WO2018178938A1 - Cgrp receptor antagonists - Google Patents

Abstract

The disclosures herein relate to novel compounds of formula (IA) wherein R¹, R², R³ and R⁴ are as defined herein, and their use in treating, preventing, ameliorating, controlling or reducing cerebrovascular or vascular disorders associated with CGRP receptor function. The disclosures herein also relates to novel compounds of formula(IB) wherein R¹, R² and R³ are as defined herein, and their use in treating, preventing, ameliorating, controlling or reducing cerebrovascular or vascular disorders associated with CGRP receptor function. The disclosures herein also relate to novel compounds of formula (IC) wherein Ar¹ and R1 are as defined herein, and their use in treating, preventing, ameliorating, controlling or reducing cerebrovascular or vascular disorders associated with CGRP receptor function.

Description

CGRP RECEPTOR ANTAGONISTS CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No.62/479,668, filed March 31, 2017, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] This application relates to novel compounds and their use as CGRP receptor antagonists. Compounds described herein may be useful in the treatment or prevention of cerebrovascular or vascular disorders such as migraine. The application is also directed to pharmaceutical compositions comprising these compounds and the manufacture and use of these compounds and compositions in the prevention or treatment of such cerebrovascular or vascular disorders. BACKGROUND OF THE INVENTION

[0003] Migraine is a highly disabling neurovascular disorder characterized by attacks of moderate to severe headache that are often associated with nausea, vomiting, photophobia, and phonophobia. The attacks can last from 4 to 72 h, and the average attack frequency is 1 or 2 per month. About 20−30% of migraine patients experience transient focal neurologic symptoms known as aura, which are usually visual and can precede or accompany the headache. Migraine afflicts about 11% of adults worldwide and results in a significant socioeconomic burden, in terms of both quality of life and lost productivity.

[0004] Whilst the pathomechanism of migraine is still unclear, one of the leading hypotheses is based on activation of the trigeminovascular system (TS). Several neuropeptides participate in this activation, calcitonin gene-related peptide (CGRP) playing a crucial role among them. CGRP exerts various biological effects through the peripheral and central nervous system (CNS). The functional CGRP-receptor (CGRP-R) complex has been well characterized, and novel therapeutic approaches target CGRP itself and its receptors. This invention relates to the development of CGRP receptor antagonists (CGRP-RA). [0005] CGRP, a 37-amino acid neuropeptide derived from the gene encoding calcitonin, is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11. In humans, CGRP has two isoforms: α- and β-CGRP. The β-isoform differs from the α-isoform in the amino acids located at positions 3, 22 and 25. The chemical structure of CGRP involves a disulphide bridge between residues 2 and 7 and an amidated C-terminus. The cyclic cysteine2-cysteine7 motif has a basic role in receptor activation. In the human trigeminal ganglia (TRIG), CGRP-immunoreactive neurons account for up to 50% of all neurons. It has been demonstrated through an in situ hybridization technique that 40% of all nerve cell bodies contain CGRP mRNA and CGRP. Double immunostaining has shown that in the human TRIG CGRP is co-localized with nitric oxide synthase, substance P (SP), pituitary adenylate cyclase activating peptide (PACAP) and nociceptin, which may play a role in the pathomechanism of migraine.

[0006] The functional CGRP-R consists of three proteins: i) Calcitonin Receptor Like Receptor (known as CRLR, CALCRL or CLR) is a seven-transmembrane spanning protein, which forms the ligand binding site with; ii) RAMP1, determining the specificity of the receptor; and iii) the CGRP-R component protein (RCP) couples the receptor to intracellular signal transduction pathways and to adenylyl cyclase.

[0007] It is thought that the C-terminal region of CGRP initially binds to the large N- terminal extracellular domain (ECD) of the receptor, likely making interactions with both CLR and RAMP1. This initial binding event greatly increases the local concentration of the N- terminal region of CGRP in the vicinity of the juxtamembrane portion of CLR, allowing their relatively weak interaction to occur and resulting in receptor activation. Since mutagenesis experiments indicated that most small molecule antagonists interacted with the ECD of

CLR/RAMP1, it was hypothesized that they bind to this region of the receptor and prevent the initial binding of CGRP to the receptor. A notable exception to this model of peptide binding and small molecule receptor antagonism is the hydroxypyridine class of antagonists, which apparently interact with transmembrane domain 7 (TM7) in CLR and not with the extracellular domain (Bell IM, J. Med. Chem., 2014, 57(19), 7838-58).

