WO2021123785A1

WO2021123785A1 - Dna polymerase theta inhibitors

Info

Publication number: WO2021123785A1
Application number: PCT/GB2020/053257
Authority: WO
Inventors: Robert Heald; Martin Stockley; Mark Charles
Original assignee: Artios Pharma Limited
Priority date: 2019-12-17
Filing date: 2020-12-17
Publication date: 2021-06-24
Also published as: GB201918587D0

Abstract

The invention relates to heterocyclic derivatives and their use in the treatment and prophylaxis of cancer, and to compositions containing said derivatives and processes for their preparation.

Description

DNA POLYMERASE THETA INHIBITORS

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Robust repair of DNA double-strand breaks (DSBs) is essential for the maintenance of genome stability and cell viability. DSBs can be repaired by one of three main pathways: homologous recombination (HR), non-homologous end-joining (NHEJ) and alternative NHEJ (alt-NHEJ). Microhomology-mediated end-joining (MMEJ) is the most well characterised alt- NHEJ mechanism. HR-mediated repair is a high-fidelity mechanism essential for accurate error-free repair, preventing cancer-predisposing genomic stability. Conversely, NHEJ and MMEJ are error-prone pathways that can leave mutational scars at the site of repair. MMEJ can function parallel to both HR and NHEJ pathways (Truong etal. PNAS 2013, 110 (19), 7720-7725).

The survival of cancer cells, unlike normal cells, is often dependent on the mis-regulation of DNA damage response (DDR) pathways. For example, an increased dependency on one pathway (often mutagenic) to cope with either the inactivation of another one, or the enhanced replication stress resulting from increased proliferation. An aberrant DDR can also sensitise cancer cells to specific types of DNA damage, thus, defective DDR can be exploited to develop targeted cancer therapies. Crucially, cancer cells with impairment or inactivation of HR and NHEJ become hyper-dependent on MMEJ-mediated DNA repair. Genetic, cell biological and biochemical data have identified RoIQ (UniProtKB - 075417 (DPOLQ_HUMAN) as the key protein in MMEJ (Kent etal. Nature Structural & Molecular Biology (2015), 22(3), 230-237, Mateos-Gomez et al. Nature (2015), 518(7538), 254-257). RoIQ is multifunctional enzyme, which comprises an N-terminal helicase domain (SF2 HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & Doublie DNA Repair (2016), 44, 22-32). Both domains have been shown to have concerted mechanistic functions in MMEJ. The helicase domain mediates the removal of RPA protein from ssDNA ends and stimulates annealing. The polymerase domain extends the ssDNA ends and fills the remaining gaps.

Therapeutic inactivation of RoIQ would thus disable the ability of cells to perform MMEJ and provide a novel targeted strategy in an array of defined tumour contexts. Firstly, RoIQ has been shown to be essential for the survival of HR-defective (HRD) cells (e.g. synthetic lethal with FA/BRCA-deficiency) and is up-regulated in HRD tumour cell lines (Ceccaldi et al. Nature (2015), 518(7538), 258-262). In vivo studies also show that RoIQ is significantly over expressed in subsets of HRD ovarian, uterine and breast cancers with associated poor prognosis (Higgins et al. Oncotarget (2010), 1 , 175-184, Lemee et al. PNAS (2010), 107(30), 13390-13395, Ceccaldi et al. (2015), supra). Importantly, RoIQ is largely repressed in normal tissues but has been shown to be upregulated in matched cancer samples thus correlating elevated expression with disease (Kawamura et al. International Journal of Cancer (2004), 109(1), 9-16). Secondly, its suppression or inhibition confers radio-sensitivity in tumour cells. Finally, RoIQ inhibition could conceivably prevent the MMEJ-dependent functional reversion of BRCA2 mutations that underlies the emergence of cisplatin and PARPi resistance in tumours.

There is therefore a need to provide effective RoIQ inhibitors for the treatment of cancer.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, there is provided a compound of formula (I):

or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein:

W represents =C(R⁴)- or =N-;

R¹, R², R³ and R⁴ independently represent hydrogen, Ci-e alkyl, Ci-e alkoxy, halogen, haloCi- 6 alkyl, C_3-8 cycloalkyl, cyano or -NR^xR^y;

X represents -C(R^6a)(R^6b)-, -N(R⁷)- or -0-; R⁵ represents hydrogen, -CH₂-R^Z or oxo, or together with R^6b may join to form a bridged group, such that when X represents -N(R⁷)- or -O-, R⁵ represents oxo and such that when R⁴ represents cyano, R⁵ represents a group other than oxo;

R^6a represents hydrogen, hydroxy, Ci-e alkyl, haloCi-6 alkyl, Ci-e alkoxy, Ci-e alkanol, C_3-8 cycloalkyl, halogen, -NR^VR^W or heterocyclyl;

R^6b represents hydrogen, or together with R⁵ may join to form a bridged group, or together with R^6a may join to form a C_3-8 cycloalkyl group;

R⁷ represents hydrogen, C_1-6 alkyl, haloCi-6 alkyl, C_3-8 cycloalkyl, heterocyclyl, Ci-e alkylsulfonimidoyl or Ci-e alkylamino optionally substituted by one or more (e.g. 1 or 2) hydroxyl groups;

R^8a represents hydrogen, -CH₂-R^Z or hydroxy;

R^8b represents hydrogen or hydroxy, such that when X represents -N(R⁷)- or -0-, R^8b represents hydrogen;

Y represents -C(R⁹)= or -N=;

R⁹ represents hydrogen, halogen or C_1-6 alkyl;

R¹⁰ represents phenyl or a 5 or 6 membered heteroaryl ring optionally fused to a 5 membered heteroaryl ring, wherein said phenyl or heteroaryl rings may optionally each be substituted by one or more (e.g. 1, 2 or 3) C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanol, -CONR‘R^u, - CH₂-NR‘R^u, C_3-8 cycloalkyl, halogen, cyano or haloCi-6 alkyl groups;

R^{1 1} represents hydrogen, halogen or C_1-6 alkyl;

R*, R^u, R^v, R^w, R^x and R^y independently represent hydrogen, C_1-6 alkyl, haloCi-6 alkyl, C_3-8 cycloalkyl, -COC_1-6 alkyl or heterocyclyl, wherein said alkyl groups may be optionally substituted with or more hydroxy, amino or sulfone groups and said heterocyclyl ring may be optionally substituted by one or more oxo or -COC_1-6 alkyl groups; and R^z represents hydrogen, C_1-6 alkyl, hydroxy, C_1-6 alkoxy or C_1-6 alkanol.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term ‘halo’ or ‘halogen’ as used herein refers to fluorine, chlorine, bromine or iodine.

The term ‘cyano’ as used herein refers to a group where a carbon atom is triple bonded to a nitrogen atom.

The term ‘C_1-6 alkyl’ as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, /so-propyl, butyl, /so-butyl, tert- butyl, pentyl, hexyl and the like. The term ‘Ci-₆alkoxy’ as used herein as a group or part of a group refers to a Ci-₆ alkyl group which contains an oxygen atom wherein Ci-₆ alkyl is as defined herein. Examples of such groups include methoxy, ethoxy or propoxy.

The term ‘Ci-₆alkanol’ as used herein as a group or part of a group refers to a Ci-₆ alkyl group which contains an oxygen atom wherein Ci-₆ alkyl is as defined herein.

The term ‘haloCi-₆ alkyl’ as used herein as a group or part of a group refers to a Ci-₆ alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen. The term ‘haloCi-₆ alkyl’ therefore includes monohaloCi-₆ alkyl and also polyhaloCi-₆ alkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi-₆ alkyl may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.

The term “C3-8 cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term ‘oxo’ as used herein refers to the group =0.

The term ‘amino’ as used herein refers to the group -NR’R”, wherein R’ and R” independently represent a hydrogen or C1-6 alkyl group.

The term ‘Ci-₆alkylamino’ as used herein refers to a C1-6 alkyl group as defined hereinbefore which is substituted with a -NR’R” group, wherein R’ and R” independently represent a hydrogen or C1-6 alkyl group.

The term ‘C1-6 alkylsulfonimidoyl’ as used herein refers to a C1-6 alkyl group as defined hereinbefore which is substituted with a -S(=0)(=NR’) group, wherein R’ represents a hydrogen or C1-6 alkyl group.

The term ‘heterocyclyl’ as used herein refers to a monocyclic or bicyclic non-aromatic, partially saturated or fully saturated ring system containing for example 3 to 12 ring members. Each ring may contain up to five heteroatoms typically selected from nitrogen, sulfur and oxygen. Particular examples of ‘heterocyclyl’ include morpholine, piperidine ( e.g . piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperidinone, pyrrolidine (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. tetrahydropyran-4-yl), imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazolin-2-yl, pyrazolidine, piperazinone and piperazine.

It will be appreciated that the term ‘heterocyclyl” includes reference to spiro and bridged heterocyclic derivatives. Examples of such spiro and bridged heterocyclic derivatives include: hexahydropyrrolo[2,3-c]pyrrolidinyl, diazaspiro[3.4]octanyl, diazaspiro[4.4]nonyl, oxa-azaspiro[3.4]octanyl, oxa-azaspiro[4.4]nonyl, tetrahydrofuro[3,4-c]pyrrolidinyl, oxa- azaspiro[3.3]heptyl, diazaspiro[4.5]decanyl, diazaspiro[3.4]octanyl, octahydro-naphthyridinyl, tetrahydropyrazino-oxazinyl, oxadiazospiro[5.5]undecanyl and oxabicyclo[2.2.1]heptanyl.

The term ‘5 or 6 membered heteroaryl ring’ as used herein refers to a monocyclic aromatic ring system containing 5 or 6 ring members. Each ring may contain up to three heteroatoms typically selected from nitrogen, sulfur and oxygen. Examples of five membered heteroaryl rings include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered heteroaryl rings include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.

The term ‘optionally substituted’ as used herein refers to a group which may be substituted or unsubstituted by a substituent as herein defined.

Embodiments

In one embodiment, the compound of formula (I) is a compound of formula (l)^a:

(l)^a wherein R¹, R², R³, R⁴, R⁵, X, R^8a, R^8b, Y, R¹⁰ and R¹¹ are as defined herein.

In one embodiment, R¹ represents hydrogen or Ci-e alkyl (such as methyl). In a further embodiment, R¹ represents Ci-e alkyl (such as methyl). In a yet further embodiment, R¹ represents hydrogen or methyl. In a still yet further embodiment, R¹ represents methyl.

In one embodiment, R² represents hydrogen or Ci-e alkyl (such as methyl). In a further embodiment, R² represents hydrogen or methyl. In a still yet further embodiment, R² represents hydrogen.

In one embodiment, R³ represents Ci-e alkyl (such as methyl or ethyl) or haloCi-₆ alkyl (such as trifluoromethyl). In a further embodiment, R³ represents methyl, ethyl or trifluoromethyl. In a yet further embodiment, R³ represents haloCi-₆ alkyl (such as trifluoromethyl).

In one embodiment, W represents =C(R⁴)-.

In one embodiment, R⁴ represents hydrogen or cyano. In a further embodiment, R⁴ represents cyano.

In one embodiment, W represents C(R⁴)- and:

R¹ represents Ci-e alkyl (such as methyl), R² represents hydrogen, R³ represents haloCi-₆ alkyl (such as trifluoromethyl) and R⁴ represents cyano; or

R¹ represents Ci-e alkyl (such as methyl), R² represents hydrogen, R³ represents Ci-e alkyl (such as methyl) and R⁴ represents cyano; or R¹ represents hydrogen, R² represents Ci-e alkyl (such as methyl), R³ represents Ci-e alkyl (such as ethyl) and R⁴ represents cyano; or

R¹ represents Ci-e alkyl (such as methyl), R² represents hydrogen, R³ represents haloCi-₆ alkyl (such as trifluoromethyl) and R⁴ represents hydrogen.

In one embodiment, R⁵ represents hydrogen, oxo, or R⁵ together with R⁷ joins to form a bridged group.

In one embodiment, X represents -C(R^6a)(R^6b)-. In an alternative embodiment, X represents - 0-. In a further alternative embodiment, X represents -N(R⁷)-.

When X represents -C(R^6a)(R^6b)-, in one embodiment, R^6a represents hydrogen, Ci-e alkyl (such as methyl), hydroxy, Ci-e alkanol (such as CH₂OH) or -NR^vR^w (such as -NHCOMe).

When X represents -C(R^6a)(R^6b)-, in one embodiment, R^6b represents hydrogen. When X represents -C(R^6a)(R^6b)-, in an alternative embodiment, R^6b together with R⁵ joins to form a bridged group. When X represents -C(R^6a)(R^6b)-, in a further alternative embodiment, R^6b together with R^6a joins to form a C_3-8 cycloalkyl group (such as a cyclopropyl group).

When X represents -N(R⁷)-, in one embodiment. R⁷ represents hydrogen, C_1-6 alkylsulfonimidoyl (such as -(CH2)2-S(=0)(=NH)(Me)) or C_1-6 alkylamino optionally substituted by one or more (e.g. 1 or 2) hydroxyl groups (such as -CH₂-CH₂0H-CH₂-N(Me)₂).

In one embodiment, R^8a and R^8b both represent hydrogen, or R^8a represents hydroxy and R^8b represents hydrogen, or R^8a represents -CH₂-R^Z (such as methyl) and R^8b represents hydroxy, or R^8a represents -CH₂-R^Z (such as -CH₂-OH) and R^8b represents hydrogen or hydroxy.

In one embodiment, X represents -C(R^6a)(R^6b)- and:

R⁵ represents hydrogen, R^6a represents hydrogen, R^6b represents hydrogen and R^8a and R^8b both represent hydrogen; or

R⁵ represents hydrogen, R^6a represents hydroxy, R^6b represents hydrogen and R^8a and R^8b both represent hydrogen; or

R⁵ represents hydrogen, R^6a represents hydroxy, R^6b represents hydrogen, R^8a represents hydroxy and R^8b represents hydrogen; or

R⁵ together with R^6b joins to form a bridged group, R^6a represents hydrogen and R^8a and R^8b both represent hydrogen; or R⁵ together with R^6b joins to form a bridged group, R^6a represents Ci-e alkanol (such as CH₂OH) and R^8a and R^8b both represent hydrogen; or

R⁵ represents hydrogen, R^6a represents NR^VR^W (such as -NHCOMe), R^6b represents hydrogen and R^8a and R^8b both represent hydrogen; or

R⁵ represents oxo, R^6a represents C_1-6 alkyl (such as methyl), R^6b represents hydrogen, R^8a represents -CH₂-R^Z (such as methyl) and R^8b represents hydroxy; or

R⁵ represents oxo, R^6a and R^6b both represent hydrogen, R^8a represents -CH₂-R^Z (such as -CH₂-OH) and R^8b represents hydroxy; or

R⁵ represents oxo, R^6a represents C_1-6 alkyl (such as methyl), R^6b represents hydrogen, R^8a represents -CH₂-R^Z (such as -CH₂-OH) and R^8b represents hydroxy; or R⁵ represents oxo, R^6a and R^6b join to form a C_3-8 cycloalkyl group (such as a cyclopropyl group), R^8a represents -CH₂-R^Z (such as -CH₂-OH) and R^8b represents hydroxy.

In an alternative embodiment, X represents -O- and:

R⁵ represents oxo and R^8a and R^8b both represent hydrogen; or R⁵ represents oxo, R^8a represents -CH₂-R^Z (such as -CH₂-OH) and R^8b represents hydrogen.

In an alternative embodiment, X represents -N(R⁷)- and:

R⁵ represents oxo, R⁷ represents hydrogen and R^8a and R^8b both represent hydrogen; or

R⁵ represents oxo, R⁷ represents hydrogen, R^8a represents -CH₂-R^Z (such as -CH₂- OH) and R^8b represents hydrogen; or

R⁵ represents oxo, R⁷ represents C_1-6 alkylamino optionally substituted by one or more (e.g. 1 or 2) hydroxyl groups (such as -CH2-CH20H-CH2-N(Me)2) and R^8a and R^8b both represent hydrogen; or

R⁵ represents oxo, R⁷ represents C_1-6 alkylsulfonimidoyl (such as -(CH₂)₂- S(=0)(=NH)(Me)) and R^8a and R^8b both represent hydrogen.

In one embodiment, Y represents -C(R⁹)=. In an alternative embodiment, Y represents -N=.

In one embodiment, R⁹ represents hydrogen, halogen (such as fluorine or chlorine) or C_1-6 alkyl (such as methyl). In a further embodiment, R⁹ represents hydrogen.

In one embodiment, R¹⁰ represents phenyl or a 5 or 6 membered heteroaryl ring (such as pyridyl or pyrazolyl) optionally fused to a 5 membered heteroaryl ring (such as pyrrolopyridinyl) wherein said phenyl or heteroaryl rings may optionally each be substituted by one or more (e.g. 1 , 2 or 3) Ci-e alkyl (such as methyl or isopropyl), Ci-e alkoxy (such as methoxy), Ci-e alkanol (such as CH₂OH), -CONR‘R^u (such as -CONH₂), -CH₂-NR‘R^U (such as -CH₂-NH₂), halogen (such as fluorine or chlorine), cyano or haloCi-₆ alkyl (such as trifluoromethyl).

In a further embodiment, R¹⁰ represents: phenyl optionally substituted by by one or more (e.g. 1, 2 or 3) C_1-6 alkyl (such as methyl or isopropyl), C_1-6 alkoxy (such as methoxy), C_1-6 alkanol (such as CH₂OH), - CONR‘R^u (such as -CONH₂), -CH₂-NR‘R^U (such as -CH₂-NH₂), halogen (such as fluorine or chlorine) or cyano; or a 5 or 6 membered heteroaryl ring (such as pyridyl or pyrazolyl) optionally fused to a 5 membered heteroaryl ring (such as pyrrolopyridinyl) wherein said heteroaryl rings may optionally each be substituted by one or more (e.g. 1, 2 or 3) C_1-6 alkyl (such as methyl), halogen (such as fluorine or chlorine) or haloCi-₆ alkyl (such as trifluoromethyl).

In a further embodiment, R¹⁰ represents phenyl optionally substituted by one or more (e.g. 1, 2 or 3) C_1-6 alkyl (such as methyl or isopropyl), C_1-6 alkoxy (such as methoxy), C_1-6 alkanol (such as CH₂OH), -CONR‘R^u (such as -CONH₂), -CH₂-NR‘R^U (such as -CH₂-NH₂), halogen (such as fluorine or chlorine) and cyano.

In an alternative embodiment, R¹⁰ represents a 5 or 6 membered heteroaryl ring (such as pyridyl or pyrazolyl) optionally fused to a 5 membered heteroaryl ring (such as pyrrolopyridinyl) wherein said heteroaryl rings may optionally each be substituted by one or more (e.g. 1 , 2 or 3) C_1-6 alkyl (such as methyl), halogen (such as fluorine or chlorine) or haloCi-₆ alkyl (such as trifluoromethyl).

In one embodiment, R¹¹ represents hydrogen, halogen (such as chlorine) or C_1-6 alkyl (such as methyl). In a further embodiment, R¹¹ represents hydrogen or methyl. In a yet further embodiment, R¹¹ represents hydrogen.

In one embodiment, the invention provides a compound of formula (I) which is the free base of a compound of Examples 1-66 or a pharmaceutically acceptable salt or solvate thereof.

A reference to a compound of the formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; preferably, the salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the salts or tautomers or N-oxides or solvates thereof, even more preferably the salts or tautomers or solvates thereof. Hereinafter, compounds and their ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof as defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

Salts

Certain compounds of the formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (I) include the salt forms of the compounds.

The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

Acid addition salts ( mono - or di- salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di- salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L- lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1, 5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L- pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins. One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the hydrochloride salt.

Where the compounds of the formula (I) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).

The compounds of the invention may exist as mono- or di- salts depending upon the pK_a of the acid from which the salt is formed.

It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates or formates may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

Solvates

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention. In one embodiment, the pharmaceutically acceptable solvates of the compounds of the invention include the hydrate thereof.

In one embodiment, said crystalline form of the compounds of formula (I) is a cocrystal or coformer. Such a cocrystal or coformer may be prepared using water-soluble molecules such as saccharin, caffeine, nicotinamide or carboxylic acids. Coformers may be prepared as described in Emami S etal (2018) Biolmpacts 8(4), 305-320, the techniques of which are herein incorporated by reference.

It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention.

As used herein "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

N-Oxides

Compounds of the formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide.

Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More particularly, N-oxides can be made by the procedure of L. W. Deady ( Syn . Commun. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

Prodrugs It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All such prodrugs of compounds of the invention are included within the scope of the invention. Examples of pro-drug functionality suitable for the compounds of the present invention are described in Drugs of Today, 19, 9, 1983, 499-538 and in Topics in Chemistry, Chapter 31, pp. 306-316 and in “Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference).

It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs ” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.

Also included within the scope of the compound and various salts of the invention are polymorphs thereof.

Enantiomers

Where chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. The invention also extends to any tautomeric forms or mixtures thereof.

Isotopes

The subject invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as ²H (D) and ³H (T), carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l, ¹²⁵l and ¹³¹1, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷0 and ¹⁸0, phosphorus, such as ³²P, and sulfur, such as ³⁵S. Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase) etc. The radioactive isotopes tritium, i.e. ³H (T), and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H (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.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵0 and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

Purity

Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are given on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

Processes

According to a further aspect of the present invention there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following schemes are examples of synthetic schemes that may be used to synthesise the compounds of the invention. In the following schemes reactive groups can be protected with protecting groups and de-protected according to well established techniques.

According to a further aspect of the invention there is provided a process for preparing a compound of formula (I) as herein defined which comprises:

(a) reacting a compound of formula (II):

wherein R⁵, X, R^8a, R^8b, Y, R¹⁰ and R¹¹ are as defined herein, with a compound of formula

(III):

wherein R¹, R², R³ and W are as defined herein and L¹ represents a suitable leaving group, such as a halogen atom (e.g. chlorine);

(b) reacting a compound of formula (IV):

wherein R¹, R², R³, W, R⁵, X, R^8a, R^8b, Y and R¹¹ are as defined herein, with a compound of formula R¹⁰-L², wherein R¹⁰ is as defined herein and L² represents a suitable leaving group, such as boronic acid or a halogen atom (e.g. fluorine);

(c) deprotection of a protected derivative of a compound of formula (I);

(d) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and

(e) optional formation of a pharmaceutically acceptable salt of a compound of formula (I).

Process (a) typically comprises reacting a compound of formula (II) with a compound of formula (III) in the presence of suitable reagents, such as DIPEA in NMP, under suitable conditions, such as heating to a suitable temperature (such as 70 °C).

Process (b) typically comprises reacting a compound of formula (IV) with a compound of formula R¹⁰-L² in a suitable solvent, such as DCM, in the presence of a suitable reagent, such as CU(0AC)2-H20 and a suitable base, such as pyridine.

Compounds of formula (II) and (IV) may be prepared in accordance with the procedures described herein. For example, compounds of formula (II) may be prepared in accordance with the experimental procedure described in Example 1 and compounds of formula (IV) may be prepared in accordance with the experimental procedure described in Example 9. Compounds of formula (III) and R¹⁰-L² are either known or may be prepared in accordance with known procedures.

A wide range of well known functional group interconversions for process (d) are known by a person skilled in the art for converting a precursor compound to a compound of formula (I) and are described in Advanced Organic Chemistry by Jerry March, 4^th Edition, John Wiley & Sons, 1992. For example possible metal catalysed functionalisations such as using organo- tin reagents (the Stille reaction), Grignard reagents and reactions with nitrogen nucleophiles are described in ‘Palladium Reagents and Catalysts’ [Jiro Tsuji, Wley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1 , Edited by Ei-ichi Negishi, Wley, ISBN 0-471-31506-0]

If appropriate, the reactions described herein are followed or preceded by one or more reactions known to the skilled of the art and are performed in an appropriate order to achieve the requisite substitutions on R¹, R², R³, R⁴, R⁵, R^6a, R^6b, R⁷, R^8a, R^8b, R⁹, R¹⁰ and R¹¹ defined herein to afford other compounds of formula (I). Non-limiting examples of such reactions whose conditions can be found in the literature include: protection of reactive functions, deprotection of reactive functions, halogenation, dehalogenation, dealkylation, alkylation of amine, aniline, alcohol and phenol,

Mitsunobu reaction on hydroxyl groups, cycloaddition reactions on appropriate groups, reduction of nitro, esters, cyano, aldehydes, transition metal-catalyzed coupling reactions, acylation, sulfonylation/introduction of sulfonyl groups, saponification/hydrolysis of esters groups, amidification or transesterification of ester groups, esterification or amidification of carboxylic groups, halogen exchange, nucleophilic substitution with amine, thiol or alcohol, reductive amination, oxime formation on carbonyl and hydroxylamine groups,

S-oxidation, N-oxidation, salification.

It is recognised that the sequence of reactions involving aryl coupling and reduction may be varied. It is also recognised that a wide range of palladium based catalysts are suitable for conducting aryl coupling reactions.

It may also be recognised that isomer separation may occur at any suitable stage in the synthetic sequence. It should be stressed that such chiral separation forms a key aspect of the invention and that such separation may be conducted in accordance with the methodology described herein or may be conducted in accordance with known methodology. It is also recognised that it may be beneficial to temporarily form a protected derivative of an intermediate in the synthesis, for example, a Boc-protected amine, or SEM-protected amide, in order to facilitate chromatographic separation, chiral resolution or to give improved solubility or yields in particular steps.

In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and de-protecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2007).

A hydroxy group may be protected, for example, as an ether (-OR) or an ester (-OC(=0)R), for example, as: a tert- butyl ether; a tetrahydropyranyl (THP) ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or te/f-butyldimethylsilyl ether; or an acetyl ester (-OC(=0)CH₃).

An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (- NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyl carbamate (-NHCO- OCH2C6H5, -NH-Cbz or NH-Z); as a tert- butyl carbamate (-NHCOOC(CH₃)3, NH-Boc); a 2- biphenyl-2-propyl carbamate (-NHCO-OCCCHs^CekUCeHs, NH-Boc), as a 9-fluorenylmethyl carbamate (-NH-Fmoc), as a 6-nitroveratryl carbamate (-NH-Nvoc), as a 2-trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc), as an allyl carbamate (-NH-Alloc), or as a 2(-phenylsulfonyl)ethyl carbamate (-NH-Psec). Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.

A carboxylic acid group may be protected as an ester for example, as: an C_1-7 alkyl ester (e.g. a methyl ester; a tert- butyl ester); a Ci-₇haloalkyl ester (e.g. a C_1-7 trihaloalkyl ester); a triCi-7 alkylsilyl-Ci-7 alkyl ester; or a C5-20 aryl-Ci-7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester; para-methoxybenzyl ester.

It will be understood by those skilled in the art that certain compounds of the invention can be converted into other compounds of the invention according to standard chemical methods.

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

Therapeutic Utility

The compounds of the invention, subgroups and examples thereof, are inhibitors of RoIQ polymerase activity, and which may be useful in preventing or treating disease states or conditions described herein. In addition the compounds of the invention, and subgroups thereof, will be useful in preventing or treating diseases or condition mediated by RoIQ. References to the preventing or prophylaxis or treatment of a disease state or condition such as cancer include within their scope alleviating or reducing the incidence of cancer.

Thus, for example, it is envisaged that the compounds of the invention will be useful in alleviating or reducing the incidence of cancer.

The compounds of the present invention may be useful for the treatment of the adult population. The compounds of the present invention may be useful for the treatment of the pediatric population.

As a consequence of their inhibition of RoIQ, the compounds will be useful in providing a means of disabling the ability of cells to perform MMEJ. It is therefore anticipated that the compounds may prove useful in treating or preventing proliferative disorders such as cancers. In addition, the compounds of the invention may be useful in the treatment of diseases in which there is a disorder associated with cell accumulation. Without being bound by theory it is expected that the RoIQ inhibitors of the present invention will demonstrate certain properties for them to be of particular utility in the therapeutic treatment of certain cancers. For example, in one embodiment, the RoIQ inhibitors of the present invention are suitably lethal in BRCA1 and BRCA2 deficient primary and secondary solid tumours, including breast, ovarian, prostate and pancreas.

In a further embodiment, the RoIQ inhibitors of the present invention are suitably lethal in a variety of primary and secondary solid tumours which are HRD by mechanisms other than BRCA deficiency, such as those with promoter hypermethylation. In these tumours where no DSB repair pathway may be fully down regulated the RoIqί may be given along with another DDR modulator such as a PARP inhibitor, a DNA-PK inhibitor, an ATR inhibitor, an ATM inhibitor, a weel inhibitor or a CHK1 inhibitor.

In a further embodiment, the RoIQ inhibitors of the present invention are suitably lethal in primary and secondary breast, ovarian, prostate and pancreatic tumours retaining BRCA1 deficiency but which, following or not following exposure to PARPi medication, are resistant to PARPi treatment.

In a further embodiment, the RoIQ inhibitors of the present invention suitably increase the ORR including CRR, will delay the onset of PARPi resistance, will increase the time to relapse and DFS, and will increase the OS of HRD (BRCA1/2 deficient and other HRD mechanisms) primary and secondary tumours (breast, ovarian, prostate and pancreas) when given with PARPi treatment programmes.

In a further embodiment, the RoIQ inhibitors of the present invention suitably show synthetic sickness and/or synthetic lethality in a variety of tumours with loss of ATM activity (ATM ^/_) particularly in the context of WT p53. Tumour types will include around 10% of all solid tumours including gastric, lung, breast, and CRC, along with CLL. Co-medicating with another DDR modifier, such as a DNA-PK inhibitor, PARP inhibitor or ATR inhibitor, may further enhance such activity. RoIQ inhibitors will resensitise CLL to classical chemotherapy and chemo-immunotherapy where drug resistance has emerged. Thus, according to a further embodiment, the pharmaceutical composition of the present invention additionally comprises a DNA-PK inhibitor, PARP inhibitor, or ATR inhibitor.

In a further embodiment, the RoIQ inhibitors of the present invention suitably show synthetic sickness and/or synthetic lethality in a variety of tumours deficient in the DNA double strand break repair process of non-homologous end-joining (NHEJ-D). Tumour types will include approximately 2-10% of all solid tumours including prostate, pancreatic, cervical, breast, lung, bladder and oesophageal. Co-medicating with another DDR modifier, such as a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor, may further enhance such activity. RoIQ inhibitors will further sensitise NHEJD cancer cells to DNA DSB inducing chemotherapies and to ionising radiation based therapies. Thus, according to a further embodiment, the pharmaceutical composition of the present invention additionally comprises a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor.

In a further embodiment, the RoIQ inhibitors of the present invention suitably reduce the DNA replication stress response during the chemotherapy of HR proficient tumours such as ovarian, NSCL and breast tumours over expressing RoIQ. This will increase the ORR to treatment and increase OS. Such effects are particularly likely with cytarabine (Ara-C) and hydroxyurea used in a wide variety of leukemias including CML, and the management of squamous cell carcinomas.

In a further embodiment, the RoIQ inhibitors of the present invention suitably selectively sensitise solid tumours to radiotherapy, including EBRT and brachytherapy, with little or no sensitisation of normal tissues. In a fractionated curative-intent setting this will increase loco- regional control driving increased survival. This will be particularly evident in the management of NSCLC, SCCH&N, rectal cancer, prostate cancer and pancreatic cancer.

In a further embodiment, the RoIQ inhibitors of the present invention suitably show synthetic sickness and/or synthetic lethality in PTEN deleted tumours such as CaP, with or without comedication with a PARPi. Furthermore, such tumours will exhibit exquisite sensitivity to radiotherapy both by dint of the PTEN deletion as well as the RoIQ inhibitor induced radiosensitivity.

In a further embodiment, the RoIQ inhibitors of the present invention suitably suppress TLS polymerase activity, sensitising primary and secondary solid tumours (e.g. breast, lung, ovarian, CRC) to drugs (e.g. cisplatin, mitomycin and cyclophosphamide) as well as reducing the acquisition of drug-induced mutations implicated in tumour resistance leading to prolongation of remission and increased TTR.

In a further embodiment, the RoIQ inhibitors of the present invention suitably resensitise BCR- ABL-positive CML which is has developed imatinib resistance, as well as other solid tumours with elevated ligase Ilia levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair. In a further embodiment, the RoIQ inhibitors of the present invention suitably show synthetic sickness and/or synthetic lethality in aromatase inhibitor resistant ER primary and secondary breast cancers, again showing elevated ligase Ilia levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.

According to a further aspect of the invention there is a provided a compound of formula (I) as defined herein for use in the treatment of tumours characterised by a deficiency in homologous recombination (HRD).

It will be appreciated that references herein to “deficiency in homologous recombination (HRD)” refer to any genetic variation which results in a deficiency or loss of function of the resultant homologous recombination gene. Examples of said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.

In one embodiment, said homologous recombination genes are selected from any of: ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4, LIG1 , RPA1, RPA2, BRIP1 and PTEN.

It will be appreciated that references herein to “non-homologous end-joining deficiency (NHEJD)” refer to any genetic variation which results in a deficiency or loss of function of the resultant homologous recombination gene. Examples of said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.

In one embodiment, said non-homologous end-joining genes are selected from any one or more of: LIG4, NHEJ1 , POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.

According to a further aspect of the invention there is a provided a compound of formula (I) as defined herein for use in the treatment of tumours which overexpress RoIQ. According to a further aspect of the invention there is a provided a compound of formula (I) as defined herein for use in the treatment of tumours which have elevated ligase Ilia levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.

Examples of cancers (and their benign counterparts) which may be treated (or inhibited) include, but are not limited to tumours of epithelial origin (adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas and other carcinomas) such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, rectum and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney, lung (for example adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas and mesotheliomas), head and neck (for example cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid (for example thyroid follicular carcinoma), adrenal, prostate, skin and adnexae (for example melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic naevus); haematological malignancies (i.e. leukemias, lymphomas) and premalignant haematological disorders and disorders of borderline malignancy including haematological malignancies and related conditions of lymphoid lineage (for example acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt’s lymphoma, mantle cell lymphoma, MALT lymphoma, T-cell lymphomas and leukaemias, natural killer [NK] cell lymphomas, Hodgkin’s lymphomas, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders), and haematological malignancies and related conditions of myeloid lineage (for example acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia); tumours of mesenchymal origin, for example sarcomas of soft tissue, bone or cartilage such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi’s sarcoma, Ewing’s sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumours, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumours of the central or peripheral nervous system (for example astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumours and schwannomas); endocrine tumours (for example pituitary tumours, adrenal tumours, islet cell tumours, parathyroid tumours, carcinoid tumours and medullary carcinoma of the thyroid); ocular and adnexal tumours (for example retinoblastoma); germ cell and trophoblastic tumours (for example teratomas, seminomas, dysgerminomas, hydatidiform moles and choriocarcinomas); and paediatric and embryonal tumours (for example medulloblastoma, neuroblastoma, Wilms tumour, and primitive neuroectodermal tumours); or syndromes, congenital or otherwise, which leave the patient susceptible to malignancy (for example Xeroderma Pigmentosum).

