Compounds for treating ras mutant cancers

Abstract

The present specification relates to compounds, and pharmaceutically acceptable salts thereof, that inhibit the growth of cancers that express G13D mutant Ras proteins. The molecules of the specification are thus indicated for use in the treatment of Ras G13D mutant cancers and for use in methods for the treatment of Ras G13D mutant cancers.

Description

[0001] Compounds for treating Ras mutant cancers

[0002] The present specification relates to compounds, and pharmaceutically acceptable salts thereof, that inhibit the growth of cancers that express G13D mutant Ras proteins. The molecules of the specification are thus indicated for use in the treatment of Ras G13D mutant cancers and for use in methods for the treatment of Ras G13D mutant cancers. The specification also relates to processes and intermediate compounds involved in the preparation of compounds according to the specification and to pharmaceutical compositions comprising them.

[0003] The KRAS, NRAS and HRAS genes encode a set of closely related small GTPase proteins KRas, NRas and HRas, collectively referred to herein as the Ras proteins or Ras, that share 82-90% overall sequence identity. Ras proteins are critical components of signalling pathways transmitting signals from cellsurface receptors to regulate cellular proliferation, survival and differentiation. Ras functions as a molecular switch cycling between an inactive GDP-bound state (the OFF state) and an active GTP-bound state (the ON state). The GDP / GTP cycle of Ras is tightly regulated in cells by guanine nucleotide exchange factors (GEFs) such as Sosl and Sos2, that promote the exchange of GDP for GTP, and GTPase activating proteins (GAPs) such as NF-1 and pl20RasGAP that stimulate the intrinsic GTPase activity of Ras hydrolysing GTP to GDP.

[0004] The Ras proteins are 188-189 amino acids in length and have a highly conserved N-terminal G-domain containing the p-loop region, which binds nucleotide, and the switch I and switch II regions which are important for regulatory and effector protein interactions. The C-terminal region of the Ras proteins are more divergent and contain elements which regulate the association of Ras with the membrane including the conserved carboxyl terminal CAXX box motif which is necessary for post-translational prenylation modifications. On binding to GTP the switch I and switch II regions of Ras undergo a conformational change which enables its interaction and activation of effector proteins to regulate down-stream signalling pathways. The best characterised effector of Ras is the serine / threonine kinase Raf which regulates the activity of the mitogen-activated protein kinase (MAPK) pathway. The PI3K pathway is another important effector pathway down-stream of Ras with the pllO catalytic subunit of the class I phosphoinositide 3 -kinases interacting with Ras. Other effectors of Ras including RaIGDS, Tiaml, PLC-E and Rassfl have also been described (see e.g. Cox, et al. Nature Reviews Drug Discovery, 2014, 13:828-851).

[0005] RAS mutations are frequently found in cancer and approximately 30% of all human cancers have a mutation in their KRAS, NRAS or HRAS genes. Oncogenic Ras is typically, but not exclusively, associated with mutations at glycine 12, glycine 13 or glutamine 61 of Ras. These residues are located at theactive site of Ras and mutations impair intrinsic and / or GAP-catalysed GTPase activity favouring the formation of GTP bound Ras that drives activation of down-stream effector pathways. KRAS is the most frequently mutated RAS gene in cancer followed by NRAS and then HRAS. There are several tumour types that exhibit a high frequency of activating mutations in KRAS including pancreatic (~90% prevalence), colorectal (~40% prevalence) and non-small cell lung cancer (~30% prevalence). KRAS mutations are also found in other cancer types including multiple myeloma, uterine cancer, bile duct cancer, stomach cancer, bladder cancer, diffuse large B cell lymphoma, rhabdomyosarcoma, cutaneous squamous cell carcinoma, cervical cancer, testicular germ cell cancer and others.

[0006] The mutation frequencies across the RAS isoforms are distinct and different. G12 mutations comprise 83% of all KRAS mutations, followed by G13 mutations (14%), while Q61 mutations are relatively rare (ca 2%). Q61, meanwhile, is the predominantly mutated hotspot in NRAS, followed by G12 and G13. HRAS displays an intermediate mutation pattern, with similar mutation frequencies found across G12, G13 and Q61. In addition, the mutation frequency within individual RAS isoforms can exhibit significant differences between cancer types.

[0007] Recently, the first Ras targeted therapy, sotorasib, was approved by the FDA. Sotorasib forms an irreversible covalent bond with the cysteine of KRas G12C mutant to hold the protein in its inactive form (the OFF state). The approval of sotorasib is the culmination of an extensive research efforts on the development of covalent inhibitors exploiting the presence of the cysteine (in place of glycine found in wild type protein) of KRas G12C. A second RasG12C inhibitor, adagrasib, was subsequently approved in December 2022. Targeting of other Ras mutants such as Ras G12D relies predominantly on non-covalent inhibitors and is currently a very active area of research.

[0008] The KRas G13D mutation is enriched in colorectal cancers, and is also found, albeit with lesser frequency, in a range of other cancers, for example in lung and pancreatic tumours. KRas G13D is therefore a significant, and to date unaddressed, target for cancer therapy, for example for the treatment of colorectal, lung and pancreatic cancer. It is an object of the present specification to provide Ras G13D inhibitors that can be used in the treatment of cancer and in particular in the treatment of Ras G13D mutant cancers.

[0009] Accordingly, in a first aspect the present specification provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0010]

[0011] wherein:

[0012] X is CH2, CHOH, CHNH2, S, SO, SO2, SO(=NH) or CHCH2OH;

[0013] Y is CH or N;

[0014] R4is H, F, Cl, OMe or CN;

[0015] R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0016] R6is H or F;

[0017] R7is F, Cl, Br, I, Me, CN, CCH or CCMe;

[0018] Ar is selected from

[0019] Ra

[0020]

[0021] wherein * denotes the point of attachment to X;

[0022] Z, where present, is independently selected from N and CH;

[0023] J, where present, is selected from 0 and S;

[0024] Rais selected from F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0025] Rbis selected from H, F, Cl, CN, OH, and Me;

[0026] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and Ci fluoroalkyl; and

[0027] Rdis selected from H, Me, Ci-C3alkyl, CHF2, CF3, Ci-C3fluoroalkyl, cyclopropyl, NH2, NHMe and NMe2.

[0028] In a related aspect, the specification provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof,R® d

[0029] R6XVJ^uNY

[0030]

[0031] R(ID

[0032] wherein:

[0033] Y is CH or N;

[0034] R4is H, F, Cl, OMe or CN;

[0035] R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0036] R6is H or F;

[0037] R7is F, Cl, Br, I, Me, CN, CCH or CCMe;

[0038] Ar is selected from

[0039]

[0040] wherein * denotes the point of attachment to the CH2group;

[0041] Z, where present, is independently selected from N and CH;

[0042] J, where present, is selected from 0 and S;

[0043] Rais selected from F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0044] Rbis selected from H, F, Cl, CN, OH, and Me; and

[0045] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and Ci fluoroalkyl.

[0046] In embodiments, the specification provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof,

[0047]

[0048] wherein:

[0049] Y is CH or N;

[0050] R4is H, F, Cl, OMe or CN;R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0051] R6is H or F;

[0052] R7is F, Cl, Br, I, Me, CN, CCH or CCMe;

[0053] Ar is selected from

[0054]

[0055] wherein * denotes the point of attachment to the CHOH group;

[0056] Z, where present, is independently selected from N and CH;

[0057] J, where present, is selected from 0 and S;

[0058] Rais selected from F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0059] Rbis selected from H, F, Cl, CN, OH, and Me; and

[0060] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and Ci fluoroalkyl.

[0061] In a related aspect, the specification provides a compound of Formula (IV), or a pharmaceutically acceptable salt thereof,

[0062]

[0063] wherein:

[0064] X is S, SO, SO2or SO(=NH);

[0065] Y is CH or N;

[0066] R4is H, F, Cl, OMe or CN;

[0067] R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0068] R6is H or F;

[0069] R7is F, Cl, Br, I, Me, CN, CCH or CCMe;

[0070] Ar is selected from

[0071]

[0072] wherein * denotes the point of attachment to X;

[0073] Z, where present, is independently selected from N and CH;

[0074] J, where present, is selected from 0 and S;

[0075] Rais selected from F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0076] Rbis selected from H, F, Cl, CN, OH, and Me; and

[0077] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and Ci fluoroalkyl.

[0078] In a related aspect the present specification provides a compound of Formula (V), or a pharmaceutically acceptable salt thereof,

[0079]

[0080] for use in the treatment of a Ras G13 mutant cancer wherein:

[0081] X is CH2, CHOH, CHNH2, S, SO, SO2, SO(=NH) or CHCH2OH;

[0082] Y is CH or N;

[0083] R4is H, F, Cl, OMe or CN;

[0084] R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0085] R6is H or F;

[0086] R7is H, F, Cl, Br, I, Me, CN or CCH;

[0087] Ar is selected from

[0088]

[0089] wherein * denotes the point of attachment to X;

[0090] Z, where present, is independently selected from N and CH;

[0091] J, where present, is selected from 0 and S;

[0092] Rais selected from H, F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0093] Rbis selected from H, F, Cl, CN, OH, and Me;

[0094] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and C1fluoroalkyl; and

[0095] Rdis selected from H, Me, C1-C3 alkyl, CHF2, CF3, C1-C3fluoroalkyl, cyclopropyl, NH2, NHMe and NMe2for use in the treatment of cancer, wherein the cancer has a RasG13 mutation.

[0096] In a related aspect the present specification provides a method of treatment of a RasG13 mutant cancer comprising administration of a compound of Formula (V), or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In such aspects a pharmaceutically effective amount of the compound of Formula (V) will be administered.

[0097] In a further aspect there is provided a compound of Formula (I), (II), (III) or (IV), or a pharmaceutical acceptable salt thereof, for use as a medicine.

[0098] In a further aspect there is provided a compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutical acceptable salt thereof, for use in the treatment of a Ras G13 mutant cancer.

[0099] In a related aspect there is provided a compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the cancer is a Ras G13 mutant cancer.

[0100] In a related aspect there is provided a method of treatment of cancer comprising administration of a compound of Formula (I), (II), (III) or (IV), or a pharmaceutical acceptable salt thereof, to a patient in need of treatment. In such aspects that cancer may be a Ras G13 mutant cancer. In such aspectsadministration of an effective amount of the compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, is envisaged.

[0101] In a further aspect there is provided a compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutical acceptable salt thereof, for use in the manufacture of a medicament, for example a medicament for the treatment of cancer. In such aspects that cancer may be a Ras G13 mutant cancer.

[0102] In a further aspect there is provided a pharmaceutical composition comprising a compound of Formula (I), (II), (III) or (IV), or a pharmaceutical acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0103] In a further aspect there is provided a kit comprising a pharmaceutical composition comprising a compound of Formula (I), (II), (III) or (IV), or a pharmaceutical acceptable salt thereof, and instructions for its use in the treatment of cancer. In such aspects the cancer may be a Ras G13 mutant cancer. In a further aspect there is provided a method of treatment comprising the steps of:

[0104] i) analysing a sample obtained from a patient;

[0105] ii) determining that the patient has a cancer that has a Ras G13 mutation; and

[0106] iii) administering a compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, to the patient.

[0107] In a further aspect there is provided a process for producing a compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof.

[0108] As described herein below, the compounds of the specification inhibit the proliferation of Ras G13 mutant cancer cells, in particular RasG13D mutant cancer cells, in vitro, yet do not exhibit significant anti-proliferative activity in cancer cells that express wild type Ras. Accordingly, compounds of Formula (I) are identified as RasG13D inhibitors, i.e. compounds that can selectively inhibit the growth of cancers with a G13D mutation in Ras protein relative to cancers or normal cells that express wild type Ras protein. The lack of significant anti-proliferative activity against wild type Ras cancers and healthy cells at pharmacologically relevant concentrations demonstrates that the anti-proliferative activity in Ras G13D cells is not a simple cytotoxic effect. The precise mechanism by which the compounds express their activity against Ras G13D mutant cancers is being investigated. As the skilled reader will understand, compounds of Formula (II), (III) and (IV) are compounds falling within the broader group of compounds of Formula (I) and possess the same ability to inhibit the growth of RasG13D cancers.The favourable molecular weight, and log D values, of compounds of Formula (I) combined with the number of hydrogen bond donors and acceptors they possess, indicate the suitability of these compounds as orally bioavailable agents as will be understood by persons of skill in the art. In addition, selected compounds according to the specification have been shown to inhibit the growth of cancers in in vivo models following oral administration. Accordingly, compounds of Formula (I) are identified herein as potential oral agents for the treatment of Ras G13D cancers, i.e. those cancers that possess a mutation in which the glycine residue at position 13 of wild type Ras is replaced with an aspartic acid residue.

[0109] In addition to disclosing the Ras G13D inhibitory properties of the compound of Formula (I), the present specification also relates to processes for the manufacture of said compounds, to pharmaceutical compositions containing them, to methods of treatment comprising administering the said compounds to patients, for example humans, in need thereof, and to the use of compounds of Formula (I) for the manufacture of medicaments, for example for use in the treatment of a patient suffering from a hyperproliferative disease such as cancer.

[0110] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0111] So that the present specification may be more readily understood, certain terms are explicitly defined below. In addition, definitions are set forth as appropriate throughout the detailed description.

[0112] Units, prefixes, and symbols are denoted in their Systeme International d'Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0113] The term "pharmaceutical composition" refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be expressed in a patient treated with such a composition, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered. Such compositions can be sterile. A pharmaceutical composition according to the present specification will comprise a compound of Formula (I), or a pharmaceutical acceptable salt thereof, and at least one pharmaceutically acceptable excipient.Terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and / or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. In certain aspects, a subject is successfully "treated" for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer.

[0114] The term "subject" refers to any animal (e.g., a mammal), including, but not limited to humans, nonhuman primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0115] References to a compound of Formula (I) herein encompasses the free base form of the compound of Formula (I), as well as pharmaceutically acceptable salts of a compound of Formula (I). In embodiments reference to a compound of Formula (I) refers to the free base form of the compound of Formula (I).

[0116] The compounds of Formula (I) include those with an indole (Y = CH) or indazole (Y = N) core substituted with a group XAr at C-3. Substitutions with groups R4, R5, R6and R7at C-4, C-5, C-6 and C-7, respectively, of the indole or indazole, are also provided.

[0117]

[0118] As the skilled person will understand the group X can, in certain instances, exist as two enantiomeric forms as is the case for example wherein X is selected from CHOH, SO and SONH2. In such instances the compound of Formula (I), (III), (IV) or (V) can exist as a mixture of stereoisomers, or as a substantially pure single enantiomeric form, for example the compound may be present with a group X that is CHOH and that is in the ( / ?)- or (S)-configuration.

[0119] As used herein the term "alkyl" refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. In instances, the alkyl group can be a deuteroalkyl group in which one or more, optionally all, hydrogens are replaced with deuterium atoms. Ha loalkyl groups are alkyl groups in which one or more, optionally all, hydrogens are replaced with chlorine or fluorine atoms. As used herein the term fluoroalkyl refers to an alkyl group in whichone or more, optionally all, hydrogens are replaced with fluorine atoms or an alkyl group in which at least one hydrogen is replaced with a fluorine atom and up to 2 hydrogen atoms are replaced with chlorine atoms. Examples of fluoroalkyl groups include CH2F, CHF2, CF3, CH2CF3, CF2CH3and CF2CF3. Examples of fluoroalkyl groups in which up to 2 hydrogen atoms are replaced with chlorine atoms include CF2Cl, CFCl2, CFCl2F and CH2CF2Cl. Cycloalkyl groups are saturated carbocycles, for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. Fluorocycloalkyl groups are saturated carbocycles, for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group in which at least one constituent hydrogen is replaced with a fluorine.

[0120] For the avoidance of doubt, in the compounds of the specification all atoms have their normal valence and all constituent atoms of the group are explicitly listed. Thus, when R5is a group CCH it is an acetylene group featuring a carbon-carbon triple bond and when R5is a CN group it is a cyano group featuring a carbon-nitrogen triple bond.

[0121] Among the examples provided herein are compounds that have been synthesized and / or isolated as single enantiomers, albeit the precise stereochemical configuration has not been established or assigned. To reflect this, in the experimental section herein, rather than specifying the absolute stereochemistry in the names of such compounds the term "re!" is used to denote an enantiomerically pure compound with unassigned absolute stereochemistry. Nonetheless in isolating and providing both possible isomers, the skilled reader will understand that one of isomers 1 and 2 must be the ( / ?)-form and the other will be the (S)-form.

[0122] Unless specifically stated, as is the case for the attachment of the group Ar wherein the atom attached to the group X is indicated with a *, the bonding of an atom or group to the rest of the molecule may be through any suitable atom of that group; for example, reference to propyl includes prop-l-yl and prop-2-yl.

[0123] The group Ar in the compounds of Formula (I) is selected from

[0124]

[0125] wherein * denotes the point of attachment i.e. the carbon atom that is connected to the group X (as illustrated below for example for a compound of Formula (I) in which X is CH2, Y is CH, Ar is a thiazole, R4is Cl, R5is F, R6is H and R7is CCH).

[0126]

[0127] As noted above, in a first embodiment the specification provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0128]

[0129] wherein:

[0130] X is CH2, CHOH, CHNH2, S, SO, SO2, SO(=NH) or CHCH2OH;

[0131] Y is CH or N;

[0132] R4is H, F, Cl, OMe or CN;

[0133] R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0134] R6is H or F;

[0135] R7is F, Cl, Br, I, Me, CN, CCH or CCMe;

[0136] Ar is selected from

[0137]

[0138] wherein * denotes the point of attachment to X;

[0139] Z, where present, is independently selected from N and CH;J, where present, is selected from 0 and S;

[0140] Rais selected from F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0141] Rbis selected from H, F, Cl, CN, OH, and Me;

[0142] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and C1fluoroalkyl; and

[0143] Rdis selected from H, Me, C1-C3 alkyl, CHF2, CF3, C1-C3 fluoroalkyl, cyclopropyl, NH2, NHMe and NMe2.

[0144] In embodiments, the compound of Formula (I) is a compound of Formula (la) wherein the group Ar is selected from

[0145] Ra

[0146]

[0147] In embodiments, the compound of Formula (I) is a compound of Formula (lb) wherein the group Ar is

[0148]

[0149] In embodiments the compound of Formula (I) is a compound of Formula (Ic) wherein the group Ar is

[0150]

[0151] In embodiments the compound of Formula (I) is a compound of Formula (Id) wherein the group Ar is Ra

[0152]

[0153] In embodiments the compound of Formula (I), (la), (lb), (Ic) or (Id) is a compound of Formula (le) wherein Y is CH.

[0154] In embodiments the compound of Formula (I), (la), (lb), (Ic) or (Id) is a compound of Formula (If) in wherein Y is N.

[0155] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le) or (If) is a compound of Formula (Ig) wherein X is CH2, in which case the compound of Formula (Ig) is a compound of Formula (Iga) asshown below, or CHOH, in which case the compound of Formula (Ig) is a compound of Formula (Igb) as shown below. It will be understood that reference to a compound of Formula (Ig) herein should be read as referring to a both a compound of Formula (Iga) and a compound Formula (Igb) or as referring to a compound of Formula (Iga) or a compound of Formula (Igb).

[0156]

[0157] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le) or (If) is a compound of Formula (Ih) wherein X is S, SO, SO2 or SO(=NH).

[0158] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Iga), (Igb) or (Ih) is a compound of Formula (li) wherein R6is H.

[0159] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Iga), (Igb), (Ih) or (li) is a compound of Formula (Ij) wherein the group Rais selected from Cl, Br, I, OMe or CN.

[0160] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Iga), (Igb), (Ih), (li) or (Ij) is a compound of Formula (Ik) wherein the group Rb, where present, is selected from H, F and Cl or the group Rc, where present, is selected from H, F, and Cl.

[0161] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Iga), (Igb), (Ih), (li), (Ij) or (Ik) is a compound of Formula (Im) wherein the group R4is Cl or F.

[0162] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Iga), (Igb), (Ih), (li), (Ij), (Ik) or (Im) is a compound of Formula (In) in which the group R7is F, CCH or CN.

[0163] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Iga), (Igb), (Ih), (li), (Ij), (Ik), (Im) or (In) is a compound of Formula (Io) in which the group R5is selected from F, Cl, Br, CN and CCH.

[0164] In embodiments the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from:

[0165] 5-chloro-3-((5-chloropyridin-2-yl)thio)-lH-indole-7-carbonitrile;

[0166] 5-chloro-3-(pyridin-2-ylthio)-lH-indole-7-carbonitrile;

[0167] 3-((lH-l,2,4-triazol-3-yl)thio)-5-chloro-1H-indole-7-carbonitrile;

[0168] 5-chloro-3-((5-chloropyridin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile;5-chloro-3-((5-ch loropyrazin-2-yl)thio)-l H-indole-7-carbon itrile;

[0169] 3-((5-chloropyridin-2-yl)thio)-5-methoxy-lH-indole-7-carbonitrile;

[0170] 3-((5-chloropyridin-2-yl)thio)-5-(difluoromethoxy)-lH-indole-7-carbonitrile;

[0171] 3-((5-chloropyridin-2-yl)thio)-7-fluoro-lH-indole-5-carbonitrile;

[0172] 5,7-dichloro-3-((5-chloropyridin-2-yl)thio)-lH-indole;

[0173] 5-chloro-3-((5-ch loropyrid in-2-yl)thio)-lH-indole;

[0174] 5-chloro-3-((5-chloropyridin-2-yl)thio)-7-fluoro-lH-indole;

[0175] 5-chloro-3-((5-cyanopyridin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile;

[0176] 4,5-dichloro-3-((5-cyanopyridin-2-yl)thio)-lH-indole-7-carbonitrile;

[0177] 5-bromo-3-( (5-ch loropyrid in-2-yl)thio)-lH-indole-7-carbon itrile;

[0178] 3-((5-chloropyridin-2-yl)thio)-5-(trifluoromethoxy)-lH-indole-7-carbonitrile;

[0179] 3-((5-bromopyrimidin-2-yl)thio)-5-chloro-1H-indole-7-carbonitrile;

[0180] 3-((5-cyanopyridin-2-yl)thio)-4-fluoro-5-methoxy-lH-indole-7-carbonitrile;

[0181] 4-chloro-3-((5-cyanopyridin-2-yl)thio)-5-methoxy-lH-indole-7-carbon itrile;

[0182] 3-((3-(aminomethyl)-4-chlorophenyl)thio)-5-chloro-1H-indole-7-carbonitrile;

[0183] 2-(3-((5-chloropyridin-2-yl)thio)-lH-indol-5-yl)aceton itrile;

[0184] 3-((2-amino-4-chlorophenyl)thio)-5-chloro-lH-indole-7-carbon itrile;

[0185] 6-((5-chloro-7-ethynyl-lH-indol-3-yl)thio)nicotinon itrile;

[0186] 5-chloro-3-((5-chloropyridin-2-yl)thio)-7-(prop-l-yn-l-yl)-lH-indole;

[0187] 5-chloro-3-((5-cyanopyrazin-2-yl)thio)-lH-indole-7-carbon itrile;

[0188] 5-chloro-3-((5-cyanopyrazin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile;

[0189] 5-chloro-3-((4-chloro-2-(hyd ro xym ethyl) phenyl)thio)-lH-indole-7-carbon itrile;

[0190] 5-chloro-3-((5-cyanopyridin-2-yl)thio)-lH-indole-7-carbon itrile;

[0191] 5-chloro-3-((5-cyanopyrimidin-2-yl)thio)-4-fluoro-lH-indole-7-carbon itrile;

[0192] 3-((5-chloropyridin-2-yl)sulfonyl)-5-methoxy-lH-indole-7-carbon itrile;

[0193] 3-(5-chloropyridine-2-sulfonimidoyl)-5-methoxy-lH-indole-7-carbonitrile;

[0194] 5-chloro-3-((5-chloropyridin-2-yl)sulfinyl)-7-fluoro-lH-indole;

[0195] 5-bromo-3-((5-chloropyridin-2-yl)sulfonyl)-lH-indole-7-carbonitrile;

[0196] 5-bromo-3-( 5-ch loropyrid ine-2-sulfonimidoyl)-lH-indole-7-carbonitrile;

[0197] (5-chloro-7-fluoro-lH-indol-3-yl)(4-chlorophenyl)(imino)-l6-sulfanone;

[0198] 5-chloro-3-((5-chloropyridin-2-yl)sulfonyl)-7-ethynyl-lH-indole;

[0199] rac-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-lH-indole-7-carbon itrile;

[0200] rac-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-4-fluoro-lH-indole-7-carbon itrile; rac-5-bromo-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;rac-5-chloro-3-((4-ch lorophenyl)(hydroxy)methyl)-l H-indole-7-carbonitrile;

[0201] rac-3-((5-bromopyridin-2-yl)(hydroxy)methyl)-5-ch loro-1 H-indole-7-carbonitrile;

[0202] rac-3-((5-bromopyrazin-2-yl)(hydroxy)methyl)-5-chloro-1H-indole-7-carbonitrile;

[0203] rac-5-chloro-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0204] rac-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0205] rac-5-chloro-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0206] rac-5-bromo-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0207] rac-4,5-dichloro-3-((5-cyanopyridin-2-yl)(hyd roxy)methyl)-lH-indole-7-carbonitrile;

[0208] rac-5-chloro-3-((4-cyanophenyl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0209] rac-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-4-fluoro-5-methoxy-lH-indole-7-carbonitrile;

[0210] rac-4-chloro-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-5-methoxy-lH-indole-7-carbonitrile;

[0211] rac-6-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile;

[0212] rac-3-((5-bromothiazol-2-yl)(hydroxy)methyl)-5-chloro-1H-indole-7-carbonitrile;

[0213] rac-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-1H-indole-7-carbonitrile;

[0214] rac-(5-bromopyrazin-2-yl)(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methanol;

[0215] rac-6-((5-chloro-7-ethynyl-4,6-difluoro-lH-indol-3-yl)(hydroxy)methyl)nicoti nonitrile;

[0216] rac-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-lH-indole-7-carbonitrile; rac-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-5-(trifluoromethoxy)-lH-indole-7-carbonitrile; rac-6-((5,7-dichloro-4-fluoro-lH-indol-3-yl)(hydroxy)methyl) nicotinonitrile;

[0217] rac-2-((7-ethynyl-4-fluoro-5-(trifluoromethyl)-lH-indol-3-yl)(hyd roxy)methyl)pyrimidine-5-carbonitrile;

[0218] rac-5-bromo-4-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile; rac-2-((5-bromo-4-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile; rac-5-chloro-4-fluoro-3-(hydroxy(5-(trifluoromethyl) pyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile; rac-2-((7-ethynyl-4-fluoro-5-iodo-lH-indol-3-yl)(hyd ro xy) methyl) pyrim id ine-5-carbonitrile;

[0219] rac-6-((7-bromo-5-chloro-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile;

[0220] rac-6-((5-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile;

[0221] rac-2-((5-chloro-7-cyano-lH-indol-3-yl)(hydroxy)methyl)thiazole-5-carbonitrile;

[0222] rac-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0223] rac-2-((5-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0224] rac-2-((5-chloro-7-cyano-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)thiazole-5-carbonitrile;

[0225] rac-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl) pyrim idine-5-carbonitrile; rac-5-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrazine-2-carbonitrile;

[0226] rac-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)thiazole-5-carbonitrile;rac-2-( (5,7-dich loro-4-fluoro-l H-indol-3-yl) (hydroxy)methyl)pyrimidine-5-carbonitrile;

[0227] 3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-5-methyl-lH-indole-7-carbonitrile;

[0228] rac-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0229] (R)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0230] (S)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0231] (R)-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0232] (S)-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0233] (R)-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0234] (S)-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0235] (R)-5-chloro-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0236] (S)-5-chloro-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0237] (R)-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile;

[0238] (S)-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile;

[0239] (R)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0240] (S)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0241] (R)-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyrimidin-2-yl)methanol;

[0242] (S)-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyrimidin-2-yl)methanol;

[0243] (R)-5-bromo-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0244] (S)-5-bromo-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0245] (R)-4,5-dichloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0246] (S)-4,5-dichloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0247] (R)-2-((5-bromo-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0248] (S)-2-((5-bromo-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0249] (R)-5-bromo-4-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0250] (S)-5-bromo-4-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;

[0251] (R)-2-((5-bromo-4-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0252] (S)-2-((5-bromo-4-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0253] (R)-5-chloro-4-fluoro-3-(hydroxy(5-(trifluoromethyl) pyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile; (S)-5-chloro-4-fluoro-3-(hydroxy(5-(trifluoromethyl) pyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile; (R)-2-((5-chloro-4-fluoro-7-methyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0254] (S)-2-((5-chloro-4-fluoro-7-methyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0255] (R)-2-((7-ethynyl-4-fluoro-5-iodo-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile, Isomer 1; (S)-2-((7-ethynyl-4-fluoro-5-iodo-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0256] ( / ?)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4,6-difluoro-lH-indole-7 -carbonitrile;(S)-5-chloro-3-((5-cya nopyrim id in-2-yl)(hyd roxy)methyl)-4,6-difluoro-lH-indole-7-ca rbonitrile; (R)-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile; (S)-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hyd roxy)methyl)pyrimidine-5-carbonitrile; rac-5-chloro-3-(l-(4-chlorophenyl)-2-hydroxyethyl)-lH-indole-7-ca rbonitrile;

[0257] rac-5-chloro-3-(l-(5-chloropyridin-2-yl)-l-hydroxyethyl)-lH-indole-7-carbonitrile;

[0258] 5-chloro-3-((5-chloropyridin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0259] 5-chloro-3-((5-cyanopyridin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0260] 5-chloro-3-(4-chlorobenzyl)-lH-indole-7-ca rbonitrile;

[0261] 5-chloro-3-(pyridin-2-ylmethyl)-lH-indole-7-ca rbonitrile;

[0262] 3-((5-bromopyridin-2-yl)methyl)-5-chloro-lH-indole-7-ca rbonitrile;

[0263] 5-chloro-3-((5-cyanopyridin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0264] 5-chloro-3-((5-chloropyrazin-2-yl)methyl)-lH-indole-7-ca rbonitrile;

[0265] 3-((5-bromothiazol-2-yl)methyl)-5-chloro-1H-indole-7-carbonitrile;

[0266] 5-chloro-3-((4,4-difluorocydohexyl)methyl)-lH-indole-7-ca rbonitrile;

[0267] 3-((5-chloropyridin-2-yl)methyl)-7-fluoro-lH-indole-5-carbonitrile;

[0268] 4, 5-dichloro-3-((5-cyanopyridin-2-yl)methyl)-lH-indole-7-ca rbonitrile;

[0269] 5-chloro-3-(4-cyano-2-fluorobenzyl)-lH-indole-7-carbonitrile;

[0270] 5-chloro-3-(4-cyanobenzyl)-lH-indole-7-carbonitrile;

[0271] 3-((5-chloropyridin-2-yl)methyl)-5-(difluoromethoxy)-lH-indole-7-ca rbonitrile;

[0272] 3-((5-chloropyridin-2-yl)methyl)-5-(trifluoromethoxy)-lH-indole-7-ca rbonitrile;

[0273] 6-((5-chloro-7-ethynyl-lH-indol-3-yl)methyl) nicotinonitrile;

[0274] 5-chloro-3-((5-cyanopyridin-2-yl)methyl)-4-methoxy-lH-indole-7-carbonitrile;

[0275] 6-((5,7-dichloro-4-fluoro-lH-indol-3-yl)methyl)nicotinonitrile;

[0276] 6-((5-bromo-4,7-difluoro-lH-indol-3-yl)methyl) nicotinonitrile;

[0277] 3-((5-bromopyridin-2-yl)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile;

[0278] 6-((5-chloro-4,7-difluoro-lH-indol-3-yl)methyl) nicotinonitrile;

[0279] 6-((7-bromo-5-chloro-4-fluoro-lH-indol-3-yl)methyl) nicotinonitrile;

[0280] 5-chloro-4-fluoro-3-((5-(trifluoromethyl)pyridin-2-yl)methyl)-lH-indole-7-ca rbonitrile;

[0281] 5-bromo-3-((5-cyanopyridin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0282] 3-((5-cyanopyridin-2-yl)methyl)-4-fluoro-5-methoxy-lH-indole-7-carbonitrile;

[0283] 4-chloro-3-((5-cyanopyridin-2-yl)methyl)-5-methoxy-lH-indole-7-carbonitrile;

[0284] 3-((5-bromopyrazin-2-yl)methyl)-5-chloro-1H-indole-7-carbonitrile;

[0285] 3-((5-bromopyrimidin-2-yl)methyl)-5-chloro-lH-indole-7-ca rbonitrile;

[0286] 2-(3-((5-chloropyridin-2-yl)methyl)-lH-indol-5-yl)acetonitrile;5-chloro-3-(4-cyano-3-fluorobenzyl)-lH-indole-7-carbonitrile;

[0287] 5-chloro-4-fluoro-3-((5-methoxypyrimidin-2-yl)methyl)-1H-indole-7-carbonitrile;

[0288] 3-((5-cyanopyrimidin-2-yl)methyl)-4-fluoro-5-(trifluoromethyl)-lH-indole-7-carbonitrile; 3-((5-cyanopyridin-2-yl)methyl)-5-methyl-lH-indole-7-carbonitrile;

[0289] 3-((5-cyanopyridin-2-yl)methyl)-5-(difluoromethyl)-lH-indole-7-carbonitrile;

[0290] 3-((5-cyanopyridin-2-yl)methyl)-5-ethynyl-lH-indole-7-carbonitrile;

[0291] 3-((5-cyanopyridin-2-yl)methyl)-5-cyclopropyl-lH-indole-7-carbonitrile;

[0292] 5-chloro-4-fluoro-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0293] 5-chloro-3-((5-(difluoromethyl)pyridin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0294] 5-chloro-4-fluoro-3-((5-methylpyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0295] 5-chloro-3-(4-chloro-3-(hydroxymethyl)benzyl)-lH-indole-7-carbonitrile;

[0296] 5-chloro-3-((5-cyanopyrazin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0297] 2-((5,7-dichloro-4-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0298] 5-chloro-3-((5-cyanopyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0299] 5-chloro-3-((5-cyano-3-methoxypyridin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile; 2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0300] 2-((5,7-dichloro-4-fluoro-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;

[0301] 2-((5-chloro-4,7-difluoro-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;

[0302] 5-((5-chloro-7-cyano-lH-indol-3-yl)methyl)thiazole-2-carbonitrile;

[0303] 2-((5-chloro-7-ethynyl-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0304] 2-((5-chloro-4,7-difluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0305] 2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;

[0306] 2-((5-chloro-7-cyano-lH-indol-3-yl)methyl)oxazole-5-carbonitrile;

[0307] 2-((5-chloro-7-cyano-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;

[0308] 5-chloro-3-((5-cyanopyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0309] 4,5-dichloro-3-((5-cyanopyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0310] 5-chloro-3-((5-cyanopyrazin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0311] 2-((5-chloro-7-cyano-4-fluoro-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;

[0312] 5-chloro-3-((6-cyanopyridin-3-yl)methyl)-lH-indole-7-carbonitrile;

[0313] 5-chloro-3-((5-ethynylpyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile;

[0314] 5-chloro-3-((5-cyclopropylpyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile; 3-(3-amino-4-chlorobenzyl)-5-chloro-1H-indole-7-carbonitrile;

[0315] 5-chloro-3-(4-chloro-2-hydroxybenzyl)-lH-indole-7-carbonitrile;

[0316] 5-chloro-3-(4-cyano-2-hydroxybenzyl)-lH-indole-7-carbonitrile;6-((7-ethynyl-5-methoxy-lH-indol-3-yl)methyl)nicotinonitrile;

[0317] 6-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methyl)nicotinonitrile;

[0318] 5-chloro-3-(4-chlorobenzyl)-lH-indazole-7-carbonitrile;

[0319] 6-((5,7-dichloro-lH-indazol-3-yl)methyl)nicotinonitrile;

[0320] 6-((5-chloro-7-ethynyl-lH-indazol-3-yl)methyl)nicotinonitrile;

[0321] 5-chloro-3-((5-cyanopyridin-2-yl)thio)-lH-indazole-7-carbonitrile;

[0322] 5-chloro-3-((4-cyanophenyl)thio)-lH-indazole-7-carbonitrile;

[0323] 4-((5-chloro-7-fluoro-lH-indazol-3-yl)thio)benzonitrile;

[0324] 6-((5-chloro-7-fluoro-lH-indazol-3-yl)thio)nicotinonitrile;

[0325] 3-((5-bromopyridin-2-yl)thio)-5-chloro-7-fluoro-lH-indazole;

[0326] 2-((5-bromo-4,7-difluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0327] 2-((5-bromo-4-chloro-7-ethynyl-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0328] 5-bromo-4-chloro-3-((5-cyanopyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0329] 2-((4,5-dichloro-7-ethynyl-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0330] ( / ?)-2-((4,5-dichloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0331] (S)-2-((4,5-dichloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;

[0332] 5-bromo-4-fluoro-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0333] 4.5-dichloro-7-ethynyl-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole;

[0334] 5-chloro-7-ethynyl-4-fluoro-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole;

[0335] 4.5-dichloro-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0336] 2-((4,5-dichloro-7-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0337] 2-((5-bromo-4-chloro-7-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0338] 2-((4,7-difluoro-5-iodo-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;

[0339] 3-((5-cyanopyrimidin-2-yl)methyl)-5-(difluoromethyl)-4-fluoro-lH-indole-7-carbonitrile;

[0340] rac-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-5-(difluoromethyl)-4-fluoro-lH-indole-7-carbonitrile; 5-chloro-4-fluoro-3-((5-nitropyridin-2-yl)methyl)-lH-indole-7-carbonitrile;

[0341] rac-2-((5-chloro-7-ethynyl-4-methyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile (R)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-7-ethynyl-lH-indole-4-carbonitrile;

[0342] (S)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-7-ethynyl-lH-indole-4-carbonitrile;

[0343] (R)-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone; and (S)-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone.

[0344] In embodiments, the specification provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0345]

[0346] " (H)

[0347] wherein:

[0348] Y is CH or N;

[0349] R4is H, F, Cl, OMe or CN;

[0350] R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0351] R6is H or F;

[0352] R7is F, Cl, Br, I, Me, CN, CCH or CCMe;

[0353] Ar is selected from

[0354]

[0355] wherein * denotes the point of attachment to the CH2group;

[0356] Z, where present, is independently selected from N and CH;

[0357] J, where present, is selected from 0 and S;

[0358] Rais selected from F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0359] Rbis selected from H, F, Cl, CN, OH, and Me; and

[0360] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and Ci fluoroalkyl.

[0361] In embodiments the compound of Formula (II) is a compound of Formula (Ila) in which Y is CH.

[0362] In embodiments the compound of Formula (II) is a compound of Formula (lib) in which Y is N.

[0363] In embodiments the compound of Formula (II), (Ila) or (lib) is a compound of Formula (lie) wherein the group Ar is

[0364]

[0365] In embodiments the compound of Formula (II), (Ila) or (lib) is a compound of Formula (lid) wherein the group Ar is

[0366] Rb\

[0367]

[0368] In embodiments the compound of Formula (II), (Ila) or (lib) is a compound of Formula (lie) wherein the group Ar is

[0369]

[0370] In embodiments the compound of Formula (II), (Ila), (lib), (lie), (lid) or (lie) is a compound of Formula (Ilf) wherein the group R4is Cl or F.

[0371] In embodiments the compound of Formula (II), (Ila), (lib), (lie), (lid), (lie) or (Ilf) is a compound of Formula (llg) wherein the group R5is selected from F, Cl, Br, CN and CCH.

[0372] In embodiments the compound of Formula (II), (Ila), (lib), (lie), (lid), (lie), (Ilf) or (llg) is a compound of Formula (I I h) wherein the group R6is H.

[0373] In embodiments the compound of Formula (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (llg) or (llh) is a compound of Formula (Hi) wherein the group R7is selected from F, CN or CCH.

[0374] In embodiments the compound of Formula (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (llg), (llh) or (Hi) is a compound of Formula (llj) wherein the group Rais selected from Cl, Br, I, OMe or CN.

[0375] In embodiments the compound of Formula (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (llg), (llh), (Hi) or (llj) is a compound of Formula (Ilk) wherein the group Rais selected from Cl, Br or CN.

[0376] In embodiments the compound of Formula (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (llg), (llh), (Hi), (llj) or (Ilk) is a compound of Formula (I I m) wherein the group Rb, where present, is selected from H, F and Cl or the group Rcwhere present is selected from H, F, and Cl.

[0377] In embodiments, the specification provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof,

[0378]

[0379] wherein:

[0380] Y is CH or N;

[0381] R4is H, F, Cl, OMe or CN;

[0382] R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0383] R6is H or F;

[0384] R7is F, Cl, Br, I, Me, CN, CCH or CCMe;

[0385] Ar is selected from

[0386]

[0387] wherein * denotes the point of attachment to the CHOH group;

[0388] Z, where present, is independently selected from N and CH;

[0389] J, where present, is selected from 0 and S;

[0390] Rais selected from F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0391] Rbis selected from H, F, Cl, CN, OH, and Me; and

[0392] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and Ci fluoroalkyl.

[0393] In embodiments the compound of Formula (III) is a compound of Formula (Illa) in which Y is CH.

[0394] In embodiments the compound of Formula (III) is a compound of Formula (lllb) in which Y is N.

[0395] In embodiments the compound of Formula (III), (Illa) or (lllb) is a compound of Formula (111 c) wherein the group Ar is

[0396]

[0397] In embodiments the compound of Formula (III), (Illa) or (lllb) is a compound of Formula (llld) wherein the group Ar is

[0398]

[0399] In embodiments the compound of Formula (III), (Illa) or (lllb) is a compound of Formula (llle) wherein the group Ar is

[0400] Ra

[0401]

[0402] In embodiments the compound of Formula (III), (Illa), (lllb), (lllc), (llld) or (llle) is a compound of Formula (lllf) wherein the group R4is Cl or F.

[0403] In embodiments the compound of Formula (III), (Illa), (lllb), (lllc), (llld), (llle) or (lllf) is a compound of Formula (Illg) wherein the group R5is selected from F, Cl, Br, CN and CCH.

[0404] In embodiments the compound of Formula (III), (Illa), (lllb), (lllc), (llld), (llle), (lllf) or (Illg) is a compound of Formula (lllh) wherein the group R6is H.

[0405] In embodiments the compound of Formula (III), (Illa), (lllb), (lllc), (Hid), (llle), (lllf), (Illg) or (lllh) is a compound of Formula (Illi) wherein the group R7is selected from F, CN and CCH.

[0406] In embodiments the compound of Formula (III), (Illa), (lllb), (lllc), (I I Id), (llle), (lllf), (Illg), (lllh) or (Illi) is a compound of Formula (lllj) wherein the group Rais selected from Cl, Br, I, OMe or CN.

[0407] In embodiments the compound of Formula (III), (Illa), (lllb), (lllc), (llld), (llle), (lllf), (Illg), (lllh), (Illi) or (lllj) is a compound of Formula (lllk) wherein the group Rb, where present, is selected from H, F and Cl or the group Rc, where present, is selected from H, F, and Cl.

