)propanoic acid (cpd 2, 20 mg, 24% Yield). LCMS (retention time, analytical method A): 4.9 min; (ESI, m / z): 496.2 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.20 (s, 1H), 7.68 (dd, J = 7.0, 2.1 Hz, 1H), 7.38 (ddd, J = 8.9, 6.5, 2.0 Hz, 1H), 7.28 (d, J = 1.2 Hz, 1H), 7.26 - 7.09 (m, 4H), 6.36 (dd, J = 9.2, 1.4 Hz, 1H), 6.21 (td, J = 6.7, 1.4 Hz, 1H), 5.64 (dd, J = 9.7, 6.4 Hz, 1H), 5.23 - 5.12 (m, 1H), 2.87 - 2.80(m, 1H), 2.73 - 2.58 (m, 1H), 1.97 (s, 6H), 1.75 - 1.62 (m, 2H), 1.27 - 1.15 (m, 1H), 0.78 (d, J = 1.9 Hz, 3H), 0.76 (d, J = 1.9 Hz, 3H).Example 14. (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoic acid

[0261] methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoate (Int 14, 0.043 mmol, 30 mg, 1.0 eq.) was treated with lithium hydroxide monohydrate (0.25 mmol, 6.5 mg, 6.0 eq.) in tetrahydrofuran (0.80 mL) and water (0.20 mL) at room temperature overnight. The solvent was removed in vacuo, redissolved in acetonitrile and water and purified via reversed phase column chromatography to obtain (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoic acid (cpd 3. 8.5 mg, 30% Yield). LCMS (retention time, analytical method A): 3.9 min; (ESI, m / z): 669.3 [M+H]+. ’H NMR (400 MHz, DMSO) 59.22 (s, 1H), 7.73 (s, 1H), 7.58 (d, 1H), 7.38 (d, 1H), 7.23 - 7.15 (m, 1H), 7.14 - 7.07 (m, 2H), 6.66 (s, 1H), 5.54 (dd, 1H), 5.21 (q, 1H), 2.80 (dd, 1H), 2.67 - 2.46 (m, 3H), 2.37 - 2.29 (m, 2H), 2.10 (s, 6H), 1.88 (d, 6H), 2.00 - 1.58 (m, 2H), 1.27 - 1.12 (m, 1H), 0.72 (t, 6H).Representative example for Method 2: Cpd 4Example 15. (S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0262] A solution of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 23, 55 mg, 0.085 mmol) in 2-methyltetrahydrofuran (1.95 mL) and water (0.29 mL) was treated with lithium hydroxide monohydrate (0.51 mmol, 13 mg, 6.0 eq.) at room temperature for 2 hours. The solvent was removed in vacuo, the crude product was dissolved in acetonitrile and water and purified via reversed phase column chromatography to obtain 2 separate diastereomers, one of which is the title compound 4. LCMS (retention time, analytical method A): 3.6 min; (ESI, m / z): 635.3 [M+H]+.1H NMR (400 MHz, DMSO) 5 9.13 (d, 1H), 7.81 (s, 1H), 7.30 (d, 1H), 7.27 - 7.19 (m, 1H), 7.19 - 7.11 (m, 3H), 6.73 (s, 1H), 5.60 (dd, 1H), 5.21 (td, 1H), 2.88 (dd, 1H), 2.74 - 2.52 (m, 3H), 2.46 - 2.35 (m, 2H), 2.18 (s, 6H), 1.97 (d, 6H), 1.89 - 1.66 (m, 2H), 1.32 - 1.17 (m, 1H), 0.78 (dd, 6H).Representative example for Method 2: Cpd 5Example 16. (S)-3-(6-cyano-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0263] A solution of methyl (3S)-3-(6-cyano-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 24, 19 mg, 0.030 mmol) in 2-methyltetrahydrofuran (0.7 mL) and water (0.1 mL) was treated with lithium hydroxide monohydrate (0.18 mmol, 5 mg, 6.0 eq.) at room temperature for 2 hours. The solvent was removed in vacuo, the crude product was dissolved in acetonitrile and water and purified via reversed phase column chromatography to obtain 2 separate diastereomers, one of which is the title compound 5. LCMS (retention time, analytical method A): 3.5 min; (ESI, m / z): 626.3 [M+H]+. ’H NMR (400 MHz, DMSO) 5 9.31 (s, 1H), 7.87 (d, 1H), 7.80 (s, 1H), 7.47 (d, 1H), 7.30 - 7.22 (m, 1H), 7.20 - 7. 14 (m, 2H), 6.72 (s, 1H), 5.59 (dd, 1H), 5.23 (dd, 1H), 2.83 (dd, 1H), 2.72 - 2.30 (m, 5H), 2.17 (s, 6H), 1.95 (d, 6H), 1.84 - 1.67 (m, 2H), 1.28 - 1.20 (m, 1H), 0.79 (dd, 6H).Example 17. (S)-3-(6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0264] A solution of methyl (3S)-3-(6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate(Int 33, 0.04 mmol, 27 mg, 1.0 eq.) in 2-methyltetrahydrofuran (0.9 mL) and water (0.1 mL) was treated with lithium hydroxide monohydrate (0.24 mmol, 6 mg, 6.0 eq.) at room temperature and stirred overnight. After completion, the solvents were removed in vacuo and the residu was subjected to reversed phase chromatography, affording 2 separate diastereomers, one of which is the desired one (S)-3-(6- (difhroromethyl)-4-(2,6-dimethylphenyl)pyri din-2 -yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (Cpd 6. 8 mg, 30% yield). LCMS (retention time, analytical method A): 3.6 min; (ESI, m / z): 651.3 [M+H]+.1H NMR (400 MHz,DMSO) 59.21 (d, J= 7.8 Hz, 1H), 7.80 (s, 1H), 7.40 (d,J= 1.4 Hz, 1H), 7.30 (s, 1H), 7.28 - 7.13 (m, 3H), 6.97 (t, J= 54.9 Hz, 1H), 6.73 (s, 1H), 5.61 (dd, J= 10.4, 5.7 Hz, 1H), 5.35 - 5.23 (m, 1H), 2.89 (dd, J = 15.9, 5.7 Hz, 1H), 2.74 - 2.51 (m, 3H), 2.44 - 2.35 (m, 2H), 2.17 (s, 6H), 1.95 (d, J= 3.6 Hz, 6H), 1.85 - 1.64 (m, 2H), 1.30 - 1.17 (m, 1H), 0.78 (dd, J= 7.8, 6.6 Hz, 6H).Representative example for Method 2: Cpd 7Example 18. (S)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0265] A solution of methyl (3S)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate(Int 36, 14 mg, 0.20 mmol, 1.0 eq.) in methanol (0.1 mL) and water (0.02 mL) was treated with lithium hydroxide monohydrate (0.60 mmol, 2 mg, 3.0 eq.) at room temperature and stirred for 4 hours. After completion, the reaction mixture was subjected to reversed phase chromatography, affording 2 separate diastereomers, one of which is the desired one (S)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin- 2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid (Cpd 7). LCMS (retention time, analytical method A): 3.6 min; (ESI, m / z): 653.3 [M+H]+. 'H NMR (400 MHz, DMSO) 59.23 (s, 1H), 7.80 (s, 1H), 7.29 (d, 1H), 7.12 (d, 1H), 7.03 (d, 2H), 6.73 (s, 1H), 5.59 (dd, 1H), 5.17 (q, 1H), 2.82 (dd, 1H), 2.70 - 2.51 (m, 3H), 2.39 (m, 2H), 2.17 (s, 6H), 1.97 (d, 6H), 1.89 - 1.61 (m, 2H), 1.31 - 1.19 (m, 1H), 0.79 (dd, 6H).Representative example for Method 2: Cpd 8Example 19. (S)-3-(6-chloro-4-mesitylpyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo- 4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0266] A solution of methyl (3S)-3-(6-chloro-4-mesitylpyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2- oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (I nt 37, 14 mg, 0.21 mmol, 1.0 eq.) in methanol (0.1 mL) and water (0.02 mL) was treated with lithium hydroxide monohydrate (0.63 mmol, 2 mg, 3.0 eq.) at room temperature and stirred for 1 hour. After completion, the reaction mixture was subjected to reversed phase chromatography, affording 2 separate diastereomers, one of which is the desired one (S)-3-(6-chloro-4-mesitylpyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (Cpd 8). LCMS (retention time, analytical method A): 3.75 min; (ESI, m / z): 649.4 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.21 (d, 1H), 7.80 (s, 1H), 7.24 (d, 1H), 7.10 (d, 1H), 6.96 (s, 2H), 6.73 (s, 1H), 5.59 (dd, 1H), 5.22 - 5.12 (m, 1H), 2.81 (dd, 1H), 2.67 - 2.54 (m, 3H), 2.44 - 2.36 (m, 2H), 2.27 (s, 3H), 2.17 (s, 6H), 1.93 (d, 6H), 1.87 - 1.67 (m, 2H), 1.32 - 1.19 (m, 1H), 0.79 (dd, 6H).Representative example for Method 2: cpd 9Example 20. (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(prop-l-yn-l-yl)pyridin-2-yl)propanoic acid

[0267] A solution of methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1 (2H)-yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(prop- 1 -yn- 1 -yl)pyridin-2-yl)propanoate (Int 38. 0.043 mmol, 28 mg, 1.0 eq.) in 2-methyltetrahydrofuran (1 mL) and water (0.2 mL), was treated with lithium hydroxide monohydrate (0.26 mmol, 6 mg, 6.0 eq.) at room temperature and the mixture was stirred for 3 hours, after which it was purified by reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin- 1 (2H)-yl)-4-methylpentanamido)-3 -(4-(2,6-dimethylphenyl)-6-(prop- 1 -yn- 1 - yl)pyridin-2-yl)propanoic acid (cpd 9, 9 mg, 33% yield). LCMS (retention time, analytical method A): 3.6 min; (ESI, m / z): 639.4 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.09 (d, 1H), 7.80 (s, 1H), 7.25-7.17 (m, 1H), 7.17-7.10 (m, 3H), 7.05 (d, 1H), 6.73 (s, 1H), 5.60 (dd, 1H), 5.27-5.15 (m, 1H), 2.88 (dd, 1H), 2.70- 2.55 (m, 3H), 2.43-2.36 (m, 2H), 2.17 (s, 6H), 2.08 (s, 3H), 1.94 (d, 6H), 1.85-1.77 (m, 1H), 1.73-1.65 (m, 1H), 1.29-1.17 (m, 1H), 0.77 (dd, 6H)Representative example for Method 2: cpd 10Example 21. (S)-3-(6-(cyclopropylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentan amido) propanoic acid

[0268] A solution of methyl (3S)-3-(6-(cyclopropylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5- (2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 39, 0.056 mmol, 39 mg, 1.0 eq.) in 2-methyltetrahydrofuran (1 mL) and water (0.2 mL), was treated with lithium hydroxide monohydrate (0.34 mmol, 8.5 mg, 6.0 eq.) at room temperature and the mixture was stirred overnight, after which it was purified by reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one (S)-3-(6-(cyclopropylethynyl)-4-(2,6- dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4-methylpentanamido) propanoic acid (cpd 10, 8 mg, 21 % yield). LCMS (retention time, analytical method A): 3.8 min; (ESI, m / z): 665.4 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.30 (s, 1H), 7.80 (s, 1H), 7.25 - 7.08 (m, 4H), 7.02 (d, J = 1.4 Hz, 1H), 6.72 (s, 1H), 5.59 (dd, J = 10.5, 5.7 Hz, 1H),5.14 (m, 1H), 2.78 - 2.70 (m, 1H), 2.67 - 2.52 (m, 3H), 2.44 - 2.33 (m, 2H), 2.16 (s, 6H), 1.93 (s, 6H), 1.87 - 1.64 (m, 2H), 1.63 - 1.52 (m, 1H), 1.29 - 1.18 (m, 1H), 0.97 - 0.86 (m, 2H), 0.83 - 0.73 (m, 8H).Example 22. (S)-3-(6-chloro-4-(4-cyano-2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethyl amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid

[0269] A solution of methyl (3S)-3-(6-chloro-4-(4-cyano-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (hit 41, 30 mg, 0.039 mmol, 1.0 eq.) in tetrahydrofuran (0.8 mL) and water (0.2 mL), was treated with lithium hydroxide monohydrate (6 mg, 0.24 mmol, 6.0 eq.) at room temperature and the mixture was stirred for 2h, after which it was purified by reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one (S)-3-(6-chloro-4-(4-cyano-2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, cpd 11. LCMS (retention time, analytical method A): 3.5 min; (ESI, m / z): 660.3 [M+H]+.1H NMR (400 MHz, DMSO) 5 9.52 (s, 1H), 7.80 (s, 1H), 7.68 (s, 2H), 7.32 (s, 1H), 7.12 (s, 1H), 6.71 (s, 1H), 5.55 (dd, 1H), 5.13 - 5.03 (m, 1H), 2.71 - 2.53 (m, 4H), 2.43 - 2.32 (m, 2H), 2.16 (s, 6H), 1.99 (s, 6H), 1.91 - 1.69 (m, 2H), 1.31 - 1.19 (m, 1H), 0.79 (dd, 6H).Illustrative example for Method 2: Cpd 12Example 23. (S)-3-(6-chloro-4-(3-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0270] A solution of methyl (3S)-3-(6-chloro-4-(3-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 44, 44 mg, 0.066 mmol, 1.0 eq.) in tetrahydrofuran (1.2 mL) and water (0.2 mL), was treated with lithium hydroxide monohydrate (10 mg, 0.40 mmol, 6.0 eq.) at room temperature and the mixture was stirred overnight, after which it was purified by preparative reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one: (S)-3-(6-chloro-4-(3-fluoro-2,6-dimethylphenyl)pyridin-2- yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid, Cpd 12. LCMS (retention time, analytical method A): 3.6 min; (ESI, m / z): 653.2 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.43 (s, 1H), 7.80 (s, 1H), 7.29 (d, J = 1.2 Hz, 1H), 7.23 - 7.10 (m, 3H), 6.71 (s, 1H), 5.66 - 5.52 (m, 1H), 5.20 - 5.01 (m, 1H), 2.70 (d, J = 15.4 Hz, 1H), 2.67 - 2.52 (m, 3H), 2.43 - 2.33 (m, 2H), 2.16 (s, 6H), 1.93 (s, 3H), 1.90 - 1.68 (m, 5H), 1.30 - 1.19 (m, 1H), 0.83 - 0.74 (m, 6H).Example 24. (S)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-((R)-3- fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0271] A solution of methyl (3S)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- ((R)-3-fluoropyrrolidin- 1 -yl)ethyl)-4-methyl-2-oxopyridin- 1 (2H)-yl)-4-methylpentanamido)propanoate (Int 52, 57 mg, 0.087 mmol, 1.0 eq.) in tetrahydrofuran (1.7 mL) and water (0.3 mL), was treated with lithium hydroxide monohydrate (13 mg, 0.52 mmol, 6.0 eq.) at room temperature and the mixture was stirred for Ih, after which it was purified by preparative reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one: (S)-3-(6-chloro-4-(4-fluoro-2,6- dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin- l(2H)-yl)-4-methylpentanamido)propanoic acid (cpd 13). LCMS (retention time, analytical method A): 3.5 min; (ESI, m / z): 643.4 [M+H]+. 'H NMR (400 MHz, DMSO) 59.00 (d, IH), 7.45 (s, IH), 7.30 (s, IH), 7.11 (s, IH), 7.04 (d, 2H), 6.19 (s, IH), 5.57 (dd, IH), 5.27 - 5.06 (m, 2H), 2.92 - 2.76 (m, 3H), 2.75 - 2.52 (m, 4H), 2.39 - 2.29 (m, IH), 2.23 - 2.01 (m, 5H), 1.97 (s, 6H), 1.94 - 1.59 (m, 4H), 1.28 - 1.14 (m, IH), 0.80 - 0.72 (m, 6H).Illustrative example for Method 2: Cpd 14Example 25. (S)-3-(6-cyano-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0272] A solution of methyl (3S)-3-(6-cyano-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 53, 21 mg, 0.032 mmol, 1.0 eq.) in tetrahydrofuran (1.7 mL) and water (0.3 mL), was treated with lithium hydroxide monohydrate (5 mg, 0.19 mmol, 6.0 eq.) at room temperature and the mixture was stirred for Ih, after which it was purified by preparative reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one: (S)-3-(6-cyano-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2- yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid (cpd 14). LCMS (retention time, analytical method A): 3.5 min; (ESI,m / z): 644.5 [M+H]+. 'H NMR (400 MHz, DMSO) 59.52 (d, 1H), 7.83 (d, 1H), 7.80 (s, 1H), 7.45 (d, 1H), 7.05 (d, 2H), 6.71 (s, 1H), 5.57 (dd, 1H), 5.20 - 5.10 (m, 1H), 2.76 - 2.62 (m, 1H), 2.65 - 2.52 (m, 3H), 2.43 - 2.33 (m, 2H), 2.16 (s, 6H), 1.96 (s, 6H), 1.91 - 1.69 (m, 2H), 1.34 - 1.16 (m, 1H), 0.80 (dd, 6H)Illustrative example for Method 2: cpd 15Example 26. (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)-4-methylpentanamido)-3-(4-(4-fluoro-2,6-dimethylphenyl)-6-(prop-l-yn-l-yl)pyri din-2- yl)propanoic acid