[0008] The first clinically tested CGRP-RA, olcegepant, was based on a dipeptide backbone, had high molecular weight, and was not orally bioavailable. Nonetheless, when dosed intravenously, olcegepant proved to be an effective antimigraine agent, and this proof-of-concept study greatly increased interest in the field. Following the success of olcegepant, a number of orally acting CGRP-RAs were advanced to clinical trials. Telcagepant and compounds BI 44370, MK-3207, and BMS-927711 have all been used for acute treatment of migraine as oral agents. Taken together, the results from these clinical studies demonstrate that CGRP-RAs can exhibit similar antimigraine efficacy to the gold standard triptan drugs but with a significantly lower incidence of adverse events than is typically observed with a triptan. It is worth noting that the available data indicate that these CGRP blockers do not cause vasoconstriction and suggest that they may have a superior cardiovascular safety profile to the triptans. One potential concern that has been reported with some CGRP-RAs is the observation of elevated levels of liver transaminases in some patients, and this reportedly led to the discontinuation of MK-3207.

Although elevated liver enzymes were also found in a small number of subjects after dosing with telcagepant for an extended period, it is not clear if these findings are in some way mechanism- based or specific to these two compounds. In clinical trials for acute migraine therapy, the CGRP-RAs displayed favorable effects, but their frequent administration was associated with liver toxicity (the elevation of liver transaminases), which limited their clinical use. Hence, there is a need to develop new CGRP-RAs which do not induce liver injury. SUMMARY OF THE INVENTION

[0009] One possibility to address the risk of liver injury is to target a non-oral route of delivery for a small molecule which will place a lower burden on the liver through first-pass exposure. The compounds of the invention can be used for sub-cutaneous, intravenous and/or intranasal routes of administration. The molecular profile for a CGRP-RA intended for such routes of administration differs from the profile required for an oral molecule: extremely high affinity and functional potency, coupled with extremely high solubility is required. Disclosed herein are novel compounds, and the first medical use of said compounds as CGRP receptor antagonists.

[0010] Compounds of the invention include a compound of formula IA-1, IA-2, IA-3, or IA-4, as well as mixtures thereof

or a salt thereof, wherein R¹ is selected from H or Q-(C₁-C₆)alkyl; where Q is a bond, C(O) or C(O)O and where the (C₁-C₆)alkyl can be optionally substituted by N(C₁-C₃alkyl)₂ or CO₂H; R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H; and

R⁴ is an optionally substituted aryl group which may be monocyclic or fused to a further ring.

[0011] Compounds of the invention also include a compound of formula IB-1 or IB-2, or mixtures thereof

thereof, wherein R¹ is selected from

R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H.

[0012] Compounds of the invention also include a compound of formula IC-1 or IC-2, or mixtures thereof

a salt thereof, wherein R¹ is H or F and Ar¹ is an optionally substituted 5 membered heterocyclic ring containing at least two nitrogen atoms. DETAILED DESCRIPTION OF THE INVENTION

[0013] The invention relates to novel compounds. The invention also relates to the use of novel compounds as CGRP receptor antagonists. The invention further relates to the use of compounds in the manufacture of medicaments for use as CGRP receptor antagonists. The invention further relates to compounds, compositions and medicaments for the treatment of cerebrovascular or vascular disorders such as migraine (including subtypes such as: migraine without aura, chronic migraine, pure menstrual migraine, menstrually-related migraine, migraine with aura, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine), status migrainosus, cluster headache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, hemicrania continua, cyclic vomiting syndrome, allergic rhinitis, or rosacea. The invention further relates to compounds, compositions and medicaments for the treatment of broader pain states and diseases involving neurogenic inflammation including dental pain, earache, middle ear inflammation, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, pain associated with inflammatory bowel disease– Crohn’s disease, gout, complex regional pain syndrome, Behçet's disease, endometriosis pain, back pain or cough.

[0014] The disclosure is directed to compounds of formula IA, IB, and IC,

stereoisomers thereof, salts thereof, mixtures of stereoisomers thereof, and mixtures of salts of stereoisomers thereof. Thus, the disclosure is directed to compounds of formula IA,

, wherein R¹ is selected from H or Q-(C1-C6)alkyl; where Q is a bond, C(O) or C(O)O and where the (C₁-C₆)alkyl can be optionally substituted by N(C₁-C₃alkyl)₂ or CO₂H;

R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H; and

R⁴ is an optionally substituted aryl group which may be monocyclic or fused to a further ring. The disclosure is also directed to stereoisomers of compounds of formula IA, mixtures of stereoisomers of compounds of formula IA, salts of compounds of formula IA, and mixtures of salts of stereoisomers of compounds of formula IA.

[0015] The disclosure is also directed to compounds of formula IB,

wherein R¹ is selected from

;

R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H. The disclosure is also directed to stereoisomers of compounds of formula IB, mixtures of stereoisomers of compounds of formula IB, salts of compounds of formula IB, and mixtures of salts of stereoisomers of compounds of formula IB.

[0016] The disclosure is also directed to compounds of formula IC,

, wherein R¹ is H or F and Ar¹ is an optionally substituted 5 membered heterocyclic ring containing at least two nitrogen atoms. The disclosure is also directed to stereoisomers of compounds of formula IC, mixtures of stereoisomers of compounds of formula IC, salts of compounds of formula IC, and mixtures of salts of stereoisomers of compounds of formula IC.