[0408] The specification provides a compound of Formula (IV), or a pharmaceutically acceptable salt thereof,

[0409]

[0410] wherein:

[0411] X is S, SO, SO2or SO(=NH);

[0412] Y is CH or N;

[0413] R4is H, F, Cl, OMe or CN;

[0414] R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0415] R6is H or F;

[0416] R7is F, Cl, Br, I, Me, CN, CCH or CCMe;

[0417] Ar is selected from

[0418]

[0419] wherein * denotes the point of attachment to X;

[0420] Z, where present, is independently selected from N and CH;

[0421] J, where present, is selected from 0 and S;

[0422] Rais selected from F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0423] Rbis selected from H, F, Cl, CN, OH, and Me; and

[0424] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and Ci fluoroalkyl.

[0425] In embodiments the compound of Formula (IV) is a compound of Formula (IVa) in which Y is CH.

[0426] In embodiments the compound of Formula (IV) is a compound of Formula (IVb) in which Y is N.

[0427] In embodiments the compound of Formula (IV), (IVa) or (IVb) is a compound of Formula (IVc) wherein the group Ar is

[0428]

[0429] In embodiments the compound of Formula (IV), (IVa) or (IVb) is a compound of Formula (IVd) wherein the group Ar isp I'bK a

[0430] . Cr

[0431] In embodiments the compound of Formula (IV), (IVa) or (IVb) is a compound of Formula (IVe) wherein the group Ar is

[0432]

[0433] In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd) or (IVe) is a compound of Formula (IVf) wherein the group R4is Cl or F.

[0434] In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf) is a compound of Formula (IVg) wherein the group R5is selected from F, Cl, Br, CN and CCH.

[0435] In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf) or (IVg) is a compound of Formula (IVh) wherein the group R6is selected from F, Cl, Br, CN and CCH.

[0436] In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg) or (IVh) is a compound of Formula (IVi) wherein the group R6is H.

[0437] In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh) or (IVi) is a compound of Formula (IVj) wherein the group Rais selected from Cl, Br, I, OMe or CN.

[0438] In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi) or (IVj) is a compound of Formula (IVk) wherein the group Rbwhere present is selected from H, F and Cl or the group Rcwhere present is selected from H, F, and Cl.

[0439] In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj) or (IVk) is a compound of Formula (IVI) wherein the group X is S.

[0440] In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj) or (IVk) is a compound of Formula (IVm) wherein the group X is SO.

[0441] In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj) or (IVk) is a compound of Formula (IVn) wherein the group X is SO2.In embodiments the compound of Formula (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj) or (IVk) is a compound of Formula (IVo) wherein the group X is SO(=NH).

[0442] In embodiments the specification provides a compound of Formula (V), or a pharmaceutically acceptable salt thereof,

[0443]

[0444] for use in the treatment of a Ras G13 mutant cancer wherein:

[0445] X is CH2, CHOH, CHNH2, S, SO, SO2, SO(=NH) or CHCH2OH;

[0446] Y is CH or N;

[0447] R4is H, F, Cl, OMe or CN;

[0448] R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;

[0449] R6is H or F;

[0450] R7is H, F, Cl, Br, I, Me, CN or CCH;

[0451] Ar is selected from

[0452]

[0453] wherein * denotes the point of attachment to X;

[0454] Z, where present, is independently selected from N and CH;

[0455] J, where present, is selected from 0 and S;

[0456] Rais selected from H, F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, OMe, OCF3, OCHF2, OCF2Cl, NO2and NMe2;

[0457] Rbis selected from H, F, Cl, CN, OH, and Me;

[0458] Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and Ci fluoroalkyl; and

[0459] Rdis selected from H, Me, Ci-C3alkyl, CHF2, CF3, Ci-C3fluoroalkyl, cyclopropyl, NH2, NHMe and NMe2.In embodiments, the compound of Formula (V) for use is a compound of Formula (Va) wherein the group Ar is selected from

[0460] Ra

[0461]

[0462] In embodiments, the compound of Formula (V) for use is a compound of Formula (Vb) wherein the group Ar is

[0463]

[0464] In embodiments the compound of Formula (V) is a compound of Formula ( Vc) wherein the group is

[0465] Ra

[0466]

[0467] In embodiments the compound of Formula (V) is a compound of Formula ( Vd) wherein the group is Ra

[0468]

[0469] In embodiments the compound of Formula (V), (Va), (Vb), (Vc) or (Vd) is a compound of Formula (Ve) in which Y is CH.

[0470] In embodiments the compound of Formula (V), (Va), (Vb), (Vc) or (Vd) is a compound of Formula (Vf) in which Y is N.

[0471] In embodiments the compound of Formula (V), (Va), (Vb), (Vc), (Vd), (Ve) or (Vf) is a compound of Formula (Vg) in which X is CH2(Vga) or CHOH (Vgb). Reference to a compound of Formula (Vg) herein should be read as reference to a both a compound of Formula (Vga) and a compound Formula (Vgb) or reference to a compound of Formula (Vga) or a compound of Formula (Vgb).

[0472]

[0473] (Vgb)

[0474] In embodiments the compound of Formula (V), (Va), (Vb), (Vc), (Vd), (Ve) or (Vf) is a compound of Formula (Vh) in which X is S, SO, SO2or SO(=NH).

[0475] In embodiments the compound of Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) or (Vh) is a compound of Formula (Vi) in which R6is H.

[0476] In embodiments the compound of Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh) or (Vi) is a compound of Formula (Vj) in which the group Rais selected from Cl, Br, OMe or CN.

[0477] In embodiments the compound of Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi) or (Vj) is a compound of Formula (Vk) in which the group Rbis selected from H, F and Cl and the group Rcis selected from H F, and Cl.

[0478] In embodiments the compound of Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj) or (Vk) is a compound of Formula (VI) in which the group R4is Cl or F.

[0479] In embodiments the compound of Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk) or (VI) is a compound of Formula (Vm) in which the group R7is CCH or CN.

[0480] In embodiments the compound of Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (VI) or (Vm) is a compound of Formula (Vn) in which the group R5is selected from F, Cl, Br, CN and CCH.

[0481] In embodiments of the present specification there are provided compounds of Formula (I), for example compounds of Formula (II), (III) and (IV), that selectively inhibit the growth of cancers that express a G13D mutation in Ras. For the avoidance of doubt, reference to compounds of Formula (I) and their medical use / pharmaceutical compositions for use / methods of treatment comprising administration of a compound of Formula (I) and the like herein equally refer to compounds of Formula (II), (III) and (IV). Selective inhibition of cancers that express a Ras G13D mutation can be evaluated in in vitro and in vivo models as described hereinbelow. A compound of Formula (I) that selectively inhibits the growth of cancers that express a G13D mutation in Ras will typically cause 50% reduction in cell growth in a Ras G13D mutant cancer cell line, for example T84 cells, at a concentrationca 10-fold lower than that required to cause a 50% reduction in cell growth of a cancer cell line that expresses wild type Ras, for example PC-9 cells. More details on assays suitable for assessing Ras G13D selectivity, i.e. identifying compounds that have a selective anti-proliferative activity against cells that express G13D mutant Ras protein are provided herein.

[0482] In embodiments of the present specification there are provided pharmaceutical compositions that comprise a compound of the Formula (I) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) or pharmaceutically acceptable salt thereof.

[0483] The compounds of Formula (I) and pharmaceutically acceptable salts thereof may be prepared, used or supplied in amorphous form, crystalline form, or semi-crystalline form and any given compound of Formula (I) or pharmaceutically acceptable salt thereof may be capable of being formed into more than one crystalline / polymorphic form, including hydrated and / or solvated forms. It is to be understood that the present specification encompasses any and all such solid forms of the compound of Formula (I) and pharmaceutically acceptable salts thereof.

[0484] The present specification is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include13C and14C. 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 using appropriate isotopically labelled reagents in place of the non-labelled reagents previously employed.

[0485] A suitable pharmaceutically acceptable salt of a compound of the Formula (I) may be, for example, an acid addition salt. A suitable pharmaceutically acceptable salt of a compound of the Formula (I) may be, for example, an acid-addition salt of a compound of the Formula (I), for example an acid-addition salt with an inorganic or organic acid. The compounds of the specification may be provided as the free base compound, i.e. in the non-salified state.

[0486] A further suitable pharmaceutically acceptable salt of a compound of the Formula (I) may be, for example, a salt formed within the human or animal body after administration of a compound of the Formula (I) to said human or animal body.

[0487] The compound of Formula (I), or a pharmaceutically acceptable salt thereof, will normally be administered via the oral route though parenteral, intravenous, intramuscular, subcutaneous or inother injectable ways, buccal, rectal, vaginal, transdermal and / or nasal route and / or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form may be possible. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses, for example in an oral dose of from 0.1 mg to 2,000 mg per day.

[0488] The pharmaceutical formulations of the compound of Formula (I) described above may be prepared e.g. for parenteral, subcutaneous, intramuscular or intravenous administration.

[0489] The pharmaceutical formulations of the compound of Formula (I) described above may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).

[0490] Pharmaceutical formulations suitable for oral administration may comprise one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binding agents; fillers; lubricants; and surfactants. Liquid compositions may contain conventional additives such as suspending agents; emulsifying agents; and preservatives Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. An exemplary oral composition would comprise a compound of Formula (I) and at least one pharmaceutically acceptable excipient filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.

[0491] According to a further embodiment there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use as a medicament. The medicament may be for use in the treatment of a subject, for example a warm-blooded animal, for example a human subject.

[0492] According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the production of an antiproliferative effect in a warm-blooded animal such as man.

[0493] According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and / or treatment of solid tumour disease.According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for the production of an antiproliferative effect in a warm-blooded animal such as man.

[0494] According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

[0495] According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and / or treatment of solid tumour disease.

[0496] According to a further embodiment, there is provided a method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[0497] In this specification, unless otherwise stated, the phrase "effective amount" means an amount of a compound or composition which is sufficient to significantly and positively modify the symptoms and / or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s) / ca rrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. The effective amount will generally be in the range of 0.1 mg to 2,000 mg.

[0498] According to a further embodiment, there is provided a method for producing an anti-invasive effect by the containment and / or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[0499] According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of cancer in a warm-blooded animal such as man. In such embodiments relating to the use of a compound ofFormula (I) for the treatment of cancer, the cancer may characteristically have a mutation at the G13 residue of KRas, for example a G13D mutation.

[0500] According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as man.

[0501] According to a further embodiment, there is provided a method for the treatment of cancer in a warmblooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof.

[0502] According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of solid tumour disease in a warmblooded animal such as man.

[0503] According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of solid tumour disease in a warm-blooded animal such as man.

[0504] According to a further embodiment, there is provided a method for the treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[0505] According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of tumours which are sensitive to inhibition of G13D mutant Ras.

[0506] According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of G13D mutant Ras.

[0507] According to a further embodiment, there is provided a method for the prevention or treatment of those tumours which are sensitive to inhibition of G13D mutant Ras, which comprises administering to a patient in need thereof an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in providing an inhibitory effect on G13D mutant Ras, i.e. inhibiting the proliferation or survival of cancer cells expressing a Ras G13D mutation through disturbing downstream signalling of RasG13D in those cells.

[0508] According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing an inhibitory effect on G13D mutant Ras.

[0509] According to a further embodiment, there is also provided a method for providing an inhibitory effect on G13D mutant RAS which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, to a patient in need thereof.

[0510] According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in providing a selective inhibitory effect on G13D mutant Ras.

[0511] According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in providing a selective inhibitory effect on G13D mutant Ras.

[0512] According to a further embodiment, there is also provided a method for providing a selective inhibitory effect on G13D mutant Ras which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0513] In embodiments of the specification relating to the use of a compound of Formula (I) for the treatment of cancer or for the manufacture of a medicine for treatment of cancer, the G13D mutation may be present in KRas, NRas or HRas. Likewise, in embodiments of the specification relating to methods of treatment of cancer, the G13D mutation may be present in KRas, NRas or HRas. In such embodiments, the use of the compound for treatment or in a method of treatment may be indicated following analysis of a sample obtained a patient that indicates that the patient has a cancer that express Ras G13D mutant protein.

[0514] Described herein are compounds of Formula (I) that can inhibit the proliferation of cancers cells that express G13D mutant Ras protein. In cell based assays, the compounds of the present specificationare shown to be potent and selective inhibitors of cells that express G13D mutant protein and the compounds of the specification may therefore be useful for the treatment of disorders mediated by KRas, NRas or HRas G13D mutations, in particular in the treatment of cancers expressing G13D mutated KRas, NRas or HRas proteins, such as a cancer selected from colorectal, endometrial, pancreatic, NSCLC, lung adenocarinoma, ovarian, acute myeloid leukaemia, and chronic lymphocytic leukaemia.

[0515] According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of disorders mediated by KRas, NRas or HRas G13D mutations.

[0516] According to a further embodiment, there is provided a method for treating disorders mediated by KRas, NRas or HRas G13D mutations, that comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, to a patient in need thereof.

[0517] According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the treatment of disorders mediated by KRas, NRas or HRas G13D mutations, for example where the disorder is a cancer selected from colorectal, endometrial, pancreatic, NSCLC, lung adenocarinoma, ovarian, acute myeloid leukaemia, and chronic lymphocytic leukaemia

[0518] According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of a cancer selected from colorectal, endometrial, pancreatic, NSCLC, lung adenocarinoma, ovarian, acute myeloid leukaemia, and chronic lymphocytic leukaemia, wherein said cancer has been identified as expressing G13D mutant Ras.

[0519] According to a further embodiment, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of colorectal cancer, for example a colorectal cancer expressing Ras G13D.

[0520] According to a further embodiment, there is provided a method for treating a cancer selected from colorectal, endometrial, pancreatic, NSCLC, lung adenocarinoma, ovarian, acute myeloid leukaemia, and chronic lymphocytic leukaemia, for example wherein the cancer has been identified as expressing Ras G13D, which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore to a patient in need thereof.According to a further embodiment, there is provided a method for treating colorectal cancer, for example a colorectal cancer expressing Ras G13D, which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0521] According to a further embodiment, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the treatment of a cancer selected from colorectal, endometrial, pancreatic, NSCLC, lung adenocarinoma, ovarian, acute myeloid leukaemia, and chronic lymphocytic leukaemia, for example wherein the cancer has been identified as expressing Ras G13D.

[0522] According to a further aspect of the specification, there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the treatment of colorectal cancer, for example a colorectal cancer expressing Ras G13D.

[0523] The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the specification, conventional surgery or radiotherapy or chemotherapy.

[0524] Accordingly, in one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an additional anti-tumour substance for the conjoint treatment of cancer. According to an embodiment of the specification there is provided a combination suitable for use in the treatment of cancer comprising a compound of the Formula (I) or a pharmaceutically acceptable salt thereof and another anti-tumour agent. In embodiments wherein the compound of Formula (I) is used in combination with a second anti-tumour agent, the compounds may be administered in a separate, simultaneous or sequential manner to achieve the optimal efficacy and tolerability.

[0525] In a further embodiment of the specification there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, in combination with another anti-tumour agent. In a related embodiment there is provided a method of treatment comprising administering a compound of Formula (I) in combination with another anti-tumour agent to a patient in need thereof, for example a patient suffering from a cancer expressing G13D mutant Ras.

[0526] Although the compounds of the Formula (I) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit G13Dmutant Ras. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

[0527] Another embodiment is based on identifying a link between the G13D KRas, HRas or NRas mutation status of a patient and potential susceptibility to treatment with a compound of Formula (I). A Ras inhibitor, such as a compound of Formula (I), may then advantageously be used to treat patients with G13D KRas, HRas or NRas mutations who may be resistant to other therapies. This therefore provides opportunities, methods and tools for selecting patients for treatment with a compound of Formula (I), particularly cancer patients. The selection is based on whether the tumour cells to be treated possess wild-type or G13D mutant KRAS, HRAS or NRAS gene. The G13D KRAS, HRAS or NRAS gene status could therefore be used as a biomarker to indicate that selecting treatment with a compound of Formula (I) may be advantageous.

[0528] According to one embodiment, there is provided a method for selecting a patient for treatment with a compound of Formula (I), the method comprising providing a tumour cell-containing sample or a blood sample from a patient; determining whether the RAS gene in the patient's tumour cellcontaining sample or circulating tumour DNA (ctDNA) in the patient's blood sample encodes for wildtype (glycine at position 13) or mutant (aspartic acid at position 13) KRas, HRas or NRas protein; and selecting a patient for treatment with a compound of Formula (I) if the RAS gene in found to encode for G13D mutant Ras protein.

[0529] The method may include or exclude the actual patient sample isolation step. Thus, according to one embodiment there is provided a method for selecting a patient for treatment with a compound of Formula (I), the method comprising determining whether the RAS gene in a sample previously isolated from the patient encodes for wild-type (glycine at position 13) or mutant (aspartic acid at position 13) KRas, HRas or NRas protein; and selecting a patient for treatment with a compound of Formula (I) if the RAS gene in the sample is found to encode for G13D mutant Ras.

[0530] In embodiments, the patient is selected for treatment with a compound of Formula (I) if the tumour DNA or ctDNA is identified as having a KRAS gene that encodes for G13D mutant Ras.

[0531] In embodiments, the patient is selected for treatment with a compound of Formula (I) if the tumour DNA or ctDNA is identified as having a HRAS gene that encodes for G13D mutant Ras.

[0532] In embodiments, the patient is selected for treatment with a compound of Formula (I) if the tumour DNA or ctDNA is identified as having a NRAS gene that encodes for G13D mutant Ras.According to another embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a patient with a cancer that has been identified as harbouring a G13D mutant KRAS gene, optionally wherein the identification is made on the basis of analysing a tumour biopsy or a blood sample. The identification of whether the cancer as harbours a G13D mutant KRAS gene may be a result of identifying the presence of a genetic mutation to the gene, the presence of mRNA encoding the G13D mutant protein, the presence of G13D mutant KRas protein, or any other suitable method to identify the genotype leading to expression of KRas G13D mutant protein.

[0533] According to another embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a patient with a cancer that has been identified as harbouring a G13D mutant HRAS gene, optionally wherein the identification is made on the basis of analysing a tumour biopsy or a blood sample. The identification of whether the cancer as harbours a G13D mutant HRAS gene may be made on the basis of identifying the presence of a genetic mutation to the gene, the presence of mRNA encoding the G13D mutant protein, the presence of G13D mutant HRas protein, or any other suitable method to identify the genotype leading to expression of HRas G13D mutant protein.

[0534] According to another embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a patient with a cancer that has been identified as harbouring a G13D mutant NRAS gene, optionally wherein the identification is made on the basis of analysing a tumour biopsy or a blood sample. The identification of whether the cancer as harbours a G13D mutant NRAS gene may be made on the basis of identifying the presence of a genetic mutation to the gene, the presence of mRNA encoding the G13D mutant protein, the presence of G13D mutant NRas protein, or any other suitable method to identify the genotype leading to expression of NRas G13D mutant protein.

[0535] According to another embodiment, there is provided a method of treatment of a cancer that expresses G13D mutant KRas, HRas or NRas protein comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0536] According to another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) for use in the treatment of a cancer that has been identified as harbouring a G13D mutant KRAS, HRAS or NRAS gene.It will be appreciated that the following examples are provided so that the nature of the invention may be fully understood. It will also be appreciated that the following examples are not intended to limit the scope of the description in any way.

[0537] Examples

[0538] The specification will now be illustrated in the following Examples in which, unless stated otherwise: (i) all syntheses were carried out at ambient temperature, i.e. in the range 17 to 30°C and, where appropriate, under an atmosphere of an inert gas such as nitrogen unless otherwise stated. Starting materials and reagents were obtained from commercial sources or prepared by literature routes. In cases where such starting materials were not available in this manner they were prepared as described below;

[0539] (ii) evaporations were carried out by rotary evaporation or utilising Genevac equipment or Biotage vlO evaporator in vacuo and work up procedures were carried out after removal of residual solids by filtration;

[0540] (iii) flash column chromatography was performed on Merck Kieselgel silica (Art. 9385) or on reversed phase silica (Fluka silica gel 90 C18) or on Silicycle cartridges (40-63 pm silica, 4 to 330 g weight) or on Grace resolv cartridges (4 - 120 g) or on RediSep Rf 1.5 Flash columns or on RediSep Rf high performance Gold Flash columns (150-415 g weight) or on RediSep Rf Gold C18 Reversed-phase columns (20 - 40 pm silica) or on Interchim puriFlash cartridges (50 pm silica, 4 - 800 g) either manually or automated using an ISCO CombiFlash Companion system or similar system;

[0541] (iv) preparative reverse phase HPLC was performed on a Waters instrument (600 / 2700 or 2525) fitted with a ZMD or ZQ. ESCi mass spectrometers and a Waters X-Terra or a Waters X-Bridge or a Waters SunFire reverse-phase column (C-18, 5 microns silica, 19 mm or 50 mm diameter, 100 mm length, flow rate of 40 mL / minute) using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile or decreasingly polar mixtures of water (containing 0.1% formic acid) and acetonitrile as eluents;

[0542] (vi) yields, where present, are not necessarily the maximum attainable;

[0543] (vii) in general, the structures of end products of the Formula I were confirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Bruker Avance 500 (500 MHz), Bruker Avance 400 (400 MHz), Bruker Avance 300 (300 MHz) or Bruker DRX (300 MHz) instrument in deuterated solvent]; measurements were taken at ambient temperature unless otherwise specified; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; bs, broad signal;(viii) in general, end products of the Formula I were also characterized by mass spectroscopy following liquid chromatography (LCMS or UPLC); in general, reverse-phase C18 silica was used with a flow rate of 1 mL / minute and detection was by Electrospray Mass Spectrometry and by UV absorbance recording a wavelength range of 220-320 nm. Analytical UPLC was performed on CSH C18 reverse-phase silica, using a Waters XSelect CSH C18 column with dimensions 2.1 x 50mm and particle size 1.7 micron). Gradient analysis was employed using decreasingly polar mixtures as eluent, for example decreasingly polar mixtures of water (containing 0.1% formic acid or 0.1% ammonia) as solvent A and acetonitrile as solvent B. A typical 2 minute analytical UPLC method would employ a solvent gradient over 1.3 minutes, at approximately 1 mL per minute, from a 97:3 mixture of solvents A and B respectively to a 3:97 mixture of solvents A and B. The reported molecular ion corresponds to the [M+H]+ unless otherwise specified;

[0544] (ix) ion exchange purification was generally performed using an SCX-2 (Biotage) cartridge;

[0545] (x) where reactions refer to the use of a microwave, one of the following microwave reactors were used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smithcreator or CEM Explorer;

[0546] (xi) intermediate purity was assessed by thin layer chromatographic, mass spectroscopy, LCMS, UPLC / MS, HPLC and / or NMR analysis;

[0547] (xii) the following abbreviations have been used:

[0548] AcOH acetic acid

[0549] ACN acetonitrile

[0550] AIBN 2,2'-azobis(2-methylpropionitrile)

[0551] BOC2O Di-tert-butyl pyrocarbonate

[0552] BrettPhos 2-(Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'- biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Bu butyl

[0553] cataCXium A Di(1-adamantyl)-n-butylphosphine

[0554] cataCXium A Pd G3 mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0555] DAST diethylaminosulfur trifluoride

[0556] DBU 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine

[0557] DCE 1,2-dichloroethane

[0558] DCM dichloromethane

[0559] DIBAL / DIBAL-H diisobutylaluminum hydride

[0560] DIEA / DIPEA A / , / V-diisopropylethylamine

[0561] DMAP 4-(dimethylamino)pyridine

[0562] DMF A / , / V-dimethylformamide

[0563] DMSO dimethylsulfoxide

[0564] dppf 1,1'-ferrocenediyl-bis(diphenylphosphine

[0565] EPhos Dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[l,l'-biphenyl]-2- yl)phosphane

[0566] EtOAc ethyl acetateEtOH ethanol

[0567] Et2O diethyl ether

[0568] FA formic acid

[0569] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[0570] HCI hydrochloric acid

[0571] Hex hexane

[0572] HFIP 1,1,1,3,3,3-hexafluoro-2-propanol

[0573] HOBt 1-Hydroxybenzotriazole

[0574] HPLC high performance liquid chromatography

[0575] IBX 2-iodoxybenzoic acid

[0576] LiHMDS lithium bis(trimethylsilyl)amide

[0577] mCPBA 3-Chloroperoxybenzoic acid

[0578] Me methyl

[0579] MeCN acetonitrile

[0580] MeOH methanol

[0581] MsOH methanesulfonic acid

[0582] NBS N-bromosuccinimide

[0583] NIS N-iodosuccinimide

[0584] NMP 1-methyl-2-pyrrolidinone

[0585] NMR nuclear magnetic resonance

[0586] Pd2(dba)3tris(dibenzylideneacetone)dipalladium(0)

[0587] Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride PdCl2(dtbpf) [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) PMHS Methylhydrogensiloxane polymer

[0588] Pd(PPh3)2Cl2triphenylphosphine palladium (II) chloride

[0589] Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)

[0590] PTSA para-toluene sulfonic acid

[0591] iPrOH iso-propanol

[0592] r.t. / RT room temperature

[0593] SCX strong cation exchange

[0594] TBME tert-butyl methyl ether

[0595] TBS tert-butyldimethylsilyl

[0596] TEA triethylamine

[0597] TFA trifluoroacetic acid

[0598] THF tetrahydrofuran

[0599] TIPS triisopropylsilyl

[0600] TMS trimethylsilyl

[0601] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0602] X-Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0603] XPhos Pd G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'- amino-l,l'-biphenyl)]palladium(ll)

[0604] XPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino- l,l'-biphenyl)]palladium(ll) methanesulfonate

[0605] The following starting materials were available commercially from the sources specified:

[0606] 2-bromo-4-(difluoromethoxy)-l-nitrobenzene [865886-83-5], MFCD18390949 is available from Enamine (www.enamine.net / ); 5-chloro-7-fluoro-lH-indazole [1352395-54-0], MFCD20923207 isavailable from BLDpharm (www.bldpharm.com / ); 5-(trifluoromethyl)pyrimidin-2-yl)methanol [944905-41-3], MFCD10696953 is available from ChemSpace (www.chem-space.com / ).

[0607] Synthesis of Intermediate indoles:

[0608] Synthesis of 7-bromo-5-chloro-4-fluoro-lH-indole (Int Al)

[0609] N

[0610] H

[0611]

[0612] To a cooled solution of l-bromo-5-chloro-4-fluoro-2-nitrobenzene (19.34 g, 76.0 mmol) in THF (114 mL) at - 40 °C was added vinylmagnesium bromide solution (IM in THF, 266 mL, 266.0 mmol) over 10 minutes. The reaction was stirred for 30 minutes then was allowed to warm to room temperature and stirred for a further 16 hours. After cooling in an ice-bath, the reaction was quenched by addition of saturated aq. NH4CI solution (400 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (200 mL), then dried over MgSO4, filtered and evaporated. The crude product was filtered through a 5cm plug of silica gel, eluting with a 2:1 mixture of heptane: EtOAc. The filtrate was evaporated, then further purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 7-bromo-5-chloro-4-fluoro-lH-indole (6.06 g, 32 %) as a beige solid. NMR spectrum:1H NMR (500 MHz, CDCl3, 27°C) 6.71 (1H, dd), 7.27 (1H, d), 7.34 (1H, d), 8.41 (1H, s). Mass spectrum: m / z: ES- [M-H]- 246, 248.

[0613] Synthesis of 5-chloro-4-fluoro-lH-indole-7-carbonitrile (Int A2) and 4-fluoro-lH-indole-5,7-dicarbonitrile (Int A3)

[0614] N N H H

[0615]

[0616] CN

[0617] To a flask containing 7-bromo-5-chloro-4-fluoro-lH-indole (1.49 g, 6.0 mmol), potassium hexacyanoferrate (II) trihydrate (1.27 g, 3.0 mmol), potassium acetate (73.5 mg, 0.75 mmol) and BrettPhos Pd G3 (272 mg, 0.3 mmol) was added methyl-THF (24.0 mL) and water (24.0 mL) and the reaction was heated atat reflux for 4 hours. After cooling to room temperature, the reaction was diluted with EtOAc (100 mL) and washed with brine (2 x 100 mL). The organic phase was dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford; A2:

[0618] 5-chloro-4-fluoro-lH-indole-7-carbonitrile (845 mg, 72 %) as a beige solid and A3: 4-fluoro-lH-indole-5,7-dicarbonitrile (125 mg, 11 %) as a light yellow solid. NMR spectrum (A2):1H NMR (500 MHz, CDCI3,27°C) 6.74 (1H, dd), 7.32 - 7.38 (1H, m), 7.52 - 7.59 (1H, m), 8.99 (1 H, s). Mass spectrum (A2): m / z: ES- [M-H]- 193; NMR spectrum (A3): NMR (500 MHz, CDCI3, 27°C) 6.88 (1H, d), 7.46 (1H, d), 7.73 (1H, d), 9.26 (1H, s). Mass spectrum (A3): m / z: ES- [M-H]- 184.

[0619] Synthesis of 5-chloro-4-methoxy-lH-indole-7-carbonitrile (Int A4)

[0620]

[0621] Sodium methoxide (540 mg, 10.0 mmol) was added to a solution of 5-chloro-4-fluoro-lH-indole-7- carbonitrile (389 mg, 2.0 mmol) in MeOH (8.0 mL) and the reaction was warmed at reflux for 16 hours. After cooling to ambient temperature, the volatiles were evaporated under vacuum. The residue was taken-up in EtOAc (25 mL) and washed with saturated aq. NH4CI solution (25 mL). The organic phase was dried over Na2SO4, filtered and evaporated. The solids were triturated with MeOH and collected by filtration to afford 5-chloro-4-methoxy-lH-indole-7-carbonitrile (207 mg, 50 %} as a beige solid.

[0622] NMR spectrum:1H NMR (500 MHz, DMSO, 27°C) 4.22 (3H, d), 6.87 - 6.97 (1H, m), 7.51 (1H, d), 7.73 (1H, d), 12.21 (1H, s). Mass spectrum: m / z: ES- [M-H]- 205.

[0623] Synthesis of te / T-butyl-[2-(5-chloro-4-fluoro-lH-indol-7-yl)ethvnyl]-dimethyl-silane (Int A5)

[0624]

[0625] XPhos Pd G3 (0.681 g, 0.80 mmol) was added to XPhos (0.384 g, 0.80 mmol), TEA (1.12 mL, 8.05 mmol), 7-bromo-5-chloro-4-fluoro-lH-indole (1.0 g, 4.02 mmol) and tert-butyl(ethynyl)dimethylsilane (1.13 g, 8.05 mmol) in DMF (18 mL) at 25°C under nitrogen. The resulting mixture was stirred at 80 °C for 4 hours. The reaction mixture was poured into saturated aq. NH4CI (75 mL) solution, extracted with EtOAc (3 x 75 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 3% to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-(( tert-butyldimethylsilyl)ethynyl)-5- chloro-4-fluoro-lH-indole (1.20 g, 97 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO) δ 0.24 (6H, d), 1.01 (9H, d), 6.64 (1H, dt), 7.22-7.41 (1H, m), 7.52 (1H, s), 11.62 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ 308.

[0626] Synthesis of 4,5-dichloro-lH-indole-7-carbonitrile (Int A6)Step 1: 7-bromo-4,5-dichloro-lH-indole

[0627] Cl

[0628] Y Y>

[0629] N

[0630]

[0631] Br

[0632] To a cooled solution of l-bromo-4,5-dichloro-2-nitrobenzene (5.0 g, 18.46 mmol) in THF (63.1 mL) at - 50 °C was added vinylmagnesium bromide solution (IM in THF, 60.0 mL, 60.0 mmol) over 5 minutes. The reaction was stirred for 30 minutes, then allowed to warm to room temperature for a further 16 hours. After cooling in an ice-bath the reaction was quenched by addition of aqueous 2N HCI solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine (100 mL), then dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 7-bromo-4,5-dichloro-lH-indole (1.15 g, 24 %) as a beige solid. NMR spectrum:

[0633] NMR (500 MHz, CDCI3, 27°C) 6.69 - 6.75 (1H, m), 7.3 - 7.35 (1H, m), 7.43 (1H, s), 8.43 (1H, s). Mass spectrum: m / z: ES- [M-H]- 262, 264.

[0634] Step 2: 4,5-dichloro-lH-indole-7-carbonitrile (Int A6)

[0635] Cl

[0636] Y O

[0637] H

[0638]

[0639] N

[0640] To a flask containing 7-bromo-4,5-dichloro-lH-indole (1.06 g, 4.0 mmol), potassium hexacyanoferrate (II) trihydrate (844 mg, 2.0 mmol), potassium acetate (49.0 mg, 0.50 mmol) and BrettPhos Pd G3 (181 mg, 0.20 mmol) was added methyl THF (16.0 mL) / water (16.0 mL) and the reaction was heated atat reflux for 4 hours. After cooling to room temperature, the reaction was diluted with EtOAc (100 mL) and washed with brine (2 x 100 mL). The organic phase was dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 4,5-dichloro-lH-indole-7-carbonitrile (415 mg, 49 %) as a beige solid. NMR spectrum:1H NMR (500 MHz, CDCl3, 27°C) 6.76 (1H, dd), 7.38 -7.44 (1H, m), 7.57-7.62 (1H, m), 8.97 (1H, s). Mass spectrum: m / z: ES- [M-H]- 209.

[0641] Synthesis of 5,7-dichloro-4-fluoro-lH-indole (Int A7)

[0642]

[0643] Vinylmagnesium bromide solution (IM in THF, 77 mL, 77 mmol) was added to l,5-dichloro-2-fluoro- 4-nitrobenzene (5.0 g, 23.81 mmol) in THF (80 mL) at -78°C. The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. After cooling in an ice-bath, the reaction was quenched by the addition of IM HCI solution (50 mL), extracted with EtOAc (3 x 50 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5,7-dichloro-4-fluoro-lH-indole (2.39 g, 49 %) as a colourless solid.

[0644]

[0645] NMR spectrum:1H NMR (500 MHz, DMSO) δ 6.65 (1H, ddd), 7.35-7.43 (1H, m), 7.55 (1H, t), 12.03 (1H, s). Mass spectrum: m / z: ES- [M-H]- 202.

[0646] of 5-chloro-4,7-difluoro-lH-indole

[0647]

[0648] N

[0649] H

[0650]

[0651] Vinylmagnesium bromide solution (IM in THF, 160 mL, 160 mmol) was added slowly to l-chloro-2,5- difluoro-4-nitrobenzene (9.50 g, 49.09 mmol) in THF (100 mL) at -78°C. The resulting solution was stirred at -78 °C for 1 hour before it was allowed to warm to room temperature for a further 4 hours. After cooling in an ice-bath, the reaction mixture was quenched with water (100 mL), extracted with EtOAc (3 x 100 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-chloro-4,7-difluoro-lH-indole (1.75 g, 19 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 26°C) δ 6.63 (1H, td), 7.18 (1H, dd), 7.54 (1H, t), 12.16 (1H, s). Mass spectrum: m / z: ES- [M-H]- 186.

[0652] is of 5-bromo-4,7-difluoro-lH-indole

[0653]

[0654] 1: 4-bromo-3,6-difluoro-2-iodoaniline

[0655] NH

[0656]

[0657] N IS (11.36 g, 50.48 mmol) was added to 4-bromo-2,5-difluoroaniline (10.0 g, 48.08 mmol) in DCM (200 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated brine (200 mL), extracted with DCM (2 x 125 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-bromo-3,6-difluoro-2-iodoaniline (12.30 g, 77 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 26°C) δ 5.70 (2H, s), 7.51 (1H, dd). Mass spectrum: m / z (ES-), [M-H]- = 332, 334.

[0658] Step 2: 4-bromo-3,6-difluoro-2-((trimethylsilyl)ethvnyl)aniline

[0659]

[0660] Copper (I) iodide (1.35 g, 7.07 mmol) was added to triphenylphosphine palladium (II) chloride (4.96 g, 7.07 mmol), TEA (9.85 mL, 70.68 mmol), 4-bromo-3,6-difluoro-2-iodoaniline (11.8 g, 35.34 mmol) and ethynyltrimethylsilane (6.94 g, 70.68 mmol) in TH F (150 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water (300 mL), extracted with EtOAc (3 x 350 mL), the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-bromo-3,6-difluoro-2-((trimethylsilyl)ethynyl)an iline (10.0 g, 93 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 25°C) δ 0.26 (9H, s), 5.86 (2H, s), 7.46 (1H, dd). Mass spectrum: m / z (ES+), [M+H]+ = 304, 306.

[0661] Step 3: 5-bromo-4,7-difluoro-lH-indole (Int A9)

[0662]

[0663] Copper (I) iodide (2.97 g, 15.61 mmol) was added to 4-bromo-3,6-difluoro-2-((trimethylsilyl)ethynyl)an iline (9.50 g, 31.23 mmol) and TEA (13.06 mL, 93.69 mmol) in DMF (110 mL) at room temperature. The resulting mixture was stirred at 100 °C for 2 hours. The reaction mixture was quenched with water (500 mL), extracted with EtOAc (3 x 400 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The reaction mixture was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporatedto dryness to afford 5-bromo-4,7-difluoro-lH-indole (2.36 g, 33 %) as a brown solid. NMR spectrum:

[0664] NMR (300 MHz, DMSO, 26°C) δ 6.62 (1H, td), 7.25 (1H, dd), 7.52 (1H, t), 12.16 (1H, s). Mass spectrum: m / z (ES-), [M-H]- 230, 232.

[0665] is of 4-fluoro-5-m '-lH-indole-7-carbonitrile (Int

[0666] 1: l-bromo-4-fluoro-5-m '-2-nitrobenzene

[0667] F

[0668] . CL J-

[0669]

[0670] l-Bromo-4,5-difluoro-2-nitrobenzene (20.0 g, 84.04 mmol) was added to NaOH (4.03 g, 100.85 mmol) in MeOH (400 mL) and the reaction was stirred at room temperature for4 hours. The reaction mixture was quenched with water (500 mL), extracted with DCM (3 x 500 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford l-bromo-4-fluoro-5-methoxy-2-nitrobenzene (20.50 g, 98 %) as a yellow solid. NMR spectrum:

[0671] NMR (300 MHz, DMSO, 26°C) δ 3.99 (3H, s), 7.66 (1H, d), 8.14 (1H, d).

[0672] 2: 7-bromo-4-fluoro-5-methoxy-lH-indole

[0673] F

[0674] -CL X- N

[0675] H

[0676]

[0677] Vinylmagnesium bromide solution (IM in THF, 26.0 mL, 26.0 mmol) was added slowly to l-bromo-4-fluoro-5-methoxy-2-nitrobenzene (2.0 g, 8.00 mmol) in THF (20 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour, then the reaction was allowed to warm to room temperature over 1 hour._The reaction mixture was poured into ice (100 mL), quenched with 2M HCI (20 mL), extracted with EtOAc (3 x 100 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-bromo-4-fluoro-5-methoxy-lH-indole (0.45 g, 23 %) as a brown solid. NMR spectrum:1H NMR (300 MHz, DMSO, 23 °C) δ 3.85 (3H, s), 6.56 (1H, dd), 7.26 (1H, d), 7.42 (1H, t), 11.44 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 244, 246.

[0678]

[0679] 3: 4-fluoro-5-m '-lH-indole-7-carbonitrile

[0680]

[0681] H

[0682]

[0683] Pd2(dba)3(0.563 g, 0.61 mmol) and dppf (0.341 g, 0.61 mmol) were added to zinc (II) cyanide (1.082 g, 9.22 mmol) and 7-bromo-4-fluoro-5-methoxy-lH-indole (1.50 g, 6.15 mmol) in DMF (25 mL). The resulting mixture was heated at 100 °C for 16 hours. The reaction mixture was washed with water (75 mL), extracted with EtOAc (3 x 50 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-fluoro-5-methoxy-lH-indole-7-carbonitrile (0.62 g, 53 %) as a yellow solid. NMR spectrum:1H NMR (400 MHz, DMSO, 24 °C) 8 3.88 (3H, s), 6.62 (1H, dd), 7.52 (1H, t), 7.61 (1H, d), 12.13 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 191.

[0684] Synthesis of 4-chloro-5-methoxy-lH-indole-7-carbonitrile (Int All)

[0685] Step 1: l-bromo-4-chloro-5-methoxy-2-nitrobenzene

[0686]

[0687] l-Bromo-4-chloro-5-fluoro-2-nitrobenzene (25.0 g, 98.26 mmol) was added to NaOH (4.72 g, 117.91 mmol) in MeOH (400 mL) at 25°C under nitrogen. The resulting mixture was stirred at room temperature for 4 hours. The organic solvent was removed under reduced pressure. The precipitate was collected by filtration, washed with water (100 mL) and dried under vacuum to afford 1-bromo-4-chloro-5-methoxy-2-nitrobenzene (25.0 g, 95 %) as a colourless solid, which was used without further purification. NMR spectrum: NMR (300 MHz, DMSO, 25.2°C) δ 4.02 (3H, s), 7.64 (1H, s), 8.28 (1H, s).

[0688] 2: 7-bromo-4-chloro-5-methoxy-lH-indole

[0689] N

[0690] H

[0691]

[0692] Br

[0693] Vinylmagnesium bromide solution (IM in THF, 122 mL, 122 mmol) was added slowly to l-bromo-4-chloro-5-methoxy-2-nitrobenzene (10.0 g, 37.53 mmol) in THF (200 mL) at -78°C. The resultingsolution was stirred at -78 °C for 1 hour, then was allowed to warm to room temperature and stirred for a further 4 hours. The reaction mixture was quenched with water (100 mL), extracted with EtOAc (3 x 100 mL), the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-bromo-4-chloro-5-methoxy-lH-indole (3.2 g, 33 %) as a yellow solid. NMR spectrum: NMR (300 MHz, DMSO, 24 °C) δ 3.87 (3H, s), 6.51 (1H, dd), 7.26 (1H, s), 7.48 (1H, t), 11.49 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 260, 262.

[0694] 3: 4-chloro-5-m '-lH-indole-7-carbonitrile

[0695]

[0696] N

[0697] H

[0698]

[0699] Pd ( PPh3)4(0.887 g, 0.77 mmol) was added to zinc cyanide (1.35 g, 11.52 mmol) and 7-bromo-4-chloro- 5-methoxy-lH-indole (2.0 g, 7.68 mmol) in DMF (30 mL). The resulting mixture was heated at 120 °C for 4 hours. After cooling to room temperature, the reaction mixture was quenched with water (150 mL), extracted with EtOAc (3 x 150 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The reaction mixture was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-chloro-5- methoxy-lH-indole-7-carbonitrile (1.2 g, 76 %) as a yellow solid. NMR spectrum: NMR (300 MHz, DMSO, 26 °C) δ 3.90 (3H, d), 6.57 (1H, dt), 7.53-7.66 (2H, m), 12.16 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 205, 207.