[0273] A solution of methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4-methylpentanamido)-3-(4-(4-fluoro-2,6-dimethylphenyl)-6-(prop-l-yn-l-yl)pyridin-2- yl)propanoate (Int 54. 33 mg, 0.050 mmol, 1.0 eq.) in tetrahydrofuran (1 mL) and water (0.2 mL), was treated with lithium hydroxide monohydrate (8 mg, 0.30 mmol, 6.0 eq.) at room temperature and the mixture was stirred overnight, after which it was purified by reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo- 4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-(4-fluoro-2,6-dimethylphenyl)-6-(prop- l-yn-l-yl)pyridin-2-yl)propanoic acid (cpd 15). LCMS (retention time, analytical method A): 3.8 min; (ESI, m / z): 657.3 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.94 (s, 1H), 7.80 (s, 1H), 7.08 - 6.94 (m, 4H), 6.71 (s, 1H), 5.55 (dd, 1H), 5.02 - 4.93 (m, 1H), 2.70 - 2.26 (m, 6H), 2.14 (s, 6H), 2.07 (s, 3H), 1.94 (s, 6H), 1.87 - 1.66 (m, 2H), 1.31 - 1.19 (m, 1H), 0.82 - 0.74 (m, 6H).Illustrative example for Method 2: Cpd 16Example 27. (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-vinylpyridin-2-yl)propanoic acid

[0274] A solution of methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-vinylpyridin-2-yl)propanoate (I nt 55. 24 mg, 0.037 mmol, 1.0 eq.) in tetrahydrofuran (1 mL) and water (0.2 mL), was treated with lithium hydroxide monohydrate (6 mg, 0.22 mmol, 6.0 eq.) at room temperature and the mixture was stirred overnight, after which it was purified by reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)- 4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-vinylpyridin-2-yl)propanoic acid (cpd 16). LCMS (retention time, analytical method A): 3.6 min; (ESI, m / z): 627.3 [M+H]+.1H NMR (400 MHz, DMSO) 5 9.69 (s, 1H), 7.81 (s, 1H), 7.24 - 7.10 (m, 4H), 6.98 (d, J = 1.4 Hz, 1H), 6.88 - 6.76 (m, 1H), 6.72 (s, 1H), 6.36 - 6.26 (m, 1H), 5.64 - 5.56 (m, 1H), 5.51 - 5.43 (m, 1H), 5.23 - 4.98 (m, 1H), 2.69 - 2.27 (m, 6H), 2.14 (s, 6H), 1.95 (s, 6H), 1.90 - 1.68 (m, 2H), 1.24 (d, J = 9.7 Hz, 1H), 0.87 - 0.66 (m, 6H).Example 28. (S)-3-(6-chloro-3',5'-dimethyl-[4,4'-bipyridin]-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentan amido) propanoic acid

[0275] A solution of methyl (3S)-3-(6-chloro-3',5'-dimethyl-[4,4'-bipyridin]-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido) propanoate (Int 56, 20 mg, 0.031 mmol, 1.0 eq.) in tetrahydrofuran (0.6 mL) and water (0.1 mL), was treated with lithium hydroxide monohydrate (5 mg, 0.18 mmol, 6.0 eq.) at room temperature and the mixture was stirred overnight, after which it was purified by reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one (S)-3-(6-chloro-3',5'-dimethyl-[4,4'-bipyridin]-2-yl)-3-((S*)- 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido) propanoic acid (cpd 18). LCMS (retention time, analytical method A): 3.2 min; (ESI, m / z): 636.3 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.54 (s, 1H), 8.38 (s, 2H), 7.80 (s, 1H), 7.35 (d, J = 1.1 Hz, 1H), 7.16 (d, J = 1.3 Hz, 1H), 6.71 (s, 1H), 5.61 - 5.51 (m, 1H), 5.16 - 5.02 (m, 1H), 2.72 - 2.30 (m, 6H), 2.16 (s, 6H), 1.97 (s, 6H), 1.88 - 1.70 (m, 2H), 1.34 - 1.17 (m, 1H), 0.79 (dd, J = 8.3, 6.5 Hz, 6H).Example 29. (S)-3-(6-bromo-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethyl- amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0276] A solution of methyl (3S)-3-(6-bromo-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate(Int 57, 16 mg, 0.023 mmol, 1.0 eq.) in tetrahydrofuran (0.6 mL) and water (0.1 mL), was treated with lithium hydroxide monohydrate (3.5 mg, 0.14 mmol, 6.0 eq.) at room temperature and the mixture was stirred overnight, after which it was purified by reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one (S)-3-(6-bromo-4-(2,6-dimethylphenyl)pyridin-2-yl)-3- ((S * )-2-(5 -(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1 (2H)-yl)-4-methylpentanamido) propanoic acid (cpd 19). LCMS (retention time, analytical method A): 3.6 min; (ESI, m / z): 679.2, 681.2 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.68 (s, 1H), 7.80 (s, 1H), 7.38 - 7.33 (m, 1H), 7.26 - 7.18 (m, 1H), 7.17 - 7.10 (m, 3H), 6.72 (s, 1H), 5.61 - 5.53 (m, 1H), 5.10 - 4.99 (m, 1H), 2.64 - 2.32 (m, 6H), 2.15 (s, 6H), 1.96 (s, 6H), 1.88 - 1.67 (m, 2H), 1.31 - 1.21 (m, 1H), 0.86 - 0.70 (m, 6H).Illustrative example for Method 2: cpd 20Example 30. (S)-3-(6-chloro-4-(2,6-dimethyl-4-((trifluoromethyl)sulfonamido)phenyl)pyridin-2- yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid

[0277] A solution of methyl (3S)-3-(6-chloro-4-(2,6-dimethyl-4-((trifluoromethyl)sulfonamido) phenyl)pyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoate lint 61, 84 mg, 0.11 mmol, 1.0 eq.) in tetrahydrofuran (0.5 mL) and water (0.5 mL), was treated with lithium hydroxide monohydrate (5 mg, 0.20 mmol, 2.0 eq.) at room temperature and the mixture was stirred for Ih, after which it was purified by reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one (S)-3-(6-chloro-4-(2,6-dimethyl-4- ((trifluoromethyl)sulfonamido)phenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, cpd 20. LCMS (retention time, analytical method A): 3.7 min; (ESI, m / z): 782.3 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.10 (d, IH), 7.84 (s, IH), 7.24 (s, IH), 7.11 (d, IH), 6.77 - 6.71 (m, 3H), 5.63 (dd, IH), 5.27 - 5.17 (m, IH), 2.94 - 2.84 (m, IH), 2.78 - 2.51 (m, 3H), 2.38 - 2.14 (m, 8H), 1.92 - 1.79 (m, 7H), 1.76 - 1.65 (m, IH), 1.30 - 1.17 (m, IH), 0.79 (dd, 6H).Example 31. (S)-3-(6-chloro-4-(2,6-dimethyl-4-((l,l,l-trifluoro-N- methylmethyl)sulfonamido)phenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0278] A solution of methyl (3S)-3-(6-chloro-4-(2,6-dimethyl-4-((l,l,l-trifluoro-N- methylmethyl) sulfonamide) phenyl)pyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifhioromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 65, 13 mg, 0.016 mmol, 1.0 eq.) in tetrahydrofuran (0.2 mL) and water (0.2 mL), was treated with lithium hydroxide monohydrate (2 mg, 0.080 mmol, 5.0 eq.) at room temperature and the mixture was stirred for Ih, after which it was purified by preparative reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one: (S)-3-(6-chloro-4-(2,6-dimethyl-4-((l,l,l-trifhioro-N-methyhnethyl)sulfonamido)phenyl)pyridin-2- yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifhioromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid (cpd 21). LCMS (retention time, analytical method A): 3.9 min; (ESI, m / z): 796.4 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.07 (d, IH), 7.81 (s, IH), 7.38 (d, IH), 7.35 - 7.29 (m, 2H), 7.17 (d, IH), 6.74 (s, IH), 5.60 (dd, IH), 5.26 - 5.16 (m, IH), 3.49 - 3.46 (m, 3H), 2.95 - 2.85 (m, IH), 2.76 - 2.54 (m, 3H), 2.48 - 2.42 (m, 2H), 2.21 (s, 6H), 2.00 (d, 6H), 1.87 - 1.66 (m, 2H), 1.30 - 1.19 (m, IH), 0.78 (dd, 6H).Example 32. (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(spiro[3.3]hept-l-en-2-yl)pyri din-2- yl)propanoic acidA solution of methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)- 4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(spiro[3.3]hept-l-en-2-yl)pyridin-2-yl)propanoate (Int 66, 39 mg, 0.055 mmol, 1.0 eq.) in tetrahydrofuran (1.0 mL) and water (0.2 mL), was treated with lithium hydroxide monohydrate (8 mg, 0.33 mmol, 6.0 eq.) at room temperature and the mixture was stirred overnight, after which it was purified by reversed phase chromatography affording 2 separate diastereomers, one of which is the desired one (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifhioromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(spiro[3.3]hept-l-en-2-yl)pyridin-2-yl)propanoic acid (cpd 22). LCMS (retention time, analytical method A): 4.4 min; (ESI, m / z): 693.3 [M+H]+. 'H NMR (400 MHz, DMSO) 5 9.76 (s, 1H), 7.80 (s, 1H), 7.23 - 7.15 (m, 1H), 7.15 - 7.09 (m, 2H), 7.09 - 7.02 (m, 1H), 6.98 - 6.93 (m, 1H), 6.78 - 6.70 (m, 2H), 5.65 - 5.56 (m, 1H), 5.10 - 5.01 (m, lH), 2.80 (s, 2H), 2.63 - 2.52 (m, 2H), 2.45 - 2.29 (m, 4H), 2.25 - 2.09 (m, 10H), 1.98 - 1.71 (m, 10H), 1.29 - 1.18 (m, 1H), 0.89 - 0.71 (m, 6H).Example 33. 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanoic acid

[0279] ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4- methylpentanoate (Int 12, 0.27 mmol, 100 mg, 1.0 eq.) was treated with lithium hydroxide monohydrate (1.59 mmol, 40 mg, 6.0 eq.) in tetrahydrofuran (4 mL) and water (1 mL) at room temperature for 2h. The mixture was purified via reversed phase column chromatography to afford the title Int 13. LCMS (ESI, m / z): 349.2 [M+H]+Example 34. lithium 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanoate

[0280] ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4- methylpentanoate (Int 12, 3.73 g, 9.8 mmol, 1.0 eq.) and lithium hydroxide monohydrate (10 mmol, 1.05 eq.) were dissolved in tetrahydrofuran (75 mL) and water (20 mL). The reaction was stirred at 40° C for 7 h, then for 2 days at room temperature. The mixture was concentrated to dryness, delivering the title cmpdInt 22. as white solid (3.50g, 100% yield). LCMS (ESI, m / z): 349.2 [M+H]+. 'H NMR (400 MHz, DMSO) 5 7.67 (s, 1H), 6.60 (s, 1H), 5.18 (dd, 1H), 2.62 - 2.52 (m, 2H), 2.43 - 2.26 (m, 2H), 2.16 (s, 6H), 1.93 (ddd, 1H), 1.80 - 1.65 (m, 1H), 1.26 - 1.13 (m, 1H), 0.81 (dd, 6H).Illustrative example for Method 2: Int 49Example 35. 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4- methylpentanoic acid

[0281] To a solution of ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)- yl)-4-methylpentanoate (Int 48, 280 mg, 0.76 mmol, 1.00 eq.) in Methanol (3.8 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (60 mg, 2.28 mmol, 3.00 eq.) and the reaction was stirred at room temperature for Ih. The mixture was concentrated and purified by reversed phase chromatography, affording the title intermediate 53 (234 mg, 91% yield). ). LCMS (ESI, m / z): 339.2 [M+H]+.

[0282] In general, the beta-amino esters are constructed by condensing an aldehyde with a chiral sulfinamide, generating a sulfoximine (method 3), followed by a diastereoselective Reformatsky reaction with an-in situ formed zincate (method 4), after which the sulfinamide is cleaved under acidic conditions (method 5).Method 3: sulfoximine formation a. Method 3a: Sulfoximine formation using Cesium carbonate

[0283] Aldehyde (1 eq.) and sulfinamide (1.2 eq.) are dissolved in tetrahydrofuran (5 mL) under nitrogen atmosphere after which cesium carbonate (1.2 eq.) is added. The remaining suspension is stirred at room temperature for 1-3 days. The reaction is quenched by addition of water and diluted with ethyl acetate. Thelayers are separated, the organic layer is washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product. It can be either used as such or purified via column chromatography .Illustrative example of method 3a: Int 3Example 36. (R)-N-[[4-(2,6-dimethylphenyl)-6-(trifluoromethyl)-2-pyridyl]methylene]-2-methyl- propane-2-sulfinamide

[0284] To a mixture of 4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridine-2-carbaldehyde (Int 2, 1.49 mmol, 0.45 g, 1.0 eq.) and (R)-2-methylpropane-2-sulfinamide (CAS# 196929-78-9, 1.79 mmol, 0.22 g, 1.2 eq.) in tetrahydrofuran (5 m ) under nitrogen atmosphere was added cesium carbonate (1.79 mmol, 0.58 g, 1.2 eq.). The remaining suspension was stirred at room temperature for 3 days. The reaction was quenched by addition of water and diluted with ethyl acetate. The layers were separated, the organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product (Int 3, 529 mg, 92% yield). It was used as such. LCMS (ESI, m / z): 383.2 [M+H]+ b. Method 3b: Sulfoximine formation using titanium (IV) ethoxide

[0285] Aldehyde (1 eq.) and sulfmamide (1 - 1.2 eq.) are dissolved in tetrahydrofuran (5 mb) under nitrogen atmosphere after which titanium(IV) ethoxide (1.2 - 1.5 eq.) is added. The remaining mixture is stirred at room temperature for 2-16h. The reaction is quenched by addition of water and ethyl acetate, upon which solids are formed. Those are filtered off, the solids are washed with ethyl acetate, the filtrate is partitioned between ethyl acetate and water. The layers are separated, the organic layer is washed with brine and either dried over anhydrous Na2SO4 and filtered or filtered over a phase separator and concentrated in vacuo to give crude product. It can be either used as such or purified via column chromatography.Illustrative example of method 3b: Int 15Example 37. (R,E)-N-((4-bromo-6-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

[0286] To a mixture of 4-bromo-6-chloro-pyridine-2-carbaldehyde (CAS# 1060811-63-3, 2.27 mmol, 0.50 g, 1.0 eq.) and (R)-2-methylpropane-2-sulfmamide (CAS# 196929-78-9, 2.50 mmol, 0.30 g, 1.1 eq.) in anhydrous tetrahydrofuran (5 mL) under nitrogen atmosphere was added titanium(IV) ethoxide (3.40 mmol, 0.84 mL, 0.91 g, 1.5 eq.) dropwise at room temperature. The reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the mixture and it was stirred at room temperature for 5 minutes, upon which solids were formed. The solids were filtered, off, washed with EtOAc and the layers of the resulting biphasic filtrate were separated. The organic layer was washed with brine, filtered over a phase separator and concentrated in vacuo to provide (R,E)-N-((4-bromo-6- chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfmamide (Int 15, 0.724 g, 96% yield) as a yellowwhite solid. LCMS (ESI, m / z): 323.0 [M+H]+Illustrative example of method 3b: Int 30Example 38. (R,E)-N-((6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)methylene)-2- methylpropane-2-sulfinamideTo a mixture of 6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridine-2-carbaldehyde (Int 29. 0.55 mmol, 0.15 g, 1.0 eq.) and (R)-2-methylpropane-2-sulfinamide (CAS# 196929-78-9, 0.71 mmol, 0.086 g, 1.3 eq.) in 2-methyltetrahydrofuran (1.8 mL) under nitrogen atmosphere was added titanium (IV) ethoxide (0.82 mmol, 0.1732 mL, 1.5 eq.) dropwise at room temperature.The reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the mixture and it was stirred at room temperature for 5 minutes, upon which solids were formed. The solidswere filtered, off, washed with EtOAc and the layers of the resulting biphasic filtrate were separated. The organic layer was washed with brine, filtered over a phase separator and concentrated in vacuo to provide the title Int 30 (198 mg, 100% yield) as white product. LCMS (ESI, m / z): 365.2 [M+H]+Method 4: Reformatsky reaction

[0287] Under nitrogen atmosphere, to a mixture of zinc (5.0 eq.) in anhydrous tetrahydrofuran is added chlorotrimethylsilane (0.2 eq.) dropwise at room temperature. The suspension is stirred at 50 °C under nitrogen atmosphere for 1 hour. The mixture is then cooled to room temperature, upon which alkyl bromoacetate (2.5 eq.) is added dropwise at room and the resulting mixture is heated to 60°C for 1 hour. The reaction mixture is then cooled to 0°C, after which a solution of sulfmamide (1.0 eq.) in anhydrous tetrahydrofuran is carefully added dropwise into the mixture at 0° and stirred at 0°C for 0.5-16h. The reaction is quenched by addition of water, IM citric acid and ethyl acetate, after which the mixture is filtered over celite. The layers of the filtrate are separated, the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography to afford the title compound.Example 39. methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoate

[0288] To a mixture of zinc (6.78 mmol, 0.44 g, 5.0 eq.) in anhydrous tetrahydrofuran (13 mb) under nitrogen atmosphere was added chlorotrimethylsilane (0.27 mmol, 0.035 mb, 0.20 eq.) dropwise at room temperature. The suspension was stirred at 50 °C under nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature, upon which methyl bromoacetate (3.39 mmol, 0.32 mb, 2.5 eq.) was added dropwise at room temperature under nitrogen atmosphere and then heated to 60°C under N2 for 1 hour. The reaction mixture was cooled to 0°C. A solution of (R,E)-N-((4-(2,6-dimethylphenyl)-6- (trifluoromethyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfmamide (Int 3, 1.36 mmol, 0.53 g, 1.0 eq.) in anhydrous tetrahydrofuran (3 mb) was added dropwise into the mixture at 0°C under nitrogen atmosphere and stirred at 0°C for 30min. The reaction was quenched by careful addition of water, IM citricacid (5mL) and ethyl acetate and the mixture was stirred at room temperature for 5 mins. The mixture was fdtered. The layers of the filtrate were separated, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with a gradient ranging from 0-75 % ethyl acetate in heptane, to obtain methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-(2,6- dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoate (Int 4, 74% Yield, 0.46 g) and methyl (R)-3- (((R)-tert-butylsulfinyl)amino)-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoate (11% Yield, 0.07 g). LCMS (ESI, m / z): 457.2 [M+H]+. 'H NMR (400 MHz, DMSO) 5 7.65 (dd, 2H), 7.30 - 7.21 (m, 1H), 7.21 - 7.14 (m, 2H), 5.96 (d, lH), 4.90 (dd, 1H), 3.57 (s, 3H), 3.09 (dd, 1H), 2.99 (dd, 1H), 1.96 (s, 6H), 1.07 (s, 9H).Illustrative example of method 4: Int 16Example 40. methyl (S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0289] To a mixture of zinc (10.96 mmol, 0.72 g, 5.0 eq.) in anhydrous tetrahydrofuran (21 m ) under nitrogen atmosphere was added chlorotrimethylsilane (0.44 mmol, 0.056 m , 0.2 eq.) dropwise at room temperature and stirred at 50 °C under nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature. Methyl bromoacetate (5.481 mmol, 0.518 mb, 2.5 eq.) was added dropwise at room temperature under nitrogen atmosphere and the resulting mixture was stirred at 60°C under N2 for 1 hour. The reaction mixture was cooled back to room temperature. A solution of (R,E)-N-((4-bromo-6- chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfmamide (Int 15, 2.19 mmol, 0.72 g, 1.0 eq.) in anhydrous tetrahydrofuran (4 mb) was added dropwise into the mixture at 0°C under nitrogen atmosphere and the resulting mixture was stirred at 0°C for one hour. After completion, water, IM citric acid (3mb) and ethyl acetate were added into the mixture and stirred at room temperature for 5 mins. The mixture was filtered. The layers of the filtrate were separated, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, filtered over a phase separator and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting the product with a gradient ranging from 0-25% ethyl acetate into obtain methyl methyl (S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (Int 16, 0.46g, 53% Yield) as yellow oil. LCMS (ESI, m / z): 397.0 [M+H]+. 'H NMR (400 MHz, DMSO) 5 7.82 (d, 1H), 7.77 (d, 1H), 5.89 (d, 1H), 4.74 (dd, 1H), 3.59 (s, 3H), 3.01 (dd, 1H), 2.91 (dd, 1H), 1.09 (s, 9H).Example 41. methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-(difluoromethyl)-4-(2,6- dimethylphenyl)pyridin-2-yl)propanoate

[0290] To a mixture of zinc (2.46 mmol, 0.16 g, 5.0 eq.) in anhydrous tetrahydrofuran (4.8 mL) under nitrogen atmosphere was added chlorotrimethylsilane (0.099 mmol, 0.013 mL, 0.2 eq.) dropwise at room temperature and then stirred at 50 °C for 1 hour. The mixture was cooled to 20-30°C. methyl bromoacetate (1.23 mmol, 0.12 mL, 0.19 g, 2.5 eq.) was added dropwise at room temperature under nitrogen atmosphere and stirred at 60°C for 1 hour. The reaction mixture was cooled to 0°C, after which a solution of (R,E)-N- ((6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (Int30, 0.49 mmol, 0.20 g, 1.0 eq.) in anhydrous tetrahydrofuran (4 mL) was added dropwise into the mixture at 0°C stirred at that temperature for two hours.Water, IM citric acid and ethyl acetate were added to the mixture and it was stirred at room temperature for 5 minutes. The residual zinc was filtered off. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and brine, filtered over a phase separator and concentrated in vacuo. The residue was purified by column chromatography (SiC>2, using a gradient ranging from 5-80% ethyl acetate in heptane), to obtain methyl (R)-3-(((R)-tert-butylsulfmyl)amino)-3-(6-(difluoromethyl)-4-(2,6- dimethylphenyl)pyridin-2-yl)propanoate (35% Yield, 0.17 mmol, 0.076 g) and the desired methyl (S)-3- (((R)-tert-butylsulfmyl)amino)-3-(6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)propanoate (Int31, 31% Yield, 0.068 g). LCMS (ESI, m / z): 439.3 [M+H]+Method 5: Sulfinamide cleavage a. Method 5. a: isolation of hydrochloric acid saltR-NH2HCI

[0291] The sulfinamide (1 eq.) is dissolved in dichloromethane, after which a solution of 4M HC1 in dioxane (2-10 eq.) is added. The resulting mixture is stirred at room temperature for 2-16h. The solvent is removed in vacuo and the crude is used as such.Example 42. methyl (S)-3-amino-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2- yl)propanoate hydrochloride

[0292] To a solution of methyl (S)-3-(((R)-tert-butylsulfmyl)amino)-3-(4-(2,6-dimethylphenyl)-6- (trifhioromethyl)pyridin-2-yl)propanoate (Int 4, 0.96 mmol, 463 mg, 1.0 eq.) in dichloromethane (4 mL) was added hydrochloric acid (4 mol / L) in 1,4-dioxane (5.78 mmol, 1.45 mL, 6.0 eq.). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the crude material methyl (S)-3-amino-3-(4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)propanoate hydrochloride (Int 5, 460 mg, 123% yield) was used as such. LCMS (ESI, m / z): 353.2 [M+H]+Illustrative example of method 5 a: Int 18Example 43. methyl (S)-3-amino-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)propanoate hydrochloride

[0293] To a solution of methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(2,6- dimethylphenyl)pyridin-2-yl)propanoate (Int 17, 0.58 mmol, 25 mg, 1.0 eq.) in dichloromethane (4 mL) was added hydrochloric acid (4 mol / L) in 1,4-dioxane (3.45 mmol, 0.86 mL, 6.0 eq.). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the crude material methyl (S)-3-amino-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)propanoate hydrochloride (Int 18, 250 mg, 110% yield) was used as such. LCMS (ESI, m / z): 319. 1 [M+H]+Illustrative example of method 5a: Int 60Example 44. methyl (S)-3-amino-3-(6-chloro-4-(2,6-dimethyl-4-((trifluoromethyl)sulfonamido) phenyl)pyridin-2-yl)propanoate hydrochloride

[0294] methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(2,6-dimethyl-4-((trifluoromethyl) sulfonamido)phenyl)pyridin-2-yl)propanoate (Int 59, 180 mg, 0.316 mmol, 1.00 eq.) was treated with hydrochloric acid (4 mol / L) in cyclopenyl methyl ether (0.5 mL, 2 mmol, 6 eq). The mixture was stirred at room temperature. LC-MS after Ih showed full conversion. Methanol was added, then the solvents were evaporated in vacuo to obtain the title intermediate 60 as hydrochloride salt. LCMS (ESI, m / z): 466.1 [M+H]+ (free base) b. Method 5.b: isolation of free baseR— NH2

[0295] The sulfinamide (1 eq.) is treated with a solution of HC1 in a solvent like dioxane or methanol (2-10 eq.) and stirred at room temperature for 2-16 h. The mixture is concentrated in vacuo. The residue isdissolved in ethyl acetate and washed with a saturated aqueous bicarbonate solution. Alternatively, the mixture is directly partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer is dried over Na2SC>4, filtered and concentrated. The crude material is used as such in the next step or is purified by normal or reversed phase chromatography.Illustrative example of method 5b: Int 21Example 45. methyl (S)-3-amino-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)propanoate methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)propanoate (Int 17, 0.20 mmol, 90 mg, 1.0 eq.) was treated with hydrochloric acid (4 mol / L) in 1,4-dioxane (1.2 mmol, 0.30 m , 6.0 eq.). The mixture was stirred at room temperature for Ih. Then, methanol was added and the mixture was concentrated in vacuo.The residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na2SC>4, filtered and concentrated, delivering methyl (S)-3- amino-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)propanoate (Int 21, 140 Yield, 94 mg), which was used as such in the next step. LCMS (ESI, m / z): 319.1 [M+H]+Illustrative example of method 5b: Int 32Example 46. methyl (S)-3-amino-3-(6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2- yl)propanoate

[0296] methyl (S)-3-(((R)-tert-butylsulfmyl)amino)-3-(6-(difluoromethyl)-4-(2,6- dimethylphenyl)pyridin-2-yl)propanoate (Int 31, 0. 16 mmol, 68 mg, 1.0 eq.) was treated with hydrochloric acid (4 mol / L) in dioxane (0.93 mmol, 0.23 mL, 6.0 eq.). The mixture was stirred at room temperature for 20 minutes, after which methanol was added. The mixture was concentrated in vacuo, the residue was suspended in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na2SC>4 and filtered. The filtrate was concentrated in vacuo, affording methyl (S)-3- amino-3-(6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)propanoate (Int 32) as white solid, which was used as such in the next step. LCMS (ESI, m / z): 319.1 [M+H]+Illustrative example of method 5b: Int 34Example 47. methyl (S)-3-amino-3-(4-bromo-6-chloropyridin-2-yl)propanoate

[0297] Hydrochloric acid (4 mol / L) in 1,4-dioxane (3.583 mmol, 10.00 eq., 0.8958 mL) was added to a solution of methyl (S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(((R)-tert-butylsulfmyl)amino)propanoate (Int 16, 0.356 mmol, 0.15 g, 1.0 eq.) in methanol (1.5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over Na2SC>4 and concentrated, yielding the title int 34 (105 mg, 100% yield). LCMS (ESI, m / z): 293.0, 295.0 [M+H]+Illustrative example of Method 5b: Int 43Example 48. methyl (S)-3-amino-3-(6-chloro-4-(3-fluoro-2,6-dimethylphenyl)pyridin-2- yl)propanoate

[0298] methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(3-fluoro-2,6-dimethylphenyl)pyridin- 2-yl)propanoate (Int 42, 185 mg, 0.42 mmol, 1.0 eq.) was treated with a 4M solution of hydrochloric acid in 1,4-dioxane (0.63 mL, 2.5 mmol, 6.0 eq.) at room temperature. After stirring overnight, LC-MS indicated full conversion, after which methanol was added. The mixture was then concentrated in vacuo, the residue was suspended in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na2SC>4 and filtered. The filtrate was concentrated in vacuo, affording methyl (S)-3-amino-3-(6-chloro-4-(3-fluoro-2,6-dimethylphenyl)pyridin-2-yl)propanoate, Int 43 (129 mg, 90% yield). LCMS (ESI, m / z): 337.2 [M+H]+Illustrative example of Method 5b: Int 51Example 49. methyl (S)-3-amino-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2- yl)propanoate

[0299] Methyl (S)-3-(((R)-tert-butylsulfmyl)amino)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin- 2-yl)propanoate (Int 50, 981 mg, 2.11 mmol, 1.00 eq.) was treated with a 4M solution of hydrochloric acid in 1,4-dioxane (3.17 mL, 12.7 mmol, 6.0 eq.) at room temperature. After stirring for Ih, LC-MS indicated full conversion, after which methanol was added. The mixture was then concentrated in vacuo, the residue was suspended in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na2SC>4 and filtered. The filtrate was concentrated in vacuo, affording methyl (S)-3-amino-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)propanoate, Int 51 (650 mg, 91% yield). LCMS (ESI, m / z): 337.2 [M+H]+Illustrative example of Method 5b: Int 64Example 50. methyl (S)-3-amino-3-(6-chloro-4-(2,6-dimethyl-4-((l,l,l-ti'ifluoro-N- methylmethyl)sulfonamido)phenyl)pyridin-2-yl)propanoate

[0300] To a solution of methyl (S)-3-(((R)-tert-butylsulfmyl)amino)-3-(6-chloro-4-(2,6-dimethyl-4- ((l,l,l-trifluoro-N-methylmethyl)sulfonamido)phenyl)pyridin-2-yl)propanoate (Int 63, 56 mg, 0.10 mmol, 1.00 eq.) in Methanol (0.5 mL) was added a 4M solution of hydrochloric acid in cylopentyl methyl ether (0.2 mL, 0.8 mmol, 10.0 eq.) at room temperature. After stirring for 1.5h, LC-MS indicated full conversion, after which the mixture was concentrated in vacuo, the residue was suspended in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, affording methyl (S)-3-amino-3-(6-chloro-4-(2,6-dimethyl- 4-((l,l,l-trifluoro-N-methylmethyl)sulfonamido)phenyl)pyridin-2-yl)propanoate, Int 64. LCMS (ESI, m / z): 480.2 [M+H]+Synthesis of carboxylic acids

[0301] Carboxylic acids are synthesized either by direct substitution of a leaving group on an acid by a nucleophile in presence of a complexing agent like magnesium tert-butoxide in presence of a base like potassium tert-butoxide (Method 6. a). Alternatively, a leaving group (eg. halogen, mesylate, tosylate) on an ester is displaced by a nucleophile in presence of a base like potassium carbonate (method 6.b), after which the ester is hydrolyzed to the corresponding carboxylic acid like in method 2.LG Nuc NucMethod 6: Substitution reactiona. Method 6. a: Substitution reaction on carboxylic acidTo a mixture of potassium tert-butoxide (1 eq) and magnesium tert-butoxide (2 eq) in tetrahydrofuran is added the nucleophile (1 eq). The mixture was stirred for lOmin, after which the carboxylic acid containing a leaving group (1.5 eq) is added dropwise and the resulting mixture is stirred at 25°C for 1-3 days. Upon completion, the mixture is cooled to 0°C and acidified to pH3 using hydrochloric acid. Then, the layers are separated and the organic layer is concentrated in vacuo. The residue is either purified by recrystallization or by column chromatography.Representative example for Method 6a: Int 6Example 51. (2S)-4-methyl-2-(2-oxo-l-pyridyl)pentanoic acid

[0302] To a mixture of potassium tert-butoxide (1.19 g, 10.5 mmol, 1.0 eq) and magnesium tert-butoxide (3.78 g, 21.0 mmol, 2.0 eq) in tetrahydrofiiran (53 mb) was added lH-pyridin-2-one (CAS# 142-08-5, 1 g, 10.5 mmol, 1.0 eq). The mixture was stirred for lOmin. (2R)-2-bromo-4-methyl-pentanoic acid (CAS# 42990-28-3, 3.0 g, 15.4 mmol, 1.5 eq) was added to the reaction mixture dropwise under N2 followed by stirring at 25°C for 40 h. The reaction was cooled to 0°C and hydrochloric acid (3.0 M in water) was added dropwise to adjust the mixture to pH 3. Then, the mixture was separated and the organic layer was concentrated in vacuo. Crude material crystallized overnight, ethyl acetate was added and the crystals were filtered off. The filtrate was concentrated in vacuo and was purified by column chromatography (SiCE), eluting the product with a gradient ranging from 5 - 100% ethyl acetate in heptane, to afford (S)-4-methyl- 2-(2-oxopyridin-l(2H)-yl)pentanoic acid (Int 6) as a white solid (878 mg, 38% yield). LCMS (ESI, m / z): 210.1 [M+H]+. 'H NMR (400 MHz, DMSO) 5 13.11 (s, 1H), 7.66 (dd, J = 6.9, 2.0 Hz, 1H), 7.42 (ddd, J = 8.9, 6.5, 2.0 Hz, 1H), 6.39 (dd, J = 9.2, 1.3 Hz, 1H), 6.26 (td, J = 6.7, 1.4 Hz, 1H), 5.34 (dd, J = 11.3, 4.6 Hz, 1H), 2. 12 - 1.97 (m, 1H), 1.85 (ddd, J = 14.3, 9.6, 4.6 Hz, 1H), 1.35 - 1. 14 (m, 1H), 0.86 (dd, J = 6.6, 3.4 Hz, 6H).Representative example for Method 6a: Int 19Example 52. 4-methyl-2-(2-oxopyridin-l(2H)-yl)pentanoic acid

[0303] To a mixture of potassium tert-butoxide (17.0 mmol, 1.93 g, 1.0 eq.) and magnesium tert-butoxide (34.1 mmol, 6.12 g, 2.0 eq.) in tetrahydrofuran (85 m ) was added lH-pyridin-2-one (CAS# 142-08-5, 17.0 mmol, 1.62 g, 1.0 eq.). The mixture was stirred for 10 minutes, after which 2-bromo-4-methyl-pentanoic acid (CAS# 42990-24-9, 25.6 mmol, 4.98 g, 1.5 eq.) was added to the reaction mixture dropwise under N2 followed by stirring at 25°C for 40 h. The reaction was cooled to 0°C and HC1 (3.0 M) was added dropwise to adjust the mixture to pH 3. Then, the mixture was separated and the organic layer was concentrated in vacuo. The crude material was purified by column chromatography (Si O2) eluting with a gradient ranging from 5 - 100% ethyl acetate in heptane to afford 4-methyl-2-(2-oxopyridin-l(2H)-yl)pentanoic acid (Int 19, 1.15g, 32% Yield) as a white solid. LCMS (ESI, m / z): 210.1 [M+H]+ b. Method 6b: Substitution reaction on ester