Many diseases are characterized by persistent and unregulated angiogenesis. Chronic proliferative diseases are often accompanied by profound angiogenesis, which can contribute to or maintain an inflammatory and/or proliferative state, or which leads to tissue destruction through the invasive proliferation of blood vessels. Tumour growth and metastasis have been found to be angiogenesis-dependent. Compounds of the invention may therefore be useful in preventing and disrupting initiation of tumour angiogenesis. In particular, the compounds of the invention may be useful in the treatment of metastasis and metastatic cancers.

Metastasis or metastatic disease is the spread of a disease from one organ or part to another non-adjacent organ or part. The cancers which can be treated by the compounds of the invention include primary tumours (i.e. cancer cells at the originating site), local invasion (cancer cells which penetrate and infiltrate surrounding normal tissues in the local area), and metastatic (or secondary) tumours ie. tumours that have formed from malignant cells which have circulated through the bloodstream (haematogenous spread) or via lymphatics or across body cavities (trans-coelomic) to other sites and tissues in the body.

Particular cancers include hepatocellular carcinoma, melanoma, oesophageal, renal, colon, colorectal, lung e.g. mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal, ovarian and prostate cancers.

A further aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as described herein, in particular cancer.

The compounds may also be useful in the treatment of tumour growth, pathogenesis, resistance to chemo- and radio-therapy by sensitising cells to chemotherapy and as an anti metastatic agent. The potency of the compounds of the invention as inhibitors of RoIQ can be measured using the biological and biophysical assays set forth in the examples herein and the level of affinity exhibited by a given compound can be defined in terms of the IC₅₀ value. Particular compounds of the present invention are compounds having an IC₅₀ value of less than 1 mM, more particularly less than 0.1 mM.

A role for the loss of RoIQ enhancing the efficacy of CRISPR mediated gene editing has been described in WO 2017/062754. Thus, RoIQ inhibitory compounds are likely to be useful in enhancing the efficiency of CRISPR based editing methodologies and/or CRISPR based editing therapeutics. Furthermore, compound mediated RoIQ inhibition is likely to reduce the frequency of random integration events and thus provide a route to ameliorate any safety concerns of CRISPR mediated technology. Thus, according to a further aspect of the invention, there is provided the use of a compound of formula (I) as defined herein in a CRISPR based editing methodology and/or CRISPR based editing therapeutics, such as the enhancement of efficiency of CRISPR based editing methodology and/or CRISPR based editing therapeutics.

Pharmaceutical Compositions

While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). In one embodiment this is a sterile pharmaceutical composition.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising (e.g admixing) at least one compound of formula (I) (and sub-groups thereof as defined herein), together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents, as described herein.

The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below. The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery. The delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump or syringe driver.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) 2004, p 201-230).

The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules, vials and prefilled syringes, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. In one embodiment, the formulation is provided as an active pharmaceutical ingredient in a bottle for subsequent reconstitution using an appropriate diluent.

The pharmaceutical formulation can be prepared by lyophilising a compound of formula (I), or sub-groups thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms.

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Pharmaceutical compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.

Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of thickening or coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include agents to adjust tonicity such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In one particular embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. For intravenous administration, the solution can be dosed as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration. In another particular embodiment, the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.

Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract.

Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.

The solid dosage forms (eg; tablets, capsules etc.) can be coated or un-coated. Coatings may act either as a protective film (e.g. a polymer, wax or varnish) or as a mechanism for controlling drug release or for aesthetic or identification purposes. The coating (e.g. a Eudragit ™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum, duodenum, jejenum or colon.

Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to release the compound in a controlled manner in the gastrointestinal tract. Alternatively the drug can be presented in a polymer coating e.g. a polymethacrylate polymer coating, which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under microbial action in the gut. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (for example formulations based on ion exchange resins) may be prepared in accordance with methods well known to those skilled in the art.

The compound of formula (I) may be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of the nanoparticles assisting their absorption.

In addition, nanoparticles offer the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in “Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13^th March 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172, and in Sinha et ai, Mol. Cancer Ther. August 1, (2006) 5, 1909.

The pharmaceutical compositions typically comprise from approximately 1% (w/w) to approximately 95% (w/w) active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient or combination of excipients. Particularly, the compositions comprise from approximately 20% (w/w) to approximately 90%,% (w/w) active ingredient and from 80% (w/w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, particularly from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, tablets or capsules.

The pharmaceutically acceptable excipient(s) can be selected according to the desired physical form of the formulation and can, for example, be selected from diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co solvents), disintegrants, buffering agents, lubricants, flow aids, release controlling (e.g. release retarding or delaying polymers or waxes) agents, binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavouring agents, taste masking agents, tonicity adjusting agents and coating agents.

The skilled person will have the expertise to select the appropriate amounts of ingredients for use in the formulations. For example tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/ or bulking agents (depending on drug dose). They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow release tablets would in addition contain 0-99% (w/w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w/w) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w/w) oils.

Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into a polymer or waxy matrix that allow the active ingredients to diffuse or be released in measured amounts.

The compounds of the invention can also be formulated as solid dispersions. Solid dispersions are homogeneous extremely fine disperse phases of two or more solids. Solid solutions (molecularly disperse systems), one type of solid dispersion, are well known for use in pharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci. , 60, 1281- 1300 (1971)) and are useful in increasing dissolution rates and increasing the bioavailability of poorly water-soluble drugs.

This invention also provides solid dosage forms comprising the solid solution described above. Solid dosage forms include tablets, capsules, chewable tablets and dispersible or effervescent tablets. Known excipients can be blended with the solid solution to provide the desired dosage form. For example, a capsule can contain the solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. In addition a capsule can contain a bulking agent, such as lactose or microcrystalline cellulose. A tablet can contain the solid solution blended with at least one disintegrant, a lubricant, a surfactant, a bulking agent and a glidant. A chewable tablet can contain the solid solution blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavours. Solid solutions may also be formed by spraying solutions of drug and a suitable polymer onto the surface of inert carriers such as sugar beads (‘non-pareils’). These beads can subsequently be filled into capsules or compressed into tablets.

The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient’s supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician’s instructions.

Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.

Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound. Solutions of the active compound may also be used for rectal administration.

Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

The compounds of the formula (I) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

Methods of Treatment

The compounds of the formula (I) and sub-groups as defined herein may be useful in the prophylaxis or treatment of a range of disease states or conditions mediated by RoIQ. Thus, according to a further aspect of the invention there is provided a method of treating a disease state or condition mediated by RoIQ (e.g. cancer) which comprises administering to a subject in need thereof a compound of formula (I) as described herein. Examples of such disease states and conditions are set out above, and in particular include cancer.

The compounds are generally administered to a subject in need of such administration, for example a human or animal patient, particularly a human.

The compounds will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic. However, in certain situations (for example in the case of life threatening diseases), the benefits of administering a compound of the formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.

The compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a continuous manner or in a manner that provides intermittent dosing (e.g. a pulsatile manner).

A typical daily dose of the compound of formula (I) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of bodyweight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of bodyweight although higher or lower doses may be administered where required. The compound of the formula (I) can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.

The compounds of the invention may be administered orally in a range of doses, for example 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particular examples of doses including 10, 20, 50 and 80 mg. The compound may be administered once or more than once each day. The compound can be administered continuously (i.e. taken every day without a break for the duration of the treatment regimen). Alternatively, the compound can be administered intermittently (i.e. taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen). Examples of treatment regimens involving intermittent administration include regimens wherein administration is in cycles of one week on, one week off; or two weeks on, one week off; or three weeks on, one week off; or two weeks on, two weeks off; or four weeks on two weeks off; or one week on three weeks off - for one or more cycles, e.g. 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles.

In one particular dosing schedule, a patient will be given an infusion of a compound of the formula (I) for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.

More particularly, a patient may be given an infusion of a compound of the formula (I) for periods of one hour daily for 5 days and the treatment repeated every three weeks.

In another particular dosing schedule, a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours.

In a further particular dosing schedule, a patient is given a continuous infusion for a period of 12 hours to 5 days, an in particular a continuous infusion of 24 hours to 72 hours.

In another particular dosing schedule, a patient is given the compound orally once a week. In another particular dosing schedule, a patient is given the compound orally once-daily for between 7 and 28 days such as 7, 14 or 28 days.

In another particular dosing schedule, a patient is given the compound orally once-daily for 1 day, 2 days, 3 days, 5 days or 1 week followed by the required amount of days off to complete a one or two week cycle.

In another particular dosing schedule, a patient is given the compound orally once-daily for 2 weeks followed by 2 weeks off.

In another particular dosing schedule, a patient is given the compound orally once-daily for 2 weeks followed by 1 week off.

In another particular dosing schedule, a patient is given the compound orally once-daily for 1 week followed by 1 week off.

Ultimately, however, the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

It will be appreciated that RoIQ inhibitors can be used as a single agent or in combination with other anticancer agents. Combination experiments can be performed, for example, as described in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22: 27- 55.

The compounds as defined herein can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds (or therapies) for treatment of a particular disease state, for example a neoplastic disease such as a cancer as hereinbefore defined. For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants (supporting agents in the therapy) in cancer therapy. Examples of other therapeutic agents or treatments that may be administered together (whether concurrently or at different time intervals) with the compounds of the formula (I) include but are not limited to:

• Topoisomerase I inhibitors;

• Antimetabolites; • Tubulin targeting agents;

• DNA binder and topoisomerase II inhibitors;

• Alkylating Agents;

• Monoclonal Antibodies;

• Anti-Hormones;

• Signal Transduction Inhibitors;

• Proteasome Inhibitors;

• DNA methyl transferase inhibitors;

• Cytokines and retinoids;

• Chromatin targeted therapies;

• Radiotherapy; and

• Other therapeutic or prophylactic agents.

Particular examples of anti-cancer agents or adjuvants (or salts thereof), include but are not limited to any of the agents selected from groups (i)-(xlvi), and optionally group (xlvii), below:

(i) Platinum compounds, for example cisplatin (optionally combined with amifostine), carboplatin or oxaliplatin;

(ii) Taxane compounds, for example paclitaxel, paclitaxel protein bound particles (Abraxane™), docetaxel, cabazitaxel or larotaxel;

(iii) Topoisomerase I inhibitors, for example camptothecin compounds, for example camptothecin, irinotecan(CPT11), SN-38, or topotecan;

(iv) Topoisomerase II inhibitors, for example anti-tumour epipodophyllotoxins or podophyllotoxin derivatives for example etoposide, or teniposide;

(v) Vinca alkaloids, for example vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine or vinvesir;

(vi) Nucleoside derivatives, for example 5-fluorouracil (5-FU, optionally in combination with leucovorin), gemcitabine, capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, or nelarabine;

(vii) Antimetabolites, for example clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, or hydroxyurea (hydroxycarbamide);

(viii) Alkylating agents, such as nitrogen mustards or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, methylcyclohexylchloroethylnitrosurea, or nimustine (ACNU);

(ix) Anthracyclines, anthracenediones and related drugs, for example daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (eg. Caelyx™, Myocet™, Doxil™), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin;

(x) Epothilones, for example ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO, epothilone A, epothilone B, desoxyepothilone B (also known as epothilone D or KOS- 862), aza-epothilone B (also known as BMS-247550), aulimalide, isolaulimalide, or luetherobin;

(xi) DNA methyl transferase inhibitors, for example temozolomide, azacytidine or decitabine, or SGI-110;

(xii) Antifolates, for example methotrexate, pemetrexed disodium, or raltitrexed;

(xiii) Cytotoxic antibiotics, for example antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, or mithramycin;

(xiv) Tubulin-binding agents, for example combrestatin, colchicines or nocodazole;

(xv) Signal Transduction inhibitors such as Kinase inhibitors (e.g. EGFR (epithelial growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MTKI (multi target kinase inhibitors), Raf inhibitors, mTOR inhibitors for example imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032/RG7204), dabrafenib, encorafenib or an IKB kinase inhibitor such as SAR- 113945, bardoxolone, BMS-066, BMS-345541, IMD-0354, IMD-2560, or IMD-1041, or MEK inhibitors such as Selumetinib (AZD6244) and Trametinib (GSK121120212);

(xvi) Aurora kinase inhibitors for example AT9283, barasertib (AZD1152), TAK-901, MK0457 (VX680), cenisertib (R-763), danusertib (PHA-739358), alisertib (MLN-8237), or MP- 470;

(xvii) CDK inhibitors for example AT7519, roscovitine, seliciclib, alvocidib (flavopiridol), dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621, BMS- 387032 (a.k.a. SNS-032), PHA533533, PD332991 , ZK-304709, or AZD-5438;

(xviii) PKA/B inhibitors and PKB (akt) pathway inhibitors for example AKT inhibitors such as KRX-0401 (perifosine/ NSC 639966), ipatasertib (GDC-0068; RG-7440), afuresertib (GSK-2110183; 2110183), MK-2206, MK-8156, AT13148, AZD-5363, triciribine phosphate (VGD-002; triciribine phosphate monohydrate (API-2; TCN-P; TCN-PM; VD- 0002), RX-0201, NL-71-101 , SR-13668, PX-316, AT13148, AZ-5363, Semaphore, SF1126, or Enzastaurin HCI (LY317615) or MTOR inhibitors such as rapamycin analogues such as RAD 001 (everolimus), CCI 779 (temsirolemus), AP23573 and ridaforolimus, sirolimus (originally known as rapamycin), AP23841 and AP23573, calmodulin inhibitors e.g. CBP-501 (forkhead translocation inhibitors), enzastaurin HCI (LY317615) or PI3K Inhibitors such as dactolisib (BEZ235), buparlisib (BKM-120; NVP- BKM-120), BYL719, copanlisib (BAY-80-6946), ZSTK-474, CUDC-907, apitolisib (G DC- 0980; RG-7422), pictilisib (pictrelisib, GDC-0941, RG-7321), GDC-0032, GDC-0068, GSK-2636771, idelalisib (formerly CAL-101, GS 1101, GS-1101), MLN1117 (INK1117), MLN0128 (INK128), IPI-145 (INK1197), LY-3023414, ipatasertib, afuresertib, MK-2206, MK-8156, LY-3023414, LY294002, SF1126 or PI-103, or sonolisib (PX-866);

(xix) Hsp90 inhibitors for example AT13387, herbimycin, geldanamycin (GA), 17-allylamino- 17-desmethoxygeldanamycin (17-AAG) e.g. NSC-330507, Kos-953 and CNF-1010, 17- dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG) e.g. NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021 an oral purine), ganetespib (STA-9090), SNX-5422 (SC-102112) or IPI-504;

(xx) Monoclonal Antibodies (unconjugated or conjugated to radioisotopes, toxins or other agents), antibody derivatives and related agents, such as anti-CD, anti-VEGFR, anti- HER2, anti-CTLA4, anti-PD-1 or anti-EGFR antibodies, for example rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ertumaxomab (HER2 and CD3), cetuximab (EGFR), panitumumab (EGFR), necitumumab (EGFR), nimotuzumab (EGFR), bevacizumab (VEGF), catumaxumab (EpCAM and CD3), abagovomab (CA125), farletuzumab (folate receptor), elotuzumab (CS1), denosumab (RANK ligand), figitumumab (IGF1R), CP751.871 (IGF1R), mapatumumab (TRAIL receptor), metMAB (met), mitumomab (GD3 ganglioside), naptumomab estafenatox (5T4), siltuximab (IL6), or immunomodulating agents such as CTLA-4 blocking antibodies and/or antibodies against PD-1 and PD-L1 and/or PD-L2 for example ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS- 936559 (anti- PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4);

(xxi) Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis, for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, or raloxifene;

(xxii) Aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrazole, testolactone aminoglutethimide, mitotane or vorozole; (xxiii) Antiandrogens (i.e. androgen receptor antagonists) and related agents for example bicalutamide, nilutamide, flutamide, cyproterone, or ketoconazole;

(xxiv) Hormones and analogues thereof such as medroxyprogesterone, diethylstilbestrol (a.k.a. diethylstilboestrol) or octreotide;

(xxv) Steroids for example dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenpropionate), fluoxymestrone or gossypol,

(xxvi) Steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor (CYP17), e.g. abiraterone;

(xxvii) Gonadotropin releasing hormone agonists or antagonists (GnRAs) for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, or deslorelin;

(xxviii) Glucocorticoids, for example prednisone, prednisolone, dexamethasone;

(xxix) Differentiating agents, such as retinoids, rexinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane, alitretinoin, bexarotene, or tretinoin;

(xxx) Farnesyltransferase inhibitors for example tipifarnib;

(xxxi) Chromatin targeted therapies such as histone deacetylase (HDAC) inhibitors for example panobinostat, resminostat, abexinostat, vorinostat, romidepsin, belinostat, entinostat, quisinostat, pracinostat, tefinostat, mocetinostat, givinostat, CUDC-907, CUDC-101, ACY-1215, MGCD-290, EVP-0334, RG-2833, 4SC-202, romidepsin, AR-42 (Ohio State University), CG-200745, valproic acid, CKD-581, sodium butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide (FR 901228), dacinostat (NVP- LAQ824), R306465/ JNJ-16241199, JNJ-26481585, trichostatin A, chlamydocin, A-173, JNJ-MGCD-0103, PXD-101, or apicidin;

(xxxii) Proteasome Inhibitors for example bortezomib, carfilzomib, delanzomib (CEP- 18770), ixazomib (MLN-9708), oprozomib (ONX-0912) or marizomib;

(xxxiii) Photodynamic drugs for example porfimer sodium or temoporfin;

(xxxiv) Marine organism-derived anticancer agents such as trabectidin;

(xxxv) Radiolabelled drugs for radioimmunotherapy for example with a beta particle-emitting isotope (e.g. , Iodine -131, Yittrium -90) or an alpha particle-emitting isotope (e.g., Bismuth-213 or Actinium-225) for example ibritumomab or Iodine tositumomab;

(xxxvi) Telomerase inhibitors for example telomestatin;

(xxxvii) Matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat;

(xxxviii) Recombinant interferons (such as interferon-g and interferon a) and interleukins (e.g. interleukin 2), for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b; (xxxix) Selective immunoresponse modulators for example thalidomide, or lenalidomide;

(xl) Therapeutic Vaccines such as sipuleucel-T (Provenge) or OncoVex;

(xli) Cytokine-activating agents include Picibanil, Romurtide, Sizofiran, Virulizin, or Thymosin;

(xlii) Arsenic trioxide;

(xliii) Inhibitors of G-protein coupled receptors (GPCR) for example atrasentan;

(xliv) Enzymes such as L-asparaginase, pegaspargase, rasburicase, or pegademase;

(xlv) DNA repair inhibitors such as PARP inhibitors for example, olaparib, velaparib, iniparib, rucaparib (AG-014699 or PF-01367338), talazoparib or AG-014699;

(xlvi)DNA damage response inhibitors such as ATM inhibitors AZD0156 MS3541, ATR inhibitors AZD6738, M4344, M6620 wee1 inhibitor AZD1775;

(xlvii) Agonists of Death receptor (e.g. TNF-related apoptosis inducing ligand (TRAIL) receptor), such as mapatumumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dulanermin, CS-1008, apomab or recombinant TRAIL ligands such as recombinant Human TRAIL/Apo2 Ligand;

(xlviii) Prophylactic agents (adjuncts); i.e. agents that reduce or alleviate some of the side effects associated with chemotherapy agents, for example

- anti-emetic agents,

- agents that prevent or decrease the duration of chemotherapy-associated neutropenia and prevent complications that arise from reduced levels of platelets, red blood cells or white blood cells, for example interleukin-11 (e.g. oprelvekin), erythropoietin (EPO) and analogues thereof (e.g. darbepoetin alfa), colony- stimulating factor analogs such as granulocyte macrophage-colony stimulating factor (GM-CSF) (e.g. sargramostim), and granulocyte-colony stimulating factor (G-CSF) and analogues thereof (e.g. filgrastim, pegfilgrastim),

- agents that inhibit bone resorption such as denosumab or bisphosphonates e.g. zoledronate, zoledronic acid, pamidronate and ibandronate,

- agents that suppress inflammatory responses such as dexamethasone, prednisone, and prednisolone,

- agents used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone-producing tumours, such as synthetic forms of the hormone somatostatin e.g. octreotide acetate,

- antidote to drugs that decrease levels of folic acid such as leucovorin, or folinic acid,

- agents for pain e.g. opiates such as morphine, diamorphine and fentanyl,

- non-steroidal anti-inflammatory drugs (NSAID) such as COX-2 inhibitors for example celecoxib, etoricoxib and lumiracoxib,

- agents for mucositis e.g. palifermin, - agents for the treatment of side-effects including anorexia, cachexia, oedema or thromoembolic episodes, such as megestrol acetate.

In one embodiment the anticancer is selected from recombinant interferons (such as interferon-g and interferon a) and interleukins (e.g. interleukin 2), for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b; interferon-a2 (500 m/ml) in particular interferon-b; and signal transduction inhibitors such as kinase inhibitors (e.g. EGFR (epithelial growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MTKI (multi target kinase inhibitors), Raf inhibitors, mTOR inhibitors for example imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032/RG7204), dabrafenib, encorafenib or an IKB kinase inhibitor such as SAR-113945, bardoxolone, BMS-066, BMS-345541, IMD-0354, IMD-2560, or IMD-1041, or MEK inhibitors such as Selumetinib (AZD6244) and Trametinib (GSK121120212), in particular Raf inhibitors (e.g. vemurafenib) or MEK inhibitors (e.g. trametinib).

Each of the compounds present in the combinations of the invention may be given in individually varying dose schedules and via different routes. As such, the posology of each of the two or more agents may differ: each may be administered at the same time or at different times. A person skilled in the art would know through his or her common general knowledge the dosing regimes and combination therapies to use. For example, the compound of the invention may be using in combination with one or more other agents which are administered according to their existing combination regimen. Examples of standard combination regimens are provided below.

The taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m²) of body surface area, for example 75 to 250 mg/m², particularly for paclitaxel in a dosage of about 175 to 250 mg/m² and for docetaxel in about 75 to 150 mg/m² per course of treatment.

The camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m²) of body surface area, for example 1 to 300 mg/m², particularly for irinotecan in a dosage of about 100 to 350 mg/m² and for topotecan in about 1 to 2 mg/m² per course of treatment. The anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m²) of body surface area, for example 50 to 250mg/m², particularly for etoposide in a dosage of about 35 to 100 mg/m² and for teniposide in about 50 to 250 mg/m² per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m²) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg/m² , for vincristine in a dosage of about 1 to 2 mg/m² , and for vinorelbine in dosage of about 10 to 30 mg/m² per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m²) of body surface area, for example 700 to 1500 mg/m², particularly for 5-FU in a dosage of 200 to 500mg/m², for gemcitabine in a dosage of about 800 to 1200 mg/m² and for capecitabine in about 1000 to 2500 mg/m² per course of treatment.

The alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m²) of body surface area, for example 120 to 200 mg/m², particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m² , for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m² , and for lomustine in a dosage of about 100 to 150 mg/m² per course of treatment.

The anti-tumour anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m²) of body surface area, for example 15 to 60 mg/m², particularly for doxorubicin in a dosage of about 40 to 75 mg/m², for daunorubicin in a dosage of about 25 to 45mg/m² , and for idarubicin in a dosage of about 10 to 15 mg/m² per course of treatment.

The antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, particularly 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about 1mg once a day. Droloxifene is advantageously administered orally in a dosage of about 20-1 OOmg once a day. Raloxifene is advantageously administered orally in a dosage of about 60mg once a day. Exemestane is advantageously administered orally in a dosage of about 25mg once a day.

Antibodies are advantageously administered in a dosage of about 1 to 5 mg per square meter (mg/m²) of body surface area, or as known in the art, if different. Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg/m²) of body surface area, particularly 2 to 4mg/m² per course of treatment.

Where the compound of the formula (I) is administered in combination therapy with one, two, three, four or more other therapeutic agents (particularly one or two, more particularly one), the compounds can be administered simultaneously or sequentially. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. When administered sequentially, they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s). These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.

In one embodiment is provided a compound of formula (I) for the manufacture of a medicament for use in therapy wherein said compound is used in combination with one, two, three, or four other therapeutic agents. In another embodiment is provided a medicament for treating cancer which comprises a compound of formula (I) wherein said medicament is used in combination with one, two, three, or four other therapeutic agents. The invention further provides use of a compound of formula (I) for the manufacture of a medicament for enhancing or potentiating the response rate in a patient suffering from a cancer where the patient is being treated with one, two, three, or four other therapeutic agents.

It will be appreciated that the particular method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein. The weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of formula (I) and another anticancer agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1 , even more in particular from 1/3 to 3/1.

The compounds of the invention may also be administered in conjunction with non- chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diets.

The compounds of the present invention also have therapeutic applications in sensitising tumour cells for radiotherapy and chemotherapy. Hence the compounds of the present invention can be used as "radiosensitizer" and/or “chemosensitizer” or can be given in combination with another "radiosensitizer" and/or “chemosensitizer”. In one embodiment the compound of the invention is for use as chemosensitiser.

The term "radiosensitizer" is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of the cells to ionizing radiation and/or to promote the treatment of diseases which are treatable with ionizing radiation.

The term “chemosensitizer” is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or promote the treatment of diseases which are treatable with chemotherapeutics.

In one embodiment the compound of the invention is administered with a "radiosensitizer" and/or “chemosensitizer”. In one embodiment the compound of the invention is administered with an "immune sensitizer". The term “immune sensitizer” is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of cells to a RoIQ inhibitor.

Many cancer treatment protocols currently employ radiosensitizers in conjunction with radiation of x-rays. Examples of x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5- bromodeoxyuridine (BUdR), 5- iododeoxyuridine (lUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same.

Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent. Examples of photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.

Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the invention; compounds which promote the incorporation of radiosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour with or without additional radiation; or other therapeutically effective compounds for treating cancer or other diseases.

Chemosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the invention; compounds which promote the incorporation of chemosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour or other therapeutically effective compounds for treating cancer or other disease. Calcium antagonists, for example verapamil, are found useful in combination with antineoplastic agents to establish chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents and to potentiate the efficacy of such compounds in drug-sensitive malignancies.

Examples of immune sensitizers include the following, but are not limited to: immunomodulating agents, for example monoclonal antibodies such as immune checkpoint antibodies [e.g. CTLA-4 blocking antibodies and/or antibodies against PD-1 and PD-L1 and/or PD-L2 for example ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti- PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4)]; or Signal Transduction inhibitors; or cytokines (such as recombinant interferons); or oncolytic viruses; or immune adjuvants (e.g. BCG).

Immune sensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the invention; compounds which promote the incorporation of immune sensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; therapeutic agents which act on the tumour or other therapeutically effective compounds for treating cancer or other disease.

For use in combination therapy with another chemotherapeutic agent, the compound of the formula (I) and one, two, three, four or more other therapeutic agents can be, for example, formulated together in a dosage form containing two, three, four or more therapeutic agents i.e. in a unitary pharmaceutical composition containing all agents. In an alternative embodiment, the individual therapeutic agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

In one embodiment is provided a combination of a compound of formula (I) with one or more (e.g. 1 or 2) other therapeutic agents (e.g. anticancer agents as described above). In a further embodiment is provided a combination of a RoIQ inhibitor as described herein and a PI3K/AKT pathway inhibitor selected from: apitolisib, buparlisib, Copanlisib, pictilisib, ZSTK- 474, CUDC-907, GSK-2636771, LY-3023414, ipatasertib, afuresertib, MK-2206, MK-8156, Idelalisib, BEZ235 (dactolisib), BYL719, GDC- 0980, GDC-0941, GDC-0032 and GDC-0068.

In another embodiment is provided a compound of formula (I) in combination with one or more (e.g. 1 or 2) other therapeutic agents (e.g. anticancer agents) for use in therapy, such as in the prophylaxis or treatment of cancer.

In one embodiment the pharmaceutical composition comprises a compound of formula (I) together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agent(s). In another embodiment the invention relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumour cells.

In a further embodiment the invention relates to a product containing a compound of formula (I) and one or more anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

EXAMPLES

The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

Abbreviations aq. Aqueous

BOC te/f-Butyloxycarbonyl

CDI 1,1'-Carbonyldiimidazole

DCM Dichloromethane

DIBAL-H Diisobutylaluminium hydride

DIPEA A/,/\/-Diisopropylethylamine

DMF A/,/\/-Dimethylformamide

DMF-DMA A/,/\/-Dimethylformamide dimethyl acetal

DMSO Dimethylsulfoxide

ES Electrospray

EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

EtOH Ethanol

EtOAc Ethyl acetate h hour(s)

HATU 1-[Bis(dimethylamino)methylene]-7/-/-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

HPLC High-performance liquid chromatography

MeCN Acetonitrile

MeOH Methanol min minutes

NMO 4-Methylmorpholine 4-oxide

NMP N-Methylpyrrolidinone

NMR Nuclear magnetic resonance

OAc Acetate Pd2(dba)3 T ris(dibenzylideneacetone)dipalladium(0)

PE Petroleum ether

RuPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1 , 1 '-biphenyl)[2-(2'- amino-1,1'-biphenyl)]palladium(ll) rt Room temperature or ambient temperature

SFC Supercritical Fluid Chromatography

TBAF Tetra-n-butylammonium fluoride

TBDPSCI tert-Butyl(chloro)diphenylsilane

TEA Triethylamine TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography (silica plates)

XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Typical Preparative HPLC method

For purification of samples by prep-HPLC the following columns were typically used; Waters XBridge, Xtimate C18, Phenomenex Gemini, Phenomenex Synergi C18, Luna C18 and Shim-pack C18. Typical mobile phases used were water and MeCN, with either acidic or basic additives (typically at 0.05 - 0.1% v/v), such as formic acid, TFA, ammonium bicarbonate or ammonium hydroxide. A typical method started with 95% water:5% MeCN and decreasingly polar ratios of water and MeCN over a period of 5 to 12 min, with a typical flow rate of 25 mL/min. For mass-directed HPLC the typical mass spectrometer used was a Waters 3100 which detected masses between 100 and 700 g/mol. Example 1

(S 6-Methyl-2-(2-(4-(/T7-tolyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)-4-(trifluoromethyl)- nicotinonitrile

Step a. To a solution of (S)-1-(te/f-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.00 g, 4.65 mmol), 3-methylaniline (547 mg, 5.11 mmol) in DMF (15 ml_) was added HATU (1.94 g, 5.11 mmol) and DIPEA (1.80 g, 13.9 mmol). The mixture was stirred at rt for 12 h. The reaction mixture was quenched by addition of water (110 ml_) and extracted with EtOAc (150 ml_ x 3). The combined organic layers were washed with brine (100 ml_ x 3), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (PE/EtOAc = 10/1 to 1/1) to give compound (S)-te/f-butyl 2-(m-fo/y/carbamoyl)pyrrolidine-1-carboxylate (1.42 g, 95% yield) as a yellow solid m/z ES+ [M+H]⁺ 305.2

Step b. To a solution of (S)-te/f-butyl 2-(m-tolylcarbamoyl)pyrrolidine-1-carboxylate (1.00 g, 3.29 mmol) in toluene (20 ml_) was added Lawesson’s reagent (1.46 g, 3.61 mmol). The mixture was stirred at 90°C for 2 h. Upon completion, the reaction mixture was quenched by addition of water (60 ml_) and extracted with EtOAc (100 ml_ x 3). The combined organic layers were washed with brine (30 ml_ x 3), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (PE/EtOAc = 10/1 to 3/1) to give (S)-te/f-butyl 2-{m- fo/y/carbamothioyl)pyrrolidine-1-carboxylate (1.23 g, 95% yield) as a brown solid m/z ES+ [M+H]⁺ 321.2

Step c. To a solution of (S)-te/f-butyl 2-(m-tolylcarbamothioyl)pyrrolidine-1-carboxylate (500 mg, 1.56 mmol), formohydrazide (187 mg, 3.12 mmol) in MeCN (10 ml_) was added Hg(OAc)2 (994 mg, 3.12 mmol). The mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was filtered and evaporated. The residue was purified by column chromatography (PE/EtOAc = 10/1 to EtOAc/MeOH = 5/1) to give (S)-te/f-butyl 2-(4-(m- fo/y/)-4/-/-1 ,2,4-triazol-3-yl)pyrrolidine-1-carboxylate (620 mg, crude) as a brown solid m/z ES+ [M+H]⁺ 329.2

Step d. To a solution of (S)-te/f-butyl 2-(4-(m-tolyl)-4/-/-1 ,2,4-triazol-3-yl)pyrrolidine-1- carboxylate (620 mg, 1.89 mmol) in dioxane (2 ml_) was added HCI/dioxane (4 M, 4.72 ml_). The mixture was stirred at rt for 2 h. Upon completion, the reaction mixture was evaporated to give compound (S)-3-(pyrrolidin-2-yl)-4-(m-fo/y/)-4/-/-1 ,2,4-triazole (520 mg, crude, HCI salt) as a light yellow solid m/z ES+ [M+H]⁺ 229.2 Step e. To a solution of (S)-3-(pyrrolidin-2-yl)-4-(m-tolyl)-4/-/-1 ,2,4-triazole (520 mg, 1.96 mmol, HCI salt), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (650 mg, 2.95 mmol) in NMP (8 ml_) was added DIPEA (761 mg, 5.89 mmol). The mixture was stirred at 70°C for 12 h. Upon completion, the reaction mixture was quenched by addition of water (120 ml_) and extracted with EtOAc (100 ml_ x 3). The combined organic layers were washed with brine (50 ml_ x 3), dried over Na2SC>4 and evaporated. The residue was purified by prep- HPLC to give the title compound (39 mg, 5% yield) as a yellow solid m/z ES+ [M+H]⁺ 413.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.88 (s, 1 H), 7.52 - 7.43 (m,

1 H), 7.40 - 7.28 (m, 3H), 7.05 (s, 1 H), 5.44 - 5.35 (m, 1H), 4.08 - 3.96 (m, 1 H), 3.94 - 3.84 (m, 1 H), 2.50 (s, 3H), 2.27 (s, 3H), 2.25 - 2.15 (m, 2H), 2.10 - 2.02 (m, 2H).