[0700] is of 5-bromo-4-fluoro-lH-indole-7-carbonitrile

[0701]

[0702]

[0703] 1: m 2-amino-5-bromo-4-fluoro-3-iodobenzoate

[0704] NH

[0705]

[0706] NIS (9.98 g, 44.35 mmol) in MeCN (100 mL) was added dropwise to methyl 2-amino-5-bromo-4- fluorobenzoate (10.0 g, 40.31 mmol) in MeCN (100 mL). The resulting mixture was stirred at room temperature for 16 hours. A further portion of NIS (9.98 g, 44.35 mmol) was added, and the mixture was was stirred at room temperature for a further 3 days. The solvent was removed under reduced pressure. The residue was quenched with Na2S2O3(100 mL), extracted with DCM (3 x 100 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified byflash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 2-amino-5-bromo-4-fluoro-3-iodobenzoate (12.58 g, 83 %) as a yellow solid. NMR spectrum: NMR (300 MHz, CDCl3, 22°C) δ 3.89 (3H, s), 6.63 (2H, s), 8.11 (1H, d). Mass m / z (ES+), [M+H]+ 374, 376.

[0707] Step 2: methyl 2-amino-5-bromo-4-fluoro-3-((trimethylsilyl)ethvnyl)benzoate

[0708]

[0709] Copper (I) iodide (0.611 g, 3.21 mmol) was added to ethynyltrimethylsilane (4.73 g, 48.14 mmol), methyl 2-amino-5-bromo-4-fluoro-3-iodobenzoate (12.0 g, 32.09 mmol), triphenylphosphine palladium chloride (2.25 g, 3.21 mmol) and TEA (13.42 mL, 96.27 mmol) in THF (100 mL). The resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (150 mL), extracted with DCM (3 x 150 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 2-amino-5-bromo-4-fluoro-3-((trimethylsilyl)ethynyl)benzoate (10.58 g, 96 %) as a yellow solid. NMR spectrum:

[0710] 1H NMR (400 MHz, CDCl3, 23 °C) δ 0.29 (9H, s), 3.87 (3H, s), 6.76 (2H, s), 8.01 (1H, d). Mass spectrum: m / z (ES+), [M+H]+ = 344, 346.

[0711] Step 3: methyl 5-bromo-4-fluoro-lH-indole-7-carboxylate

[0712] F

[0713] N

[0714]

[0715] Copper (I) iodide (2.77 g, 14.52 mmol) was added to methyl 2-amino-5-bromo-4-fluoro-3-((trimethylsilyl)ethynyl)benzoate (10.0 g, 29.05 mmol) and TEA (12.15 mL, 87.14 mmol) in DMF (80 mL). The resulting mixture was heated at 100 °C for 16 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in HCI (0.5%). Pure fractions were evaporated to dryness to afford methyl 5-bromo-4-fluoro-lH-indole-7-carboxylate (2.4 g, 30 %) as a colourless solid. NMR spectrum:1H NMR (400 MHz, DMSO, 23 °C) δ 3.94 (3H, s), 6.66 (1H, d), 7.50 (1H, s), 7.88 (1H, d), 11.65 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 270, 272.

[0716] 4: 5-bromo-4-fluoro-lH-indole-7-carboxylic acid

[0717]

[0718] Methyl 5-bromo-4-fluoro-lH-indole-7-carboxylate (2.3 g, 8.45 mmol) was added to NaOH (1.35 g, 33.81 mmol) in water (50 mL). The resulting mixture was heated at 80 °C for 1 hour. The reaction mixture was acidified with 2M HCI. The solid was filtered, then dried under vacuum to afford 5-bromo-4-fluoro-lH-indole-7-carboxylic acid (2.0 g, 92 %) as a colourless solid which was used in the next step directly without further purification. NMR spectrum:JH NMR (300 MHz, DMSO, 27°C) 66.63 (1H, dd), 7.44 (1H, t), 7.87 (1H, d), 11.53 (1H, s), 13.44 (1H, s).

[0719] Step 5: 5-bromo-4-fluoro-lH-indole-7-carboxamicle

[0720]

[0721] HATU (3.54 g, 9.3 mmol) was added to 5-bromo-4-fluoro-lH-indole-7-carboxylic acid (2.0 g, 7.75 mmol), ammonium chloride (0.829 g, 15.5 mmol) and DIEA (4.06 mL, 23.25 mmol) in DMF (27 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water (75 mL), extracted with EtOAc (3 x 50 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-4-fluoro-lH-indole-7-carboxamide (1.53 g, 77 %) as a pale yellow solid. NMR spectrum: ¹H NMR (500 MHz, DMSO, 26 °C) δ 6.57 (1H, dd), 7.40 (1H, t), 7.97 (1H, d), 11.49-11.62 (1H, m). Mass spectrum: m / z (ES-), [M-H]- = 255, 257.

[0722] Step 6: 5-bromo-4-fluoro-lH-indole-7-carbonitrile (Int A12)

[0723] F

[0724]

[0725] Phosphorus oxychloride (2.68 g, 17.51 mmol) was added to 5-bromo-4-fluoro-lH-indole-7-carboxamide (1.50 g, 5.84 mmol) in DMF (35 mL) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 mL) at 0 °C. The mixture was basified with saturated NaHCO3solution to pH 8, then extracted with Et2O (5 x 75 mL). The combined organiclayers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-4-fluoro-lH-indole-7-carbonitrile (1.23 g, 88 %) as a colourless solid.

[0726]

[0727] NMR spectrum: ¹H NMR (300 MHz, DMSO, 26°C) δ 5.88 (1H, dd), 6.76 (1H, t), 7.13 (1H, d), 11.71 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 237, 239.

[0728] Synthesis of 5-bromo-7-ethvnyl-4-fluoro-lH-inclole (Int A13)

[0729] 1: l-bromo-2-fluoro-5-iodo-4-nitrobenzene

[0730]

[0731] Cui (68.1 g, 357.43 mmol) was added to 5-bromo-4-fluoro-2-nitroaniline (42.0 g, 178.71 mmol) in MeCN (700 mL) at 0 °C. After stirring for 5 minutes, tert-butylnitrite, (36.9 g, 357.43 mmol) was added and the resulting mixture was stirred at 60 °C for 16 hours. The reaction mixture was diluted with water (750 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 2% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford l-bromo-2-fluoro-5-iodo-4-nitrobenzene (38.0 g, 62 %) as a yellow solid. NMR spectrum:JH NMR (300 MHz, DMSO, 26°C) 88.19 (1H, d), 8.53 (1H, d).

[0732] Step 2: ((5-bromo-4-fluoro-2-nitrophenyl)ethvnyl)(te / 't-butyl)dimethylsilane

[0733]

[0734]

[0735] TBS

[0736] Cui (3.96 g, 20.82 mmol) and Pd(PPh3)2Cl2 (7.31 g, 10.41 mmol) were added to l-bromo-2-fluoro-5- iodo-4-nitrobenzene (36.0 g, 104.08 mmol), TEA (29.0 mL, 208.16 mmol) and tert- butyl(ethynyl)dimethylsilane (14.60 g, 104.08 mmol) in THF (400 mL). The resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water (400 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The mixture was purified by flash silica chromatography, elution gradient 0 to 8% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford ((5-bromo-4-fluoro-2- nitrophenyl)ethynyl)(tert-butyl)dimethylsilane (25.0 g, 67 %) as a yellow solid. NMR spectrum: NMR (300 MHz, DMSO, 22°C) 80.17 (6H, s), 0.96 (9H, s), 8.19 (1H, d), 8.24 (1H, d).

[0737] Step 3: 5-bromo-7-((te / 't-butyldimethylsilyl)ethvnyl)-4-fluoro-lH-indole

[0738]

[0739] TBS

[0740]

[0741] Vinylmagnesium bromide solution (IM in THF, 100 mL, 99.78 mmol) was added slowly to (5-bromo- 4-fluoro-2-nitrophenyl)ethynyl)(tert-butyl)dimethylsilane (11 g, 30.7 mmol) in THF (195 mL) at -78°C under nitrogen. The resulting solution was stirred at -78 °C for 1 hour, then was allowed to warm to room temperature and stirred for a further 4 hours. The reaction mixture was quenched with saturated NH4CI solution (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The mixture was purified by flash silica chromatography, elution gradient 0 to 6% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-7-((tert-butyldimethylsilyl)ethynyl)-4-fluoro-lH-indole (2.0 g, 18 %) as a yellow solid. NMR spectrum:JH NMR (300 MHz, DMSO, 23°C) 60.23 (6H, s), 1.00 (9H, s), 6.62 (1H, dd), 7.41 (1H, d), 7.50 (1H, t), 11.63 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 350.

[0742] Step 4: 5-bromo-7-ethvnyl-4-fluoro-lH-indole (Int A13)

[0743] N

[0744] H

[0745]

[0746] Tetraethylammonium fluoride hydrate (1.10 g, 6.58 mmol) was added to 5-bromo-7-((tert- butyldimethylsilyl)ethynyl)-4-fluoro-lH-indole (773 mg, 2.19 mmol) in THF (20 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water (25 mL), extracted with EtOAc (3 x 25 mL), the organic layer was dried over Na2SO4, filtered and evaporated. The mixture was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-7-ethynyl-4-fluoro- lH-indole (475 mg, 91 %) as a yellow solid. NMR spectrum:JH NMR (300 MHz, DMSO, 27°C) 84.58 (1H, d), 6.61 (1H, dt), 7.45 (1H, d), 7.47 (1H, d), 11.89 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 236.

[0747] Synthesis of 7-ethvnyl-4-fluoro-5-iodo-lH-indole (Int A14)

[0748] Step 1: 7-((te / 't-butyldimethylsilyl)ethvnyl)-4-fluoro-5-iodo-lH-indole

[0749]

[0750] HNCui (0.162 g, 0.85 mmol) was added to 5-bromo-7-((tert-butyldimethylsilyl)ethynyl)-4-fluoro-lH- indole (1.0 g, 2.84 mmol), sodium iodide (2.98 g, 19.87 mmol) and trans-( 1 R, 2 R)-N, N '-bismethyl-1, 2- cyclohexane diamine (0.121 g, 0.85 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined the organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 8% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-(( tert-butyldimethylsilyl)ethynyl)-4- fluoro-5-iodo-lH-indole (0.8 g, 71 %} as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 25°C) 80.23 (6H, s), 1.00 (9H, s), 6.58 (1H, dd), 7.44 (1H, t), 7.51 (1H, d), 11.59 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 398.

[0751] Step 2: 7-ethvnyl-4-fluoro-5-iodo-lH-indole (Int A14)

[0752] I

[0753] = — y— F

[0754]

[0755] HN^

[0756] Tetraethylammonium fluoride hydrate (1.0 g, 6.01 mmol) was added to 7-((tert- butyldimethylsilyl)ethynyl)-4-fluoro-5-iodo-lH-indole (800 mg, 2.0 mmol) in THF (15 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-ethynyl-4-fluoro-5-iodo-lH-indole (465 mg, 81 %) as a colourless solid. NMR spectrum:

[0757]

[0758] NMR (300 MHz, DMSO, 27°C) 84.55 (1H, d), 6.57 (1H, dd), 7.41 (1H, t), 7.55 (1H, d), 11.85 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 284.

[0759] Synthesis of 7-ethvnyl-4-fluoro-5-(trifluoromethyl)-lH-indole (Int A15)

[0760] Step 1: 2-bromo-5-fluoro-4-(trifluoromethyl)aniline

[0761] 1

[0762] FlUL

[0763] ^Y^NH2

[0764]

[0765] Br

[0766] NBS (6.02 g, 33.83 mmol) was added to 3-fluoro-4-(trifluoromethyl)aniline (6.0 g, 33.5 mmol) in DCM (80 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20%EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-bromo-5-fluoro-4-(trifluoromethyl)aniline (5.5 g, 64 %} as a colourless solid. NMR spectrum:1H NMR (300 MHz, DMSO, 23°C) 86.37 (2H, s), 6.68 (1 H, d), 7.63 ( 1 H, d). Mass spectrum: m / z (ES-), [M-H]- = 256.

[0767] Step 2: 6-bromo-3-fluoro-2-iodo-4-(trifluoromethyl)aniline

[0768] F

[0769]

[0770] NIS (13.08 g, 58.14 mmol) was added to 2-bromo-5-fluoro-4-(trifluoromethyl)aniline (15.0 g, 58.14 mmol) in AcOH (150 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and diluted with EtOAc (150 mL), then washed sequentially with water (3 x 150 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 6-bromo-3-fluoro-2-iodo-4-(trifluoromethyl)aniline (20.0 g, 90 %) as a yellow solid. NMR spectrum: NMR (300 MHz, DMSO, 23°C) 86.23 (2H, s), 7.76 (1H, d). Mass spectrum: m / z (ES-), [M-H]- = 382.

[0771] Step 3: 6-bromo-3-fluoro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline

[0772] TMS I NH2

[0773]

[0774] Ethynyltrimethylsilane (13.25 mL, 93.77 mmol) was added to a solution of 6-bromo-3-fluoro-2-iodo-4-(trifluoromethyl)aniline (18.0 g, 46.89 mmol), copper (I) iodide (2.68 g, 14.07 mmol), PdCI2(dppf) (6.86 g, 9.38 mmol) and TEA (13.07 mL, 93.77 mmol) in THF (100 mL). The resulting solution was stirred at 40 °C for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 6-bromo-3-fluoro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)an iline (9.6 g, 58 %) as a colourless solid. NMR spectrum:JH NMR (400 MHz, DMSO, 23°C) 80.27 (9H, s), 6.36 (2H, s), 7.74 (1H, d). Mass spectrum: m / z (ES-), [M-H]- = 352.

[0775] Step 4: 7-bromo-4-fluoro-5-(trifluoromethyl)-lH-indole

[0776]

[0777] Potassium tert-butoxide (6.08 g, 54.2 mmol) was added to 6-bromo-3-fluoro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)an iline (9.60 g, 27.1 mmol) in NMP (80 mL). The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (3 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-bromo-4-fluoro-5-(trifluoromethyl)-lH-indole (7.1 g, 93 %) as a colourless solid. NMR spectrum: NMR (500 MHz, DMSO) 6 6.83 (1H, dd), 7.58 (1H, d), 7.64 (1H, t), 12.17 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 280.

[0778] Step 5: 4-fluoro-5-(trifluoromethyl)-7-((trimethylsilyl)ethvnyl)-lH-indole

[0779]

[0780] Ethynyltrimethylsilane (7.02 mL, 49.64 mmol) was added to a solution of 7-bromo-4-fluoro-5-(trifluoromethyl)-lH-indole (7.0 g, 24.82 mmol), copper (I) iodide (1.418 g, 7.45 mmol), PdCI2(dppf) (3.63 g, 4.96 mmol) and TEA (6.92 mL, 49.64 mmol) in DMF (60 mL). The resulting solution was stirred at 100 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-fluoro-5-(trifluoromethyl)-7-((trimethylsilyl)ethynyl)-lH-indole (4.1 g, 55 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 23°C) 80.28 (9H, s), 6.76 (1H, dd), 7.44 (1H, d), 7.61 (1H, t), 11.97 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 298.

[0781] Step 6: 7-ethvnyl-4-fluoro-5-(trifluoromethyl)-lH-indole (Int A15)

[0782]

[0783] 4-fluoro-5-(trifluoromethyl)-7-((trimethylsilyl)ethynyl)-lH-indole (4.0 g, 13.36 mmol) was added to potassium fluoride (1.55 g, 26.73 mmol) in MeOH (40 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and diluted with EtOAc (100 mL), then washed sequentially with water (3 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-ethynyl-4-fluoro-5-(trifluoromethyl)-lH-indole (2.8 g, 92 %) as a brown solid. NMR spectrum: NMR (400 MHz, DMSO, 23°C) 84.63 (1H, s), 6.76 (1H, dd), 7.50 (1H, d), 7.59 (1H, t), 12.18 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 226.

[0784] Synthesis of 4-fluoro-5-(trifluoromethyl)-lH-inclole-7-carbonitrile (Int A16)

[0785]

[0786] To a flask containing 7-bromo-4-fluoro-5-(trifluoromethyl)-lH-indole (2.65 g, 9.40 mmol), zinc cyanide (1.65 g, 14.09 mmol) and Pd(PPh3)4 (0.542 g, 0.47 mmol) was added DMF (28.5 mL). The reaction was degassed, then heated at 130 °C for 3 hours. After cooling, the reaction was poured onto brine (150 mL) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 4-fluoro-5-(trifluoromethyl)-lH-indole-7-carbonitrile (1.15 g, 54 %) as a beige solid. NMR spectrum:1H NMR (500 MHz, CDCI3, 27°C) 6.86 (1H, dd), 7.39 - 7.46 (1H, m), 7.76 (1H, d), 9.53 (1H, s). Mass spectrum: m / z: ES- [M-H]- 227.

[0787] Synthesis of 5-bromo-4-chloro-lH-indole-7-carbonitrile (Int A17)

[0788] Step 1: 5-bromo-4-chloro-2,7-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole

[0789]

[0790] Dimethoxobis(l,5-cyclooctadiene)diiridium (I) (144 mg, 0.22 mmol) was added to 5-bromo-4-chloro-lH-indole (500 mg, 2.17 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.65 g,6.51 mmol) and 4,4'-di-te / T-butyl-2,2'-dipyridyl (116 mg, 0.43 mmol) in THF (20 mL). The resulting mixture was stirred at 80 °C for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-4-chloro-2,7-bis(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole (550 mg, 53 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 24°C) 81.34 (12H, s), 1.37 (12H, s), 7.00 (1H, d), 7.67 (1H, s), 9.87 (1H, d). Mass spectrum: m / z (ES+), [M+H]+ = 482.

[0791] Step 2: 5-bromo-4-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole

[0792]

[0793] Bismuth triacetate (440 mg, 1.14 mmol) was added to 5-bromo-4-chloro-2,7-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole (550 mg, 1.14 mmol) and MeOH (5.77 mL, 142.51 mmol) in THF (20 mL). The resulting mixture was stirred at 80 °C for 30 minutes. The reaction mixture was diluted with water and extracted with EtOAc (3x 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-4-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole (210 mg, 52 %) as a brown solid. NMR spectrum:JH NMR (300 MHz, DMSO, 22°C) 8 1.35 (12H, s), 6.52-6.56 (1H, m), 7.46 (1H, t), 7.57 (1H, s), 10.79 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 356.

[0794] Step 3: 5-bromo-4-chloro-lH-indole-7-carbonitrile (Int A17)

[0795]

[0796] Zinc cyanide (6.92 g, 58.91 mmol) was added to 5-bromo-4-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole (7 g, 19.64 mmol), cesium fluoride (2.98 g, 19.64 mmol) and cupric nitrate 2.5 hydrate (18.27 g, 39.28 mmol) in DMF (140 mL), MeOH (70 mL) and water (70 mL). The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na2SO4, filtered andevaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-4-chloro-lH-indole-7-carbonitrile (2.4 g, 48 %) as a colourless solid. NMR spectrum:1H NMR (500 MHz, DMSO) 6 6.68 (1H, d), 7.68 (1H, d), 8.04 (1H, s), 12.48 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 255.

[0797] Synthesis of 5-bromo-4-chloro-7-ethvnyl-lH-indole (Int A18)

[0798] Step 1: 5-bromo-4-chloro-7-((triisopropylsilyl)ethvnyl)-lH-indole

[0799] Br

[0800] TIPS— = — / V- Cl

[0801]

[0802] HNQ

[0803] (Bromoethynyl)triisopropylsilane (2.73 mL, 11.22 mmol) was added to 5-bromo-4-chloro-7-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole (2.0g, 5.61 mmol), Pd(PPh3)4 (0.648 g, 0.56 mmol) and potassium carbonate (2.326 g, 16.83 mmol) in toluene (30 mL), EtOH (12 mL) and water (12 mL). The resulting mixture was stirred at 60 °C for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-4-chloro-7-((triisopropylsilyl)ethynyl)-lH-indole (1.88 g, 82 %) as a colourless solid. NMR spectrum: NMR (300 MHz, DMSO, 24°C) 8 1.14 (21H, d), 6.56-6.62 (1H, m), 7.49 (1H, s), 7.56 (1H, t), 11.53 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 408.

[0804] Step 2: 5-bromo-4-chloro-7-ethvnyl-lH-indole (Int A18)

[0805] Br

[0806]

[0807] Tetraethylammonium fluoride hydrate (1.09 g, 5.89 mmol) was added to 5-bromo-4-chloro-7-((triisopropylsilyl)ethynyl)-lH-indole (2.2 g, 5.35 mmol) in THF (40 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 20 to 40% DCM in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-4-chloro-7-ethynyl-lH-indole (1.23 g, 90 %) as a pink solid. NMR spectrum:JH NMR (500 MHz, DMSO) 6 0.99 (1H, d), 4.68 (1H, s), 6.57 (1H, dd), 7.49-7.56 (2H, m), 11.93 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 252.Synthesis of 5-chloro-4-fluoro-7-methyl-lH-indole (Int A19)

[0808]

[0809] PdCI2(dppf) (0.294 g, 0.40 mmol) was added to 7-bromo-5-chloro-4-fluoro-lH-indole (1.0 g, 4.02 mmol), methylboronic acid (0.289 g, 4.83 mmol) and K2CO3(1.112 g, 8.05 mmol) in 1,4-dioxane (16 mL) / water (4 mL). The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-chloro-4-fluoro-7-methyl-lH-indole (0.68 g, 92 %) as a brown solid. NMR spectrum: NMR (300 MHz, DMSO, 24°C) 8 2.44 (3H, d), 6.53 (1H, dd), 6.97 (1H, dd), 7.45 (1H, t), 11.58 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 184.

[0810] Synthesis of 5-chloro-7-ethvnyl-4,6-clifluoro-lH-inclole (Int A20)

[0811] Step 1: 4-chloro-3,5-difluoro-2,6-cliiocloaniline

[0812]

[0813] To a solution of 4-chloro-3,5-difluoroaniline (4.09 g, 25.0 mmol) in AcOH (62.5 mL) was added NIS (12.37 g, 55.0 mmol) and the reaction was warmed at 50 °C for 2 hours. After cooling, the reaction was poured onto ice-water (500 mL) and stirred for 10 min. The solids were collected by filtration, washed with additional water (200 mL), then dried under vacuum to afford 4-chloro-3,5-difluoro-2,6- diiodoaniline (10.15 g, 98 %) as a beige solid. NMR spectrum: NMR (500 MHz, CDCI3, 27°C) 5.01 (2H, s). Mass spectrum: m / z: ES- [M-H]- 414.

[0814] Step 2: 4-chloro-3,5-difluoro-2,6-bis((trimethylsilyl)ethvnyl)aniline

[0815]

[0816] To a suspension of 4-chloro-3,5-difluoro-2,6-diiodoaniline (4.15 g, 10 mmol), triethylamine (5.58 mL, 40.0 mmol) and ethynyltrimethylsilane (4.16 mL, 30.0 mmol) in 1,4-dioxane (30.0 mL) was addedPd(PPh3)2Cl2(0.701 g, 1.0 mmol) and Cui (0.190 g, 1.0 mmol). The reaction was degassed, then heated at 80 °C for 2 hours. Aftercooling, the mixture was pre-absorbed onto silica gel, then the crude product was purified by flash silica chromatography, elution gradient Oto 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 4-chloro-3,5-difluoro-2,6-bis((trimethylsilyl)ethynyl)aniline (3.35 g, 94 %) as a beige solid. NMR spectrum: NMR (500 MHz, CDCI3, 27°C) 0.27 (18H, s), 5.04 (2H, s). Mass spectrum: m / z ES- [M-H]- 354.

[0817] Step 3: 5-chloro-7-ethynyl-4,6-difluoro-1H-indole (Int A20)

[0818] N

[0819] H

[0820]

[0821] To a solution of 4-chloro-3,5-difluoro-2,6-bis((trimethylsilyl)ethynyl)aniline (3.2 g, 9 mmol) in NMP (45.0 mL) was added potassium tert-butoxide (3.82 g, 36.0 mmol) and the reaction was stirred at room temperature for 2 hours. The mixture was poured onto IN HCI solution (500 mL), then extracted with EtOAc (2 x 200 mL). The combined organics were washed with brine (200 mL), then dried over MgSO, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 5-chloro-7-ethynyl-4,6-difluoro-lH-indole (1.64 g, 86 %) as a beige solid. NMR spectrum:1H NMR (500 MHz, CDCI3, 27°C) 3.60 (1H, s), 6.64 (1H, dd), 7.24 (1H, dd), 8.55 (1H, s). Mass spectrum: m / z ES- [M-H]- 210.

[0822] Synthesis of 5-chloro-4,6-difluoro-lH-indole-7-carbonitrile (Int A21)

[0823] Step 1: 4-chloro-3,5-difluoro-2-iodo-6-((trimethylsilyl)ethynyl)aniline

[0824] TMS

[0825]

[0826] To a suspension of 4-chloro-3,5-difluoro-2,6-diiodoaniline (5.81 g, 14 mmol), ethynyltrimethylsilane (2.13 mL, 15.40 mmol) and triethylamine (4.88 mL, 35.0 mmol) in 1,4-dioxane (49.0 mL) was added Pd(PPh3)2Cl2(0.491 g, 0.7 mmol) and Cui (0.133 g, 0.7 mmol). The reaction was degassed, then heated at 50 °C for 2 hours. The volatiles were evaporated, then the crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford a 1:1 mixture of 4-chloro-3,5-difluoro-2-iodo-6-((trimethylsilyl)ethynyl)aniline and 4-chloro-3,5-difluoro-2,6-bis((trimethylsilyl)ethynyl)aniline which could not be separated. The reaction mixture was taken to the next step without further purification.Step 2: 5-chloro-4,6-difluoro-7-iodo-1H-indole

[0827]

[0828] To a solution containing a 1:1 mixture of 4-chloro-3,5-difluoro-2-iodo-6-((trimethylsilyl)ethynyl)aniline and 4-chloro-3,5-difluoro-2,6-bis((trimethylsilyl)ethynyl)aniline (3.86 g, 4.5 mmol) in NMP (22.5 mL) was added potassium tert-butoxide (1.908 g, 18.0 mmol) and the reaction was stirred at room temperature for 2 hours. The mixture was poured onto IN HCI solution (500 mL), then extracted with EtOAc (x2). The combined organics were washed with brine, then dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 5-chloro-4,6-difluoro-7-iodo-lH-indole (1.14 g, 81%, based on 50% weight of mono-acetylene in the starting material). Mass spectrum: m / z: ES- [M-H]- 312.

[0829] Step 3: 5-chloro-4,6-difluoro-lH-indole-7-carbonitrile (Int A21)

[0830]

[0831] To a solution of 5-chloro-4,6-difluoro-7-iodo-lH-indole (1.05 g, 3.35 mmol) in DMF (10.15 mL) was added zinc cyanide (0.588 g, 5.02 mmol), followed by Pd tetrakis (0.193 g, 0.17 mmol). The reaction was degassed then heated at 130 °C for 3 hours. After cooling the reaction was diluted with EtOAc (100 mL) and washed with brine (2 x 100 mL). The combined organics were dried with MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 5-chloro-4,6-difluoro-lH-indole-7-carbonitrile (0.525 g, 74 %) as a beige solid. NMR spectrum:1H NMR (500 MHz, DMSO, 27°C) 6.76 (1H, d), 7.64 (1H, d), 12.71 (1H, s). Mass spectrum: m / z: ES- [M-H]- 211.

[0832] Synthesis of 5-chloro-1H-indole-7-carbonitrile (Int A22)

[0833]

[0834] To a flask containing 7-bromo-5-chloro-lH-indole (5.0 g, 21.69 mmol), potassium hexacyanoferrate (II) trihydrate (4.58 g, 10.85 mmol), potassium acetate (0.266 g, 2.71 mmol) and BrettPhos Pd G3 (0.983 g, 1.08 mmol) was added methyl THF (87 mL) / water (87 mL) and the reaction was heated at 70 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc (200 mL) and washed with brine (2 x 200 mL). The organic phase was dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 5-chloro-1H-indole-7-carbonitrile (3.1 g, 81 %) as a beige solid. NMR spectrum:1H NMR (500 MHz, CDCl3, 27°C) 6.61 (1H, dd), 7.35 - 7.4 (1H, m), 7.46 - 7.51 (1H, m), 7.84 (1H, dd), 8.86 (1H, s). Mass spectrum: m / z: ES- [M-H]- 175.

[0835] Synthesis of 5-bromo-lH-indole-7-carbonitrile (Int A23)

[0836] Step 1: 5-bromo-lH-indole-7-carboxamide

[0837] Br

[0838] N

[0839] H

[0840]

[0841] I2I

[0842] Propane phosphonic acid anhydride in EtOAc (6.63 g, 20.83 mmol) was added to 5-bromo-lH-indole-7-carboxylic acid (5.0 g, 20.83 mmol), DIEA (7.28 mL, 41.66 mmol) and ammonia in THF (1.3M, 42 mL, 41.7 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous saturated NaHCO3(100 mL), extracted with DCM (2 x 50 mL), then the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-lH-indole-7-carboxamide (4.5 g, 90 %) as a colourless solid. NMR spectrum: NMR (400 MHz, DMSO, 23°C) 8 6.48 (1H, dd), 7.36-7.43 (1H, m), 7.52 (1H, s), 7.86 (1H, q), 7.92 (1H, d), 8.19 (1H, s), 11.30 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 239, 241.

[0843] Step 2: 5-bromo-lH-indole-7-carbonitrile (Int A23)

[0844] Bi<

[0845] N

[0846] H

[0847]

[0848] Phosphorus oxychloride (1.92 g, 12.55 mmol) was added to 5-bromo-lH-indole-7-carboxamide (1.0 g, 4.18 mmol) in toluene (20 mL). The resulting mixture was heated at 100 °C for 16 hours. The reaction mixture was poured into water (200 mL) at 0 °C. The mixture was made basic with aqueous saturated NaHCO3, then extracted with Et2O (5 x 75 mL). The organic layer was dried over Na2SO4, filtered andevaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-lH-indole-7-carbonitrile (0.5 g, 54 %) as a colourless solid. NMR spectrum:1H NMR (300 MHz, DMSO) δ 6.63 (1H, dd), 7.58 (1H, t), 7.80 (1H, d), 8.14 (1H, d), 12.24 (1H, s). Mass spectrum: m / z: ES- [M-H]- 218, 220.

[0849] Synthesis of 5-(difluoromethyl)-lH-indole-7-carbonitrile (Int A24)

[0850] N

[0851] H

[0852]

[0853] Pd2dba3(164 mg, 0.18 mmol) and Ephos (97 mg, 0.18 mmol) were added to 5-bromo-lH-indole-7-carbonitrile (200 mg, 0.9 mmol) and (l,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene)(difluoromethyl)silver (485 mg, 0.9 mmol) in toluene (5 mL). The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was evaporated, then purified by flash C18-flash chromatography, elution gradient 0 to 60% MeCN in water (0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford 5-(difluoromethyl)-lH-indole-7-carbonitrile (78 mg, 45 %) as a red solid. NMR spectrum: NMR (300 MHz, DMSO, 22°C) 8 6.76 (1H, d), 7.13 (1H, t), 7.63 (1H, d), 7.82 (1H, d), 8.16 (1H, d). 1 x exchangeable not observed. Mass spectrum: m / z (ES-), [M-H]- = 191.

[0854] Synthesis of 7-fluoro-1H-indole-5-carbonitrile (Int A25)

[0855] N

[0856]

[0857] F

[0858] To a flask containing 5-bromo-7-fluoro-lH-indole (1.07 g, 5 mmol), potassium hexacyanoferrate (II) trihydrate (1.06 g, 2.5 mmol), potassium acetate (61.3 mg, 0.63 mmol) and BrettPhos Pd G3 (227 mg, 0.25 mmol) was added methyl THF (20.0 mL) / water (20.0 mL) and the reaction was heated at 70 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc (100 mL) and washed with brine (2 x 100 mL). The organic phase was dried over MgSCU, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 7-fluoro-lH-indole-5-carbonitrile (603 mg, 75 %) as a colourless solid. NMR spectrum: NMR (500 MHz, CDCI3, 27°C) 6.69 (1H, td), 7.16 (1H, dd), 7.34-7.41 (1H, m), 7.77-7.83 (1H, m), 8.67 (1H, s). Mass spectrum: m / z: ES- [M-H]- 159. Synthesis of 5-methoxy-lH-indole-7-carbonitrile (Int A26)

[0859]

[0860] Copper (I) cyanide (7.92 g, 88.47 mmol) was added to 7-bromo-5-methoxy-lH-indole (2 g, 8.85 mmol) in DMF (30 mL). The resulting mixture was heated at 145 °C for 16 hours. After cooling to room temperature, the reaction mixture was washed with aqueous saturated NH4CI solution (125 mL), then extracted with EtOAc (3 x 125 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated._The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 5-methoxy-lH-indole-7-carbonitrile (0.77 g, 51 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 23°C) 6 3.80 (3H, s), 6.53 (1H, dd), 7.26 (1H, d), 7.43-7.52 (2H, m), 11.81 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 173.

[0861] Synthesis of 5-(difluoromethoxy)-1H-indole-7-carbonitrile

[0862]

[0863] Step 1: 7-bromo-5-(difluoromethoxy)-1H-indole

[0864]

[0865] Br

[0866] Vinylmagnesium bromide solution (IM in THF, 14.92 mL, 14.92 mmol) was added slowly to 2-bromo-4-(difluoromethoxy)-l-nitrobenzene (1.0 g, 3.73 mmol) in THF (30 mL) at -78 °C over a period of 5 minutes under nitrogen. The resulting solution was stirred at -40 °C for 2 hours. The reaction mixture was quenched with aqueous saturated NH4CI solution (100 mL), then extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 7-bromo-5-(difluoromethoxy)-lH-indole (0.64 g, 66 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO) δ 6.60 (1H, dd), 6.87-7.4 (2H, m), 7.41 (1H, d), 7.49 (1H, t), 11.49 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 260, 262.

[0867] Step 2: 5-(difluoromethoxy)-lH-indole-7-carbonitrile (Int A27)

[0868]

[0869] NCopper(l) cyanide (1.71 g, 19.08 mmol) was added to 7-bromo-5-(difluoromethoxy)-lH-indole (0.5 g, 1.91 mmol) in DMF (10 mL) and the reaction was heated at 145 °C for 16 hours. The reaction mixture was quenched with washed water (100 mL) and extracted with EtOAc (3 x 125 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 4 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 5-(difluoromethoxy)-lH-indole-7-carbonitrile (0.2 g, 50 %) as a yellow solid. NMR spectrum:TH NMR (300 MHz, DMSO, 22°C) 8 6.64 (1H, dd), 7.17 (1H, t), 7.51 (1H, d), 7.58 (1H, t), 7.76 (1H, d), 12.15 (1H, s).

[0870] Synthesis of 5-(trifluoromethoxy)-1H-indole-7-carbonitrile (Int A28)

[0871] Step 1: 2-bromo-6-iodo-4-(trifluoromethoxy)aniline

[0872]

[0873] Br

[0874] 2-Bromo-4-(trifluoromethoxy)aniline (5.0 g, 19.53 mmol) was added dropwise to l2(4.96 g, 19.53 mmol) and silver sulfate (6.09 g, 19.53 mmol) in EtOH (60 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water (75 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford 2-bromo-6-iodo-4-(trifluoromethoxy)aniline (4.3 g, 58 %) as a yellow solid which was used directly in the next step. NMR spectrum: NMR (300 MHz, DMSO, 23°C) δ 5.40 (2H, s), 7.56 (1H, dd), 7.67 (1H, dd).

[0875] Step 2: 2-bromo-4-(trifluoromethoxy)-6-((trimethylsilyl)ethynyl)aniline

[0876] Si^

[0877] FT XX NH2

[0878]

[0879] Br

[0880] Ethynyltrimethylsilane (1.22 g, 12.38 mmol) was added to 2-bromo-6-iodo-4-(trifluoromethoxy)aniline (4.3 g, 11.26 mmol), copper (I) iodide (0.214 g, 1.13 mmol), TEA (4.71 mL, 33.78 mmol) and Pd(PPh3)2Cl2 (0.79 g, 1.13 mmol) in THF (50 mL) at 0°C. The resulting mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction mixture was washed with water (75 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 2-bromo-4-(trifluoromethoxy)-6-((trimethylsilyl)ethynyl)aniline (3.9 g, 98 %) as a yellow solid. NMRNMR (300 MHz, DMSO) δ 0.26 (9H, s), 5.52 (2H, s), 7.24-7.32 (1H, m), 7.53-7.6 (1H, m). Mass m / z (ES+), [M+H]+ 352, 354.

[0881] Step 3: 7-bromo-5-(trifluoromethoxy)-lH-indole

[0882]

[0883] Br

[0884] 2-Bromo-4-(trifluoromethoxy)-6-((trimethylsilyl)ethynyl)aniline (2.0 g, 5.68 mmol) was added to copper (I) iodide (2.163 g, 11.36 mmol) in DMF (13 mL). The resulting mixture was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (10 mL), filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 4 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 7-bromo-5- (trifluoromethoxy)-lH-indole (0.75 g, 47 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO) δ 6.66 (1H, dd), 7.38 (1H, d), 7.55 (1H, t), 7.62 (1H, s), 11.65 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 278.

[0885] Step 4: 5-(trifluoromethoxy)-lH-indole-7-carbonitrile (Int A28)

[0886]

[0887] N

[0888] 7-Bromo-5-(trifluoromethoxy)-lH-indole (1.4 g, 5.0 mmol) was added to copper (I) cyanide (4.48 g, 49.99 mmol) in DMF (13 mL). The resulting mixture was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (10 mL), then filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 4 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 5-(trifluoromethoxy)-lH- indole-7-carbonitrile (0.56 g, 50 %) as a yellow solid. NMR spectrum: NMR (300 MHz, DMSO) δ 6.72 (1H, dd), 7.66 (1H, t), 7.75 (1H, s), 7.99 (1H, s), 12.33 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 225.

[0889] Synthesis of 7-((tert-butyldimethylsilyl)ethynyl)-5-chloro-1H-indole (Int A29)

[0890]

[0891] XPhos Pd G3 (0.367 g, 0.43 mmol) was added to 7-bromo-5-chloro-lH-indole (1.0 g, 4.34 mmol), TEA (1.814 mL, 13.02 mmol), tert-butyl(ethynyl)dimethylsilane (0.609 g, 4.34 mmol) and 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-l,r-biphenyl (0.207 g, 0.43 mmol) in THF (15 mL). The resulting mixture was heated at 80 °C for 1 hour. The reaction mixture was washed with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-((tert- butyldimethylsilyl)ethynyl)-5-chloro-lH-indole (1.3 g, >100 %) as a brown gum which was used without further purification. NMR spectrum:1H NMR (300 MHz, DMSO) δ 0.24 (6H, s), 0.85-1.21 (9H, m), 6.5-6.57 (1H, m), 7.20 (1H, d), 7.44-7.5 (1H, m), 7.68 (1H, d), 11.29 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 288.

[0892] Synthesis of 7-((tert-butyldimethylsilyl)ethynyl)-5-methoxy-1H-indole (Int A30)

[0893]

[0894] Step 1: 7-bromo-5-methoxy-lH-indole

[0895] N

[0896] H

[0897]

[0898] Vinylmagnesium bromide solution (IM in THF, 70.0 mL, 70.0 mmol) was added slowly to 2-bromo-4- methoxy-l-nitrobenzene (5.0 g, 21.55 mmol) in THF (40 mL) at-78°C. The resulting solution was stirred at -78 °C for 1 hour, then was allowed to warm to room temperature for 4 hours. The reaction mixture was quenched with water (100 mL) and IN HCI (120 mL), then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-bromo-5-methoxy-lH-indole (1.37 g, 28 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 26°C) δ 3.76 (3H, s), 6.48 (1H, dd), 6.99 (1H, d), 7.10 (1H, d), 7.36 (1H, t), 11.14 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 226.

[0899] Step 2: 7-((tert-butyldimethylsilyl)ethynyl)-5-methoxy-1H-indole (Int A30)

[0900] Si- \

[0901] HN

[0902]

[0903] XPhos Pd G3 (0.749 g, 0.88 mmol) was added to 7-bromo-5-methoxy-lH-indole (1.0 g, 4.42 mmol), TEA (1.23 mL, 8.85 mmol), XPhos (0.422 g, 0.88 mmol) and tert-butyl(ethynyl)dimethylsilane (1.24 g, 8.85 mmol) in DMF (15 mL). The resulting mixture was heated at 80 °C for 4 hours. The reaction mixture was poured into aqueous saturated NH4CI solution (75 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude productwas purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-((tert-butyldimethylsilyl)ethynyl)-5-methoxy-lH-indole (1.39 g, >100 %) as a yellow solid that was used without further purification. NMR spectrum:

[0904] NMR (300 MHz, DMSO) δ 0.1–0.34 (6H, m), 0.98 (9H, d), 3.74-3.78 (3H, m), 6.83 (1H, d), 6.89-7.05 (1H, m), 7.16 (1H, d), 7.24-7.38 (1H, m), 10.84 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 286. Synthesis of 5-methyl-lH-indole-7-carbonitrile (Int A31)

[0905]

[0906] Pd(PPh3)4(275 mg, 0.24 mmol) was added to 7-bromo-5-methyl-lH-indole (500 mg, 2.38 mmol) and zinc cyanide (419 mg, 3.57 mmol) in DMF (10 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with saturated NaHCO3(50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-methyl-lH-indole-7-carbonitrile (360 mg, 97 %) as a colourless solid. NMR spectrum: NMR (300 MHz, DMSO, 27°C) δ 2.38 (3H, s), 6.51 (1H, dd), 7.37-7.47 (2H, m), 7.66-7.72 (1H, m), 11.82 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 155.

[0907] Synthesis of 5-ethynyl-1H-indole-7-carbonitrile (Int A32)

[0908] Step 1: 5-((tert-butyldimethylsilyl)ethynyl)-1H-indole-7-carbonitrile

[0909] TBS

[0910]

[0911] XPhos Pd G3 (115 mg, 0.14 mmol) and XPhos (64.7 mg, 0.14 mmol) were added to 5-bromo-lH-indole-7-carbonitrile (300 mg, 1.36 mmol), tert-butyldimethylsilylacetylene (190 mg, 1.36 mmol) and triethanolamine (607 mg, 4.07 mmol) in DMF (10 mL). The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was washed with saturated NaHCO3solution (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-((tert-butyldimethylsilyl)ethynyl)-lH-indole-7-carbonitrile (288 mg, 76 %) as a yellow solid. NMR spectrum:NMR (300 MHz, DMSO, 23°C) δ 0.15–0.21 (6H, m), 0.99 (9H, d), 6.66 (1H, dd), 7.58 (1H, t), 7.69 (1H, d), 8.05 (1H, s), 12.25 (1H, s).

[0912] Step 2: 5-ethynyl-lH-indole-7-carbonitrile (Int A32)

[0913]

[0914] Tetraethylammonium fluoride hydrate (571 mg, 3.08 mmol) was added to 5-((tert-butyldimethylsilyl)ethynyl)-lH-indole-7-carbonitrile (288 mg, 1.03 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-ethynyl-lH-indole-7-carbonitrile (170 mg, 100 %) as a yellow solid. NMR spectrum: NMR (300 MHz, DMSO, 23°C) δ 4.11 (1H, s), 6.66 (1H, dd), 7.58 (1H, t), 7.72 (1H, d), 8.06 (1H, d), 12.25 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 167.