[0304] To a mixture of the ester containing a leaving group (1-1.5 eq) and nucleophile (1 eq) in acetonitrile is added potassium carbonate (2-5 eq.) The mixture is stirred at 80°C for 2-24h, or until completion of reaction. The reaction mixture is either purified by recrystallization or by column chromatography.Example 53. ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate

[0305] ethyl 4-methyl-2-((methylsulfonyl)oxy)pentanoate (Int 8, 31 mmol, 7.38 g, 1.5 eq.), 5-bromo-4- (trifhroromethyl)pyridin-2-ol (CAS# 109919-32-6, 20.7 mmol, 5.00 g , 1.0 eq.) and potassium carbonate (72 mmol, 10 g, 3.5 eq.) were dissolved in acetonitrile (80 m ) and stirred overnight at 80°C. After completion of the reaction, the mixture was concentrated on silica and subjected to flash column chromatography, eluting with a gradient ranging from 0-20% ethyl acetate in heptane to obtain the title compound as a solid (Int 9, 3.58g, 45% yield). LCMS (ESI, m / z): 384.1 [M+H]+Illustrative example for Method 6b: Int 45Example 54. ethyl 2-(5-bromo-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate

[0306] 5-bromo-4-methyl-pyridin-2-ol (CAS# 164513-38-6, 6.00 g, 31.9 mmol), ethyl 4-methyl-2- methylsulfonyloxy-pentanoate (Int 8, 9.13 g, 38.3 mmol, 1.2 eq.) and potassium carbonate (15.4 g, 112 mmol, 3.5 eq.) were dissolved in acetonitrile (210 m ) and stirred at 80°C for 3 days. After completion of the reaction, the mixture was concentrated on silica and subjected to flash column chromatography, eluting with a gradient ranging from 10-40% ethyl acetate in heptane to obtain the title compound as a solid (Int 45, 6.52g, 62% yield). LCMS (ESI, m / z): 330.1, 332.1.1 [M+H]+'H-NMR (400 MHz, DMSO- 6) 5 8.01 (s, IH), 6.45 (d, IH), 5.25 (dd, IH), 4.11 (q, 2H), 2.19 (d, 3H), 2.11 (m, IH), 1.90 - 1.78 (m, IH), 1.37 - 1.22 (m, IH), 1.16 (t, 3H), 0.85 (dd, 6H).Method 7: Suzuki reactionR5-B(OH)2R5-B(pin)(het)Ar- X - (het)Ar-R5

[0307] (hetero)-Aryl halide or pseudo halide (1 eq.), boronic acid / ester (1-1.5 eq.) and a base like N,N- diisopropylethylamine or potassium carbonate (3 eq.) are dissolved in a solvent like 1,4-di oxane and water. The mixture is degassed with N2 and palladium catalyst (0.05 eq) is added. The mixture is heated at 80°- 100°C for Ih - 20h. The mixture is partitioned between water and ethyl acetate. The organic layer is washed with brine, dried and filtered and concentrated in vacuo. The residue is purified by column chromatography.Example 55. methyl 4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridine-2-carboxylate

[0308] methyl 4-bromo-6-(trifluoromethyl)pyridine-2 -carboxylate (CAS# 1211579-71-3, 2 mmol, 500 mg, 1.0 eq.), (2,6-dimethylphenyl)boronic acid (CAS# 100379-00-8, 2 mmol, 400 mg, 1.0 eq.) and N,N- diisopropylethylamine (5 mmol, 0.9 mL, 3.0 eq.) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). The mixture was degassed by bubbling with N2, after which bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) (CAS# 887919-35-9, 0.09 mmol, 70 mg, 0.05 eq.) was added and the resulting mixture was stirred overnight at 80°C under N2. The mixture was cooled down to room temperature, diluted with water and ethyl acetate, the layers were separated. The organic one was washed with brine, filtered over a phase separator, concentrated in vacuo and coated on silica. Elash chromatography (SiCfi) with an elution gradient ranging from 0-30% ethyl acetate in heptane over 20CV, delivered methyl 4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridine-2-carboxylate (Int 1, 80% Yield, 426 mg). LCMS (ESI, m / z): 310.1 [M+H]+Illustrative example of method 7: Int 17Example 56. methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(2,6- dimethylphenyl)pyridin-2-yl)propanoate

[0309] (2,6-dimethylphenyl)boronic acid (CAS# 100379-00-8, 0.80 mmol, 120 mg, 1.1 eq.), methyl (S)- 3-(4-bromo-6-chloropyridin-2-yl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (Int 16, 0.73 mmol, 305 mg, 1.0 eq.), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (CAS# 887919- 35-9, 0.036 mmol, 27 mg, 0.05 eq.) and N,N-diisopropylethylamine (2.19 mmol, 0.38 mL, 3.0 eq.) were dissolved in dry 1,4-dioxane (3.7mL) and water (0.9 mL) and stirred at 80°C under N2. After 1 hour, the mixture was cooled down to room temperature, partitioned between water and ethyl acetate, washed with brine, filtered over a phase separator, concentrated in vacuo and coated on silica. The product was purified by flash chromatography using a gradient ranging from 0- 30% ethyl acetate in heptane over 20 CV to obtain methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2- yl)propanoate (Int 17, 250 mg, 79% yield). LCMS (ESI, m / z): 423.2 [M+H]+Illustrative example of Method 7: Int 10Example 57. ethyl (E)-2-(5-(2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanoate

[0310] ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (Int 9, 8.30 mmol, 3.58 g, 1.0 eq.), (E)-l-ethoxyethene-2-boronic acid pinacol ester (CAS# 1201905-61-4, 9.97 mmol, 2.04 g, 1.2 eq.), N,N-diisopropylethylamine (24.9 mmol, 4.35 m , 3.0 eq.) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.41 mmol, 320 mg, 0.05 eq.) were dissolved in 1,4-dioxane (46 mL) and water (9 m ) and stirred at 80°C under N2 for Ih. The mixture was cooled down to room temperature, extracted with water and ethyl acetate, washed with brine, filtered over a phase separator, concentrated in vacuo and coated on silica. Column chromatography (SiCL) with an elution gradient ranging from 0-40% ethyl acetate in heptane delivered Int 10 as yellow oil (1.56 g, 50% yield). LCMS (ESI, m / z): 376.2 [M+H]+Illustrative example of Method 7: Int 26Example 58. 2-chloro-6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridine

[0311] (2,6-dimethylphenyl)boronic acid (CAS# 100379-00-8, 4.55 mmol, 683 mg, 1.1 eq.) and 4-bromo- 2-chloro-6-(difluoromethyl)pyridine (Int 25, 4.14 mmol, 1.02 g, 1.0 eq.), were dissolved in 2- methyltetrahydrofuran (25 mL) and water (5 mL). N,N-diisopropylethylamine (12.4 mmol, 2.2 mL, 3.0 eq.) was added and the mixture was degassed by bubbling N2. Then, bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) (0.207 mmol, 154 mg, 0.05 eq.) was added and the mixture was stirred at 80°C. After overnight reaction, the mixture was cooled down to room temperature, the mixture was partitioned between with water and ethyl acetate, washed with brine, dried and concentrated in vacuo. The residu was purified by reversed phase chromatography to obtain 2-chloro-6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridine (Int. 26. 450 mg, 40% yield) as a colorless oil. LCMS (ESI, m / z): 268.0 [M+H]+Illustrative example of Method 7: Int 36Example 59. methyl (3S)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoate

[0312] (4-fluoro-2,6-dimethyl-phenyl)boronic acid (CAS# 1392512-54-7, 33 mg, 0.20 mmol, 1.1 eq.), methyl (3S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 35. 0.18 mmol, 153 mg, 1.0 eq.), l,r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.009 mmol, 7.4 mg, 0.05 eq.) and potassium carbonate (74 mg, 0.54 mmol, 3.0 eq.) were dissolved in 1,4-dioxane (0.9 mL) and water (0.2 mL) and heated at 80°C for 4h. The mixture was cooled down, partitioned between ethyl acetate and brine. The layers were separated, the organic layer was dried and concentrated. The residue was purified on silica gel using a gradient ranging from 0-10% methanol (containing a 7N NHs-solution) in dichloromethane, affording the title int 36 as mixture of diastereomers (14 mg, 12% yield). LCMS (ESI, m / z): 667.5 [M+H]+Example 60. methyl (3S)-3-(6-chloro-4-mesitylpyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2- oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate

[0313] To a solution of (2,4,6-trimethylphenyl)boronic acid (CAS#5980-97-2, 0.20 mmol, 32 mg, 1.1 eq.) and methyl (3S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 35, 0.18 mmol, 153 mg, 1.0 eq.) in 1,4-dioxane (0.9 m ) and water (0.2 mL) was added N,N-diisopropylethylamine (0.54 mmol, 0.094 m , 3.0 eq.) , followed by bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.009 mmol, 6.7 mg, 0.05 eq.) and the mixture was heated at 80°C for Ih. The mixture was cooled down, partitioned between ethyl acetate and brine. The layers were separated, the organic layer was dried and concentrated. The residue was purified by reversed phase chromatography affording the title int 37 (14 mg, 11% yield) as a mix of 2 diastereomers. LCMS (ESI, m / z): 663.3 [M+H]+Illustrative example of Method 7: Int 41Example 61. methyl (3S)-3-(6-chloro-4-(4-cyano-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentan amido) propanoate

[0314] To a solution of (4-cyano-2,6-dimethylphenyl)boronic acid (CAS# 1451391-43-7, 0.09 mmol, 16 mg, 1.2 eq.) and methyl (3S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo- 4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 35, 0.08 mmol, 50 mg, 1.0 eq.) in 1,4-dioxane (0.4 mL) and water (0.1 mL) was added potassium carbonate (0.23 mmol, 32 mg, 3.0 eq.), followed by (l,r-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.008 mmol, 6 mg, 0.1 eq.) and the mixture was heated at 80°C overnight. The mixture was cooled down, partitioned between ethyl acetate and brine . The layers were separated, the organic layer was dried and concentrated. The residue was purified by reversed phase chromatography affording the title int 41 (30 mg, 51% yield) as a mix of 2 diastereomers. LCMS (ESI, m / z): 674.5 [M+H]+Example 62. methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(3-fluoro-2,6- dimethylphenyl)pyridin-2-yl)propanoate

[0315] To a solution of 2-Bromo-4-fluoro-l,3-dimethylbenzene (CAS# 26829-82-3, 180 mg, 0.89 mmol, 1.2 eq.) and methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(4,4,5,5-tetraethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)propanoate (Int 40, 450 mg, 0.74 mmol, 1.0 eq.) in 1,4-dioxane (3.7 mb) and water (0.7 mb) was added potassium carbonate (191 mg, 1.38 mmol, 1.9 eq.), followed by (1,1’- bis(diphenylphosphino)ferrocene)dichloropalladium(II) (55 mg, 0.08 mmol, 0.1 eq.) and the mixture was heated at 90°C for Ih. The mixture was cooled down, partitioned between ethyl acetate and brine. The layers were separated, the organic layer was dried and concentrated. The residue was purified by reversed phase chromatography affording the title int 42 (185 mg, 57% yield). LCMS (ESI, m / z): 441.2 [M+H]+Illustrative example of Method 7: Int 46Example 63. ethyl (E)-2-(5-(2-ethoxyvinyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate

[0316] To a solution of ethyl 2-(5-bromo-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (Int 45, 6.52 g, 19.4 mmol, 1.0 eq.) in 1,4-dioxane (100 mb) and water (20 mL) was added (E)-l-ethoxyethene-2- boronic acid pinacol ester (CAS# 1201905-61-4, 5.1 mL, 23.2 mmol, 1.2 eq.), N,N-diisopropylethylamine (10.1 mL, 58.1 mmol, 3 eq.) and (l,l'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (721 mg, 0.97 mmol, 0.05 eq.). The mixture was degassed by evacuating and backfilling with N2, and stirred at 80°C for 2h. The mixture was cooled down to room temperature, partitioned between brine and ethyl acetate,washed with brine, dried over MgSC concentrated in vacuo. The residu was purified by flash column chromatography (SiCh) with an elution gradient ranging from 5-60% ethyl acetate in heptane. Product containing fractions were collected and concentrated under very high vacuum, delivering Int 46 (5.70g, 91% yield). LCMS (ESI, m / z): 322.3 [M+H]+Illustrative example of Method 7: Int 50Example 64. methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(4-fluoro-2,6- dimethylphenyl)pyridin-2-yl)propanoate

[0317] To a suspension of (4-fluoro-2,6-dimethyl-phenyl)boronic acid (CAS# 1392512-54-7, 542 mg, 3.22 mmol, 1.10 eq.), methyl (S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(((R)-tert- butylsulfmyl)amino)propanoate (Int 16, 1.24 g 2.93 mmol, 1.00 eq.), and potassium carbonate (1.22 g, 8.79 mmol, 3.00 eq.) in 1,4-dioxane (15 m ) and water (3.7 m ) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (226 mg, 0.2931 mmol,g, 0.10 eq.) and the resulting mixture was stirred at 80°C for Ih. The mixture was cooled down to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with brine, filtered over a phase separator, and concentrated in vacuo. The residue was purified by flash chromatography (SiCh) using a gradient ranging from 0-80% ethyl acetate in heptane, to obtain methyl (S)-3-(((R)-tert-butylsulfmyl)amino)-3-(6- chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)propanoate (Int 50, 981 mg, 72% yield) as an orange oil. LCMS (ESI, m / z): 441.2 [M+H]+. 'H NMR (400 MHz, DMSO) 5 7.30 (d, 2H), 7.03 (d, 2H), 5.88 (d, IH), 4.85 - 4.73 (m, IH), 3.58 (s, 3H), 3.11 - 3.00 (m, IH), 2.99 - 2.89 (m, IH), 1.98 (s, 6H), 1.05 (s, 9H).Example 65. methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-vinylpyridin-2-yl)propanoate

[0318] To a solution of of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 23, 0.070 mmol, 50 mg, 1.0 eq.), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (CAS# 75927-49-0, 0.11 mmol, 0.018 mL, 1.5 eq.) and potassium carbonate (0.21 mmol, 29 mg, 3.0 eq.) in 1,4-dioxane (0.36 m ) and water (0.09 mL). The solvent was degassed by bubbling N2. Next, SPhos Pd G4 (0.007 mmol, 6.0 mg, 0.10 eq.) was added and the resulting mixture was heated to 80°C overnight. After completion, the mixture was cooled down and directly purified via reversed phase chromatography to obtain int 55 as a mixture of 2 diastereomers. LCMS (ESI, m / z): 641.5 [M+H]+.Illustrative example of Method 7: Int 56Example 66. methyl (3S)-3-(6-chloro-3',5'-dimethyl-[4,4'-bipyridin]-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentan amido) propanoate

[0319] To a solution of of methyl (3S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 35, 0.10 mmol, 64 mg, 1.0 eq.), (3,5-dimethyl-4-pyridyl)boronic acid (CAS# 1430325-87-3, 0.12 mmol, 18 mg, 1.2 eq.) and potassium carbonate (0.30 mmol, 40 mg, 3.0 eq.) in 1,4-dioxane (0.5 mL) and water (0.1 mL). The solvent was degassed by bubbling N2. Next, Pd(dppf)C12 (0.01 mmol, 7.1 mg, 0.1 eq.) was added and the resulting mixture was heated to 80°C overnight. After completion, the mixture was cooled down and directly purified via reversed phase chromatography to obtain int 56 as a mixture of 2 diastereomers. LCMS (ESI, m / z): 650.5 [M+H]+.Illustrative example of Method 7: Int 59Example 67. methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(2,6-dimethyl-4-((trifluoromethyl)sulfonamido)phenyl)pyridin-2-yl)propanoate

[0320] To a suspension of methyl (S)-3-(((R)-tert-butylsulfmyl)amino)-3-(6-chloro-4-(4,4,5,5-tetraethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl)propanoate (Int 40, 450 mg, 0.83 mmol, 1.00 eq.), N-(4-bromo-3,5- dimethyl -phenyl)- 1,1,1-trifluoro-methanesulfonamide (Int 58, 300 mg, 0.90 mmol, 1.1 eq.) and potassium carbonate (215 mg, 1.56 mmol, 1.9 eq.) in 1,4-dioxane (4.1 mb) and water (0.8 ml) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (61 mg, 0.08 mmol, 0. 1 eq.). The resulting mixture was stirred at 90°C. UPLC showed full conversion after Ih. The mixture was cooled down then diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residu was purified using reversed phase chromatography, delivering the title intermediate 59 (183 mg, 39% yield). LCMS (ESI, m / z): 570.2 [M+H]+Example 68. methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(2,6-dimethyl-4-((l,l,l- trifluoro-N-methylmethyl)sulfonamido)phenyl)pyridin-2-yl)propanoate

[0321] To a suspension of methyl (S)-3-(((R)-tert-butylsulfmyl)amino)-3-(6-chloro-4-(4,4,5,5-tetraethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl)propanoate (Int 40, 92 mg, 0.18 mmol, 1.0 eq.), N-(4-bromo-3,5- dimethylphenyl)-l,l,l-trifluoro-N-methylmethanesulfonamide (Int 62, 66 mg, 0.19 mmol, 1.0 eq.) andpotassium carbonate (48 mg, 0.35 mmol, 2 eq.) in 1,4-dioxane (0.9 mL) and water (0.2 mL) was added [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg, 0.018 mmol,g, 0.10 eq.) and the resulting mixture was stirred at 90°C for Ih, after which full conversion was obtained. The mixture was allowed to cool down and purified by reversed phase chromatography, affording the title intermediate 63 (56 mg, 52% yield).Illustrative example of Method 7: Int 66methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(spiro[3.3]hept-l-en-2-yl)pyridin-2-yl)propanoate