Example 2

(S 6-Methyl-2-(2-(5-methyl-4-(/T7-tolyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)-4-

(trifluoromethyl)nicotinonitrile

Step a. To a solution of (S)-tert- butyl 2-(m-tolylcarbamothioyl)pyrrolidine-1-carboxylate (320 mg, 1.00 mmol), acetohydrazide (148 mg, 2.00 mmol) in MeCN (15 ml_) was added Hg(OAc)2 (477 mg, 1.50 mmol). The mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was filtered and evaporated. The residue was purified by column chromatography (PE/EtOAc = 10/1 to EtOAc/MeOH = 5/2) to give (S)-te/f-butyl 2-(5-methyl- 4-(m-fo/y/)-4/-/-1 ,2,4-triazol-3-yl)pyrrolidine-1-carboxylate as a light yellow solid m/z ES+ [M+H]⁺ 343.2

Step b. To a solution of (S)-tert- butyl 2-(5-methyl-4-(m-tolyl)-4/-/-1 ,2,4-triazol-3-yl)pyrrolidine- 1-carboxylate (300 mg, 0.88 mmol) in MeOH (3 ml_) was added HCI/dioxane (4 M, 2.19 ml_). The mixture was stirred at rt for 2 h. Upon completion, the reaction mixture was evaporated to give compound (S)-3-methyl-5-(pyrrolidin-2-yl)-4-(m-tolyl)-4/-/-1 ,2,4-triazole (240 mg, 98% yield, HCI salt) as a light yellow solid which was used in the next step directly m/z ES+ [M+H]⁺ 243.2

Step c. To a solution of (S)-3-methyl-5-(pyrrolidin-2-yl)-4-(m-tolyl)-4/-/-1 ,2,4-triazole (240 mg, 0.99 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (284 mg, 1.29 mmol) in DMF (10 ml_) was added DIPEA (384 mg, 2.97 mmol). The mixture was stirred at 90°C for 12 h. Upon completion, the reaction mixture was quenched by addition of water (120 ml_) and extracted with EtOAc (100 ml_ x 3). The combined organic layers were washed with brine (50 ml_ x 3), dried over Na2SC>4 and evaporated. The residue was purified by prep-HPLC to give the title compound (83 mg, 19% yield) as a yellow solid. m/z ES+ [M+H]⁺ 427.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.60 - 7.25 (m, 4H), 7.12 (s,

1 H), 5.33 - 5.20 (m, 1 H), 4.01 - 3.78 (m, 2H), 2.38 (s, 6H), 2.32 (s, 3H), 2.24 - 1.99 (m, 4H).

Example 3

2-((2S,4S)-4-Hydroxy-2-(4-(/T7-tolyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)-6-methyl-4-

(trifluoromethyl)nicotinonitrile

Step a. A mixture of (2S,4S)-1-(te/f-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.00 g, 21.6 mmol), te/f-butylchlorodimethylsilane (3.91 g, 25.9 mmol), imidazole (2.21 g, 32.4 mmol) in DCM (30 ml_) was degassed and purged with N2 3 times, and then the mixture was stirred at rt for 12 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by addition of aq. NH₄CI solution (60 ml_) and water (100 ml_), and then extracted with DCM (200 ml_ x 3). The combined organic layers were washed with brine (100 ml_ x 3), dried over Na2SC>4 and evaporated to give (2S,4S)-1-(te/f-butoxycarbonyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (7.2 g, crude) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6) d ppm 4.42 - 4.20 (m, 1 H), 4.26 - 4.07 (m, 1 H), 3.64 - 3.44 (m, 1 H), 3.14 - 2.99 (m, 1H), 2.43 - 2.31 (m, 1H), 1.91 - 1.76 (m, 1 H), 1.40 - 1.33 (m, 9H), 0.85 - 0.76 (m, 9H), 0.23 - 0.16 (m, 6H).

Step b. To a solution of (2S,4S)-1-(te/f-butoxycarbonyl)-4-((te/f-butyldimethylsilyl)oxy)- pyrrolidine-2-carboxylic acid (1 g, 2.89 mmol), 3-methylaniline (376 mg, 3.47 mmol) in pyridine (2 ml_) was added propylphosphonic anhydride (5.53 g, 50% wt.% in DMF). The mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was evaporated to give a residue. The residue was purified by column chromatography (PE/EtOAc = 10/1 to 5/1) to give (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(m-fo/y/carbamoyl)pyrrolidine- 1-carboxylate (688 mg, 49% yield) as a yellow oil. m/z ES+ [M+H]⁺ 436.3

Step c. To a solution of {2S,4S)-tert- butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(m-fo/y/- carbamoyl)pyrrolidine-1-carboxylate (1.00 g, 3.29 mmol) in toluene (20 ml_) was added Lawesson’s reagent (1.46 g, 3.61 mmol). The mixture was stirred at 90°C for 2 h. Upon completion, the reaction mixture was quenched by addition of water (60 ml_) and extracted with EtOAc (150 ml_ x 3). The combined organic layers were washed with brine (30 ml_ x 3), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (PE/EtOAc = 10/1 to 3/1) to give (2S,4S)-tert- butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(m- fo/y/carbamothioyl)pyrrolidine-1-carboxylate (550 mg, 45% yield) as a brown solid m/z ES+ [M+H]⁺ 451.3

Step d. To a solution of (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(m- fo/y/carbamothioyl)pyrrolidine-1-carboxylate (500 mg, 1.11 mmol), formohydrazide (200 mg, 3.33 mmol) in MeCN (10 ml_) was added Hg(OAc)2 (707 mg, 2.22 mmol). The mixture was stirred at rt for 12 h. The reaction mixture was filtered and evaporated. The residue was purified by column chromatography (PE/EtOAc = 10/1 to 5/1) to give {2S,4S)-tert- butyl 4- ((te/f-butyldimethylsilyl)oxy)-2-(4-(m-fo/y/)-4/-/-1 ,2,4-triazol-3-yl)pyrrolidine-1-carboxylate (288 mg, crude) as a red solid m/z ES+ [M+H]⁺ 459.2

Step e. To a solution of (2S,4S)-tert- butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(4-(m-fo/y/)-4/-/- 1 ,2,4-triazol-3-yl)pyrrolidine-1-carboxylate (300 mg, 0.88 mmol) in MeOH (3 ml_) was added HCI/dioxane (4 M, 2.19 ml_). The mixture was stirred at rt for 2 h. Upon completion, the reaction mixture was evaporated to give (3S,5S)-5-(4-(m-fo/y/)-4/-/-1 ,2,4-triazol-3-yl)- pyrrolidin-3-ol (240 mg, 98% yield, HCI salt) as a yellow solid which was used in the next step directly m/z ES+ [M+H]⁺ 245.2

Step f. To a solution of (3S,5S)-5-(4-(m-fo/y/)-4/-/-1 ,2,4-triazol-3-yl)pyrrolidin-3-ol (140 mg, 0.57 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (190 mg, 0.86 mmol) in NMP (10 ml_) was added DIPEA (222 mg, 1.72 mmol). The mixture was stirred at 60°C for 12 h. Upon completion, the reaction mixture was quenched by addition of water (120 ml_) and extracted with EtOAc (100 ml_ x 3). The combined organic layers were washed with brine (50 ml_ x 3), dried over Na₂S0₄ and evaporated. The residue was purified by prep-HPLC to give the title compound (5 mg, 20% yield) as a yellow solid. m/z ES+ [M+H]⁺ 429.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.95 - 8.90 (m, 1 H), 7.53 - 7.46 ( , 1 H), 7.43 - 7.38 ( , 1 H), 7.36 - 7.28 ( , 2H), 7.08 (s, 1 H), 5.45 (t, J =7.2 Hz, 1 H), 4.48 - 4.35 (m, 1H), 4.01 (dd, J= 10.0, 6.4 Hz, 1H), 3.77 (dd, J = 9.2, 5.6 Hz, 1H), 2.58 — 2.54 (m, 1 H), 2.37 (s, 3H), 2.27 (s, 3H), 2.17 - 2.06 (m, 1 H).

Example 4

2-((2S,4S)-4-Hydroxy-2-(4-(/77-fo/y/)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)-4,6-dimethyl- nicotinonitrile

The title compound was prepared in a similar manner to Example 3, using 2-chloro-4,6- dimethylnicotinonitrile in step f. m/z ES+ [M+H]⁺ 375.0; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.60 (s, 1 H), 7.52 - 7.46 (m,

1 H), 7.42 - 7.37 (m, 1 H), 7.36 - 7.31 (m, 1 H), 7.30 - 7.27 (m, 1 H), 6.58 (s, 1 H), 5.54 (s, 1 H), 5.37 (t, J = 7.6 Hz, 1 H), 4.45 - 4.35 (m, 1 H), 4.03 - 3.95 (m, 1 H), 3.78 - 3.71 (m, 1 H), 2.57 - 2.56 (m, 1 H), 2.41 (s, 3H), 2.33 (s, 3H), 2.11 (s, 3H), 2.09 - 2.04 (m, 1 H).

Example 5

4-Ethyl-2-((2S,4S)-4-hydroxy-2-(4-(/T7-fo/y/)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)-5- methylnicotinonitrile

The title compound was prepared in a similar manner to Example 3, using 2-chloro-4-ethyl- 5-methyl-3-pyridinecarbonitrile (CAS Number 125731-31-9, prepared as described in European Journal of Medicinal Chemistry, 85, 450-457; 2014) in step f. m/z ES+ [M+H]⁺ 389.1; ¹H NMR (400MHz, CD₃OD) d ppm 9.15 (s, 1H), 8.01 (s, 1 H), 7.62 - 7.46 (m, 4H), 5.68 - 5.64 (m, 1 H), 4.67 - 4.59 (m, 1 H), 4.27 - 4.20 (m, 1 H), 4.08 - 4.04 (m,

1 H), 2.88 - 2.82 (m, 2H), 2.49 (s, 3H), 2.47 - 2.41 (m, 1H), 2.22 (s, 3H), 2.21 - 2.15 (m, 1 H), 1.22 (t, J = 7.6 Hz, 3H). Example 6

2-((2S,4S)-4-Hydroxy-2-(4-(6-methylpyridin-2-yl)-4tf-1,2,4-triazol-3-yl)pyrrolidin-1-yl)-6- methyl-4-(trifluoromethyl)nicotinonitrile

Step a. A mixture of (2S,4S)-1-(te/f-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (20.00 g, 86.5 mmol), te/f-butylchlorodimethylsilane (18.25 g, 121.1 mmol) and imidazole (8.83 g, 129.7 mmol) in DCM (150 ml_) was degassed and purged with N2 3 times, and then the mixture was stirred at rt for 36 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by addition of aq. NH₄CI solution (200 ml_) and water (200 ml_), and then extracted with EtOAc (500 ml_ x 3). The combined organic layers were washed with brine (100 ml_ x 3), dried over Na2SC>4 and evaporated to give compound (2S,4S)-1-(te/f- butoxycarbonyl)-4-((fe/f-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (32 g, crude) as a colorless oil.

Step b. To a solution of (2S,4S)-1-(te/f-butoxycarbonyl)-4-((te/f-butyldimethylsilyl)oxy)- pyrrolidine-2-carboxylic acid (5.00 g, 14.5 mmol), 6-methylpyridin-2-amine (1.88 g, 17.37 mmol) in pyridine (50 ml_) was added propylphosphonic anhydride (27.63 g, 43.41 mmol, 50% wt.% in DMF). The mixture was stirred at 30°C for 12 h. Upon completion, the reaction mixture was quenched by addition of water (250 ml_) and extracted with EtOAc (250 ml_ x 3). The combined organic layers were washed with brine (100 ml_ x 3), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (PE/EtOAc = 10/1 to 1/1) to give (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-((6-methylpyridin-2-yl)carbamoyl)- pyrrolidine-1-carboxylate (4.3 g, 65% yield) as a yellow oil. m/z ES+ [M+H]⁺ 436.1 Step c. To a solution of (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-((6-methylpyridin- 2-yl)carbamoyl)pyrrolidine-1-carboxylate (0.50 g, 1.15 mmol) in o-xylene (20 ml_) was added Lawesson’s reagent (696 mg, 1.72 mmol). The mixture was stirred at 120°C for 2 h. Upon completion, the reaction mixture was filtered and evaporated. The residue was purified by prep-HPLC to give (2S,4S)-tert- butyl 4-((te/f-butyldimethylsilyl)oxy)-2-((6-methylpyridin-2- yl)carbamothioyl)pyrrolidine-1-carboxylate (300 mg, 58% yield) as a brown solid m/z ES+ [M+H]⁺ 452.2

Step d. A mixture of (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-((6-methylpyridin-2- yl)carbamothioyl)pyrrolidine-1-carboxylate (320 mg, 0.71 mmol), hydrazine hydrate (71 mg, 1.42 mmol) in THF (5 ml_) was degassed and purged with N23 times, and then the mixture was stirred at rt for 1.5 h under N2 atmosphere. Upon completion, the reaction mixture was filtered and evaporated to give (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-((Z)-A/-(6- methylpyridin-2-yl)carbamohydrazonoyl)pyrrolidine-1-carboxylate (300 mg, crude) as a brown solid which was used in the next step directly m/z ES+ [M+H]⁺ 450.2

Step e. A mixture of (2S,4S)-tert- butyl 4-((te/f-butyldimethylsilyl)oxy)-2-((Z)-A/-(6-methyl- pyridin-2-yl)carbamohydrazonoyl)pyrrolidine-1-carboxylate (318 mg, 0.71 mmol), diethoxymethoxyethane (314 mg, 2.12 mmol) in EtOH (10 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 80°C for 12 h under N2 atmosphere.

Upon completion, the reaction mixture was evaporated. The obtained residue was purified by prep-HPLC to give compound (2S,4S)-tert- butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(4-(6- methylpyridin-2-yl)-4/-/-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate (100 mg, 31% yield) as a brown solid m/z ES+ [M+H]⁺ 460.1

Step f. A solution of (2S,4S)-tert- butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(4-(6-methylpyridin-2- yl)-4/-/-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate (100 mg, 0.22 mmol) in HCI/dioxane (4 M,

3 mL) was stirred at rt for 2 h. Upon completion, the reaction mixture was evaporated to give (3S, 5S)-5-(4-(6-methylpyridin-2-yl)-4/-/-1, 2, 4-triazol-3-yl)pyrrolidin-3-ol (60 mg, crude, HCI salt) as a brown solid which was used in the next step directly m/z ES+ [M+H]⁺ 246.2

Step g. To a solution of (3S, 5S)-5-(4-(6-methylpyridin-2-yl)-4/-/-1, 2, 4-triazol-3-yl)pyrrolidin-3- ol (60 mg, 0.22 mmol, HCI salt), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile in NMP (5 mL) was added DIPEA (84 mg, 0.65 mmol). The mixture was stirred at 60°C for 12 h. Upon completion, the reaction mixture was evaporated. The obtained residue was purified by prep- HPLC to give the title compound (12 mg, 13% yield) as a yellow solid m/z ES+ [M+H]⁺ 430.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 9.25 (s, 1H), 8.05 (t, J= 7.6 Hz, 1 H), 7.61 (d, J= 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 5.78 (t, J= 7.6 Hz, 1 H), 4.55 - 4.40 (m, 1H), 3.93 - 3.85 (m, 3H), 2.80 - 2.70 (m, 1H), 2.56 (s, 3H), 2.30 -2.20 (m, 1 H), 2.12 (s, 3H).

Example 7 2-((2S,4S)-2-(4-(3-Fluorophenyl)-4H-1 ,2,4-triazol-3-yl)-4-hydroxypyrrolidin-1 -yl)-6- methyl-4-(trifluoromethyl)nicotinonitrile

Step a. To a solution of (2S,4S)-1-te/f-butoxycarbonyl-4-[te/f-butyl(dimethyl)silyl]oxy- pyrrolidine-2-carboxylic acid (5.00 g, 14.5 mmol) and benzyl hydrazinecarboxylate (2.89 g, 17.4 mmol) in DCM (125 ml_) was added EDCI (3.33 g, 17.4 mmol), hydroxybenzotriazole (2.74 g, 20.3 mmol) and TEA (2.93 g, 29 mmol). The mixture was stirred at rt for 12 h. On completion, the reaction mixture was diluted with water (100 ml_) and extracted with DCM (80 ml_ ^c 2). The combined organic layers were washed with brine (80 ml_), dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 8/1 to 1/1) to afford tert- butyl ( 2S,4S)-2 - (benzyloxycarbonylaminocarbamoyl)-4-[fe/f-butyl(dimethyl)silyl]oxy-pyrrolidine-1-carboxylate (3.5 g, 49% yield) as colorless oil. m/z ES+ [M+H]⁺ 494.2; Step b. To a solution of tert- butyl (2S,4S)-2-(benzyloxycarbonylaminocarbamoyl)-4-[te/f- butyl(dimethyl)silyl]oxy-pyrrolidine-1-carboxylate (3.50 g, 7.09 mmol) in MeOH (20 ml_) was added Pd/C (150 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) atmosphere at rt for 1 h. The reaction mixture was filtered and evaporated to afford tert- butyl (2S,4S)-4-[tert- butyl(dimethyl)silyl]oxy-2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (2.5 g, 98% yield) as a colorless oil.

¹H NMR (400 MHz, CDCh) d ppm 7.53-7.50 (m, 1H), 4.38 (m, 2H), 3.83-3.74 (m, 1H), 3.58- 3.21 (m, 2H), 2.40-2.10 (m, 2H), 1.47 (s, 9H), 0.88 (s, 9H), 0.07 (d, J = 7.2 Hz, 6H).

Step c. To a solution of tert- butyl (2S, 4S)-4-[te/f-butyl(dimethyl)silyl]oxy-2- (hydrazinecarbonyl)pyrrolidine-l-carboxylate (1.00 g, 2.78 mmol) in MeCN (25 ml_) was added DMF-DMA (365 mg, 3.06 mmol). The mixture was stirred at 50°C for 30 minutes. On completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 ml_) and extracted with EtOAc (15 ml_ ^c 2). The combined organic layers were washed with brine (15 ml_ ^c 2), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EtOAc = 3/1 followed by DCM/MeOH = 10/1) to afford tert- butyl (2S,4S)-4-[te/f-butyl(dimethyl)silyl]- oxy-2-[[(Z)-dimethylaminomethyleneamino]carbamoyl]pyrrolidine-1-carboxylate (1.1 g, 95% yield) as a white solid.

¹H NMR (400 MHz, CDCh) d ppm 8.53-8.19 (m, 1H), 7.95-7.65 (m, 1H), 4.42-4.26 (m, 2H), 3.58-3.51 (m, 1H), 3.49-3.39 (m, 1H), 2.89 (s, 6H), 2.45-2.15 (m, 2H), 1.46 (s, 9H), 0.87 (s, 9H), 0.07 (d, J=4.4 Hz, 6H).

Step d. To a solution of te/f-butyl (2S,4S)-4-[te/f-butyl(dimethyl)silyl]oxy-2-[[(Z)-dimethyl- aminomethyleneamino]carbamoyl]pyrrolidine-1-carboxylate (300 mg, 0.72 mmol) and 3- fluoroaniline (402 mg, 3.62 mmol) in toluene (5 ml_) was added acetic acid (217 mg, 3.62 mmol). The mixture was stirred at 150°C under microwave irradiation for 2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give compound tert- butyl (2S,4S)-4-[te/f-butyl(dimethyl)silyl]oxy-2-[4-(3- fluorophenyl)-1 ,2,4-triazol-3-yl]pyrrolidine-1-carboxylate (70 mg, 15% yield) as a yellow oil. Step e. A solution of tert- butyl (2S,4S)-4-[te/f-butyl(dimethyl)silyl]oxy-2-[4-(3-fluorophenyl)- 1 ,2,4-triazol-3-yl]pyrrolidine-1- carboxylate (70 mg, 0.11 mmol) in HCI/dioxane (4 M, 2 ml_) was stirred at rt for 2 h. The mixture was concentrated in vacuo to give compound ( 3S,5S)-5 - [4-(3-fluorophenyl)-1 ,2,4-triazol-3-yl]pyrrolidin-3-ol (80 mg, crude, HCI) as a yellow solid.

Step f. A solution of (3S,5S)-5-[4-(3-fluorophenyl)-1 ,2,4-triazol-3-yl]pyrrolidin-3-ol (75 mg, 0.26 mmol, HCI salt), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (58 mg,

0.26 mmol) and DIPEA (102 mg, 0.79 mmol) in NMP (2 ml_) was stirred at 100°C for 12 h under N2. On completion, the mixture was purified by prep-HPLC to give the title compound (20 mg, 17% yield) as a white solid. m/z ES+ [M+H]+ 433.1; ¹H NMR (400 MHz, CDCh) d ppm 8.22 (s, 1 H), 7.64-7.55 (m, 1 H), 7.34-7.28 (m, 3H), 6.76 (s, 1 H), 5.68 (d, J = 12 Hz, 1H), 5.61 (d, J = 8.4 Hz, 1 H), 4.76-4.68 (m, 1H), 4.56-4.50 (m, 1H), 4.45-4.38 (m, 1 H), 2.49-2.40 (m, 1H), 2.33-2.27 (m, 1H), 2.21 (s, 3H)

Example 8 2-((2S,4S)-2-(4-(3,4-Difluorophenyl)-4H-1,2,4-triazol-3-yl)-4-hydroxypyrrolidin-1-yl)-6- methyl-4-(trifluoromethyl)nicotinonitrile

The title compound was prepared in a similar manner to Example 7, using 3,4-difluoroaniline in step d. m/z ES+ [M+H]+ 451.1; ¹H NMR (400 MHz, CDCh) d ppm 8.20 (s, 1 H), 7.52-7.37 (m, 2H), 7.32-7.27 (m, 1H), 6.79 (s, 1 H), 5.60-5.50 (m, 2H), 4.76-4.68 (m, 1H), 4.54-4.48 (m, 1 H), 4.44-4.37 (m, 1H), 2.47-2.38 (m, 1H), 2.29-2.25 (m, 1H), 2.24 (s, 3H)

Example 9

(S 6-Methyl-2-(2-(1-(p-tolyl)-7H-imidazol-2-yl)pyrrolidin-1-yl)-4-(trifluoromethyl)- nicotinonitrile

Step a. A solution of tert- butyl (2S)-2-(7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (2.00 g,

8.43 mmol) in HCI/MeOH (4 M, 10 ml_) was stired at rt for 1 h. The mixture was then concentrated in vacuo to afford compound 2-[(2S)-pyrrolidin-2-yl]-7/-/-imidazole (1.73 g, crude, HCI salt) as a brown solid.

¹H NMR (400 MHz, DMSO-d6) d ppm 10.44 (s, 1H), 7.72 (s, 2H), 5.03 (t, J = 8.4 Hz, 1 H), 3.31 - 3.46 (m, 2H), 2.37 - 2.49 (m, 2H), 2.13 - 2.24 (m, 1 H), 1.92 - 2.04 (m, 1 H).

Step b. To a solution of 2-[(2S)-pyrrolidin-2-yl]-7/-/-imidazole (1.00 g, 5.76 mmol, HCI salt), 2- chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (1.27 g, 5.76 mmol) in NMP (10 ml_) was added DIPEA (2.23 g, 17.28 mmol). The reaction mixture was stirred at 60°C for 12 h. Upon completion, the mixture was added water (20 ml_) and extracted with EtOAc (60 ml_ x 3). The combined organic layers were washed with brine (15 mL x 3) and then evaporated. The residue was purified by column chromatography (PE/EtOAc = 6/1 to 0/1) to afford compound 2-[(2S)-2-(7/-/-imidazol-2-yl)pyrrolidin-1-yl]-6-methyl-4-(trifluoromethyl)pyridine-3- carbonitrile (1.9 g, 92% yield) as a brown solid.

¹H NMR (400 MHz, CDCh) d ppm 6.97 (s, 2H), 6.83 (s, 1 H), 5.63 (dd, J = 7.6, 4.4 Hz, 1 H), 4.29 (ddd, J = 10.4, 7.6, 4.8 Hz, 1 H), 3.95 (dt, J = 10.4, 7.2 Hz, 1 H), 2.78 - 2.70 (m, 1 H),

2.52 (s, 3H), 2.40 - 2.25 (m, 2H), 2.19 - 2.12 (m, 1H).

Step c. To a solution of 2-[(2S)-2-(7/-/-imidazol-2-yl)pyrrolidin-1-yl]-6-methyl-4- (trifluoromethyl)pyridine-3-carbonitrile (100 mg, 0.31 mmol), p-tolylboronic acid (63.5 mg,

0.47 mmol) in DCM (2 mL) was added Cu(0Ac)₂-H₂0 (57 mg, 0.31 mmol) and pyridine (50 mg, 0.62 mmol). The reaction mixture was stirred at rt for 16 h under O2 balloon (15 psi). Upon completion, the reaction mixture was filtered and evaporated. The residue was purified by prep-HPLC to give the title compound (9 mg, 7% yield) as a yellow solid m/z ES+ [M+H]⁺ 412.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.42 - 7.34 (m, 4H), 7.20 (d, J = 0.96 Hz, 1 H), 6.95 (s, 1 H), 6.87 (s, 1 H), 5.34 (d, J = 7.6 Hz, 1 H), 4.11 - 4.03 (m, 1 H), 3.87 (dd, J = 10.0, 6.0 Hz, 1 H), 2.39 (s, 3H), 2.29 - 2.16 (m, 5H), 2.06 - 1.92 (m, 2H).

Example 10

(Sj-6-Methyl-2-(2-(1-(pyridin-2-yl)-7tf-imidazol-2-yl)pyrrolidin-1-yl)-4-(trifluoromethyl)- nicotinonitrile

To a solution of 2-[(2S)-2-(7/-/-imidazol-2-yl)pyrrolidin-1-yl]-6-methyl-4-(trifluoromethyl)- pyridine-3-carbonitrile (100 mg, 0.31 mmol) in DMF (2.5 ml_) was added CS2CO3 (202 mg, 0.62 mmol) and 2-fluoropyridine (45 mg, 0.47 mmol). The mixture was stirred at 100°C for 12 h. Upon completion, the reaction mixture was quenched by addition of water (5 ml_), and then extracted with EtOAc (5 ml_ x 3). The combined organic layers were washed with brine (3 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep-TLC (PE/EtOAc = 1/1) to give the title compound (49 mg, 39% yield) as a yellow solid m/z ES+ [M+H]⁺ 399.1; ¹H NMR (400 MHz, CDCI₃) d ppm 8.63 - 8.57 (m, 1 H), 7.91 - 7.85 (m, 1 H), 7.43 - 7.39 (m, 1 H), 7.37 - 7.32 (m, 1 H), 7.20 (d, J = 1.6 Hz, 1 H), 7.03 (d, J = 1.6 Hz, 1H), 6.60 (s, 1 H), 5.84 - 5.78 (m, 1 H), 4.36 - 4.30 (m, 1 H), 4.08 - 4.01 (m, 1 H), 2.51 - 2.40 (m, 2H), 2.39 - 2.32 (m, 1H), 2.13 (s, 3H), 2.10 - 2.03 (m, 1 H)

Example 11

(S 6-Methyl-2-(2-(1-(6-methylpyridin-2-yl)-7H-imidazol-2-yl)pyrrolidin-1-yl)-4-

(trifluoromethyl)nicotinonitrile

Step a. A mixture of (S)-tert- butyl 2-(7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (500 g,

2.11 mmol), 2-bromo-6-methyl-pyridine (725 mg, 4.21 mmol), Cul (441 mg, 2.32 mmol) and CS2CO3 (2.06 g, 6.32 mmol) in DMSO (15 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 120°C for 16 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by addition of water (60 ml_) and extracted with EtOAc (100 ml_ x 3). The combined organic layers were washed with brine (50 ml_ x 3), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (PE/EtOAc = 3/1 to 0/1) to give (S)-te/f-butyl 2-(1-(6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidine-1- carboxylate (427 mg, 93% yield) as a light yellow oil. m/z ES+ [M+H]⁺ 329.2

Step b. To a solution of (S)-te/f-butyl 2-(1-(6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidine- 1-carboxylate (380 mg, 1.16 mmol) in dioxane (10 ml_) was added HCI/dioxane (4 M, 2.89 ml_). The mixture was stirred at rt for 2 h. Upon completion, the reaction mixture was evaporated to provide (S)-2-methyl-6-(2-(pyrrolidin-2-yl)-7/-/-imidazol-1-yl)pyridine (300 mg, crude, HCI salt) as a light yellow oil, which was used for the next step directly. m/z ES+ [M+H]⁺ 229.1

Step c. To a solution of (S)-2-methyl-6-(2-(pyrrolidin-2-yl)-7/-/-imidazol-1-yl)pyridine (300 mg, 1.13 mmol, HCI salt), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (300 mg, 1.36 mmol) in NMP (10 ml_) was added DIPEA (440 mg, 3.40 mmol). The mixture was stirred at 70°C for 12 h. Upon completion, the reaction mixture was quenched by addition of water (60 ml_), and then extracted with EtOAc (100 ml_ x 3). The combined organic layers were washed with brine (50 ml_ x 3), dried over Na2SC>4 and evaporated. The residue was purified by prep- HPLC to give the title compound (14 mg, 14% yield) as a light brown solid m/z ES+ [M+H]⁺ 413.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.16 - 8.07 (m, 2H), 7.78 (d, J = 2.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.56 (d, J = 7.6 Hz, 1 H), 7.04 (s, 1 H), 5.54 ( t, J = 7.2

Hz, 1 H), 4.42 - 4.29 (m, 1 H), 3.95 - 3.84 (m, 1 H), 2.68 - 2.59 (m, 1 H), 2.42 - 2.31 (m, 1 H), 2.57 (s, 3H), 2.18 - 2.06 (m, 4H), 2.30 - 2.20 (m, 1H).

Example 12 (S 6-Methyl-2-(2-(1 -(m-fo/y/)-7H-imidazol-2-yl)pyrrolidin-1 -yl)-4-(trifluoromethyl)- nicotinonitrile

Step a. To a solution of tert- butyl (2S)-2-cyanopyrrolidine-1-carboxylate (300 mg, 1.53 mmol) and 3-methylaniline (180 mg, 1.68 mmol) in toluene (8 ml_) was added trimethylaluminium (2 M in toluene, 0.84 ml_, 1.68 mmol) at 0°C. The mixture was stirred at 90°C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 ml_) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na₂S0₄and evaporated. The residue was purified by column chromatography (PE/EtOAc = 3/1 to 0/1) to afford compound tert- butyl (2S)-2-[N-(m-fo/y/)carbamimidoyl]pyrrolidine-1-carboxylate (150 g, 32% yield) as a brown oil. m/z ES+ [M+H]⁺ 304.1

Step b. To a solution of te/f-butyl (2S)-2-[A/-(m-fo/y/)carbamimidoyl]pyrrc>lidine-1-carboxylate (150 mg, 0.49 mmol) and Na2CC>3 (157 mg, 1.48 mmol) in isopropanol (8 ml_) was added 2- chloroacetaldehyde (194 mg, 0.99 mmol). The mixture was stirred at 100°C for 12 h under N2 atmosphere in a sealed tube. On completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 ml_) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na₂S0₄and evaporated. The residue was purified by column chromatography (PE/EtOAc = 5/1 to 0/1) to afford compound tert- butyl (2S)-2-[1-(m-fo/y/)imidazol-2- yl]pyrrolidine-1-carboxylate (100 mg, 62% yield) as a brown oil.

¹H NMR (400 MHz, CDC ) d ppm 7.42 - 7.29 (m, 2H), 7.27 - 7.20 (m, 1H), 7.18 - 6.93 (m, 3H), 5.01 - 4.73 (m, 1H), 3.74 - 3.62 (m, 1H), 3.53 - 3.36 (m, 1 H), 2.44 (s, 3H), 2.21 - 2.12 (m, 1 H), 2.04 - 1.97 (m, 1H), 1.86 - 1.81 (m, 1H), 1.69 - 1.58 (m, 1 H), 1.47 - 1.26 (m, 9H). Step c. A solution of tert- butyl (2S)-2-[1-(m-fo/y/)imidazol-2-yl]pyrrolidine-1-carboxylate (90 mg, 0.28 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at rt for 1 h. The reaction mixture was evaporated to afford compound 1-(m-fo/y/)-2-[(2S)-pyrrolidin-2-yl]imidazole (50 mg, 80% yield, TFA salt) as a brown oil.

Step d. To a solution of 1-(m-fo/y/)-2-[(2S)-pyrrolidin-2-yl]imidazole (50 mg, 0.22 mmol) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (58 mg, 0.26 mmol) in NMP (3 mL) was added DIPEA (57 mg, 0.44 mmol). The mixture was stirred at 80°C for 5 h. On completion, the reaction mixture was quenched by addition of water (5 mL) at 0°C and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na₂S0₄and evaporated. The residue was purified by prep-HPLC to give the title compound (19 mg, 21% yield) as a yellow solid. m/z ES+ [M+H]⁺ 412.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.49 - 7.43 (m, 1H), 7.35 - 7.28 (m, 3H), 7.24 - 7.20 (m, 1H), 6.96 (s, 1H), 6.89 - 6.86 (m, 1H), 5.40 - 5.33 (m, 1H), 4.11 - 4.01 (m, 1 H), 3.93 - 3.83 (m, 1H), 2.39 (s, 3H), 2.27 - 2.18 (m, 5H), 2.04 - 1.97 (m, 2H). The Examples in Table 1 were prepared using methods similar to those described in the synthesis of Examples 9-12.