[0017] The compounds of the invention described herein have chiral centers. The absolute configuration of each chiral center can be identified in structural drawings or in chemical names using the Cahn-Ingold-Prelog nomenclature whereby each chiral center is designated as either (R) or (S) according to the Cahn-Ingold-Prelog priority rules that will be understood by a person of ordinary skill in the art. In cases in which the chiral center derives from an amino acid moiety, the absolute configuration of the chiral center also can be described using the D- or L- nomenclature for amino acids that will be understood by a person of ordinary skill in the art. Where a compound of the invention has a single chiral center, the compound may exist as resolved individual enantiomers, or as mixtures of enantiomers in any ratio, including 1:1 mixtures of enantiomers (i.e., racemates). Compounds of the invention having more than one chiral center may exist in up to 2ⁿ different stereoisomers, where n is the number of chiral centers in the compound. Such compounds may exist as resolved individual stereoisomers, or as mixtures of stereoisomers of any stereoisomeric composition, including for example as mixtures of enantiomers, or as mixtures of diastereomers. [0018] Some of the compounds exemplified herein are based around the structures of formula IA-1, IA-2, IA-3, and IA-4:

wherein R¹ is selected from H or Q-(C1-C6)alkyl; where Q is a bond, C(O) or C(O)O and where the (C1-C6)alkyl can be optionally substituted by N(C1-C3alkyl)2 or CO2H;

R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H; and

R⁴ is an optionally substituted aryl group which may be monocyclic or fused to a further ring.

[0019] The optional substituents for R⁴ in compounds of Formula IA-1, IA-2, IA-3, and IA-4 may be selected from halo, hydroxyl or methyl. More particularly, the substituent for R⁴ is a substituted phenyl group wherein the substituents are selected from halo or hydroxyl. In a particular embodiment, R⁴ is a moiety according to formula II

wherein X is halo.

[0020] In a more particular embodiment, X is Br.

[0021] In a particular embodiment, the substituent for R⁴ is

[0022] In a particular embodiment, the substituent for R² is H and R³ is selected from:

[0023] In a particular embodiment, R² forms a spirocyclic heterocyclic ring with R³ to form:

[0024] In a particular embodiment, the substituent for R¹ is H, CO ^t

2Bu, CH2CH3, CH₂CH₂CH₃, COCH₂CH₂CH₂CH₃, CH₂CH₂N(CH₃)₂ or COCH₂CO₂H. In a more particular embodiment, the substituent for R¹ is H.

[0025] Compounds of the invention also include those of formulae IA-1, IA-2, IA-3, and IA-4:

wherein R¹ is selected from H or Q-(C₁-C₆)alkyl; where Q is a bond, C(O) or C(O)O and where the (C₁-C₆)alkyl can be optionally substituted by N(C₁-C₃alkyl)₂ or CO₂H;

R² is H or forms a spirocyclic heterocyclic ring with R³ to form:

and wherein when R² is H, R³ is selected from:

R⁴ is selected from

[0026] In a more particular embodiment, the substituent for R¹ is H.

[0027] Further embodiments of the invention include methods of treatment comprising administering a compound of formula IA, IA-1, IA-2, IA-3, or IA-4 as a CGRP receptor antagonist. The treatment using a compound of formula IA, IA-1, IA-2, IA-3, or IA-4 may be in the treatment of cerebrovascular or vascular disorders such as migraine (including subtypes such as: migraine without aura, chronic migraine, pure menstrual migraine, menstrually-related migraine, migraine with aura, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine), status migrainosus, cluster headache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, hemicrania continua, cyclic vomiting syndrome, allergic rhinitis, or rosacea. The invention further relates to compounds, compositions and medicaments for the treatment of broader pain states and diseases involving neurogenic inflammation including dental pain, earache, middle ear inflammation, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, pain associated with inflammatory bowel disease– Crohn’s disease, gout, complex regional pain syndrome, Behçet's disease, endometriosis pain, back pain or cough.

[0028] Certain novel compounds of formula IA, IA-1, IA-2, IA-3, and IA-4 show particularly high activities as CGRP receptor antagonists.

[0029] Exemplary compounds of formula IA, IA-1, IA-2, IA-3, and IA-4 include:

[0030] The NMR and LCMS properties, as well as the biological activities of exemplary compounds are set out in Tables 2A and 3A.

[0031] Compounds exemplified herein are also based around the structures IB-1 and IB-2:

R¹ is selected from

, ;

R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H.

[0032] In a more particular embodiment, the substituent for R¹ is

[0033] In a particular embodiment, the substituent for R² is H and R³ is selected from:

, or

In a more particular embodiment, R³ is

[0034] In a particular embodiment, R² forms a spirocyclic heterocyclic ring with R³ to form:

[0035] Further embodiments of the invention include methods of treatment comprising administering a compound of formula IB, IB-1 or IB-2 as a CGRP receptor antagonist. The treatment using a compound of formula IB, IB-1 or IB-2 may be in the treatment of

cerebrovascular disorders such as migraine (including subtypes such as: migraine without aura, chronic migraine, pure menstrual migraine, menstrually-related migraine, migraine with aura, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine), status migrainosus, cluster headache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, hemicrania continua, cyclic vomiting syndrome, allergic rhinitis, or rosacea. The invention further relates to compounds, compositions and medicaments for the treatment of broader pain states and diseases involving neurogenic inflammation including dental pain, earache, middle ear inflammation, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, pain associated with inflammatory bowel disease– Crohn’s disease, gout, complex regional pain syndrome, Behçet's disease, endometriosis pain, back pain or cough.