[0322] To a solution of of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 23, 0.077 mmol, 50 mg, 1.0 eq.), 4,4,5,5-tetramethyl-2-(spiro[3.3]hept-l-en-2-yl)-l,3,2-dioxaborolane (CAS# 2014373-97-6, 0.154 mmol, 34 mg, 2.0 eq.) and potassium carbonate (0.23 mmol, 32 mg, 3.0 eq.) in 1,4-dioxane (1.0 mL) and water (0.25 mL). The solvent was degassed by bubbling N2. Next, SPhos Pd G4 (0.008 mmol, 6.0 mg, 0.10 eq.) was added and the resulting mixture was heated to 80°C overnight. After completion, the mixture was cooled down and directly purified via reversed phase chromatography to obtain int 58 as a mixture of 2 diastereomers. LCMS (ESI, m / z): 707.4 [M+H]+.Method 8: reduction of ester to aldehyde

[0323] To a solution of ester (1 eq.) in dry (2 -Methyl) tetrahydrofuran is added a solution of diisobutylaluminum hydride in toluene (1 - 2 eq.) dropwise at -78°C. The mixture is stirred at -78°C until reaction is complete, after which it is quenched by addition of a saturated aqueous Rochelle’s salt solution. The resulting mixture is allowed to reach room temperature and stirred until adequate separation of theorganic and aqueous layer. The layers are separated, the organic phase is treated with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product is either used as such or purified by column chromatography.Illustrative example of method 8: synthesis of Int 2Example 69. 4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridine-2-carbaldehyde

[0324] To a solution of methyl 4-(2,6-dimethylphenyl)-6-(trifluoromethyl)pyridine-2-carboxylate (Int 1, 1.38 mmol, 0.43 g, 1.0 eq.) in dry 2-methyltetrahydrofuran (6.9 mL) at - 78 °C was added diisobutylaluminum hydride (25 wt% in toluene) (2.87 mmol, 1.93 mL, 2.0 eq.) and the mixture was stirred at -78°C for 90 min. The mixture was carefully quenched by addition of an aqueous saturated solution of Rochelle’s salt at -78°C and then allowed to stir at room temperature for Ih. The biphasic mixture was diluted with ethyl acetate and then partitioned between ethyl acetate and water. The organic phase was treated with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo, delivering 4-(2,6- dimethylphenyl)-6-(trifluoromethyl)pyridine-2-carbaldehyde (Int 2, 450 mg, 117% yield). The crude was used as such. 'H NMR (400 MHz, DMSO) 5 10.08 (s, IH), 8.14 (d, IH), 7.99 (d, IH), 7.28 (dd, IH), 7.23 - 7.15 (m, 2H), 1.98 (s, 6H).a. Method 9. a: Hydrolysis of enol ether using TFA

[0325] The enol ether (1 eq) is dissolved in water and TFA and stirred at room temperature for l-24h. After completion, the reaction mixture is concentrated and either used as such or purified by flash column chromatography .Illustrative example of method 9. a: synthesis of Int 11Example 70. ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)- yl)pentanoate

[0326] ethyl (E)-2-(5-(2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (Int 10, 6.2 mmol, 2.5 g, 1.0 eq.) was dissolved in water (6 mL) and trifluoroacetic acid (8 mL) was added. The resulting mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo, and subjected to normal phase chromatography (SiCL). The product was eluted with a gradient ranging from 0-40% ethyl acetate in heptane to obtain ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4- (trifluoromethyl)pyridin-l(2H)-yl)pentanoate (Int 11, 1.1 g, 42% Yield). LCMS (ESI, m / z): 348.2 [M+H]+b. Method 9.b: Hydrolysis of enol ether using pTSA

[0327] To a solution of the enol ether (1 eq.) in acetone, is added p-toluenesulfonic acid (1-2 eq.) and the reaction is heated to 50-80°C for l-24h. After completion, the reaction is partitioned between ethyl acetate and a saturated aqueous solution of NaHCOs. The organic layer is separated, dried and concentrated, delivering the aldehyde which is used as such.Example 71. ethyl 4-methyl-2-(4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)pentanoate

[0328] To a solution of ethyl (E)-2-(5-(2-ethoxyvinyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4- methylpentanoate (Int 46, 1.00 g, 2.8 mmol, 1.00 eq.) in acetone (l l mL) was added p-toluenesulfonic acid (760 mg, 4.2 mmol, 1.5equiv, 760 mg). The resulting mixture was heated at 50°C and stirred for 3h, after which LCMS showed full conversion. The reaction was partitioned between ethyl acetate and a saturatedaqueous solution of NaHCOs. The organic layer was separated, dried over MgSCL and concentrated, delivering the aldehyde, int 47 which was used as such. LCMS (ESI, m / z): 294.2 [M+H]+Method 10: reductive amination

[0329] The aldehyde (1 eq) and amine (1-1.5 eq.) are dissolved in dichloroethane and subsequently treated with sodium triacetoxyborohydride (1-2 eq.). The resulting reaction mixture is stirred at room temperature for l-16h. After completion, the solvent is concentrated and the crude mixture is purified by column chromatography .Representative example of method 10: Int 12Example 72. ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanoate

[0330] To a mixture of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)- yl)pentanoate (Int 11, 2.7 mmol, 1.10 g, 1.0 eq.), and dimethylamine hydrochloride (CAS# 506-59-2, 3.2 mmol, 260 mg, 1.2 eq.) in 1,2-dichloroethane (25 mL) was added sodium triacetoxyborohydride (4.0 mmol, 850 mg, 1.5 eq.) at room temperature. The mixture was stirred at that temperature overnight. After completion, the solvent was removed in vacuo and the residue was purified by column chromatography (SiCE). The product was eluted using a gradient ranging from 0-15% methanol in dichloromethane to provide ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanoate (Int 12, 72% Yield, 1.93 mmol, 720 mg). LCMS (ESI, m / z): 377.2 [M+H]+Illustrative example of Method 10: Int 48Example 73. ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4- methylpentanoate

[0331] To a solution of ethyl 4-methyl-2-(4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)pentanoate (Int 47, 800 mg, 2.73 mmol, 1.00 eq.) in 2-methyltetrahydrofuran (11 mL) was added (3R)-3- fluoropyrrolidine (CAS# 679431-51-7, 730 mg, 8.18 mmol, 3.00 eq.) followed by sodium triacetoxyborohydride (1.19 g, 5.45 mmol, 2.00 eq.). Next, methanol (0.011 mL, 0.27 mmol, 0.1 eq.) and acetic acid (0.016 ml, 0.27 mmol, 0.10 eq.) were added. The resulting mixture was stirred at room temperature for 3h. The mixture was carefully quenched with water and was then partitioned between ethyl acetate and 2N HC1 in water. The organic layer was separated and discarded. The aqueous layer was basified till pH 9 using solid K2CO3 and was then re-extracted using dichloromethane. The combined organic layers were dried over MgSCL and concentrated. The residue was purified on normal phase chromatography (SiCL) using a gradient ranging from 0-10% 7N NH3 in Methanol in dichloromethane. Relevant fractions were pooled and concentrated yielding the title intermediate 52 (382 mg, 38% yield). LCMS (ESI, m / z): 367.3 [M+H]+Method 11: Mesylation

[0332] A solution of an alcohol (1.0 eq.) in dichloromethane is treated at 0°C with a base like triethylamine (1.2-1.5 eq.), followed by methane sulfonyl chloride (1.1 eq.) After the addition, the reaction mixture is allowed to warm slowly to room temperature and stirring is continued for 1- 16h. The reaction mixture is diluted with dichloromethane and water is added. The organic layer is separated, dried over MgSO4, filtered and concentrated under reduced pressure. The product is used as such.Representative example of Method 11: Int 8Example 74. ethyl 4-methyl-2-((methylsulfonyl)oxy)pentanoate

[0333] To a solution of ethyl 2-hydroxy-4-methyl-pentanoate (CAS# 10348-47-7, 37.5 mmol, 6.2 mL, 6.0 g, 1.0 eq.) in dichloromethane (187 mL) at 0°C was added triethylamine (52.4 mmol, 7.31 mL, 1.4 eq.) followed by methane sulfonyl chloride (CAS# 124-63-0, 41.2 mmol, 3.25 mL, 1.1 eq.). After the addition, the reaction mixture was allowed to slowly warm to room temperature and stirring was continued overnight. The reaction mixture was diluted with dichloromethane and water was added. The organic layer was separated, dried over MgSCL, filtered and concentrated under reduced pressure, delivering ethyl 4- methyl-2-methylsulfonyloxy-pentanoate (Int 8, 8.9 g, 100% yield).1H NMR (400 MHz, DMSO) 5 5.02 (dd, 1H), 4.19 (qd, 2H), 3.25 (s, 3H), 1.80 - 1.58 (m, 3H), 1.22 (t, 3H), 0.92 (dd, 6H).Method 12: Cyanation(het)Ar- X - ► (het)Ar- CN

[0334] A solution of (hetero)-Aryl halide (1 eq.) in an organic solvent like N,N-dim ethylacetamide is treated with a base like N,N-diisopropylethylamine (5-15 eq.) and a zinc source like zinc cyanide (l-2eq.). The mixture is then degassed, after which a palladium catalyst (0. 1 eq) is added. The reaction mixture is heated and stirred until completion. The crude mixture is purified by reversed phase chromatography. Alternatively, the mixture is partitioned between brine and ethyl acetate. The organic layer is washed with brine, dried over MgSCL and concentrated, then purified by normal phase chromatography.Representative example of Method 12: Int 24Example 75. methyl (3S)-3-(6-cyano-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoate

[0335] To a mixture of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 23, 0.073 mmol, 50 mg, 1.0 eq.), inN,N-dimethylacetamide (1 mL) was added N,N-diisopropylethylamine (0.73 mmol, 0.13 mL, 10 eq.), followed by zinc cyanide (0.073 mmol, 8.6 mg, 1.0 eq.). The reaction mixture was degassed by bubbling N2, after which [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (0.007 mmol, 5.6 mg, 0.1 eq.) was added. The resulting mixture was stirred at 90°C overnight. After cooling down, the crude mixture was purified via reversed phase column chromatography to obtain the title cmpd Int 24 as a mix of two diastereomers. LCMS (ESI, m / z): 640.5 [M+H]+Example 76. methyl (3S)-3-(6-cyano-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoate

[0336] To a mixture of methyl (3S)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 36, 0.033 mmol, 22 mg, 1.0 eq.), inN,N-dimethylacetamide (1 mL) was added N,N-diisopropylethylamine (0.33 mmol, 0.06 mL, 10 eq.), followed by zinc cyanide (0.066 mmol, 8 mg, 2.0 eq.). The reaction mixture was degassed by bubbling N2, after which SPhos Pd G4 (0.003 mmol, 3 mg, 0.1 eq.) was added. The resulting mixture was stirred at 90°C overnight. After cooling down, the mixture was diluted with ethyl acetate and subsequently washed with a saturated aqueous NaHCOs-solution, water and brine. The organic layer was separated, dried over MgSCL and concentrated. The crude was purified using normal phase chromatography using a gradient ranging from 0-10% methanolic 7N ammonia solution in DCM. Therelevant fractions were pooled and concentrated obtain the title cmpd Int 53 as a mix of two diastereomers.LCMS (ESI, m / z): 658.4 [M+H]+Method 13: DifluoromethylationF\FFT ~H

[0337] To a solution of the aldehyde (1 eq.) in dichloromethane are added triethylamine trihydrofluoride (3 eq., CAS# 73602-61-6) and difluoro(morpholino)sulfonium tetrafluoroborate (3eq., CAS# 63517-33-9). The resulting mixture is stirred at room temperature. After completion, the reaction is quenched by addition of a saturated aqueous solution of sodium bicarbonate. The layers are separated, the aqueous layer is extracted with dichloromethane. The combined organic layers are dried and concentrated in vacuo. The residue can be used as such or purified by column chromatography.Representative example of Method 13: Int 25Example 77. 4-bromo-2-chloro-6-(difluoromethyl)pyridine

[0338] To a solution of 4-bromo-6-chloro-pyridine-2-carbaldehyde (CAS# 1060811-63-3, 4.86 mmol, 1.07 g, 1.0 eq.) in dry dichloromethane (16 mL) were added triethylamine trihydrofluoride (CAS# 73602- 61-6, 14.6 mmol, 2.43 mL, 3.0 eq.) and difluoro(morpholino)sulfonium tetrafluoroborate (CAS# 63517- 33-9, 14.6 mmol, 3.73 mg, 3.0 eq.) and the mixture was stirred at room temperature overnight.The mixture was treated with a saturated aqueous solution of sodium bicarbonate. The layers were separated, the aqueous layer was extracted with dichloromethane. The combined organic layers were filtered over a phase separator and concentrated in vacuo, delivering the title intermediate 25 as red oil (1.0 g, 86% yield). It was used as such. 'H NMR (400 MHz, DMSO) 5 8.15 (dd, 1H), 8.01 (d, 1H), 6.97 (t, 1H).Method 14: CO-insertion a. Method 14.a: CO-insertion using 2,4,6-trichlorophenyl formate

[0339] A mix of a (hetero)-Aryl halide (1 eq.), 2,4,6-trichlorophenyl formate (CAS# 4525-65-9, 1-2 eq.), a ligand like eg. Xantphos (0.3 eq.) and a palladium catalyst like eg. Xantphos Pd G4 (0.3 eq.) are dissolved in an organic solvent like toluene. Then a base like triethylamine is carefully added, the mixture is heated at 70°C - 110°C and stirred until completion. The mixture is partitioned between ethyl acetate and water. The organic phase is treated with brine, dried and concentrated in vacuo. The crude is purified via flash chromatography .Representative example of Method 14a: Int 27Example 78. 2,4,6-trichlorophenyl 6-(difluoromethyl)-4-(2,6-dimethylphenyl)picolinate

[0340] In a pressure tube, 2-chloro-6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridine (Int 26. 780 mg, 2.91 mmol, 1.0 eq.), 2,4,6-trichlorophenyl formate (CAS# 4525-65-9, 700 mg, 3.04 mmol, 1.05 eq.), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (48 mg, 0.082 mmol, 0.03 eq.) and methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2’-methylamino-l,r-biphenyl-2- yl)palladium(II) (Xantphos Pd G4) (82 mg, 0.084 mmol, 0.03 eq.) were weighed and dissolved in dry toluene (4 m ). Then, triethylamine (0.77 m , 5.5 mmol, 1.9 eq.) was slowly added and the resulting dark orange mixture was stirred at 80°C. After 4 hours, the mixture had turned yellow and was cooled down to room temperature.The mixture was partitioned between ethyl acetate and water. The organic phase was treated with brine, filtered over a phase separator and concentrated in vacuo. The crude was purified via flash chromatography (silica, using a gradient ranging from 2% to 15% ethyl acetate in heptane to obtain the title int 27 (1.01g, 68% yield), still contaminated with some starting material. LCMS (ESI, m / z): 455.8, 457.8 [M+H]+Method 15: Reduction of ester to alcohol

[0341] A solution of ester (1 eq.) in an organic solvent like tetrahydrofuran is treated with a reducing agent like sodium borohydride (1-3 eq.) at 0°C. The temperature is allowed to reach room temperature and the reaction is stirred until completion. The mixture is partitioned between ethyl acetate and water. The layers are separated, the organic phase is washed with brine, dried and concentrated in vacuo. The crude is purified via flash chromatography.Representative example of Method 15a: Int 28Example 79. (6-(difluoromethyl)-4-(2,6-dimethylphenyl)-2-pyridyl)methanol

[0342] To a solution of (2,4,6-trichlorophenyl) 6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridine-2- carboxylate (Int 27, 1.14 mmol, 0.87 g, 1.0 eq.) in tetrahydrofuran (7 mb) at 0°C was added sodium borohydride (2.28 mmol, 0.086 g, 2.0 eq.). The solution was stirred 5 min at 0°C then allowed to warm to room temperature and stirred for 1 hour.The mixture was partitioned between ethyl acetate and water. The layers were separated, the organic phase was washed with brine, dried and concentrated in vacuo. The residue was purified via flash chromatography (silica, using a gradient ranging from 0% to 60% ethyl acetate in heptane) to obtain (6- (difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)methanol (Int 28, 102% Yield, 0.323 g,) as a colorless oil. LCMS (ESI, m / z): 264.1 [M+H]+ 1H NMR (400 MHz, DMSO) 5 7.45 - 7.31 (m, 2H), 7.28 - 7.13 (m, 3H), 6.97 (t, 1H), 5.56 (t, 1H), 4.67 (d, 2H), 1.97 (s, 6H).