[0915] Synthesis of 5-cyclopropyl-lH-indole-7-carbonitrile (Int A33)

[0916]

[0917] CataCXium A (0.243 g, 0.68 mmol) and cataCXium A Pd G3 (0.494 g, 0.68 mmol) were added to 5-bromo-lH-indole-7-carbonitrile (1.0 g, 4.52 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.988 g, 5.88 mmol) and K2CO3(1.88 g, 13.57 mmol) in 1,4-dioxane (8.0 mL) / water (2.0 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with saturated NaHCO3(75 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-cyclopropyl-lH-indole-7-carbonitrile (0.68 g, 82 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 28°C) δ 0.66–0.82 (2H, m), 0.83-1.07 (2H, m), 2.04 (1H, tt), 6.52 (1H, dd), 7.1-7.22 (1H, m), 7.44 (1H, t), 7.63 (1H, d), 11.83 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 181.

[0918] Synthesis of 4,5-dichloro-7-fluoro-lH-indole (Int A34)

[0919] JO

[0920]

[0921] Vinylmagnesium bromide solution (IM in THF, 155 mL, 154.77 mmol) was added slowly to 1,2-dichloro-4-fluoro-5-nitrobenzene (10.0 g, 47.62 mmol) in THF (180 mL) at -78°C under nitrogen. The resulting solution was stirred at -78 °C for 1 hour, then was allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated NH4CI (200 mL), extracted with EtOAc (3 x 250 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4,5-dichloro-7-fluoro-lH-indole (1.550 g, 15.95 %) as a yellow solid. NMR spectrum:1H NMR (400 MHz, DMSO, 23°C) δ 6.58 (1H, td), 7.30 (1H, d), 7.61 (1H, t), 12.21 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 202.

[0922] Synthesis of 5-bromo-4-chloro-7-fluoro-lH-indole (Int A35)

[0923]

[0924] Vinylmagnesium bromide solution (IM in THF, 128 mL, 127.73 mmol) was added slowly to 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (10.0 g, 39.30 mmol) in THF (200 mL) at -78°C under nitrogen. The resulting solution was stirred at -78 °C for 1 hour. The reaction mixture was quenched with saturated NH4CI (200 mL), extracted with EtOAc (3 x 200 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-4-chloro-7-fluoro-lH-indole (2.10 g, 21.50 %) as a yellow solid. NMR spectrum: NMR (400 MHz, DMSO, 22°C) δ 6.58 (1H, td), 7.39 (1H, d), 7.59 (1H, t), 12.22 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 246.

[0925] Synthesis of 4,7-difluoro-5-iodo-lH-indole (Int A36)

[0926] F

[0927]

[0928] FCui (123 mg, 0.65 mmol) was added to 5-bromo-4,7-difluoro-lH-indole (500 mg, 2.15 mmol), sodium iodide (2261 mg, 15.08 mmol) and trans-(lR,2R)-N, N'-bismethyl-l,2-cyclohexane diamine (92 mg, 0.65 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched with water (25 mL), extracted with EtOAc (5 x 25 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4,7-difluoro-5-iodo-lH-indole (580 mg, 96 %) as a yellow solid. NMR spectrum:1H NMR (400 MHz, DMSO, 22°C) 86.56 (1H, dd), 7.28 (1H, dd), 7.47 (1H, t), 12.12 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 278.

[0929] Synthesis of 5-(difluoromethyl)-4-fluoro-lH-indole-7-carbonitrile

[0930]

[0931] Step 1: tert-butyl 5-bromo-7-cyano-4-fluoro-lH-indole-l-carboxylate

[0932]

[0933] N

[0934]

[0935] BOC2O (0.321 mL, 1.38 mmol) was added to 5-bromo-4-fluoro-lH-indole-7-carbonitrile (220 mg, 0.92 mmol) and triethylamine (0.257 mL, 1.84 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL), extracted with DCM (3 x 50 mL), then the organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl 5-bromo-7-cyano-4-fluoro-lH-indole-l-carboxylate (300 mg, 96 %) as a white solid. NMR spectrum:

[0936] NMR (300 MHz, DMSO, 23°C) 8 1.64 (9H, s), 6.93 (1H, d), 7.86 (1H, d), 8.17 (1H, d). Mass spectrum: m / z (ES+), [M+H]+ = 339.

[0937] 2: 5-(difluoromethyl)-4-fluoro-lH-indole-7-carbonitrile (Int A37

[0938] N

[0939] H

[0940]

[0941] Pd2(dba)3(107 mg, 0.12 mmol) and Ephos (63.1 mg, 0.12 mmol) were added to tert-butyl 5-bromo-7-cyano-4-fluoro-lH-indole-l-carboxylate (200 mg, 0.59 mmol) and (l,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene)(difluoromethyl)silver (316 mg, 0.59 mmol) in toluene (4.0mL). The resulting mixture was stirred at 80 °C for 16 hours. The solvent was removed under reduced pressure, then the crude product was purified by flash C18-flash chromatography, elution gradient 0 to 50% MeCN in water(0.1% FA). Pure fractions were evaporated to dryness to afford 5-(difluoromethyl)-4-fluoro-lH-indole-7-carbonitrile (35.0 mg, 28.2 %) as a pale yellow solid. NMR: NMR (300 MHz, DMSO, 22°C) 86.83 (1H, d), 7.30 (1H, t), 7.68 (1H, d), 7.91 (1H, d), 12.68 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 209.

[0942] Synthesis of 5-chloro-7-ethynyl-4-methyl-lH-indole

[0943] Step 1: 2-bromo-4-chloro-5-methylaniline

[0944]

[0945] NCS (3.59 g, 26.87 mmol) was added to 2-bromo-5-methylaniline (5.0 g, 26.87 mmol) in AcOH (100 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was removed under reduced pressure. The residue was diluted with EtOAc (100 mL) and basified with saturated NaHCO3to pH 8. The aqueous layer was extracted with EtOAc (2 x 75 mL), then the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-bromo-4-chloro-5-methylaniline (4.00 g, 67.5 %) as a colourless solid. NMR spectrum:1H NMR (300 MHz, DMSO, 26°C) δ 2.16 (3H, s), 5.36 (2H, s), 6.74 (1H, s), 7.36 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 220.

[0946] Step 2: 6-bromo-4-chloro-2-iodo-3-methylaniline

[0947]

[0948] NIS (4.02 g, 17.86 mmol) was added to 2-bromo-4-chloro-5-methylaniline (3.75 g, 17.01 mmol) in AcOH (70 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (100 mL) and the resulting mixture was basified with saturated NaHCO3to pH 8. The aqueous was extracted with EtOAc (2 x 100 mL), then the combined organics were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 6-bromo-4-chloro-2-iodo-3-methylaniline (5.50 g, 93%) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 25°C) δ 2.48 (3H, s), 5.36 (2H, s), 7.58 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 346.

[0949] Step 3: 6-bromo-4-chloro-3-methyl-2-((trimethylsilyl)ethvnyl)aniline

[0950] II

[0951] ^NH2

[0952]

[0953] Cui (0.550 g, 2.89 mmol) and triphenylphosphine palladium chloride (1.01 g, 1.44 mmol) were added to 6-bromo-4-chloro-2-iodo-3-methylaniline (5 g, 14.43 mmol), ethynyltrimethylsilane (4.25 g, 43.30 mmol) and triethylamine (6.04 mL, 43.30 mmol) in THF (100 mL). The resulting mixture was heated to 60 °C for 16 hours. The reaction mixture was quenched with saturated brine (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 6-bromo-4-chloro-3-methyl-2-((trimethylsilyl)ethynyl)an iline (1.91 g, 41.8 %) as a yellow solid. NMR spectrum:1H NMR (300 MHz, DMSO, 24°C) 80.27 (9H, s), 2.33 (3H, s), 5.38 (2H, s), 7.49 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 316.

[0954] Step 4: 7-bromo-5-chloro-4-methyl-lH-indole

[0955] N

[0956]

[0957] Cui (0.571 g, 3.00 mmol) was added to 6-bromo-4-chloro-3-methyl-2-((trimethylsilyl)ethynyl)aniline (1.90 g, 6.00 mmol) and triethylamine (1.67 mL, 12.00 mmol) in DMF (30 mL). The resulting mixture was heated to 100 °C for 16 hours. The reaction mixture was quenched with saturated brine (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-bromo-5-chloro-4-methyl-lH-indole (0.810 g, 55.2 %) as a yellow solid. NMR spectrum: NMR (300 MHz, DMSO, 25°C) 8 2.47 (3H, s), 6.66 (1H, t), 7.35 (1H, s), 7.46 (1H, t), 11.51 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 244.

[0958] Step 5: 7-((tert-butyldimethylsilyl)ethvnyl)-5-chloro-4-methyl-lH-indole

[0959]

[0960] TBS

[0961] Copper iodide (15.58 mg, 0.08 mmol) and tetrakis(triphenylphosphine)palladium (47.3 mg, 0.04 mmol) were added to 7-bromo-5-chloro-4-methyl-lH-indole (100 mg, 0.41 mmol) and tert-butyl(ethynyl)dimethylsilane (172 mg, 1.23 mmol) in Et3N (2.0 mL). The resulting mixture was heated to 100 °C for 1.5 hours. The reaction mixture was poured into saturated NH4CI (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative TLC (pentane: EtOAc = 50: 1), to afford 7-((tert-butyldimethylsilyl)ethynyl)-5-chloro-4-methyl-lH-indole (98 mg, 79 %) as a pale yellow solid. NMR spectrum: NMR (300 MHz, DMSO, 23°C) 80.23 (6H, s), 1.00 (9H, s), 2.51 (3H, s), 6.61 (1H, dd), 7.21 (1H, s), 7.44 (1H, t), 11.24 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 302.

[0962] Step 6: 5-chloro-7-ethvnyl-4-methyl-lH-indole (Int A38)

[0963]

[0964] Tetraethylammonium fluoride hydrate (896 mg, 4.84 mmol) was added to 7-((tert-butyldimethylsilyl)ethynyl)-5-chloro-4-methyl-lH-indole (490 mg, 1.61 mmol) in THF (25 mL). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into saturated NaHCO3(75 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-chloro-7-ethynyl-4-methyl-lH-indole (230 mg, 75 %) as a brown solid. NMR spectrum: NMR (300 MHz, DMSO, 23°C) 82.51 (3H, s), 4.52 (1H, s), 6.60 (1H, dd), 7.25 (1H, s), 7.41 (1H, t), 11.51 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 190.

[0965] Synthesis of 5-chloro-7-((triisopropylsilyl)ethvnyl)-lH-indole-4-carbonitrile (int A39)

[0966] Step 1: 4-bromo-5-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indoleBr

[0967]

[0968] Boron tribromide in DCM (IM, 18.18 mL, 18.18 mmol) was added to l-(4-bromo-5-chloro-lH-indol-l-yl)-2,2-dimethylpropan-l-one (2.60 g, 8.26 mmol) in DCM (40 mL). The resulting mixture was stirred at 0 °C for 2 hours. Pinacol (3.42 g, 28.92 mmol) in TEA (30 mL, 215.23 mmol) was added to the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with DCM (3 x 50 mL), then the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-bromo-5-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole (2.100 g, 71.3 %) as a white solid. NMR spectrum: NMR (300 MHz, CDCI3, 23°C) 8 1.42 (12H, s), 6.60 (1H, dd), 7.3–7.38 (1H, m), 7.70 (1H, s), 9.34 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 356.

[0969] Step 2: 4-bromo-5-chloro-7-((triisopropylsilyl)ethvnyl)-lH-indole

[0970]

[0971] Bromoethynyltriisopropylsilane (2.73 mL, 11.22 mmol) was added to 4-bromo-5-chloro-7-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole (2.0 g, 5.61 mmol), tetrakis (triphenylphosphine)palladium(O) (0.648 g, 0.56 mmol) and potassium carbonate (2.33 g, 16.83 mmol) in toluene (15 mL) / EtOH (6 mL) / water (6 mL). The resulting mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford yellow gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-bromo-5-chloro-7-((triisopropylsilyl)ethynyl)-lH-indole (1.400 g, 60.7 %) as a white solid. NMR spectrum:1H NMR (300 MHz, CDCI3, 23°C) 81.19 (21H, d), 6.64 (1H, dd), 7.35 (1H, dd), 7.43 (1H, s), 8.46 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 410.

[0972] Step 3: 5-chloro-7-((triisopropylsilyl)ethvnyl)-lH-indole-4-carbonitrile (int A39)N

[0973]

[0974] TIPS

[0975] Di-p-chlorobis[(l,2,3-4)-l-phenyl-2-propenyl]dipalladium (II) (0.088 g, 0.16 mmol) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.170 g, 0.32 mmol) were added to 4-bromo-5-chloro-7-((triisopropylsilyl)ethynyl)-lH-indole (1.3 g, 3.16 mmol), potassium acetate (0.932 g, 9.49 mmol) and potassium ferrocyanide (II) trihydrate (4.01 g, 9.49 mmol) in 2-MeTHF (10 mL) / water (10 mL). The resulting mixture was stirred at 80 °C for 5 hours. The reaction mixture was poured into saturated brine (50 mL), extracted with EtOAc (3 x 25 mL), then the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-chloro-7-((triisopropylsilyl)ethynyl)-lH-indole-4-carbonitrile (0.800 g, 70.8 %) as a yellow solid. NMR spectrum: NMR (300 MHz, CDCI3, 24°C) 8 1.15-1.26 (21H, m), 6.78 (1H, dd), 7.41 (1H, s), 7.48 (1H, t), 8.59 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 357.

[0976] Synthesis of Indazole Intermediates:

[0977] Synthesis of 5-chloro-3-iodo-lH-indazole-7-carbonitrile (Int Bl)

[0978] Step 1: 5-chloro-lH-indazole-7-carbonitrile

[0979] Ck

[0980] Yj

[0981] H

[0982] N

[0983] 7-Bromo-5-chloro-lH-indazole (2.0 g, 8.64 mmol) were added to zinc cyanide (5.07 g, 43.20 mmol), zinc (0.113 g, 1.73 mmol) and PdCI2(dppf) (0.632 g, 0.86 mmol) in DMF (20 mL). The resulting mixture was stirred at 100 °C for 16 hours. The crude material was combined with 2 other batches of equal scale. The combined reaction mixtures were filtered through celite, then the crude product was purified by flash C18-flash chromatography, elution gradient 0 to 90% MeCN in water. Pure fractions were evaporated to dryness to afford 5-chloro-lH-indazole-7-carbonitrile (2.3 g, 38 %) as a yellow solid. NMR Spectrum: NMR (300 MHz, DMSO, 23°C) 88.09 (1H, d), 8.29 (2H, d), 14.23 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 176.

[0984] 2: 5-chloro-3-iodo-lH-indazole-7-carbonitrile

[0985]

[0986]

[0987] 5-Chloro-lH-indazole-7-carbonitrile (2.3 g, 12.95 mmol) was added to l2(6.57 g, 25.9 mmol) and KOH (1.453 g, 25.9 mmol) in DMF (20 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (3 x 20 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 90% MeCN in water. Pure fractions were evaporated to dryness to afford 5-chloro-3-iodo-lH-indazole-7-carbonitrile (2.0 g, 51 %) as a colourless solid. NMR Spectrum:1H NMR (300 MHz, DMSO, 22°C) δ 7.89 (1H, d), 8.19 (1H, d), 14.64 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 302.

[0988] Synthesis of 5-chloro-7-fluoro-3-iodo-lH-indazole (Int B2)

[0989]

[0990] I2 (1.67 g, 6.57 mmol) was added to 5-chloro-7-fluoro-lH-indazole (560 mg, 3.28 mmol) and KOH (737 mg, 13.13 mmol) in DMF (10 mL). The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with saturated brine (75 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-chloro-7-fluoro-3-iodo-lH-indazole (630 mg, 65 %) as a yellow solid. NMR: NMR (300 MHz, DMSO, 24°C) 8 7.37 (1H, d), 7.52 (1H, dd), 14.31 (1H, s). Mass

[0991]

[0992] m / z (ES-), [M-H]- = 295.

[0993] Synthesis of Intermediate aldehydes and thiols:

[0994]

[0995] is of sodium 5-i zine-2-thiolate

[0996]

[0997] Step 1: Synthesis of ethyl 3-((5-chloropyrazin-2-yl)thio)propanoate

[0998]

[0999] Pd2(dba)3(1.184 g, 1.29 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.748 g, 1.29 mmol) were added to 2-bromo-5-chloropyrazine (5.0 g, 25.85 mmol), ethyl 3-mercaptopropanoate(3.47 g, 25.85 mmol) and DIEA (13.54 mL, 77.55 mmol) in 1,4-dioxane (100 mL). The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched with water (200 mL), extracted with EtOAc (3 x 100 mL), then the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford ethyl 3-((5-chloropyrazin-2-yl)thio)propanoate (5.5 g, 86 %) as a pale yellow liquid. NMR spectrum:1H NMR (300 MHz, DMSO, 26°C) 8 1.18 (3H, t), 2.74 (2H, t), 3.37 (2H, t), 4.08 (2H, q), 8.48 (1H, d), 8.66 (1H, d). Mass spectrum: m / z (ES+), [M+H]+ = 247.

[1000] Step 2: sodium 5-chloropyrazine-2-thiolate (Int Cl)

[1001]

[1002] A mixture of ethyl 3-((5-chloropyrazin-2-yl)thio)propanoate (4.8 g, 19.46 mmol) and a 20% solution of sodium ethoxide in EtOH (8.61 g, 25.29 mmol) in THF (65 mL) were stirred for 10 minutes at 0 °C followed by warming to room temperature for 30 minutes. The solvent was removed under reduced pressure. Et2O (200 mL) was added. The precipitate was collected by filtration, washed with Et2O (50 mL) and dried under vacuum to afford sodium 5-chloropyrazine-2-thiolate (2.9 g, 88 %) as a yellow solid, which was used in the next step directly without further purification. NMR spectrum: NMR (300 MHz, DMSO, 26°C) δ 7.77 (1H, d), 7.84 (1H, d).

[1003] Synthesis of methyl 5-chloro-2-mercaptobenzoate (Int C2)

[1004] Step 1: methyl 5-chloro-2-((4-methoxybenzyl)thio)benzoate

[1005] O

[1006] Yr°

[1007] nn

[1008]

[1009] Pd2(dba)3(0.927 g, 1.01 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.585 g, 1.01 mmol) were added to methyl 5-chloro-2-iodobenzoate (3.0 g, 10.12 mmol), (4-methoxyphenyl)methanethiol (1.56 g, 10.12 mmol) and DIEA (5.30 mL, 30.36 mmol) in 1,4-dioxane (30 mL). The resulting mixture was stirred at 90 °C for 2 hours. The reaction mixture was quenched with water (75 mL), extracted with EtOAc (3 x 50 mL), then the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 5-chloro-2-((4-methoxybenzyl)thio)benzoate (4.12 g, >100 %) as a pale yellow solid that was used without further purification. NMR spectrum:JH NMR (400 MHz, DMSO) 83.74 (3H, s), 3.82(3H, s), 4.20 (2H, s), 6.86-6.94 (2H, m), 7.34 (2H, dd), 7.47 (1H, d), 7.61 (1H, dd), 7.85 (1H, d). Mass spectrum: m / z ( ES-), [M-H]- = 321.

[1010] Step 2: methyl 5-chloro-2-mercaptobenzoate (Int C2)

[1011] O

[1012] Yj0

[1013]

[1014] Methyl 5-chloro-2-((4-methoxybenzyl)thio)benzoate (2.5 g, 7.74 mmol) was added to TFA (30 mL) at room temperature. The resulting mixture was stirred at 80 °C for 16 hours. The solvent was removed under reduced pressure. The crude was diluted with EtOAc (100 mL) and quenched with saturated NaHCO3solution (100 mL). The aqueous phase was extracted with EtOAc (2 x 100 mL), then the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient Oto 100% MeCN in water (0.1% FA). Pure fractions were evaporated to dryness to afford methyl 5-chloro-2-mercaptobenzoate (0.3 g, 19 %) as a yellow solid. NMR spectrum: NMR (500 MHz, DMSO, 23°C) 83.90 - 3.93 (4H, m), 7.19-7.28 (1H, m), 7.62 (1H, d), 7.70 (1H, dd). Mass spectrum: m / z (ES-), [M-H]- = 201.

[1015] Synthesis of 3-(aminomethyl)-4-chlorobenzenethiol (Int C3)

[1016] Step 1: (3-bromo-4-chlorophenyl)(4-methoxybenzyl)sulfane

[1017]

[1018] Pd2(dba)3(1.154 g, 1.26 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.729 g, 1.26 mmol) were added to 2-bromo-l-chloro-4-iodobenzene (4.0 g, 12.6 mmol), (4-methoxyphenyl)methanethiol (1.94 g, 12.6 mmol) and DIEA (6.60 mL, 37.81 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 90 °C for 2 hours. The reaction mixture was poured into saturated aqueous NH4CI solution (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford (3-bromo-4-chlorophenyl)(4-methoxybenzyl)sulfane (3.3 g, 76 %) as a white solid. NMR spectrum:1H NMR (500 MHz, DMSO, 24°C) δ 3.72 (3H, s), 4.25 (2H, s), 6.84-6.9 (2H, m), 7.27-7.3 (2H, m), 7.33 (1H, dd), 7.50 (1H, dd), 7.67-7.7 (1H, m).

[1019] Step 2: tert-butyl (2-chloro-5-((4-methoxybenzyl)thio)benzyl)carbamateBocx

[1020]

[1021] CataCXium A Pd G3 (0.318 g, 0.44 mmol) and CataCXium A (0.156 g, 0.44 mmol) were added to Cs2CO3(4.27 g, 13.09 mmol), and potassium N-Boc-aminomethyltrifluoroborate (1.035 g, 4.36 mmol) in 1,4-dioxane (16 mL) and water (4 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (100 mL), extracted with EtOAc (3 x 100 mL), then the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl (2-chloro-5-((4-methoxybenzyl)thio)benzyl)carbamate (1.35 g, 79 %) as a white solid. NMR spectrum:1H NMR (500 MHz, DMSO, 23°C) 81.41 (9H, s), 3.72 (3H, s), 4.16 (4H, d), 6.82-6.88 (2H, m), 7.22 (1H, dd), 7.24-7.29 (3H, m), 7.34 (1H, d), 7.45 (1H, t). Mass spectrum: m / z (ES-), [M-H]- = 392.

[1022] Step 3: 3-(aminomethyl)-4-chlorobenzenethiol (Int C3)

[1023]

[1024] Tert-butyl (2-chloro-5-((4-methoxybenzyl)thio)benzyl)carbamate (800 mg, 2.03 mmol) was added to TFA (15 mL). The resulting mixture was stirred at 60 °C for 16 hours. The crude product mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1M NH3 / MeOH and pure fractions were evaporated to dryness to afford 3-(aminomethyl)-4-chlorobenzenethiol (250 mg, 71 %) as a red solid. NMR spectrum: NMR (400 MHz, DMSO, 23°C) 83.33 (2H, s), 3.81 (1H, d), 6.69 (1H, s), 7.29 (1H, s), 7.36 (1H, dd), 7.43 (1H, d), 7.70 (1H, d). Mass spectrum: m / z (ES+), [M+H]+ = 174.

[1025] Synthesis of 2-formylpyrimidine-5-carbonitrile (Int DI)

[1026] Step 1: 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine

[1027]

[1028] TEA (29.5 mL, 211.63 mmol) was added slowly to (5-bromopyrimidin-2-yl)methanol (20.0 g, 105.81 mmol) and TBS-CI (17.54 g, 116.39 mmol) in DMF (500 mL) cooled to 0°C. The resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (2.0 L) and extracted with EtOAc (2 x 1.0 L). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc inpetroleum ether. Pure fractions were evaporated to dryness to afford 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine (30.0 g, 93 %) as a yellow liquid. NMR spectrum: NMR (300 MHz, DMSO, 28°C) 80.07 (6H, s), 0.88 (9H, s), 4.79 (2H, s), 8.97 (2H, s). Mass spectrum: m / z (ES+), [M+H]+ = 303.

[1029] Step 2: 2-(((te / 't-butyldimethylsilyl)oxy)methyl)pyrimidine-5-carbonitrile

[1030]

[1031] Pd(PPh3)4 (10.67 g, 9.23 mmol) was added to 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine (28.0 g, 92.33 mmol) and zinc cyanide (11.92 g, 101.56 mmol) in DMF (360 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into saturated brine (1.0 L) and extracted with EtOAc (2 x 400 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-(((te / T-butyldimethylsilyl)oxy)methyl)pyrimidine-5-carbonitrile (15.0 g, 65 %) as a yellow solid. NMR spectrum: NMR (300 MHz, DMSO) 80.08 (6H, s), 0.88 (9H, s), 4.90 (2H, s), 9.28 (2H, s). Mass spectrum: m / z (ES+), [M+H]+ = 250.

[1032] Step 3: 2-(hydroxymethyl)pyrimidine-5-carbonitrile

[1033]

[1034] Et3N.3HF (48.5 g, 300.73 mmol) was added to 2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine-5-carbonitrile (15.0 g, 60.15 mmol) in THF (300 mL) and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into saturated NaHCO3(300 mL) and extracted with DCM (10 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-(hydroxymethyl)pyrimidine-5-carbonitrile (6.0 g, 74 %) as a colourless solid. NMR spectrum:1H NMR (300 MHz, DMSO, 26°C) δ 4.71 (2H, d), 5.58 (1H, t), 9.28 (2H, s). Mass spectrum: m / z (ES+), [M+H]+ = 136.

[1035] Step 4: 2-formylpyrimidine-5-carbonitrile (Int DI)

[1036]

[1037] Manganese (IV) oxide (10.94 g, 125.81 mmol) was added to 2-(hydroxymethyl)pyrimidine-5-carbonitrile (3.4 g, 25.16 mmol) in 1,4-dioxane (200 mL) at room temperature. The resulting mixture was stirred at 100 °C for 4 hours. The reaction mixture was filtered through celite, then the filtrate was evaporated to dryness to afford 2-formylpyrimidine-5-carbonitrile (2.9 g, 87 %) as a yellow solid which was used in the next step directly without further purification. NMR spectrum: NMR (300 MHz, DMSO, 23°C) 89.55 (2H, s), 9.98 (1H, s).

[1038] Synthesis of 5-formylpyrazine-2-carbonitrile (Int D2)

[1039] Step 1: 2-(((te / 't-butyldimethylsilyl)oxy)methyl)-5-chloropyrazine

[1040]

[1041] TBS' J

[1042] TEA (1.928 mL, 13.84 mmol) was added slowly to a cooled solution of (5-chloropyrazin-2-yl)methanol (1.0 g, 6.92 mmol) and TBS-CI (1.147 g, 7.61 mmol) in DMF (15 mL) at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloropyrazine (1.6 g, 89 %) as a yellow liquid. NMR spectrum:1H NMR (300 MHz, DMSO, 27°C) 80.11 (6H, s), 0.91 (9H, s), 4.84 (2H, d), 8.50 (1H, dt), 8.75 (1H, d). Mass spectrum: m / z (ES+), [M+H]+ = 259.

[1043] Step 2: 5-(((tert-butyldimethylsilyl)oxy)methyl)pyrazine-2-carbonitrile

[1044]

[1045] Pd(PPh3)4 (15.63 g, 13.52 mmol) was added to zinc cyanide (19.05 g, 162.27 mmol) and 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloropyrazine (35.0 g, 135.23 mmol) in DMF (500 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-(((tert-butyldimethylsilyl)oxy)methyl)pyrazine-2-carbonitrile (29.0 g, 86 %) as a yellow solid. NMR spectrum:

[1046] JH NMR (300 MHz, DMSO, 24°C) 8 0.13 (6H, s), 0.93 (9H, s), 4.94 (2H, s), 8.84 (1H, d), 9.18 (1H, d).

[1047] Mass spectrum: m / z (ES+), [M+H]+ = 250.

[1048] Step 3: 5-(hydroxymethyl)pyrazine-2-carbonitrile

[1049]

[1050] Et3N.3HF (3.88 g, 24.06 mmol) was added to 5-(((tert-butyldimethylsilyl)oxy)methyl)pyrazine-2-carbonitrile (1.20 g, 4.81 mmol) in THF (24 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into saturated NaHCO3solution (300 mL) and extracted with DCM (10 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-(hydroxymethyl)pyrazine-2-carbonitrile (0.48 g, 74 %) as a yellow solid. NMR spectrum:1H NMR (400 MHz, DMSO, 22°C) 84.74 (2H, d), 5.86 (1H, t), 8.88 (1H, d), 9.14 (1H, d).

[1051] Step 4: 5-formylpyrazine-2-carbonitrile (Int D2)

[1052]

[1053] Manganese (IV) oxide (926 mg, 10.66 mmol) was added to 5-(hydroxymethyl)pyrazine-2-carbonitrile (480 mg, 3.55 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at 100 °C for 4 hours. The mixture was filtered through a celite pad, then the filtrate was evaporated to afford 5-formylpyrazine-2-carbonitrile (400 mg, 85 %) as a yellow soild which was used in the next step directly without further purification. NMR spectrum: NMR (400 MHz, DMSO, 22°C) δ 9.25 (1H, d), 9.37 (1H, d), 9.45 (1H, d).

[1054] Synthesis of 5-(trifluoromethyl)pyrimidine-2-carbaldehvde (Int D3)

[1055]

[1056] Manganese (IV) oxide (5.55 g, 56.14 mmol) was added to (5-(trifluoromethyl)pyrimidin-2-yl)methanol (2.0 g, 11.23 mmol) in 1,4-dioxane (80 mL). The resulting mixture was stirred at 100 °C for 1 hour. The reaction mixture was filtered through celite, then the filtrate evaporated to afford 5-(trifluoromethyl)pyrimidine-2-carbaldehyde (1.5 g, 76 %) as a pale yellow oil which was used in thenext step directly without further purification. NMR spectrum:1H NMR (400 MHz, DMSO, 23°C) 69.55 (2H, d), 10.03 (1H, s). Mass spectrum: m / z (ES+), [M+H]+ = 177.

[1057] Synthesis of 3-(((te / T-butyldimethylsilyl)oxy)methyl)-4-chlorobenzaldehvde (Int D4)

[1058] Step 1: ((5-bromo-2-chlorobenzyl)oxy)(te / T-butyl)dimethylsilane

[1059]

[1060] ^x^CI

[1061]

[1062] " TBS

[1063] To a solution of (5-bromo-2-chlorophenyl)methanol (1.0 g, 4.52 mmol) in DCM (22.50 mL) was added imidazole (0.369 g, 5.42 mmol) and tert-butylchlorodimethylsilane (0.749 g, 4.97 mmol). The reaction was stirred at room temperature for 2 hours, then was washed sequentially with IN HCI solution (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4, filtered and evaporated to afford ((5-bromo-2-chlorobenzyl)oxy)(tert-butyl)dimethylsilane (1.55 g, >100 %} as a light yellow liquid, which was used directly in the next step without further purification. NMR spectrum: NMR (500 MHz, CDCI3, 27°C) 0.14 (6H, s), 0.97 (9H, s), 4.74 (2H, s), 7.16 (1H, d), 7.31 (1H, ddd), 7.69 (1H, dt).

[1064] Step 2: 3-(((te / 't-butyldimethylsilyl)oxy)methyl)-4-chlorobenzaldehyde (Int D4)

[1065]

[1066] To a cooled solution of ((5-bromo-2-chlorobenzyl)oxy)(tert-butyl)dimethylsilane (1.51 g, 4.5 mmol) in THF (18 mL) at -78 °C was added n-BuLi solution (1.6M in hexanes, 3.38 mL, 5.40 mmol). The reaction was stirred for 20 min, then DMF (523 pl, 6.75 mmol) was added and the reaction was allowed to warm to 5 °C over 1 hour. The reaction was quenched by addition of IN HCI solution (50 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (50 mL), then was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chlorobenzaldehyde (715 mg, 56 %) as a colourless liquid.

[1067] NMR spectrum:1H NMR (500 MHz, CDCl3, 27°C) 0.16 (6H, s), 0.99 (9H, s), 4.83 (2H, s), 7.48 (1H, d), 7.69 - 7.77 (1H, m), 8.06 - 8.12 (1H, m), 9.98 - 10.04 (1H, m).

[1068] General thioether formation Method A:

[1069] Example 1: 5-chloro-3-((5-chloropyridin-2-yl)thio)-lH-indole-7-carbonitrile

[1070]

[1071] 5-chloro-1H-indole-7-carbonitrile (200 mg, 1.13 mmol) was added to 5-chloropyridine-2-thiol (165 mg, 1.13 mmol) in TFA (2 mL) and DMSO (2 mL). The resulting mixture was stirred at 60 °C for 16 hours. The reaction mixture was diluted with EtOAc (20 mL), and washed sequentially with water (3 x 20 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 10 to 80% MeCN in water. Pure fractions were evaporated to dryness to afford 5-chloro-3-((5-chloropyridin-2-yl)thio)-lH-indole-7-carbonitrile (325 mg, 90 %) as a colourless solid. NMR spectrum: NMR (300 MHz, DMSO, 24°C) δ 6.78 (1H, d), 7.67 (1H, dd), 7.75 (1H, d), 7.89 (1H, d), 8.10 (1H, s), 8.44 (1H, d), 12.98 (1H, s). Mass spectrum: m / z (ES-), [M-H]- = 318.

[1072] General thioether formation Method B:

[1073] Example 2: 5-chloro-3-(pyridin-2-ylthio)-lH-indole-7-carbonitrile

[1074]

[1075] To a flask containing 5-chloro-1H-indole-7-carbonitrile (45 mg, 0.25 mmol), pyridine-2-thiol (56.7 mg, 0.51 mmol) and potassium iodide (85 mg, 0.51 mmol) in EtOH (1.80 mL) / water (0.60 mL) was added diiodine (129 mg, 0.51 mmol) and the reaction was heated at reflux for 4 hours. After cooling the reaction was diluted with EtOAc (10 mL) and washed with 10% sodium thiosulfate solution (10 mL) and brine (10 mL). The organic phase was dried with Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5p silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-(pyridin-2-ylthio)-1H-indole-7-carbonitrile (10.3 mg, 14%) as a beige solid. NMR spectrum: NMR (500 MHz, DMSO 27°C) 6.73 (1H, d), 7.10 (1H, ddd), 7.55 (lH, td), 7.71 (1H, d), 7.86 (1H, d), 8.05 (1H, s), 8.3 -8.39 (1H, m), 12.91 (1H, s). Mass spectrum: m / z: ES+ [M+H]+ 286.The compounds presented in Table S-Tl were synthesised in an analogous fashion to the Examples 1 & 2 above using the appropriate indole and thiol reagent (either as free thiol or sodium salt) and the specified general thioether formation method except where specified.

[1076] Table S-Tl:

[1077] Example Structure Compound Name Coupling Method 3-(( 1 H-l,2,4-triazol-3-yl )thio)- 3 5-chloro-lH-indole-7- carbonitrile

[1078] Cl-x,

[1079] NMR^H NMR (500 MHz,

[1080] B DMSO, 27°C) 7.81 (1H, d),

[1081] J~"z \ ^ z 7.84 (1H, d), 7.99 (1H, s), 8.34

[1082] (1H, s), 13.30 (1H, s). LCMS:

[1083] T o m / z: ES+ [M+H]+ 276

[1084] 5-chloro-3-((5-chloropyridin- 4 O 2-yl)thio)-4-fluoro-lH-indole- 7-carbonitrile

[1085] ^ (Z

[1086] V NMR^H NMR (500 MHz,

[1087] DMSO, 27°C) 6.96 (1H, dd), B 7.70 (1H, dd), 8.03 (1H, s),

[1088] N 8.05 (lH, d), 8.42 (1H, dd),

[1089] 13.15 (1H, s). LCMS: m / z: ES+ [M+H]+ 338.

[1090] 5-chloro-3-((5-chloropyrazin- 5 2-y l)thio)-l H-indole-7- carbonitrile

[1091] CI^C

[1092] NMR:JH NMR (300 MHz, A Y DMSO, 24°C) 67.86 (2H, dd),

[1093] 8.05 (1H, d), 8.11 (1H, s), 8.57

[1094] (1H, d), 12.99 (1H, s). LCMS:

[1095] N

[1096] m / z (ES+), [M+H]+ = 321.

[1097] 3-((5-chloropyridin-2-yl)thio)- 6 5-methoxy-lH-indole-7- s-^ J carbonitrile

[1098] X. 7 N-^

[1099] ¥ NMR:JH NMR (300 MHz,

[1100] A DMSO, 26°C) 83.77 (3H, s),

[1101] H 6.71 (1H, dd), 7.21 (1H, d),

[1102] r 1 7.42 (1H, d), 7.66 (1H, dd),

[1103] 7.95 (1H, s), 8.44 (1H, dd),

[1104] 12.60 (1H, s). LCMS: m / z

[1105]

[1106] (ES+), [M+H]+ = 316.3-((5-chloropyrid in-2-yl)th io)- 5-(difluoromethoxy)-lH- indole-7-carbonitrile

[1107] NMR: NMR (300 MHz,

[1108] DMSO, 24°C) 66.78 (1H, dd),

[1109] A

[1110] 7.20 (t, 1H), 7.52-7.55 (m,

[1111] z 1H), 7.63-7.73 (2H, m), 8.10

[1112] (1H, d), 8.44 (1H, dd), 12.93

[1113] (1H, s). LCMS: m / z (ES+),

[1114] [M+H]+ = 352.

[1115] 4 XZ~ 3-((5-chloropyrid in-2-yl)th io)- 7-fluoro-lH-indole-5- carbonitrile

[1116] - - o A o NMR: NMR (500 MHz,

[1117] o Reaction DMSO 27°C) 6.79 (1H, dd),

[1118] performed 7.60 (1H, dd), 7.68 (1H, dd),

[1119] at 100 °C 7.77 (1H, d), 8.13 (1H, s), 8.44

[1120] (1H, dd), 12.96 (1H, s). LCMS:

[1121] m / z: ES+ [M+H]+ 304.

[1122] 5,7-dich loro-3-((5- chloropyridi n-2-yl)th io)-l H- A-ci

[1123] s-^ J indole

[1124] NNMR:1H NMR (400 MHz,

[1125] T X>

[1126] DMSO, 22°C) 66.74 (1H, dd),

[1127] N A

[1128] Cl 7.38 (1H, d), 7.43 (1H, d), 7.67

[1129] (1H, dd), 8.01 (1H, d), 8.44

[1130] (1H, dd), 12.48-12.52 (1H, m).

[1131] LCMS: m / z (ES+), [M+H]+ =

[1132] 330.

[1133] 5-chloro-3-((5-chloropyridin- 2-y l)thio)-l H-indole

[1134] NMR:1H NMR (400 MHz,

[1135] DMSO, 22°C) 66.68 (1H, dd),

[1136] 7.23 (1H, dd), 7.37 (1H, d), A 7.55 (1H, dd), 7.67 (1H, dd),

[1137] 7.92 (1H, d), 8.44 (1H, dd),

[1138] 12.03 (1H, s). LCMS: m / z

[1139] (ES+), [M+H]+ = 295.

[1140]

[1141] 5-chloro-3-((5-chloropyridin- 2-yl)thio)-7-fluoro-lH-indole

[1142] s- j^X J / rcl

[1143] NMR:1H NMR (400 MHz,

[1144] Y X> DMSO, 23°C) 66.73 (1H, dd),

[1145] A

[1146] 7.21-7.29 (2H, m), 7.68 (1H,

[1147] N

[1148] F dd), 8.01 (1H, d), 8.45 (1H,

[1149] dd), 12.62 (1H, s). LCMS: m / z

[1150] (ES+), [M+H]+ = 313.

[1151] 5-chloro-3-((5-cyanopyridin-2- yl)thio)-4-fluoro-lH-indole-7- F s-4 carbonitrile

[1152] Clx J; / N"^

[1153] A Y NMR: NMR (500 MHz,

[1154] Reaction DMSO 27°C) 7.14 (1H, dd),

[1155] H performed 8.03 (1H, dd), 8.05 - 8.09 (2H,

[1156] at 100 °C N m), 8.80 (lH, dd), 13.23 (1H,

[1157] s). LCMS: m / z: ES+ [M+H]+

[1158] 329.

[1159] 4,5-dichloro-3-((5- A==\---^Ncyanopyridin-2-yl)thio)-lH- C1s-Y / / indole-7-carbonitrile CI^ J:

[1160] A Y NMR:1H NMR (500 MHz,

[1161] S^N Reaction DMSO 27°C) 7.03 (1H, d), 8.00

[1162] H performed (1H, dd), 8.07 (1H, s), 8.11

[1163] at 100 °C N (1H, s), 8.72 -8.84 (1H, m),

[1164] 13.24 (1H, s). LCMS: m / z: ES+ [M+H]+ 345.

[1165] 5-bromo-3-((5-chloropyridin- 2-y l)thio)-l H-indole-7- YYrcl

[1166] s--\> J / carbonitrile

[1167] Br-^. / N-^

[1168] JA NMR: H NMR (300 MHz,

[1169] Reaction DMSO, 24°C) 86.78 (1H, dd),

[1170] H performed 7.68 (1H, dd), 7.87 (1H, d),

[1171] at 80 °C N 7.99 (1H, d), 8.08 (1H, d), 8.44

[1172] (1H, dd), 12.99 (1H, s). LCMS:

[1173] m / z (ES+), [M+H]+ = 364.

[1174]

[1175] 3-((5-chloropyrid in-2-yl)th io)- 5-(trifluoromethoxy)-lH- rVci

[1176] S"-^ / / indole-7-carbonitrile

[1177] NFT CO NMR:1H NMR (400 MHz, DMSO, 23°C) 86.82 (1H, dd), A H

[1178] 7.65-7.73 (2H, m), 7.93 (1H, N d), 8.17 (1H, d), 8.43 (1H, dd),

[1179] 13.08 (1H, s). LCMS: m / z

[1180] (ES+), [M+H]+ = 370.

[1181] 3-((5-bromopyrimidin-2- yl)thio)-5-chloro-lH-indole-7- / N==:\-'Br

[1182] s-A / / carbonitrile

[1183] NNMR: NMR (500 MHz,

[1184] A DMSO, 24°C) 67.82 (2H, dd), H 8.02 (1H, s), 8.74 (2H, s),

[1185] J 12.70 (1H, s). LCMS: m / z (ES-),

[1186] [M-H]- = 363, 365.

[1187] 3-((5-cyanopyridin-2-yl)th io)- 4-fluoro-5-methoxy-lH- F S-A indole-7-carbonitrile

[1188] NMR:1H NMR (400 MHz, xT DMSO, 24°C) 83.87 (3H, s),

[1189] H A

[1190] =17.05 (1H, dd), 7.74 (1H, d),

[1191] 1

[1192] h 1 7.97 (1H, s), 8.01 (1H, dd),

[1193] 8.80 (1H, dd), 12.82 (lH, s).

[1194] LCMS: m / z (ES+), [M+H]+ = 325.