[0036] Certain novel compounds of formula IB, IB-1 and IB-2 show particularly high activities as CGRP receptor antagonists.

[0037] Exemplary compounds of formula IB, IB-1, and IB-2 include:

[0038] The NMR and LCMS properties, as well as the biological activities of exemplary compounds are set out in Tables 2B and 3B, herein.

[0039] Compounds exemplified herein are also based around the structure of formula IC-1 or IC-2,

a salt thereof, wherein R¹ is H or F and Ar¹ is an optionally substituted 5 membered heterocyclic ring containing at least two nitrogen atoms.

In a particular embodiment, Ar¹ is an optionally substituted five-membered heterocyclic ring including at least two nitrogen atoms, wherein the optional substituents are selected from (C1- C₆)alkyl, CO₂R² where R² is H or (C₁-C₃)alkyl.

In a particular embodiment, R¹ is H.

[0040] In a more particular embodiment Ar¹ is a five-membered heterocyclic ring including two or three nitrogen atoms, optionally substituted with (C1-C6)alkyl.

In a particular embodiment, Ar¹ is selected from:

or

[0041] Further embodiments of the invention include methods of treatment comprising administering a compound of formula IC, IC-1 or IC-2 as a CGRP receptor antagonist. The treatment using a compound of formula IC, IC-1 or IC-2 may be in the treatment of

cerebrovascular disorders such as migraine (including subtypes such as: migraine without aura, chronic migraine, pure menstrual migraine, menstrually-related migraine, migraine with aura, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine), status migrainosus, cluster headache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, hemicrania continua, cyclic vomiting syndrome, allergic rhinitis, or rosacea. The invention further relates to compounds, compositions and medicaments for the treatment of broader pain states and diseases involving neurogenic inflammation including dental pain, earache, middle ear inflammation, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, pain associated with inflammatory bowel disease– Crohn’s disease, gout, complex regional pain syndrome, Behçet's disease, endometriosis pain, back pain or cough.

[0042] Certain novel compounds of formula IC, IC-1 and IC-2 show particularly high activities as CGRP receptor antagonists.

[0043] Exemplar compounds of formula IC, IC-1, and IC-2 include:

[0044] The NMR and LCMS properties, as well as the biological activities of exemplary compounds are set out in Tables 2C and 3C.

[0045] The invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared. To the extent that any of the compounds and intermediates disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically acceptable salt.

[0046] Pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. [0047] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, or preferably, potassium and calcium.

[0048] Examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2- sulfonic, naphthalene-1,5-disulfonic and p-toluenesulfonic), ascorbic (e.g. L-ascorbic), L- aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+)-camphoric, camphor-sulfonic, (+)-(1S)- camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g. (-)-L- malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (e.g.(+)-L-tartaric), thiocyanic, undecylenic and valeric acids.

[0049] Particular examples of salts are salts derived from mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulfonic, pamoic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.

[0050] Also encompassed are any solvates of the compounds and their salts. Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide.

Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography. [0051] The solvates can be stoichiometric or non-stoichiometric solvates. Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.

[0052] For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0053] “Pharmaceutically functional derivatives” of compounds as defined herein includes ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound of the invention. Thus, for the purposes of this invention, the term also includes prodrugs of compounds as defined herein.

[0054] The term“prodrug” of a relevant compound includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).

[0055] Prodrugs of compounds may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds wherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in a compound is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group, respectively.

[0056] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H.

“Design of Prodrugs” p.1-92, Elsevier, New York-Oxford (1985).

Definitions

C₁-C₆ Alkyl

[0057] Alkyl means an aliphatic hydrocarbon group. The alkyl group may be straight or branched.“Branched” means that at least one carbon branch point is present in the group, for example isopropyl or tertiarybutyl. C₁-C₃ alkyl groups include methyl, ethyl, n-propyl, i-propyl. The alkyl group may be optionally substituted. Heterocyclic

[0058] Heterocyclic means a cyclic group which may be aromatic in which at least one ring member is other than carbon. For example, at least one ring member (for example one, two or three ring members) may be selected from nitrogen, oxygen and sulphur. The point of attachment of heteroaryl groups may be via any atom of the ring system. Exemplary heteroaryl groups include pyridyl, indazolyl, 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one, 1,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one, 3,4-dihydroquinazolin-2(1H)-one, quinolin-2(1H)-one, piperidinyl, piperazinyl, pyrrolidinyl, 2,8-diazaspiro[4.5]decane, imidazolyl, 1,2,4-triazolyl, quinolin-2(1H)-one, and the like. Optionally substituted

[0059] “Optionally substituted” as applied to any group means that the said group may if desired be substituted with one or more substituents, which may be the same or different. [0060] The term“pharmaceutical composition” in the context of this invention means a composition comprising an active agent and comprising additionally one or more

pharmaceutically acceptable carriers. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions may take the form, for example, of tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations.