[0343] A solution of the alcohol (1 eq.) in an organic solvent like dichloromethane is treated with an oxidizing agent like (l,l-Diacetoxy-3-oxo-l,2-benziodoxol-l-yl) acetate (Dess-Martin periodinane) (1-3 eq.) at 0°C. The temperature is then raised (23°C - 60°C) and stirred until completion. Water is added and the layers are separated. The organic phase is washed with brine, dried and concentrated in vacuo. The crude is purified via flash chromatography.Representative example of Method 16: Int 29Example 80. 6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridine-2-carbaldehyde

[0344] To a solution of (6-(difluoromethyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)methanol (Int 28. 1.17 mmol, 0.32 g, 1.0 eq.) in dichloromethane (6 mb) was added Dess-Martin periodinane (2.33 mmol, 0.99 g, 2.0 eq.) at 0°C, and the mixture was heated to 60°C for 3h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiC>2, with a gradient ranging from 0-25% ethyl acetate in heptane), affording 6-(difluoromethyl)-4-(2,6- dimethylphenyl)pyridine-2-carbaldehyde (Int 29. 49% yield, 0. 15 g) as a colorless oil. LCMS (ESI, m / z): 262.1 [M+H]+Method 17: S cids

[0345] A mix of a (hetero)-Aryl halide (1 eq.), an alkynyl carboxylic acid (1- 2eq.), a ligand like eg. bis(diphenylphosphino)ferrocene (0.2 eq.), a palladium catalyst like eg. bis(triphenylphosphine)palladium(II) dichloride (0.1 eq.) and abase like DBU, are combined in an organic solvent like DMSO. The mixture is degassed and then heated to 70°C - 110°C and stirred until completion. The mixture is partitioned between ethyl acetate and water. The organic phase is treated with brine, dried and concentrated in vacuo. The crude is purified via flash chromatography. Alternatively, the crude mixture is purified by reversed phase chromatography.Example 81. methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-(prop-l-yn-l-yl)pyri din-2- yl)propanoate

[0346] A mixture of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 23, 42 mg, 0.061 mmol, 1.0 eq.), but-2-ynoic acid (CAS# 590-93-2, 0.065 mmol, 5.4 mg, 1.05 eq.), bis(triphenylphosphine)palladium(II) dichloride (0.0006 mmol, 0.4 mg, 0.01 eq.), 1,1'- bis(diphenylphosphino)ferrocene (0.001 mmol, 0.7 mg, 0.02 eq.) and l,8-diazabicyclo[5.4.0]undec-7-ene (0. 12 mmol, 0.018 m , 2.0 eq.) was dissolved in DMSO (2 m ). The solvent was degassed by purging with N2 and stirred overnight at 80°C. After completion, the mixture was purified via reversed phase column chromatography to obtain methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin- 1 (2H)-yl)-4-methylpentanamido)-3 -(4-(2,6-dimethylphenyl)-6-(prop- 1 -yn- 1 - yl)pyridin-2-yl)propanoate (Int 38, 28 mg, 70% yield) as a mix of two diastereomers. LCMS (ESI, m / z): 653.5 [M+H]+Representative example of Method 17: Int 39Example 82. methyl (3S)-3-(6-(cyclopropylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5- (2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoate

[0347] A mixture of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 23, 0.070 mmol, 50 mg, 1.0 eq.), 3-cyclopropylpropiolic acid (CAS# 7358-93-2, 0.074 mmol, 8 mg, 1.05 eq.), bis(triphenylphosphine)palladium(II) dichloride (0.0007 mmol, 0.5 mg, 0.01 eq.), 1,1'- bis(diphenylphosphino)ferrocene (0.0014 mmol, 0.8 mg, 0.02 eq.) and l,8-diazabicyclo[5.4.0]undec-7-ene(0.14 mmol, 0.021 mL, 21 mg, 2.0 eq.) were dissolved in DMSO (2 mL). The solvent was degassed by bubbling with N2 and stirred overnight at 80°C. After completion, the mixture was purified via reversed phase column chromatography to obtain methyl (3S)-3-(6-(cyclopropylethynyl)-4-(2,6- dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)-4-methylpentanamido)propanoate (Int 39. 39 mg, 92% yield) as a mix of two diastereomers. LCMS (ESI, m / z): 697.5 [M+H]+Representative example of Method 17: Int 54Example 83. methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4-methylpentanamido)-3-(4-(4-fluoro-2,6-dimethylphenyl)-6-(prop-l-yn-l-yl)pyridin-2- yl)propanoate

[0348] A mixture of methyl (3S)-3-(6-chloro-4-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 36, 47 mg, 0.068 mmol, 1.0 eq.), but-2-ynoic acid (CAS# 590-93-2, 0.071 mmol, 6 mg, 1.05 eq.), bis(triphenylphosphine)palladium(II) dichloride (0.0007 mmol, 0.5 mg, 0.01 eq.), 1,1'- bis(diphenylphosphino)ferrocene (0.001 mmol, 0.8 mg, 0.02 eq.) and l,8-diazabicyclo[5.4.0]undec-7-ene (0. 14 mmol, 0.020 mL, 2.0 eq.) was dissolved in DMSO (2 mL). The solvent was degassed by purging with N2 and stirred overnight at 80°C. After completion, the mixture was purified via reversed phase column chromatography to obtain methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-(4-fluoro-2,6-dimethylphenyl)-6-(prop-l- yn-l-yl)pyridin-2-yl)propanoate (Int 38, 33 mg, 73% yield) as a mix of two diastereomers. LCMS (ESI, m / z): 671.5 [M+H]+Method 18: Borylation(het)Ar- X (het)

[0349] A mixture of (hetero)aryl halide (1.0 eq.), a 2,2'-bi-l,3,2-dioxaborolane species like 4, 4, 5, 5- tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1-2 eq.), a base like potassium acetate (1.5-3 eq.) and a catalyst like [l,T-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.1 eq.) are dissolved in an organic solvent like 1,4-dioxane. The mixture is degassed and heated at 80-100°C. After completion the reaction is allowed to cool down, diluted with ethyl acetate and washed with brine. The organic layer is dried, filtered and concentrated in vacuo. The crude product can be used as such, or purified by column chromatography.Example 84. methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6-chloro-4-(4,4,5,5-tetraethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)propanoate

[0350] A mixture of methyl (S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(((R)-tert-butylsulfinyl)amino) propanoate (Int 16, 3.7 g, 8.6 mmol, 1.0 eq.), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2- yl)-l,3,2-dioxaborolane (CAS# 2247367-07-1, 4.7 g, 13 mmol, 1.5 eq.), Potassium acetate (1.6 g, 16 mmol, 1.9 eq), and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (630 mg, 0.860 mmol, 0.10 eq) was suspended in 1,4-dioxane (29 mL). The mixture was degassed by vacuum and backfill with N2. The resulting mixture was stirred at 80 °C until completion. The reaction was cooled down then diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSO4, filtered over a layer of celite and concentrated in vacuo. The residu was purified using flash chromatography (SiC>2, using a gradient ranging from 0 to 100% ethyl acetate in heptane), delivering the title intermediate 41.1H NMR (400 MHz, DMSO) 5 7.73 (s, 1H), 7.46 (s, 1H), 5.87 (d, 1H), 4.82 - 4.72 (m, 1H), 3.58 (s, 3H), 3.01 (dd, 1H), 2.91 (dd, 1H), 1.79 - 1.64 (m, 8H), 1.11 (s, 9H), 0.90 (t, 12H).Method 19: Buchwald-Hartwig amination(het)Ar- X +R,'~NH Ri(het)Ar-NR2

[0351] A mixture of (hetero)aryl halide (1.0 eq.), an amine (1-2 eq.), a base like sodium tert-butoxide (1.5- 3 eq.) and a catalyst like RuPhos Pd G4 (0. 1 eq.) are dissolved in an organic solvent like 1,4-dioxane. The mixture is degassed and heated at 60-100°C. After completion the reaction is allowed to cool down, diluted with ethyl acetate and washed with brine. The organic layer is dried, filtered and concentrated in vacuo. The crude product can be used as such, or purified by column chromatography. Alternatively, the crude reaction mixture is directly purified by reversed phase column chromatography.Example 85. (S)-3-(6-(azetidin-l-yl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

[0352] To a mixture of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (J nt 23, 0.07 mmol, 50 mg, 1.0 eq.) in 1,4-dioxane (1 mL) were added RuPhos Pd G4 (0.007 mmol, 6.3 mg, 0.1 eq.), azetidine (CAS# 503-29-7, 0.077 mmol, 0.005 mL, 4, 1.1 equiv.) and sodium tert-butoxide (2 mol / L) in THF (0.2103 mmol, 0.11 mL, 3.0 eq.). The mixture was degassed by bubbling N2 and stirred for Ih at 70°C. After completion of the reaction (concomitant hydrolysis of the ester was observed), the mixture was purified by reversed phase chromatography, affording the desired cpd 17, (S)-3-(6-(azetidin-l-yl)-4-(2,6- dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4-methylpentanamido)propanoic acid. LCMS (retention time, analytical method A): 3.3 min; (ESI, m / z): 656.3 [M+H]+. 'H NMR (400 MHz, DMSO) 5 8.99 (s, IH), 7.81 (s, IH), 7.20 - 7.06 (m, 3H), 6.73 (s, IH), 6.31 (d, J = 1.1 Hz, IH), 5.97 (d, J = 1.1 Hz, IH), 5.61 (dd, J = 10.6, 5.6 Hz, IH), 5.16 - 5.06 (m, IH), 3.94 (t, J = 7.4 Hz, 4H), 2.86 - 2.76 (m, IH), 2.65 - 2.52 (m, 3H), 2.45 - 2.26 (m, 4H), 2.16 (s, 6H), 1.98 (s, 6H), 1.92 - 1.78 (m, IH), 1.77 - 1.65 (m, IH), 1.24 (s, IH), 0.80 - 0.73 (m, 6H).Method 20: Halogen substitution.Cl / Br(het) Ar - ► (het) Ar

[0353] A solution of a (hetero)arylchloride (1 eq.) in an organic solvent like proprionitrile is treated with a nucleophilic halogen source (1-3 eq.) like TMSBr and stirred at elevated temperatures (90-120°C) overnight. After completion, the reaction is cooled down and purified via reversed phase chromatography.Example 86. methyl (3S)-3-(6-bromo-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-(dimethyl- amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate

[0354] A solution of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 23, 0.070 mmol, 50 mg, 1.0 eq.) and bromo(trimethyl)silane (0.140 mmol, 0.019 m , 2.0 eq.) in propionitrile (1 m ) was heated at 100°C overnight. After completion, the reaction was cooled down and purified via reversed phase chromatography, to afford int 57 as a mixture of diastereomers. LCMS (ESI, m / z): 693.4, 695.4 [M+H]+Method 21: Sulfonamide formation

[0355] A solution of an amine (1 eq.) in an organic solvent like dichloromethane is treated with a sulfonating reagent (1-2 eq.) like a sulfonyl chloride or a sulfonic anhydride at 0°C, with our without presence of an organic base. The mixture is allowed to reach room temperature and stirred until completion. The mixture is quenched by addition of a saturated aqueous solution of NaHCOs. The layers are separated,the organic phase is treated with brine, dried and concentrated in vacuo. The crude is purified via column chromatography or used as such.Representative example of method 21: Int 58Example 87. N-(4-bromo-3,5-dimethylphenyl)-l,l,l-trifluoromethanesulfonamide

[0356] To a solution of 4-bromo-3, 5 -dimethylaniline (CAS# 59557-90-3, 1.00 g , 4.94 mmol, 1.00 eq.) in dichloromethane (60 m ) was added, trifluoromethylsulfonyl trifluoromethanesulfonate (CAS# 358-23-6, 1.3 m , 7.7 mmol, 1.6 eq.) dropwise at 0°C. After 5 minutes, the ice bath was removed and the mixture was allowed to stir at room temperature. After 4h, TLC (heptane: ethyl acetate 1: 1) showed complete conversion. The mixture was quenched by addition of a saturated aqueous solution of NaHCOs. The layers were separated, the organic phase was treated with brine, dried and concentrated in vacuo to deliver the title compound as a solid, which was used as such. ‘H NMR (400 MHz, DMSO) 5 7.06 (s, 2H), 2.35 (s, 6H).Method 22: Sulfonamide N-Alkylation

[0357] To a solution of the sulfonamide (1.0 eq.) in an organic aprotic solvent like N,N- dimethylformamide is added a base like potassium carbonate (1-2 eq.), followed by an alkylating reagent (1-2 eq.). The resulting mixture is stirred at a temperature ranging from 20-80°C. After completion, the reaction is allowed to cool down, diluted with ethyl acetate and washed with brine. The organic layer is dried, filtered and concentrated in vacuo. The crude product can be used as such, or purified by column chromatography. Alternatively, the crude reaction mixture is directly purified by reversed phase chromatography .Example 88. N-(4-bromo-3,5-dimethylphenyl)-l,l,l-ti'ifluoro-N-methylmethanesulfonamide

[0358] To a solution of N-(4-bromo-3,5-dimethylphenyl)-l,l,l-trifluoromethanesulfonamide (100 mg, 0.30 mmol, 1.0 eq.) in N,N-dimethylformamide (0.75 mL) was added potassium carbonate (50 mg, 0.36 mmol, 1.2 eq.), followed by iodomethane (0.023 mL, 0.36 mmol, 1.2 eq.). The resulting mixture was stirred at 60°C overnight. The reaction was directly purified by reversed phase chromatography, affording the title Int 62 (66 mg, 63% yield) 'H NMR (400 MHz, DMSO) 5 7.35 (s, 2H), 3.44 (m, 3H), 2.39 (s, 6H).Example 89. Synthesis of intermediate 72

[0359] Potassium tert-butoxide (14.1 g, 124 mmol, 1.7 eq.) was added portionwise at 0°C to a suspension of methoxymethyl(triphenyl)phosphonium chloride (CAS# 4009-98-7, 40 g, 117 mmol, 1.6 eq.) in 2- methyltetrahydrofuran (150 mL). The reaction mixture was stirred at 0-5 °C for 20min, after which a solution of 6-methoxy-4-(trifluoromethyl)pyridine-3-carbaldehyde (CAS# 1005171-85-6, 15 g, 73 mmol, 1.0 eq.) in tetrahydrofuran (75 mL) was added to the reaction mixture dropwise whilst maintaining a temperature below 5°C. The reaction was allowed to warm to room temperature and stirred for Ih. The reaction was partitioned between a saturated aqueous solution of NFLC1 and EtOAc. The combined organic layers were washed with brine, dried over Na2SC>4, filtered and evaporated. Purification by normal phase chromatography (silica), using a gradient ranging from 0% to 100% ethyl acetate in heptane delivered 2-methoxy-5-(2-methoxyvinyl)-4-(trifluoromethyl)pyridine (Int 67, 15.4 g, 90% yield). LCMS (ESI, m / z): 233.9 [M+H]+

[0360] p-Toluenesulfonic acid monohydrate (7.42 g, 38.6 mmol, 1.5 eq.) was added to a flask containing 2-methoxy-5-(2-methoxyvinyl)-4-(trifluoromethyl)pyridine (6 g, 25.7 mmol, 1.0 eq.). Then, acetone (60 mL) was added and the mixture was stirred at 50 °C for 6h. After completion, the mixture was partitioned between 2-MeTHF and a saturated aqueous solution of NaHC’CF. The aqueous layer was extracted with 2- MeTHF, the combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated at 25 °C till around 5V of 2-Me-THF, delivering a solution of 2-(6-methoxy-4-(trifluoromethyl)pyridin-3- yl)acetaldehyde (Int 68) in 2-Me-THF. LCMS (ESI, m / z): 220.0 [M+H]+

[0361] (R)-3 -fluoropyrrolidine (7.17 g, 77.2 mmol, 3.0 eq.) and sodium triacetoxyborohydride (10.9 g, 51.5 mmol, 2.0 eq.) were added respectively to a solution of 2-(6-methoxy-4-(trifluoromethyl)pyridin-3- yl)acetaldehyde (5.64 g, 25.7 mmol, 1.0 eq.) in 2-Me-THF (56 ml). The mixture was stirred overnight. No full conversion was obtained, so extra sodium triacetoxyborohydride (5.45 g, 25.7 mmol, 1.0 eq.). The reaction was stirred for an additional 1,5 h at rt, after which it was poured on ice, basified using 30% NaOH (aq.) until pH 10. The mixture was transferred to a separatory funnel and diluted with EtOAc. The aqueous layer was reextracted EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by normal phase chromatography (120 g silica, solvent A: EtOAc / solvent B: 1% Et3N in MeOH; elution: 100% EtOAc for 5 CV, then from 0% to 15% solvent B in 15 CV) affording (R)-5-(2-(3-fluoropyrrolidin-l-yl)ethyl)-2-methoxy-4- (trifluoromethyl)pyridine (Int 69, 4.84g, 66% yield). LCMS (ESI, m / z): 293.1 [M+H]+

[0362] Hydrochloric acid (12 mol / L) in water (23.5 ml, 282 mmol, 18 eq.) was added to (R)-5-(2-(3- fluoropyrrolidin-l-yl)ethyl)-2-methoxy-4-(trifluoromethyl)pyridine (4.69 g, 16.1 mmol, 1.0 eq.) and the reaction was stirred at 100 °C for 3 h. The reaction mixture was basified. By addition of solid K2CO3 until pH reached 8. The mixture was transferred to a separatory funnel and the product was extracted with n- BuOH / EtOAc (1: 1) (3x). The combined organic layers were dried over MgSCE, filtered and evaporated to dryness to afford (R)-5-(2-(3-fluoropyrrolidin-l-yl)ethyl)-4-(trifluoromethyl)pyridin-2-ol (Int 70, 4.3 g, 96% yield), which was used as such. LCMS (ESI, m / z): 279.1 [M+H]+

[0363] (R)-5-(2-(3-fluoropyrrolidin-l-yl)ethyl)-4-(trifluoromethyl)pyridin-2-ol (4.30 g, 15.5 mmol, 1.0 eq.), ethyl 4-methyl-2-methylsulfonyloxy-pentanoate (Int 8, 1.2 equiv., 18.544 mmol, 98 mass%, 1.2000eq.) and potassium carbonate (3.5 equiv., 54.088 mmol, 100 mass%, 3.5000eq.) were dissolved in anhydrous acetonitrile (0.15 M, 1960 mmol, 100 mass%, 127eq.). Reaction was stirred under N2 at 80°C overnight. A saturated aqueous solution of NH4CI was added until most of the solids dissolved. Then, the mixture was partitioned between EtOAc and water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography, after which the product was transferred to a separatory funnel and extracted with 0.5 M citric acid. The organic layer was discarded. The aqueous layer was basified using 2M KOH (aq.) and then solid K2CO3 until pH 8. Then, the aqueous layer was re-extracted with EtOAc (2x). The organic layer was dried over Na2SO4, filtered and evaporated to dryness to afford ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-l- yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (Int 71, 3.62 g, 55% yield). LCMS (ESI, m / z): 421.1 [M+H]+'H NMR (400 MHz, DMSO) 5 7.90 (d, 1H), 6.80 (s, 1H), 5.34 (dd, 1H), 5.29 - 5.07 (m, 1H), 4.14 (q, 2H), 2.91 - 2.76 (m, 2H), 2.73 - 2.54 (m, 5H), 2.41 - 2.29 (m, 1H), 2.21 - 2.01 (m, 2H), 1.96 - 1.77 (m, 2H), 1.39 - 1.25 (m, 1H), 1.18 (m, 3H), 0.97 - 0.83 (m, 6H).