Table 1

Example 21

(S 2-(2-(1-(2-(Hydroxymethyl)phenyl)-7H-imidazol-2-yl)pyrrolidin-1-yl)-6-methyl-4-

(trifluoromethyl)nicotinonitrile

Step a. To a solution of tert- butyl (2S)-2-(7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (500 mg, 2.11 mmol), 2-fluorobenzonitrile (306 mg, 2.53 mmol) and CS2CO3 (1.37 g, 4.21 mmol) in DMF (10 ml_) was stirred at 100°C for 12 h under N2 atmosphere. On completion, the mixture was diluted with water (30 ml_) and extracted with EtOAc (50 ml_ x 3). The combined organic layers were washed with brine (30 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (PE/EtOAc = 1/1 to 0/1) to afford tert- butyl (2S)-2-[1-(2-cyanophenyl)imidazol-2-yl]pyrrolidine-1-carboxylate (700 mg, 94% yield) as a yellow solid m/z ES+ [M+H]⁺ 339.1

Step b. To a solution of te/f-butyl (2S)-2-[1-(2-cyanophenyl)imidazol-2-yl]pyrrolidine-1- carboxylate (250 mg, 0.74 mmol) in toluene (5 ml_) was added DIBAL-H (1 M, 1.11 mmol) at 0°C over 30 min. The mixture was then stirred at 0°C for 1.5 h. On completion, the reaction mixture was quenched by addition of aqueous NaOH solution (1 M, 10 ml_) at 0°C, and extracted with EtOAc (5 ml_ x 3). The combined organic layers were washed with brine (10 ml_ x 2), dried over Na₂S0₄ and evaporated to afford tert- butyl (2S)-2-[1-(2-formylphenyl)- imidazol-2-yl]pyrrolidine-1-carboxylate (300 mg, crude) as a yellow solid m/z ES+ [M+H]⁺ 342.1

Step c. To a solution of tert- butyl (2S)-2-[1-(2-formylphenyl)imidazol-2-yl]pyrrolidine-1- carboxylate (300 mg, 0.88 mmol) in MeOH (5 ml_) was added NaBhU (66.5 mg, 1.76 mmol) portionwise at 0°C. The mixture was stirred at rt for 1 h. On completion, the reaction mixture was quenched by addition of water (10 ml_) at 0°C and extracted with EtOAc (5 ml_ x 3). The combined organic layers were washed with brine (5 ml_ x 2), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (PE/EtOAc = 5/1 to 0/1) to afford tert- butyl (2S)-2-[1-[2-(hydroxymethyl)phenyl]imidazol-2-yl]pyrrolidine-1-carboxylate (50 mg, 16% yield) as a brown oil. m/z ES+ [M+H]⁺ 344.1

Step d. A solution of tert- butyl (2S)-2-[1-[2-(hydroxymethyl)phenyl]imidazol-2-yl]pyrrolidine- 1-carboxylate (50 mg, 0.15 mmol) in HCI/dioxane (4 M, 5 ml_) was stirred at rt for 1 h. The reaction mixture was evaporated to afford compound [2-[2-[(2S)-pyrrolidin-2-yl]imidazol-1- yl]phenyl]methanol (20 mg, 49% yield, HCI salt) as a colorless oil. Step e. To a solution of [2-[2-[(2S)-pyrrolidin-2-yl]imidazol-1-yl]phenyl]methanol (20 mg, 0.072 mmol, HCI salt) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (16 mg, 0.072 mmol) in NMP (1.5 mL) was added DIPEA (19 mg, 0.14 mmol). The mixture was stirred at 80°C for 6 h. On completion, the reaction mixture was diluted with water (8 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na₂S0₄ and evaporated. The residue was purified by prep-HPLC to give the title compound (6 mg, 18% yield) as a brown gum. m/z ES+ [M+H]⁺ 428.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.73 - 7.49 (m, 3H), 7.48 - 7.30 (m, 1 H), 7.21 - 7.16 (m, 1H), 7.04 - 6.97 (m, 1H), 6.90 (d, J = 1.2 Hz, 1 H), 5.44 - 5.19 (m, 2H), 4.51 - 4.32 (m, 1H), 4.30 - 3.97 (m, 2H), 3.89 - 3.76 (m, 1 H), 2.42 - 2.25 (m, 3H), 2.21 - 2.00 (m, 2H), 1.98 - 1.74 (m, 2H).

Example 22

(S 2-(2-(1-(3-Cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-yl)-7H- imidazol-1 -yl)benzamide

Step a. A solution of tert- butyl (2S)-2-[1-(2-cyanophenyl)imidazol-2-yl]pyrrolidine-1- carboxylate (200 mg, 0.59 mmol) and K2CO3 (163 mg, 1.18 mmol) in DMSO (5 ml_) was treated dropwise with aq. H2O2 (335 mg, 2.96 mmol, 30%) at 0°C. The mixture was warmed to rt and stirred for 8 h under N2 atmosphere. The mixture was quenched with water (15 ml_) and extracted with EtOAc (30 ml_ x 3). The combined organic phases were washed with brine (15 ml_), dried over Na2SC>4 and evaporated. The residue was purified by prep-TLC (PE/EtOAc = 3/1) to afford compound tert- butyl (2S)-2-[1-(2-carbamoylphenyl)-imidazol-2- yl]pyrrolidine-1-carboxylate (300 mg, 90% yield) as a colorless oil. m/z ES+ [M+H]⁺ 357.1 ; ¹H NMR (400 MHz, CDC ) d ppm 7.83 - 7.70 (m, 2H), 7.55 - 7.45 (m, 2H), 7.04 (s, 1 H), 6.91 (s, 1 H), 5.56 (s, 1 H), 3.73 - 3.61 (m, 1 H), 3.43 - 3.31 (m, 1 H), 2.30 - 2.10 (m, 2H), 1.90 (td, J = 12.0, 6.4 Hz, 2H), 1.27 (s, 9H).

Step b. A solution of tert- butyl (2S)-2-[1-(2-carbamoylphenyl)imidazol-2-yl]pyrrolidine-1- carboxylate (300 mg, 0.53 mmol) in HCI/MeOH (5 ml_) was stirred at rt for 2 h. The mixture was then evaporated. The residue was dissolved in sat. Na2CC>3 solution (30 ml_) and extracted with EtOAc (30 ml_ x 3). The combined organic layers were dried over Na₂S0₄ and evaporated. The obtained residue was purified by column chromatography (PE/EtOAc = 1/1 to 0/1) to afford 2-[2-[(2S)-pyrrolidin-2-yl]imidazol-1-yl]benzamide (140 mg, 97% yield) as a yellow oil. m/z ES+ [M+H]⁺ 257.0

Step c. A solution of 2-[2-[(2S)-pyrrolidin-2-yl]imidazol-1-yl]benzamide (140 mg, 0.52 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (127 mg, 0.57 mmol) and DIPEA (135 mg, 1.04 mmol) in DMF (2 ml_) was stirred at 100°C for 12 h. The reaction mixture was evaporated and the residue was purified by prep-HPLC to give the title compound (39 mg, 16% yield) as a red solid. m/z ES+ [M+H]⁺ 441.1 ; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.72 (s, 1 H), 7.67 - 7.60 (m, 3H), 7.59 (s, 1 H), 7.12 (s, 1 H), 7.46 (s, 1 H), 7.00 (s, 1 H), 6.85 (s, 1 H), 5.40 - 5.35 (m, 1 H), 4.15 - 4.05 (m, 1 H), 3.87 - 3.75 (m, 1 H), 2.34 (s, 3H), 2.24 - 2.14 (m, 1 H), 2.07 - 1.96 (m, 2H), 1.94 - 1.85 (m, 1 H).

Example 23

(S 2-(2-(1-(2-(Aminomethyl)phenyl)-7H-imidazol-2-yl)pyrrolidin-1-yl)-6-methyl-4-

(trifluoromethyl)nicotinonitrile

Step a. To a solution of tert- butyl (2S)-2-[1-(2-cyanophenyl)imidazol-2-yl]pyrrolidine-1- carboxylate (200 mg, 0.59 mmol) in MeOH (10 ml_) and ammonium hydroxide (1 ml_) was added Raney-Ni (101 mg, 1.18 mmol). The mixture was stirred at rt for 2 h under 15 psi H2. On completion, the reaction mixture was evaporated to afford tert- butyl (2S)-2-[1-[2- (aminomethyl)-phenyl]imidazol-2-yl]pyrrolidine-1-carboxylate (130 mg, 64% yield) as a brown oil. m/z ES+ [M+H]⁺ 343.2 Step b. To a solution of tert- butyl (2S)-2-[1-[2-(aminomethyl)phenyl]imidazol-2-yl]pyrrolidine- 1-carboxylate (130 mg, 0.38 mmol) in THF (8 ml_) was added NaHCC>3 (1 M, 2 ml_) and benzyl chloroformate (78 mg, 0.46 mmol) dropwise at 0°C. The mixture was stirred at rt for 12 h. On completion, the reaction mixture was diluted with water (8 ml_) and extracted with EtOAc (5 ml_ x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography

(PE/EtOAc = 10/1 to 1/1) to afford tert- butyl (2S)-2-[1-[2-(benzyloxycarbonylaminomethyl)- phenyl]imidazol-2-yl]pyrrolidine-1-carboxylate (100 mg, 55% yield) as a colorless oil. m/z ES+ [M+H]⁺ 477.2

Step c. A solution of tert- butyl (2S)-2-[1-[2-(benzyloxycarbonylaminomethyl)phenyl]imidazol- 2-yl]pyrrolidine-1-carboxylate (80 mg, 0.17 mmol) in HCI/MeOH (4 M, 5 mL) was stirred at rt for 2 h. Then the reaction mixture was evaporated to afford benzyl A/-[[2-[2-[(2S)-pyrrolidin-2- yl]imidazol-1-yl]phenyl]methyl]carbamate (60 mg, 87% yield, HCI) as a white solid m/z ES+ [M+H]⁺ 377.1

Step d. To a solution of benzyl A/-[[2-[2-[(2S)-pyrrolidin-2-yl]imidazol-1-yl]phenyl]methyl]- carbamate (60 mg, 0.15 mmol, HCI) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3- carbonitrile (35 mg, 0.16 mmol) in NMP (3 mL) was added DIPEA (38 mg, 0.29 mmol). The mixture was stirred at 80°C for 5 h. On completion, the reaction mixture was poured into water (6 ml_), and then extracted with EtOAc (5 ml_ x 3). The combined organic layers were washed with brine (5 ml_ x 2), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (PE/EtOAc = 5/1 to 1/1) to afford benzyl N-[[2-[2-[(2S)-1-[3- cyano-6-methyl-4-(trifluoromethyl)-2-pyridyl]pyrrolidin-2-yl]imidazol-1-yl]phenyl]methyl]- carbamate (60 mg, 74% yield) as a white solid m/z ES+ [M+H]⁺ 561.2

Step e. To a solution of benzyl N-[[2-[2-[(2S)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2- pyridyl]pyrrolidin-2-yl]imidazol-1-yl]phenyl]methyl]carbamate (60 mg, 0.11 mmol) in EtOH (5 ml_) was added Pd/C (10 mg, 10% loading) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was then stirred under H2 atmosphere (15 psi) at rt for 2 h. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (19 mg, 39% yield) as a white solid. m/z ES+ [M+H]⁺ 427.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.72 -7.67 (m, 1 H), 7.65 - 7.52 (m, 1 H), 7.52 - 7.45 (m, 1H), 7.45 - 7.34 (m, 1H), 7.30 - 7.21 (m, 1 H), 7.05 - 6.97 (m, 1 H), 6.90 (s, 1 H), 5.40 - 5.25 (m, 1 H), 4.11 - 3.94 (m, 1 H), 3.85 - 3.75 (m, 1 H), 3.70 - 3.49 (m,

1 H), 3.42 - 3.34 (m, 1H), 2.41 - 2.28 (m, 3H), 2.21 - 2.03 (m, 2H), 1.98 - 1.90 (m, 2H).

Example 24

(S 2-(2-(1-(2-((Dimethylamino)methyl)phenyl)-7H-imidazol-2-yl)pyrrolidin-1-yl)-6- methyl-4-(trifluoromethyl)nicotinonitrile

Step a. To a solution of tert- butyl (2S)-2-[1-[2-(aminomethyl)phenyl]imidazol-2-yl]pyrrolidine- 1-carboxylate (90 mg, 0.26 mmol) in THF (2 ml_) and MeOH (2 ml_) was added formaldehyde (19 mg, 0.63 mmol) and NaBHsCN (40 mg, 0.63 mmol). The mixture was stirred at rt for 3 h. The mixture was evaporated, the residue was treated with water (10 ml_) and extracted into EtOAc (30 ml_ x 3). The combined organic layers were washed with brine (15 ml_), dried over Na2SC>4, filtered and evaporated. The residue was purified by column chromatography (PE/EtOAc = 1/0 followed by EtOAc/EtOH = 20/1 with 0.1% of TEA) to afford tert- butyl (2S)-2-[1-[2-[(dimethylamino)methyl]phenyl]imidazol-2-yl]pyrrolidine-1- carboxylate (140 mg, 84% yield) as a white solid m/z ES+ [M+H]⁺ 371.2

Step b. A solution of te/f-butyl (2S)-2-[1-[2-[(dimethylamino)methyl]phenyl]imidazol-2- yl]pyrrolidine-1-carboxylate (140 g, 0.38 mmol) in HCI/dioxane (5 ml_) was stirred at rt for 2 h. The reaction mixture was then evaporated to afford A/,A/-dimethyl-1-[2-[2-[(2S)-pyrrolidin- 2-yl]imidazol-1-yl]phenyl]methanamine (90 mg, 88% yield) as a pink solid, which was used in next step without further purification m/z ES+ [M+H]⁺ 271.1

Step c. To a solution of A/,/\/-dimethyl-1-[2-[2-[(2S)-pyrrolidin-2-yl]imidazol-1-yl]phenyl]- methanamine (90 mg, 0.30 mmol) and DIPEA (108 mg, 0.83 mmol) in NMP (2 ml_) was added 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (88 mg, 0.40 mmol). The mixture was stirred at 80°C for 5 h. Upon completion, the reaction mixture was quenched with water (15 ml_) and extracted into EtOAc (30 ml_ x 3). The combined organic layers were washed with brine (15 ml_), dried over Na2SC>4 and evaporated. The residue was purified by prep-HPLC to give the title compound (21 mg, 13% yield) as a brown solid m/z ES+ [M+H]⁺ 455.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.67 - 7.52 (m, 2H), 7.51 - 7.38 (m, 2H), 7.33 - 7.16 (m, 1H), 7.04 - 6.98 (m, 1H), 6.90 (s, 1 H), 5.45 - 5.40 (m, 1 H), 4.03 - 3.97 (m, 1 H), 3.85 - 3.75 (m, 1H), 3.11 - 3.01 (m, 2H), 2.40 (s, 3H), 2.30 - 2.10 (m, 2H), 2.07 (s, 6H), 2.00 - 1.79 (m, 2H).

Example 25

2-((2S,4S)-2-(1-(4,6-Dimethylpyridin-2-yl)-7H-imidazol-2-yl)-4-hydroxypyrrolidin-1-yl)-6- methyl-4-(trifluoromethyl)nicotinonitrile

Step a. A mixture of (2S,4S)-1-te/f-butoxycarbonyl-4-[te/f-butyl(dimethyl)silyl]oxy-pyrrolidine- 2-carboxylic acid (10.00 g, 28.9 mmol), L/,O-dimethylhydroxylamine hydrochloride (3.11 g, 31.8 mmol), HATU (13.21 g, 34.7 mmol) and DIPEA (7.48 g, 57.9 mmol) in DCM (100 ml_) was stirred at 15°C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was evaporated. The obtained residue was purified by column chromatography (PE/EtOAc 10/1 to 5/1) to give (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(methoxy(methyl)- carbamoyl)pyrrolidine-1-carboxylate (7.5 g, 67% yield) as a white solid m/z ES+ [M+H]⁺ 389.3

Step b. To a solution of (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(methoxy(methyl)- carbamoyl)pyrrolidine-1-carboxylate (5.00 g, 12.87 mmol) in DCM (50 ml_) was added DIBAL-H (1 M, 38.6 ml_) dropwise at -78°C. The mixture was stirred at -78°C for 2 h. The reaction mixture was quenched by dropwise addition of MeOH (2 ml_) at -78°C, warmed to rt, filtered and washed with MeOH (250 ml_). The filtrate was evaporated and the residue was purified by column chromatography (PE/EtOAc = 20/1 to 4/1) to afford (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-formylpyrrolidine-1-carboxylate (3.1 g, 73% yield) as a colorless oil.

Step c. To a solution of (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-formylpyrrolidine- 1-carboxylate (2.00 g, 6.07 mmol), glyoxal (3.07 g, 21.2 mmol) in MeOH (20 ml_) was added ammonium hydroxide (5.60 g, 39.9 mmol, 25% aq.). The mixture was stirred at 10°C for 16 h. The reaction mixture was evaporated and the residue was purified by column chromatography (PE/EtOAc = 10/1 to 0/1) to afford (2S,4S)-tert- butyl 4-((te/f-butyldimethyl- silyl)oxy)-2-(7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (1.1 g, 49% yield) as a yellow solid m/z ES+ [M+H]⁺ 368.3; ¹H NMR (400 MHz, CDC ) d ppm 6.95 (br s, 2H), 5.07 (br d, J = 9.6 Hz, 1H), 4.61 - 4.34 (m, 1 H), 3.79 - 3.54 (m, 1H), 3.25 (br s, 1 H), 2.74 - 2.38 (m, 1H), 2.21 - 1.99 (m, 1 H), 1.60 - 1.19 (m, 9H), 0.99 - 0.78 (m, 9H), 0.25 -0.06 (m, 6H)

Step d. A mixture of (2S,4S)-tert-buty\ 4-((te/f-butyldimethylsilyl)oxy)-2-(7/-/-imidazol-2- yl)pyrrolidine-1-carboxylate (70 mg, 0.19 mmol), 2-bromo-4,6-dimethylpyridine (71 mg, 0.38 mmol), Cul (40 mg, 0.21 mmol) and CS2CO3 (187 mg, 0.57 mmol) in DMSO (1.5 ml_) was degassed and purged with N2 3 times, and then the mixture was stirred at 120°C for 16 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by EtOAc (100 mL) and water (50 ml_). The organic phase was separated, washed with brine (50 ml_), dried over Na2SC>4, filtered and evaporated. The residue was purified by column chromatography (PE/EtOAc = 10/1 to 1/3) to afford (2S,4S)-ierf-butyl 4-((ferf-butyldimethylsilyl)oxy)-2-(1-(4,6- dimethylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (60 mg, 88% yield) as a yellow oil.

Step e. To a solution of (2S,4S)-tert- butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(1-(4,6- dimethylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (60 mg, 0.17 mmol) in dioxane (0.5 mL) was added HCI/dioxane (4 M, 0.5 mL). The mixture was stirred at rt for 1 h. On completion, the mixture was concentrated in vacuo to afford (3S, 5S)-5-(1 -(4,6- dimethylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidin-3-ol (43 mg, crude, HCI) as a yellow oil which was used in the next step without further purification.

Step f. To a solution of (3S,5S)-5-(1-(4,6-dimethylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidin-3- ol (43 mg, 0.17 mmol, HCI), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (55 mg, 0.25 mmol) in NMP (0.5 mL) was added DIPEA (64 mg, 0.50 mmol). The mixture was stirred at 60°C for 16 h. On completion, the reaction mixture was quenched by EtOAc (100 mL) and water (20 mL). The organic phase was separated, washed with brine (50 mL), dried over Na₂S0₄, filtered and evaporated. The residue was purified by prep-HPLC to give the title compound (5 mg, 7% yield) as a yellow solid. m/z ES+ [M+H]⁺ 443.2; ¹H NMR (400 MHz, CDCh) d ppm 7.37 (br d,J = 16.8 Hz, 2H), 7.20 (s, 1H), 7.12 (br s, 1H), 6.78 (s, 1 H), 5.80 - 5.65 (m, 1 H), 5.02 (br d, J = 10.8 Hz, 1 H), 4.78 (br s, 1 H), 4.21 (br d, J = 10.0 Hz, 1 H), 2.88 - 2.78 (m, 1 H), 2.66 - 2.43 (m, 7H), 2.20 (s, 3H)

Example 26

(3S,5S)-1-(6-Methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(1-(6-methylpyridin-2-yl)-7H- imidazol-2-yl)pyrrolidin-3-ol

Step a. A mixture of (2S,4S)-tert- butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(7/-/-imidazol-2- yl)pyrrolidine-1-carboxylate (370 mg, 1.01 mmol), 2-bromo-6-methyl-pyridine (208 mg, 1.21 mmol), Cul (192 mg, 1.01 mmol), K2CO3 (417 mg, 3.02 mmol), -proline (232 mg, 2.01 mmol) in DMSO (10 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 100°C for 12 h under N2 atmosphere. On completion, the reaction mixture was quenched by aq. NhUCI (60 ml_) at rt, diluted with water (100 ml_) and extracted with EtOAc (150 ml_ x 3). The combined organic layers were washed with brine (100 ml_ x 3), dried over Na2SC>4, filtered and evaporated. The residue was purified by prep-TLC (PE/EtOAc = 15/85 ) to give (2S,4S)-tert- butyl 4-((ferf-butyldimethylsilyl)oxy)-2-(1-(6-methylpyridin-2-yl)-7H- imidazol-2-yl)pyrrolidine-1-carboxylate (100 g, 14% yield) as a light yellow solid.

Step b. A solution of (2S,4S)-te/f-butyl 4-((te/f-butyldimethylsilyl)oxy)-2-(1-(6-methylpyridin- 2-yl)-7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in HCI/dioxane (5 ml_) was stirred at rt for 2 h. Upon completion, the reaction mixture was evaporated to give (3S,5S)-5-(1-(6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidin-3-ol (40 mg, crude HCI salt) as a yellow solid.

Step c. A mixture of (3S,5S)-5-(1-(6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidin-3-ol (40 mg, 0.20 mmol, crude HCI salt), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (77 mg, 0.39 mmol), CS2CO3 (255 mg, 0.78 mmol), RuPhos-Pd-G2 (15 mg, 0.020 mmol) in dioxane (2 ml_) was degassed and purged with N2 3 times, and then stirred at 70°C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The obtained residue was purified by prep-HPLC to give the title compound (17 mg, 21% yield) as a white solid. m/z ES+ [M+H]⁺ 404.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.97 (dd, J = 7.6, 7.6 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.38 (d, J = 7.6 Hz, 1 H), 6.96 (s, 1 H), 6.75 (bs, 1 H), 6.57 (s, 1 H), 6.42 (s, 1 H), 5.73 (d, J = 7.2 Hz, 1 H), 4.50 - 4.39 (m, 1 H), 3.73 - 3.67 (m, 1 H), 3.65 - 3.59 (m,

1 H), 2.65 - 2.55 (m, 1 H), 2.54 (s, 3H), 2.20 - 2.10 (m, 1 H), 1.97 (s, 3H).

Example 27

2-((2S,4S)-2-(1-(5-Fluoropyridin-2-yl)-7H-imidazol-2-yl)-4-hydroxypyrrolidin-1-yl)-6- methyl-4-(trifluoromethyl)nicotinonitrile

Step a. To a solution of (2S,4S)-1-(te/f-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.00 g, 43.24 mmol) in THF (150 ml_) was added NaH (3.81 g, 95.1 mmol, 60% dispersion in mineral oil) portionwise at 0°C and then benzyl bromide (8.88 g, 51.89 mmol) was added. The mixture was stirred at rt for 16 h. On completion, the mixture was poured into 200 ml_ water slowly and carefully adjusted to pH ~ 2 with aq. HCI (2 M). The mixture was then extracted with EtOAc (400 ml_ x 3). The combined organic phase was dried over Na₂S0₄ and evaporated. The residue was triturated with PE/EtOAc = 10/1 (500/50 ml_) for 30 min and filtered to give (2S,4S)-4-(benzyloxy)-1-(fe/f-butoxycarbonyl)pyrrolidine-2- carboxylic acid (12.5 g, 90% yield) as a white solid.

Step b. A mixture of (2S,4S)-4-(benzyloxy)-1-(te/f-butoxycarbonyl)pyrrolidine-2-carboxylic acid (20 g, 62.2 mmol), L/,O-dimethylhydroxylamine hydrochloride (6.68 g, 68.5 mmol), DIPEA (16.09 g, 124.5 mmol), HATU (26.03 g, 68.46 mmol) in DCM (270 ml_) was stirred at rt for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography (PE/EtOAc = 10/1 to 1/1) to give (2S,4S)-te/f-butyl 4-(benzyloxy)-2- (methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (20.8 g, 92% yield) as a colorless oil. m/z ES+ [M+H]⁺ 365.3

Step c. To a solution of (2S,4S)-te/f-butyl 4-(benzyloxy)-2-(methoxy(methyl)carbamoyl)- pyrrolidine-1-carboxylate (30 g, 82.32 mmol) in DCM (300 ml_) was added DIBAL-H (1 M, 247 ml_) slowly at -78°C. The mixture was stirred at -78°C for 2 h. On completion, the reaction mixture was quenched by MeOH (100 ml_) at -78°C, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc = 15/1 to 8/1) to give (2S,4S)-te/f-butyl 4-(benzyloxy)-2-formylpyrrolidine-1-carboxylate (16.5 g, 66% yield) as a colorless oil.

Step d. A mixture of (2S,4S)-te/f-butyl 4-(benzyloxy)-2-formylpyrrolidine-1-carboxylate (14 g, 45.8 mmol), glyoxal (33.26 g, 229 mmol), ammonium hydroxide (38.56 g, 275 mmol, 25% aq.) in MeOH (35 ml_) was stirred at rt for 16 h under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (30 ml_) and extracted with EtOAc (50 ml_ x 3). The combined organic layers were washed with brine (100 ml_ x 3), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (PE/EtOAc = 5/1 to 1/2) to give (2S,4S)-tert- butyl 4-(benzyloxy)-2-(7/-/- imidazol-2-yl)pyrrolidine-1-carboxylate (10.5 g, 67% yield) as a yellow solid m/z ES+ [M+H]⁺ 344.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 11.56 (br s, 1 H), 7.40 - 7.21 (m, 5H), 7.17 (br s, 1 H), 6.84 (br s, 1 H), 4.96 - 4.68 (m, 1 H), 4.50 - 4.31 (m, 2H), 4.22 - 4.09 (m, 1 H), 3.68 (dd, J = 11.2, 6.0 Hz, 1 H), 3.41 (dd, J = 11.2, 4.4 Hz, 2H), 2.07 (br s, 1 H), 1.41 - 1.13 (m, 9H).

Step e. A mixture of tert- butyl (2S,4S)-4-benzyloxy-2-(7/-/-imidazol-2-yl)pyrrolidine-1- carboxylate (200 mg, 0.58 mmol), 2,5-difluoropyridine (80 mg, 0.70 mmol) and CS2CO3 (284 mg, 0.87 mmol) in DMSO (1 ml_) was stirred at 80°C for 12 h under N2 atmosphere. On completion, the reaction mixture was diluted with water (10 ml_) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc = 3/1 to 1/1) to give (2S,4S)-te/f-butyl 4-(benzyloxy)-2-(1-(5- fluoropyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (80 mg, 30% yield) as a colorless oil. m/z ES+ [M+H]⁺ 439.3

Step f. A mixture of (2S,4S)-te/f-butyl 4-(benzyloxy)-2-(1-(5-fluoropyridin-2-yl)-7/-/-imidazol- 2-yl)pyrrolidine-1-carboxylate (138 mg, 0.31 mmol) and Pd/C (20 mg, 10% loading) in EtOH (1 mL) was stirred at rt for 12 h under H2 balloon atmosphere. On completion, the reaction mixture was filtered and evaporated to give (2S,4S)-te/f-butyl 2-(1-(5-fluoropyridin-2-yl)-7/-/- imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (150 mg, crude) as a colorless oil. m/z ES+ [M+H]⁺ 349.2

Step g. To a solution of (2S,4S)-tert- butyl 2-(1-(5-fluoropyridin-2-yl)-7/-/-imidazol-2-yl)-4- hydroxypyrrolidine-1-carboxylate (150 mg, 0.43 mmol) in dioxane (1 mL) was added HCI/dioxane (4 M, 1 mL). The reaction mixture was stirred at rt for 2 h. On completion, the reaction mixture was evaporated to give (3S, 5S)-5-(1-(5-fluoropyridin-2-yl)-7/-/-imidazol-2- yl)pyrrolidin-3-ol (120 mg, 90 % yield) as a yellow solid m/z ES+ [M+H]⁺ 249.1

Step h. A mixture of (3S,5S)-5-(1-(5-fluoropyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidin-3-ol (100 mg, 0.35 mmol, HCI), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (93 mg,

0.42 mmol) and DIPEA (91 mg, 0.70 mmol) in NMP (2 mL) was stirred at 60°C for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (30 mg, 19 % yield) as a white solid m/z ES+ [M+H]⁺ 433.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.65 (d, J = 2.8 Hz, 1 H), 8.06 (dt, J = 3.2, 8.4 Hz, 1 H), 7.75 (dd, J = 4.0, 8.8 Hz, 1 H), 7.51 (s, 1 H), 6.96 (d, J = 1.6 Hz, 1 H), 6.93 (s, 1 H), 6.05 (d, J = 8.0 Hz, 1 H), 5.76 (t, J = 7.2 Hz, 1 H), 4.51 - 4.36 (m, 1 H), 4.09 (dd, J = 6.4, 10.0 Hz, 1 H), 3.92 (dd, = 5.6, 10.4 Hz, 1 H), 2.74 - 2.60 (m, 1 H), 2.14 (td, J = 6.4, 12.8 Hz, 1 H), 2.00 (s, 3H).

Example 28 2-((2S,4S)-4-Hydroxy-2-(1 -(1 -methyl-7H-pyrazol-3-yl)-7H-imidazol-2-yl)pyrrolidin-1 -yl)-

6-methyl-4-(trifluoromethyl)nicotinonitrile

Step a. A mixture of (2S,4S)-tert- butyl 4-(benzyloxy)-2-(7/-/-imidazol-2-yl)pyrrolidine-1- carboxylate (500 g, 1.46 mmol), 3-iodo-1 -methyl- 7/-/-pyrazole (908 mg, 4.37 mmol), Cul (111 mg, 0.58 mmol), .-proline (134 mg, 1.16 mmol) and K2CO3 (1.01 g, 7.28 mmol) in DMSO (5 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 110°C for 16 h under N2 atmosphere. On completion, the reaction mixture was quenched by EtOAc (100 ml_) and water (50 ml_). The organic phase was separated, washed with brine (50 ml_), dried over Na₂S0₄, filtered and evaporated. The obtained residue was purified by column chromatography (PE/EtOAc = 10/1 to 1/3) to afford (2S,4S)-tert-b ty\ 4-(benzyloxy)- 2-(1-(1 -methyl- 7/-/-pyrazol-3-yl)-7/-/-imidazol-2-yl)pyrrolidine-1 -carboxylate (140 mg, 23% yield) as a yellow solid.

Step b. (2S,4S)-tert- butyl 4-(benzyloxy)-2-(1-(1 -methyl- 7/-/-pyrazol-3-yl)-7/-/-imidazol-2- yl)pyrrolidine-1 -carboxylate (140 mg, 0.33 mmol) in HCI/dioxane (4 M, 2.33 ml_) was stirred at rt for 2 h. On completion, the reaction mixture was concentrated in vacuo to afford 3-(2- ((2S,4S)-4-(benzyloxy)pyrrolidin-2-yl)-7/-/-imidazol-1-yl)-1-methyl-7/-/-pyrazole (100 mg, crude) as a yellow oil. Step c. A mixture of 3-(2-((2S,4S)-4-(benzyloxy)pyrrolidin-2-yl)-7/-/-imidazol-1-yl)-1-methyl- 1H- pyrazole (100 g, 0.31 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (82 mg, 0.37 mmol) and DIPEA (120 mg, 0.93 mmol) in NMP (2 ml_) was stirred at 60°C for 16 h. On completion, the reaction mixture was quenched by EtOAc (100 ml_) and water (20 ml_). The organic phase was separated, washed with brine (50 ml_), dried over Na₂S0₄, filtered and evaporated. The residue was purified by prep-TLC (PE/EtOAc = 1/1) to afford 2-((2S,4S)-4- (benzyloxy)-2-(1-(1 -methyl- 7/-/-pyrazol-3-yl)-7/-/-imidazol-2-yl)pyrrolidin-1-yl)-6-methyl-4- (trifluoromethyl)nicotinonitrile (100 mg, 64% yield) as a yellow solid.

Step d. To a solution of 2-((2S,4S)-4-(benzyloxy)-2-(1-(1-methyl-7/-/-pyrazol-3-yl)-7/-/- imidazol-2-yl)pyrrolidin-1-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile (60 mg, 0.12 mmol) in DCM (2 ml_) was added BCh (1 M in toluene, 2.36 ml_) dropwise at 0°C. The mixture was stirred at 0°C for 30 min. On completion, the reaction mixture was quenched by water (5 ml_) at 0°C, and then adjusted to pH = 8 with aq. NaOH (5% wt). The mixture was extracted with EtOAc (25 ml_ x 2). The combined organic layers were washed with brine (20 ml_), dried over Na₂S0₄, filtered and evaporated. The residue was purified by prep-HPLC. The obtained product was treated with aq. HCI (2 M, 2 ml_) and then lyophilized to give the hydrochloride salt of the title compound (25 mg, 46% yield) as a yellow solid. m/z ES+ [M+H]⁺ 418.0; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.03 (dd, J = 2.0, 10.4 Hz,

2H), 7.75 (d, J = 2.0 Hz, 1 H), 7.12 (s, 1H), 6.76 (d, J = 2.0 Hz, 1H), 5.68 (dd, J = 4.4, 8.8 Hz, 1 H), 4.59 - 4.50 (m, 1 H), 4.23 - 4.04 (m, 2H), 3.95 (s, 3H), 2.63 - 2.57 (m, 1 H), 2.20 (s, 3H),

2.20 - 2.10 (m, 1H).

The Examples in Table 2 were prepared using methods similar to those described in the synthesis of Examples 25-28.

Table 2

Example 35

2-((2S,4S)-2-(1-(3-Chloro-4-fluorophenyl)-4-methyl-7H-imidazol-2-yl)-4- hydro xypyrrolidin-1-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile

Step a. A mixture of (2S,4S)-tert- butyl 4-(benzyloxy)-2-formylpyrrolidine-1-carboxylate (1.90 g, 6.22 mmol), 2-oxopropanal (1.79 g, 24.89 mmol), ammonium hydroxide (7.63 g, 43.55 mmol, 20% purity) in MeOH (30 ml_) was degassed and purged with N23 times, and then the mixture was stirred at rt for 12 h under N2 atmosphere. Upon completion, the reaction mixture was concentrated and the residue purified by prep-HPLC to give (2S,4S)-te/f-butyl 4- (benzyloxy)-2-(4-methyl-7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (950 mg, 33% yield) as a yellow solid.