[0061] The dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with the smaller dosages which are less than the optimum dose of the compound.

Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0062] The magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. The selection of appropriate dosages is within the ability of one of ordinary skill in this art, without undue burden. In general, the daily dose range may be from about 10 μg to about 30 mg per kg body weight of a human and non-human animal, preferably from about 50 μg to about 30 mg per kg of body weight of a human and non-human animal, for example from about 50 μg to about 10 mg per kg of body weight of a human and non-human animal, for example from about 100 μg to about 30 mg per kg of body weight of a human and non-human animal, for example from about 100 μg to about 10 mg per kg of body weight of a human and non-human animal and most preferably from about 100 μg to about 1 mg per kg of body weight of a human and non-human animal.

PREPARATION OF THE COMPOUNDS OF THE INVENTION [0063] Compounds of the invention having a formula IA-1, IA-2, IA-3, and IA-4 may be prepared by procedures including those in Scheme 1A. Those of ordinary skill in the art readily understand that particular enantiomers and diastereomers not expressly set forth in Scheme 1A, or the following synthetic examples, can be prepared by using alternative chiral starting materials. Alternatively, the compounds can be prepared using racemic starting materials and the stereoisomers separated using techniques known in the art, for example chiral HPLC methods. Details of many of the standard transformations such as those in the routes below and others which could be used to perform the same transformations can be found in standard reference textbooks such as“Organic Synthesis”, M. B. Smith, McGraw-Hill (1994) or “Advanced Organic Chemistry”, 4^th edition, J. March, John Wiley & Sons (1992).

Scheme 1A

[0064] Urea formations between amino acid intermediates, for example methyl esters of amino acids, and amine intermediates can be formed under conditions using a coupling agent such as DSC or CDI in the presence of a base such as triethylamine or DIPEA in solvents such as DMF and/or DCM. The methyl ester portion of the subsequently formed urea derivatives can be saponified using aqueous bases such as lithium hydroxide or sodium hydroxide in a suitable solvent such as THF, MeOH, 1,4-dioxane, EtOAc or a mixture thereof. The acid intermediates thus formed can be converted into amide examples under standard conditions, for example using a coupling agent such as HATU or HBTU, in the presence of a base such as DIPEA in a suitable solvent such as DMF. Alternatively an acid chloride can be coupled with an amine to yield an amide, in the presence of a base such as Et3N, in a suitable solvent such as DCM. The amine partners for such amide couplings can be prepared using an appropriate combination of standard transformations (for example reductive aminations using an amine, an aldehyde or ketone, and a reducing agent such as sodium triacetoxyborohydride in a solvent such as DCM in the presence of acetic acid; or amide formation under conditions such as those detailed above) and removal of standard protecting groups under conditions which can be found in reference textbooks, for example“Protecting Groups”, 3^rd edition, P. J. Kocieński, Georg Thieme Verlag (2005). One such transformation is the removal of a tert-butoxycarbonyl group (commonly known as a Boc group) from an amine under acidic conditions such as HCl in a solvent such as 1,4-dioxane, MeOH, EtOH, DCM or combinations thereof. It can be appreciated that Boc deprotection of amine intermediates of the invention which possess additional basic centres may result in hydrochloride salts of different stoichiometries. For example the Boc deprotection of an intermediate with one additional basic centre will result in the formation of a new amine intermediate which is for example the mono-hydrochloride or di-hydrochloride salt, which will often be used without neutralisation of the hydrochloride salt to produce the free base of the intermediate, as it can be appreciated that in the subsequent amide formation an excess of a base such as DIPEA or triethylamine is typically used to neutralise the hydrochloride salt. Amine intermediates of the invention formed by Boc-deprotection which are used without neutralisation to the free base are named herein as the hydrochloride (x HCl), and the present invention extends to all salt forms of the said intermediates. Another such protecting group removal is the deprotection of a carbobenzyloxy-protected amine (commonly known as a Cbz or Z group) using reductive conditions such as catalysis by palladium on carbon in a solvent such as EtOH in the presence of gaseous H₂ or by using a commercially available hydrogenation reactor which combines continuous-flow chemistry with in-situ hydrogen generation (for example an H-Cube hydrogenation reactor, ThalesNano Nanotechnology Inc., Budapest, Hungary). Alternative conditions for the removal of a Cbz-protecting group include transfer hydrogenation, for example using a palladium on carbon catalyst in the presence of ammonium formate or cyclohexa-1,4-diene, or both ammonium formate and cyclohexa-1,4-diene, in a solvent such as EtOH or aqueous EtOH at an elevated temperature such as 70ºC.