[1195] 4-chloro-3-((5-cyanopyridin-2- yl)thio)-5-methoxy-lH-indole- c:|s-A jj 7-carbonitrile

[1196] NMR:1H NMR (400 MHz, XT DMSO, 24°C) 83.90 (3H, s), A H 6.97 (1H, d), 7.70 (1H, s), h 1 7.96-8.05 (2H, m), 8.79 (1H,

[1197] d), 12.90 (1H, s). LCMS: m / z (ES+), [M+H]+ = 341.

[1198]

[1199] 3-((3-(aminomethyl)-4- 19 chlorophenyl)thio)-5-chloro- lH-indole-7-carbonitrile

[1200] NMR: NMR (400 MHz,

[1201] DMSO, 24°C) 63.70 (2H, s),

[1202] 6.77 (1H, dd), 7.22 (1H, d), A 7.43 (1H, d), 7.69 (1H, d), 7.85

[1203] (1H, d), 8.06 (1H, s). 3 x

[1204] exchangeables not observed.

[1205] LCMS: m / z (ES+), [M+H]+ =

[1206] 348.

[1207] 2-(3-((5-ch loropyrid in-2- 20Nf^\ ri yl)thio)-l H-indol-5- "s<rciyl)acetonitrile

[1208] NMR: NMR (500 MHz, TX?

[1209] DMSO 27°C) 4.06 (2H, s), 6.59

[1210] H A

[1211] -6.7 (1H, m), 7.19 (1H, dd),

[1212] O 7.41 (1H, s), 7.55 (1H, d), 7.65

[1213] (1H, dd), 7.86 (1H, d), 8.37- 8.49 (1H, m), 11.90 (1H, s).

[1214] LCMS: m / z: ES+ [M+H]+ 300.

[1215] 3-((2-amino-4- 21 Cl chlorophenyl)thio)-5-chloro- / X NH2lH-indole-7-carbonitrile o

[1216] xx j T 1 NMR:1H NMR (400 MHz, X HN--7DMSO, 24°C) 85.79 (2H, s),

[1217] A

[1218] 6.46 (1H, dd), 6.71 (1H, d),

[1219] 7.17 (1H, d), 7.81 (1H, d), 7.91

[1220] (1H, d), 8.06 (1H, s), 12.64

[1221] (1H, s). LCMS: m / z (ES-), [M- H]- = 332.

[1222]

[1223] Example 22: 6-((5-chloro-7-ethvnyl-lH-indol-3-yl)thio)nicotinonitrile

[1224] Step 1: 6-((7-((te / T-butyldimethylsilyl)ethyn yl)-5-ch loro-1 H-indol-3-yl)th iolnicotinonitrile

[1225] Cl

[1226] T

[1227]

[1228] BS

[1229] The thiolation was performed starting from 7-((tert-butyldimethylsilyl)ethynyl)-5-chloro-lH-indole according to the general thioether formation conditions method A and the product was used directly in the next step.Step 2: 6-((5-chloro-7-ethvnyl-lH-indol-3-yl)thio)nicotinonitrile, Example 22

[1230] Cl

[1231]

[1232] Tetramethylammonium fluoride (32.9 mg, 0.35 mmol) was added to 6-((7-((tert- butyldimethylsilyl)ethynyl)-5-chloro-l H-indol-3-yl)thio)nicotinonitrile (50 mg, 0.12 mmol) in THF (3 mL). The resulting mixture was stirred at 40 °C for 1 hour. The reaction mixture was quenched with saturated brine (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organics were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC Gradient: 5% B to 30% B in 8 min, fractions containing the desired compound were evaporated to dryness to afford 6-((5-chloro-7-ethynyl-lH-indol-3-yl)thio)nicotinonitrile (20.0 mg, 55 %) as a colourless solid. NMR Spectrum: NMR (400 MHz, DMSO, 24°C) 84.74 (1H, s), 6.86 (1H, dd), 7.41 (1H, d), 7.46 (1H, d), 7.98 (2H, d), 8.82 (1H, dd). 1 x exchangeable not observed. Mass Spectrum: m / z (ES+), [M+H]+ = 310.

[1233] Example 23: 5-chloro-3-((5-chloropyridin-2-yl)thio)-7-(prop-l-vn-l-yl)-lH-indole

[1234] Step 1: 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)thio)-lH-indole

[1235]

[1236] The thiolation was performed starting from 7-bromo-5-chloro-lH-indole (1.0 g, 4.34 mmol) according to the general thioether formation conditions method A to afford 7-bromo-5-chloro-3-((5- chloropyridin-2-yl)thio)-l H-ind ole (1.5 g, 92 %} as a yellow solid. NMR Spectrum:1H NMR (300 MHz, DMSO, 22°C) 66.72 (1H, dd), 7.39 (1H, d), 7.52 (1H, d), 7.65 (1H, dt), 7.94 (1H, dd), 8.42 (1H, dd), 12.34 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 373, 375.

[1237] Step 2: 5-chloro-3-((5-chloropyridin-2-yl)thio)-7-(prop-l-vn-l-yl)-lH-indole, Example 23

[1238]

[1239] Pd(PPh3)2Cl2 (37.5 mg, 0.05 mmol) was added to 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)thio)-lH- indole (100 mg, 0.27 mmol), trimethyl(prop-l-yn-l-yl)silane (150 mg, 1.34 mmol), Cui (25.5 mg, 0.13 mmol) and CS2CO3 (131 mg, 0.4 mmol) in MeOH (1.0 mL), DMA (1.0 mL) and water (1.0 mL). Theresulting mixture was stirred at 110 °C for 16 hours. The reaction mixture was filtered, then the filtrate was poured into water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 5-chloro-3-((5-chloropyridin-2-yl)thio)-7-(prop-l-yn-l-yl)-lH-indole (20.0 mg, 23 %) as a colourless solid. NMR Spectrum:JH NMR (300 MHz, DMSO) 82.19 (3H, s), 6.70 (1H, d), 7.31 (2H, dd), 7.66 (1H, dd), 7.93 (1H, s), 8.44 (1H, d), 12.28 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 333.

[1240] Example 24: 5-chloro-3-((5-cvanopyrazin-2-yl)thio)-lH-indole-7-carbonitrile

[1241] Cl

[1242]

[1243] Pd2(dba)3(80.0 mg, 0.09 mmol) and dppf (48.3 mg, 0.09 mmol) were added to zinc cyanide (154 mg, 1.31 mmol) and 5-chloro-3-((5-chloropyrazin-2-yl)thio)-lH-indole-7-carbonitrile (280 mg, 0.87 mmol) in DMF (4.0 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC column. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro- 3-((5-cyanopyrazin-2-yl)thio)-lH-indole-7-carbonitrile (80 mg, 29 %) as a yellow solid. NMRSpectrum: NMR (400 MHz, DMSO, 23°C) 8 7.85 (1H, d), 7.90 (1H, d), 8.14 (1H, s), 8.43 (1H, d), 8.92 (1H, d), 13.00 (1H, s). Mass Spectrum: m / z (ES+), [M-H]- = 310.

[1244] Example 25: 5-chloro-3-((5-cvanopyrazin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile

[1245] Step 1: 5-chloro-3-((5-chloropyrazin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile

[1246]

[1247] The thiolation was performed starting from 5-chloro-4-fluoro-lH-indole-7-carbonitrile (400 mg, 2.06 mmol) using the general thioether formation conditions B. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-chloro-3-((5-chloropyrazin-2-yl)thio)-4-fluoro-lH-indole-7- carbonitrile (600 mg, 86 %) as a colourless solid. NMR Spectrum:1H NMR (300 MHz, DMSO, 26°C) 6 8.08 (2H, d), 8.23 ( 1 H, d), 8.58 ( 1 H, d), 13.20 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 339.Step 2: 5-chloro-3-((5-cvanopyrazin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile, Example 25

[1248]

[1249] Pd2(d ba )3(94.0 mg, 0.1 mmol) and dppf (57.2 mg, 0.1 mmol) were added to zinc cyanide (182 mg, 1.55 mmol) and 5-chloro-3-((5-chloropyrazin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile (350 mg, 1.03 mmol) in DMF (5 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC Column. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro- 3-((5-cyanopyrazin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile (50.0 mg, 15 %} as a pale yellow solid.

[1250] NMR Spectrum: NMR (400 MHz, DMSO, 24°C) 87.99 (1H, d), 8.05 (1H, s), 8.53 (1H, d), 8.92 (1H, d).

[1251] 1 x exchangeable not observed. Mass Spectrum: m / z (ES-), [M-H]- = 328.

[1252] Example 26: 5-chloro-3-((4-chloro-2-(hvdroxymethyl)phenyl)thio)-lH-indole-7-carbonitrile

[1253] Step 1: methyl 5-chloro-2-((5-chloro-7-cyano-lH-indol-3-yl)thio)benzoate

[1254] I

[1255] Cl o o

[1256] jf L A

[1257]

[1258] N H

[1259] The thiolation was performed starting from 5-chloro-4-fluoro-lH-indole-7-carbonitrile (250 mg, 1.42 mmol) using the general thioether formation conditions B. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 5-chloro-2-((5-chloro-7-cyano-lH-indol-3-yl)thio)benzoate (80 mg, 15%) as a colourless solid. NMR Spectrum: NMR (500 MHz, DMSO) 63.93 (3H, s), 6.65 (1H, d), 7.32-7.42 (2H, m), 7.67 (1H, d), 7.91 (1H, dd), 8.08 (1H, d), 12.99 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 375.

[1260] Step 2: 5-chloro-3-((4-chloro-2-(hvdroxymethyl)phenyl)thio)-lH-indole-7-carbonitrile Example 26

[1261]

[1262] Sodium borohydride (12.03 mg, 0.32 mmol) was added to methyl 5-chloro-2-((5-chloro-7-cyano-lH- indol-3-yl)thio)benzoate (60 mg, 0.16 mmol) in MeOH (3 mL) at 0 °C under nitrogen. The resultingmixture was stirred at 25 °C for 10 days. The reaction mixture was quenched with saturated NH4CI solution (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-((4-chloro-2-(hydroxymethyl)phenyl)thio)-lH-indole-7-carbonitrile (20.0 mg, 36 %} as a colourless solid. NMR Spectrum: NMR (400 MHz, DMSO) 84.69 (2H, s), 5.53 (1H, s), 6.63 (1H, d), 7.10 (1H, dd), 7.47 (1H, d), 7.66 (1H, d), 7.83 (1H, d), 8.05 (1H, s). 1 x exchangeable not observed. Mass Spectrum: m / z (ES-), [M-H]- = 347.

[1263] Example 27: 5-chloro-3-((5-cvanopyridin-2-yl)thio)-lH-indole-7-carbonitrile

[1264] Cl

[1265]

[1266] 6-Mercaptonicotinonitrile (0.20 g, 1.47 mmol) was added to 5-chloro-3-iodo-lH-indole-7-carbonitrile (0.222 g, 0.73 mmol), xantphos (0.085 g, 0.15 mmol), DIEA (0.385 mL, 2.20 mmol) and Pd2(dba)3(0.134 g, 0.15 mmol) in 1,4-dioxane (3 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was washed with water (75 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 5-chloro-3-((5-cyanopyridin-2-yl)thio)-lH-indole-7-carbonitrile (0.02 g, 9 %) as a yellow solid. NMR Spectrum: NMR (400 MHz, DMSO, 23°C) 86.93 (1H, dd), 7.77 (1H, d), 7.90 (1H, d), 7.99 (1H, dd), 8.13 (1H, s), 8.81 (1H, dd), 13.06 (1H, s). Mass Spectrum: m / z (ES-), [M-H]-= 309.

[1267] Example 28: 5-chloro-3-((5-cvanopyrimidin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile

[1268] Step 1: 3-((5-bromopyrimidin-2-yl)thio)-5-chloro-4-fluoro-lH-indole-7-carbonitrile

[1269]

[1270] Was synthesised according to the general thiolation conditions B detailed above using sodium 5-bromopyrimidine-2-thiolate as the thiol source, to afford 3-((5-bromopyrimidin-2-yl)thio)-5-chloro-4-fluoro-lH-indole-7-carbonitrile as an impure pale yellow solid. Mass Spectrum: m / z (ES-), [M-H]- = 381.Step 2: 5-chloro-3-((5-cvanopyrimidin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile, Example 28

[1271]

[1272] Pd2(dba)3(9.55 mg, 10.43 nmol) and dppf (5.78 mg, 10.43 pmol) were added to zinc cyanide (24.49 mg, 0.21 mmol) and 3-((5-bromopyrimidin-2-yl)thio)-5-chloro-4-fluoro-lH-indole-7-carbonitrile (40 mg, 0.1 mmol) in DMF (2 mL). The resulting mixture was stirred at 120 °C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-((5-cyanopyrimidin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile (10.0 mg, 29 %} as a colourless solid.

[1273] NMRSpectrum: NMR (400 MHz, DMSO, 27°C) 88.00 (2H, d), 9.02 (2H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 330.

[1274] General thioether oxidation to sulfoxide, sulfone and sulfoximine

[1275] Method A: sulfoxide and sulfone:

[1276] Example 29: 3-((5-chloropyridin-2-yl)sulfonyl)-5-methoxy-lH-indole-7-carbonitrile

[1277] — O

[1278]

[1279] mCPBA (0.077 g, 0.44 mmol) was added to 3-((5-chloropyridin-2-yl)thio)-5-methoxy-lH-indole-7-carbonitrile (0.07 g, 0.22 mmol) in DCM (1.5 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched by addition of NaHCO3solution (25 mL). The reaction mixture was extracted with EtOAc (3 x 25 mL), then the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 3-((5-chloropyridin-2-yl)sulfonyl)-5-methoxy-lH-indole-7-carbonitrile (0.05 g, 65 %) as a yellow solid. NMR Spectrum:JH NMR (300 MHz, DMSO) 83.85 (3H, s), 7.50 (1H, d), 7.63 (1H, d), 8.2-8.31 (3H, m), 8.76 (1H, t), 13.24 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 348.

[1280] Method B: sulfoximine:

[1281] 30: 3-1 idine-2-su

[1282]

[1283] -5-methoxy-lH-indole-7-carbonitrile

[1284]

[1285] lodobenzene diacetate (0.357 g, 1.11 mmol) was added to 3-((5-chloropyridin-2-yl)thio)-5-methoxy-lH-indole-7-carbonitrile (0.14g, 0.44 mmol) and ammonium carbamate (0.138 g, 1.77 mmol) in MeOH □□

[1286] (2.0 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction was washed with water (75 mL) and extracted with EtOAc (3 x 75 mL). The combined organics were dried over Na2SO4, filtered and evaporated. _The crude product was purified by preparative HPLC column. Fractions containing the desired compound were evaporated to dryness to afford 3-(5-chloropyridine-2-sulfonimidoyl)-5-methoxy-lH-indole-7-carbonitrile (10.0 mg, 7 %} as a yellow solid. NMR Spectrum: NMR (300 MHz, DMSO, 24°C) 83.82 (3H, s), 5.17 (1H, s), 7.44 (1H, d), 7.75 (1H, d), 8.06 (1H, s), 8.16 o

[1287] (1H, dd), 8.24 (1H, dd), 8.67 (1H, dd), 12.90 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 347.

[1288] The compounds presented in Table S-T2 were synthesised in an analogous fashion to Examples 29 and 30 above using the appropriate indole thioether except where specified.

[1289] Table S-T2

[1290] Example Structure Compound Name Coupling Method 5-chloro-3-((5-chloropyridin-2- 31 yl)sulfi nyl)-7-fl uoro-1 H-indole

[1291] Ox

[1292] Xs-A J

[1293] NNMR^H NMR (300 MHz,

[1294] A DMSO, 23°C) 67.12 (1H, d),

[1295] 1.1 equiv 7.21 (1H, dd), 8.19-8.31 (2H,

[1296] 1 H mCPBA F m), 8.33 (1H, s), 8.62 (1H, dd),

[1297] 12.84 (1H, s). LCMS: m / z (ES+),

[1298] [M+H]+ = 329.

[1299] 5-bromo-3-((5-chloropyridin-2- 32 yl)sulfonyl)-lH-indole-7- carbonitrile

[1300] NMR^H NMR (300 MHz, A DMSO) 68.09 (1H, d), 8.26 5 equiv (2H, d), 8.29 (lH, d), 8.43 (1H, mCPBA s), 8.77 (1H, t), 13.64 (lH, s).

[1301] LCMS: m / z (ES+), [M+H]+ =

[1302] 396, 398.

[1303]

[1304] 5-bromo-3-(5-chloropyridine- 33 0. _, 2-sulfonimidoyl)-lH-indole-7- HN^^A_CIcarbonitrile

[1305] N= / /

[1306] NMR:1H NMR (400 MHz,

[1307] L O DMSO, 24°C) 65.33 (1H, s),

[1308] H B

[1309] 8.01 (1H, d), 8.13-8.21 (2H,

[1310] I I

[1311] N m), 8.25 (1H, d), 8.40 (1H, d),

[1312] 8.68 (1H, d), 13.31 (1H, s).

[1313] LCMS: m / z (ES+), [M+H]+ =

[1314] 395, 397.

[1315] (5-chloro-7-fluoro-lH-indol-3- 34 yl)(4-chlorophenyl)(imino)-l6- sulfanone

[1316] NMR:JH NMR (300 MHz,

[1317] DMSO, 22°C) 65.11 (1H, s),

[1318] B

[1319] 7.26 (1H, dd), 7.53-7.63 (1H,

[1320] m), 7.69 (1H, d), 7.95-8.06

[1321] O (2H, m), 8.15 (1H, s), 12.90

[1322] (1H, s). LCMS: m / z (ES+),

[1323] [M+H]+ = 343.

[1324]

[1325] \ / /

[1326] _ z \ /

[1327] Example 35: 5-chloro-3-((5-c Thloropyridin-2-yl)sulfonyl)-7-ethvnyl-l H-indole

[1328] Step 1: 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)thio)-l H-indole

[1329] o

[1330] Was synthesised according to the general thiolation conditions A detailed above to afford 7-bromo- 5-chloro-3-((5-chloropyridin-2-yl)thio)-l H-indole as a pale yellow solid. NMR Spectrum:1H NMR (400 MHz, DMSO, 22°C) 8 6.74 (1H, d), 7.41 (1H, d), 7.55 (1H, d), 7.67 (1H, dd), 7.99 (1H, d), 8.44 (1H, d), 12.36 (1H, d). Mass Spectrum: m / z (ES-), [M-H]- = 371.

[1331] Step 2: 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)sulfonyl)-l H-indole

[1332]

[1333] Was synthesised according to the general oxidation conditions A detailed above to afford 7-bromo- 5-chloro-3-((5-chloropyridin-2-yl)sulfonyl)-lH-indole as a colourless solid. NMR Spectrum:1H NMR (400 MHz, DMSO, 24°C) 67.61-7.7 (1H, m), 7.87 (1H, dd), 8.25 (2H, d), 8.32 (1H, s), 8.75 (1H, t), 13.05 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 403.

[1334] Step 3: 5-chloro-3-((5-chloropyridin-2-yl)sulfonyl)-7-((trimethylsilyl)ethvnyl)-lH-indole

[1335]

[1336] Pd(PPh3)2Cl2 (173 mg, 0.25 mmol) was added to 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)sulfonyl)- lH-indole (200 mg, 0.49 mmol), ethynyltrimethylsilane (242 mg, 2.46 mmol), Cui (75 mg, 0.39 mmol) and TEA (0.686 mL, 4.93 mmol) in THF (4.0 mL) under nitrogen. The resulting mixture was stirred at 60 °C for 16 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed with water (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 5-chloro-3-((5-chloropyridin-2-yl)sulfonyl)-7- ((trimethylsilyl)ethynyl)-lH-indole (180 mg, 86 %) as a yellow solid. NMRSpectrum: NMR (400 MHz, DMSO, 25°C) 8 0.29 (9H, s), 7.43 (2H, d), 7.86 (1H, d), 8.25 (2H, d), 8.76 (1H, t), 12.77 (1H, s). Mass: m / z (ES-), [M-H]- = 421.

[1337] 4: 5-chloro-3-l idin-2-' i-7-< 1-lH-indole le 35

[1338] Ox / O

[1339] N

[1340] N

[1341]

[1342] K2CO3(261 mg, 1.89 mmol) was added to 5-chloro-3-((5-chloropyridin-2-yl)sulfonyl)-7- ((trimethylsilyl)ethynyl)-lH-indole (160 mg, 0.38 mmol) in MeOH (1.5 mL) and THF (1.5 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite. The filtrate was evaporated, then crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-((5- chloropyridin-2-yl)sulfonyl)-7-ethynyl-lH-indole (36 mg, 27 %) as a colourless solid. NMR Spectrum:JH NMR (400 MHz, DMSO, 23°C) 84.76 (1H, s), 7.47 (1H, d), 7.87 (1H, d), 8.22-8.27 (3H, m), 8.75 (1H, t), 9.42 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 349.201: rel-(5-chloro-7-i l-4-fluoro-lH-indol-3jidin-2-yl)(imino)-l6-sulfanone, Isomer 1

[1343] 1: 7-bromo-5-chloro-3-| idin-2-yl)thio)-4-fluoro-lH-indole

[1344]

[1345] Was synthesised according to the general thioether formation conditions method B from 7-bromo-5-chloro-4-fluoro-lH-indole (1.00 g, 4.02 mmol). The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)thio)-4-fluoro-lH-indole (1.10 g, 70%) as a colourless solid. NMR Spectrum: NMR (300 MHz, DMSO, 24°C) 8 6.91 (1H, dd), 7.63 (1H, d), 7.69 (1H, dd), 7.94 (1H, d), 8.43 (1H, dd), 12.52 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 391.

[1346] Step 2: tert-butyl 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)thio)-4-fluoro-lH-indole-l-carboxylate

[1347]

[1348] DMAP (62.3 mg, 0.51 mmol) was added to TEA (0.213 mL, 1.53 mmol), Boc2O (0.237 mL, 1.02 mmol) and 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)thio)-4-fluoro-lH-indole (200 mg, 0.51 mmol) in DCM (3.0 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water (10 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)thio)-4-fluoro-lH-indole-l-carboxylate (230 mg, 92 %) as a colourless solid. NMR Spectrum:1H NMR (300 MHz, DMSO, 22°C) 6 1.64 (9H, s), 7.20 (1H, dd), 7.71 (1H, dd), 7.88 (1H, d), 8.28 (1H, s), 8.44 (1H, dd). Mass Spectrum: m / z (ES+), [M+H]+ = 491.

[1349] 3: (7-bromo-5-chloro-4-fluoro-lH-indol-3-'

[1350]

[1351] in-2-yl)(imino)-l6-sulfanone

[1352]

[1353] Was synthesised from tert-butyl 7-bromo-5-chloro-3-((5-chloropyridin-2-yl)thio)-4-fluoro-lH-indole- 1-carboxylate (200 mg, 0.41 mmol) using the general sulfoximine synthesis method B. The resulting mixture was purified by flash C18-flash chromatography, elution gradient 0 to 50% MeCN in water (0.1% FA). Pure fractions were evaporated to dryness to afford (7-bromo-5-chloro-4-fluoro-lH-indol- 3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone (50.0 mg, 29%) as a colourless solid.. NMR Spectrum: NMR (300 MHz, DMSO, 23°C) 6 5.24 (1H, s), 7.69 (1H, d), 8.17 (1H, s), 8.24 (2H, t), 8.63 (1H, dd).

[1354] Mass Spectrum: m / z (ES+), [M+H]+ = 422.

[1355] Step 4: (5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone

[1356]

[1357] Tetraethylammonium fluoride hydrate (106 mg, 0.57 mmol) was added to (7-(ftert- butyldimethylsilyl)ethynyl)-5-chloro-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone (110 mg, 0.23 mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (15 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford (5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone (25.00 mg, 29.8 %) as a colourless solid. NMR Spectrum: NMR (300 MHz, DMSO, 23°C) δ 4.72 (1H, s), 5.21 (1H, s), 7.54 (1H, d), 8.12 (1H, s), 8.18-8.29 (2H, m), 8.63 (1H, dd), 12.87 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 368.

[1358] Step 5: rel-(5-chloro-7-ethvnyl-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone, Isomer 1, Example 201

[1359] OR Enantiomer

[1360]

[1361] Rac-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone (20.0 mg, 0.05 mmol), was separated by preparative chiral-HPLC on a Column: CHIRALCelluloseSB4.6*100mm, 3um; Mobile Phase A: MTBE (0.1%DEA): EtOH=50:50; Flow rate: l. OmL / min; Gradient: isocratic; Injection Volume: 2.0L. The fractions containing the first eluting isomer (the most active in testing)were evaporated to dryness to afford rel-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone, Isomer 1 (5.0 mg, 25.0 %) as a colourless solid. NMRSpectrum:1H NMR (500 MHz, DMSO, 23°C) δ 4.68 (1H, s), 5.13 (1H, s), 7.50 (1H, d), 8.11 (1H, s), 8.19-8.27 (2H, m), 8.58-8.66 (1H, m), 12.86 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 368.

[1362] General indole alkylation Method A:

[1363] Example 36: rac-5-chloro-3-((5-chloropyridin-2-yl)(hvdroxy)methyl)-lH-indole-7-carbonitrile

[1364]

[1365] KOH (318 mg, 5.66 mmol) was added to 5-chloro-1H-indole-7-carbonitrile (500 mg, 2.83 mmol) in EtOH (25 mL). The reaction was stirred for 10 min until dissolution of the solids, then 5-chloropicolinaldehyde (802 mg, 5.66 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4CI solution (50 mL), then extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5p silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile (92 mg, 10 %) as a colourless solid. NMR Spectrum:1H NMR (400 MHz, DMSO, 21°C) δ 6.00 (1H, d), 6.17 (1H, d), 7.37 (1H, d), 7.72 (2H, d), 7.9-8 (2H, m), 8.52 (1H, d), 12.13 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 316.

[1366] General indole alkylation Method B:

[1367] Example 37: rac-3-((5-bromopyrimidin-2-yl)(hvdroxy)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile

[1368]

[1369] To a solution of 5-chloro-4-fluoro-lH-indole-7-carbonitrile (311 mg, 1.6 mmol) in DCM (7.5 mL) was added DBU (0.478 mL, 3.2 mmol). The reaction was stirred for 10 min then 5-bromopyrimidine-2-carbaldehyde (374 mg, 2.0 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with DCM (20 mL) and washed with NH4CI solution (20 mL). The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified bypreparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford rac-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile as a beige solid (508 mg, 83%). NMR Spectrum: NMR (500 MHz, DMSO, 27°C) 6.06 (1 H, d), 6.10 (1H, d), 7.46 (1H, s), 7.90 (1H, d), 8.98 (2H, s), 12.45 (1H, s). Mass Spectrum: m / z: ES- [M-H]- 379, 381.

[1370] General indole alkylation Method C:

[1371] Example 38: rac-5-bromo-3-((5-cvanopyrimidin-2-yl)(hvdroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile

[1372]

[1373] TiCU (317 mg, 1.67 mmol) was added to 5-bromo-4-fluoro-lH-indole-7-carbonitrile (200 mg, 0.84 mmol) and 2-formylpyrimidine-5-carbonitrile (223 mg, 1.67 mmol) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into saturated NaHCO3(50 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in DCM. Pure fractions were evaporated to dryness to afford rac-5-bromo-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile (240 mg, 77 %) as a yellow solid. NMR Spectrum: *H NMR (300 MHz, DMSO, 25°C) δ 6.17 (2H, s), 7.44 (1H, d), 7.99 (1H, d), 9.29 (2H, d), 12.51 (1H, s). Mass Spectrum: m / z ( ES-), [M-H]- = 370.

[1374] The compounds presented In Table CHOH-T1 were synthesised in an analogous fashion to Examples 36, 37 and 38 above using the appropriate indole and aldehyde reagent and the specified general indole alkylation method except where specified.

[1375] Table CHOH-T1

[1376] Example Structure Compound Name Alkylation Method rac-5-chloro-3-((4- 39 Cl chlorophenyl)(hydroxy)methyl)- HO lH-indole-7-carbonitrile

[1377] NMR^H NMR (400 MHz, DMSO,

[1378] HbH ^^Cl 22°C) 85.96 (1H, d), 6.00 (1H, d), A 7.35 (1H, s), 7.36-7.42 (2H, m),

[1379] 7.43-7.52 (2H, m), 7.71 (1H, d),

[1380] 7.85 (1H, d), 12.12 (1H, s). LCMS:

[1381] m / z (ES-), [M-H]- = 315.05

[1382]

[1383] rac-3-((5-bromopyridin-2- yl)(hydroxy)methyl)-5-chloro-lH- indole-7-carbonitrile

[1384] NMR:1H NMR (400 MHz, DMSO, 25°C) δ 5.98 (1H, d), 6.15 (1H, d), A 7.37 (1H, s), 7.63-7.76 (2H, m),

[1385] 7.93 (lH, d), 8.07 (1H, dd), 8.60

[1386] (1H, d), 12.04 (1H, s). LCMS: m / z (ES+), [M+H]+ = 364.

[1387] rac-3-((5-bromopyrazin-2- Cl \ T yl)(hydroxy)methyl)-5-chloro-lH- ° /

[1388] O / H Z— indole-7-carbonitrile

[1389] / /

[1390] z \ liNNMR: NMR (400 MHz, DMSO, A HN-^ NX A CD

[1391] B - 1 23°C) δ 6.10 (1H, d), 6.34 (1H, d), r 7.45 (1H, s), 7.73 (1H, d), 8.00 (1H, d), 8.78 (2H, dd), 12.19 (1H, s).

[1392] LCMS: m / z (ES+), [M+H]+ = 363.

[1393] rac-5-chloro-3-((5-cyanopyridin-2- Cl yl)(hydroxy)methyl)-lH-indole-7- ) —. HO carbonitrile

[1394] , / P \ JyJ M N k NMR:1H NMR (400 MHz, DMSO, 23°C) δ 6.07 (1H, d), 6.31 (1H, d), A

[1395] 7.41 (1H, d), 7.71 (1H, d), 7.92 (1H, d), 7.98 (1H, d), 8.33 (1H, dd), 8.92 (1H, dd), 12.14-12.19 (1H, m).

[1396] LCMS: m / z (ES+), [M+H]+ = 309.

[1397] rac-5-chloro-3-((5-chloropyridin-2- Cl. F yl)(hydroxy)methyl)-4-fluoro-lH- \ _ / HO indole-7-carbonitrile QrVx NMR:1H NMR (500 MHz, DMSO 27°C) δ 6.04 (1H, d), 6.11 (1H, d), A

[1398] 7.37 (1H, s), 7.68 (1H, d), 7.90 (1H, d), 7.94 (1H, dd), 8.43 - 8.51 (1H, m), 12.42 (1H, s). LCMS: m / z: ES+ [M+H]+ 336.

[1399]

[1400] rac-5-chloro-3-((5-cyanopyridin-2-Clyl)(hydroxy)methyl)-4-fluoro-lH- \ F

[1401] ) — / HO indole-7-carbonitrile

[1402] NMR: NMR (500 MHz, DMSO

[1403] / / R

[1404] 27°C) δ 6.11 (1H, d), 6.26 (1H, d), A

[1405] 7.42 (1H, s), 7.88 (1H, d), 7.91 (1H, zxd), 8.34 (1H, dd), 8.88 (1H, dd), o

[1406] XT 12.47 (1H, s). LCMS: m / z: ES+

[1407] [M+H]+ 327.

[1408] TZ / \

[1409] rac-5-bromo-3-((5-chloropyridin-2- Br ° / yl)(hydroxy)methyl)-lH-indole-7- \ _ HO

[1410] carbonitrile

[1411] Q

[1412] r~\ I] N^ / ^CI NMR: NMR (300 MHz, DMSO, / / ,N

[1413] N7H m Z 24°C) δ 6.00 (1H, d), 6.16 (1H, d), A 7.35 (1H, d), 7.72 (1H, d), 7.79 (1H, d), 7.95 (1H, dd), 8.07 (1H, d), 8.52 (1H, d), 12.13 (1H, s). LCMS: m / z (ES+), [M+H]+ = 362.

[1414] rac-4,5-dichloro-3-((5- cyanopyridin-2- yl)(hydroxy)methyl)-lH-indole-7- carbonitrile

[1415] NMR:1H NMR (500 MHz, DMSO

[1416] B

[1417] 27°C) 6.22 (1H, d), 6.48 (1H, d),

[1418] 7.29 (1H, s), 7.80 (1H, d), 7.97 (1H, s), 8.32 (1H, dd), 8.91 (1H, d),

[1419] 12.52 (1H, s). LCMS: m / z: ES+

[1420] [M+H]+ 343.

[1421] rac-5-chloro-3-((4- Cl cyanophenyl)(hydroxy)methyl)-lH- )=\H° indole-7-carbonitrile MZ'CK NMR:1H NMR (400 MHz, DMSO, / / / hH "'N22°C) 86.07-6.15 (2H, m), 7.39 A NZH

[1422] (1H, s), 7.63-7.69 (2H, m), 7.72

[1423] (1H, d), 7.77-7.86 (2H, m), 7.89

[1424] (1H, d), 12.00 (1H, s). LCMS: m / z (ES+), [M-OH]+ = 290.

[1425]

[1426] rac-3-((5-cyanopyridin-2- yl)(hydroxy)methyl)-4-fluoro-5- methoxy-lH-indole-7-carbonitrile

[1427] A NMR:1H NMR (400 MHz, DMSO,

[1428] K2CO3used as base 24°C) δ 3.84 (3H, s), 6.08 (1H, d), 6.17 (1H, d), 7.29 (1H, s), 7.59 (1H,

[1429] base d), 7.86 (1H, d), 8.33 (1H, dd),

[1430] 8.82-8.91 (1H, m), 12.02 (1H, s).

[1431] LCMS: m / z (ES+), [M-OH] = 305.

[1432] rac-4-chloro-3-((5-cyanopyridin-2- yl)(hydroxy)methyl)-5-methoxy- lH-indole-7-carbonitrile

[1433] A NMR: NMR (400 MHz, DMSO,

[1434] K2CO324°C) δ 3.88 (3H, s), 6.12 (1H, d),

[1435] used as 6.49 (1H, d), 7.17 (1H, s), 7.57 (1H,

[1436] base s), 7.77 (1H, d), 8.31 (1H, dd), 8.91

[1437] (1H, dd), 12.10 (1H, s). LCMS: m / z z z (ES-), [M-H]- = 337.

[1438] z

[1439] rac-6-((5-chloro-7-ethynyl-4- / 4 / / / fluoro-lH-indol-3-CIL 7 y z } z— —

[1440] / === / OH yl)(hydroxy)methyl)nicotinonitrile

[1441] (

[1442] x X o < o——

[1443] _ \ \ LMVL NMR:1H NMR (500 MHz, DMSO, / A O

[1444] \X-- 26°C) 64.59 (1H, s), 6.09 (1H, d), B X HNJN<YX. JY1J 7X6.17 (1H, d), 7.25 (1H, d), 7.36 (1H,

[1445] I d), 7.87 (1H, d), 8.33 (1H, dd), 8.88 i zzx(1H, dd), 11.78 (1H, s). LCMS: m / z

[1446] (ES-), [M-H]- = 324.

[1447] rac-3-((5-bromothiazol-2- Cl yl) (hydroxy)methyl)-5-ch loro-1 H- indole-7-carbonitrile )==,H0

[1448] l YYv\ NMR:1H NMR (300 MHz, DMSO, 26°C) δ 6.21 (1H, d), 6.93 (1H, d), / HN S~A

[1449] Br 7.54 (1H, d), 7.71-7.8 (2H, m), 7.93

[1450] (1H, d), 12.24 (1H, d). LCMS: / z (ES- ), [M-H]- = 366.

[1451]

[1452] rac-(5-bromopyrazin-2-yl)(5- chloro-7-ethynyl-4-fluoro-lH- indol-3-yl)methanol

[1453] NMR:JH NMR (300 MHz, DMSO,

[1454] B

[1455] 26°C) 64.57 (1H, s), 6.09 (1H, d), 6.22 (1H, d), 7.3-7.38 (2H, m),

[1456] 8.67-8.75 (2H, m), 11.79 (1H, s).

[1457] LCMS: m / z (ES-), [M-H]- = 378.

[1458] rac-6-((5-chloro-7-ethynyl-4,6- difluoro-lH-indol-3- yl)(hydroxy)methyl)nicotinonitrile NMR:1H NMR (500 MHz, DMSO, 27°C) δ 4.88 (1H, s), 6.06 (1H, d), B 6.20 (1H, d), 7.27 (1H, s), 7.86 (1H, d), 8.33 (1H, dd), 8.83 - 8.93 (1H, m), 11.95 (1H, s). LCMS: m / z: ES- [M-H]- 342.

[1459] z

[1460] m o

[1461] rac-3-((5-chloropyridin-2- F yl)(hydroxy)methyl)-5- 7 4. - z~~o d y z— (difluoromethoxy)-lH-indole-7- < 2 o— z — y z— / 4 /

[1462] carbonitrile

[1463] F?==\ _ < o

[1464] _ I _ ( I \ oHI \—0—

[1465] \

[1466] NMR:1H NMR (400 MHz, DMSO, fX ci 23°C) 66.00 (1H, d), 6.1 / XJ - HN>N^CI5 (1H, d), A XJ -\^ O4'

[1467] 7.15 (1H, s), 7.31-7.4 (1H, m), 7.52 (1H, d), 7.69-7.75 (2H, m), 7.94

[1468] (1H, dd), 8.52 (1H, d), 12.03-12.08 (1H, m). LCMS: m / z (ES+), [M+H]+ = 352.

[1469] rac-3-((5-chloropyridin-2- yl)(hydroxy)methyl)-5- (trifluoromethoxy)-lH-indole-7- carbonitrile

[1470] NMR:1H NMR (400 MHz, DMSO,

[1471] A

[1472] 24°C) 86.02 (1H, d), 6.19 (1H, d), 7.44 (1H, d), 7.69-7.76 (2H, m),

[1473] 7.88 (1H, dd), 7.95 (1H, dd), 8.52

[1474] (1H, d), 12.22 (1H, s). LCMS: m / z

[1475] (ES-), [M-H]- = 366.

[1476]

[1477] rac-2-((7-ethynyl-4-fluoro-5- (trifluoromethyl)-lH-indol-3-Fy yl)(hydroxy)methyl)pyrimidine-5- \ F

[1478] / === / OH carbonitrile

[1479] NMR:1H NMR (400 MHz, DMSO, C 23°C) δ 4.65 (1H, s), 6.09-6.34 (2H, m), 7.41 (1H, s), 7.50 (1H, d), 9.31

[1480] (2H, s), 12.11 (1H, s). LCMS: m / z

[1481] (ES-), [M-H]- = 359.

[1482] rac-3-((5-bromopyrimidin-2-F\ F yl)(hydroxy)methyl)-4-fluoro-5- (trifluoromethyl)-lH-indole-7- " W H° carbonitrile

[1483] B

[1484] Z / / NJ NMR: NMR (500 MHz, DMSO, Z NNYYBr

[1485] N H 27°C) 6.13 (2H, s), 7.54 (1H, s),

[1486] 8.04 (1H, d), 8.99 (2H, s), 12.75

[1487] (1H, s). LCMS: m / z: ES- [M-H]- 413.

[1488] rac-5-bromo-4-chloro-3-((5- cyanopyrimidin-2- yl)(hydroxy)methyl)-lH-indole-7- d d

[1489] carbonitrile

[1490] ( < O o——

[1491] _ \ ZE \ I C o o NMR:JH NMR (300 MHz, DMSO, Reaction at -78 °C 23°C) δ 6.28 (1H, d), 6.50 (1H, dd), 7.46 (1H, s), 8.04 (1H, s), 9.28 (2H, m mT

[1492] s), 12.55 (1H, s). LCMS: m / z (ES-), z ^ [M-H]- = 386.

[1493] rac-2-((5-bromo-4-chloro-7- ethynyl-lH-indol-3- yl)(hydroxy)methyl)pyrimidine-5- carbonitrile

[1494] C NMR:JH NMR (300 MHz, DMSO- Reaction d6) 611.85 (s, 1H), 9.26 (s, 2H), at -78 °C 7.53 (s, 1H), 7.31 (d, 1H), 6.50 (dd,

[1495] 1H), 6.15 (d, 1H), 4.68 (s, 1H).

[1496] LCMS: m / z (ES-), [M-H]- = 385.

[1497]

[1498] rac-5-chloro-4-fluoro-3- (hydroxy(5-(trifluoromethyl)

[1499] CIV F

[1500] / === / H° pyrimidin-2-yl)methyl)-lH-indole- 7-carbonitrile

[1501] NJV NMR:1H NMR (400 MHz, DMSO, C 23°C) δ 6.21 (2H, s), 7.49 (1H, s),

[1502] 7.91 (1H, d), 9.27 (2H, s), 12.49

[1503] (1H, s). LCMS: m / z (ES-), [M-H]- =

[1504] 369.

[1505] rac-2-((7-ethynyl-4-fluoro-5-iodo- \ F lH-indol-3- )=- / OH yl)(hydroxy)methyl)pyrimidine-5- carbonitrile

[1506] C

[1507] / N-“N'Jk<>

[1508] 7 / NMR: NMR (400 MHz, DMSO, Reaction H

[1509] 22°C) 84.57 (1H, t), 6.11 (1H, dt), at -78 °C 6.15 (1H, d), 7.24 (1H, d), 7.54 (1H, dd), 9.30 (2H, d), 11.79 (lH, s).

[1510] LCMS: m / z (ES-), [M-H]- = 417.

[1511] rac-6-((7-bromo-5-chloro-lH- Cl indol-3-yl)(hydroxy)methyl)

[1512] HO nicotinonitrile

[1513] NMR:1H NMR (500 MHz, CDCI3,

[1514] 27°C) 6.07 (1H, d), 7.30 (1H, d),

[1515] Brr B 7.35 (1H, d), 7.41 (1H, dd), 7.44- 7.48 (1H, m), 7.93 (1H, dd), 8.37

[1516] (1H, s), 8.90 (1H, dd). l x

[1517] exchangeable not observed.

[1518] LCMS: m / z: ES- [M-H]- 360, 362.

[1519] rac-2-((4,5-dichloro-7-ethynyl-lH- indol-3-clHtM yl)(hydroxy)methyl)pyrimidine-5- carbonitrile

[1520] H NMR:1H NMR (300 MHz, DMSO, C 24°C) δ 4.68 (1H, s), 6.15 (1H, d),

[1521] I I 6.51 (1H, d), 7.33 (1H, d), 7.43 (1H,

[1522] s), 9.26 (2H, s), 11.85 (1H, s).

[1523] LCMS: m / z (ES+), [M+H]+ = 343.

[1524]

[1525] rac-3-((5-cyanopyrimidin-2- 196 yl)(hydroxy)methyl)-5- (difluoromethyl)-4-fluoro-lH- indole-7-carbonitrile

[1526] NMR:1H NMR (400 MHz, DMSO, C 21°C) δ 6.19 (1H, d), 6.27 (1H, d),

[1527] 7.23 (1H, t), 7.48 (1H, s), 7.89 (1H,

[1528] d), 9.30 (2H, s), 12.61 (1H, s).

[1529] LCMS: m / z (ES-), [M-H]- = 342.