Step b. A mixture of (2S,4S)-te/f-butyl 4-(benzyloxy)-2-(4-methyl-7/-/-imidazol-2- yl)pyrrolidine-1-carboxylate (550 mg, 1.54 mmol), 2-chloro-1-fluoro-4-iodo-benzene (1.18 g, 4.62 mmol), Cul (146 mg, 0.77 mmol), quinolin-8-ol (223 mg, 1.54 mmol) and CsF (701 mg, 4.62 mmol) in DMSO (2 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 120°C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by aq. NH₄CI (60 ml_) at rt, further diluted with water (100 ml_) and extracted with EtOAc (150 ml_ x 3). The combined organic layers were washed with brine (100 ml_ x 3), dried over Na2SC>4 and evaporated. The residue was purified by prep-HPLC to give {2S,4S)-tert- butyl 4-(benzyloxy)-2-(1-(3-chloro-4-fluorophenyl)-4-methyl-7/-/-imidazol-2- yl)pyrrolidine-1-carboxylate (135 mg, 18% yield) as a brown solid.

Step c. A solution of (2S,4S)-tert-b ty\ 4-(benzyloxy)-2-(1-(3-chloro-4-fluorophenyl)-4- methyl- 7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (130 g, 0.27 mmol) in HCI/dioxane (4 M, 5 ml_) was stirred at rt for 2 h. Upon completion, the reaction mixture was concentrated in vacuo to give 2-((2S,4S)-4-(benzyloxy)pyrrolidin-2-yl)-1-(3-chloro-4-fluorophenyl)-4-methyl- 7 /-/-imidazole (110 mg, crude, HCI salt) as a yellow solid.

Step d. A mixture of 2-((2S,4S)-4-(benzyloxy)pyrrolidin-2-yl)-1-(3-chloro-4-fluorophenyl)-4- methyl-7/-/-imidazole (110 mg, 0.26 mmol, HCI), 2-chloro-6-methyl-4-(trifluoromethyl)- nicotinonitrile (86 mg, 0.39 mmol) and DIPEA (101 mg, 0.78 mmol) in NMP (3 ml_) was stirred at 60°C for 12 h. Upon completion, the reaction mixture was quenched by aq. NH4CI (60 ml_) at rt, further diluted with water (100 ml_) and extracted with EtOAc (100 ml_ x 3). The combined organic layers were washed with brine (20 ml_ x 3), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (PE/EtOAc = 10/1 to 1/1) to give 2-((2S,4S)-4-(benzyloxy)-2-(1-(3-chloro-4-fluorophenyl)-4-methyl-7/-/-imidazol-2- yl)pyrrolidin-1-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile (180 mg, 78% yield) as a brown solid.

Step e. To a solution of 2-((2S,4S)-4-(benzyloxy)-2-(1-(3-chloro-4-fluorophenyl)-4-methyl- 7/-/-imidazol-2-yl)pyrrolidin-1-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile (120 mg, 0.21 mmol) in DCM (2 ml_) was added BCI₃ (1 M in toluene, 2.11 ml_) dropwise at 0°C. Then the mixture was stirred at 0°C for 0.5 h. On completion, the reaction mixture was quenched by aq. NaOH solution (20 ml_, 10% wt) at 0°C, further diluted with water (20 ml_) and extracted with DCM (50 ml_ x 3). The combined organic layers were washed with brine (20 ml_ x 3), dried over Na₂S0₄ and evaporated. The residue was purified by prep-HPLC to give the title compound (80 mg, 15% yield) as a yellow solid. m/z ES+ [M+H]⁺ 480.1; ¹H NMR (400 MHz, CD₃OD) d ppm 7.63 (dd, J= 2.8, 6.4 Hz, 1H), 7.50 - 7.35 (m, 2H), 6.91 (s, 1 H), 6.83 (s, 1 H), 5.44 (t, J = 7.2 Hz, 1 H), 4.45 - 4.40 (m, 1 H), 4.15- 3.97 (m, 2H), 2.63 - 2.48 (m, 1H), 2.29 (s, 3H), 2.21 - 2.16 (m, 1H), 2.15 (s, 3H).

Example 36

2-((2R, 3R,4S)-3, 4-Dihydro xy-2-(1-(6-methylpyridin-2-yl)-7H-imidazol-2-yl)pyrrolidin-1- yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile

Step a. (S)-tert- Butyl 2-( 7/-/-imidazol-2-yl)-2, 5-dihydro- 7/-/-pyrrole-1-carboxylate was prepared from (S)-1-(te/f-butoxycarbonyl)-2, 5-dihydro- 7/-/-pyrrole-2-carboxylic acid in a similar manner to the preparation of (2S,4S)-te/f-butyl 4-(benzyloxy)-2-(7/-/-imidazol-2- yl)pyrrolidine-1-carboxylate as described in Example 27, steps b-d.

Step b. A mixture of (S)-te/f-butyl 2-(7/-/-imidazol-2-yl)-2, 5-dihydro- 7/-/-pyrrole-1-carboxylate (500 mg, 2.13 mmol), 2-bromo-6-methyl-pyridine (1.10 g, 6.38 mmol), Cul (202 mg, 1.06 mmol), CsF (2.77 g, 8.50 mmol) and -proline (245 mg, 2.13 mmol) in DMSO (10 ml_) was degassed and purged with N2 3 times, and then the mixture was stirred at 120°C for 12 h under N2 atmosphere. On completion, NH4CI (aq, 60 ml_) was added to the reaction mixture and then diluted with water (100 ml_) and extracted with EtOAc (100 ml_ ^c 3). The organic phase was separated, washed with brine (90 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep-HPLC to give (S)-te/f-butyl 2-(1-(6-methyl-pyridin-2-yl)-7/-/- imidazol-2-yl)-2,5-dihydro-7/-/-pyrrole-1-carboxylate (480 mg, 59% yield) as a brown solid. Step c. A mixture of (S)-te/f-butyl 2-(1-(6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)-2,5-dihydro- 7 /-/-pyrrole-1 -carboxylate (320 mg, 0.98 mmol) in HCI/dioxane (4 M, 10 ml_) was stirred at rt for 2 h. On completion, the reaction mixture was concentrated in vacuo to afford (S)-2-(2- (2,5-dihydro-7/-/-pyrrol-2-yl)-7/-/-imidazol-1-yl)-6-methylpyridine (257 mg, crude, HCI salt) as a brown solid.

Step d. A mixture of (S)-2-(2-(2,5-dihydro-7/-/-pyrrol-2-yl)-7/-/-imidazol-1-yl)-6-methylpyridine (257 mg, 0.98 mmol, HCI salt), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (323 mg, 1.47 mmol) and DIPEA (379 mg, 2.93 mmol) in NMP (10 ml_) was stirred at 60°C for 12 h.

On completion, the reaction mixture was quenched with NH4CI (60 ml_, aq) and then diluted with H2O (100 ml_), then extracted with EtOAc (100 ml_ ^c 3). The organic phase was separated, washed with brine (90 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep-HPLC and the desired stereoisomer was isolated by further purification using prep chiral SFC (column: DAICEL CHIRALPAK IC, 250mm x 30mm, 10pm) to give (S)- 6-methyl-2-(2-(1-(6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)-2, 5-dihydro- 7/-/-pyrrol-1-yl)-4- (trifluoromethyl)-nicotinonitrile (290 mg, 71% yield) as a brown solid.

Step e. A mixture of (S)-6-methyl-2-(2-(1-(6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)-2,5- dihydro-7/-/-pyrrol-1-yl)-4-(trifluoromethyl)nicotinonitrile (290 mg, 0.71 mmol), OSO4 (36 mg, 0.14 mmol), NMO (108 mg, 0.92 mmol) in water (5 ml_), MeCN (5 ml_), f-butanol (5 ml_) was degassed and purged with N2 3 times, and stirred at rt for 12 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by addition of aq. Na2sC>3 (20 ml_), filtered and concentrated. The crude product was purified by prep-HPLC to give the title compound (150 mg, 47% yield) as a white solid. m/z ES+ [M+H]⁺ 445.1; ¹H NMR (400 MHz, CD₃OD) d ppm 7.95 (t, J =8.0 Hz, 1 H), 7.87 (d, J =2.0 Hz, 1 H), 7.69 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 5.2 Hz, 1 H), 7.04 (s, 1H), 5.49 (d, J = 8.4 Hz, 1H), 4.45 (t, J = 3.2 Hz, 1H), 4.19 (d, J = 11.2 Hz, 1 H), 3.75 (d, J = 11.2 Hz, 1 H), 3.31 (s, 1 H), 2.65 (s, 3 H), 2.24 (s, 3H).

Example 37

2-((2F?,3F?,4S)-2-(1-(4-Fluoro-3-methylphenyl)-7tf-imidazol-2-yl)-3,4- dihydroxypyrrolidin-1-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile

The title compound was prepared in a similar manner to Example 36, using 1-fluoro-4-iodo- 2-methyl-benzene in step b. m/z ES+ [M+H]⁺ 462.2; ¹H NMR (400 MHz, CD₃OD) d ppm 7.58-7.56 (m, 2H), 7.22 (t, J = 9.2 Hz, 1 H), 7.18 (d, J = 1.2 Hz, 1 H), 7.00 (s, 1 H), 6.88 (s, 1 H), 5.23 (d, J = 6.4 Hz, 1 H), 4.50-4.38 (m, 3H), 3.78 (dd, J = 10.8 Hz, 2.8 Hz, 1H), 2.35 (s, 1 H), 2.65 (s, 3 H), 2.24 (s, 3H).

Example 38

2-((7/?,3S,5/?)-3-(1-(5-Fluoro-6-methylpyridin-2-yl)-7F/-imidazol-2-yl)-2-aza- bicyclo[3.1.0]hexan-2-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile

Step a. To a solution of (7F?,3S,5F?)-2-(te/f-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxylic acid (CAS Number 197142-34-0; 1.00 g, 4.40 mmol), L/,O-dimethylhydroxylamine hydrochloride (0.64 g, 6.60 mmol) in DMF (5 ml_) was added FIATU (2.01 g, 5.28 mmol) and DIPEA (1.71 g, 13.20 mmol). The mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was filtered and evaporated. The obtained residue was purified by prep- FIPLC to give (1R,3S,5R)-tert- butyl 3-(methoxy(methyl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (1.2 g, 74% yield) as a brown solid.

Step b. To a solution of (1R,3S,5R)-tert- butyl 3-(methoxy(methyl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 3.70 mmol) in DCM (10 ml_) was added DIBAL-FI (1 M, 11.1 ml_) at -78°C. The mixture was stirred at -78°C for 2 h. Upon completion, the reaction mixture was quenched by aq. NFUCI solution (30 ml_) at rt, diluted with water (30 ml_) and extracted with EtOAc (100 ml_ x 3). The combined organic layers were washed with brine (30 ml_ x 3), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (PE/EtOAc = 15/1 to 5/1) to give (1 R,3S,5R)-tert- butyl 3- formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (700 mg, 90% yield) as a yellow solid.

Step c. To a solution of (1R,3S,5R)-tert- butyl 3-formyl-2-azabicyclo[3.1.0]hexane-2- carboxylate (650 mg, 3.08 mmol), glyoxal (1.79 g, 12.31 mmol) in MeOFI (10 mL) was added ammonium hydroxide (3.77 g, 21.54 mmol, 20% aq.). The mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was filtered and evaporated. The residue was purified by prep-FIPLC to give (1 R,3S,5R)-tert- butyl 3-(7/-/-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane- 2-carboxylate (600 mg, 78% yield) as a light yellow solid.

Step d. A mixture of (1R,3S,5R)-tert- butyl 3-(7/-/-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2- carboxylate (300 mg, 1.20 mmol), 6-bromo-3-fluoro-2-methyl-pyridine (457 mg, 2.41 mmol), CS2CO3 (1.18 g, 3.61 mmol), Cul (229 mg, 1.20 mmol) and L-proline (277 mg, 2.41 mmol) in DMSO (15 mL) was degassed and purged with N23 times. Then the mixture was stirred at 120°C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by aq. NFUCI (60 mL) at rt, diluted with water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na₂S0₄ and evaporated. The residue was purified by prep-TLC (PE/EtOAc = 15/85) to give (1R,3S,5R)-tert- butyl 3-(1-(5-fluoro-6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (150 mg, 22% yield) as a brown solid.

Step e. A solution of (1 R,3S,5R)-tert- butyl 3-(1-(5-fluoro-6-methylpyridin-2-yl)-7/-/-imidazol-2- yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (125 g, 0.35 mmol) in HCI/dioxane (5 ml_) was stirred at 30°C for 2 h. The reaction mixture was evaporated to give (1R,3S,5R)- 3-(1-(5- fluoro-6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (102 mg, crude) as a brown solid which was used for the next step directly.

Step f. A mixture of (7ft,3S,5ft)-3-(1-(5-fluoro-6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)-2- azabicyclo[3.1.0]hexane (102 mg, 0.35 mmol, HCI), 2-chloro-6-methyl-4-(trifluoromethyl)- nicotinonitrile (114 mg, 0.52 mmol) and DIPEA (134 mg, 1.04 mmol) in NMP (3 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 60°C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by aq. NH4CI (60 mL) at rt, diluted with water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SC>4, filtered and evaporated. The residue was purified by prep-HPLC to give the title compound (11 mg, 7% yield) as a brown solid. m/z ES+ [M+H]⁺ 443.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.87 (t, J = 8.8 Hz, 1 H), 7.50 - 7.45 (m, 2H), 6.94 (s, 1 H), 6.91 (s, 1 H), 5.73 (dd, J = 7.6, 4.4 Hz, 1 H), 3.95 - 3.85 (m, 1 H), 2.50 - 2.45 (m, 3H), 2.45 - 2.36 (m, 2H), 2.08 (s, 3H), 2.05 - 1.95 (m, 1 H), 1.09 - 0.97 (m,

1 H), 0.80 - 0.70 (m, 1 H).

Example 39

2-((1R,3S,5S)-3-(1-(3-Chloro-4-fluorophenyl)-7H-imidazol-2-yl)-5-(hydroxymethyl)-2- azabicyclo[3.1.0]hexan-2-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile

Step a. To a solution of 2-(te/f-butyl) 3-ethyl (1R,3S,5S)- 5-(hydroxymethyl)-2- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (CAS Number 1386461-22-8, prepared as described in WO 2014002058 A2; 500 g, 1.72 mmol) in DMF (5 ml_) was added NaH (137 mg, 3.43 mmol, 60% dispersion in mineral oil), portionwise at 0°C. After stirring for 30 min, benzylbromide (441 mg, 2.58 mmol) was added at 0°C. The resulting suspension was allowed to warm to 30°C, and stirred at 30°C for 1.5 h. Upon completion, it was diluted with water (10 ml_) and then adjusted to pH 1 with KHSO4 (aq.), washed with brine (50 ml_), dried over Na2SC>4, filtered and concentrated in vacuo to afford the product (3S)-2-te/f-butyl 3-ethyl 5-((benzyloxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.2 g, crude).

Step b. To a solution of (3S)-2-te/f-butyl 3-ethyl 5-((benzyloxy)methyl)-2- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.20 g, crude) in THF (10 ml_) and water (1 ml_) and MeOH (1 ml_) at 0°C was added a solution of NaOH (4.8 ml_, aq. 1 M). The solution was stirred for 14 h at 30°C. Upon completion, it was concentrated to give the residue, then it was extracted with a solution (PE/EtOAc = 1/1), the aqueous phase was separated and adjusted to pH 2 with aq. KHSO4. Then the aqueous phase was extracted with EtOAc (20 ml_ x 2), the organic layers were collected, dried over Na2SC>4, filtered and concentrated to give the crude product. The crude product was purified by prep-HPLC to give (1R,3S,5S)- 5- ((benzyloxy)methyl)-2-(te/f-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (150 mg) as a white solid and (7S,3S,5F?)-5-((benzyloxy)methyl)-2-(te/f-butoxycarbonyl)-2- azabicyclo[3.1.0]hexane-3-carboxylic acid (80 mg) as a yellow oil. m/z ES+ [M+H]⁺ 248.0; ¹H NMR (400 MHz, CDCh) d ppm 7.36-7.28 (m, 5H), 4.57-4.48 (m, 2H), 4.15 (s, 1H), 3.53-3.27 (m, 3H), 2.70-2.30 (m, 2H), 1.46 (s, 9H), 0.97-0.90 (m, 1H), 0.80-0.70 (m, 1 H).

Step c. A mixture of (7 ,3S,5S)-5-((benzyloxy)methyl)-2-(te/f-butoxycarbonyl)-2- azabicyclo[3.1.0]hexane-3-carboxylic acid (500 mg, 1.44 mmol), /V-methoxymethanamine (210 mg, 2.16 mmol, HCI), DIPEA (558 mg, 4.32 mmol) and HATU (711 mg, 1.87 mmol) in DMF (5 ml_) was stirred at rt for 2 h. On completion, the reaction mixture was quenched by addition NH4CI (aq, 25 ml_), then diluted with water (100 ml_) and extracted with EtOAc (150 ml_ x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc = 10/1 to 3/1) to give (1R,3S,5S)-tert- butyl 5- ((benzyloxy)methyl)-3-(methoxy(methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 89% yield) as a brown oil.

Step d. To a solution of (1 R,3S,5S)-tert- butyl 5-((benzyloxy)methyl)-3- (methoxy(methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (670 mg, 1.72 mmol) in THF (10 ml_) was added DIBAL-H (1 M, 5.15 ml_) slowly at -78°C. The mixture was stirred at -78°C for 2 h. On completion, the reaction mixture was quenched by addition of MeOH (230 ml_) at -78°C, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc = 10/1 to 5/1) to give ( 1R,3S,5S )- tert- butyl 5-((benzyloxy)methyl)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (470 mg, 83% yield) as a brown oil.

Step e. A mixture of (1 R,3S,5S)-tert- butyl 5-((benzyloxy)methyl)-3-formyl-2- azabicyclo[3.1.0]hexane-2-carboxylate (470 mg, 1.42 mmol), glyoxal (1.03 g, 7.09 mmol), ammonium hydroxide (1.74 g, 9.93 mmol, 20% aq.) in MeOH (5 ml_) was stirred at rt for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc = 2/1 to 1/3) to give (1R,3S,5S)-te/f-butyl 5- ((benzyloxy)methyl)-3-(7/-/-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (270 mg, 39% yield) as a brown solid.

Step f. A mixture of (1R,3S,5S)-tert- butyl 5-((benzyloxy)methyl)-3-(7/-/-imidazol-2-yl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (250 mg, 0.68 mmol), 2-chloro-1-fluoro-4- iodobenzene (521 mg, 2.03 mmol), Cul (64 mg, 0.34 mmol), CsF (411 mg, 2.71 mmol) and quinolin-8-ol (98 mg, 0.68 mmol) in DMSO (10 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 100°C for 12 h under N2 atmosphere. On completion, NH₄CI (aq, 60 ml_) was added to the reaction mixture and then diluted with water (100 ml_), extracted with EtOAc (100 ml_ ^c 3). The organic phase was separated, washed with brine (90 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep- HPLC to give (1 R,3S,5S)-tert- butyl 5-((benzyloxy)methyl)-3-(1-(3-chloro-4-fluorophenyl)-7/-/- imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (100 mg, 19% yield) as a brown solid.

Step g. (1R,3S,5S)-tert- butyl 5-((benzyloxy)methyl)-3-(1-(3-chloro-4-fluorophenyl)-7/-/- imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (100 g, 0.20 mmol) in HCI/dioxane (4 M, 5 ml_) was stirred at rt for 2 h. On completion, the reaction mixture was concentrated in vacuo to afford (7 ,3S,5S)-5-((benzyloxy)methyl)-3-(1-(3-chloro-4-fluorophenyl)-7/-/- imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (87 mg, crude, HCI) as a brown solid.

Step h. A mixture of (7 ,3S,5S)-5-((benzyloxy)methyl)-3-(1-(3-chloro-4-fluorophenyl)-7/-/- imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (87 mg, 0.20 mmol, HCI), 2-chloro-6-methyl-4- (trifluoromethyl)nicotinonitrile (66 mg, 0.30 mmol) and DIPEA (78 mg, 0.60 mmol) in NMP (5 ml_) was stirred at 60°C for 12 h. On completion, the reaction mixture was diluted with water (100 ml_) and then extracted with EtOAc (100 ml_ ^c 3). The organic phase was separated, washed with brine (90 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by silica gel column chromatography (PE/EtOAc = 5/1 to 3/1) to afford 2-((1R,3S,5S)-5- ((benzyloxy)methyl)-3-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-2- azabicyclo[3.1.0]hexan-2-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile (70 mg, 77% yield) as a brown solid.

Step i. To a solution of 2-((7 ,3S,5S)-5-((benzyloxy)methyl)-3-(1-(3-chloro-4-fluorophenyl)- 7/-/-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile (70 mg, 0.12 mmol) in DCM (5 ml_) was added BCh (1 M in toluene, 1.2 ml_) dropwise at 0°C. The mixture was stirred at 0°C for 15 min. On completion, the reaction mixture was quenched by NaOH (10 ml_, 15%) at rt, and then diluted with water (20 ml_), extracted with DCM (50 ml_ ^c 3). The combined organic layers were washed with brine (60 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep-HPLC and the desired stereoisomer was isolated by further purification using prep chiral SFC (column: DAICEL CHIRALCEL OD, 250mm x 30mm, 10pm) to give the title compound (17 mg, 25% yield) as a yellow solid. m/z ES+ [M+H]⁺ 492.0; ¹H NMR (400 MHz, CD₃OD) d ppm 7.69 - 7.58 (m, 1H), 7.50 - 7.38 (m, 2H), 7.24 (s, 1H), 7.09 (s, 1H), 6.95 (s, 1H), 5.59-5.56 (m, 1 H), 3.94-3.93 (m, 1 H), 3.71 (d, J = 11.6 Hz, 1 H) , 3.61 (d, J = 11.6 Hz, 1 H), 2.52 - 2.39 (m, 2H), 2.30 (s, 3H), 1.20 - 1.16 (m, 1 H), 0.95-0.93 (m, 1 H).

Example 40

N-((3S,5S)-1-(3-Cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(1-(5-fluoro-6-methyl- pyridin-2-yl)-7H-imidazol-2-yl)pyrrolidin-3-yl)acetamide

Step a. To a solution of (2S,4S)- 1-te/f-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (5.00 g, 17.8 mmol, HCI) and Na2CC>3 (5.66 g, 53.4 mmol) in a mixed solvent of dioxane (80 ml_) and water (40 ml_) was added benzyl chloroformate (3.34 g, 19.6 mmol) dropwise at 0°C. The reaction mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (40 ml_), extracted into EtOAc (100 ml_), dried over Na2SC>4 and evaporated to give (2S,4S)-1-te/f-butyl 2-methyl 4- (((benzyloxy)carbonyl)-amino)pyrrolidine-1,2-dicarboxylate (6.7 g, 99% yield) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6) d ppm 7.55 - 7.45 (m, 1 H), 7.40 - 7.28 (m, 5H), 5.10 - 4.95 (m, 2H), 4.19 (t, J = 8.0 Hz, 1 H), 4.12 - 4.03 (m, 1 H), 3.72 - 3.58 (m, 4H), 3.07 (t, J = 9.2 Hz, 1 H), 2.48 - 2.39 (m, 1H), 1.86 - 1.68 (m, 1H), 1.45 - 1.26 (m, 9H). Step b. To a solution of (2S,4S)- 1 -te/f-butyl 2-methyl 4-(((benzyloxy)carbonyl)amino)- pyrrolidine-1,2-dicarboxylate (6.00 g, 15.90 mmol) in THF (100 mL) was added DIBAL-H (1 M, 47.6 mL) dropwise at -70°C. The reaction mixture was stirred at -70°C for 1 h. Upon completion, the reaction was slowly quenched with MeOH (100 mL) at -65°C. The quenched reaction was warmed to rt, stirred for a further 30 min and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc = 1/1) to give (2S,4S)-te/f-butyl 4-(((benzyloxy)carbonyl)amino)-2-formylpyrrolidine-1- carboxylate (2.4 g, 43% yield) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6) d ppm 9.52 - 9.36 (m, 1 H), 7.67 - 7.49 (m, 1 H), 7.43 - 7.24 (m, 5H), 5.01 (s, 2H), 4.11 - 3.96 (m, 2H), 3.67 - 3.55 (m, 1H), 3.27 - 3.17 (m, 1 H), 2.38 - 2.20 (m, 1 H), 1.94 - 1.78 (m, 1H), 1.46 - 1.28 (m, 9H).

Step c. A mixture of (2S,4S)-te/f-butyl 4-(((benzyloxy)carbonyl)amino)-2-formylpyrrolidine-1- carboxylate (2.30 g, 6.60 mmol), glyoxal (4.79 g, 33.0 mmol) and ammonium hydroxide (5.55 g, 39.6 mmol, 25% aq.) in MeOH (20 mL) was stirred at rt for 12 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (40 mL), extracted into EtOAc (3 x 40 mL), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (PE/EtOAc = 1/1) to give (2S,4S)-te/f-butyl 4- (((benzyloxy)-carbonyl)amino)-2-(7/-/-imidazol-2-yl)pyrrolidine-1-carboxylate (1.5 g, 59% yield) as a colorless oil. m/z ES+ [M+H]⁺ 387.2.

Step d. A mixture of (2S,4S)-te/f-butyl 4-(((benzyloxy)carbonyl)amino)-2-(7/-/-imidazol-2- yl)pyrrolidine-1-carboxylate (1.40 g, 3.62 mmol), 6-bromo-3-fluoro-2-methyl-pyridine (1.38 g, 7.25 mmol), K2CO3 (1.50 g, 10.9 mmol), -proline (834 mg, 7.25 mmol) and Cul (690 mg, 3.62 mmol) in DMSO (10 mL) was stirred at 120°C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was diluted with water (50 mL) and filtered. The filtrate was extracted with EtOAc (50 mL x 3). The combined organic layer was dried over Na₂S0₄ and evaporated. The residue was purified by prep-HPLC to give (2S,4S)-te/f-butyl 4- (((benzyloxy)carbonyl)amino)-2-(1-(5-fluoro-6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)- pyrrolidine-1 -carboxylate (160 mg, 6% yield) as a brown solid m/z ES+ [M+H]⁺ 496.3

Step e. A mixture of (2S,4S)-te/f-butyl 4-(((benzyloxy)carbonyl)amino)-2-(1-(5-fluoro-6- methylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidine-1 -carboxylate (160 mg, 0.23 mmol) in HCI/dioxane (4 M, 3.55 mL) was stirred at rt for 30 min. Upon completion, the reaction mixture was concentrated in vacuo to give benzyl ((3S,5S)-5-(1-(5-fluoro-6-methylpyridin-2- yl)-7/-/-imidazol-2-yl)pyrrolidin-3-yl)carbamate (90 mg, 91% yield, HCI salt) as a white solid which was used in the next step directly m/z ES+ [M+H]⁺ 396.2 Step f. A mixture of benzyl ((3S, 5S)-5-(1-(5-fluoro-6-methylpyridin-2-yl)-7/-/-imidazol-2- yl)pyrrolidin-3-yl)carbamate (90 g, 0.21 mmol, HCI salt), 2-chloro-6-methyl-4- (trifluoromethyl)-pyridine-3-carbonitrile (55 mg, 0.25 mmol) and DIPEA (135 mg, 1.04 mmol) in NMP (5 ml_) was stirred at 60°C for 12 h. Upon completion, the reaction mixture was diluted with water (30 ml_), extracted into EtOAc (3 x 30 ml_), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (PE/EtOAc = 1/1) to give benzyl ((3S,5S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(1-(5-fluoro-6- methylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidin-3-yl)carbamate (100 mg, 82% yield) as a yellow solid m/z ES+ [M+H]⁺ 580.3

Step g. To a solution of benzyl ((3S,5S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)- 5-(1-(5-fluoro-6-methylpyridin-2-yl)-7/-/-imidazol-2-yl)pyrrolidin-3-yl)carbamate (80 mg, 0.14 mmol) in THF (5 ml_) was added Pd/C (10 mg, 10% loading). The reaction mixture was stirred at rt for 1 h under hydrogen atmosphere (15 psi). Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE/EtOAc = 1/1) to give 2-((2S,4S)-4-amino-2-(1-(5-fluoro-6-methylpyridin-2-yl)-7/-/- imidazol-2-yl)pyrrolidin-1-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile (50 mg, 81% yield) as a yellow solid.

Step h. To a solution of 2-((2S,4S)-4-amino-2-(1-(5-fluoro-6-methylpyridin-2-yl)-7/-/-imidazol- 2-yl)pyrrolidin-1-yl)-6-methyl-4-(trifluoromethyl)nicotinonitrile (15 mg, 0.034 mmol) and TEA (7 mg, 0.067 mmol) in DCM (2 ml_) was added acetyl chloride (3 mg, 0.037 mmol). The reaction mixture was stirred at rt for 2 h. Upon completion, the reaction mixture was concentrated and the crude product purified by prep-HPLC to give the title compound (7 mg, 42% yield) as a yellow solid. m/z ES+ [M+H]⁺ 488.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.44 (d, J = 7.2 Hz, 1 H), 7.91 (t, J = 8.8 Hz, 1 H), 7.50 (dd, J = 3.2, 8.8 Hz, 1 H), 7.44 (d, J = 1.2 Hz, 1 H), 6.97 - 6.88 (m, 2H), 5.64 (t, J= 8.0 Hz, 1 H), 4.50 - 4.36 (m, 1 H), 4.20 - 4.10 (m, 1H), 3.81 - 3.69 (m, 1 H), 2.86 - 2.73 (m, 1 H), 2.53 - 2.51 (m, 3H), 2.22 - 2.11 (m, 1 H), 2.08 (s, 3H), 1.85 (s, 3H).

Example 41

(R)-4-(1-(3-Chloro-4-fluorophenyl)-7H-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)- pyridin-2-yl)oxazolidin-2-one

Step a. To a solution of imidazole (14.0 g, 206 mmol) in DMSO (300 ml_) was added 2- chloro-1-fluoro-4-iodobenzene (79.1 g, 308 mmol), Cul (19.6 g, 103 mmol), CsF (93.7 g, 617 mmol, 22.8 ml_) and quinolin-8-ol (29.9 g, 206 mmol) under a N2 atmosphere. The mixture was stirred at 100°C for 12 h. On completion, the reaction mixture was diluted with water

(300 ml_) and extracted with EtOAc (3 x 300 ml_). The combined organic layers were washed with brine (900 ml_ x 2), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (50-66% EtOAc in PE) to give 1-(3- chloro-4-fluoro-phenyl)imidazole (11.0 g, 27%) as a black-green solid. Step b. To a solution of 1-(3-chloro-4-fluoro-phenyl)imidazole (816 mg, 4.15 mmol) in THF (10 ml_) was added LDA (2 M in THF/heptane/ethylbenzene, 3.1 ml_, 6.2 mmol) at -78°C under a N2 atmosphere and the reaction mixture was stirred for 30 min. A solution of (R)-N- (2-((te/f-butyldiphenylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (CAS Number 1029701-59-4, prepared as described in J. Am. Chem. Soc. 2008, 130, 6910-6911; 2.00 g, 4.98 mmol) in THF (10 ml_) was added dropwise at -78°C, then the reaction mixture was warmed to rt and stirred for 12 h. On completion, the reaction was quenched with the addition of sat. aq. NhUCI (30 ml_) and extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (2 x 90 ml_), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (25-50% EtOAc in PE) to give (F?)-A/-((F?)-2-((te/f-butyldiphenylsilyl)oxy)-1-(1-(3-chloro-4-fluorophenyl)- 7/-/-imidazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (1.20 g, 34%) as a yellow oil.

Step c. A solution of (F?)-A/-((F?)-2-((te/f-butyldiphenylsilyl)oxy)-1-(1-(3-chloro-4-fluorophenyl)- 7/-/-imidazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 0.70 mmol) in HCI/dioxane (4 M, 6 ml_) was stirred at rt for 1 h. On completion, the reaction mixture was concentrated in vacuo, diluted with water (30 ml_) and extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (2 x 90 ml_), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give (F?)-2-((te/f-butyldiphenylsilyl)oxy)-1-(1-(3-chloro-4- fluorophenyl)-7/-/-imidazol-2-yl)ethanamine (0.8 g, crude) as a yellow oil which was used without further purification.

Step d. To a solution of (F?)-2-((te/f-butyldiphenylsilyl)oxy)-1-(1-(3-chloro-4-fluorophenyl)-7/-/- imidazol-2-yl)ethanamine (200 mg, 0.24 mmol) in THF (2 ml_) was added tetramethylammonium fluoride (57 mg, 0.61 mmol) at rt and stirred for 4 h. On completion, the reaction mixture was concentrated in vacuo. The resulting residue was was purified by column chromatography (0-10% EtOH in EtOAc) to give (F?)-2-amino-2-(1-(3-chloro-4- fluorophenyl)-7/-/-imidazol-2-yl)ethanol (50 mg, 81%) as a yellow oil.

Step e. A solution of (F?)-2-amino-2-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)ethanol (20 mg, 0.078 mmol), K2CO3 (12 mg, 0.086 mmol) and KHCO3 (9 mg, 0.086 mmol) in water (0.5 ml_) was stirred at rt for 30 min. To the mixture was added a solution of triphosgene (12 mg, 0.039 mmol) in toluene (0.5 ml_) at 0°C and the mixture was stirred at rt for 2 h. On completion, the reaction mixture was diluted with water (5 ml_) and extracted with EtOAc (3 x 5 ml_). The combined organic layers were washed with brine (2 x 10 ml_), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The crude product was purified by prep-TLC (100% EtOAc) to give (F?)-4-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2- yl)oxazolidin-2-one (20 mg, 91%) as a colorless oil.