[0065] In some cases, the general procedures described above will produce a mixture of stereoisomers. In some cases, a reversed-phase chiral method is used to separate the

stereoisomers. In such reversed-phase chiral method, a Chiralpak IF-3 column (250 x 4.6mm; 3 µm packing; Daicel Part Number: 86525) is used along with a binary gradient mobile phase of 0.1% trifluoroacetic acid in deionized water (Mobile Phase A) and 0.1% trifluoroacetic acid in methanol (Mobile Phase B). The chiral stationary phase is immobilized on the packing’s silica backbone, allowing for both normal-phase isocratic and reversed-phase gradient operation. The mobile phase components are delivered using a binary high-pressure mixing pump along with a flow rate of 0.8 mL/minute (Agilent 1200 HPLC system). The gradient program is 35-50% B in 30 minutes. Compound solutions are prepared at a concentration of 1.0 mg/mL in 50/50 pH 4.5, 10 mM ammonium acetate buffer/methanol, and analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and a column temperature of 35 °C.

[0066] In other cases, particularly with respect to several of the intermediates, a normal-phase chiral method is used to separate the stereoisomers. In such normal-phase method, a Chiralpak AD-H column (250 X 4.6 mm; 5 µm packing; Daicel Part Number: 19325) is used along with a binary isocratic mobile phase of 70% Heptane and 30% Isopropanol. The isopropanol mobile phase component is modified with 0.2% Diethylamine in order to facilitate elution of the basic analyte. The mobile phase components are delivered using a binary high- pressure mixing pump along with a flow rate of 1.0 mL/minute (Agilent 1200 HPLC system). If desired, the mobile phase components may be pre-mixed in the proper ratio (70:30 Heptane : 0.2% Diethylamine in Isopropanol), degassed, and delivered from a single container. Compound solutions with a concentration of 2 mg/mL in methanol are analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and ambient column temperature. If this normal-phase method is used to separate intermediates, the chiral intermediates can then be used to prepare chiral final compounds.

[0067] In still further cases, particularly with respect to several of the intermediates, a normal-phase chiral method is used to separate the stereoisomers. In such normal-phase method, a Chiralpak AD-H column (250 X 4.6 mm; 5 µm packing; Daicel Part Number: 19325) is used along with a binary isocratic mobile phase of 85% Heptane and 15% Isopropanol. The isopropanol mobile phase component is modified with 0.2% Diethylamine in order to facilitate elution of the basic analyte. The mobile phase components are delivered using a binary high- pressure mixing pump along with a flow rate of 1.0 mL/minute (Agilent 1200 HPLC system). If desired, the mobile phase components may be pre-mixed in the proper ratio (85:15 Heptane : 0.2% Diethylamine in Isopropanol), degassed, and delivered from a single container. Compound solutions with a concentration of 2 mg/mL in methanol are analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and ambient column temperature. If this normal-phase method is used to separate intermediates, the chiral intermediates can then be used to prepare chiral final compounds. General procedures

[0068] Where no preparative routes are included, the relevant intermediate is commercially available. Commercial reagents were utilized without further purification. Room temperature (rt) refers to approximately 20-27^oC.¹H NMR spectra were recorded at 400 MHz, 500 MHz, or 600 MHz on Bruker, Varian or JEOL instruments at ambient temperature unless otherwise specified. Chemical shift values are expressed in parts per million (ppm), i.e. (δ)- values. The following abbreviations are used for the multiplicity of the NMR signals: s=singlet, br=broad, d=doublet, t=triplet, q=quartet, quin=quintet, h=heptet, dd=doublet of doublets, dt=double of triplets, m=multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectroscopy results were corrected to account for background peaks. Where complex NMR spectra of intermediates or examples exist due to the presence of tautomeric forms data are provided for the major form observed. Chromatography refers to column chromatography performed using silica and executed under positive pressure (flash

chromatography) conditions. LCMS experiments were carried out using electrospray conditions under the conditions below. LCMS data are given in the format: Mass ion, electrospray mode (positive or negative), retention time (experimental text and Tables 1A, 1B, and 1C); Mass ion, electrospray mode (positive or negative), retention time, approximate purity (Tables 2A, 2B, and 2C). [0069] Method A. Instruments: Hewlett Packard 1100 with G1315A DAD, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1 x 20 mm or Phenomenex Gemini-NX C- 18, 3 micron, 2.0 x 30 mm; Gradient [time (min)/solvent D in C (%)]: 0.00/2, 0.10/2, 8.40/95, 10.00/95; Solvents: solvent C = 2.5 L H2O + 2.5 mL 28% ammonia in water solution; solvent D = 2.5 L MeCN + 135 mL H₂O + 2.5 mL 28% ammonia in water solution; Injection volume 1 ^L; UV detection 230 to 400 nM; column temperature 45ºC; Flow rate 1.5 mL/min. [0070] Method B. Instruments: Agilent Technologies 1260 Infinity LC with