[1530] rac-(5-bromopyrimidin-2-yl)(5- chloro-7-ethynyl-4-methyl-lH- HO _ indol-3-yl)methanol

[1531] NMR: NMR (300 MHz, DMSO,

[1532] B

[1533] 24°C) δ 2.67 (3H, s), 4.54 (1H, s),

[1534] 5.97 (1H, d), 6.19 (1H, d), 7.01 (1H,

[1535] d), 7.27 (1H, s), 9.01 (2H, s), 11.38

[1536] (1H, d). LCMS: m / z (ES-), [M-H]- =

[1537]

[1538] 374.

[1539] rac-2-((4,5-dichloro-7-ethvnyl-lH-indol-3-yl)(hvdroxy)methyl)pyrimidine-5-carbonitrile

[1540] Step 1: rac-6-((7-((te / T-butyldimethylsilyl)ethvnyl)-5-chloro-lH-indol-3-yl)(hvdroxy)methyl)

[1541]

[1542] nicotinonitrile

[1543]

[1544] The indole alkylation reaction was carried out according to general conditions A to afford rac-6-((7- ((tert-butyldimethylsilyl)ethynyl)-5-chloro-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile as a beige solid, which was used in the next step without further purification.

[1545] Step 2: rac-6-((5-chloro-7-ethvnyl-lH-indol-3-yl)(hvdroxy)methyl)nicotinonitrile, Example 63

[1546] Cl

[1547]

[1548] Tetramethylammonium fluoride (59.6 mg, 0.64 mmol) was added to rac-6-((7-((tert- butyldimethylsilyl)ethynyl)-5-chloro-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile (90 mg, 0.21 mmol) in THF (1 mL). The resulting mixture was stirred at 40 °C for 2 hours. The reaction mixture waswashed with water (25 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford rac-6-((5-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile (40.0 mg, 61 %) as a colourless solid. NMR Spectrum:1H NMR (400 MHz, DMSO) δ 4.59 (1H, s), 6.03 (2H, s), 7.09–7.34 (2H, m), 7.66 (1H, d), 7.90 (1H, d), 8.32 (1H, dd), 8.92 (1H, dd), 11.48 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 308.

[1549] rac-5-chloro-3-((5-cvanopyrimidin-2-yl)(hvdroxy)methyl)-7-ethvnyl-lH-indole-4-carbonitrile Step 1: rac-5-chloro-3-((5-cvanopyrimidin-2-yl)(hvdroxy)methyl)-7-((triisopropylsilyl)ethvnyl) -1H-indole-4-carbonitrile

[1550]

[1551] 5-chloro-7-((triisopropylsilyl)ethynyl)-l H-indole-4-carbon itrile was reacted according to general indole alkylation conditions C to afford rac-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-7-((triisopropylsilyl)ethynyl)-lH-indole-4-carbonitrile. NMR Spectrum:1H NMR (300 MHz, DMSO, 24°C) δ 1.08–1.29 (21H, m), 6.31 (1H, d), 6.46 (1H, d), 7.50 (1H, s), 7.55 (1H, d), 9.31 (2H, s), 11.78 (1H, d).

[1552] Mass Spectrum: m / z (ES-), [M-H]- = 488.

[1553] Step 2: rac-5-chloro-3-((5-cvanopyrimidin-2-yl)(hvdroxy)methyl)-7-ethvnyl-lH-indole-4-carbon itrile

[1554]

[1555] TBAF solution in THF (0.306 mL, 0.31 mmol) was added to rac-5-chloro-3-((5-cyanopyrimidin-2-yl) (hyd roxy)methyl)-7-((triisopropylsilyl)ethynyl)-lH-indole-4-ca rbonitrile (150 mg, 0.31 mmol) in THF (2.0 mL) at -20 °C. The resulting mixture was stirred at -20 °C for 15 minutes. The reaction mixture was poured into saturated NH4CI (10 mL) solution and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford rac-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-7-ethynyl-lH-indole-4-carbonitrile (63.0 mg, 61.7 %) as a white solid. NMR Spectrum: NMR (400 MHz, DMSO,22°C) δ 4.99 (1H, s), 6.25 (1H, s), 6.43 (1H, s), 7.45 (1H, s), 7.56 (1H, s), 9.31 (2H, s), 12.23 (1H, s). Mass

[1556]

[1557] m / z (ES-), [M-H]- = 332.

[1558] General Cyanation conditions A:

[1559] Example 64: rac-2-((5-chloro-7-cyano-1H-indol-3-yl)(hydroxy)methyl)thiazole-5-carbonitrile

[1560]

[1561] Dppf (45.1 mg, 0.08 mmol) and Pd2(dba)3(74.5 mg, 0.08 mmol) were added to zinc cyanide (143 mg, 1.22 mmol) and rac-3-((5-bromothiazol-2-yl)(hydroxy)methyl)-5-chloro-1H-indole-7-carbonitrile (300 mg, 0.81 mmol) in DMF (5 mL). The resulting mixture was stirred at 100 °C for 2 hours. The reaction mixture was poured onto saturated brine (10 mL) and extracted with EtOAc (3 x20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford rac-2-((5-chloro-7-cyano-lH-indol-3-yl)(hydroxy)methyl)thiazole-5-carbonitrile (180 mg, 70 %) as a colourless solid. NMR Spectrum:1H NMR (500 MHz, DMSO, 24°C) δ 6.36 (1H, d), 7.22 (1H, d), 7.57 (1H, s), 7.76 (1H, d), 7.96 (1H, d), 8.55 (1H, d), 12.29 (1H, s). Mass Spectrum: m / z (ES+), [M-OH] = 297.

[1562] General Cyanation Conditions B:

[1563] Example 65: rac-5-chloro-3-((5-cvanopyrimidin-2-yl)(hvdroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile

[1564]

[1565] BrettPhos Pd G3 (35.6 mg, 0.04 mmol) was added to rac-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile (150 mg, 0.39 mmol), potassium ferrocyanide (II) trihydrate (498 mg, 1.18 mmol) and potassium acetate (4.82 mg, 0.05 mmol) in Me-THF (2.0 mL) / water (2.0 mL). The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with EtOAc (100 mL). The reaction mixture was washed sequentially with water (3 x 150 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness. The crude product was further purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford rac-5-chloro-3-((5-cyanopyrim idin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbon itrile (55 mg, 43 %) as a colourless solid. NMR Spectrum:1H NMR (400 MHz, DMSO, 23°C) δ 6.18 (2H, s), 7.47 (1H, s), 7.92 (1H, d), 9.30 (2H, s), 9.98 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 326.

[1566] The compounds presented in Table CHOH-T2 were synthesised in an analogous fashion to the Examples 64 & 65 above using the appropriate aryl halide and cyanation reagent except where specified.

[1567] Table CHOH-T2

[1568] Example Structure Compound Name Cyanation Method rac-2-((5-chloro-7-ethynyl-lH- 66 indol-3- HC1 / / yl)(hydroxy)methyl)pyrimidine- BClJ

[1569] \^ 5-carbonitrile

[1570] Indole NMRPH NMR (400 MHz, alkylation H DMSO) 84.59 (1H, s), 6.09 (2H, method A s), 7.23 (1H, d), 7.36 (1H, s), (K2CO3as 7.83 (1H, d), 9.30 (2H, s), 11.51 base) used (1H, s). LCMS: m / z (ES-), [M-H]- in first step = 307

[1571] rac-2-((5-chloro-7-cyano-4- 67 fluoro-lH-indol-3- B yl)(hydroxy)methyl)thiazole-5-Cl^ carbonitrile

[1572] vp ■ Indole alkylation NMR:1H NMR (400 MHz, DMSO,

[1573] H method A 23°C) 66.30 (1H, d), 7.18 (lH, d),

[1574] (K2CO3as J 7.62 (1H, s), 7.96 (1H, d), 8.52

[1575] base) used (1H, s), 12.60 (1H, s). LCMS: m / z

[1576] in first step (ES-), m / z (ES-), [M-H]- = 331.

[1577] rac-2-((5-chloro-7-ethynyl-4- 68 fluoro-lH-indol-3- B yl)(hydroxy)methyl)pyrimidine-Cl5-carbonitrile

[1578] ^ Indole alkylation •T NMR:1H NMR (400 MHz, DMSO,

[1579] H method A 26°C) 64.59 (1H, s), 6.12 (1H, d),

[1580] (K2CO3as 6.17 (1H, d), 7.32 (1H, s), 7.36

[1581] base) used (1H, d), 9.29 (2H, s), 11.81 (1H,

[1582] in first step s). LCMS: m / z (ES-), [M-H]- = 325.

[1583]

[1584] rac-5-((5-chloro-7-ethynyl-4- / A^N fluoro-lH-indol-3- HO, / /

[1585] F yl)(hydroxy)methyl)pyrazine-2- carbonitrile

[1586] Cl\^ YS NMR:1H NMR (400 MHz, DMSO, 26°C) δ 4.59 (1H, s), 6.20 (2H, s),

[1587] 6.42 (1H, s), 7.34-7.43 (2H, m),

[1588] 9.08 (1H, d), 9.13 (1H, d). LCMS:

[1589] m / z (ES-), [M-H]- = 325.

[1590] rac-2-((5-chloro-7-ethynyl-4- fluoro-lH-indol-3- yl)(hydroxy)methyl)thiazole-5- B ■ v X

[1591] Cl\^ carbonitrile

[1592] M? - Indole NMR:1H NMR (400 MHz, DMSO, 27°C) δ 4.60 (1H, s), 6.28 (1H, s), method B 7.07 (1H, s), 7.40 (1H, d), 7.46 used in (1H, s), 8.52 (1H, s), 11.90 (1H, s). first step LCMS: m / z (ES-), [M-H]- = 330.

[1593] rac-2-((5,7-dichloro-4-fluoro-lH-Findol-3- HO / / B yl)(hydroxy)methyl)pyrimidine- C! 5-carbonitrile

[1594] Indole L O alkylation NMR:1H NMR (400 MHz, DMSO,

[1595] 1 H method B Cl 22°C) 6 6.17 (2H, s), 7.33-7.47

[1596] used in (2H, m), 9.30 (2H, s), 11.98 (1H,

[1597] first step s). LCMS: m / z (ES-), [M-H]- = 335.

[1598] rac-2-((5-bromo-7-ethynyl-4- N-^^N fluoro-lH-indol-3- A (from p- yl)(hydroxy)methyl)pyrimidine- iodo Br\^ 5-carbonitrile pyrimidine)

[1599] NMR:1H NMR (300 MHz, DMSO, 23 °C) δ 4.03 (1H, q), 6.16 (2H, s), alkylation 7.30 (1H, d), 7.44 (1H, d), 7.95 method B (1H, s), 9.28 (1H, s), 11.83 (1H, s). used in LCMS: m / z (ES-), [M-H]- = 369. first step

[1600]

[1601] rac-4,5-dichloro-3-((5- cyanopyrimidin-2- yl)(hydroxy)methyl)-lH-indole- 7-carbonitrile

[1602] NMR:1H NMR (500 MHz,

[1603] DMSO, 27°C) 6.26 (1H, d), 6.51

[1604] (1H, d), 7.48 (lH, s), 7.95 (lH, s),

[1605] 9.28 (2H, s), 12.54 (1H, s).

[1606] LCMS: m / z: ES- [M-H]- 342.

[1607] rac-3-((5-cyanopyrimidin-2- yl)(hydroxy)methyl)-4-fluoro-5- (trifluoromethyl)-lH-indole-7- carbonitrile

[1608] NMR: NMR (500 MHz,

[1609] DMSO, 27°C) 6.21 (1H, d), 6.29

[1610] (1H, d), 7.54 (lH, s), 8.07 (1H,

[1611] d), 9.30 (2H, s), 12.78 (lH, s).

[1612] LCMS: m / z: ES- [M-H]- 360.

[1613] rac-2-((5-chloro-4-fluoro-7- methyl-lH-indol-3- yl)(hydroxy)methyl)pyrimidine- 5-carbonitrile

[1614] Indole NMR: NMR (300 MHz,

[1615] alkylation DMSO, 21°C ) 82.40 (3H, t),

[1616] method B 6.02 (1H, d), 6.18 (1H, d), 6.96

[1617] used in (1H, dd), 7.29 (lH, d), 9.29 (2H,

[1618] first step s), 11.52 (1H, s). LCMS: m / z (ES- ), [M-H]- = 315.

[1619] rac-5-chloro-3-((5- cyanopyrimidin-2- yl)(hydroxy)methyl)-4,6- difluoro-lH-indole-7- carbonitrile

[1620] NMR:1H NMR (500 MHz,

[1621] DMSO, 27°C) 6.15 (1H, d), 6.25

[1622] (1H, d), 7.46 (lH, s), 9.29 (2H, s),

[1623] 12.65 (1H, s). LCMS: m / z: ES- [M-H]- 344.

[1624]

[1625] Example 72: rac-5-chloro-3-((5-cvanopyrimidin-2-yl)(hvdroxy)methyl)-lH-indole-7-carbonitrileCl

[1626]

[1627] Nickel(ll) chloride (7.13 mg, 0.06 mmol) was added to rac-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-1H-indole-7-carbonitrile (400 mg, 1.1 mmol), zinc cyanide (78 mg, 0.66 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (31.8 mg, 0.06 mmol) and PMHS (56 mg, 0.22 mmol) in DMF (4 mL). The resulting mixture was stirred at 60 °C for 16 hours. The reaction mixture was poured onto water (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford rac-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile (70 mg, 21 %) as a colourless solid. NMR Spectrum:1H NMR (400 MHz, DMSO, 24°C) δ 6.13 (1H, d), 6.19 (1H, d), 7.51 (1H, s), 7.72 (1H, d), 8.15 (1H, d), 9.30 (2H, s), 12.18 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 308.

[1628] Example 198: rac-2-((5-chloro-7-ethvnyl-4-methyl-lH-indol-3-yl)(hvdroxy)methyl) pyrimidine-5-carbonitrile

[1629]

[1630] Dichlorobis[(l,2,3-4)-l-phenyl-2-propenyl]dipalladium(ll) (7.36 mg, 0.01 mmol) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (14.30 mg, 0.03 mmol) were added to rac-(5-bromopyrimidin-2-yl)(5-chloro-7-ethynyl-4-methyl-lH-indol-3-yl)methanol (100 mg, 0.27 mmol), potassium acetate (52.1 mg, 0.53 mmol) and potassium ferrocyanide (II) trihydrate (196 mg, 0.53 mmol) in 2-methyl THF (2.5 mL) / water (2.5 mL). The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was poured into water (25 mL), extracted with EtOAc (3 x 25 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford rac-2-((5-chloro-7-ethynyl-4-methyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile (30.0 mg, 35.0 %) as a colourless solid. NMR Spectrum:1H NMR (500 MHz, DMSO, 24°C) δ 2.67 (3H, s), 4.53 (1H, s), 6.12 (1H, d), 6.26 (1H, d), 7.00 (1H, d), 7.27 (1H, s), 9.30 (2H, s), 11.43 (1H, s). Mass

[1631]

[1632] : m / z (ES-), [M-H]- = 321.Separation of enantiomers

[1633] Example 73 and Example 74: rel-5-chloro-3-((5-cvanopyrimidin-2-yl)(hvdroxy)methyl)-4-fluoro-lH- indole-7-carbonitrile, Isomer 1 and 2

[1634]

[1635] Rac-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile (165 mg, 0.5 mmol) was dissolved in 1 mL MeOH: DCM and 4 mL DMSO. The solution was purified on Sepiatec using the SFC conditions detailed below; Column: Chiralpak IK, 21 x 250 mm, 5 micron; Mobile phase: 40% MeOH + 0.1% NH3 / 60% scCO2; 60 mL / min; 120 bar; 40 °C; UV max 230nm. Fractions containing desired product were evaporated to afford: Isomer 1: rel-5-chloro-3-((5-cyanopyrimidin-2- yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile (76 mg, 46 %) as a beige solid and Isomer 2: rel- 5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile (74.2 mg, 45 %) as a beige solid. NMR Spectrum: Isomer 1:

[1636]

[1637] 1H NMR (500 MHz, DMSO, 27°C) 6.18 (1H, d), 6.22 (1H, d), 7.46 (1H, s), 7.91 (1H, d), 9.29 (2H, s), 12.49 (1H, s). Isomer 2:1H NMR (500 MHz, DMSO, 27°C) 6.18 (1H, d), 6.22 (1H, d), 7.46 (1H, s), 7.91 (1H, d), 9.29 (2H, s), 12.49 (1H, s). Mass Spectrum: Isomer 1: m / z: ES- [M-H]- 326; Isomer 2: m / z ES- [M-H]- 326.

[1638] Racemic samples were separated by either chiral HPLC or SFC according to the conditions detailed in Table CHOH-T3 below. Isomer 1 and Isomer 2 are defined as the 1steluted and 2ndeluted isomers respectively under the specific separation conditions described for that example.

[1639] Table CHOH-T3

[1640] Example Structure Compound Name Separation Conditions rel-5-chloro-3-((5-chloropyridin- 75 and 76 OR Enantiomer 2-yl)(hydroxy)methyl)-4-fluoro- lH-indole-7-carbonitrile, Isomer Column: YMC SZ,HO, 1 and Isomer 2 20 x 250 mm, 5 CL micron; Mobile T o NMR: Isomer 1:1H NMR (500 MHz, CDCl327°C) 4.58 (1H, d), 6.02 (1H, d), 7.20 (1H, d), 7.31 / 50% scCO2; 50 N

[1641] (1H, s), 7.47 (1H, d), 7.65 (1H, mL / min; 120 bar;

[1642] Isomer 1 and Isomer 2 dd), 7.73 (1H, d), 8.60 (1H, d), 40 °C; 220nm.

[1643] 8.78 (1H, s). Isomer 2:JH NMR

[1644]

[1645] (500 MHz, CDCl3, 27°C) 4.58 (1H,d), 6.02 (lH,d), 7.20 (lH,d), 7.32

[1646] (1H, s), 7.47 (1H, d), 7.65 (1H,

[1647] dd), 7.73 (1H, d), 8.60 (1H, d),

[1648] 8.72 (1H, s). LCMS: Isomer 1:

[1649] m / z: ES- [M-H]- 316, Isomer 2:

[1650] m / z: ES- [M-H]- 316.

[1651] rel-5-chloro-3-((5-chloropyridin- and 78 OR Enantiomer 2-yl)(hydroxy)methyl)-4-fluoro- lH-indole-7-carbonitrile, Isomer

[1652] FHO, 1 and Isomer 2

[1653] Cl

[1654] T TO NMR: Isomer 1: NMR (500

[1655] Column: YMC SZ, T i NhHMHz, DMSO 27°C) 6.04 (1H, s),

[1656] 20 x 250 mm, 5 6.09 (1H, s), 7.37 (1H, s), 7.68

[1657] micron; Mobile (1H, d), 7.88 (1H, d), 7.94 (1H,

[1658] phase: 50% Isomer 1 and Isomer 2 dd), 8.48 (1H, d), 12.42 (1H, s).

[1659] MeOH + 0.1% NH Isomer 2:1H NMR (500 MHz,

[1660] / 50% scCO2; 50 DMSO 27°C) 6.04 (1H, s), 6.08

[1661] mL / min; 120 bar; (1H, s), 7.37 (1H, s), 7.68 (1H, d),

[1662] 40 °C; 220nm.

[1663] 7.88 (1H, d), 7.94 (1H, dd), 8.44 - 8.53 (1H, m), 12.40 (1H, s).

[1664] LCMS: Isomer 1: m / z: ES+

[1665] [M+H]+ 336, Isomer 2: m / z: ES+

[1666] [M+H]+ 336.

[1667] rel-5-chloro-3-((5-cyanopyridin- and 80 OR Enantiomer 2-yl)(hydroxy)methyl)-4-fluoro- lH-indole-7-carbonitrile, Isomer

[1668] FH°'-O 1 and Isomer 2

[1669] a l J

[1670] NMR: Isomer 1:1H NMR (500 MHz, DMSO 27°C) 6.11 (1H, d),

[1671] N 6.24 (1H, s), 7.41 (1H, s), 7.88 micron; Mobile (2H, d), 8.34 (1H, dd), 8.78 - 8.97 phase: 35% Isomer 1 and Isomer 2 (1H, m), 12.43 (1H, s). Isomer 2: MeOH + 0.1% NH3

[1672] JH NMR (500 MHz, DMSO 27°C) / 65% scCO2; 60 6.11 (1H, s), 6.24 (1H, s), 7.41 mL / min; 120 bar; (1H, s), 7.81 - 7.94 (2H, m), 8.34 40 °C; 220nm. (1H, dd), 8.76 - 9.01 (1H, m),

[1673] 12.46 (1H, s). LCMS: Isomer 1:

[1674] m / z: ES+ [M+H]+ 327, Isomer 2:

[1675] m / z: ES+ [M+H]+ 327.

[1676]

[1677] rel-3-((5-bromopyrimidin-2- and 82 OR Enantiomer yl)(hydroxy)methyl)-5-chloro-4- fluoro-lH-indole-7-carbonitrile,

[1678] FHO „ Isomer 1 and Isomer 2

[1679] Column: NMR: Isomer 1:1H NMR (500 MHz, DMSO, 27°C) 6.06 (1H, d), 6.10 (1H, d), 7.46 (1H, s), 7.90

[1680] (1H, d), 8.98 (2H, s), 12.45 (1H, phase: 30% Isomer 1 and Isomer 2 s); Isomer 2:JH NMR (500 MHz, MeOH + 0.1% NH3

[1681] DMSO, 27°C) 6.06 (1H, d), 6.10 / 70% scCO2; 60 (1H, d), 7.46 (1H, s), 7.90 (1H, d), mL / min; 120 bar; 8.98 (2H, s), 12.45 (1H, s). LCMS: 40 °C. Isomer 1: m / z: ES- [M-H]- 379,

[1682] 381; Isomer 2: m / z (ES-), [M-H]- = 379, 381.

[1683] rel-5-chloro-3-((5- and 84 OR Enantiomer cyanopyrimidin-2- -ssN yl)(hydroxy)methyl)-lH-indole- HO J / 7""^ 7-carbonitrile, Isomer 1 and

[1684] Isomer 2 Column: f n Chiralpak IK, 20 x T H NMR: Isomer 1:JH NMR (500 250 mm, 5 ill

[1685] N MHz, DMSO, 27°C) 6.12 (1H, d), micron; Mobile 6.17 (1H, d), 7.50 (1H, s), 7.71 phase: 30% Isomer 1 and Isomer 2 (1H, d), 8.14 (lH, d), 9.29 (2H, s), MeOH + 0.1% NH3

[1686] 12.16 (1H, s); Isomer 2:JH NMR / 70% scCO2: 60 (500 MHz, DMSO, 27°C) 6.13 mL / min; 120 bar; (1H, d), 6.17 (lH, d), 7.50 (lH, s), 40 °C; 230nm 7.71 (1H, d), 8.14 (1H, d), 9.29

[1687] (2H, s), 12.16 (1H, s). LCMS:

[1688] Isomer 1: m / z: ES- [M-H]- 308,

[1689] Isomer 2: m / z: ES- [M-H]- 308.

[1690] OR Enantiomer rel-(5-chloro-7-ethynyl-4-fluoro- and 86 pi 1 H-indol-3-yl) (5- FHO / chloropyrimidin-2-yl)methanol,

[1691] Isomer 1 and Isomer 2

[1692] W Column:

[1693] H NMR: Isomer 1:JH NMR (500 Chiralpak IK, 21 x MHz, DMSO 27°C) 4.57 (1H, s), 250 mm, 5 5.96 (1H, d), 6.11 (1H, d), 7.32 micron; Mobile Isomer 1 and Isomer 2 (1H, s), 7.34 (1H, d), 8.91 (2H, s), phase: 25%

[1694] 11.75 (1H, s). Isomer 2:JH NMR MeOH + 0.1% NH3(500 MHz, DMSO, 27°C) 4.57 / 75% scCO2; 60 (1H, s), 5.96 (lH, d), 6.11 (lH, d), mL / min; 120 bar; 7.31 (1H, d), 7.34 (1H, d), 8.91 40 °C; 220nm (2H, s), 11.75 (1H, s). LCMS:

[1695] Isomer 1: m / z: ES- [M-H]- 334;

[1696] Isomer 2: m / z: ES- [M-H]- 334.

[1697]

[1698] rel-5-bromo-3-((5- and 88 OR Enantiomer cyanopyrimidin-2- yl)(hydroxy)methyl)-4-fluoro-fho, / / lH-indole-7-carbonitrile, Isomer

[1699] Br. X. Column:

[1700] 1 and Isomer 2

[1701] CHIRALPAK SB

[1702] NMR: Isomer 1:1H NMR (400 MHz, DMSO, 23°C) δ 6.17 (1H,

[1703] Hex (0.5% 2 M d), 6.23 (1H, d), 7.44 (1H, d), 7.99

[1704] Isomer 1 and Isomer 2 NH3-MeOH),

[1705] (1H, d), 9.30 (2H, s), 12.51 (1H,

[1706] Mobile Phase B: s). Isomer 2: NMR (400 MHz,

[1707] DMSO, 23°C) δ 6.17 (1H, dd),

[1708] Gradient: 6.23 (1H, d), 7.44 (1H, s), 7.99

[1709] isocratic 30; (1H, d), 9.30 (2H, s), 12.51 (1H,

[1710] 220 / 254 nm. s). LCMS: Isomer 1: m / z (ES-),

[1711] [M-H]- = 370, Isomer 2: m / z (ES- ), [M-H]- = 370.

[1712] rel-4,5-dichloro-3-((5- and 90 OR Enantiomer cyanopyrimidin-2- -gN yl)(hydroxy)methyl)-lH-indole-C|ho„ / / y- 7-carbonitrile, Isomer 1 and CLIJNColumn: YMC SZ Isomer 2

[1713] 3.0 x 150 mm 3.0 uo pm; Mobile T

[1714] iliHNMR: Isomer 1:JH NMR (500

[1715] phase: A = SCCO2, N MHz, DMSO, 27°C) 6.26 (1H, d),

[1716] B MeOH + 0.1% 6.52 (1H, d), 7.49 (1H, s), 7.95

[1717] Isomer 1 and Isomer 2 NH3; Gradient 0-1

[1718] (1H, s), 9.28 (2H, s), 12.53 (1H, s).

[1719] min 5% B, 1-5 min Isomer 2:JH NMR (500 MHz,

[1720] 5-50% B, 5-10 min DMSO, 27°C) 6.26 (1H, d), 6.52

[1721] 50% B; 2.0 (1H, d), 7.48 (1H, s), 7.95 (1H, s),

[1722] mL / min; 120 bar; 9.28 (2H, s), 12.53 (1H, s). LCMS:

[1723] 40 °C. Isomer 1: m / z (ES-), [M-H]- =

[1724] 325. Isomer 2: m / z (ES-), [M-H]- = 325.

[1725] rel-2-((5-bromo-7-ethynyl-4- and 92 OR Enantiomer fluoro-lH-indol-3- yl)(hydroxy)methyl)pyrimidine- Column:fho, / / 5-carbonitrile, Isomer 1 and CHIRALPAK IC Br Isomer 2 2*25 cm, 5 pm; w Mobile Phase A:

[1726] H NMR: Isomer 1:JH NMR (400 Hex (0.5% 2 M I I MHz, DMSO, 23°C) 64.60 (1H, s), NH3-MeOH),

[1727] 6.12 (1H, d), 6.15 (1H, s), 7.30 Mobile Phase B: Isomer 1 and Isomer 2 (1H, d), 7.45 (lH, d), 9.29 (2H, s), EtOH; 20 mL / min;

[1728] 11.83 (1H, s). Isomer 2:JH NMR Gradient: (400 MHz, DMSO, 23°C) 8 4.60 isocratic 30; (1H, s), 6.12 (lH, d), 6.16 (lH, d), 220 / 254 nm 7.30 (1H, d), 7.45 (1H, d), 9.29

[1729]

[1730] (2H, s), 11.83 (1H, s). LCMS:Isomer 1: m / z (ES-), [M-H]- =

[1731] 369. Isomer 2: m / z (ES-), [M-H]- = 369.

[1732] rel-5-bromo-4-chloro-3-((5- and 94 OR Enantiomer cyanopyrimidin-2-CIH°„ yl)(hydroxy)methyl)-lH-indole- » y- 7-carbonitrile, Isomer 1 and Column: Br JCNIsomer 2 CHIRALPAK IC, m 2*25 cm, 5 pm; T NMR: Isomer 1: NMR (400 Mobile Phase A: illH

[1733] N MHz, DMSO, 24°C) 8 6.29 (1H, Hex (0.5% 2 M d), 6.51 (1H, d), 7.47 (1H, s), 8.04 NH3-MeOH), Isomer 1 and Isomer 2 (1H, s), 9.28 (2H, s), 12.53 (1H, s). Mobile Phase B:

[1734] Isomer 2: NMR (400 MHz, EtOH; 20 mL / min; DMSO, 24°C) 86.29 (1H, d), 6.51 Gradient: (1H, d), 7.47 (1H, s), 8.04 (1H, s), isocratic 30; 9.28 (2H, s), 12.53 (1H, s). LCMS: 220 / 254 nm Isomer 1: m / z (ES-), [M-H]- =

[1735] 386. Isomer 2: m / z (ES-), [M-H]- = 386.

[1736] rel-2-((5-bromo-4-chloro-7- and 96 OR Enantiomer ethynyl-lH-indol-3-CIH° -gN yl)(hydroxy)methyl)pyrimidine- » y- 5-carbonitrile, Isomer 1 and

[1737] BrNIsomer 2 Column: YYS CHIRALPAK IC3;

[1738] H NMR: Isomer 1:JH NMR (400 Mobile Phase A: I I MHz, DMSO, 24°C) 84.70 (1H, s), (Hex: DCM=3: 1)

[1739] 6.17 (1H, d), 6.52 (1H, d), 7.33 (0.1% DEA):

[1740] Isomer 1 and Isomer 2 (1H, d), 7.55 (1H, s), 9.29 (2H, s), IPA=85: 15;

[1741] 11.87 (1H, d). Isomer 2:JH NMR l. OmL / min (400 MHz, DMSO, 24°C) 8 4.70 mL / min; (1H, s), 6.17 (1H, d), 6.46-6.58 Gradient: (1H, m), 7.33 (1H, d), 7.55 (1H, s), isocratic 9.29 (2H, d), 11.87 (1H, d). LCMS:

[1742] Isomer 1: m / z (ES-), [M-H]- =

[1743] 385. Isomer 2: m / z (ES-), [M-H]- = 385.

[1744] rel-5-chloro-4-fluoro-3- Column: Xselect and 98 OR Enantiomer (hydroxy(5-(trifluoromethyl)

[1745] F CSH Prep C18 pyrimidin-2-yl)methyl)-lH-FHN-^ L-F OBD, 30*150mm, O,. / / y^Findole-7-carbonitrile, Isomer 1

[1746] 5um; Mobile and Isomer 2

[1747] ckl jNPhase A: Water m (lOmmol / L NMR: Isomer 1:JH NMR (400

[1748] T H NH4HCO3+ 0.05% ill MHz, DMSO, 22°C) 86.22 (2H, s), N NH3 H2O), Mobile 7.49 (1H, s), 7.91 (1H, d), 9.27

[1749] Phase B: MeCN Isomer 1 and Isomer 2 (2H, d), 12.53 (1H, s). Isomer 2:

[1750] J60 mL / min; H NMR (400 MHz, DMSO, 22°C)

[1751] Gradient: 37% B 8 6.22 (2H, s), 7.49 (1H, s), 7.91

[1752] to 49% B in 10

[1753]

[1754] (1H, d), 9.27 (2H, d), 12.53 (1H,s). LCMS: Isomer 1: m / z (ES-), min; 254 nm /

[1755] [M-H]- = 369. Isomer 2: m / z (ES- 220 nm ), [M-H]- = 369.

[1756] rel-2-((5-chloro-4-fluoro-7- and OR Enantiomer methyl-lH-indol-3- 0 yl)(hydroxy)methyl)pyrimidine-FN-"\ ==N

[1757] HO / / 5-carbonitrile, Isomer 1 and CL Isomer 2

[1758] Column: W CHIRALPAK IG, THNMR: Isomer 1: NMR (400

[1759] 2*25 cm, 5 pm; MHz, DMSO, 23°C) 82.40 (3H, t),

[1760] Mobile Phase A:

[1761] Isomer 1 and Isomer 2 6.03 (1H, d), 6.18 (1H, d), 6.96

[1762] Hex (0.5% 2 M (1H, dd), 7.29 (1H, d), 9.29 (2H,

[1763] NH3-MeOH), s), 11.53 (1H, s). Isomer 2:JH

[1764] Mobile Phase B: NMR (400 MHz, DMSO, 22°C) 8

[1765] EtOH; 20 mL / min; 2.40 (3H, d), 6.03 (1H, d), 6.17

[1766] Gradient: (1H, d), 6.96 (1H, dd), 7.29 (1H,

[1767] isocratic 15; 220 / d), 9.29 (2H, s), 11.52 (1H, s).

[1768] 254 nm. LCMS: Isomer 1: m / z (ES-), [M- H]- = 315, Isomer 2: m / z (ES-),

[1769] [M-H]- = 315.

[1770] rel-2-((7-ethynyl-4-fluoro-5- and OR Enantiomer iodo-lH-indol-3- 2

[1771] Fyl)(hydroxy)methyl)pyrimidine- HO, JI

[1772] 5-carbonitrile, Isomer 1 and

[1773] Column: Isomer 2

[1774] CHIRALPAK IC, H 2*25 cm, 5 pm;

[1775] NMR: Isomer 1:JH NMR (400

[1776] Mobile Phase A: MHz, DMSO, 23°C) 84.57 (1H, s),

[1777] Hex (0.5% 2 M Isomer 1 and Isomer 2 6.10 (1H, d), 6.15 (1H, d), 7.24

[1778] NH3-MeOH), (1H, s), 7.53 (1H, d), 9.29 (2H, s),

[1779] Mobile Phase B: 11.78 (1H, s). Isomer 2:JH NMR

[1780] EtOH; 20 mL / min; (400 MHz, DMSO, 23°C) 8 4.57

[1781] Gradient: (1H, s), 6.10 (lH, d), 6.15 (lH, d),

[1782] isocratic 50; 220 / 7.23 (1H, s), 7.53 (1H, d), 9.29

[1783] 254 nm; (2H, s), 11.78 (1H, s). LCMS:

[1784] Isomer 1: m / z (ES-), [M-H]- =

[1785] 417, Isomer 2: m / z (ES-), [M-H]- = 417.

[1786] rel-5-chloro-3-((5- and OR Enantiomer cyanopyrimidin-2- Column: 4 yl)(hydroxy)methyl)-4,6- Chiralpak IK, 20 xfh°, / / difluoro-lH-indole-7- 250 mm, 5 micron carbonitrile, Isomer 1 and Mobile phase: Y jn Isomer 2 35% MeOH +

[1787] 0.1% NH3 / 65% ill NMR: Isomer 1:JH NMR (500 SCCO2; 60 N

[1788] Isomer 1 and Isome MHz, DMSO, 27°C) 6.15 (1H, d), mL / min;

[1789]

[1790] r 26.25 (1H, d), 7.47 (1H, s), 9.29 120 bar; 40 °C;

[1791] (2H, s), 12.65 (1H, s). Isomer 2: 230 nm NMR (500 MHz, DMSO, 27°C)

[1792] 6.15 (1H, d), 6.24 (1H, d), 7.46

[1793] (1H, s), 9.29 (2H, s), 12.65 (1H,

[1794] s). LCMS: m / z: ES- [M-H]- 344.

[1795] o

[1796] rel-2-((4,5-dichloro-7-ethynyl- 186 and OR Enantiomer lH-indol-3- 187 yl)(hydroxy)methyl)pyrimidine- c;|HO. / / y^

[1797] 5-carbonitrile, Isomer 1 and Column: Cl^. Isomer 2 CHIRALPAK LUX-4

[1798] 2*25 cm, 5 pm; H NMR: Isomer 1: NMR (400 Mobile Phase A:

[1799] 1 1 MHz, DMSO, 24°C) 84.70 (1H, HEX (0.5% 2 M Iso mer 1 and Isomer 2 s), 6.18 (lH, s), 6.53 (1H, s), 7.35 NH3-MeOH),

[1800] (1H, s), 7.45 (1H, s), 9.29 (2H, s), Mobile Phase B: 11.89 (1H, s). Isomer 2: 1H NMR EtOH; Flow rate: (400 MHz, DMSO, 23°C) 84.70 20 mL / min; (1H, d), 6.12-6.22 (1H, m), 6.53 Gradient: (1H, d), 7.34 (1H, d), 7.45 (1H, isocratic 50; s), 9.29 (2H, s), 11.87 (lH, s). Wave Length:

[1801] LCMS: Isomer 1: m / z (ES-), [M- 220 / 254 nm H]- = 341. Isomer 2: m / z (ES-),

[1802] [M-H]- = 341.

[1803] rel-5-chloro-3-((5- 199 and OR Enantiomer cyanopyrimidin-2- 200 yl)(hydroxy)methyl)-7-ethynyl- IH0< J / y ^ lH-indole-4-carbonitrile, Isomer

[1804] 1 and Isomer 2

[1805] JO Column: H CHIRALPAKIC- NMR: Isomer 1:JH NMR (400

[1806] 1 34.6*50mm3um;

[1807] MHz, DMSO, 22°C) 84.98 (1H,

[1808] Isomer 1 and Isomer 2 Mobile Phase A:

[1809] s), 6.24 (lH, d), 6.43 (lH, d),

[1810] MtBE (0.1% DEA): 7.45 (1H, s), 7.56 (1H, s), 9.31

[1811] EtOH=50: 50; (2H, s), 12.22 (1H, s). Isomer 2:

[1812] JFlow rate: H NMR (400 MHz, DMSO, 22°C)

[1813] l. OmL / min 84.98 (1H, s), 6.24 (1H, d), 6.43

[1814] Gradient: (1H, d), 7.45 (1H, s), 7.56 (1H, s),

[1815] isocratic 9.31 (2H, s), 12.22 (1H, s).

[1816] LCMS: Isomer 1: m / z (ES-), [M- H]- = 332. Isomer 2: m / z (ES-),

[1817] [M-H]- = 332.

[1818]

[1819] Example 105 and Example 106: rel-2-((5-chloro-7-ethvnyl-4-fluoro-lH-indol-3-yl)(hvdroxy)methyl) pyrimidine-5-carbonitrile, Isomer 1 and 2OR Enantiomer OR Enantiomer

[1820]

[1821] BrettPhos Pd G3 (35.7 mg, 0.04 mmol) was added to (5-bromopyrimidin-2-yl)(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methanol (300 mg, 0.79 mmol), potassium ferrocyanide (II) trihydrate (999 mg, 2.36 mmol) and potassium acetate (19.34 mg, 0.2 mmol) in Me-THF (3.0 mL) / water (3.0 mL). The resulting mixture was kept away from light and stirred at 80 °C for 16 hours. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (3 x 20 mL), the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 50% MeCN in water (0.1 % FA). Pure fractions were evaporated to dryness. The mixture was purified by preparative chiral-HPLC. The fractions containing the desired compound were evaporated to dryness to afford: Isomer 1: rel-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile (55 mg, 21 %) as a colourless solid and Isomer 2: rel-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile (54 mg, 21 %) as a colourless solid. NMR Spectrum: Isomer 1:

[1822]

[1823] NMR (400 MHz, DMSO, 22°C) 84.59 (1H, s), 5.89-6.31 (2H, m), 7.31 (1H, d), 7.36 (1H, d), 9.29 (2H, s), 11.82 (1H, s).: Isomer 2:

[1824]

[1825] NMR (400 MHz, DMSO, 22°C) 84.59 (1H, s), 5.93-6.19 (2H, m), 7.31 (1H, d), 7.36 (1H, d), 9.29 (2H, s), 11.82 (1H, s). Mass rum Isomer 1: m / z ES-), [M-H]- 325. Isomer 2: m / z (ES-), [M-H]- = 325.

[1826] Example 107: rac-5-chloro-3-(l-(4-chlorophenyl)-2-hvdroxyethyl)-lH-indole-7-carbonitrile

[1827] Step 1: rac-2-(7-bromo-5-chloro-lH-indol-3-yl)-2-(4-chlorophenyl)ethan-l-ol

[1828]

[1829] InBra (0.154 g, 0.43 mmol) was added to 7-bromo-5-chloro-lH-indole (2.0 g, 8.68 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 10 minutes.2-(4-Chlorophenyl)oxirane (1.08 g, 6.94 mmol) in DCM (4.0 mL) was added to the above mixture. The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether.Pure fractions were evaporated to dryness to afford rac-2-(7-bromo-5-chloro-lH-indol-3-yl)-2-(4-chlorophenyl)ethan-l-ol (1.35 g, 40 %} as a pale yellow solid. NMR Spectrum:1H NMR (500 MHz, DMSO, 24°C) 6 3.95 (2H, dq), 4.29 (1H, q), 4.86 (1H, s), 7.33 (5H, q), 7.37-7.42 (1H, m), 7.45 (1H, d), 11.42-11.46 (1H, m). Mass Spectrum: m / z (ES-), [M-H]- = 382.

[1830] Step 2: rac-5-chloro-3-(l-(4-chlorophenyl)-2-hvdroxyethyl)-lH-indole-7-carbonitrile, Example 107

[1831]

[1832] PdtPPha (39 mg, 0.03 mmol) was added to rac-2-(7-bromo-5-chloro-lH-indol-3-yl)-2-(4-chlorophenyl)ethan-l-ol (130 mg, 0.34 mmol), Zn(CN)2(198 mg, 1.69 mmol) and Zn (4.4 mg, 0.07 mmol) in DMF (2 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered through celite. The filtrate was diluted with EtOAc (50 mL), and washed with water (2 x 10 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (0.1% FA). Pure fractions were evaporated to dryness to afford rac-5-chloro-3-(l-(4-chlorophenyl)-2-hydroxyethyl)-lH-indole-7-carbonitrile (45 mg, 40 %) as a colourless solid. NMR Spectrum: NMR (300 MHz, DMSO) 83.97 (2H, dq), 4.35 (1H, t), 4.88 (1H, t), 7.27-7.4 (4H, m), 7.55 (1H, s), 7.67 (1H, d), 7.75 (1H, d), 12.11 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 329.

[1833] Example 108: rac-5-chloro-3-(l-(5-chloropyridin-2-yl)-l-hvdroxyethyl)-lH-indole-7-carbonitrile Step 1: 5-chloro-3-(5-chloropicolinoyl)-lH-indole-7-carbonitrile

[1834] Cl

[1835]

[1836] Anhydrous aluminum chloride (0.604 g, 4.53 mmol) was added slowly to 5-chloropicolinoyl chloride (0.399 g, 2.26 mmol) and 5-chloro-1H-indole-7-carbonitrile (0.4 g, 2.26 mmol) in DCM (5 mL). The resulting solution was stirred at room temperature for 6 hours. The solids were collected by filtration and dried to afford 5-chloro-3-(5-chloropicolinoyl)-lH-indole-7-carbonitrile (0.3 g, 42 %) as a yellow solid which was used directly in the next step without further purification. NMR Spectrum:JH NMR (300 MHz, DMSO, 24°C) 87.98 (1H, d), 8.11 (1H, d), 8.21 (1H, dd), 8.66 (1H, d), 8.87 (1H, d), 8.99 (1H, s), 13.28 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 314.