Step f. To the solution of (F?)-4-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)oxazolidin-2- one (40 mg, 0.14 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (51 mg, 0.21 mmol), CS2CO3 (93 mg, 0.28 mmol) and XantPhos (16 mg, 0.028 mmol) in dioxane (0.5 ml_) was added Pd2(dba)3 (13 mg, 0.014 mmol) and the mixture was stirred at 80°C for 4 h under a N2 atmophere. On completion, the mixture was filtered, diluted with water (5 ml_) and extracted with EtOAc (3 x 5 ml_). The combined organic layers were washed with brine (2 x 10 ml_), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in PE) and prep-HPLC to give the title compound (19 mg, 30%) as a yellow gum. m/z ES+ [M+H]⁺ 441.0; ¹H NMR (400MHz, DMSO-d6) d ppm 8.14 (s, 1H), 7.93 (dd, J= 6.8, 2.8 Hz, 1 H), 7.72 - 7.62 (m, 2H), 7.38 (d, J = 1.2 Hz, 1 H), 7.32 (s, 1 H), 6.96 (s, 1 H), 5.77 (dd, J= 8.8, 3.2 Hz, 1H), 4.72 (t, J= 8.8 Hz, 1H), 4.53 (dd, J= 8.8, 3.2 Hz, 1 H), 2.30 (s, 3H). Example 42

(R)-4-(1-(3-Chloro-4-fluorophenyl)-4-fluoro-1H-imidazol-2-yl)-3-(6-methyl-4-

(trifluoromethyl)pyridin-2-yl)oxazolidin-2-one

Step a. To a solution of (3-chloro-4-fluorophenyl)boronic acid (1.22 g, 7.0 mmol), 4-fluoro- 7 /-/-imidazole (500 mg, 5.8 mmol), pyridine (1.38 g, 17.4 mmol) in DCM (10 ml_) was added

CU(OAC)2 (211 mg, 1.2 mmol). The mixture was degassed and purged with O2 3 times and then stirred at rt for 12 h under oxygen atmosphere. Upon completion, the mixture was diluted with water (100 ml_) and extracted with EtOAc (3 x 100 ml_). The combined organic layers were washed with brine (80 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (10% EtOAc in PE) to give 1-(3-chloro-4- fluorophenyl)-4-fluoro-7/-/-imidazole (1 g, 86%) as a white solid m/z ES+ [M+H]⁺ 215.0

Steps b-f. Conducted in a similar manner to Example 41, steps b-f. m/z ES+ [M+H]⁺ 459.0; ¹H NMR (400 MHz, CD₃OD) d ppm 8.25 (s, 1H), 7.87 (dd, J= 2.4, 6.4 Hz, 1 H), 7.65 - 7.58 (m, 1 H), 7.55 - 7.49 (m, 1 H), 7.23 (s, 1 H), 6.95 (d, J = 8.0 Hz, 1 H),

5.90 - 5.82 (m, 1 H), 4.76 (t, J = 8.8 Hz, 1 H), 4.53 (dd, J = 4.4, 8.8 Hz, 1 H), 2.43 (s, 3H). Example 43

(R)-4-(4-Chloro-1-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)-3-(6-methyl-4-

(trifluoromethyl)pyridin-2-yl)oxazolidin-2-one

Step a. A mixture of 4-chloro- 7/-/-imidazole (1.00 g, 9.8 mmol), (3-chloro-4-fluorophenyl)- boronic acid (2.04 g, 11.7 mmol), pyridine (2.31 g, 29.3 mmol) and Cu(OAc)2 (354 mg, 2.0 mmol) in DCM (50 ml_) was degassed and purged with O23 times, and then stirred at rt for 12 h under O2 atmosphere. Upon completion, ammonium hydroxide (30% aq., 10 ml_) was added into the reactiom mixture, and stirring continued for 10 min at rt. The reaction mixture was diluted with water (30 ml_) and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated in vacuo. The residue was purified by prep-HPLC to give 4-chloro-1-(3-chloro-4-fluorophenyl)-7/-/-imidazole (0.25 g, 11%) as a white solid m/z ES+ [M+H]⁺ 230.9 Steps b-f. Conducted in a similar manner to Example 41 steps b-f. m/z ES+ [M+H]⁺ 475.0; ¹H NMR (400 MHz, CD₃OD) d ppm 8.25 (s, 1H), 7.84 (dd, J= 2.4,

6.4 Hz, 1 H), 7.61 - 7.57 (m, 1 H), 7.51 (t, J = 8.4 Hz, 1 H), 7.31 (s, 1 H), 7.23 (s, 1 H), 5.88 (dd, J = 4.4, 9.2 Hz, 1H), 4.76 (t, J= 9.2 Hz, 1H), 4.53 (dd, J= 4.8, 8.8 Hz, 1 H), 2.43 (s, 3H).

Example 44

(R)-4-(1-(3-Chloro-4-fluorophenyl)-5-methyl-1H-imidazol-2-yl)-3-(6-methyl-4-

(trifluoromethyl)pyridin-2-yl)oxazolidin-2-one

Step a. A mixture of (3-chloro-4-fluoro-phenyl)boronic acid (2 g, 11.5 mmol), 4-methyl- 1H imidazole (785 mg, 9.6 mmol), pyridine (1.51 g, 19.1 mmol), Cu(OAc)2 (1.74 g, 9.6 mmol) in DCM (30 ml_) was degassed and purged with O23 times, and then stirred at rt for 12 h under O2 atmosphere. On completion, the reaction mixture was diluted with ammonium hydroxide (30% aq., 50 ml_) and water (50 ml_). The mixture was filtered, and the filtrate was extracted with DCM (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (10-50% EtOAc in PE) to give 1-(3-chloro-4-fluorophenyl)-5-methyl-7/-/- imidazole (800 mg, 40%) as a white solid m/z ES+ [M+H]⁺ 211.0 Steps b-f. Conducted in a similar manner to Example 41 steps b-f. m/z ES+ [M+H]⁺ 455.1; ¹H NMR (400 MHz, CD₃OD) d ppm 8.28 (s, 1H), 7.85 (dd, J = 2.4,

6.4 Hz, 1 H), 7.69 - 7.64 (m, 1 H), 7.64 - 7.58 (m, 1 H), 7.57 (s, 1 H), 7.35 (s, 1 H), 6.06 (dd, J = 5.2, 9.6 Hz, 1 H), 4.95 - 4.90 (m, 1 H), 4.83 - 4.77 (m, 1H), 2.46 (s, 3H), 2.40 (m, 3H).

Example 45

(R)-4-(1-(3-Chloro-2,4-difluorophenyl)-1H-imidazol-2-yl)-3-(6-methyl-4-

(trifluoromethyl)pyridin-2-yl)oxazolidin-2-one

Steps a-c (One-pot). A solution of 3-chloro-2,4-difluoro-aniline (500 mg, 3.06 mmol), glyoxal (444 mg, 3.06 mmol) in MeOH (5 ml_) was stirred at rt for 12 h. Then NhUCI (327 mg, 6.11 mmol) was added, followed by formaldehyde (496 mg, 6.11 mmol). The mixture was diluted with MeOH (20 ml_) and then stirred at 70°C for 1 h. Phosphoric acid (705 mg, 6.11 mmol) was added slowly and the mixture was stirred at 70°C for 4 h. On completion, the reaction mixture was concentrated under vacuum. Then ice-cold water (30 ml_) was added followed by aq. KOH solution (40% w/w) to adjust to pH 9. The mixture was then extracted with EtOAc (3 x 40 ml_). The combined organic layers were washed with brine (2 x 120 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (30-50% EtOAc in PE) to afford 1-(3-chloro-2,4-difluorophenyl)-7/-/- imidazole (620 mg, 94%) as a white solid.

¹H NMR (400 MHz, DMSO-d6) d ppm 8.04 (s, 1H), 7.76 - 7.70 (m, 1 H), 7.58 (s, 1 H), 7.55 - 7.50 (m, 1 H), 7.14 (s, 1 H).

Steps d-h. Conducted in a similar manner to Example 41 steps b-f. m/z ES+ [M+H]⁺ 459.2; ¹H NMR (400 MHz, CD₃OD) d ppm 8.19 (s, 1H), 7.70 - 7.61 (m, 1H), 7.41 - 7.36 (m, 1H), 7.26 (s, 1H), 7.16 (s, 1 H), 7.08 (d, J = 1.6 Hz, 1 H), 5.85 - 5.81 (m, 1 H),

4.80 - 4.78 (m, 1H), 4.51 - 4.48 (m, 1H), 2.33 (s, 3H). Example 46

(4R,5S)-4-(1-(3-Chloro-4-fluorophenyl)-1H-imidazol-2-yl)-5-(hydroxymethyl)-3-(6- methyl-4-(trifluoromethyl)pyridin-2-yl)oxazolidin-2-one

Step a. To a solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (2.00 g, 15.4 mmol) and (R)-2-methylpropane-2-sulfinamide (2.24 g, 18.4 mmol) in THF (50 ml_) was added Ti(OEt)4 (10.5 g, 46.1 mmol). The reaction mixture was stirred at 15°C for 12 h. Upon completion, the reaction mixture was quenched with EtOAc (100 ml_) and water (30 ml_).

The mixture was filtered and concentrated in vacuo. The residue was diluted with water (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (100 ml_), dried over Na₂S0₄, filtered and concentrated in vacuo. Purification by column chromatography (0-30% EtOAc in PE) gave (R)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4- yl)methylene)-2-methylpropane-2-sulfinamide (1.82 g, 48%) as a colorless oil.

¹H NMR (400 MHz, CDCh) d ppm 8.08 - 8.00 (m, 1H), 4.84 (t, = 4.4 Hz, 1 H), 4.30 - 4.20 (m, 1 H), 4.07 - 3.98 (m, 1 H), 1.48 (s, 3H), 1.46 (s, 3H), 1.30 - 1.24 (m, 9H).

Step b. To a solution of 1-(3-chloro-4-fluorophenyl)-7/-/-imidazole (1.01 g, 5.14 mmol) in THF (20 ml_) was added a solution of LDA (2 M in THF, 6.18 mmol) dropwise at -78°C. The mixture was stirred at -78°C for 30 min before a solution of (R)-N-(((S)-2,2-dimethyl-1,3- dioxolan-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.20 g, 5.14 mmol) in THF (5 ml_) was added dropwise and the mixture was stirred at -78°C for another 2.5 h. Upon completion, the reaction mixture was quenched with sat. aq. NhUCI (5 ml_), then diluted with water (50 ml_) and extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na2SC>4 and concentrated in vacuo. The residue was purified by prep-HPLC to give (R)-N-((R)-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)((S)- 2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl)-2-methylpropane-2-sulfinamide (0.71 g, 31%) as a white solid. m/z ES+ [M+H]⁺ 430.0; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.87 (dd, J= 6.8, 2.4 Hz, 1 H), 7.64 (t, J = 8.8 Hz, 1 H), 7.58 - 7.53 (m, 1 H), 7.37 (s, 1 H), 7.07 (s, 1 H), 5.58 (d, J = 6.8 Hz,

1 H), 4.49 (dd, J= 13.2, 6.4 Hz, 1 H), 4.39 (t, J = 6.8 Hz, 1 H), 3.91 (d, = 6.4 Hz, 1H), 1.22 (s, 3H), 1.08 (s, 3H), 1.05 (s, 9H).

Step c. A mixture of (R)-N-((R)-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)((S)-2,2- dimethyl-1 ,3-dioxolan-4-yl)methyl)-2-methylpropane-2-sulfinamide (0.5 g, 1.16 mmol) in HCI/MeOH (4 M, 6 ml_) was stirred at rt for 0.5 h. Upon completion, the reaction mixture was concentrated in vacuo to give (2S,3R)-3-amino-3-(1-(3-chloro-4-fluorophenyl)-1 H-imidazol-2- yl)propane-1 ,2-diol (0.37 g, crude, HCI) as a white solid, which was used in the next step without further purification.

Step d. To a solution of (2S,3R)-3-amino-3-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2- yl)propane-1,2-diol (0.3 g, 0.93 mmol, HCI) in DCM (10 ml_) was added TEA (471 mg, 4.66 mmol). Then TBDPSCI (307 mg, 1.12 mmol) in DCM (3 ml_) was added at 0°C, and the mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give (1R,2S)-1-amino-3-((tert- butyldiphenylsilyl)oxy)-1-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)propan-2-ol (0.25 g, 49%) as a white solid m/z ES+ [M+H]⁺ 524.2

Step e. To a solution of (1R,2S)-1-amino-3-((tert-butyldiphenylsilyl)oxy)-1-(1-(3-chloro-4- fluorophenyl)-7/-/-imidazol-2-yl)propan-2-ol (0.2 g, 0.38 mmol) in water (1.5 mL) was added K2CO3 (60.1 mg, 0.44 mmol) and KHCO3 (44.3 mg, 0.44 mmol). The mixture was stirred at 15°C for 0.5 h. A solution of triphosgene (60 mg, 0.20 mmol) in toluene (1.5 mL) was added at 0°C, and the reaction mixture was stirred at 15°C for 1.5 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (25-100% EtOAc in PE) to afford (4R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(1-(3- chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)oxazolidin-2-one (0.15 g, 64%) as a white solid m/z ES+ [M+H]⁺ 550.2; ¹H NMR (400 MHz, CDCI₃) d ppm 7.59 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.48 - 7.40 (m, 2H), 7.39 - 7.35 (m, 5H), 7.25 - 7.13 (m, 3H), 7.06 (s, 1 H), 5.75 (s, 1 H), 5.10 - 5.06 (m, 1 H), 5.02 (d, J = 5.2 Hz, 1 H), 3.91 (dd, J = 11.6, 3.2 Hz, 1H), 3.68 (d, J = 11.6 Hz, 1H), 1.00 (s, 9H).

Step f. A mixture of (4R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(1-(3-chloro-4- fluorophenyl)-7/-/-imidazol-2-yl)oxazolidin-2-one (70 g, 0.13 mmol), 2-bromo-6-methyl-4- (trifluoromethyl)pyridine (45.8 mg, 0.19 mmol), Pd2(dba)3 (5.8 mg, 0.0065 mmol), XantPhos (5.9 mg, 0.01 mmol) and K₂CO₃ (35.2 mg, 0.26 mmol) in dioxane (2 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 100°C for 1 h under N2 atmosphere. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (10-100% EtOAc in PE then 0-50% MeOH in EtOAc) to afford (4R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(1-(3-chloro-4- fluorophenyl)-7/-/-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)oxazolidin-2-one (80 mg, crude) as a yellow oil which was used without further purification m/z ES+ [M+H]⁺ 709.2

Step g. To a solution of (4R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(1-(3-chloro-4- fluorophenyl)-7/-/-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)oxazolidin-2-one (70 mg, 0.099 mmol) in THF (2 ml_) was added TBAF (1 M, 0.49 mmol). The reaction was stirred at rt for 12 h. Upon completion, the reaction mixture was diluted with water (5 ml_) and extracted with EtOAc (3 x 5 ml_). The combined organic layers were washed with brine (5 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (10 mg, 18%) as a brown solid. m/z ES+ [M+H]⁺ 471.1; ¹H NMR (400 MHz, CD₃OD) d ppm 8.26 (s, 1H), 7.85 - 7.81 (m, 2H),

7.75 (d, J = 2.0 Hz, 1 H), 7.72 - 7.67 (m, 1 H), 7.65 - 7.58 (m, 1 H), 7.35 (s, 1 H), 5.95 (d, J = 4.4 Hz, 1 H), 5.03 (q, J = 3.6 Hz, 1 H), 3.87 (dd, J = 12.4, 3.6 Hz, 1H), 3.68 (dd, J = 12.4, 2.8 Hz, 1H), 2.47 (s, 3H).

Example 47

Rel-(3R,4R,5R)-5-(1-(3-Chloro-4-fluorophenyl)-1H-imidazol-2-yl)-4-hydroxy-3,4- dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one Example 48

Rel-(3S,4R,5R)-5-(1-(3-Chloro-4-fluorophenyl)-1H-imidazol-2-yl)-4-hydroxy-3,4- dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one

Step a. To a solution of methyl 7/-/-imidazole-2-carboxylate (5.00 g, 39.7 mmol) and (3- chloro-4-fluoro-phenyl)boronic acid (7.60 g, 43.6 mmol) in DCM (80 ml_) and MeOH (80 ml_) was added Cu(0Ac)₂-H₂0 (792 mg, 3.96 mmol) and pyridine (6.27 g, 79.3 mmol). The mixture was stirred at rt for 12 h under O2 (15 psi). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with 25% EtOAc in PE (50 ml_) and filtered. The collected solid was dried under vacuum to afford methyl 1-(3-chloro-4-fluoro-phenyl)imidazole-2-carboxylate (5 g, 50%) as a white solid. ¹H NMR (400 MHz, CDC ) d ppm 7.46 - 7.41 (m, 1H), 7.31 (s, 1H), 7.29 - 7.23 (m, 2H),

7.19 (s, 1H), 3.88 (s, 3H).

Step b. To a solution of methyl 1-(3-chloro-4-fluoro-phenyl)imidazole-2-carboxylate (4.7 g, 18.5 mmol) in DCM (150 ml_) was added DIBAL-H (1 M, 55.4 mmol) dropwise at -78°C. The mixture was stirred at -78°C for 2 h. On completion, the reaction mixture was quenched with sat. aq. NH4CI solution (50 ml_) at -78°C, then warmed to rt and extracted with DCM (2 x 150 ml_). The combined organic layers were washed with brine (100 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was triturated with 50% EtOAc in PE (50 ml_) and filtered. The collected solid was dried under vacuum to give 1-(3-chloro-4-fluoro- phenyl)imidazole-2-carbaldehyde (2.7 g, 65%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) d ppm 9.69 (s, 1H), 7.94 - 7.88 (m, 1H), 7.83 (s, 1H), 7.63 - 7.57 (m, 2H), 7.45 (s, 1H).

Step c. To a solution of 1-(3-chloro-4-fluoro-phenyl)imidazole-2-carbaldehyde (1 g, 4.45 mmol) and (2,4-dimethoxyphenyl)methanamine (819 mg, 4.90 mmol) in DCM (15 ml_) was added molecular sieves (4 A, 0.5 g) and acetic acid (267 g, 4.45 mmol). The mixture was stirred at rt for 15 min and then cooled to 0°C. NaBH(OAc)3 (1.89 g, 8.90 mmol) was added and the mixture was stirred at rt for 1 h. On completion, the reaction mixture was quenched with MeOH (5 ml_) at 0°C, diluted with water (50 ml_) and extracted with DCM (3 x 30 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (20-100%

EtOAc in PE, then 0-20% MeOH in DCM) to give 1-(1-(3-chloro-4-fluorophenyl)-1 H-imidazol- 2-yl)-N-(2,4-dimethoxybenzyl)methanamine (1.3 g, 78%) as a brown oil. m/z ES+ [M+H]⁺ 376.0

Step d. To a solution of 2-methyl-3-oxo-butanoic acid (1.00 g, 8.61 mmol) and 1-(1-(3- chloro-4-fluorophenyl)-1 H-imidazol-2-yl)-N-(2,4-dimethoxybenzyl)methanamine (1.29 g, 3.44 mmol) in pyridine (20 ml_) was added T3P (16.4 g, 25.7 mmol, 50 wt.% in EtOAc). The mixture was stirred at rt for 12 h. On completion, the reaction mixture was diluted with water (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (2 x 50 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (20-100% EtOAc in PE) to give N-[[1-(3-chloro-4-fluoro- phenyl)imidazol-2-yl]methyl]-N-[(2,4-dimethoxyphenyl)methyl]-2-methyl-3-oxo-butanamide (950 mg, 23%) as a brown oil.

¹H NMR (400 MHz, CDCh) d ppm 7.33 - 7.28 (m, 1H), 7.25 - 7.20 (m, 1H), 7.20 - 7.18 (m,

1 H), 7.18 - 7.12 (m, 1H), 7.05 - 7.01 (m, 1 H), 6.92 - 6.86 (m, 2H), 6.39 - 6.33 (m, 2H), 4.71 - 4.26 (m, 4H), 3.74 - 3.68 (m, 6H), 3.61 (s, 1 H), 2.067 (s, 3H), 1.32 - 1.20 (m, 3H).

Step e. To a solution of N-[[1-(3-chloro-4-fluoro-phenyl)imidazol-2-yl]methyl]-N-[(2,4- dimethoxyphenyl)methyl]-2-methyl-3-oxo-butanamide (900 mg, 1.90 mmol) and di-te/f-butyl dicarbonate (829 mg, 3.80 mmol) in xylene (25 ml_) was added DIPEA (736 mg, 5.70 mmol). The mixture was stirred at 130°C for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (50 ml_) and extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (20-100% EtOAc in PE) to give tert- butyl [(2R,3R)-2-[1-(3-chloro-4-fluoro-phenyl)imidazol-2- yl]-1-[(2,4-dimethoxyphenyl)methyl]-3,4-dimethyl-5-oxo-pyrrolidin-3-yl] carbonate (530 mg, 49%) as a yellow solid.

¹H NMR (400 MHz, CDCh) d ppm 7.25 - 7.19 (m, 1H), 7.18 - 7.08 (m, 3H), 6.84 (s, 1 H),

6.54 - 6.48 (m, 1 H), 6.38 (d, J = 4.0 Hz, 1 H), 6.28 - 6.22 (m, 1 H), 4.68 (s, 1 H), 4.43 (d, J = 8.0 Hz, 1 H), 3.94 - 3.81 (m, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H), 1.30 (s, 9H). Step f. To a solution of tert- butyl [(2R,3R)-2-[1-(3-chloro-4-fluoro-phenyl)imidazol-2-yl]-1- [(2,4-dimethoxyphenyl)methyl]-3,4-dimethyl-5-oxo-pyrrolidin-3-yl] carbonate (350 mg, 0.61 mmol) in toluene (5 ml_) was added methanesulfonic acid (3 ml_). The mixture was stirred at 120°C for 2 h. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (20 ml_) and extracted with EtOAc (2 x 15 ml_). The organic layers were discarded, and the aqueous phase was adjusted to pH = 7~8 with sat. NaHCOs solution (20 ml_), which was further extracted with EtOAc (2 x 15 ml_). The combined organic layers were washed with brine (15 ml_), dried over Na2S04 and concentrated in vacuo to give compound (4R,5R)-5-[1-(3-chloro-4-fluoro-phenyl)imidazol-2-yl]-4-hydroxy-3, 4-dimethyl- pyrrolidin-2-one (200 mg, crude) as a yellow solid which was used without further purification.

¹H NMR (400 MHz, CDCh) d ppm 7.56 - 7.52 (m, 1H), 7.38 - 7.29 (m, 2H), 7.12 - 7.10 (m,

1 H), 7.06 - 6.99 (m, 2H), 4.88 (s, 1 H), 4.27 (d, J = 1.2 Hz, 1 H), 3.06 - 2.93 (m, 1 H), 1.29 (s, 3H), 1.14 (d, J = 8.0 Hz, 3H).

Step g. To a solution of (4R,5R)-5-[1-(3-chloro-4-fluoro-phenyl)imidazol-2-yl]-4-hydroxy-3,4- dimethyl-pyrrolidin-2-one (180 mg, 0.56 mmol) and 2-bromo-6-methyl-4-(trifluoromethyl)- pyridine (200 mg, 0.83 mmol) in dioxane (8 ml_) was added Pd2(dba)3 (50.9 mg, 0.056 mmol), XantPhos (64.3 mg, 0.11 mmol) and CS2CO3 (362 mg, 1.11 mmol). The mixture was stirred at 85°C for 2 h under N2. On completion, the reaction mixture was evaporated. The residue was diluted with water (15 ml) and extracted with EtOAc (3 x 10 ml_). The combined organic layers were washed with brine (10 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep-HPLC to give Example 47 (103 mg, 37% yield) as a white solid, m/z ES+ [M+H]⁺ 483.0; ¹H NMR (400 MHz, CD₃OD) d ppm 8.59 (s, 1H), 8.12 (dd, J= 6.4,

2.8 Hz, 1 H), 7.91 - 7.85 (m, 1 H), 7.77 (d, J = 4.0 Hz, 1 H), 7.65 (t, J = 8.4 Hz, 1 H), 7.59 - 7.53 (m, 1 H), 7.29 (s, 1 H), 5.53 (s, 1 H), 3.22 (q, J= 7.2 Hz, 1 H), 2.44 (s, 3H), 1.32 (s, 3H), 1.27 (d, J = 7.2 Hz, 3H) and Example 48 (16 mg, 6% yield) as a white solid, m/z ES+ [M+H]⁺ 483.0; ¹H NMR (400 MHz, CD₃OD) d ppm 8.43 (s, 1H), 8.22 - 8.10 (m, 1H), 7.93 - 7.85 (m, 1H), 7.80 (d, = 2.0 Hz, 1 H), 7.65 - 7.53 (m, 2H), 7.31 (s, 1H), 5.82 (s, 1 H), 2.83 (q, J = 7.2 Hz, 1 H), 2.42 (s, 3H), 1.28 (d, J = 7.2 Hz, 3H), 1.26 (s, 3H).

Example 49

Rel-(3R,4R,5R)-5-(1 -(1 H-pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)-4-hydroxy-3,4- dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one

Example 50 Rel-(3S,4R,5R)-5-(1 -(1 H-pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)-4-hydroxy-3,4- dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one

Step a. To a solution of 6-bromo-7/-/-pyrrolo[2,3-b]pyridine (2.7 g, 13.7 mmol) in DMF (50 ml_) was added NaH (60% dispersion in mineral oil, 822 mg, 20.6 mmol) portionwise at 0°C. The mixture was stirred at 0°C for 15 min before 2-(trimethylsilyl)ethoxymethyl chloride (3.43 g, 20.6 mmol) was added slowly and stirring continued at 0°C for 30 min. Upon completion, the reaction mixture was quenched with sat. aq. NhUCI (50 ml_) and then extracted with

EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (3 x 20 ml_), dried over Na2SC>4 and concentrated in vacuo. The residue was purified by column chromatography (0-3% EtOAc in PE) to give 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-7/-/- pyrrolo[2,3-b]pyridine (4.5 g, 96%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d6) d ppm 7.95 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 3.6 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 6.57 (d, J= 3.6 Hz, 1 H), 5.57 (s, 2H), 3.54 - 3.45 (m, 2H), 0.86 - 0.79 (m, 2H), -0.12 (s, 9H).

Step b. A mixture of 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-b]pyridine (4.60 g, 13.4 mmol), imidazole (1.83 g, 26.9 mmol), Cul (1.28 g, 6.72 mmol), L-proline (1.55 g, 13.4 mmol) and CS2CO3 (13.1 g, 40.3 mmol) in DMSO (50 ml_) was degassed and purged with N2 3 times. The mixture was stirred at 120°C for 12 h under N2. Upon completion, the reaction mixture was quenched with sat. aq. NhUCI (50 ml_) and then extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (3 x 20 ml_), dried over Na2SC>4 and concentrated in vacuo. The residue was purified by reverse-phase column to give 6-(7/-/-imidazol-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-b]pyridine (3.3 g, 76%) as a white solid.

¹H NMR (400 MHz, DMSO-d6) d ppm 8.59 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 8.01 (s, 1H),

7.66 (d, J = 3.6 Hz, 1H), 7.57 (d, J= 8.4 Hz, 1H), 7.13 (s, 1H), 6.60 (d, J= 3.6 Hz, 1H), 5.66 (s, 2H), 3.54 (t, J = 8.00 Hz, 2H), 0.91 - 0.80 (m, 2H), -0.15 (s, 9H).

Step c. To a solution of 6-(7/-/-imidazol-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-7/-/- pyrrolo[2,3-b]pyridine (3.3 g, 10.5 mmol) in THF (50 ml_) was added a solution of n- butyllithium (2.5 M in hexane, 6.30 ml_) dropwise at 0°C. The mixture was stirred at 0°C for 30 min under N2. DMF (1.15 g, 15.7 mmol) was added, and the mixture was stirred at 0°C for 2 h. Upon completion, the reaction mixture was quenched with sat. aq. NH₄CI solution (10 ml_) and extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (3 x 10 ml_), dried over Na2S04 and evaporated to give 1-(1-((2- (trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazole-2-carbaldehyde (3.8 g, crude) as a brown oil which was used in the next step without further purification m/z ES+ [M+H]⁺ 343.0

Steps d-g. Conducted in a similar manner to Examples 47/48, steps c-f.

Step h. A solution of (4R,5R)-5-(1-(7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)-4- hydroxy-3,4-dimethylpyrrolidin-2-one (120 mg, 0.39 mmol), di-te/f-butyl dicarbonate (168 mg, 0.77 mmol) and TEA (117 mg, 1.16 mmol) in DCM (2 ml_) was stirred at rt for 2 h. Upon completion, the reaction mixture was quenched with water (5 ml_) and extracted with EtOAc (3 x 10 ml_). The combined organic layers were washed with brine (5 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep-TLC (10% EtOH in EtOAc) to give tert- butyl 6-(2-((2R,3R)-3-hydroxy-3,4-dimethyl-5-oxopyrrolidin-2-yl)-7/-/-imidazol-1-yl)- 7/-/-pyrrolo[2,3-b]pyridine-1-carboxylate (50 mg, 17%) as a yellow oil. m/z ES+ [M+H]⁺ 412.2

Step i. A solution of tert- butyl 6-(2-((2R,3R)-3-hydroxy-3,4-dimethyl-5-oxopyrrolidin-2-yl)-7/-/- imidazol-1-yl)-7/-/-pyrrolo[2,3-b]pyridine-1-carboxylate (45 mg, 0.11 mmol), 2-bromo-6- methyl-4-(trifluoromethyl)pyridine (39.5 mg, 0.16 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), XantPhos (13 mg, 0.022 mmol) and K₂CO₃ (30 mg, 0.22 mmol) in dioxane (2 ml_) was degassed and purged with N23 times. The mixture was stirred at 80°C for 2 h under N2.

Upon completion, the reaction mixture was quenched with water (5 ml_) and extracted with EtOAc (3 x 10 ml_). The combined organic layers were washed with brine (5 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep-TLC (100% EtOAc) to give tert- butyl 6-(2-((2R,3R)-3-hydroxy-3,4-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5- oxopyrrolidin-2-yl)-7/-/-imidazol-1-yl)-7/-/-pyrrolo[2,3-b]pyridine-1-carboxylate (25 mg, 40%) as a yellow oil. m/z ES+ [M+H]⁺ 571.2 Step j. A solution of tert- butyl 6-(2-((2R,3R)-3-hydroxy-3,4-dimethyl-1-(6-methyl-4-

(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidin-2-yl)-7/-/-imidazol-1-yl)-7/-/-pyrrolo[2,3-b]pyridine- 1-carboxylate (20 g, 0.018 mmol) in DCM (2 ml_) and TFA (0.04 ml_) was stirred at rt for 30 min. Upon completion, the reaction mixture was evaporated and the residue was purified by prep-HPLC to give Example 49 (4 mg, 24%) as a brown oil, m/z ES+ [M+H]⁺ 471.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 12.14 (s, 1 H), 8.44 (s, 1 H), 8.36 (d, J = 8.0 Hz, 1H), 8.07 (s, 1 H), 7.71 (t, J= 3.2 Hz, 1 H), 7.62 (d, J= 8.0 Hz, 1 H), 7.58 (s, 1H), 7.32 (s, 1 H), 6.66 (q, J= 1.6 Hz, 1 H), 5.88 (s, 1 H), 3.29 (q, J= 7.5 Hz, 1 H), 2.21 (s, 3H), 1.41 (s, 3H), 1.15 (d, J = 7.5 Hz, 3H). and Example 50 (0.5 mg, 3%) as a white solid. m/z ES+ [M+H]⁺ 471.1; ¹H NMR (400 MHz, CD₃OD) d ppm 8.40 (s, 1 H), 8.33 (d, J = 8.0 Hz, 1 H), 8.03 (s, 1 H), 7.70 - 7.64 (m, 1 H), 7.64 (d, J = 3.6 Hz, 1 H), 7.56 (s, 1 H), 7.22 (s, 1 H), 6.70 (d, J = 3.6 Hz, 1 H), 6.26 (s, 1 H), 2.89 (q, J = 6.8 Hz, 1 H), 2.31 (s, 3H), 1.58 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H). Example 51

Rel-(4R,5R)-5-(1-(3-Chloro-4-fluorophenyl)-1H-imidazol-2-yl)-4-hydroxy-4-

(hydroxymethyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one

Step a. To a solution of 1-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-N-(2,4- dimethoxybenzyl)methanamine (described in Example 47/48, steps a-c; 1.00 g, 2.66 mmol) and 4-(benzyloxy)-3-oxobutanoic acid (CAS Number 67354-37-4; 831 mg, 3.99 mmol) in pyridine (5 ml_) and DMF (5 ml_) was added T3P (5.08 g, 7.98 mmol, 50 wt.% in EtOAc). The reaction mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was diluted with water (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with water (2 x 50 ml_) and brine (50 ml_), dried over Na₂S0₄ and evaporated to give 4-(benzyloxy)-N-((1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)methyl)-N-(2,4- dimethoxybenzyl)-3-oxobutanamide (1.4 g, crude) as a brown oil, which was used without further purification m/z ES+ [M+H]⁺ 566.2

Step b. To a solution of 4-(benzyloxy)-N-((1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2- yl)methyl)-N-(2,4-dimethoxybenzyl)-3-oxobutanamide (0.70 g, 1.24 mmol) in xylene (30 ml_) was added di-te/f-butyl dicarbonate (1.35 g, 6.18 mmol). The mixture was stirred at 130°C for 12 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give (2R,3R)-3-((benzyloxy)methyl)-2-(1-(3-chloro-4-fluorophenyl)- 7/-/-imidazol-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-3-yl tert-butyl carbonate (80 mg, 9%) as a brown oil. m/z ES+ [M+H]⁺ 666.3

Step c. A solution of (2R,3R)-3-((benzyloxy)methyl)-2-(1-(3-chloro-4-fluorophenyl)-7/-/- imidazol-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-3-yl tert- butyl carbonate (80 mg, 0.12 mmol) in toluene (0.5 ml_) and methanesulfonic acid (0.3 ml_) was stirred at 120°C for 30 min. Upon completion, the reaction mixture was diluted with water (3 ml_) and extracted with EtOAc (3 x 5 ml_). The aqueous layer was quenched with 1 M NaOH solution to pH 9, and then extracted with EtOAc (3 x 5 ml_). The combined organic layers were washed with brine (5 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by reverse- phase column chromatography to give (4R,5R)-5-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2- yl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-2-one (21 mg, 51%) as a white solid. m/z ES+ [M+H]⁺ 326.0; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.16 (s, 1H), 7.87 - 7.80 (m,

1 H), 7.78 (s, 1 H), 7.60 - 7.55 ( , 1 H), 7.39 (s, 1 H), 7.08 (s, 1 H), 5.58 (s, 1 H), 5.04 (br s,

1 H), 4.53 (s, 1 H), 2.39 (d, = 16.4 Hz, 1H), 2.22 (d, J = 16.4 Hz, 1 H).

Step d. A mixture of (4R,5R)-5-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-4-hydroxy-4- (hydroxymethyl)pyrrolidin-2-one (20.0 mg, 0.061 mmol), 2-bromo-6-methyl-4-

(trifluoromethyl)pyridine (29.5 mg, 0.12 mmol), Pd2(dba)3 (5.6 mg, 0.006 mmol), XantPhos (7.1 mg, 0.012 mmol) and K₂CO₃ (25.5 mg, 0.18 mmol) in 1,4-dioxane (1 ml_) was degassed and purged with N23 times. The mixture was stirred at 100°C for 1 h under N2. Upon completion, the reaction mixture was evaporated, purified by column chromatography (10- 100% EtOAc in PE then 0-50% MeOH in EtOAc) and further purified by prep-HPLC to give the title compound (4 mg, 12%, HCI) as a yellow solid. m/z ES+ [M+H]⁺ 485.1; ¹H NMR (400 MHz, CD₃OD) d ppm 8.54 (s, 1H), 8.09 - 8.05 (m, 1H), 7.89 - 7.84 (m, 1 H), 7.82 (d, J = 2.0 Hz, 1 H), 7.67 (d, J = 2.0 Hz, 1 H), 7.61 (t, J = 8.8 Hz,

1 H), 7.33 (s, 1 H), 5.90 (s, 1 H), 3.58 - 3.53 (m, 1H), 3.51 - 3.47 (m, 1 H), 2.98 (s, 2H), 2.45 (s, 3H).

Example 52

Rel-(3R,4R,5R)-5-(1-(3-Chloro-4-fluorophenyl)-1H-imidazol-2-yl)-4-hydroxy-4- (hydroxymethyl)-3-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one Example 53

Rel-(3S,4R,5R)-5-(1-(3-Chloro-4-fluorophenyl)-1H-imidazol-2-yl)-4-hydroxy-4-

(hydroxymethyl)-3-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one

The title compounds were prepared in a similar manner to Example 51 , using 4-(benzyloxy)- 2-methyl-3-oxobutanoic acid (CAS Number 1035815-57-6, prepared as described in Org. Biomol. Chem. 2012, 10, 3472-3485) in step a and separated by prep-HPLC.