Chemstation software, Diode Array Detector, Agilent 6120B Single Quadrupole MS with API- ES Source; Column: Phenomenex Gemini-NX C-18, 3 micron, 2.0 x 30 mm; Gradient [time (min)/solvent D in C (%)]: 0.00/5, 2.00/95, 2.50/95, 2.60/5, 3.00/5; Solvents C and D are as described above in Method A; Injection volume 0.5 µL; UV detection 190 to 400 nM; column temperature 40ºC; Flow rate 1.5 mL/min. [0071] Method C-1. As detailed for method A, except with Gradient [time

(min)/solvent D in C (%)]: 0.00/2, 0.10/2, 2.50/95, 3.50/95. [0072] Method C-2. Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector; Column: BEH C18, 1.7 micron, 2.1 x 50 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/5, 0.40/5, 0.8/35, 1.20/55, 2.50/100, 3.30/1004.00/5; Solvents: solvent A = 5 mM ammonium acetate and 0.1% formic acid in H₂O; solvent B = 0.1% formic acid in MeCN;

Injection volume 2 µL; UV detection 200 to 400 nM; Mass detection 100 to 1200 AMU (+ve electrospray); column at ambient temperature; Flow rate 0.5 mL/min. [0073] Method D-1. Instruments: Acquity UPLC coupled with SQD mass

spectrometer; Column: Acquity UPLC BEH C18, 1.7 micron, 2.1 x 50 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/3, 1.50/100, 1.90/100, 2.00/3; Solvents: solvent A = 10 mM aqueous solution of NH₄HCO₃ (adjusted to pH 10 with ammonia); solvent B = MeCN; Injection volume 1 µL; UV detection 210 to 350 nM; column temperature 40ºC; Flow rate 0.9 mL/min. [0074] Method D-2. Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector; Column: X-Bridge C18, 5 micron, 150 x 4.6 mm; Gradient [time (min)/solvent E in F (%)]: 0.01/10, 5.00/90, 7.00/100, 11.00/100, 11.01/1012.00/10; Solvents: solvent E = 0.1% ammonia in H2O; solvent F = 0.1% ammonia in MeCN; Injection volume 10 µL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min. [0075] Method E. Instruments: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18, 1.7 micron, 2.1 x 50 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/5, 1.50/5, 8.75/80, 9.50/90, 9.80/90, 12.00/5; Solvents: solvent A = 10 mM aqueous solution of NH4HCO3 (adjusted to pH 10 with ammonia); solvent B = MeCN; Injection volume 2 µL; UV detection 210 to 350 nM; column temperature 40ºC; Flow rate 0.9 mL/min. Abbreviations

CDI = 1,1′-carbonyldiimidazole

DCE = 1,2-dichloroethane

DCM = dichloromethane

DIPEA = N,N-diisopropylethylamine

DMAC = N,N-dimethylacetamide

DMF = dimethylformamide

DSC = N,N’-disuccinimidyl carbonate

DMSO = dimethylsulfoxide

ES = electrospray

EtOAc = ethyl acetate

h = hour(s)

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

3-oxid hexafluorophosphate

HBTU = N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium

hexafluorophosphate

L = litre

LC = liquid chromatography LCMS = liquid chromatography mass spectrometry

MeCN = acetonitrile

min = minute(s)

MS = mass spectrometry

NMR = nuclear magnetic resonance

rcf = relative centrifugal force

rpm = revolutions per minute

rt = room temperature

s = second(s)

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin-layer chromatography Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary. SYNTHESIS OF INTERMEDIATES Preparation of carboxylic acid intermediates Typical procedure for the preparation of carboxylic acid intermediates via urea formation and subsequent saponification, as exemplified by the preparation of Intermediate 7A, (2R)- 3-(7-methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1- l)carbon l]amino}propanoic acid.

Intermediate 5 Intermediate 4 Intermediate 7

[0076] Step 1) Et3N (2.26 mL, 16.3 mmol) was added to a solution of (R)-methyl 2- amino-3-(7-methyl-1H-indazol-5-yl)propanoate dihydrochloride (Intermediate 5, 995 mg, 3.3 mmol) and DSC (917 mg, 3.6 mmol) in DMF (20 mL) and the mixture stirred at rt for 30 min. Spiro[piperidine-4,4'-[4H]pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one (Intermediate 4, 785 mg, 3.6 mmol) was then added portionwise and the reaction mixture stirred at rt for 18 h before concentration in vacuo. The residue was partitioned between H₂O and MeOH / DCM (1:9), the phases were separated and the aqueous layer was washed with H2O. Residual solid from the separation step was dissolved in MeOH and the combined organic layers were concentrated in vacuo and purified by flash chromatography, eluting with EtOAc in MeOH (20:1), to yield methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'- pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoate (1.06 g, 2.22 mmol) as a white solid. LCMS (Method A): m/z 479.3 (ES+), at 2.61 min, 100%.