[1837] Step 2: tert-butyl 5-chloro-3-(5-chloropicolinoyl)-7-cvano-lH-indole-l-carboxylate

[1838]

[1839] DMAP (0.059 g, 0.48 mmol) was added slowly to 5-chloro-3-(5-chloropicolinoyl)-lH-indole-7-carbonitrile (0.76 g, 2.4 mmol) and (Boc)2O (1.116 mL, 4.81 mmol) in DCM (10 mL). The resulting solution was stirred at room temperature for 6 hours. The reaction mixture was evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 60 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford tert-butyl 5-chloro-3-(5-chloropicolinoyl)-7-cyano-lH-indole-l-carboxylate (0.55 g, 55 %) as a yellow solid. NMR Spectrum: NMR (300 MHz, DMSO) 8 1.69 (9H, s), 8.11 (1H, d), 8.16 (1H, d), 8.24 (1H, d), 8.71 (1H, d), 8.91 (1H, dd), 9.24 (1H, s).

[1840] Mass Spectrum: m / z (ES+), [M+H]+ = 416.

[1841] Step 3: rac-tert-butyl-5-chloro-3-(l-(5-chloropyridin-2-yl)-l-hvdroxyethyl)-7-cyano-lH-indole-l-carboxylate

[1842] Cl

[1843]

[1844] Tert-butyl 5-chloro-3-(5-chloropicolinoyl)-7-cyano-lH-indole-l-carboxylate (300 mg, 0.72 mmol) was added to methyl magnesium bromide solution (1.0 mL2.88 mmol) in THF (1 mL) at -40°C. The resulting mixture was stirred at -40 °C for 5 hours. The reaction mixture was diluted with EtOAc (10 mL), and washed sequentially with water (3 x 10 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (water: MeCN = 3: 7), to afford rac-tert-butyl-5-chloro-3-(l-(5-chloropyridin-2-yl)-l-hydroxyethyl)-7-cyano-lH-indole-l-carboxylate (150 mg, 48 %) as a yellow solid. NMRSpectrum: *H NMR (400 MHz, DMSO, 24°C) 81.65 (9H, s), 1.91 (3H, s), 6.34 (1H, s), 7.76 (1H, s), 7.81-7.9 (3H, m), 7.96 (1H, dd), 8.51 (1H, d). Mass Spectrum: m / z (ES-), [M-H]- = 431.

[1845] Step 4: rac-5-chloro-3-(l-(5-chloropyridin-2-yl)-l-hvdroxyethyl)-lH-indole-7-carbonitrile, Example 108

[1846]

[1847] rac-tert-butyl-5-chloro-3-(l-(5-ch loropyridin-2-yl)-l-hyd roxyethyl)-7-cyano-l H-indole-l-ca rboxylate (50 mg, 0.12 mmol) was stirred in H2O (1 mL) at 20 °C for 5 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford rac-5-chloro-3-(l-(5-chloropyridin-2-yl)-l-hydroxyethyl)-lH-indole-7-carbonitrile (16 mg, 42 %} as a brown oil. NMR Spectrum:1H NMR (300 MHz, DMSO, 26°C) 8 1.91 (3H, s), 6.07 (1H, s), 7.46 (1H, s), 7.66 (1H, d), 7.79-7.87 (2H, m), 7.92 (1H, dd), 8.50 (1H, dd), 12.07 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 332.

[1848] General reduction conditions Method A:

[1849] Example 109: 5-chloro-3-((5-chloropyridin-2-yl)methyl)-lH-indole-7-carbonitrile

[1850]

[1851] TFA (0.484 mL, 6.29 mmol) was added to triethylsilane (365 mg, 3.14 mmol) and rac-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile (200 mg, 0.63 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3(25 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-((5-chloropyridin-2-yl)methyl)-lH-indole-7-carbonitrile (124 mg, 65 %} as a colourless solid. NMR Spectrum:JH NMR (400 MHz, DMSO, 21°C) δ 4.22 (2H, s), 7.35 (1H, d), 7.47 (1H, s), 7.71 (1H, d), 7.82 (1H, dd), 7.94 (1H, d), 8.53 (1H, d), 12.05-12.19 (1H, m). Mass Spectrum: m / z (ES+), [M+H]+ = 302.

[1852] General reduction conditions Method B:

[1853] General alkylation-reduction conditions Method CA and CB: telescoping of general indole alkylation method A or B and general reduction method A:

[1854] According to this procedure, general indole alkylation conditions A or B (or a variation thereof) are followed, and the crude material is used directly following aqueous work-up and without further purification (unless otherwise specified) into the general reduction conditions method A.The method is defined by the choice of general indole alkylation method as either method CA (indole alkylation method A, followed directly by general reduction conditions method A) or method CB (indole alkylation method B, followed directly by general reduction conditions method A).

[1855] Example 110: 5-chloro-3-((5-cvanopyridin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile

[1856]

[1857] 5-chloro-4-fluoro-lH-indole-7-carbonitrile (146 mg, 0.75 mmol) was reacted according to general indole alkylation conditions B, with the exception that the crude material was taken directly without purification into the general reduction conditions method A to afford 5-chloro-3-((5-cyanopyridin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile (66.6 mg, 29 %) as a beige solid. NMR Spectrum:1H NMR (500 MHz, DMSO, 27°C) 4.39 (2H, s), 7.42 (1H, d), 7.51 (1H, s), 7.90 (1H, d), 8.20 (1H, dd), 8.92 (1H, d), 12.41 (1H, s). Mass Spectrum: m / z: ES+ [M+H]+ 311.

[1858] The compounds presented in Table C-Tl were synthesised in an analogous fashion to the Examples 109 or 110 above using the appropriate indole and aldehyde reagent and the specified general indole alkylation-reduction method or general reduction method, except where specified. In the latter case, unless specified explicitly the reduction-precursors were synthesised by the general indole alkylation method A or B (or a variant thereof).

[1859] Table C-Tl

[1860] Example Structure Compound Name Method 5-chloro-3-(4-chlorobenzyl)- 111 lH-indole-7-carbonitrile

[1861] NMR^H NMR (400 MHz,

[1862] Y DMSO, 21°C) 64.07 (2H, s),

[1863] A

[1864] 7.32 (4H, d), 7.45 (1H, s), 7.70

[1865] THHI (1H, d), 7.88 (1H, d), 12.07 N (1H, s). LCMS: m / z (ES-), [M- H]- = 299.

[1866]

[1867] 5-chloro-3-(pyridin-2- ylmethyl)-lH-indole-7- carbonitrile

[1868] NMR^H NMR (400 MHz, DMSO, 21°C) 64.20 (2H, s),

[1869] THA

[1870] ill 7.20 (1H, dd), 7.29 (2H, d),

[1871] N 7.46 (1H, d), 7.64-7.76 (2H,

[1872] m), 7.93 (1H, d), 8.49 (1H, dt), 12.06 (1H, s). LCMS: m / z (ES+), [M+H]+ = 268.

[1873] 3-((5-bromopyridin-2- yl)methyl)-5-chloro-lH- indole-7-carbonitrile

[1874] NMR: NMR (400 MHz, DMSO, 24°C) 64.20 (2H, s), A 7.29 (1H, d), 7.47 (1H, d),

[1875] N 7.70 (1H, d), 7.9-7.97 (2H,

[1876] m), 8.61 (1H, d), 12.08 (1H, s). LCMS: m / z (ES+), [M+H]+

[1877] = 348.

[1878] 5-chloro-3-((5-cyanopyridin- ==^N 2-yl)methyl)-lH-indole-7- JT carbonitrile

[1879] NMR:1H NMR (400 MHz, DMSO, 23°C) 64.32 (2H, s),

[1880] IHA

[1881] ill 7.48-7.56 (2H, m), 7.71 (1H,

[1882] N d), 7.97 (1H, d), 8.20 (1H, dd),

[1883] 8.94 (1H, d), 12.12 (1H, s).

[1884] LCMS: m / z (ES+), [M-H]- =

[1885] 291.

[1886] 5-chloro-3-((5-chloropyrazin- 2-yl)methyl)-lH-indole-7- rNyc|

[1887] carbonitrile

[1888] ci^ T^

[1889] NMR:1H NMR (400 MHz, DMSO, 23°C) δ 4.28 (2H, s), A i IllH7.48 (lH, s), 7.70 (1H, d), 8.00 N (1H, d), 8.53 (lH, d), 8.68

[1890] (1H, d), 12.12 (1H, s). LCMS:

[1891] m / z (ES+), [M+H]+ = 303.

[1892]

[1893] 3-((5-bromothiazol-2- yl)methyl)-5-chloro-lH- j / XRindole-7-carbonitrile

[1894] Cly^yJ

[1895] NMR:1H NMR (400 MHz,

[1896] DMSO, 23°C) 64.47 (2H, s), A TH

[1897] ill 7.61 (1H, d), 7.72-7.82 (2H,

[1898] N m), 7.98 (1H, d), 12.23 (1H,

[1899] s). LCMS: m / z (ES+), [M+H]+

[1900] = 352.

[1901] 5-chloro-4-fluoro-3-((5- methoxypyridin-2-yl)methyl)- lH-indole-7-carbonitrile

[1902] NMR: NMR (400 MHz, A DMSO, 22°C) 83.78 (3H, s),

[1903] 4.20 (2H, s), 7.12 (lH, d), 7.28 Intermediate (1H, dd), 7.40 (1H, d), 7.87 purified by N (1H, dd), 8.18 (1H, d), 12.33 silica (1H, s).

[1904] LCMS: m / z (ES+), [M+H]+ =

[1905] 316.00

[1906] 3-( (5-chloropyridin-2- yl)methyl)-7-fluoro-lH- jryci

[1907] indole-5-carbonitrile

[1908] NMR:1H NMR (500 MHz,

[1909] ^J^N

[1910] T H DMSO, 27°C) 4.24 (2H, s),

[1911] F CA

[1912] 7.37 (1H, d), 7.41 (1H, dd),

[1913] 7.50 (1H, s), 7.82 (1H, dd),

[1914] 7.93 (1H, d), 8.53 (1H, d),

[1915] 12.10 (1H, s). LCMS: m / z: ES+

[1916] [M+H]+ 286.

[1917] 4,5-dichloro-3-((5- cyanopyridin-2-yl)methyl)- Cl lH-indole-7-carbonitrile ci^X ^TN

[1918] NMR:1H NMR (500 MHz,

[1919] DMSO, 27°C) 4.54 (2H, s), CB T H

[1920] ill 7.30 (1H, d), 7.58 (1H, s), 7.94

[1921] N (1H, s), 8.16 (1H, dd), 8.87- 8.97 (1H, m), 12.46 (1H, s).

[1922] LCMS: m / z: ES+ [M+H]+ 327.

[1923]

[1924] 5-ch Io ro-3-(4-cya n o-2- F fluorobenzyl)-lH-indole-7- F carbonitrile

[1925] NMR:1H NMR (400 MHz,

[1926] 1 O DMSO, 24°C) δ 4.18 (2H, s),

[1927] A IH7.42 (1H, d), 7.49 (1H, t), 7.62 ill (1H, dd), 7.73 (lH, d), 7.82

[1928] N

[1929] (1H, dd), 7.97 (1H, d), 12.13- 12.18 (1H, m). LCMS: m / z

[1930] (ES-), [M-H]- = 308.

[1931] 5-chloro-3-(4-cyanobenzyl)- lH-indole-7-carbonitrile NMR:1H NMR (400 MHz,

[1932] Y O DMSO, 22°C) δ 4.17 (2H, s),

[1933] A

[1934] 7.47-7.53 (3H, m), 7.67-7.78 TH

[1935] ili (3H, m), 7.92 (1H, q), 12.12

[1936] N (1H, s). LCMS: m / z (ES-), [M- O H]- = 290.

[1937] \ z 3-((5-chloropy ridin-2- yl)methyl)-5- ZT (difluoromethoxy)-lH-indole- 7-carbonitrile

[1938] r C^z

[1939] o NMR:1H NMR (500 MHz,

[1940] DMSO) δ 4.22 (2H, s), 7.15 A (1H, t), 7.34 (lH, d), 7.47 (1H, s), 7.51 (1H, d), 7.70 (lH, d), 7.82 (1H, dd), 8.53 (1H, d), 12.01 (1H, s). LCMS: m / z

[1941] (ES+), [M+H]+ = 336.

[1942] 3-( (5-chloropyridin-2- yl)methyl)-5- rvci(trifluoromethoxy)-lH- indole-7-carbonitrile XJ> NMR:1H NMR (400 MHz,

[1943] TH

[1944] ill DMSO, 23°C) δ 4.24 (2H, s),

[1945] N A

[1946] 7.37 (1H, d), 7.53 (1H, d),

[1947] 7.73 (1H, d), 7.82 (1H, dd),

[1948] 7.87-7.92 (1H, m), 8.52 (1H, d), 12.16-12.21 (1H, m).

[1949] LCMS: m / z (ES+), [M+H]+ =

[1950] 352.

[1951]

[1952] 6-((5-chloro-7-ethynyl-lH- indol-3-y l)methyl)

[1953] JT nicotinonitrile

[1954] NMR:1H NMR (400 MHz,

[1955] ^ / '" N DMSO, 23°C) δ 4.28 (2H, s),

[1956] H A

[1957] 4.61 (lH, s), 7.23 (1H, d), 7.36

[1958] I I (1H, d), 7.50 (1H, d), 7.63

[1959] (lH, d), 8.19 (lH, dd), 8.94

[1960] (1H, d), 11.46 (1H, s). LCMS:

[1961] m / z (ES+), [M+H]+ = 292.

[1962] 5-chloro-3-((5-cyanopyridin- 2-yl)methyl)-4-methoxy-lH- O, _ (' / indole-7-carbonitrile

[1963] NMR:1H NMR (500 MHz,

[1964] DMSO, 27°C) 3.74 (3H, s),

[1965] THCB ill 4.40 (2H, s), 7.35 (lH, d), 7.39

[1966] N (1H, s), 7.76 (1H, s), 8.17 (1H,

[1967] dd), 8.89 -8.96 (lH, m),

[1968] 12.17 (1H, s). LCMS: m / z: ES+

[1969] [M+H]+ 323.

[1970] 6-((5,7-dichloro-4-fluoro-lH- >Nindol-3- F j Y yl)methyl) nicotinonitrile

[1971] CA

[1972] ClN

[1973] NMR:1H NMR (400 MHz,

[1974] Intermediate DMSO, 24°C) 64.37 (2H, s),

[1975] T H purified by Cl 7.37 (2H, dd), 7.44 (1H, s),

[1976] silica 8.20 (1H, d), 8.92 (1H, d). l x exchangeable not observed.

[1977] LCMS: m / z (ES+), [M+H]+ =

[1978] 319.

[1979] 6-((5-bromo-4,7-difluoro-lH- indol-3-y l)methyl)

[1980] F J nicotinonitrile

[1981] CA

[1982] Br^^k ^A^N

[1983] NMR:1H NMR (400 MHz,

[1984] Intermediate DMSO, 24°C) 64.36 (2H, s),

[1985] T H purified by F 7.24 (1H, dd), 7.35-7.44 (2H,

[1986] silica m), 8.19 (1H, dd), 8.93 (1H,

[1987] d), 12.03 (1H, s). LCMS: m / z

[1988] (ES+) = 348, 350.

[1989]

[1990] 3-((5-bromopyridin-2- yl)methyl)-5-chloro-4-fluoro-Fxy lH-indole-7-carbonitrile

[1991] TNNMR:1H NMR (400 MHz,

[1992] DMSO, 24°C) δ 4.23 (2H, s), 7.18 (1H, d), 7.47 (1H, s),

[1993] ill

[1994] N 7.86-7.97 (2H, m), 8.59 (1H,

[1995] d), 12.38 (1H, s). LCMS: m / z (ES+), [M+H]+ = 364, 366.

[1996] 6-((5-chloro-4,7-difluoro-lH- indol-3-y l)methyl)

[1997] F r-ty1nicotinonitrile

[1998] NNMR: NMR (400 MHz,

[1999] T H DMSO, 24°C) 64.36 (2H, s),

[2000] A

[2001] F 7.16 (1H, dd), 7.38 (1H, d),

[2002] 7.43 (1H, s), 8.19 (1H, dd),

[2003] 8.93 (1H, dd), 12.04 (lH, s).

[2004] LCMS: m / z (ES+), [M+H]+ =

[2005] 304.

[2006] 6-((7-bromo-5-chloro-4- fluoro-lH-indol-3-yl)methyl)

[2007] F JY nicotinonitrile

[2008] NL T > NMR:1H NMR (400 MHz,

[2009] T H DMSO, 24°C) δ 4.37 (2H, s), 7.39 (1H, d), 7.41-7.5 (2H,

[2010] m), 8.19 (1H, dd), 8.92 (1H, dd), 11.75 (1H, s). LCMS: m / z (ES+), [M+H]+ = 364, 366.

[2011] 5-chloro-4-fluoro-3-((5- F (trifluoromethyl)pyridin-2- r-^x. J-F yl)methyl)-lH-indole-7- F carbonitrile

[2012] cixj^rN

[2013] NMR:1H NMR (400 MHz,

[2014] I DMSO, 24°C) δ 4.40 (2H, s), 7.42 (1H, d), 7.52 (1H, s), 7.90 N (1H, d), 8.10 (1H, dd), 8.84- 8.89 (1H, m), 12.43 (1H, s).

[2015] LCMS: m / z (ES+), [M+H]+ =

[2016] 354.

[2017]

[2018] 5-bromo-3-((5-cyanopyridin- 2-yl)methyl)-lH-indole-7- carbonitrile

[2019] NMR:1H NMR (400 MHz, ^ / "■N DMSO,25°C) 64.32 (2H, s),

[2020] THA

[2021] ih 7.48 (IH, s), 7.52 (IH, dd),

[2022] N 7.80 (IH, d), 8.10 (IH, d),

[2023] 8.20 (IH, dd), 8.94 (IH, dd), 12.13 (IH, s). LCMS: m / z

[2024] (ES+), [M+H]+ = 337, 339.

[2025] 3-((5-cyanopyridin-2- yl)methyl)-4-fluoro-5-FjyNmethoxy-lH-indole-7- / O^X TNcarbonitrile

[2026] NMR: NMR (400 MHz,

[2027] TH

[2028] ih DMSO, 24°C) δ 3.84 (3H, s), 4.36 (2H, s), 7.37 (lH, d), 7.40

[2029] (IH, s), 7.59 (IH, d), 8.18 (IH, dd), 8.88-8.94 (IH, m), 11.99 (IH, s). LCMS: m / z (ES+),

[2030] [M+H]+ = 307.

[2031] 4-chloro-3-((5-cyanopyridin- i — > 2-yl)methyl)-5-methoxy-lH- ClN

[2032] indole-7-carbonitrile ^o l TN

[2033] 1 L? NMR:1H NMR (400 MHz,

[2034] DMSO, 24°C) 63.86 (3H, s),

[2035] THA

[2036] ih 4.52 (2H, s), 7.24 (IH, dd),

[2037] N 7.47 (IH, s), 7.56 (IH, s), 8.15

[2038] (IH, dd), 8.93 (IH, dd), 12.06 (IH, s). LCMS: m / z (ES+),

[2039] [M+H]+ = 323.

[2040] 3-((5-bromopyrazin-2- yl)methyl)-5-chloro-lH- indole-7-carbonitrile

[2041] NMR:1H NMR (400 MHz, DMSO, 23°C) 64.26 (2H, s),

[2042] A TH7.49 (IH, d), 7.71 (IH, d), ill

[2043] N 8.01 (IH, d), 8.53 (IH, d),

[2044] 8.76 (IH, d), 12.13 (IH, s).

[2045] LCMS: m / z (ES+), [M+H]+ =

[2046] 347, 349.

[2047]

[2048] 3-((5-bromopyrimidin-2- yl)methyl)-5-chloro-lH- indole-7-carbonitrile

[2049] /

[2050] NMR:1H NMR (500 MHz,

[2051] H DMSO, 27°C) 4.34 (2H, s), CB 1 7.47 (1H, d), 7.70 (1H, d),

[2052] N 7.96 (1H, d), 8.91 (2H, s),

[2053] 12.07 (1H, s). LCMS: m / z: ES+ [M+H]+ 347, 349.

[2054] 2-(3-((5-chloropyridin-2- yl)methyl)-lH-indol-5- / v yl)acetonitrile

[2055] NMR:1H NMR (500 MHz,

[2056] H DMSO, 27°C) 3.99 (2H, s),

[2057] 4.18 (2H, s), 7.03 (1H, dd), CA 7.21 -7.27 (2H, m), 7.36 (1H, d), 7.41 (1H, s), 7.78 (1H, dd), 8.45 - 8.56 (lH, m), 11.00

[2058] (1H, s). LCMS: m / z: ES+

[2059] [M+H]+ 282.

[2060] 5-ch Io ro-3-(4-cya n o-3- >Nfluorobenzyl)-lH-indole-7- carbonitrile

[2061] NMR:1H NMR (500 MHz, DMSO, 27°C) 4.19 (2H, s),

[2062] CA IH7.35 (1H, d), 7.49 (1H, d),

[2063] ill

[2064] N 7.53 (lH, s), 7.70 (1H, d), 7.82

[2065] (1H, t), 7.98 (1H, d), 12.12

[2066] (1H, s). LCMS: m / z: ES- [M- H]- 308.

[2067] 5-bromo-2-((5-chloro-7-,N^\ ethynyl-4-fluoro-lH-indol-3- Jl >-^D yl)methyl)thiazole

[2068] , i y 's^Br

[2069] YS NMR:JH NMR (300 MHz, / " N DMSO, 22°C) 64.45 (2H, s), A H

[2070] 4.63 (lH, s), 7.39 (1H, d), 7.51 1 1 (1H, d), 7.76 (1H, s), 11.86

[2071] (1H, s). LCMS: m / z (ES+),

[2072] [M+H]+ = 369, 371.

[2073]

[2074] 5-chloro-4-fluoro-3-((5- methoxypyrimidin-2- yl)methyl)-lH-indole-7- carbonitrile

[2075] Cl I jfN

[2076] NMR:1H NMR (400 MHz,

[2077] T H A DMSO, 23°C) 63.87 (3H, s),

[2078] ill

[2079] N 4.37 (2H, s), 7.43 (1H, s), 7.87

[2080] (1H, d), 8.45 (2H, s), 12.32

[2081] (1H, s). LCMS: m / z (ES+),

[2082] [M+H]+ = 317.

[2083] 3-((5-cyanopyrimidin-2- yl)methyl)-4-fluoro-5- (trifluoromethyl)-lH-indole- 7-carbonitrile

[2084] NMR:1H NMR (500 MHz, DMSO, 27°C) 4.60 (2H, s),

[2085] N 7.61 (lH, s), 8.03 (1H, d), 9.21

[2086] (2H, s), 12.68 (1H, s). LCMS:

[2087] m / z: ES+ [M+H]+ 346.

[2088] 3-((5-cyanopyridin-2- yl)methyl)-5-methyl-lH- indole-7-carbonitrile

[2089] A NMR:1H NMR (400 MHz,

[2090] Intermediate DMSO, 23°C) δ 2.37 (3H, s),

[2091] T

[2092] ihHpurified by 4.29 (2H, s), 7.37 (lH, d), 7.41

[2093] silica N (1H, d), 7.47 (1H, d), 7.65

[2094] (1H, s), 8.18 (1H, dd), 8.94

[2095] (1H, d), 11.74 (1H, s). LCMS:

[2096] m / z (ES+), [M+H]+ = 273.

[2097] 3-((5-cyanopyridin-2- yl)methyl)-5-F(difluoromethyl)-lH-indole-7- 1 ] N=^ carbonitrile

[2098] FLJO T H NMR:1H NMR (400 MHz,

[2099] ill DMSO, 23°C) δ 4.37 (2H, s), 7.10 (1H, t), 7.47— 7.57 (2H,

[2100] m), 7.82 (1H, d), 8.10 (1H, q),

[2101] 8.20 (1H, dd), 8.94 (1H, dd),

[2102] 12.23 (1H, s). LCMS: m / z

[2103] (ES+), [M+H]+ = 309.

[2104]

[2105] 3-((5-cyanopyridin-2- yl)methyl)-5-ethynyl-lH- indole-7-carbonitrile

[2106] J NMR: NMR (400 MHz, CB A>^N

[2107] T i NhHDMSO, 23°C) δ 4.12 (1H, s), 4.33 (2H, s), 7.47-7.56 (2H, purified by m), 7.71 (IH, d), 8.02 (IH, d), silica 8.20 (IH, dd), 8.94 (IH, d),

[2108] 12.15 (IH, s). LCMS: m / z

[2109] (ES+), [M+H]+ = 283.

[2110] 3-((5-cyanopyridin-2- yl)methyl)-5-cyclopropyl-lH- indole-7-carbonitrile

[2111] A N^7

[2112] NMR: NMR (400 MHz,

[2113] AJ^N CB DMSO,23°C) δ 0.63–0.72 (2H,

[2114] T ihHIntermediate m), 0.86-0.97 (2H, m), 1.95- N purified by 2.1 (IH, m), 4.30 (2H, s), 7.33

[2115] silica (2H, dd), 7.48 (IH, d), 7.58

[2116] (IH, d), 8.18 (IH, dd), 8.94

[2117] (IH, d), 11.73 (IH, s). LCMS:

[2118] m / z (ES+), [M+H]+ = 299.

[2119] 5-chloro-4-fluoro-3-((5- N'A^F fluoropyrimidin-2-yl)methyl)- lH-indole-7-carbonitrile

[2120] NMR:1H NMR (500 MHz,

[2121] = DMSO 27°C) 4.45 (2H, s), CB 7.46 (lH, s), 7.87 (IH, d), 8.79

[2122] N (2H, d), 12.34 (IH, s). LCMS:

[2123] m / z: ES+ [M+H]+ 305.

[2124] 5-chloro-3-((5- (difluoromethyl)pyridin-2- yl)methyl)-lH-indole-7- carbonitrile

[2125] CA

[2126] K2CO3 used NMR:1H NMR (400 MHz,

[2127] as base. DMSO, 24.5°C) 64.29 (2H, s),

[2128] =?' Intermediate 7.10 (IH, t), 7.45 (IH, d), 7.49

[2129] N purified by (IH, s), 7.69 (IH, d), 7.91 (IH,

[2130] silica ddt), 7.95 (IH, d), 8.70 (IH,

[2131] q), 12.10 (IH, s). LCMS: m / z

[2132] (ES+), [M+H]+ = 318.

[2133]

[2134] 5-chloro-4-fluoro-3-((5- methylpyrimidin-2- F 7 yl)methyl)-lH-indole-7- carbonitrile

[2135] CyLfN

[2136] CB NMR:1H NMR (400 MHz, Intermediate T H

[2137] ill DMSO, 24°C) δ 2.22 (3H, s), 4.39 (2H, s), 7.44 (1H, s), 7.87 silica (1H, d), 8.54 (2H, d), 12.32

[2138] (1H, s). LCMS: m / z (ES+),

[2139] o = — [M+H]+ = 301.

[2140] IZ 5-chloro-3-(4-chloro-3- = zZ? (hydroxymethyl)benzyl)-lH- Z \

[2141] rZYCIindole-7-carbonitrile

[2142] \\

[2143] L L? z NMR: NMR (500 MHz, CBk5V>"'N DMSO, 27°C) 4.08 (2H, s), From OTBS TH

[2144] ili 4.51 (2H, d), 5.32 (1H, t), 7.20 protected N (1H, dd), 7.30 (1H, d), 7.43 benzyl (1H, d), 7.46 (1H, d), 7.69 alcohol (1H, d), 7.86 (1H, d), 12.04

[2145] (1H, s). LCMS: m / z: ES- [M- H]- 329.

[2146] 5-bromo-3-((5- N" V_Br bromopyrimidin-2- F, _ < / yl)methyl)-4,7-difluoro-lH- Br^ JL / ^Nindole

[2147] L D T H NMR:1H NMR (400 MHz,

[2148] F A DMSO, 23°C) 64.39 (2H, s),

[2149] 7.22 (1H, dd), 7.37 (1H, d),

[2150] 8.90 (2H, s), 11.97 (1H, s).

[2151] LCMS: m / z (ES+), [M+H]+ =

[2152] 402.

[2153] 2-((5-bromo-4-chloro-7- ethynyl-lH-indol-3- yl)methyl) pyrimidine-5- carbonitrile

[2154] NMR:1H NMR (400 MHz,

[2155] A DMSO, 24°C) 64.66 (2H, s),

[2156] 4.69 (1H, s), 7.42 (1H, s), 7.52

[2157] (1H, s), 9.19 (2H, s), 11.76

[2158] (1H, s). LCMS: m / z (ES+),

[2159] [M+H]+ = 370.

[2160]

[2161] 5-bromo-4-chloro-3-((5- cyanopyrimidin-2-yl)methyl)- lH-indole-7-carbonitrile

[2162] NMR:1H NMR (400 MHz,

[2163] A DMSO, 24°C) 64.68 (2H, s),

[2164] 7.57 (lH, s), 8.00 (1H, d), 9.19 (2H, s), 12.44 (1H, s). LCMS:

[2165] m / z (ES-), [M-H]- = 370.

[2166] O Z -= — 2-((4,5-dichloro-7-ethynyl- lH-indol-3- c IZ IZ yl)methyl)pyrimidine-5- l J. carbonitrile

[2167] NMR: NMR (400 MHz,

[2168] A

[2169] ~z ~z.. DMSO, 24°C) 64.68 (2H, s),

[2170] 4.69 (1H, s), 7.42 (1H, s), 7.44 (1H, d), 9.20 (2H, s), 11.76

[2171] (1H, s). LCMS: m / z (ES-), [M- H]- = 325.

[2172] 5-bromo-4-fluoro-3-((5- fluoropyrimidin-2-yl)methyl)- 7, ^V

[2173] F / FlH-indole-7-carbonitrile

[2174] Br i r N=^

[2175] ifS NMR:1H NMR (400 MHz, t / "-N A DMSO, 23°C) 64.44 (2H, s),

[2176] IHII 7.44 (lH, s), 7.93 (1H, t), 8.79 N (2H, s), 12.35 (1H, s). LCMS:

[2177] m / z (ES+), [M+H]+ = 349.

[2178] 4,5-dichloro-7-ethynyl-3-((5- fluoropyrimidin-2-yl)methyl)- Cl / H / rFlH-indole

[2179] Cl I j N=^

[2180] NMR:1H NMR (400 MHz,

[2181] H DMSO, 23°C) δ 4.58 (2H, s), 4.68 (1H, s), 7.37 (1H, s), 7.41 (1H, s), 8.78 (2H, d), 11.70

[2182] (1H, s). LCMS: m / z (ES+),

[2183] [M+H]+ = 320.

[2184]

[2185] 5-chloro-7-ethynyl-4-fluoro- 3-((5-fluoropyrimidin-2- yl)methyl)-lH-indole

[2186] NMR:1H NMR (400 MHz, DMSO, 22°C) δ 4.43 (2H, s), 4.58 (1H, s), 7.13-7.52 (2H, m), 8.79 (2H, d), 11.46-11.85 (1H, m). LCMS: m / z (ES+), [M+H]+ = 304.

[2187] 4,5-dichloro-3-((5- fluoropyrimidin-2-yl)methyl)- Cl r-A / H / rFlH-indole-7-carbonitrilec|Uv4NNMR: NMR (400 MHz,

[2188] A DMSO, 22°C) 64.58 (2H, s),

[2189] T H

[2190] ill 7.52 (1H, s), 7.89 (1H, s), 8.78 N (2H, s), 12.38 (1H, s). LCMS:

[2191] m / z (ES+), [M+H]+ = 321.

[2192] 2-((4,5-dichloro-7-fluoro-lH- z \ indol-3-yl)methyl)pyrimidine- Cl _ ^ Z / 5-carbonitrile

[2193] ci I fN

[2194] T L? NMR:1H NMR (400 MHz,

[2195] A T H DMSO, 23°C) 64.68 (2H, s),

[2196] F 7.29 (1H, d), 7.50 (1H, s), 9.20 o (2H, s), 12.09 (1H, s). LCMS:

[2197] m / z (ES+), [M+H]+ = 321.

[2198] 2-((5-bromo-4-chloro-7- N-^x. fluoro-lH-indol-3- Cl yl)methyl)pyrimidine-5-Ncarbonitrile

[2199] T H NMR:1H NMR (400 MHz,

[2200] A F DMSO, 22°C) 4.66 (2H, s),

[2201] 7.38 (1H, d), 7.48 (1H, d),

[2202] 9.20 (2H, s), 12.08 (1H, s).

[2203] LCMS: m / z (ES+), [M+H]+ =

[2204] 365.

[2205]

[2206] 2-((4,7-difluoro-5-iodo-lH- 194 indol-3-y l)methyl)

[2207] F A J pyrimidine-5-carbonitrile

[2208] NMR: NMR (400 MHz,

[2209] T H DMSO, 23°C) 64.50 (2H, s), A

[2210] F 7.25 (1H, dd), 7.34 (1H, d),

[2211] 9.21 (2H, s), 11.96 (1H, s).

[2212] LCMS: m / z (ES+), [M+H]+ =

[2213] 397.

[2214] 3-((5-cyanopyrimidin-2- 195 yl)methyl)-5- (difluoromethyl)-4-fluoro-lH- indole-7-carbonitrile

[2215] NMR: NMR (500 MHz,

[2216] A DMSO, 23°C) 64.58 (2H, s),

[2217] N

[2218] 7.22 (1H, t), 7.55 (1H, s), 7.88

[2219] (1H, d), 9.22 (2H, s), 12.52

[2220] (1H, s). LCMS: m / z (ES+),

[2221] [M+H]+ = 328.

[2222] 5-chloro-4-fluoro-3-((5- 197 nitropyridin-2-yl)methyl)-lH- indole-7-carbonitrile

[2223] NMR:1H NMR (500 MHz,

[2224] DMSO, 27°C) 4.45 (2H, s), CB 7.48 (1H, d), 7.54 (1H, s), 7.90

[2225] N (1H, d), 8.49 (1H, dd), 9.27

[2226] (1H, dd), 12.44 (lH, s). LCMS:

[2227] m / z: ES+ [M+H]+ 331.

[2228]

[2229] General cyanation conditions:

[2230] The relevant aryl halides were accessed by the general indole alkylation methods detailed above.

[2231] Method A:

[2232] Example 149: 5-chloro-3-((5-cvanopyrazin-2-yl)methyl)-lH-indole-7-carbonitrile

[2233] Cl

[2234]

[2235] To a flask containing 3-((5-bromopyrazin-2-yl)methyl)-5-chloro-1H-indole-7-carbonitrile (30 mg, 0.09 mmol), dicyanozinc (20.3 mg, 0.17 mmol) and Pd(PPh3)4(10 mg, 8.63 μmol) was added DMF (1.0 mL). The reaction was degassed, then heated at 125 °C for 1 hour. After cooling the reaction was dilutedwith EtOAc (10 mL) and washed with brine (10 mL). The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-((5-cyanopyrazin-2-yl)methyl)-lH-indole-7-carbonitrile (14.5 mg, 57 %) as a beige solid. NMR Spectrum:1H NMR (500 MHz, DMSO, 27°C) 4.41 (2H, s), 7.52 (1H, s), 7.72 (1H, d), 8.03 (1H, d), 8.87 (1H, d), 9.11 (1H, d), 12.15 (1H, s). Mass Spectrum: m / z: ES+ [M+H]+ 294.

[2236] Method B:

[2237] Example 150: 2-((5,7-dichloro-4-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile

[2238]

[2239] BrettPhos Pd G3 (21.73 mg, 0.02 mmol) was added to 3-((5-bromopyrimidin-2-yl)methyl)-5,7-dichloro-4-fluoro-lH-indole (180 mg, 0.48 mmol), potassium ferrocyanide (II) trihydrate (101 mg, 0.24 mmol) and potassium acetate (5.9 mg, 0.06 mmol) in methyl THF (2.0 mL) / water (2.0 mL). The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 2-((5,7-dichloro-4-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile (50 mg, 32 %) as a colourless solid. NMR Spectrum:1H NMR (400 MHz, DMSO) δ 4.53 (2H, s), 7.35 (1H, d), 7.44 (1H, s), 9.21 (2H, s), 11.86 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 319.

[2240] The compounds presented in Table C-T2 were synthesised in an analogous fashion to the Example 149 or Example 150 above using the appropriate aryl halide and cyanation reagent, except where specified.

[2241] Table C-T2

[2242] Example Structure Compound Name Method 5-chloro-3-((5-cyanopyrimidin- 151 2-yl)methyl)-lH-indole-7- / / carbonitrile

[2243] C|^J

[2244] L O NMR:1H NMR (500 MHz, DMSO, 27°C) 4.47 (2H, s), 7.50

[2245] I

[2246] illH(1H, s), 7.71 (1H, d), 7.98 (1H, N d), 9.22 (2H, s), 12.12 (lH, s).

[2247]

[2248] LCMS: m / z: ES- [M-H]- 292.5-chloro-3-((5-cyano-3- ^0 methoxypyridin-2-yl)methyl)-4- fluoro-lH-indole-7-carbonitrile

[2249] F j Y A NMR:1H NMR (400 MHz, DMSO) δ 3.93 (3H, s), 4.32 (2H, dppf (10 O THs), 7.33 (lH, s), 7.87 (lH, d), mol% each) as ill

[2250] N 7.93 (1H, d), 8.43 (1H, d), 12.32 catalyst (1H, s). LCMS: m / z (ES+),

[2251] [M+H]+ = 341.

[2252] IZ

[2253] 2-((5-chloro-7-ethynyl-4-fluoro- lH-indol-3- yl)methyl)pyrimidine-5- carbonitrile

[2254] A

[2255] Z.

[2256] Pd2dba3 / NMR: NMR (400 MHz,

[2257] dppf (10 DMSO, 22°C) 64.52 (2H, s),

[2258] mol% each) as 4.58 (1H, s), 7.33 (1H, d), 7.36

[2259] catalyst (1H, s), 9.20 (2H, s), 11.71 (1H,

[2260] s). LCMS: m / z (ES+), [M+H]+ =

[2261] 311.

[2262] 2-((5,7-dichloro-4-fluoro-lH- N-a indol-3-yl)methyl)thiazole-5- F < ZZO carbonitrile

[2263] ClyM / S^N

[2264] NMR: NMR (400 MHz,

[2265] B T H DMSO) 84.59 (2H, s), 7.42 (1H,

[2266] Cl d), 7.63 (1H, s), 8.57 (1H, s),

[2267] 12.06 (1H, s). LCMS: m / z (ES+),

[2268] [M+H]+ = 326.

[2269] 2-((5-chloro-4,7-difluoro-lH-,N^\ indol-3-yl)methyl)thiazole-5- F carbonitrile

[2270] A

[2271] ciO / / S^NPd2dba3 /

[2272] NMR:1H NMR (400 MHz,

[2273] ^V'^'N dppf (10 T H DMSO,25°C) 84.58 (2H, s), 7.24

[2274] mol% each) as F (1H, dd), 7.62 (1H, s), 8.58 (1H,

[2275] catalyst s), 12.20 (1H, s). LCMS: m / z

[2276] (ES+), [M+H]+ = 310.

[2277]

[2278] 5-((5-chloro-7-cyano-lH-indol- 3-yl)methyl)thiazole-2- carbonitrile

[2279] A NMR:1H NMR (400 MHz, Pd2dba3 / DMSO, 25°C) 64.50 (2H, s), dppf (10 T iliH7.58 (1H, d), 7.75 (1H, d), 8.04 mol% each) as N (1H, d), 8.11 (1H, d), 12.20 (1H, catalyst s). LCMS: m / z (ES-), [M-H]- =

[2280] 297.

[2281] 2-((5-chloro-7-ethynyl-lH- N^\ _^N indol-3-yl)m ethyl) pyrimidine-5- A carbonitrile

[2282] l - A NMR:1H NMR (400 MHz, DMSO) δ 4.42 (2H, s), 4.59 (1H, dppf (10 H

[2283] s), 7.23 (lH, d), 7.35 (lH, s), mol% each) as 1 7.66 (1H, d), 9.22 (2H, s), 11.45 catalyst (1H, s). LCMS: m / z (ES+),

[2284] [M+H]+ = 293.

[2285] 2-((5-chloro-4,7-difluoro-lH- indol-3-yl)m ethyl) pyrimidine-5- carbonitrile

[2286] A

[2287] Pd2dba3 / NMR:1H NMR (400 MHz,

[2288] ' ' dppf (10

[2289] DMSO, 27°C) 64.53 (2H, s),

[2290] F mol% each) as 7.16 (1H, dd), 7.42 (1H, d), 9.21

[2291] catalyst (2H, s), 11.99 (1H, s). LCMS:

[2292] m / z (ES+), [M+H]+ = 305.

[2293] 2-((5-chloro-7-ethynyl-4-fluoro-,N“\\ lH-indol-3-yl)methyl)thiazole- F > _ _ 5-carbonitrile

[2294] 1 f

[2295] ClxX A VS NMR:1H NMR (400 MHz, Pd2dba3 / X"-N

[2296] H DMSO, 27°C) 64.58 (2H, s), dppf (10

[2297] 4.60 (1H, s), 7.42 (1H, d), 7.55 mol% each) as 1

[2298] (s, 1H), 8.52 (1H, s), 11.90 (1H, catalyst s). LCMS: m / z (ES+), [M+H]+ =

[2299] 316.

[2300]

[2301] 2-((5-chloro-7-cyano-lH-indol- 160 3-yl)methyl)oxazole-5- carbonitrile

[2302] / °^NA NMR:1H NMR (400 MHz, DMSO, 23°C) δ 4.44 (2H, s), dppf (10 ih 7.61 (IH, s), 7.76 (IH, d), 8.03 mol% each) as N

[2303] (IH, d), 8.20 (lH, s), 12.22 (IH, catalyst s). LCMS: m / z (ES-), [M-H]- =

[2304] 281.

[2305] 2-((5-chloro-7-cyano-lH-indol- 161 3-yl)methyl)thiazole-5- carbonitrile

[2306] S^N

[2307] T O NMR: NMR (400 MHz,

[2308] THDMSO, 22°C) 64.61 (2H, s), A ih 7.66 (IH, s), 7.77 (IH, d), 8.04 N

[2309] (IH, d), 8.58 (IH, s). l x

[2310] exchangeable not observed.

[2311] LCMS: m / z (ES+), [M+H]+ = 299.

[2312] 2-((5-bromo-4,7-difluoro-lH- 182 indol-3-yl)m ethyl) pyrimidine-5- F J carbonitrile

[2313] A

[2314] BrJyfNPd2dba3 /

[2315] NMR:1H NMR (400 MHz,

[2316] dppf (10 T H DMSO, 23°C) 64.51 (2H, s),

[2317] mol% each) as F 7.22 (IH, dd), 7.40 (IH, s), 9.21

[2318] catalyst (2H, s), 12.01 (IH, s). LCMS:

[2319] m / z (ES+), [M+H]+ = 349.