Example 52 m/z ES+ [M+H]⁺ 499.1; ¹H NMR (400 MHz, CD₃OD) d ppm 8.60 (s, 1H), 8.03 (dd, J = 2.8,

6.4 Hz, 1 H), 7.81 - 7.75 (m, 1H), 7.51 (t, J = 8.8 Hz, 1H), 7.29 (d, J = 1.2 Hz, 1 H), 7.15 (s, 1 H), 7.00 (d, J = 1.2 Hz, 1 H), 5.76 (s, 1 H), 3.65 - 3.55 (m, 2H), 3.50 (q, J = 7.2 Hz, 1 H), 2.38 (s, 3H), 1.26 (d, J= 7.2 Hz, 3H).

Example 53 m/z ES+ [M+H]⁺ 499.1; ¹H NMR (400 MHz, CD₃OD) d ppm 8.27 (s, 1H), 7.93 (dd, J= 2.4, 6.8 Hz, 1 H), 7.65 - 7.58 ( , 1 H), 7.38 (d, = 8.8 Hz, 1H), 7.22 - 7.14 ( , 2H), 7.00 (d, J =

1.2 Hz, 1 H), 5.84 (s, 1 H), 3.48 (s, 2H), 2.89 (q, J= 7.2 Hz, 1 H), 2.38 (s, 3H), 1.38 (d, J= 7.6 Hz, 3H).

Example 54 Rel-(6R,7R)-6-(1 -(3-Chloro-4-fluorophenyl)-1 H-imidazol-2-yl)-7-hydroxy-7-

(hydroxymethyl)-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-4- one

Step a. To a solution of ethyl 4-benzyloxy-3-oxo-butanoate (5 g, 21.2 mmol) and 1,2- dibromoethane (5.17 g, 27.5 mmol) in DMF (50 ml_) was added K₂CO₃ (7.31 g, 52.9 mmol) and TBAB (34 mg, 0.11 mmol). The mixture was stirred at 80°C for 12 h. On completion, the reaction mixture was filtered and evaporated. The residue was diluted with water (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (2 x 50 ml_), dried over Na₂S0₄ and evaporated. The residue was partially purified by column chromatography (10-25% EtOAc in PE) to afford ethyl 1-(2-benzyloxyacetyl)- cyclopropanecarboxylate (3.5 g) as a brown oil which was used without further purification m/z ES+ [M+H]⁺ 263.1

Step b. To a solution of ethyl 1-(2-benzyloxyacetyl)cyclopropanecarboxylate (3.2 g, 12.2 mmol) in water (40 ml_) was added aq. NaOH solution (1 M, 36.6 ml_). The mixture was stirred at rt for 2 h. On completion, the reaction mixture was adjusted to pH = 3~4 with 2 M HCI solution. The aqueous layer was then extracted with EtOAc (2 x 20 ml_). The combined organic layers were washed with brine (2 x 10 ml_), dried over Na2S04 and evaporated to give 1-(2-benzyloxyacetyl)cyclopropanecarboxylic acid (1.5 g, 52%) as a white solid.

¹H NMR (400 MHz, DMSO-d6) d ppm 12.84 (br s, 1 H), 7.41 - 7.27 (m, 5H), 4.56 (s, 2H), 4.50 (s, 2H), 1.40 - 1.34 (m, 4H).

Step c. To a solution of 1-(2-benzyloxyacetyl)cyclopropanecarboxylic acid (1.2 g, 5.12 mmol) and N-[[1-(3-chloro-4-fluoro-phenyl)imidazol-2-yl]methyl]-1-(2,4-dimethoxyphenyl)- methanamine (1.60 g, 2.56 mmol) in DCM (50 ml_) was added TEA (1.04 g, 10.3 mmol) and HATU (2.92 g, 7.68 mmol). The mixture was stirred at rt for 2 h. On completion, the reaction mixture was diluted with water (100 ml_) and extracted with DCM (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (20-100% EtOAc in PE) to afford 1-(2- benzyloxyacetyl)-N-[[1-(3-chloro-4-fluoro-phenyl)imidazol-2-yl]methyl]-N-[(2,4- dimethoxyphenyl)methyl]cyclopropanecarboxamide (2.1 g, 69%) as a brown oil. m/z ES+ [M+H]⁺ 592.3

Step d. To a solution of 1-(2-benzyloxyacetyl)-N-[[1-(3-chloro-4-fluoro-phenyl)imidazol-2- yl]methyl]-N-[(2,4-dimethoxyphenyl)methyl]cyclopropanecarboxamide (2.2 g, 3.7 mmol) and di-te/f-butyl dicarbonate (1.62 g, 7.4 mmol) in xylene (40 ml_) was added DIPEA (1.44 g,

11.1 mmol). The mixture was stirred at 130°C for 12 h. On completion, the reaction mixture was evaporated. The residue was diluted with water (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by prep-HPLC to give [(6R,7R)-7- (benzyloxymethyl)-6-[1-(3-chloro-4-fluoro-phenyl)imidazol-2-yl]-5-[(2,4-dimethoxyphenyl)- methyl]-4-oxo-5-azaspiro[2.4]heptan-7-yl] tert- butyl carbonate (1.03 g, 40%) as a brown oil.

¹H NMR (400 MHz, CDCh) d ppm 7.32 - 7.27 (m, 3H), 7.23 - 7.16 (m, 2H), 6.97 - 6.89 (m, 4H), 6.83 - 6.78 (m, 1H), 6.76 - 6.69 (m, 1 H), 6.41 - 6.38 (m, 1H), 6.36 - 6.31 (m, 1 H), 4.95 (d, J = 14.4 Hz, 1H), 4.73 (s, 1H), 4.24 - 4.03 (m, 4H), 3.82 (s, 3H), 3.59 (s, 3H), 3.42 - 3.33 (m, 1 H), 1.38 (s, 9H), 1.36 - 1.27 (m, 2H), 1.23 - 1.13 (m, 2H).

Step e. To a solution of [(6R,7R)-7-(benzyloxymethyl)-6-[1-(3-chloro-4-fluoro- phenyl)imidazol-2-yl]-5-[(2,4-dimethoxyphenyl)methyl]-4-oxo-5-azaspiro[2.4]heptan-7-yl] tert- butyl carbonate (500 mg, 0.72 mmol) in MeCN (15 ml_) and water (1.5 ml_) was added CAN (1.19 g, 2.17 mmol). The mixture was stirred at rt for 2 h. On completion, the reaction mixture was quenched with sat. aq. NaHCOs (15 ml_), and then extracted with EtOAc (3 x 10 ml_). The combined organic layers were washed with brine (10 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep-TLC (100% EtOAc) to give [(6R,7R)-7- (benzyloxymethyl)-6-[1-(3-chloro-4-fluoro-phenyl)imidazol-2-yl]-4-oxo-5-azaspiro[2.4]heptan- 7-yl] tert- butyl carbonate (50 mg, 13%) as a brown solid.

Step f. To a solution of [(6R,7R)-7-(benzyloxymethyl)-6-[1-(3-chloro-4-fluoro- phenyl)imidazol-2-yl]-4-oxo-5-azaspiro[2.4]heptan-7-yl] tert- butyl carbonate (90 g, 0.17 mmol) and 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (48 mg, 0.20 mmol) in dioxane (3 ml_) was added Pd2(dba)3 (15 mg, 0.017 mmol), XantPhos (19 mg, 0.033 mmol) and K₂CO₃ (69 mg, 0.50 mmol) under N2 atmosphere. The mixture was stirred at 100°C for 1.5 h under N2 atmosphere. On completion, the reaction mixture was diluted with water (8 ml_) and extracted with EtOAc (3 x 8 ml_). The combined organic layers were washed with brine (10 ml_), dried over Na₂S0₄ and evaporated. The residue was partially purified by prep-TLC

(50% EtOAc in PE) to give [(6R,7R)-7-(benzyloxymethyl)-6-[1-(3-chloro-4-fluoro-phenyl)- imidazol-2-yl]-5-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-4-oxo-5-azaspiro[2.4]heptan-7-yl] tert- butyl carbonate (100 mg) as a yellow oil which was used without further purification m/z ES+ [M+H]⁺ 701.4 Step g. To a solution of [(6R,7R)-7-(benzyloxymethyl)-6-[1-(3-chloro-4-fluoro- phenyl)imidazol-2-yl]-5-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-4-oxo-5-azaspiro[2.4]heptan- 7-yl] tert- butyl carbonate (100 mg, 0.14 mmol) in DCM (2 ml_) was added a solution of BCI₃ (1 M in toluene, 1.43 ml_) dropwise at 0°C. The mixture was stirred at rt for 1 h. On completion, the reaction mixture was quenched by sat. aq. NH₄CI (5 ml_) at 0°C, and then extracted with DCM (2 x 5 ml_). The combined organic layers were washed with brine (5 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep-TLC (50% EtOAc in PE) and then further purified by prep-HPLC to give the title compound (11 mg, 14%) as a yellow solid. m/z ES+ [M+H]⁺ 511.1 ; ¹H NMR (400 MHz, CD₃OD) d ppm 8.56 (s, 1H), 7.99 (dd, J = 2.4, 6.4 Hz, 1 H), 7.76 - 7.71 (m, 1H), 7.48 (t, J = 8.8 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.15 (s,

1 H), 6.99 (d, J = 1.2 Hz, 1 H), 5.99 (s, 1 H), 3.51 (s, 2H), 2.41 (s, 3H), 1.32 - 1.19 (m, 3H), 1.07 - 0.99 (m, 1 H).

Example 55

(S)-5-(1 -(3-Chloro-4-fluorophenyl)-1 H-imidazol-2-yl)-1 -(6-methyl-4- (trifluoromethyl)pyridin-2-yl)imidazolidin-2-one

Step a. To a solution of 2,2-dimethoxyethanamine (10.0 g, 95.1 mmol) and TEA (8.75 g,

86.5 mmol) in DCM (100 ml_) was added allyl carbonochloridate (10.4 g, 86.5 mmol) dropwise at 0°C. The mixture was then stirred at 0°C for 1 h. On completion, the reaction mixture was diluted with water (100 ml_) and extracted with DCM (3 x 100 ml_). The combined organic layers were washed with saturated NhUCI solution (400 ml_ x 3), dried over Na₂S0₄ and evaporated to afford allyl (2,2-dimethoxyethyl)carbamate (17.0 g, crude) as a colorless liquid which was used in the next step without further purification.

¹H NMR (400 MHz, DMSO-d6) d ppm 7.29 (t, J = 5.6 Hz, 1 H), 5.93 - 5.86 (m, 1 H), 5.25 (dd, J = 15.6, 14.0 Hz, 1H), 5.17 (dd, J = 10.4, 1.6 Hz, 1 H), 4.56 (d, J = 5.2 Hz, 2H), 4.34 (t, J = 5.6 Hz, 1 H), 3.25 (s, 6H), 3.07 (t, J = 6.0 Hz, 2H). Step b. To a solution of allyl (2,2-dimethoxyethyl)carbamate (17.0 g, 89.9 mmol) in DMF (200 ml_) was added NaH (4.31 g, 108 mmol, 60% dispersion in mineral oil) portionwise at 0°C under N2 atmophere. The mixture was then stirred at 0°C for 30 min. Then 3- bromoprop-1-ene (12.0 g, 98.8 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 h. On completion, the reaction mixture was diluted with water (200 ml_) and extracted with EtOAc (3 x 200 ml_). The combined organic layers were washed with brine (4 x 600 ml_), dried and evaporated to afford allyl allyl(2,2-dimethoxyethyl)carbamate (20.0 g, crude) as a yellow oil which was used in the next step without further purification.

¹H NMR (400 MHz, DMSO-d6) d ppm 5.93 - 5.88 (m, 2H), 5.29 - 5.10 (m, 4H), 5.53 (d, J = 4.0, 2H), 4.47 (t, J = 5.6 Hz, 1 H), 3.88 (d, J = 4.4 Hz, 2H), 3.28 - 3.25 (m, 8H).

Step c. A solution of allyl allyl(2,2-dimethoxyethyl)carbamate (20.0 g, 87.2 mmol) in formic acid (200 ml_) and water (40 ml_) was stirred at 15°C for 1 h. On completion, the reaction mixture was concentrated in vacuo. The mixture was diluted with water (60 ml_) and extracted with EtOAc (3 x 100 ml_). The combined organic layers were washed with brine (2 x 300 ml_), dried over Na₂S0₄ and evaporated to give allyl allyl(2-oxoethyl)carbamate (14.7 g, crude) as a yellow liquid which was used in the next step without further purification.

¹H NMR (400 MHz, DMSO-d6) d ppm 9.49 (d, J = 10.4 Hz, 1H), 5.91 - 5.78 (m, 2H), 5.27 - 5.12 (m, 4H), 4.54 (t, J = 4.4 Hz, 2H), 4.09 - 3.88 (m, 4H).

Step d. To a solution of allyl allyl(2-oxoethyl)carbamate (14.7 g, 80.2 mmol) and (S)-2- methylpropane-2-sulfinamide (11.9 g, 98.3 mmol) in THF (300 ml_) was added Ti(OEt)4 (56.0 g, 245.6 mmol) under N2 atmophere. The mixture was then stirred at 10°C for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (60 ml_) and extracted with EtOAc (3 x 100 ml_). The combined organic layers were washed with sat. aq. NaHCOs (2 x 300 ml_) and brine (2 x 300 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (10-15% EtOAc in PE) to give (S)-allyl allyl(2-((tert-butylsulfinyl)imino)ethyl)carbamate (14.6 g, 64%) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) d ppm 7.85 (s, 1H), 5.90 - 5.81 (m, 2H), 5.28 - 5.11 (m, 4H), 4.54 - 4.25 (m, 4H), 3.94 - 3.85 (m, 2H), 1.09 (s, 9H).

Step e. To a solution of 1-(3-chloro-4-fluoro-phenyl)imidazole (2.00 g, 10.2 mmol) in THF (26 ml_) was added a solution of LDA (2 M in THF, 7.63 ml_) dropwise at -78°C under N2 atmophere. The mixture was stirred at -78°C for 0.5 h. Then a solution of (S,E)-allyl allyl(2- ((tert-butylsulfinyl)imino)ethyl)carbamate (3.50 g, 12.2 mmol) in THF (26 ml_) was added.

The mixture was stirred at -78°C for 2 h. On completion, the reaction mixture was slowly quenched with sat. aq. NH4CI (30 ml_) and extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (2 x 90 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by prep HPLC to give allyl allyl((2S)-2-(1-(3-chloro-4-fluorophenyl)-7/-/- imidazol-2-yl)-2-(1,1-dimethylethylsulfinamido)ethyl)carbamate (1.50 g, 31%) as a yellow oil. m/z ES+ [M+H]⁺ 483.1

Step f. A solution of allyl allyl((2S)-2-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-2-(1,1- dimethylethylsulfinamido)ethyl)carbamate (1.50 g, 3.11 mmol), 1,3-dimethylbarbituric acid (3.15 g, 20.20 mmol) in MeOH (15 ml_) was added Pd(PPh3)4 (359 mg, 0.31 mmol) under N2 atmophere. Then the mixture was stirred at 70°C for 6 h under N2 atmophere. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (100% EtOAc, then 0-10% MeOH in DCM) and further purified by prep HPLC to give (S)-N-((S)-2-amino-1-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)ethyl)- 2-methylpropane-2-sulfinamide (800 mg, 72%) as a yellow solid. m/z ES+ [M+H]⁺ 359.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.80 (dd, J= 6.8, 2.8 Hz, 1 H), 7.65 - 7.59 (m, 2H), 7.38 (s, 1 H), 7.04 (s, 1 H), 5.46 (d, J = 8.4 Hz, 1 H), 4.43 - 4.38 (m, 1 H), 3.44 (d, J = 6.4 Hz, 1 H), 3.20 - 3.10 (m, 1 H), 0.93 (s, 9H).

Step g. To a solution of (S)-N-((S)-2-amino-1-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2- yl)ethyl)-2-methylpropane-2-sulfinamide (750 mg, 2.09 mmol) and NaHCOs (351 mg, 4.18 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was added benzyl chloroformate (357 mg, 2.09 mmol). The mixture was stirred at rt for 1 h. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over Na₂S0₄ and evaporated. The crude product was purified by prep HPLC to give benzyl ((S)- 2-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-2-((S)-1 ,1-dimethylethylsulfinamido)ethyl)- carbamate (700 mg, 68%) as a yellow oil. m/z ES+ [M+H]⁺ 493.1

Step h. A solution of benzyl ((S)-2-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-2-((S)-1 ,1- dimethylethylsulfinamido)ethyl)carbamate (650 mg, 1.32 mmol) in HCI/dioxane (4 M, 7 mL) was stirred at rt for 1 h. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (15 mL), then adjusted to pH = 8~9 with sat. aq. NaHCOs solution, and further extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over Na₂S0₄ and evaporated to give (S)-benzyl (2- amino-2-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)ethyl)carbamate (550 mg, crude) as a yellow oil which was used in the next step without further purification m/z ES+ [M+H]⁺ 389.1 ; ¹H NMR (400 MHz, DMSO-d6) d ppm 7.86 (d, = 6.0 Hz, 1 H), 7.58 - 7.56 (m, 2H), 7.34 -7.29 (m, 6H), 7.00 (s, 1 H), 4.94 (s, 2H), 3.81 (t, J = 6.8 Hz, 1 H), 3.31 - 3.26 (m, 2H). Step i. To a solution of (S)-benzyl (2-amino-2-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2- yl)ethyl)carbamate (550 mg, 1.41 mmol) in DCM (9 ml_) was added CDI (275 mg, 1.70 mmol). The mixture was stirred at rt for 1 h. On completion, the reaction mixture was diluted with water (20 ml_) and extracted with DCM (3 x 20 ml_). The combined organic layers were washed with brine (2 x 60 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (100% EtOAc, then 0-2% MeOH in DCM), further purified by prep HPLC, and finally by prep-TLC (10% MeOH in DCM) to give (S)-benzyl 4-(1-(3-chloro- 4-fluorophenyl)-7/-/-imidazol-2-yl)-2-oxoimidazolidine-1-carboxylate (130 mg, 37%) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) d ppm 7.99 (s, 1 H), 7.84 (d, J= 2.4 Hz, 1 H), 7.59 (d, J= 8.8 Hz, 1 H), 7.34 - 7.29 (m, 6H), 7.00 (s, 1 H), 4.94 (s, 2H), 3.81 (t, J= 6.8 Hz, 1 H), 3.31 - 3.26 (m, 2H).

Step j. To a solution of (S)-benzyl 4-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-2- oxoimidazolidine-1-carboxylate (130 mg, 0.31 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)- pyridine (105 mg, 0.44 mmol), K₂CO₃ (87 mg, 0.63 mmol) and XantPhos (36 mg, 0.063 mmol) in 1,4-dioxane (2 ml_) was added Pd2(dba)3 (29 mg, 0.031 mmol) under N2. The mixture was stirred at 80°C for 1 h under N2 atmophere. On completion, the reaction mixture was evaporated, diluted with water (5 ml_) and extracted with EtOAc (3 x 5 ml_). The combined organic layers were washed with brine (2 x 15 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by column chromatography (25-35% EtOAc in PE) and then further purified by prep HPLC to give (S)-benzyl 4-(1-(3-chloro-4-fluorophenyl)-7/-/- imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (130 mg, 72%) as a yellow oil.

¹H NMR (400 MHz, CD₃OD) d ppm 8.32 (s, 1 H), 7.76 (d, J= 2.4 Hz, 1 H), 7.47 - 7.35 (m,

7H), 7.23 (s, 1 H), 7.16 (s, 1 H), 6.99 (s, 1 H), 5.80 - 5.76 (m, 1H), 5.30 (d, J= 2.8 Hz, 1 H),

4.27 (t, J = 10.0 Hz, 1 H), 3.98 (dd, J= 10.4, 4.4 Hz, 1 H), 3.49 - 3.10 (m, 1 H), 2.37 (s, 3H). Step k. To a solution of (S)-benzyl 4-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-3-(6- methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (130 mg, 0.23 mmol) in DCM (5 mL) was added TFA (7.70 g, 67.5 mmol). The mixture was stirred at 40°C for 4 h. On completion, the reaction mixture was diluted with water (8 mL), adjusted to pH = 8-9 with sat. aq. NaHC0₃ and extracted with DCM (3 x 8 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na₂S0₄ and evaporated. A 40 mg sample of crude product was purified by prep-HPLC to give the title compound (27 mg, 67%) as an off-white solid. m/z ES+ [M+H]⁺ 440.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.28 (s, 1H), 7.92 - 7.89 (m,

1 H), 7.83 (s, 1 H), 7.77 - 7.72 (m, 2H), 7.68 - 7.63 (m, 1H), 7.50 (br s, 1 H), 7.19 (s, 1H), 5.70 (dd, J = 4.4, 10.0 Hz, 1 H), 3.81 (t, J = 10.0 Hz, 1 H), 3.71 - 3.56 (m, 1 H), 2.29 (s, 3H).

Intermediate 1

Rel-Benzyl (4S,5S)-5-(tert-butoxymethyl)-4-(1 -(3-chloro-4-fluorophenyl)-1 H-imidazol-2- yl)-2-oxoimidazolidine-1-carboxylate

Intermediate 2

Rel-Benzyl (4S,5R)-5-(tert-butoxymethyl)-4-(1 -(3-chloro-4-fluorophenyl)-1 H-imidazol-2- yl)-2-oxoimidazolidine-1-carboxylate

Step a. A mixture of (R)-2-(((benzyloxy)carbonyl)amino)-3-(te/f-butoxy)propanoic acid (7.0 g, 23.7 mmol), N,O-dimethylhydroxylamine hydrochloride (2.5 g, 26.1 mmol), HATU (10.8 g, 28.4 mmol), DIPEA (9.2 g, 71.0 mmol) in DCM (150 ml_) was degassed and purged with N2 3 times, and then the mixture was stirred at rt for 12 h under N2 atmosphere. Upon completion, the reaction mixture was diluted with DCM/water (150/150 ml_) and then separated. The organic layers were washed with brine (100 ml_), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (10-20% EtOAc in PE) to give (R)-benzyl (3-(te/f-butoxy)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (7.2 g, 90%) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6) d ppm 7.41 - 7.26 (m, 5H), 5.08 - 4.95 (m, 2H), 4.64 (s, 1 H), 3.73 (s, 3H), 3.52 - 3.45 (m, 1 H), 3.40 (d, J = 7.2 Hz, 1 H), 3.36 - 3.35 (m, 1 H), 3.12 (s, 3H), 1.10 (s, 9H).

Step b. To a solution of 1-(3-chloro-4-fluoro-phenyl)imidazole (2.0 g, 10.20 mmol) in THF (20 ml_) was added a solution of LDA (2 M in THF, 13.2 mmol) at -70°C under N2 atmosphere. The mixture was stirred at -70°C for 30 min. Then (R)-benzyl (3-(te/f-butoxy)-1- (methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (3.61 g, 10.7 mmol) in THF (10 ml_) was added dropwise into the reaction. The mixture was stirred at -70°C for 2 h. Upon completion, the reaction mixture was quenched with sat. aq. NhUCI solution (20 ml_) at - 70°C, then diluted with water (100 ml_). The mixture was extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na2SC>4 and evaporated. The residue was purified by reverse-phase column chromatography to give benzyl (3-(te/f-butoxy)-1-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-1-oxopropan-2- yl)carbamate (1.3 g, 26%) as a colourless oil. m/z ES+ [M+H]⁺ 474.1

Step c. A mixture of benzyl (3-(tert-butoxy)-1-(1-(3-chloro-4-fluorophenyl)-1 H-imidazol-2-yl)- 1-oxopropan-2-yl)carbamate (1.2 g, 2.50 mmol), hydroxylamine hydrochloride (1.2 g, 17.70 mmol) in pyridine (10 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 60°C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was evaporated and the residue was purified by prep-HPLC to give benzyl (3-(te/f-butoxy)-1- (1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-1-(hydroxyimino)propan-2-yl)carbamate (1.0 g, 80%) as an off-white solid. m/z ES+ [M+H]⁺ 489.2

Step d. A mixture of benzyl (3-(te/f-butoxy)-1-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)- 1-(hydroxyimino)propan-2-yl)carbamate (2.0 g, 4.10 mmol), NaBhU (1.6 g, 40.90 mmol), NiCh-ehhO (972 mg, 4.1 mmol) in MeOH (20 ml_) and EtOH (20 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 16°C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc (300 ml_) and water (10 ml_), then filtered and evaporated. The residue was purified by prep-HPLC to give benzyl (1-amino-3-(te/f-butoxy)-1-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)propan-2- yl)carbamate (750 mg, 39%) as a yellow oil. m/z ES+ [M+H]⁺ 475.2

Step e. A mixture of benzyl (1-amino-3-(te/f-butoxy)-1-(1-(3-chloro-4-fluorophenyl)-7/-/- imidazol-2-yl)propan-2-yl)carbamate (300 mg, 0.63 mmol), CDI (123 mg, 0.76 mmol) in DCM (5 mL) was degassed and purged with N23 times, and then the mixture was stirred at rt for 4 h under N2 atmosphere. Upon completion, the reaction mixture was evaporated and the residue was purified by prep-HPLC to give Intermediate 1 (130 mg, 41%) as a white solid, m/z ES+ [M+H]⁺ 501.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.00 (s, 1H), 7.83 (dd, J= 2.4, 6.4 Hz, 1 H), 7.69 - 7.60 (m, 1 H), 7.55 - 7.50 (m, 1 H), 7.44 - 7.33 (m, 6H), 7.08 (s, 1 H), 5.28 - 5.11 (m, 2H), 4.38 (s, 1H), 4.32 - 4.24 (m, 1H), 3.47 - 3.40 (m, 1H), 3.37 (d, J = 7.6 Hz,

1 H), 0.92 (s, 9H). and Intermediate 2 (60 mg, 18% yield) as a white solid. m/z ES+ [M+H]⁺ 501.1; ¹H NMR (400 MHz, DMS0-d6) d ppm 7.83 (d, J = 4.0 Hz, 2H), 7.72

- 7.60 (m, 1H), 7.58 - 7.48 (m, 1 H), 7.47 - 7.28 (m, 6H), 7.10 (s, 1H), 5.21 (dd, J = 8.0, 12.4

Hz, 2H), 4.85 (d, J = 8.4 Hz, 1 H), 4.43 - 4.28 (m, 1 H), 3.67 - 3.46 (m, 2H), 0.83 (s, 9H).

Example 56

(4S,5S)-5-(1 -(3-Chloro-4-fluorophenyl)-1 H-imidazol-2-yl)-4-(hydroxymethyl)-1 -(6- methyl-4-(trifluoromethyl)pyridin-2-yl)imidazolidin-2-one

Step a. A mixture of Intermediate 1 (110 mg, 0.22 mmol), 2-bromo-6-methyl-4- (trifluoromethyl)pyridine (79 mg, 0.33 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), XantPhos (25 mg, 0.044 mmol) and K₂CO₃ (60 mg, 0.44 mmol) in dioxane (1 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 100°C for 2 h under N2 atmosphere. Upon completion, the reaction mixture was filtered and evaporated and the residue was purified by prep-TLC (33% EtOAc in PE) to give frans-benzyl 5 -(tert- butoxymethyl)-4-(1-(3-chloro-4-fluorophenyl)-7/-/-imidazol-2-yl)-3-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (110 mg, 76 %) as an off-white solid. m/z ES+ [M+H]⁺ 660.3

Step b. A suspension of frans-benzyl 5-(te/f-butoxymethyl)-4-(1-(3-chloro-4-fluorophenyl)- 7/-/-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-1- carboxylate (110 mg, 0.17 mmol) in DCM (5 ml_) and TFA (5 ml_) was stirred at 40°C for 6 h. Upon completion, the reaction mixture was evaporated and the residue was purified by prep- HPLC. The desired enantiomer was isolated by further purification using prep chiral SFC to give the title compound (28 mg, 47%) as a yellow solid. m/z ES+ [M+H]⁺ 470.1 ; ¹H NMR (400 MHz, CD₃OD) d ppm 8.32 (s, 1H), 7.83 (dd, J = 2.8,

6.4 Hz, 1 H), 7.62 (td, J = 3.6, 8.0 Hz, 1 H), 7.52 - 7.42 (m, 1 H), 7.24 (s, 1 H), 7.05 (d, J = 6.0 Hz, 2H), 5.70 (d, J = 3.6 Hz, 1H), 3.76 (dd, J = 4.4, 8.4 Hz, 1 H), 3.52 (d, J = 4.8 Hz, 2H),

2.39 (s, 3H). Example 57

(4R,5S)-5-(1 -(3-chloro-4-fluorophenyl)-1 H-imidazol-2-yl)-4-(hydroxymethyl)-1 -(6- methyl-4-(trifluoromethyl)pyridin-2-yl)imidazolidin-2-one

The title compound was prepared in a similar manner to Example 56, using Intermediate 2 in step a. m/z ES+ [M+H]⁺ 470.1; ¹H NMR (400 MHz, CD₃OD) d ppm 8.37 (s, 1 H), 8.04 (d, J = 5.6 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.50 (t, J = 8.8 Hz, 1 H), 7.28 (s, 1 H), 7.05 (d, J= 6.4 Hz, 2H), 5.93 (d, J = 9.6 Hz, 1H), 4.18 - 4.07 (m, 1 H), 3.55 - 3.47 (m, 1H), 3.46 - 3.38 (m, 1 H), 2.38 (s, 3H).

Example 58

Rel-(4S,5S)-5-(5-Chloro-1-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl)-4-

(hydroxymethyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)imidazolidin-2-one

Step a. A mixture of frans-benzyl 5-(tert-butoxymethyl)-4-(1-(3-chloro-4-fluorophenyl)-1 H- imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (45 g, 0.068 mmol), N-chlorosuccinimide (9.1 mg, 0.068 mmol), acetic acid (4 mg, 0.067 mmol) in DMF (1 ml_) was degassed and purged with N2 3 times. The mixture was stirred at 60°C for 12 h under N2. Upon completion, the reaction mixture was evaporated and the residue was purified by prep-HPLC to give frans-benzyl 5-(tert-butoxymethyl)-4-(5-chloro-1- (3-chloro-4-fluorophenyl)-1 H-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-2- oxoimidazolidine-1-carboxylate (40 mg, 77%) as a yellow solid. m/z ES+ [M+H]⁺ 694.2

Step b. A solution of frans-benzyl 5-(tert-butoxymethyl)-4-(5-chloro-1-(3-chloro-4- fluorophenyl)-1 H-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2- oxoimidazolidine-1-carboxylate (34 mg, 0.049 mmol) in TFA (0.5 ml_) and DCM (0.5 ml_) was degassed and purged with N2 3 times. The mixture was stirred at 40°C for 4 h under N2.

Upon completion, the reaction mixture was evaporated and the residue was purified by prep- HPLC to give the title compound (5 mg, 17%) as a pink solid. m/z ES+ [M+H]⁺ 504.1; ¹H NMR (400 MHz, CD₃OD) d ppm 8.36 - 8.24 (m, 1H), 8.05 - 7.65 (m, 1 H), 7.60 - 7.41 (m, 1 H), 7.35 - 7.25 (m, 1 H), 7.09 (s, 1 H), 7.00 (s, 1 H), 5.53 (d, J = 9.2 Hz, 1H), 3.81 - 3.69 (m, 1 H), 3.56 - 3.43 (m, 2H), 2.51 - 2.40 (m, 3H).

Example 59

(S)-5-(1 -(1 -Methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)-1 -(6-methyl-4- (trifluoromethyl)pyridin-2-yl)imidazolidin-2-one

Step a. To a solution of 6-bromo-7/-/-pyrrolo[2,3-b]pyridine (2.40 g, 12.2 mmol) in THF (30 ml_) was added NaH (585 mg, 14.6 mmol, 60% dispersion in mineral oil) portionwise at 0°C. The mixture was stirred at 0°C for 30 min. lodomethane (2.07 g, 14.6 mmol) was added slowly to the reaction and the mixture was stirred at 0°C for 2 h. Upon completion, the reaction mixture was quenched with sat. aq. NhUCI (50 ml_) and extracted with EtOAc (3 x 100 ml_). The combined organic layers were washed with brine (3 x 30 ml_), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (6-10%

EtOAc in PE) to give 6-bromo-1 -methyl- 7/-/-pyrrolo[2,3-b]pyridine (2.47 g, 96%) as a yellow solid. m/z ES+ [M+H]⁺ 211.0

Step b. A mixture of 6-bromo-1 -methyl- 7/-/-pyrrolo[2,3-b]pyridine (2.40 g, 11.4 mmol), imidazole (1.70 g, 25.0 mmol), Cul (1.08 g, 5.7 mmol), CS2CO3 (11.1 g, 34.1 mmol) and L- proline (1.31 g, 11.4 mmol) in DMSO (30 ml_) was degassed and purged with N2 3 times, and then the mixture was stirred at 120°C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by aq. ammonium hydroxide solution (5 ml_), then diluted with water (100 ml_) and extracted with EtOAc (3 x 100 ml_). The combined organic layers were washed with brine (3 x 30 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by reverse-phase column chromatography to give 6-(7/-/-imidazol-1-yl)-1 -methyl- 1H- pyrrolo[2,3-b]pyridine (1.87 g, 83%) as a yellow solid. m/z ES+ [M+H]⁺ 199.7; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.59 (s, 1 H), 8.13 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.53 (d, J = 3.6 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.14 (s, 1 H), 6.52 (d, J = 3.6 Hz, 1 H), 3.84 (s, 3H).