[0364] Lithium hydroxide monohydrate (380 mg, 9.04 mmol, 1.05 eq.) was added to a solution of ethyl 2- (5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (3.62 g, 8.61 mmol, 1.0 eq.) in tetrahydrofuran (75 mL) and water (20 mL). The reaction was stirred at 40 °C for 3 days, after which it was evaporated to dryness to afford lithium 2-(5-(2-((R)-3-fluoropyrrolidin-l- yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate as a white powder (Int 72, 3.22 g, 89% yield). LCMS (ESI, m / z): 393.1 [M+H]+'H NMR (400 MHz, DMSO) 57.70 (d, J = 5.7 Hz, 1H), 6.60 (s, 1H), 5.28 - 5.06 (m, 2H), 2.92 - 2.73 (m, 2H), 2.72 - 2.52 (m, 5H), 2.39 - 2.27 (m, 1H), 2.20 - 2.00 (m, 1H), 1.98 - 1.76 (m, 2H), 1.75 - 1.64 (m, 1H), 1.29 - 1.11 (m, 1H), 0.89 - 0.74 (m, 6H).Example 90. (S)-3-(6-(cyclopropylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2- ((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid, cpd 23

[0365] lithium 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanoate (Int 72, 1.79 mmol, 752 mg, 1.05 equiv.), methyl (S)-3-amino-3-(4-bromo-6- chloropyridin-2-yl)propanoate (Int 34, 1.71 mmol, 570 mg, 1.0 eq.) and N,N-diisopropylethylamine (4.27 mmol, 0.745 mL, 2.5 eq.) were mixed in N,N-dimethylformamide (7 mL) after which HATU (2.56 mmol, 975 mg, 1.5 equiv.) was added and the mixture was stirred overnight at room temperature. The crude mixture was purified via reversed phase column chromatography 0.5% NIL in water : MeCN (100:0 for 3min, 30:70 to 05:95 in 17min) to obtain methyl (3S)-3-(4-bromo-6-chloropyridin-2-yl)-3-(2-(5-(2-((R)- 3 -fluoropyrrolidin- 1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1 (2H)-yl)-4-methylpentanamido) propanoate (Int 73, 670 mg, 57% yield) as a mix of two diastereomers. LCMS (ESI, m / z): 667.3, 669.3 [M+H]+

[0366] (2,6-dimethylphenyl)boronic acid (0.59 mmol, 88 mg, 1.2 eq.), methyl (3S)-3-(4-bromo-6- chloropyridin-2-yl)-3-(2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- l(2H)-yl)-4-methylpentanamido) propanoate (Int 73, 0.49 mmol, 335 mg, 1.0 eq.), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.049 mmol, 36 mg, 0.1 eq.) and N,N- diisopropylethylamine (1.48 mmol, 0.26 mb, 3.0 eq.) were mixed in dry 1,4-dioxane (2.5 mb) and water (0.6 mb) and stirred at overnight at 80°C under N2.The mixture was cooled down to room temperature, extracted with water and EtOAc, washed with brine, filtered over a phase separator and concentrated in vacuo. The residue was purified via reversed phase column chromatography 0.5% NH3 in water : MeCN (100:0 for 3min, 30:70 to 05:95 in 17min) to obtain methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-((R)-3-fluoropyrrolidin-l- yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 74, 162 mg, 48% yield) as a mix of two diastereomers. LCMS (ESI, m / z): 693.5 [M+H]+

[0367] A mixture of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-((R)-3- fluoropyrrolidin- 1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1 (2H)-yl)-4-methylpentanamido) propanoate (Int 74, 0.078 mmol, 54 mg, 1.0 eq.), 3-cyclopropylprop-2-ynoic acid (CAS# 7358-93-2, 0.10 mmol, 11 mg, 1.3 equiv.), bis(triphenylphosphine)palladium(II) dichloride (0.01 mmol, 7 mg, 0.13 eq.) and l,l'-bis(diphenylphosphino)ferrocene (0.021 mmol, 12 mg, 0.27 equiv.) was dissolved in DMSO (2 mb). Next, l,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mmol, 0.03 mb, 3 eq.) was added and the mixture was stirred overnight at 80°C. The mixture was cooled down and directly purified via reversed phase column chromatography 0.5% NH3 in water : MeCN (100:0 for 3min, 30:70 to 0: 100 in 17min) to obtain methyl (3S)-3-(6-(cyclopropylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-((R)-3-fluoropyrrolidin-l- yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 75, 40 mg, 71% yield) as a mix of two diastereomers. LCMS (ESI, m / z): 723.6 [M+H]+

[0368] methyl (3S)-3-(6-(cyclopropylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-((R)-3- fluoropyrrolidin- 1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1 (2H)-yl)-4-methylpentanamido) propanoate (Int 75, 0.055 mmol, 40 mg, 1.0 equiv.) was treated with lithium hydroxide monohydrate (0.33 mmol, 8 mg, 6.0 eq.) in tetrahydrofuran (ImL) and water (0.2 mb.) and stirred at room temperature overnight. The solvent was removed in vacuo and the diastereomers were separated by preparative reversed phase purification, delivering (S)-3-(6-(cyclopropylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)- 2-(5-(2-((R)-3-fluoropyrrolidin- 1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1 (2H)-yl)-4- methylpentanamido)propanoic acid (cpd 23) LCMS (retention time, analytical method A): 3.9 min; (ESI, m / z): 709.4 [M+H]+.NMR (400 MHz, DMSO) 5 9.11 (d, 1H), 7.87 (s, 1H), 7.25 - 7.10 (m, 4H), 7.04 (d, 1H), 6.73 (s, 1H), 5.66 - 5.57 (m, 1H), 5.29 - 5.03 (m, 2H), 2.93 - 2.52 (m, 12H), 2.37 - 2.27 (m, 1H), 2.18 - 2.00 (m, 2H), 1.92 - 1.49 (m, 6H), 1.28 - 1.17 (m, 1H), 0.97 - 0.86 (m, 2H), 0.83 - 0.72 (m, 8H).Example 91. Synthesis of (S)-3-(6-(cyclobutylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3- ((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido) propanoic acid, cpd 24Cpd 24

[0369] Compound 24 can be synthesized in an analogous fashion as compound 23 as described herein above, by treating Int 74 with 3-cyclobutylpropiolic acid (CAS# 1341446-83-0), according to method 17, followed by hydrolysis and separation of diastereomers, delivering (S)-3-(6-(cyclobutylethynyl)-4-(2,6- dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2 -oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido) propanoic acid, cpd 24 LCMS (retention time, analytical method A): 4.2 min; (ESI, m / z): 723.3 [M+H]+. 'H NMR (400 MHz, DMSO) 59.10 (d, J = 7.9 Hz, 1H), 7.88 (s, 1H), 7.24 - 7.09 (m, 4H), 7.06 (s, 1H), 6.73 (s, 1H), 5.62 (dd, J = 10.4, 5.8 Hz, 1H), 5.27 - 5.03 (m, 2H), 3.38 - 3.27 (m, 1H), 2.96 - 2.86 (m, 1H), 2.85 - 2.76 (m, 2H), 2.74 - 2.64 (m, 2H), 2.63 - 2.54 (m, 4H), 2.36 - 2.26 (m, 3H), 2.20 - 2.13 (m, 2H), 2.13 - 1.98 (m, 1H), 1.94 (s, 6H), 1.93 - 1.83 (m, 3H), 1.82 - 1.75 (m, 1H), 1.73 - 1.63 (m, 1H), 1.25 - 1.19 (m, 1H), 0.89 - 0.66 (m, 6H).Example 92. Synthesis of (S)-3-(4-(2,6-dimethylphenyl)-6-((3-methyloxetan-3-yl)ethynyl)pyridin- 2-yl)-3-((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)- 4-methylpentanamido)propanoic acid, cpd 25

[0370] Compound 25 can be synthesized in an analogous fashion as compound 23 as described herein above, by treating Int 74 with 3-(3-methyloxetan-3-yl)propiolic acid (CAS# 2241142-47-0), according to method 17, followed by hydrolysis and separation of diastereomers, delivering (S)-3-(4-(2,6- dimethylphenyl)-6-((3-methyloxetan-3-yl)ethynyl)pyridin-2-yl)-3-((S*)-2-(5-(2-((R)-3-fluoropyrrolidin- l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, cpd 25.LCMS (retention time, analytical method A): 3.8 min; (ESI, m / z): 739.4 [M+H]+.1H NMR (400 MHz, DMSO) 5 9.18 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.26 - 7.07 (m, 5H), 6.73 (s, 1H), 5.62 (dd, J = 10.3, 5.8 Hz, 1H), 5.27 - 5.04 (m, 2H), 4.78 (d, J = 5.5 Hz, 2H), 4.45 (d, J = 5.5 Hz, 2H), 2.92 - 2.75 (m, 3H), 2.75 - 2.62 (m, 3H), 2.62 - 2.53 (m, 3H), 2.37 - 2.27 (m, 1H), 2.18 - 2.00 (m, 1H), 1.95 (s, 6H), 1.90 - 1.75 (m, 2H), 1.75 - 1.66 (m, 1H), 1.65 (s, 3H), 1.29 - 1.19 (m, 1H), 0.87 - 0.70 (m, 6H).Example 93. Synthesis of (S)-3-(4-(2,6-dimethylphenyl)-6-((l-methoxycyclopropyl)ethynyl) pyridin-2-yl)-3-((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl) pyridin- l(2H)-yl) -4-methylpentanamido)propanoic acid, cpd 26Cpd 26

[0371] Compound 26 can be synthesized in an analogous fashion as compound 23 as described herein above, by treating Int 74 with 3 -(1 -methoxycyclopropyl )propiolic acid (CAS# 2995290-11-2), according to method 17, followed by hydrolysis and separation of diastereomers, delivering (S)-3-(4-(2,6- dimethylphenyl)-6-((l-methoxycyclopropyl)ethynyl)pyridin-2-yl)-3-((S*)-2-(5-(2-((R)-3- fluoropyrrolidin- 1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1 (2H)-yl)-4-methylpentanamido)propanoic acid, cpd 26. LCMS (retention time, analytical method A): 3.9 min; (ESI, m / z): 739.3 [M+H]+'H NMR (400 MHz, DMSO) 5 9.14 (d, J = 7.9 Hz, 1H), 7.88 (s, 1H), 7.32 - 7.19 (m, 2H), 7.20 - 7.09 (m, 3H), 6.74 (s, 1H), 5.63 (dd, J = 10.4, 5.8 Hz, 1H), 5.28 - 5.05 (m, 2H), 3.37 (s, 3H), 2.96 - 2.86 (m, 1H), 2.86 - 2.76 (m, 2H), 2.76 - 2.55 (m, 6H), 2.38 - 2.28 (m, 1H), 2.19 - 1.99 (m, 1H), 1.96 (s, 6H), 1.92 - 1.75 (m, 2H), 1.74 - 1.63 (m, 1H), 1.30 - 1.19 (m, 1H), 1.19 - 1.12 (m, 2H), 1.12 - 1.01 (m, 2H), 0.85 - 0.71 (m, 6H).Example 94. Synthesis of (S)-3-(4-(2,6-dimethylphenyl)-6-(3-methylbut-l-yn-l-yl)pyridin-2-yl)-3- ((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid, cpd 27Cpd 27

[0372] Compound 27 can be synthesized in an analogous fashion as compound 23 as described herein above, by treating Int 74 with 4-methylpent-2-ynoic acid (CAS# 65199-69-1), according to method 17, followed by hydrolysis and separation of diastereomers, delivering (S)-3-(4-(2,6-dimethylphenyl)-6-(3- methylbut-l-yn-l-yl)pyridin-2-yl)-3-((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, cpd 27.LCMS (retention time, analytical method A): 4.1 min; (ESI, m / z): 711.4 [M+H]+'H NMR (400 MHz, DMSO) 59.70 (s, 1H), 7.87 (s, 1H), 7.22 - 7.17 (m, 1H), 7.14 - 7.09 (m, 2H), 7.08 - 7.00 (m, 2H), 6.72 (s, 1H), 5.63 - 5.54 (m, 1H), 5.30 - 4.97 (m, 2H), 2.88 - 2.73 (m, 3H), 2.69 - 2.54 (m, 5H), 2.47 - 2.38 (m, 2H), 2.34 - 2.27 (m, 1H), 2.17 - 1.98 (m, 1H), 1.93 (s, 6H), 1.92 - 1.68 (m, 3H), 1.27 - 1.19 (m, 7H), 0.80 - 0.73 (m, 6H).Example 95. Synthesis of (S)-3-(4-(2,6-dimethylphenyl)-6-(3-methylbut-l-yn-l-yl)pyridin-2-yl)-3- ((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid, cpd 28Cpd 28

[0373] Compound 28 can be synthesized in an analogous fashion as compound 23 as described herein above, by treating Int 73 with 3-(l-methylcyclopropyl)propiolic acid (CAS# 1876993-80-4), according to method 17, followed by hydrolysis and separation of diastereomers, delivering (S)-3-(4-(2,6- dimethylphenyl)-6-(3-methylbut-l-yn-l-yl)pyridin-2-yl)-3-((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l- yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, cpd 28.LCMS (retention time, analytical method A): 4.2 min; (ESI, m / z): 723.4 [M+H]+'H NMR (400 MHz, DMSO) 5 10.01 (d, J = 7.0 Hz, 1H), 7.87 (s, 1H), 7.22 - 7.17 (m, 1H), 7.14 - 7.09 (m, 2H), 7.04 - 6.99 (m, 2H), 6.72 (s, 1H), 5.56 (dd, J = 9.6, 6.3 Hz, 1H), 5.26 - 5.06 (m, 1H), 5.01 - 4.92 (m, 1H), 2.85 - 2.74 (m, 2H), 2.69 - 2.53 (m, 6H), 2.37 - 2.26 (m, 3H), 2.16 - 2.02 (m, 1H), 1.95 - 1.90 (m, 6H), 1.90 - 1.72 (m, 2H), 1.33 (s, 3H), 1.29 - 1.21 (m, 1H), 1.03 - 0.96 (m, 2H), 0.81 - 0.73 (m, 8H).Example 96. Synthesis of (3R)-l-(2-(l-((S*)-l-(((S)-2-carboxy-l-(6-chloro-4-(2,6- dimethylphenyl)pyridin-2-yl)ethyl)amino)-4-methyl-l-oxopentan-2-yl)-6-oxo-4-(trifluoromethyl)- l,6-dihydropyridin-3-yl)ethyl)-3-fluoropyrrolidin-l-ium formate, cpd 29Cpd 29

[0374] Compound 29 can be synthesized in an analogous fashion as described herein above, by subjecting Int 74 to basic hydrolysis according to method 2, followed by separation of diastereomers, delivering (3R)- l-(2-(l-((S*)-l-(((S)-2-carboxy-l-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)ethyl)amino)-4-methyl- l-oxopentan-2-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridin-3-yl)ethyl)-3-fluoropyrrolidin- 1-ium formate, cpd 29.LCMS (retention time, analytical method A): 3.7 min; (ESI, m / z): 679.3 [M+H]+JH NMR (400 MHz, DMSO) 59.13 (d, J = 7.8 Hz, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.30 (d, J = 1.1 Hz, 1H), 7.28 - 7.19 (m, 1H), 7.19 - 7.11 (m, 3H), 6.73 (s, 1H), 5.62 (dd, J = 10.3, 5.9 Hz, 1H), 5.26 - 5.03 (m, 2H), 2.96 - 2.86 (m, 1H), 2.86 - 2.55 (m, 8H), 2.38 - 2.28 (m, 1H), 2.19 - 1.99 (m, 1H), 1.99 - 1.94 (m, 6H), 1.93 - 1.65 (m, 3H), 1.31 - 1.18 (m, 1H), 0.82 - 0.73 (m, 6H).Example 97. Synthesis of (S)-3-(6-(cyclopropylethynyl)-3',5'-dimethyl-[4,4'-bipyridin]-2-yl)-3- ((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid, cpd 30Cpd 30