[2320]

[2321] General procedure for the sequential reductive alkylation - cyanation, method A:

[2322] The following method is a sequential combination of the general alkylation-reduction method and the general cyanation methods detailed above.

[2323] Example 162: 5-chloro-3-((5-cvanopyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile

[2324]

[2325] To a solution of 5-chloro-4-fluoro-lH-indole-7-carbonitrile (156 mg, 0.8 mmol) in DCM (5.5 mL) was added DBU (0.239 mL, 1.6 mmol). The reaction was stirred for 10 min then 5-bromopyrimidine-2-carbaldehyde (299 mg, 1.6 mmol) was added and the reaction was stirred at room temperature for 2hours. The reaction was diluted with DCM (20 mL) and washed with aq. NH4Cl solution (25 mL). The organic phase was dried over Na2SO4, filtered and evaporated. The residue was dissolved in DCM (5.50 mL), then triethylsilane (0.637 mL, 4.0 mmol) and TFA (0.5 mL) were added, and the reaction was warmed to 40 °C for 1 hour. After cooling the reaction was diluted with DCM (20 mL) and washed with aq. NaHCO3solution (25 mL). The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was triturated with MeOH, the solids were collected by filtration and dried under vacuum. The residue was dissolved in DMF (4 mL), then dicyanozinc (140 mg, 1.2 mmol) and Pd(PPh3)4(44.6 mg, 0.04 mmol) were added. The reaction was degassed then heated at 130 °C for 1 hour. After cooling the reaction was diluted with EtOAc (50 mL) and washed with brine (2 x 50 mL). The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 5-chloro-3-((5-cyanopyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile (135 mg, 54 %) as a beige solid. NMR Spectrum:1H NMR (500 MHz, DMSO, 27°C) 4.55 (2H, s), 7.51 (1H, s), 7.88 (1H, d), 9.21 (2H, s), 12.39 (1H, s). Mass Spectrum: m / z: ES+ [M+H]+ 312.

[2326] The compounds presented in Table C-T3 were synthesised in an analogous fashion to the example 162, except where specified.

[2327] Table C-T3

[2328] Example Structure Compound Name Method 4,5-dichloro-3-((5- 163 cyanopyrimidin-2-yl)methyl)- Cl _ lH-indole-7-carbonitrile

[2329] C!N

[2330] NMR^H NMR (500 MHz,

[2331] DMSO, 27°C) 4.70 (2H, s), 7.59 A i IllH(1H, s), 7.93 (lH, d), 9.20 (2H, N d), 12.43 (1H, s). LCMS: m / z:

[2332] ES+ [M+H]+ 328.

[2333] 5-chloro-3-((5-cyanopyrazin-2- 164 yl)methyl)-4-fluoro-lH-indole- F 7-carbonitrile

[2334] ciUvCNNMR^H NMR (500 MHz,

[2335] DMSO, 27°C) 4.48 (2H, s), 7.53 A (1H, s), 7.90 (1H, d), 8.81 (1H,

[2336] 1 TI1H

[2337] N d), 9.10 (1H, d), 12.45 (lH, s).

[2338] LCMS: m / z: ES+ [M+H]+ 312.

[2339]

[2340] 2-((5-chloro-7-cyano-4-fluoro- 165,N^\ lH-indol-3-yl)methyl)thiazole- 5-carbonitrile A Pd2dba3 / NMR:1H NMR (500 MHz, CDCl3, dppf (5 mol% 27°C) 4.53 (2H, s), 7.29 (1H, s), each) as IH

[2341] ill 7.51 (1H, d), 8.11 (1H, s), 8.91 catalyst N (1H, s). LCMS: m / z: ES- [M-H]- 315.

[2342] 5-chloro-3-((6-cyanopyridin-3- 166Nyl)methyl)-lH-indole-7- carbonitrile

[2343] A NMR:1H NMR (500 MHz,

[2344] KOH used as ^J^N DMSO, 27°C) 4.21 (2H, s), 7.52

[2345] base in 1 TH(1H, s), 7.71 (1H, d), 7.85 -7.98sti Nll step (2H, m), 8.01 (1H, d), 8.77 (1H,

[2346] s), 12.13 (1H, s). LCMS: m / z:

[2347] ES+ [M+H]+ 293.

[2348]

[2349] Example 167: 5-chloro-3-((5-ethvnylpyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile Step 1: 3-((5-((te / T-butyldimethylsilyl)ethvnyl)pyrimidin-2-yl)methyl)-5-chloro-4-fluoro-lH-indole-7-

[2350]

[2351] carbonitrile

[2352]

[2353] CuI (39.1 mg, 0.21 mmol) and Pd(PPh3)2Cl2(57.6 mg, 0.08 mmol) were added to TEA (0.172 mL, 1.23 mmol), tert-butyl(ethynyl)dimethylsilane (173 mg, 1.23 mmol) and 3-((5-bromopyrimidin-2-yl)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile (150 mg, 0.41 mmol) in THF (4 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 3-((5-((te / T-butyldimethylsilyl)ethynyl)pyrimidin-2-yl)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile (170 mg, 97 %) as a grey solid. NMR Spectrum:1H NMR (400 MHz, DMSO, 23°C) 6 0.19 (6H, s), 0.97 (9H, s), 4.47 (2H, s), 7.60 (1H, ddd), 7.89 (1H, d), 8.83 (2H, s), 12.37 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 425.

[2354] Step 2: 5-chloro-3-((5-ethvnylpyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile, Example 167

[2355]

[2356] Tetraethylammonium fluoride dihydrate (131 mg, 0.71 mmol) was added to 3-((5-((tert-butyldimethylsilyl)ethynyl)pyrimidin-2-yl)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile (150 mg, 0.35 mmol) in THF (4 mL) in the dark. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-((5-ethynylpyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile (34.9 mg, 32 %) as a pale yellow solid. NMR Spectrum:1H NMR (400 MHz, DMSO, 23°C) δ 4.47 (2H, s), 4.65 (1H, s), 7.49 (1H, d), 7.89 (1H, d), 8.85 (2H, s), 12.37 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 311.

[2357] Example 168: 5-chloro-3-((5-cvclopropylpyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile

[2358]

[2359] l,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (26.7 mg, 0.04 mmol) was added to 3-((5-bromopyrimidin-2-yl)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile (150 mg, 0.41 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (83 mg, 0.49 mmol) and Cs2CO3(267 mg, 0.82 mmol) in 1,4-dioxane (4.0 mL) / water (0.8 mL). The resulting mixture was stirred at 90 °C for 3 days. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (petroleum ether: EtOAc = 1: 3), to afford 5-chloro-3-((5-cyclopropylpyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile (16.9 mg, 13 %) as a pale yellow solid. NMR Spectrum:1H NMR (500 MHz, DMSO, 26°C) δ 0.75–0.84 (2H, m), 0.99 (2H, dt), 1.89 (1H, td), 4.38 (2H, s), 7.43 (1H, d), 7.87 (1H, d), 8.46 (2H, s), 12.31 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 327.

[2360] Example 169: 3-(3-amino-4-chlorobenzyl)-5-chloro-1H-indole-7-carbonitrile

[2361] Cl

[2362]

[2363] 5-Chloro-lH-indole-7-carbonitrile (106 mg, 0.6 mmol) was reacted with 4-chloro-3-nitrobenzaldehyde (167 mg, 0.9 mmol) according to the general indole alkylation-reduction conditions CB. The crude residue was dissolved in AcOH (5 mL), then zinc (168 mg, 3.0 mmol) was added, and the reaction was stirred at room temperature for a further 2 hours. The reaction was filtered through celite and the solids were washed with DCM (50 mL). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using IM NH3 / MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 3-(3-amino-4-chlorobenzyl)-5-chloro-1H-indole-7-carbonitrile (98 mg, 52 %} as a beige solid. NMR Spectrum: NMR (500 MHz, DMSO, 27°C) 3.92 (2H, s), 5.21 (2H, s), 6.48 (1H, dd), 6.64 (1H, d), 7.07 (1H, d), 7.39 (1H, s), 7.69 (1H, d), 7.79 (1H, d), 12.02 (1H, s). Mass Spectrum: m / z: ES+ [M+H]+ 316.

[2364] Example 170: 5-chloro-3-(4-chloro-2-hvdroxybenzyl)-lH-indole-7-carbonitrile

[2365] Cl

[2366]

[2367] 5-Chloro-lH-indole-7-carbonitrile (106 mg, 0.6 mmol) was reacted with 4-chloro-2-methoxybenzaldehyde (154 mg, 0.9 mmol) according to the general indole alkylation-reduction conditions CA. The crude residue was dissolved in DCM (5 mL) and cooled in an ice-bath. IN BBr3solution (0.9 mL, 0.9 mmol) was added, and the reaction was allowed to warm to room temperature over 2 hours. The reaction was diluted with DCM (20 mL) and quenched by addition of NaHCO3solution (25 mL). The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-(4-chloro-2-hydroxybenzyl)-lH-indole-7-carbonitrile (39.8 mg, 21 %) as a beige solid. NMR Spectrum:1H NMR (500 MHz, CDCl3, 27°C) 4.02 (2H, s), 5.16 (1H, s), 6.83 (1H, d), 6.87 (1H, dd), 7.04 (1H, d), 7.11 - 7.14 (1H, m), 7.47 (1H, d), 7.72 – 7.77 (1H, m), 8.65 (1H, s). Mass Spectrum: m / z: ES- [M-H]- 315.

[2368] Example 171: 5-chloro-3-(4-cvano-2-hvdroxybenzyl)-lH-indole-7-carbonitrile

[2369]

[2370] 5-Chloro-lH-indole-7-carbonitrile (124 mg, 0.7 mmol) was reacted with 4-formyl-3-methoxybenzonitrile (169 mg, 1.05 mmol) according to the general indole alkylation-reduction conditions CA. The solid was dissolved in DCM (4 mL) then IN BBr3solution (1.4 mL, 1.4 mmol) was added and the reaction was stirred at room temperature for 4 hours. The reaction was diluted with DCM (10 mL) and carefully quenched by addition of NaHCO3solution (10 mL). The layers were separated and the aqueous was extracted with DCM (10 mL). The combined organics were washed with brine (20 mL), then dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-(4-cyano-2-hydroxybenzyl)-lH-indole-7-carbonitrile (25.4 mg, 12 %} as a colourless solid. NMR Spectrum:JH NMR (500 MHz, DMSO, 27°C) 4.03 (2H, s), 7.12 (1H, d), 7.15 (1H, dd), 7.23 (1H, d), 7.38 (1H, s), 7.68 (1H, d), 7.94 (1H, d), 10.42 (1H, s), 12.02 (1H, s). Mass Spectrum: m / z: ES-[M-H]- 306.

[2371] Example 172: 6-((7-ethvnyl-5-methoxy-lH-indol-3-yl)methyl)nicotinonitrile

[2372] Step 1: rac- 6-((7-((te / T-butyldimethylsilyl)ethvnyl)-5-methoxy-lH-indol-3-yl)(hvdroxy)methyl) nicotinonitrile

[2373]

[2374] Synthesised according to the general indole alkylation conditions A detailed above, with K2CO3used as base to afford 6-((7-((tert-butyldimethylsilyl)ethynyl)-5-methoxy-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile as a yellow solid. NMR Spectrum:1H NMR (300 MHz, DMSO) δ 0.22 (6H, s), 0.99 (9H, s), 3.72 (3H, s), 6.00 (1H, d), 6.11 (1H, d), 6.80 (1H, d), 7.13 (1H, d), 7.19 (1H, d), 7.89 (1H, d), 8.31 (1H, dd), 8.91 (1H, dd), 10.75 (1H, s). Mass Spectrum: m / z (ES-), [M-H]- = 416.

[2375] Step 2: 6-((7-((te / T-butyldimethylsilyl)ethvnyl)-5-methoxy-lH-indol-3-yl)methyl)nicotinonitrile

[2376]

[2377] Synthesised according to the general reduction conditions A detailed above to afford 6-((7-((tert-butyldimethylsilyl)ethynyl)-5-methoxy-lH-indol-3-yl)methyl)nicotinonitrile as a beige solid. NMR Spectrum:1H NMR (300 MHz, DMSO, 24°C) δ 0.23 (6H, s), 0.89 (9H, td), 3.71 (3H, d), 4.27 (2H, s), 6.81(1H, d), 7.20 (1H, s), 7.28 (1H, d), 7.45 (1H, d), 8.17 (1H, dd), 8.91-8.98 (1H, m), 10.74 (1H, s). Mass m / z (ES+), [M+H]+ = 402.

[2378] Step 3: 6-((7-ethvnyl-5-methoxy-lH-indol-3-yl)methyl)nicotinonitrile (ex 172)

[2379] — O

[2380]

[2381] Et3N.3HF (1.20 g, 7.47 mmol) was added to 6-((7-((tert-butyldimethylsilyl)ethynyl)-5-methoxy-lH- indol-3-yl)methyl)nicotinonitrile (100 mg, 0.25 mmol) in THF (20 mL) at 25°C under nitrogen. The mixture was stirred at 60 °C for 4 days. The reaction mixture was poured into saturated NaHCO3(50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative TLC (petroleum ether: EtOAc = 2: 1) to afford the impure product which was purified further by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 6-((7-ethynyl-5-methoxy-lH- indol-3-yl)methyl)nicotinonitrile (11 mg, 15 %) as a pale yellow solid. NMR Spectrum:1H NMR (400 MHz, DMSO, 26°C) 83.73 (3H, s), 4.26 (2H, s), 4.45 (1H, s), 6.86 (1H, d), 7.08 (1H, d), 7.22 (1H, d), 7.46 (1H, dd), 8.17 (1H, dd), 8.94 (1H, dd), 11.02 (1H, d). Mass Spectrum: m / z (ES+), [M+H]+ = 288.

[2382] Example 173: 6-((5-chloro-7-ethvnyl-4-fluoro-lH-inclol-3-yl)methyl)nicoti nonitrile

[2383] Step 1: rac-6-((7-((te / T-butyldimethylsilyl)ethvnyl)-5-chloro-4-fluoro-lH-indol-3-yl)(hvdroxy)methyl)

[2384]

[2385] nicotinonitrile

[2386]

[2387] Synthesised according to the general indole alkylation conditions A detailed above to afford rac-6- ((7-((tert-butyldimethylsilyl)ethynyl)-5-chloro-4-fluoro-lH-indol-3-yl)(hydroxy)methyl) nicotinonitrile as a colourless solid. Mass Spectrum: m / z ( ES-), [M-H]- = 438.00.

[2388] imethylsi i-5-chloro-4-fluoro-lH-indol-3-yl)methyl)nicotinonitrile

[2389]

[2390] TBSSynthesised according to the general reduction conditions A detailed above to afford 6-((7-((tert-butyldimethylsilyl)ethynyl)-5-chloro-4-fluoro-lH-indol-3-yl)methyl)nicotinonitrile as a colourless solid. Mass Spectrum: m / z (ES+), [M+H]+ = 424.00.

[2391] Step 3: 6-((5-chloro-7-ethvnyl-4-fluoro-lH-indol-3-yl)methyl)nicotinonitrile, Example 173

[2392]

[2393] Tetramethylammonium fluoride (65.9 mg, 0.71 mmol) was added to 6-((7-((tert-butyldimethylsilyl)ethynyl)-5-chloro-4-fluoro-lH-indol-3-yl)methyl)nicotinonitrile (100 mg, 0.24 mmol) in THF (3 mL) at 25°C under nitrogen. The resulting mixture was stirred at 40 °C for 1 hour. The reaction mixture was diluted with saturated NaHCO3solution (50 mL) and extracted with DCM (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 6-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methyl)nicotinonitrile (6 mg, 8 %) as a colourless solid. NMR Spectrum:1H NMR (400 MHz, DMSO) δ4.37 (2H, s), 4.59 (1H, s), 7.34-7.38 (3H, m), 8.18 (1H, dd), 8.92 (1H, dd), 11.74 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 310.

[2394] Example 174: 5-chloro-3-(4-chlorobenzyl)-lH-indazole-7-carbonitrile

[2395] Step 1: 5-chloro-3-iodo-l-(tetrahvdro-2H-pyran-2-yl)-lH-indazole-7-carbonitrile

[2396]

[2397] PTSA hydrate (45.4 mg, 0.26 mmol) was added to 3,4-dihydro-2H-pyran (443 mg, 5.27 mmol) and 5-chloro-3-iodo-lH-indazole-7-carbonitrile (400 mg, 1.32 mmol) in THF (8 mL) under nitrogen. The resulting mixture was stirred at 80 °C overnight. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (0.1% formic acid). Pure fractions were evaporated to dryness to afford 5-chloro-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-7-carbonitrile (490 mg, 96 %) as a yellow solid. NMR Spectrum:1H NMR (300 MHz, DMSO, 22°C) δ 1.58 (2H, d), 1.63-1.81 (1H, m), 1.98-2.15 (2H, m), 2.23-2.4 (1H, m), 3.6-3.76 (1H, m), 3.89 (1H, d), 6.02 (1H, dd), 7.94 (1H, d), 8.28 (1H, d). Step 2: 5-chloro-3-(4-chlorobenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carbonitrile

[2398]

[2399] l,l'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (42.1 mg, 0.05 mmol) was added to potassium carbonate (214 mg, 1.55 mmol), 5-chloro-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-7-carbonitrile (200 mg, 0.52 mmol) and 2-(4-chlorobenzyl)-4, 4,5,5-tetramethyl-l,3,2-dioxaborolane (261 mg, 1.03 mmol) in 1,4-dioxane (4.0 mL) and water (1.0 mL). The resulting mixture was stirred at 80 °C overnight. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (3 x 10 mL), then the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (0.1% formic acid). Pure fractions were evaporated to dryness to afford 5-chloro-3-(4-chlorobenzyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-7-carbonitrile (80 mg, 40 %) as a yellow solid. NMR Spectrum: NMR (300 MHz, DMSO, 23°C) 8 1.56 (2H, s), 2.07 (2H, t), 2.36 (1H, t), 2.84 (1H, s), 3.75 (1H, t), 3.89 (1H, d), 4.32 (2H, s), 5.94-6.03 (1H, m), 7.32 -7.36 (4H, m), 8.13 (1H, d), 8.28 (1H, d). Mass Spectrum: m / z (ES+), [M+H]+ = 386.

[2400] Step 3: 5-chloro-3-(4-chlorobenzyl)-lH-indazole-7-carbonitrile, Example 174

[2401] Cl

[2402]

[2403] 5-Chloro-3-(4-chlorobenzyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-7-carbonitrile (70 mg, 0.18 mmol) was stirred in TFA (1.0 mL) and DCM (2.0 mL) at room temperature for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 5-chloro-3-(4-chlorobenzyl)-lH-indazole-7-carbonitrile (20 mg, 37 %) as a colourless solid. NMR Spectrum: NMR (300 MHz, DMSO) 84.33 (2H, s), 7.32 - 7.39 (4H, m), 8.05 (1H, d), 8.24 (1H, d), 14.03 (1H, s). Mass Spectrum: m / z (ES+), [M+H]+ = 302.

[2404] Example 175: 6-((5,7-dichloro-lH-indazol-3-yl)methyl)nicotinonitrile

[2405]

[2406] To a cooled solution of 6-methylnicotinonitrile (142 mg, 1.2 mmol) and methyl 3,5-dichloro-2-fluorobenzoate (401 mg, 1.80 mmol) in THF (3.3 mL) at 5 °C was added LiHMDS solution (IM in THF, 2.4 mL, 2.40 mmol). The reaction was stirred for 15 min then allowed to warm to room temperature for 2 hours. The reaction was quenched by addition of NH4CI solution (20 mL) and extracted with EtOAc (20 mL). The organic phase was dried over Na2SO4, filtered and evaporated. The residue was triturated with MeOH (10 mL) and the solids were collected by filtration and dried to afford (Z)-6-(2-(3,5-dichloro-2-fluorophenyl)-2-hydroxyvinyl)nicotinonitrile (235 mg) as a pale yellow solid. The residue was suspended in 1,4-dioxane (5.0 mL), then hydrazine hydrate (0.291 mL, 6.0 mmol) was added, and the reaction was heated at reflux for 3 hours. After cooling, the reaction was diluted with EtOAc (20 mL) and washed with NH4CI solution (20 mL). The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 80% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 6-((5,7-dichloro-lH-indazol-3-yl)methyl)nicotinonitrile (131 mg, 36 %) as a colourless solid. NMR Spectrum: NMR (500 MHz, DMSO, 27°C) 4.57 (2H, s), 7.54 - 7.6 (2H, m), 7.83 (1H, d), 8.23 (1H, dd), 8.93 (1H, dd), 13.62 (1H, s). Mass Spectrum: m / z: ES+ [M+H]+ 303.

[2407] Example 176: 6-((5-chloro-7-ethvnyl-lH-indazol-3-yl)methyl)nicotinonitrile

[2408] Step 1: 6-(2-(3-bromo-5-chloro-2-fluoro-phenyl)-2-oxo-ethyl]pyridine-3-carbonitrile

[2409]

[2410] LiHMDS solution (IM in THF, 4.98 mL, 4.98 mmol) was added to a cooled solution of 6-methylnicotinonitrile (0.294g, 2.49 mmol) and methyl 3-bromo-5-chloro-2-fluorobenzoate (1.0 g, 3.74 mmol) in THF (10 mL) cooled to 5°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4CI (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 6-[2-(3-bromo-5-chloro-2-fluoro-phenyl)-2-oxo-ethyl]pyridine-3-carbonitrile (0.577 g, 66 %) as a yellow solid, which appeared to bepredominantly in the enol form. NMR Spectrum:1H NMR (300 MHz, DMSO, 26°C) δ7.46 (2H, d), 7.76–7.83 (1H, m), 7.97–8.03 (1H, m), 8.14 (1H, dd), 8.84 (1H, s), 15.12 (1H, d). Mass Spectrum: m / z (ES+), [M+H]+ = 353.

[2411] Step 2: 6-((7-bromo-5-chloro-lH-indazol-3-yl)methyl)nicotinonitrile

[2412]

[2413] Hydrazine hydrate (397 mg, 7.78 mmol) was added to 6-[2-(3-bromo-5-chloro-2-fluoro-phenyl)-2-oxo- ethyl]pyridine-3-carbonitrile (550 mg, 1.56 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at reflux for 4 hours. The reaction mixture was diluted with saturated NH4CI (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 6-((7-bromo-5-chloro- lH-indazol-3-yl)methyl)nicotinonitrile (244 mg, 45 %) as a yellow solid. NMR Spectrum:1H NMR (300 MHz, DMSO, 26°C) δ4.56 (2H, d), 7.58 (1H, d), 7.68 (1H, d), 7.87 (1H, d), 8.24 (1H, dd), 8.93 (1H, d), 13.54 (1H, d). Mass Spectrum: m / z (ES+), [M+H]+ = 347.

[2414] Step 3: 6-((5-chloro-7-((trimethylsilyl)ethvnyl)-lH-indazol-3-yl)methyl)nicotinonitrile

[2415]

[2416] TMS

[2417] XPhos Pd G3 (24.35 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-l,l'-biphenyl ...

Claims

Claims1) A compound of Formula (I), or a pharmaceutically acceptable salt thereof,wherein:X is CH2, CHOH, CHNH2, S, SO, SO2, SO(=NH) or CHCH2OH;Y is CH or N;R4is H, F, Cl, OMe or CN;R5is F, Cl, Br, I, CN, CH2CN, CCH, Me, Et, CHCF2, CF3, Ci-C2-fluoroalkyl, OMe, OCHF2, OCClF2, OCF3or cyclopropyl;R6is H or F;R7is F, Cl, Br, I, Me, CN, CCH or CCMe;Ar is selected fromwherein * denotes the point of attachment to X;Z, where present, is independently selected from N and CH;J, where present, is selected from 0 and S;Rais selected from F, Br, Cl, I, CN, Me, CCH, CF3, CHF2, CH2F, CF2Cl, CFCl2, cyclopropyl, CH2OH, Ome, OCF3, OCHF2, OCF2Cl, NO2and NMe2;Rbis selected from H, F, Cl, CN, OH, and Me;Rcis selected from H, F, Cl, Br, I, CN, Me, CF3, CHF2and Ci fluoroalkyl; andRdis selected from H, Me, Ci-C3alkyl, CHF2, CF3, Ci-C3fluoroalkyl, cyclopropyl, NH2, NHMe and NMe2.2) A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the group Ar is selected from3) A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the group Y is CH.4) A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the group Y is N.5) A compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein the group X is selected from CH2 or CHOH.6) A compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein the group R4and / or the group R6is H.7) A compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein the group R7is selected from CN, CCH or CCMe.8) A compound, or a pharmaceutically acceptable salt thereof, according to claim 1 that is selected from:5-chloro-3-((5-chloropyridin-2-yl)thio)-lH-indole-7-carbonitrile;5-chloro-3-(pyridin-2-ylthio)-lH-indole-7-carbonitrile;3-((lH-l,2,4-triazol-3-yl)thio)-5-chloro-1H-indole-7-carbonitrile;5-chloro-3-((5-chloropyridin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile;5-chloro-3-((5-chloropyrazin-2-yl)thio)-lH-indole-7-carbonitrile;3-((5-chloropyridin-2-yl)thio)-5-methoxy-lH-indole-7-carbonitrile;3-((5-chloropyridin-2-yl)thio)-5-(difluoromethoxy)-lH-indole-7-carbonitrile;3-((5-chloropyridin-2-yl)thio)-7-fluoro-lH-indole-5-carbonitrile;5,7-dichloro-3-((5-chloropyridin-2-yl)thio)-lH-indole;5-chloro-3-((5-ch loropyrid in-2-yl)thio)-lH-indole;5-chloro-3-((5-chloropyridin-2-yl)thio)-7-fluoro-lH-indole;5-chloro-3-((5-cyanopyridin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile;4,5-dichloro-3-((5-cyanopyridin-2-yl)thio)-lH-indole-7-carbonitrile;5-bromo-3-( (5-ch loropyrid in-2-yl)thio)-lH-indole-7-carbon itrile;3-((5-chloropyridin-2-yl)th io)-5-(trifluoromethoxy)-l H-indole-7-carbonitrile;3-((5-bromopyrimidin-2-yl)thio)-5-chloro-1H-indole-7-carbonitrile;3-((5-cyanopyridin-2-yl)thio)-4-fluoro-5-methoxy-lH-indole-7-carbonitrile;4-chloro-3-((5-cyanopyridin-2-yl)thio)-5-methoxy-lH-indole-7-carbonitrile;3-((3-(aminomethyl)-4-chlorophenyl)thio)-5-chloro-1H-indole-7-carbonitrile;2-(3-((5-chloropyridin-2-yl)th io)-l H-indol-5-yl)aceton itrile;3-((2-amino-4-chlorophenyl)thio)-5-chloro-1H-indole-7-carbonitrile;6-((5-chloro-7-ethynyl-lH-indol-3-yl)thio)nicotinon itrile;5-chloro-3-((5-chloropyridin-2-yl)thio)-7-(prop-l-yn-l-yl)-lH-indole;5-chloro-3-((5-cyanopyrazin-2-yl)thio)-lH-indole-7-carbon itrile;5-chloro-3-((5-cyanopyrazin-2-yl)thio)-4-fluoro-lH-indole-7-carbonitrile;5-chloro-3-((4-chloro-2-(hyd ro xym ethyl) phenyl)thio)-lH-indole-7-carbon itrile;5-chloro-3-((5-cyanopyridin-2-yl)thio)-lH-indole-7-carbon itrile;5-chloro-3-((5-cyanopyrimidin-2-yl)thio)-4-fluoro-lH-indole-7-carbon itrile;3-((5-chloropyridin-2-yl)sulfonyl)-5-methoxy-lH-indole-7-carbon itrile;3-(5-chloropyridine-2-sulfonimidoyl)-5-methoxy-lH-indole-7-carbonitrile;5-chloro-3-((5-chloropyridin-2-yl)sulfinyl)-7-fluoro-lH-indole;5-bromo-3-((5-chloropyridin-2-yl)sulfonyl)-lH-indole-7-carbonitrile;5-bromo-3-(5-chloropyridine-2-sulfonimidoyl)-lH-indole-7-carbonitrile;(5-chloro-7-fluoro-lH-indol-3-yl)(4-chlorophenyl)(imino)-l6-sulfanone;5-chloro-3-((5-chloropyridin-2-yl)sulfonyl)-7-ethynyl-lH-indole;rac-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-lH-indole-7-carbon itrile;rac-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-4-fluoro-lH-indole-7-carbon itrile; rac-5-bromo-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile; rac-5-chloro-3-((4-chlorophenyl)(hydroxy)methyl)-lH-indole-7-carbonitrile;rac-3-((5-bromopyridin-2-yl)(hydroxy)methyl)-5-ch loro-1 H-indole-7-carbonitrile;rac-3-((5-bromopyrazin-2-yl)(hydroxy)methyl)-5-chloro-lH-indole-7-carbon itrile;rac-5-chloro-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;rac-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile; rac-5-chloro-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile; rac-5-bromo-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;rac-4,5-dichloro-3-((5-cyanopyridin-2-yl)(hyd roxy)methyl)-lH-indole-7-carbon itrile; rac-5-chloro-3-((4-cyanophenyl)(hydroxy)methyl)-lH-indole-7-carbonitrile;rac-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-4-fluoro-5-methoxy-lH-indole-7-carbonitrile;rac-4-chloro-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-5-methoxy-lH-indole-7-carbonitrile;rac-6-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile;rac-3-((5-bromothiazol-2-yl)(hydroxy)methyl)-5-chloro-1H-indole-7-carbonitrile;rac-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-1H-indole-7-carbonitrile;rac-(5-bromopyrazin-2-yl)(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methanol;rac-6-((5-chloro-7-ethynyl-4,6-difluoro-lH-indol-3-yl)(hydroxy)methyl)nicoti nonitrile;rac-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-lH-indole-7-carbonitrile; rac-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-5-(trifluoromethoxy)-lH-indole-7-carbonitrile; rac-6-((5,7-dichloro-4-fluoro-lH-indol-3-yl)(hydroxy)methyl) nicotinonitrile;rac-2-((7-ethynyl-4-fluoro-5-(trifluoromethyl)-lH-indol-3-yl)(hyd roxy)methyl)pyrimidine-5-carbonitrile;rac-5-bromo-4-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile; rac-2-((5-bromo-4-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile; rac-5-chloro-4-fluoro-3-(hydroxy(5-(trifluoromethyl) pyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile; rac-2-((7-ethynyl-4-fluoro-5-iodo-lH-indol-3-yl)(hyd ro xy) methyl) pyrim id ine-5-carbonitrile;rac-6-((7-bromo-5-chloro-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile;rac-6-((5-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)nicotinonitrile;rac-2-((5-chloro-7-cyano-lH-indol-3-yl)(hydroxy)methyl)thiazole-5-carbonitrile;rac-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;rac-2-((5-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;rac-2-((5-chloro-7-cyano-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)thiazole-5-carbonitrile;rac-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl) pyrim idine-5-carbonitrile; rac-5-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrazine-2-carbonitrile;rac-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)thiazole-5-carbonitrile;rac-2-((5,7-dichloro-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-5-methyl-lH-indole-7-carbonitrile;rac-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;(R)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;(S)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;(R)-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;(S)-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;(R)-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;(S)-5-chloro-3-((5-chloropyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;(R)-5-chloro-3-((5-cyanopyridin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;(S)-5-chloro-3-((5-cya nopyrid in-2-yl)( hydroxy)methyl)-4-fluoro-lH-indole-7-ca rbonitrile;(R)-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile;(S)-3-((5-bromopyrimidin-2-yl)(hydroxy)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile;(R)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-carbonitrile;(S)-5-chloro-3-((5-cyanopyrim id in-2-yl)(hydroxy)methyl)-lH-indole-7-ca rbonitrile;(R)-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyrimidin-2-yl)methanol;(S)-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyrimidin-2-yl)methanol;( / ?)-5-bromo-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;(S)-5-bromo-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4-fluoro-lH-indole-7-carbonitrile;( / ?)-4,5-dichloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-ca rbonitrile;(S)-4,5-dichloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-ca rbonitrile;(R)-2-((5-bromo-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;(S)-2-((5-bromo-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrim id ine-5-ca rbonitrile;(R)-5-bromo-4-chloro-3-((5-cyanopyrim id in-2-yl)(hydroxy)methyl)-lH-indole-7-ca rbonitrile;(S)-5-bromo-4-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-lH-indole-7-ca rbonitrile;(R)-2-((5-bromo-4-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-ca rbonitrile;(S)-2-((5-bromo-4-chloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;(R)-5-chloro-4-fluoro-3-(hydroxy(5-(trifluoromethyl) pyrimidin-2-yl)methyl)-lH-indole-7-ca rbonitrile; (S)-5-chloro-4-fluoro-3-(hydroxy(5-(trifluoromethyl) pyrimidin-2-yl)methyl)-lH-indole-7-ca rbonitrile; (R)-2-((5-chloro-4-fluoro-7-methyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;(S)-2-((5-chloro-4-fluoro-7-methyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-ca rbonitrile;(R)-2-((7-ethynyl-4-fluoro-5-iodo-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile, Isomer 1; (S)-2-((7-ethynyl-4-fluoro-5-iodo-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;( / ?)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-4,6-difluoro-lH-indole-7 -carbonitrile; (S)-5-chloro-3-((5-cyanopyrim id in-2-yl)(hydroxy)methyl)-4,6-difluoro-lH-indole-7-ca rbonitrile; ( / ?)-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;(S)-2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(hyd roxy)methyl)pyrimidine-5-carbonitrile; rac-5-chloro-3-(l-(4-chlorophenyl)-2-hydroxyethyl)-lH-indole-7-ca rbonitrile;rac-5-chloro-3-(l-(5-chloropyridin-2-yl)-l-hydroxyethyl)-lH-indole-7-carbonitrile;5-chloro-3-((5-chloropyridin-2-yl)methyl)-lH-indole-7-carbonitrile;5-chloro-3-((5-cyanopyridin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile;5-chloro-3-(4-chlorobenzyl)-lH-indole-7-ca rbonitrile;5-chloro-3-(pyridin-2-ylmethyl)-lH-indole-7-ca rbonitrile;3-((5-bromopyridin-2-yl)methyl)-5-chloro-lH-indole-7-ca rbonitrile;5-chloro-3-((5-cyanopyridin-2-yl)methyl)-l H-indole-7-carbonitrile;5-chloro-3-((5-chloropyrazin-2-yl)methyl)-lH-indole-7-carbonitrile;3-((5-bromothiazol-2-yl)methyl)-5-chloro-1H-indole-7-carbonitrile;5-chloro-3-((4,4-difluorocyclohexyl)methyl)-lH-indole-7-carbonitrile;3-((5-chloropyridin-2-yl)methyl)-7-fluoro-lH-indole-5-carbonitrile;4,5-dichloro-3-((5-cyanopyridin-2-yl)methyl)-lH-indole-7-carbonitrile;5-chloro-3-(4-cyano-2-fluorobenzyl)-lH-indole-7-carbonitrile;5-chloro-3-(4-cyanobenzyl)-lH-indole-7-carbonitrile;3-((5-chloropyridin-2-yl)methyl)-5-(difluoromethoxy)-lH-indole-7-carbonitrile;3-((5-chloropyridin-2-yl)methyl)-5-(trifluoromethoxy)-lH-indole-7-carbonitrile;6-((5-chloro-7-ethynyl-lH-indol-3-yl)methyl) nicotinonitrile;5-chloro-3-((5-cyanopyridin-2-yl)methyl)-4-methoxy-lH-indole-7-carbonitrile;6-((5,7-dichloro-4-fluoro-lH-indol-3-yl)methyl)nicotinonitrile;6-((5-bromo-4,7-difluoro-lH-indol-3-yl)methyl) nicotinonitrile;3-((5-bromopyridin-2-yl)methyl)-5-chloro-4-fluoro-lH-indole-7-carbonitrile;6-((5-chloro-4,7-difluoro-lH-indol-3-yl)methyl) nicotinonitrile;6-((7-bromo-5-chloro-4-fluoro-lH-indol-3-yl)methyl) nicotinonitrile;5-chloro-4-fluoro-3-((5-(trifluoromethyl)pyridin-2-yl)methyl)-lH-indole-7-carbonitrile; 5-bromo-3-((5-cyanopyridin-2-yl)methyl)-lH-indole-7-carbonitrile;3-((5-cyanopyridin-2-yl)methyl)-4-fluoro-5-methoxy-lH-indole-7-carbonitrile;4-chloro-3-((5-cyanopyridin-2-yl)methyl)-5-methoxy-lH-indole-7-carbonitrile;3-((5-bromopyrazin-2-yl)methyl)-5-chloro-1H-indole-7-carbonitrile;3-((5-bromopyrimidin-2-yl)methyl)-5-chloro-1H-indole-7-carbonitrile;2-(3-((5-chloropyridin-2-yl)methyl)-lH-indol-5-yl)acetonitrile;5-chloro-3-(4-cyano-3-fluorobenzyl)-lH-indole-7-carbonitrile;5-chloro-4-fluoro-3-((5-methoxypyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;3-((5-cyanopyrimidin-2-yl)methyl)-4-fluoro-5-(trifluoromethyl)-lH-indole-7-carbonitrile; 3-((5-cyanopyridin-2-yl)methyl)-5-methyl-lH-indole-7-carbonitrile;3-((5-cyanopyridin-2-yl)methyl)-5-(difluoromethyl)-lH-indole-7-carbonitrile;3-((5-cyanopyridin-2-yl)methyl)-5-ethynyl-lH-indole-7-carbonitrile;3-((5-cyanopyridin-2-yl)methyl)-5-cyclopropyl-lH-indole-7-carbonitrile;5-chloro-4-fluoro-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;5-chloro-3-((5-(difluoromethyl)pyridin-2-yl)methyl)-lH-indole-7-carbonitrile;5-chloro-4-fluoro-3-((5-methylpyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;5-chloro-3-(4-chloro-3-(hydroxymethyl)benzyl)-l H-indole-7-carbonitrile;5-chloro-3-((5-cyanopyrazin-2-yl)methyl)-lH-indole-7-carbonitrile;2-((5,7-dichloro-4-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;5-chloro-3-((5-cyanopyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;5-chloro-3-((5-cyano-3-methoxypyridin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile; 2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;2-((5,7-dichloro-4-fluoro-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;2-((5-chloro-4,7-difluoro-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;5-((5-chloro-7-cyano-lH-indol-3-yl)methyl)thiazole-2-carbonitrile;2-((5-chloro-7-ethynyl-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;2-((5-chloro-4,7-difluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;2-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;2-((5-chloro-7-cyano-lH-indol-3-yl)methyl)oxazole-5-carbonitrile;2-((5-chloro-7-cyano-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;5-chloro-3-((5-cyanopyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile;4,5-dichloro-3-((5-cyanopyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;5-chloro-3-((5-cyanopyrazin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile;2-((5-chloro-7-cyano-4-fluoro-lH-indol-3-yl)methyl)thiazole-5-carbonitrile;5-chloro-3-((6-cyanopyridin-3-yl)methyl)-lH-indole-7-carbonitrile;5-chloro-3-((5-ethynylpyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile;5-chloro-3-((5-cyclopropylpyrimidin-2-yl)methyl)-4-fluoro-lH-indole-7-carbonitrile; 3-(3-amino-4-chlorobenzyl)-5-chloro-1H-indole-7-carbonitrile;5-chloro-3-(4-chloro-2-hydroxybenzyl)-lH-indole-7-carbonitrile;5-chloro-3-(4-cyano-2-hydroxybenzyl)-lH-indole-7-carbonitrile;6-((7-ethynyl-5-methoxy-lH-indol-3-yl)methyl)nicotinonitrile;6-((5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)methyl)nicotinonitrile;5-chloro-3-(4-chlorobenzyl)-lH-indazole-7-carbonitrile;6-((5,7-dichloro-lH-indazol-3-yl)methyl)nicotinonitrile;6-((5-chloro-7-ethynyl-lH-indazol-3-yl)methyl)nicotinonitrile;5-chloro-3-((5-cyanopyridin-2-yl)thio)-lH-indazole-7-carbonitrile;5-chloro-3-((4-cyanophenyl)thio)-lH-indazole-7-carbonitrile;4-((5-chloro-7-fluoro-lH-indazol-3-yl)thio)benzonitrile;6-((5-chloro-7-fluoro-lH-indazol-3-yl)thio)nicotinonitrile;3-((5-bromopyridin-2-yl)thio)-5-chloro-7-fluoro-lH-indazole;2-((5-bromo-4,7-difluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;2-((5-bromo-4-chloro-7-ethynyl-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;5-bromo-4-chloro-3-((5-cyanopyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;2-((4,5-dichloro-7-ethynyl-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;( / ?)-2-((4,5-dichloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;(S)-2-((4,5-dichloro-7-ethynyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile;5-bromo-4-fluoro-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;4.5-dichloro-7-ethynyl-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole;5-chloro-7-ethynyl-4-fluoro-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole;4.5-dichloro-3-((5-fluoropyrimidin-2-yl)methyl)-lH-indole-7-carbonitrile;2-((4,5-dichloro-7-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;2-((5-bromo-4-chloro-7-fluoro-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;2-((4,7-difluoro-5-iodo-lH-indol-3-yl)methyl)pyrimidine-5-carbonitrile;3-((5-cyanopyrimidin-2-yl)methyl)-5-(difluoromethyl)-4-fluoro-lH-indole-7-carbonitrile;rac-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-5-(difluoromethyl)-4-fluoro-lH-indole-7-carbonitrile; 5-chloro-4-fluoro-3-((5-nitropyridin-2-yl)methyl)-lH-indole-7-carbonitrile;rac-2-((5-chloro-7-ethynyl-4-methyl-lH-indol-3-yl)(hydroxy)methyl)pyrimidine-5-carbonitrile (R)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-7-ethynyl-lH-indole-4-carbonitrile;(S)-5-chloro-3-((5-cyanopyrimidin-2-yl)(hydroxy)methyl)-7-ethynyl-lH-indole-4-carbonitrile;(R)-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone; and (S)-(5-chloro-7-ethynyl-4-fluoro-lH-indol-3-yl)(5-chloropyridin-2-yl)(imino)-l6-sulfanone,.9) A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any preceding claim, and at least one pharmaceutically acceptable excipient.10) A compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 8, for use as a medicine.11) A compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 8, for use as in the treatment of cancer, for example a cancer that expresses Ras G13D mutant protein. 12) A method of treatment comprising administering an effective amount of a compound according to any of claims 1 to 8, or a pharmaceutically acceptable salt thereof, to a patient, wherein the patient has been identified as having a cancer that expresses Ras G13D mutant protein.13) A compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 8, for use in the manufacture of a medicament, optionally wherein the medicament is for use in the treatment of a cancer that expresses Ras G13D mutant protein.14) A kit comprising a pharmaceutical composition according to claim 9 and instructions for its use in the treatment of a cancer, wherein the cancer expresses Ras G13D mutant protein.

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