Step c. To a solution of 6-(7/-/-imidazol-1-yl)-1 -methyl- 7/-/-pyrrolo[2,3-b]pyridine (0.84 g, 4.24 mmol) in THF (10 ml_) was added a solution of LDA (2 M in THF, 5.08 mmol) dropwise at - 78°C and the mixture was stirred at -78°C for 30 min. Then (R)-allyl allyl(2 -((tert- butylsulfinyl)imino)ethyl)carbamate (prepared in a similar manner to Example 55, steps a-d;

1.82 g, 6.36 mmol) in THF (3 ml_) was added slowly into the reaction and the mixture was stirred at -78°C for 11.5 h. Upon completion, the reaction mixture was quenched with sat. aq. NH₄CI (50 ml_) and then extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (3 x 20 ml_), dried over Na₂S0₄ and evaporated. The residue was purified by reverse-phase column chromatography to give allyl allyl((2S)-2-(1,1- dimethylethylsulfinamido)-2-(1-(1 -methyl- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)- 7/-/-imidazol-2- yl)ethyl)carbamate (1.1 g, 54%) as a yellow solid m/z ES+ [M+H]⁺ 485.3

Step d. A mixture of allyl allyl((2S)-2-(1, 1-dimethylethylsulfinamido)-2-(1-(1 -methyl-1 H- pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)ethyl)carbamate (1.1 g, 2.27 mmol), 1 ,3- dimethylbarbituric acid (2.3 g, 14.76 mmol), Pd(PPh3)4 (262 mg, 0.23 mmol) in MeOH (20 ml_) was degassed and purged with N2 3 times. The mixture was stirred at 70°C for 5 h under N2. Upon completion, the reaction mixture was filtered and evaporated and the residue was purified by column chromatography (0-50% EtOAc in PE) to give (R)-N-((S)-2- amino-1-(1-(1 -methyl-1 /-/-pyrrolo[2,3-b]pyridin-6-yl)-1 /-/-imidazol-2-yl)ethyl)-2-methylpropane- 2-sulfinamide (0.7 g, 86%) as a yellow solid m/z ES+ [M+H]⁺ 361.2

Step e. To a solution of (R)-N-((S)-2-amino-1-(1-(1 -methyl- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)- 1H- imidazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (0.7 g, 1.94 mmol) in MeCN (20 ml_) was added di-te/f-butyl dicarbonate (1.27 g, 5.83 mmol) and TEA (590 mg, 5.83 mmol). The mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was evaporated and the residue was purified by reverse-phase column chromatography to give tert- butyl ((S)-2- ((R)-1 ,1-dimethylethylsulfinamido)-2-(1-(1 -methyl- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol- 2-yl)ethyl)carbamate (800 mg, 89%) as a yellow solid m/z ES+ [M+H]⁺ 461.2

Step f. To a solution of tert- butyl ((S)-2-((R)-1 ,1-dimethylethylsulfinamido)-2-(1-(1-methyl- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)ethyl)carbamate (0.8 g, 1.74 mmol) in MeOH (20 ml_) was added HCI/dioxane (4 M, 3.48 mmol). The mixture was stirred at rt for 2 h.

Upon completion, the reaction mixture was quenched with aq. NaOH solution (4 M, 1 ml_), and evaporated to give (S)-tert-butyl (2-amino-2-(1-(1 -methyl- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)- 7/-/-imidazol-2-yl)ethyl)carbamate (0.5 g, 81%) as a yellow solid which was used without further purification m/z ES+ [M+H]⁺ 357.1

Step g. To a solution of (S)-te/f-butyl (2-amino-2-(1-(1 -methyl- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)- 7/-/-imidazol-2-yl)ethyl)carbamate (0.5 g, 1.40 mmol) in DCM (20 ml_) was added CDI (273 mg, 1.68 mmol). The mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was evaporated and the residue was purified by prep-HPLC to give (S)-ferf-butyl 4-(1-(1- methyl-7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)-2-oxoimidazolidine-1-carboxylate (130 mg, 24%) as a yellow solid. m/z ES+ [M+H]⁺ 383.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.18 (d, J = 8.4 Hz, 1 H), 7.71 (d, J = 1.2 Hz, 1 H), 7.69 - 7.66 (m, 1 H), 7.60 (d, J = 3.6 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.07 (d, J = 1.2 Hz, 1 H), 6.57 (d, J = 3.6 Hz, 1H), 5.18 (dd, J = 9.2, 4.4 Hz, 1H), 3.85 (s, 3H), 3.30 - 3.25 (m, 2H), 1.43 (s, 9H).

Step h. A mixture of (S)-te/f-butyl 4-(1-(1 -methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)- 7/-/-imidazol- 2-yl)-2-oxoimidazolidine-1-carboxylate (130 mg, 0.34 mmol), 2-bromo-6-methyl-4- (trifluoromethyl)pyridine (122 mg, 0.51 mmol), Pd2(dba)3 (31 mg, 0.034 mmol), XantPhos (39 mg, 0.07 mmol) and K₂CO₃ (141 mg, 1.02 mmol) in 1,4-dioxane (3 ml_) was degassed and purged with N23 times, and then the mixture was stirred at 100°C for 2 h under N2. Upon completion, the reaction mixture was filtered and evaporated and the residue was purified by column chromatography (20-50% EtOAc in PE) to give (S)-te/f-butyl 4-(1-(1 -methyl -1H- pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2- oxoimidazolidine-1-carboxylate (130 mg, 71%) as a yellow solid m/z ES+ [M+H]⁺ 542.3

Step i. To a solution of (S)-te/f-butyl 4-(1-(1 -methyl- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)- 1H- imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (130 mg, 0.24 mmol) in DCM (5 ml_) was added TFA (2.74 g, 24.0 mmol) and the mixture was stirred at rt for 30 min. Upon completion, the reaction mixture was quenched with sat. aq. NaHCC>3 (20 ml_), diluted with water (30 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (3 x 20 ml_), dried over Na2SC>4 and concentrated in vacuo. The obtained residue was purified by prep-HPLC to give the title compound (100 mg, 94%) as a white solid. m/z ES+ [M+H]⁺ 442.2; ¹H NMR (400 MHz, CD₃OD) d ppm 8.32 - 8.23 (m, 2H), 7.95 (d, J = 2.0 Hz, 1 H), 7.59 (d, J = 3.2 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.4, 2.4 Hz,

1 H), 7.03 (s, 1 H), 6.67 (dd, J = 3.2, 2.0 Hz, 1H), 6.34 - 6.22 (m, 1H), 4.34 (t, J = 10.0 Hz, 1 H), 4.01 (dd, J = 10.0, 5.6 Hz, 1 H), 3.94 (s, 3H), 2.19 (s, 3H).

Example 60

(S)-5-(4-Fluoro-1 -(1 -methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)-1 -(6-methyl- 4-(trifluoromethyl)pyridin-2-yl)imidazolidin-2-one

The title compound was prepared in a similar manner to Example 59, using 5-fluoro -1H- imidazole (CAS Number 30086-17-0) in step b. m/z ES+ [M+H]⁺ 460.2; ¹H NMR (400 MHz, CD₃OD) d ppm 8.20 (s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.48 (d, J = 3.6 Hz, 1 H), 7.26 (d, J= 8.0 Hz, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.95 (s, 1 H), 6.60 (d, J = 3.6 Hz, 1 H), 6.19 (dt, J = 5.6, 4.8 Hz, 1H), 4.21 (t, J= 9.6 Hz, 1 H), 3.92 (s, 3H),

3.83 (dd, J= 9.2, 5.2 Hz, 1 H), 2.16 (s, 3H). Example 61

(S)-1 -((R)-3-(Dimethylamino)-2-hydroxypropyl)-4-(1 -(1 -methyl-1 H-pyrrolo[2,3-b]pyridin- 6-yl)-1H-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)imidazolidin-2-one Example 62 (S)-1 -((S)-3-(Dimethylamino)-2-hydroxypropyl)-4-(1 -(1 -methyl-1 H-pyrrolo[2,3-b]pyridin-

6-yl)-1H-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)imidazolidin-2-one

Step a. To a solution of (S)-5-(1 -(1 -methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)-1- (6-methyl-4-(trifluoromethyl)pyridin-2-yl)i idazolidin-2-one (200 g, 0.45 mmol), 2-

(bromomethyl)oxirane (93 mg, 0.68 mmol) in DMF (3 ml_) was added CS2CO3 (443 mg, 1.36 mmol). The mixture was stirred at 80°C for 1 h. Upon completion, the reaction mixture was quenched with sat. aq. NH₄CI solution (30 ml_), and then extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (3 x 20 ml_), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (25-50% EtOAc in PE) to give (4S)-4-(1-(1 -methyl- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)- 7/-/-imidazol-2-yl)-3-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-1-(oxiran-2-ylmethyl)imidazolidin-2-one (140 mg, 62%) as a yellow solid m/z ES+ [M+H]⁺ 498.1 Step b. To a solution of (4S)-4-(1-(1 -methyl- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)- 7/-/-imidazol-2-yl)- 3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(oxiran-2-ylmethyl)imidazolidin-2-one (140 mg, 0.28 mmol) in MeOH (3 ml_) was added a solution of dimethylamine (2 M in THF, 16.9 mmol). The mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was filtered and evaporated and the residue was purified by prep-HPLC and the stereoisomers were isolated by further purification using prep chiral SFC to give Example 61 (22 mg, 27%) as a yellow solid, m/z ES+ [M+H]⁺ 543.2; ¹H NMR (400 MHz, CD₃OD) d ppm 8.29 (s, 1 H), 8.19 (d, J = 8.4 Hz,

1 H), 7.50 (d, J = 1.6 Hz, 1 H), 7.48 (d, J= 3.6 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 6.98 (d, J = 1.2 Hz, 1 H), 6.93 (s, 1 H), 6.61 (d, J = 3.6 Hz, 1H), 6.20 (dd, J= 9.6, 4.8 Hz, 1H), 4.37 (t, J = 9.6 Hz, 1 H), 4.19 (s, 1 H), 3.96 (dd, J= 9.2, 5.2 Hz, 1 H), 3.93 (s, 3H), 3.56 (dd, J = 14.4, 4.4 Hz, 1H), 3.34 (d, J= 6.8 Hz, 1 H), 2.91 - 2.73 (m, 2H), 2.61 (s, 3H), 2.59 (s, 3H), 2.11 (s, 3H). and Example 62 (46 mg, 57%) as a yellow oil. m/z ES+ [M+H]⁺ 543.2; ¹H NMR (400 MHz, CD₃OD) d ppm 8.33 (s, 1 H), 8.24 (d, J = 8.0 Hz,

1 H), 7.68 (s, 1 H), 7.52 (d, J = 3.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 6.97 (s,

1 H), 6.63 (dd, J= 3.6, 1.2 Hz, 1H), 6.24 (dd, J= 10.0, 4.4 Hz, 1 H), 4.41 - 4.25 (m, 2H), 4.12 (dd, J = 9.2, 4.4 Hz, 1 H), 3.93 (s, 3H), 3.72 - 3.56 (m, 1 H), 3.40 - 3.25 (m, 3H), 2.95 (s, 6H), 2.12 (s, 3H).

Example 63

(S)-1 -((R)-3-(Dimethylamino)-2-hydroxypropyl)-4-(4-fluoro-1 -(1 -methyl-1 H-pyrrolo[2,3- b]pyridin-6-yl)-1H-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2- yl)imidazolidin-2-one Example 64

(S)-1 -((S)-3-(Dimethylamino)-2-hydroxypropyl)-4-(4-fluoro-1 -(1 -methyl-1 H-pyrrolo[2,3- b]pyridin-6-yl)-1H-imidazol-2-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2- yl)imidazolidin-2-one

The title compounds were prepared in a similar manner to Examples 61/62, using Example 60 in step a.

Example 63 m/z ES+ [M+H]⁺ 561.2; ¹H NMR (400 MHz, CD₃OD) d ppm 8.29 (s, 1 H), 8.21 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 3.6 Hz, 1 H), 7.36 (d, J= 8.0 Hz, 1 H), 7.17 (d, = 8.0 Hz, 1 H), 6.98 (s, 1 H), 6.62 (d, J = 3.6 Hz, 1H), 6.22 - 6.17 (m, 1 H), 4.28 - 4.40 (m, 2H), 3.98 (dd, J= 9.2, 4.4 Hz, 1 H), 3.93 (s, 3H), 3.62 (dd, J = 14.4, 6.0 Hz, 1 H), 3.46 - 3.35 (m, 2H), 3.29 - 3.21 (m, 1 H), 2.98 (s, 3H), 2.93 (s, 3H), 2.13 (s, 3H).

Example 64 /z ES+ [M+H]⁺ 561.2; ¹H NMR (400 MHz, CD₃OD) d ppm 8.31 (s, 1 H), 8.21 (d, J = 8.4 Hz, 1 H), 7.50 (d, = 3.6 Hz, 1 H), 7.37 (d, = 8.4 Hz, 1 H), 7.17 (d, = 8.0 Hz, 1 H), 6.97 (s, 1 H), 6.62 (d, J = 3.6 Hz, 1H), 6.23 - 6.17 (m, 1 H), 4.35 - 4.30 (m, 1H), 4.27 (t, J= 9.6 Hz, 1 H), 4.14 (dd, J= 9.6, 3.6 Hz, 1H), 3.92 (s, 3H), 3.77 (dd, J= 14.8, 4.8 Hz, 1 H), 3.49 (dd, J =

12.8, 11.2 Hz, 1 H), 3.29 - 3.23 (m, 2H), 2.98 (s, 3H), 2.92 (s, 3H), 2.12 (s, 3H).

Example 65

(4S)-4-(1 -(1 -Methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)-3-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-1-(2-(S-methylsulfonimidoyl)ethyl)imidazolidin-2-one

Step a. To a solution of (S)-5-(1 -(1 -methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)-1- (6-methyl-4-(trifluoromethyl)pyridin-2-yl)imidazolidin-2-one (130 mg, 0.30 mmol), Kl (147 mg, 0.88 mmol) in DMF (3 ml_) was added (2-chloroethyl)(methyl)sulfane (163 mg, 1.47 mmol) and Cs₂C0₃ (288 mg, 0.88 mmol). The mixture was stirred at 60°C for 12 h. Upon completion, the reaction mixture was quenched by sat. aq. NH₄CI solution (30 ml_) and extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (3 x 20 ml_), dried over Na2SC>4 and evaporated. The residue was purified by prep-TLC (50% EtOAc in PE) to give (S)-4-(1 -(1 -methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)-3-(6- methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(2-(methylthio)ethyl)imidazolidin-2-one (30 mg, 20%) as a yellow solid m/z ES+ [M+H]⁺ 516.3

Step b. To a solution of (S)-4-(1 -(1 -methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)-3- (6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(2-(methylthio)ethyl)imidazolidin-2-one (30 mg, 0.06 mmol) in MeOH (3 ml_) was added NH2COONH4 (11 mg, 0.15 mmol) and Phl(OAc)2 (47 mg, 0.15 mmol). The mixture was stirred at -10°C for 1 h. Upon completion, the reaction mixture was filtered and evaporated. The crude residue was purified by prep-HPLC to give the title compound (1 mg, 4%) as a brown gum. m/z ES+ [M+H]⁺ 547.2; ¹H NMR (400 MHz, CD₃OD) d ppm 8.38 (s, 1 H), 8.34 (d, J = 8.4 Hz,

1 H), 8.03 (d, J = 7.2 Hz, 1 H), 7.61 (dd, J = 3.6, 1.2 Hz, 1 H), 7.60 - 7.53 (m, 2H), 7.09 (d, J = 4.0 Hz, 1 H), 6.70 (d, J = 2.8 Hz, 1 H), 6.29 (td, J = 10.0, 4.8 Hz, 1 H), 4.80 - 4.75 (m, 1 H),

4.51 - 4.37 (m, 1H), 4.17 - 4.04 (m, 2H), 4.04 - 3.99 (m, 2H), 3.97 (s, 3H), 3.53 (t, J = 4.4 Hz, 3H), 2.19 (d, J = 6.4 Hz, 3H).

Example 66

Step a. To a solution of N-((S)-2-amino-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrrolo[2,3-b]pyridin-6-yl)-1 H-imidazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (prepared in a similar manner to Example 55, steps a-f, using 6-(7/-/-imidazol-1-yl)-1-((2-(trimethylsilyl)- ethoxy)-methyl)-7/-/-pyrrolo[2,3-b]pyridine (Example 50, steps a-b) in step e; 800 mg, 1.68 mmol) in MeCN (10 ml_) was added di-te/f-butyl dicarbonate (1.10 g, 5.03 mmol) and TEA (510 mg, 5.03 mmol). The mixture was stirred at rt for 2 h. Upon completion, the reaction mixture was filtered and evaporated. The residue was purified by reverse-phase flash column to give tert- butyl ((2S)-2-(1,1-dimethylethylsulfinamido)-2-(1-(1-((2- (trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)ethyl)carbamate (950 mg, 98%) as a yellow solid. m/z ES+ [M+H]⁺ 577.3; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.19 - 8.14 (m, 1 H), 7.76 - 7.71 (m, 1 H), 7.59 (d, J = 1.2 Hz, 1 H), 7.34 - 7.29 (m, 1 H), 7.08 - 6.99 (m, 1H), 6.71 - 6.56 (m, 2H), 5.72 - 5.59 (m, 2H), 5.39 - 5.21 (m, 2H), 3.76 - 3.67 (m, 1H), 3.64 - 3.48 (m, 3H), 1.36 (s, 9H), 1.00 (s, 1 H), 0.92 - 0.83 (m, 1 H), 0.72 (s, 9H), -0.12 (s, 9H).

Step b. To a solution of te/f-butyl ((2S)-2-(1,1-dimethylethylsulfinamido)-2-(1-(1-((2- (trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)ethyl)carbamate (920 mg, 1.59 mmol) in MeOH (15 mL) was added HCI/dioxane (4 M, 1.0 ml_). The mixture was stirred at rt for 2 h. Upon completion, the reaction mixture was quenched by aq. NaOH solution (20 wt%, 1 mL), and then dried over Na2SC>4, filtered and evaporated to give (S)- tert-butyl (2-amino-2-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/- imidazol-2-yl)ethyl)carbamate (750 mg, crude) as a yellow solid, which was used without further purification m/z ES+ [M+H]⁺ 473.2

Step c. To a solution of (S)-te/f-butyl (2-amino-2-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-7/-/- pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)ethyl)carbamate (730 mg, 1.54 mmol) in DCM (15 mL) was added CDI (301 mg, 1.85 mmol). The mixture was stirred at rt for 2 h. Upon completion, the reaction mixture was filtered and evaporated. The residue was purified by reverse-phase flash column to give (S)-te/f-butyl 2-oxo-4-(1-(1-((2-

(trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)imidazolidine-1- carboxylate (440 mg, 57%) as a yellow solid. m/z ES+ [M+H]⁺ 499.3; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.23 (d, J = 8.4 Hz, 1 H), 8.14 (s, 1 H), 7.76 - 7.72 (m, 1 H), 7.68 (s, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.08 (d, J = 1.2 Hz, 1 H), 6.67 - 6.61 (m, 1H), 5.76 - 5.66 (m, 1H), 5.61 - 5.56 (m, 1 H), 5.20 (dd, J = 9.2, 4.4 Hz, 1 H), 4.19 (t, J = 10.0 Hz, 1H), 4.04 (dd, J= 10.4, 4.4 Hz, 1 H), 3.52 (t, J= 8.0 Hz, 2H), 1.44 (s,

9H), 0.86 - 0.76 (m, 2H), -0.12 (s, 9H).

Step d. A mixture of (S)-te/f-butyl 2-oxo-4-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-7/-/- pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)imidazolidine-1 -carboxylate (430 mg, 0.86 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (290 mg, 1.21 mmol), K2CO₃ (358 mg, 2.59 mmol), XantPhos (100 mg, 0.17 mmol) and Pd2(dba)3 (79 mg, 0.086 mmol) in 1,4-dioxane (6 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100°C for 2 h under N2 atmosphere. Upon completion, the reaction mixture was quenched with sat. aq. NH4CI (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (15-20% EtOAc in PE) to give (S)-te/f-butyl 3-(6- methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-4-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2-yl)imidazolidine-1-carboxylate (500 mg, 88%) as a yellow solid. m/z ES+ [M+H]⁺ 658.2; ¹H NMR (400 MHz, DMSO-d6) d ppm 8.29 (d, J = 8.0 Hz, 1 H), 8.25 (s, 1H), 7.76 (d, J= 3.6 Hz, 1 H), 7.66 (s, 1 H), 7.47 (d, J= 8.0 Hz, 1H), 7.18 (s, 1H), 6.91 (s,

1 H), 6.67 (d, J = 3.6 Hz, 1 H), 6.19 (dd, J = 9.2, 2.8 Hz, 1H), 5.72 - 5.60 (m, 2H), 4.06 - 3.98 (m, 2H), 3.58 - 3.44 (m, 2H), 2.03 (s, 3H), 1.51 (s, 9H), 0.91 - 0.69 (m, 2H), -0.21 (s, 9H). Step e. To a solution of (S)-te/f-butyl 3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-4-(1- (1-((2-(trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-b]pyridin-6-yl)-7/-/-imidazol-2- yl)imidazolidine-1-carboxylate (540 mg, 0.82 mmol) in DCM (10 mL) was added TFA (9.36 g, 82.1 mmol). The mixture was stirred at 45°C for 12 h. Upon completion, the reaction mixture was evaporated and the residue was purified by reverse-phase flash column to give (S)-5-(1- (1 -(hydroxymethyl)- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)- 7/-/-imidazol-2-yl)-1-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)imidazolidin-2-one (360 mg, 96%) as a yellow solid m/z ES+ [M+H]⁺ 458.3

Step f. To a solution of (S)-5-(1-(1 -(hydroxymethyl)- 7/-/-pyrrolo[2,3-b]pyridin-6-yl)- 1H- imidazol-2-yl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)imidazolidin-2-one (360 mg, 0.79 mmol) in MeOH (10 mL) was added NaOH (126 mg, 3.15 mmol). The mixture was stirred at rt for 2 h. Upon completion, the reaction mixture was filtered and evaporated. The residue was purified by prep-HPLC to give the title compound (55 mg, 16%) as a yellow solid m/z ES+ [M+H]⁺ 428.1; ¹H NMR (400 MHz, DMSO-d6) d ppm 11.88 (s, 1 H), 8.29 (s, 1 H),

8.21 (d, J = 8.0 Hz, 1 H), 7.65 - 7.55 (m, 3H), 7.37 (d, J = 7.8 Hz, 1 H), 7.01 (s, 1 H), 6.86 (s,

1 H), 6.56 (d, J = 3.2 Hz, 1 H), 6.10 (dd, J = 9.6, 3.6 Hz, 1 H), 4.10 (t, J= 9.6 Hz, 1 H), 3.50 (dd, J= 9.2, 3.6 Hz, 1 H), 2.06 (s, 3H).

BIOLOGICAL DATA

RoIQ Full Length Enzyme Potency Assay

PicoGreen assay was used to measure the ability of compounds to inhibit the activity of RoIQ in vitro. N-His, C-term FLAG tagged RoIQ protein (amino acids 2-2590) expressed in baculovirus was purified and stored at -80°C in aliquots. Assay measurements were performed with 1X buffer comprising 25 mM Tris HCI pH 7.5, 12.5 mM NaCI, 0.5 mM MgCI2, 5% glycerol, 0.01% Triton X-100, 0.01% BGG and 1 mM DTT. Test compounds were prepared by dilution in 100% DMSO to give the correct dose range for 12 point concentration response and appropriate volume (60 nL) dispensed into 384 well micro assay plates (Perkin Elmer low volume black ProxiPlates product code 6008269) using a Labcyte Echo 550 acoustic dispenser. DMSO concentration was maintained at 1% by back filling with DMSO solution. 3 mI_ purified recombinant RoIQ and primer (5’ - GCG GCT GTC ATA AG - 3’ (SEQ ID NO: 1)): template (5’ - GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC GCG - 3’ (SEC I D NO: 2)) duplex (1 : 1.1 ) was diluted in assay buffer to a 2X working concentration (4 nM RoIQ and 100 nM PTD). This was dispensed into each well of the compound plate using a VIAFLO 16 channel manual pipette (Integra) and pre incubated at rt for 30 min. 3 mI_ of 2X working solution of dNTPs (40 mM) (dATP, dCTP, dGTP, dTTP; Sigma D6500, D4635, D4010, T0251) diluted in assay buffer was then added and the reaction incubated for 60 min at rt. The reaction was stopped by addition of 10 mM EDTA, 25 mM Tris pH 7.5 and 1:200 dilution of PicoGreen dye (Invitrogen P7581). After 90 minutes at rt in the dark, fluorescence was read on a BMG Pherastar FS plate reader using 485/520nm module and raw data analysed using IDBS Activity Base to generate IC50 values.

The compounds of Examples 1 to 66 were tested in the above mentioned enzyme potency assay and the results are shown in the following table:

Claims

1. A compound of formula (I):

W represents =C(R⁴)- or =N-;

R¹, R², R³ and R⁴ independently represent hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, haloCi- 6 alkyl, C_3-8 cycloalkyl, cyano or -NR^xR^y;

X represents -C(R^6a)(R^6b)-, -N(R⁷)- or -0-;

R⁵ represents hydrogen, -CH₂-R^Z or oxo, or together with R^6b may join to form a bridged group, such that when X represents -N(R⁷)- or -0-, R⁵ represents oxo and such that when R⁴ represents cyano, R⁵ represents a group other than oxo;

R^6a represents hydrogen, hydroxy, C_1-6 alkyl, haloCi-₆ alkyl, C_1-6 alkoxy, C_1-6 alkanol, C_3-8 cycloalkyl, halogen, -NR^VR^W or heterocyclyl;

R⁷ represents hydrogen, C_1-6 alkyl, haloCi-₆ alkyl, C_3-8 cycloalkyl, heterocyclyl, C_1-6 alkylsulfonimidoyl or C_1-6 alkylamino optionally substituted by one or more (e.g. 1 or 2) hydroxyl groups;

R^8a represents hydrogen, -CH2-R^Z or hydroxy;

Y represents -C(R⁹)= or -N=;

R⁹ represents hydrogen, halogen or C_1-6 alkyl; R¹⁰ represents phenyl or a 5 or 6 membered heteroaryl ring optionally fused to a 5 membered heteroaryl ring, wherein said phenyl or heteroaryl rings may optionally each be substituted by one or more (e.g. 1, 2 or 3) Ci-₆ alkyl, Ci-₆ alkoxy, Ci-₆ alkanol, -CONR‘R^u, - CH2-NR‘R^u, C3-8 cycloalkyl, halogen, cyano or haloCi-₆ alkyl groups;

R¹¹ represents hydrogen, halogen or C1-6 alkyl;

R‘, R^u, R^v, R^w, R^x and R^y independently represent hydrogen, C1-6 alkyl, haloCi-₆ alkyl, C3-8 cycloalkyl, -COC1-6 alkyl or heterocyclyl, wherein said alkyl groups may be optionally substituted with or more hydroxy, amino or sulfone groups and said heterocyclyl ring may be optionally substituted by one or more oxo or -COC1-6 alkyl groups; and R^z represents hydrogen, C1-6 alkyl, hydroxy, C1-6 alkoxy or C1-6 alkanol.

2. The compound as defined in claim 1 , which is a compound of formula (l)^a:

(l)^a wherein R¹, R², R³, R⁴, R⁵, X, R^8a, R^8b, Y, R¹⁰ and R¹¹ are as defined in claim 1.

3. The compound as defined in claim 1 or claim 2, wherein R¹ represents hydrogen or Ci-₆ alkyl (such as methyl).

4. The compound as defined in any one of claims 1 to 3, wherein R² represents hydrogen or Ci-₆ alkyl (such as methyl).

5. The compound as defined in any one of claims 1 to 4, wherein R³ represents Ci-₆ alkyl (such as methyl or ethyl) or haloCi-₆ alkyl (such as trifluoromethyl).

6. The compound as defined in any one of claims 1 to 5, wherein R⁴ represents hydrogen or cyano.

7. The compound as defined in claim 1 , wherein W represents C(R⁴)- and:

R¹ represents Ci-e alkyl (such as methyl), R² represents hydrogen, R³ represents Ci-e alkyl (such as methyl) and R⁴ represents cyano; or

R¹ represents hydrogen, R² represents Ci-e alkyl (such as methyl), R³ represents Ci-e alkyl (such as ethyl) and R⁴ represents cyano; or

8. The compound as defined in any one of claims 1 to 7, wherein R⁵ represents hydrogen, oxo, or R⁵ together with R^6b joins to form a bridged group.

9. The compound as defined in any one of claims 1 to 8, wherein X represents - C(R^6a)(R^6b)- and: R^6a represents hydrogen, Ci-e alkyl (such as methyl), hydroxy, Ci-e alkanol (such as CH2OH) or -NR^VR^W (such as -NHCOMe); R^6b represents hydrogen; or R^6b together with R⁵ joins to form a bridged group; or R^6b together with R^6a joins to form a C3-8 cycloalkyl group (such as a cyclopropyl group).

10. The compound as defined in any one of claims 1 to 8, wherein X represents -N(R⁷)- and R⁷ represents hydrogen, C1-6 alkylsulfonimidoyl (such as -(CH₂)₂-S(=0)(=NH)(Me)) or C1-6 alkylamino optionally substituted by one or more (e.g. 1 or 2) hydroxyl groups (such as - CH2-CH₂OH-CH2-N(Me)₂).

11. The compound as defined in any one of claims 1 to 10, wherein R^8a and R^8b both represent hydrogen, or R^8a represents hydroxy and R^8b represents hydrogen, or R^8a represents -CH2-R^Z (such as methyl) and R^8b represents hydroxy, or R^8a represents -CH2-R^Z (such as -CH2-OH) and R^8b represents hydrogen or hydroxy.

12. The compound as defined in any one of claims 1 to 11 , wherein X represents - C(R^6a)(R^6b)- and:

R⁵ represents hydrogen, R^6a represents hydrogen, R^6b represents hydrogen and R^8a and R^8b both represent hydrogen; or R⁵ represents hydrogen, R^6a represents hydroxy, R^6b represents hydrogen and R^8a and R^8b both represent hydrogen; or

R⁵ together with R^6b joins to form a bridged group, R^6a represents hydrogen and R^8a and R^8b both represent hydrogen; or

R⁵ together with R^6b joins to form a bridged group, R^6a represents Ci-e alkanol (such as CH2OH) and R^8a and R^8b both represent hydrogen; or

R⁵ represents oxo, R^6a represents C1-6 alkyl (such as methyl), R^6b represents hydrogen, R^8a represents -CH2-R^Z (such as methyl) and R^8b represents hydroxy; or

R⁵ represents oxo, R^6a and R^6b both represent hydrogen, R^8a represents -CH2-R^Z (such as -CH2-OH) and R^8b represents hydroxy; or

13. The compound as defined in any one of claims 1 to 11 , wherein X represents -O- and:

R⁵ represents oxo and R^8a and R^8b both represent hydrogen; or R⁵ represents oxo, R^8a represents -CH2-R^Z (such as -CH2-OH) and R^8b represents hydrogen.

14. The compound as defined in any one of claims 1 to 11 , wherein X represents -N(R⁷)- and:

R⁵ represents oxo, R⁷ represents hydrogen, R^8a represents -CH2-R^Z (such as -CH2- OH) and R^8b represents hydrogen; or

R⁵ represents oxo, R⁷ represents C1-6 alkylamino optionally substituted by one or more (e.g. 1 or 2) hydroxyl groups (such as -CH₂-CH₂0H-CH₂-N(Me)₂) and R^8a and R^8b both represent hydrogen; or

R⁵ represents oxo, R⁷ represents C1-6 alkylsulfonimidoyl (such as -(CH₂)₂-S(=0)(=NH)(Me)) and R^8a and R^8b both represent hydrogen.

15. The compound as defined in any one of claims 1 to 14, wherein R⁹ represents hydrogen, halogen (such as fluorine or chlorine) or Ci-e alkyl (such as methyl).

16. The compound as defined in any one of claims 1 to 15, wherein R¹⁰ represents phenyl or a 5 or 6 membered heteroaryl ring (such as pyridyl or pyrazolyl) optionally fused to a 5 membered heteroaryl ring (such as pyrrolopyridinyl) wherein said phenyl or heteroaryl rings may optionally each be substituted by one or more (e.g. 1, 2 or 3) Ci-e alkyl (such as methyl or isopropyl), Ci-e alkoxy (such as methoxy), Ci-e alkanol (such as CH2OH), - CONR‘R^u (such as -CONH2), -CH2-NR‘R^U (such as -CH2-NH2), halogen (such as fluorine or chlorine), cyano or haloCi-₆ alkyl (such as trifluoromethyl).

17. The compound as defined in any one of claims 1 to 16, wherein R¹¹ represents hydrogen, halogen (such as chlorine) or C1-6 alkyl (such as methyl).

18. The compound as defined in claim 1, wherein the compound is the free base of a compound of Examples 1-66 or a pharmaceutically acceptable salt or solvate thereof.

19. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 18.

20. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 18, in combination with one or more therapeutic agents.

21. A compound as defined in any of claims 1 to 18 for use in therapy.

22. A compound as defined in any of claims 1 to 18 for use in the prophylaxis or treatment of cancer.

23. A process for preparing a compound of formula (I) as herein defined in claim 1 which comprises:

(a) reacting a compound of formula (II):

wherein R⁵, X, R^8a, R^8b, Y, R¹⁰ and R¹¹ are as defined in claim 1, with a compound of formula

(III):

wherein R¹, R², R³ and W are as defined in claim 1 and L¹ represents a suitable leaving group, such as a halogen atom (e.g. chlorine);

(b) reacting a compound of formula (IV):

(IV) wherein R¹, R², R³, W, R⁵, X, R^8a, R^8b, Y and R¹¹ are as defined in claim 1, with a compound of formula R¹⁰-L², wherein R¹⁰ is as defined in claim 1 and L² represents a suitable leaving group, such as boronic acid or a halogen atom (e.g. fluorine);

(c) deprotection of a protected derivative of a compound of formula (I);