[0375] Compound 30 can be synthesized in an analogous fashion as compound 23 as described herein above, by treating Int 74 with (3,5-dimethylpyridin-4-yl)boronic acid (CAS# 1430325-87-3) according to method 7, followed by treatment with 3-cyclopropylpropiolic acid (CAS# 7358-93-2), according to method 17, followed by hydrolysis and separation of diastereomers, delivering (S)-3-(6-(cyclopropylethynyl)-3',5'- dimethyl-[4,4'-bipyridin]-2-yl)-3-((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2 -oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, cpd 30.LCMS (retention time, analytical method A): 2.9 min; (ESI, m / z): 710.3 [M+H]+'H NMR (400 MHz, DMSO) 59.53 (s, 1H), 8.36 (s, 2H), 7.87 (s, 1H), 7.17 (s, 1H), 7.05 (s, 1H), 6.71 (s, 1H), 5.57 (dd, 1H), 5.26 - 5.02 (m, 2H), 2.84 - 2.72 (m, 2H), 2.70 - 2.59 (m, 2H), 2.58 - 2.53 (m, 4H), 2.35 - 2.27 (m, 1H), 2.08 (m, 2H), 1.94 (s, 6H), 1.83 - 1.71 (m, 3H), 1.62 - 1.55 (m, 1H), 1.28 - 1.19 (m, 1H), 0.92 (m, 2H), 0.82 - 0.72 (m, 8H).Example 98. Synthesis of (S)-3-(6-(cyclopropylethynyl)-4-mesitylpyridin-2-yl)-3-((S*)-2-(5-(2- ((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid, cpd 31Cpd 31

[0376] Compound 31 can be synthesized in an analogous fashion as compound 23 as described herein above, by treating Int 74 with mesitylboronic acid (CAS# 5980-97-2) according to method 7, followed by treatment with 3-cyclopropylpropiolic acid (CAS# 7358-93-2), according to method 17, followed by hydrolysis and separation of diastereomers, delivering (S)-3-(6-(cyclopropylethynyl)-4-mesitylpyridin-2-yl)-3-((S*)-2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4- methylpentanamido)propanoic acid, cpd 31.LCMS (retention time, analytical method A): 4.1 min; (ESI, m / z): 723.3 [M+H]+'H NMR (400 MHz, DMSO) 5 9.18 (d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.07 (s, 1H), 7.01 (s, 1H), 6.95 (s, 2H), 6.72 (s, 1H), 5.61 (dd, J = 10.4, 5.7 Hz, 1H), 5.25 - 5.05 (m, 2H), 2.84 - 2.79 (m, 2H), 2.70 - 2.65 (m, 2H), 2.63 - 2.59 (m, 2H), 2.57 - 2.55 (m, 2H), 2.35 - 2.31 (m, 1H), 2.27 (s, 3H), 2.17 - 2.00 (m, 2H), 1.90 (s, 6H), 1.85 - 1.76 (m, 2H), 1.72 - 1.64 (m, 1H), 1.62 - 1.54 (m, 1H), 1.27 - 1.18 (m, 1H), 0.95 - 0.89 (m, 2H), 0.81 - 0.73 (m, 8H).Example 99. (S)-3-(6-(cyclobutylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, cpd 32

[0377] A mixture of methyl (3S)-3-(6-chloro-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (Int 23, 0.098 mmol, 65 mg, 1.0 eq.), 3-cyclobutylpropiolic acid (CAS# 1341446-83-0, 0.12 mmol, 15 mg, 1.2 eq.), bis(triphenylphosphine)palladium(II) dichloride (0.01 mmol, 7 mg, 0.1 eq.) and 1,1'- bis(diphenylphosphino)ferrocene (0.02 mmol, 11 mg, 0.2 eq.) was dissolved in DMSO (2 mL). Next, 1,8- diazabicyclo[5.4.0]undec-7-ene (0.29 mmol, 0.044 mL, 3 eq.) was added and the mixture was stirred overnight at 80°C. The mixture was cooled down and directly purified via reversed phase column chromatography 0.5% NHs in water : MeCN (100:0 for 3min, 30:70 to 0:100 in 17min) to obtain methyl (3S)-3-(6-(cyclobutylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2- oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (51 mg, 75% yield) as a mix of two diastereomers. LCMS (ESI, m / z): 693.5 [M+H]+

[0378] methyl (3S)-3-(6-(cyclobutylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (0.074 mmol, 51 mg, 1.0 eq.) was treated with lithium hydroxide monohydrate (0.27 mmol, 11 mg, 3.6 eq.) in tetrahydrofuran (1.4 mL) and water (0.25 mL) and stirred at room temperature overnight. The solventwas removed in vacuo and the diastereomers were separated by preparative reversed phase purification, delivering (S)-3-(6-(cyclobutylethynyl)-4-(2,6-dimethylphenyl)pyridin-2-yl)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (cpd 32) LCMS (retention time, analytical method A): 3.9 min; (ESI, m / z): 679.3 [M+H]+.1H NMR (400 MHz, DMSO) 5 1H NMR (400 MHz, DMSO) 59.57 (s, 1H), 7.80 (s, 1H), 7.26 - 7.06 (m, 4H), 7.05 - 7.00 (m, 1H), 6.72 (s, 1H), 5.63 - 5.55 (m, 1H), 5.13 - 5.03 (m, 1H), 3.38 - 3.25 (m, 1H), 2.64 - 2.52 (m, 3H), 2.42 - 2.24 (m, 5H), 2.22 - 2.10 (m, 8H), 2.04 - 1.67 (m, 10H), 1.29 - 1.18 (m, 1H), 0.81 - 0.73 (m, 6H).Example 100. Synthesis of (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-((3- methyloxetan-3-yl)ethynyl)pyridin-2-yl)propanoic acid, cpd 33Cpd 33

[0379] Compound 33 can be synthesized in an analogous fashion as compound 32 as described herein above, by treating Int 36 with 3-(3-methyloxetan-3-yl)propiolic acid (CAS# 2241142-47-0), according to method 17, followed by hydrolysis and separation of diastereomers, delivering (S)-3-((S*)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6- dimethylphenyl)-6-((3-methyloxetan-3-yl)ethynyl)pyridin-2-yl)propanoic acid, cpd 33.LCMS (retention time, analytical method A): 3.63 min; (ESI, m / z): 695.4 [M+H]+'H NMR (400 MHz, DMSO) 5 9.12 (d, 1H), 7.80 (s, 1H), 7.26 - 7.08 (m, 5H), 6.73 (s, 1H), 5.65 - 5.57 (m, 1H), 5.26 - 5.16 (m, 1H), 4.77 (d, 2H), 4.45 (d, 2H), 2.91 - 2.81 (m, 1H), 2.71 - 2.53 (m, 3H), 2.44 - 2.36 (m, 2H), 2.17 (s, 6H), 1.95 (s, 6H), 1.85 - 1.76 (m, 1H), 1.73 - 1.64 (m, 4H), 1.23 (m, 1H), 0.81 - 0.73 (m, 6H) 30mol% formic acid.Example 101. Synthesis of (S)-3-((S*)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6-dimethylphenyl)-6-((l- methylcyclopropyl)ethynyl)pyridin-2-yl)propanoic acid, cpd 34

[0380] Compound 34 can be synthesized in an analogous fashion as compound 32 as described herein above, by treating Int 36 with 3-(l-methylcyclopropyl)propiolic acid (CAS# 1876993-80-4), according to method 17, followed by hydrolysis and separation of diastereomers, delivering (S)-3-((S*)-2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-(2,6- dimethylphenyl)-6-((l-methylcyclopropyl)ethynyl)pyridin-2-yl)propanoic acid, cpd 34.LCMS (retention time, analytical method A): 4.04 min; (ESI, m / z): 679.4 [M+H]+'H NMR (400 MHz, DMSO) 5 9.07 (d, 1H), 7.80 (s, 1H), 7.24 - 7.18 (m, 1H), 7.17 - 7.09 (m, 3H), 7.04 (s, 1H), 6.73 (s, 1H), 5.65 - 5.57 (m, 1H), 5.24 - 5.17 (m, 1H), 2.91 - 2.81 (m, 1H), 2.71 - 2...

Claims

CLAIMS1. A compound of Formula (I) :whereinR1is a hydrogen atom; orCi-6 alkyl unsubstituted or substituted with one or more independently selected R8; orC2-6 alkenyl unsubstituted or substituted with one or more independently selected R8; orC2-6 alkynyl unsubstituted or substituted with one or more independently selected R8; orC3-7 cycloalkyl unsubstituted or substituted with one or more substituents independently selected R6a; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6a; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6a; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6a; or aryl, preferably phenyl, which is unsubstituted or substituted with one or more independently selected R6a;R2is a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6b; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6b; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6b; or-N(C=0)CI-6 alkoxy; or- -NH-C(=O)NH2; or- -NH-C(=0)NH(CI-6) alkyl); or- -NH-C(=0)N(CI.6) alkyl)2;R3is hydroxyl, Ci-6 alkyl, Ci-6 alkoxy, cyano, nitro, halogen, Ci-6 haloalkyl, Ci-6 haloalkoxy, -SO2(Ci- e)alkyl, -SO2(Ci.6)haloalkyl, -SO2(C3-6)cycloalkyl, -CHO, -CO2(Ci.6)alkyl, -C(O)NH2, -C(O)NH(CI.4alkyl), -C(O)N(CI-4 alkyl)2, -NRnR12, where R11and R12are each independently hydrogen or C1-C3 alkyl or R11and R12together with the nitrogen atom form a 4- to 6-membered heterocyclic ring, which ring is unsubstituted or substituted with one or more substituents independently selected from C1.4 alkyl, Ci- 4 haloalkyl and C3-7 cycloalkyl; orR3is C2alkenyl, which alkenyl is unsubstituted or substituted with one or more substituents independently selected from C1.4 alkyl, C1-4 haloalkyl and C3-7 cycloalkyl; orR3is C4-8 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkenyl, which cycloalkenyl is unsubstituted or substituted with one or more substituents independently selected from halogen, C1.4 alkyl and C1-4 haloalkyl; orR3is C2alkynyl, which alkynyl is unsubstituted or substituted with one or more substituents independently selected from C1.3 alkyl and C1-3 haloalkyl; orR3is C2alkynyl, which alkynyl is substituted with a C3-6 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one or more independently selected R6c; or a 3-6 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl containing at least one heteroatom selected from O, N, and S, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;R4is a hydrogen atom or C1-6 alkyl;R5is: aryl, preferably phenyl, which is unsubstituted or substituted with one or more independently selected R6c; or a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6c; or a 5-7 membered monocyclic heterocycloalkenyl comprising one or two double bonds and one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkenyl is unsubstituted or substituted with one or more independently selected R6c; or heteroaryl, which heteroaryl is unsubstituted or substituted with one or more independently selected R6c; or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic cycloalkyl, which is unsubstituted or substituted with one or more independently selected R6c;each R6ais independently selected from: cyano; hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen; andCi-6 alkyl unsubstituted or substituted with one or more independently selected halogen; each R6bis independently selected from: cyano; hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen and (C1.4 alkyl)2amino;C1.4 alkylamino, which is unsubstituted or the alkyl group of which is substituted with a (Ci-4 alkyl)2amino;(C1.4 alkyl)2amino, which is unsubstituted or an alkyl group of which is substituted with a (Ci-4 alkyl)2amino;-NHSChheterocycloalkyl, which heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which is unsubstituted or substituted with a C1-4 alkyl;C1-6 alkyl unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino or a 4-10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6d;- -NHSO2(Ci.4)alkyl;- -NHSO2(Ci.4)haloalkyl;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more independently selected - CN, -OH, C1.4 alkoxy, halo, (C1-4 alkyl)2amino or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; and4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which heterocycloalkyl is unsubstituted or substituted with a C1.4 alkyl; or an oxo group; each R6cis independently selected from: cyano; hydroxy; halogen;Ci-4 alkoxy unsubstituted or substituted with one or more substituents independently selected from halogen;Ci-6 alkyl unsubstituted or substituted with one or more or more substituents independently selected from halogen;C2-6 alkenyl unsubstituted or substituted with one or more independently selected halogen;C2-6 alkynyl unsubstituted or substituted with one or more independently selected halogen;- -NHSO2(Ci.4)alkyl;-NHS O2(C 1 -4)haloalkyl ;-P(O)(Ci_4 alkyl)2, or -P(O)(R13)(R14) wherein R13and R14together with the phosphorous atom form a 3-6 membered monocyclic heterocycloalkyl;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more independently selected - CN, -OH, C1.4 alkoxy, halo, or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; and4-7 membered monocyclic heterocycloalkyl comprising one or two independently selected N, O or S, and which heterocycloalkyl is unsubstituted or substituted with a C1.4 alkyl; each R6dis independently selected from: cyano; hydroxy; halogen; andC1-6 alkyl unsubstituted or substituted with one or more independently selected cyano, hydroxy, halogen;R7is hydrogen or C1-6 alkyl; each R8is independently selected from: cyano; hydroxy; halogen;- -NH(CI-6alkyl);- -N(CI_6alkyl)( C1.6 alkyl);C1.4 alkoxy unsubstituted or substituted with one or more independently selected halogen;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one or more substituents independently selected from halogen, C1.4 haloalkyl, cyano and hydroxy; a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected R6d; and R9and R10are each independently selected from: hydrogen; cyano;halogen;Ci -e alkyl;Ci-ehaloalkyl; andC3-6 cycloalkyl; or a pharmaceutically acceptable salt and / or solvate thereof.

2. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, wherein R1is:C2-5 alkyl unsubstituted or substituted with one, two, three or four independently selected R8; orC2-5 alkenyl unsubstituted or substituted with one, two, three or four independently selected R8; or C2-5 alkynyl unsubstituted or substituted with one, two, three or four independently selected R8; or C3-6 cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected R6a; wherein each R6ais independently selected from: cyano; hydroxy; halogen;C1.4 alkoxy unsubstituted or substituted with one, two, three or four substituents independently selected from halogen; andC1-6 alkyl unsubstituted or substituted with one, two, three or four independently selected halogen; and each R8is independently selected from: cyano; hydroxy; halogen;- -NH(CI.6 alkyl);- -N(CI.6alkyl)2;C1.4 alkoxy unsubstituted or substituted with one, two, three or four independently selected halogen;C3-6 monocyclic cycloalkyl unsubstituted or substituted with one, two, three or four substituents independently selected from halogen, C1.2 haloalkyl, cyano and hydroxy; and a 4- 10 membered monocyclic, spiro bicyclic, fused bicyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is unsubstituted or substituted with one, two, three or four independently selected R6d; and each R6dis independently selected from halogen; and C1-6 alkyl unsubstituted or substituted with one or more independently selected cyano, hydroxy, halogen.

3. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1 or 2,4. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2 or 3, wherein R3is C1-2 alkoxy, cyano, fluoro, chloro, bromo, C1-2 haloalkyl, C1-2 haloalkoxy, -SC>2(Ci.2)alkyl, -SC>2(Ci.2)haloalkyl, -C(0)NH2, -C(0)NH(CH3), or C2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; or R3is C2 alkynyl, which alkynyl is substituted with a C3-6 cycloalkyl or a 3-6 membered monocyclic heterocycloalkyl containing one heteroatom selected from O and N, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl or Ci -4 alkoxy.

5. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2, 3 or4, wherein R4is a hydrogen atom.

6. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2, 3, 4 or 5, wherein7. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2, 3, 4, 5 or 6, wherein R7is a hydrogen atom.

8. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2, 3,4, 5, 6 or 7, wherein R1is selected from ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl and neopentyl, each of which is unsubstituted or substituted with one, two or three fluorine atoms; orR1is allyl or propargyl;9. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2, 3,10. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2, 3,4, 5, 6, 7, 8 or 9, wherein R3is difluoromethyl, trifluoromethyl, chloro, fluoro, cyano, -SO2CH3, - CH2CF3, -CF2CF3, CF2CH3 or C2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; or R3is C2 alkynyl, which alkynyl is substituted with a C3-5 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently11. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2, 3,4, 5, 6, 7, 8, 9 or 10, wherein R5is12. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein R9and R10are each independently selected from: hydrogen; fluoro; chloro;Ci-2haloalkyl;C3-4 cycloalkyl; and methyl.

13. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein R9and R10are each independently selected from hydrogen and fluoro (preferably R9is hydrogen and R10is fluoro; or R9is fluoro and R10is hydrogen; or both of R9and R10are hydrogen).

14. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, wherein R1is selected from propyl, butyl, iso-butyl, sec-butyl, tert-butyl, neopentyl and propargyl; or R1is -CH2CF(CH3)2, -CF2CH(CH3)2, -CH2CF2CH3or -CH2CH2CF3; orR3is difluoromethyl, trifluoromethyl, chloro, fluoro, cyano, -SO2CH3, -CH2CF3, -CF2CF3, CF2CH3 or C2 alkynyl, which alkynyl is unsubstituted or substituted with methyl, ethyl, propyl or isopropyl; or R3is C2 alkynyl, which alkynyl is substituted with a C3-5 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from fluorine, hydroxyl, methyl, trifluoromethyl or methoxy;R4is a hydrogen atom;R5isR7is hydrogen; andR9and R10are each independently selected from hydrogen and fluoro, wherein preferably R9is hydrogen and R10is fluoro, or R9is fluoro and R10is hydrogen, or both of R9and R10are hydrogen.

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1-14.

16. A compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1-14, or a pharmaceutical composition according to claim 15, for use in medicine.

17. A compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1-14, or a pharmaceutical composition according to claim 15, for use in the prophylaxis and / or treatment of a disease, disorder or condition that is mediated by a4p7 integrin.

18. A compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1-14, or a pharmaceutical composition according to claim 15, for use in the prophylaxis and / or treatment of inflammatory bowel disease, in particular Crohn’s disease and / or ulcerative colitis.

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