1H NMR: (400 MHz, DMSO-d₆) δ: 1.59-1.75 (m, 2H), 1.78-1.90 (m, 2H), 2.45 (s, 3H), 2.90- 3.08 (m, 4H), 3.59 (s, 3H), 3.86-3.96 (m, 2H), 4.28-4.38 (m, 1H), 6.94-7.06 (m, 3H), 7.32 (dd, J=7.4, 1.2, 1H), 7.39 (s, 1H), 7.95 (s, 1H), 8.18 (dd, J=5.1, 1.6, 1H), 10.79 (s, 1H), 13.04 (s, 1H). [0077] Step 2) Methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro- 1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoate (1.06 g, 2.22 mmol) was dissolved in THF (15 mL) and MeOH (3 mL) and an aqueous solution of LiOH (1M, 4.4 mL, 4.4 mmol) was added dropwise. After stirring at rt for 3.5 h further aqueous LiOH (1M, 2.2 mL, 2.2 mmol) was added dropwise and the mixture stirred for 1 h at rt before concentration under a stream of nitrogen. The residue was dissolved in a minimum volume of H2O and cooled to 0ºC. Aqueous 1M HCl was added dropwise to adjust the pH to≤ 3 and the resulting precipitate was isolated by filtration, washed with cold H2O and Et2O to yield the title compound (877 mg, 1.89 mmol) as a pale yellow solid.

Data in Table 1A. Intermediate 8A, (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoic acid

Intermediate 5 Intermediate 1 Intermediate 8 [0078] The title compound (1.50 g, 3.2 mmol) was prepared over two steps from (R)- methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate (Intermediate 5A, 1.00 g, 4.3 mmol) and 1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Intermediate 1, 1.02 g, 4.7 mmol) using the methods of Intermediate 7A.

Data in Table 1A. Intermediate 14A, 3,5-dibromo-N-[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'- pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]-D-tyrosine

I^{ntermediate 6 Intermediate 4 Intermediate 14}

[0079] The title compound (561 mg, 1.0 mmol) was prepared over two steps from 3,5- dibromo-D-tyrosine methyl ester (Intermediate 6A, 530 mg, 1.5 mmol) and spiro[piperidine-4,4'- [4H]pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one (Intermediate 4, 362 mg, 1.7 mmol) using the methods of Intermediate 7A.

Data in Table 1A. Intermediate 11A, 3,5-dibromo-N-{[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)piperi

Intermediate 6 Intermediate 1 Intermediate 11

[0080] The title compound (214 mg, 0.37 mmol) was prepared over two steps from 3,5- dibromo-D-tyrosine methyl ester (Intermediate 6A, 357 mg, 1.01 mmol) and 1-(piperidin-4-yl)- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Intermediate 1, 362 mg, 1.42 mmol) using the methods of Intermediate 7A.

Data in Table 1A. Intermediate 12A, 3,5-dibromo-N-{[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1- yl]carbon l}-D-t rosine

Intermediate 6 Intermediate 3 Intermediate 12

[0081] The title compound (224 mg, 0.38 mmol) was prepared over two steps from 3,5- dibromo-D-tyrosine methyl ester (Intermediate 6A, 353 mg, 1.00 mmol) and 3-(piperidin-4-yl)- 3,4-dihydroquinazolin-2(1H)-one (Intermediate 3A, 254 mg, 1.10 mmol) using the methods of Intermediate 7A.

Data in Table 1A. Intermediate 13A, (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,4-dihydroquinazolin- 3(2H)-yl)piperidin-1- l]carbon l}amino)propanoic acid

Intermediate 5 Intermediate 3 Intermediate 13

[0082] The title compound (561 mg, 1.18 mmol) was prepared over two steps from (R)- methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate (Intermediate 5A, 917 mg, 3.93 mmol) and 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (Intermediate 3, 1.00 g, 4.32 mmol) using the methods of Intermediate 7A.

Data in Table 1A. Intermediate 10A, 3,5-dibromo-N-{[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1- yl]carbonyl}-D-tyrosine

Intermediate 6 Intermediate 2 Intermediate 10

[0083] The title compound (77 mg, 0.13 mmol) was prepared over two steps from 3,5- dibromo-D-tyrosine methyl ester (Intermediate 6A, 103 mg, 0.29 mmol) and 3-(piperidin-4-yl) quinolin-2(1H)-one (Intermediate 2A, 73 mg, 0.32 mmol) using the methods of Intermediate 7A. Data in Table 1A. Intermediate 9A, (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)pip

Intermediate 5 Intermediate 2 Intermediate 9

[0084] Step 1) To a solution of (R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl) propanoate (Intermediate 5A, 6.05 g, 25.9 mmol) in DMF (60 mL) under N₂ at approximately - 20ºC was added CDI (8.40 g, 51.8 mmol) and the mixture was stirred for 15 mins while keeping the temperature below -10ºC. A solution of H2O (2.34 mL) in a few mL of DMF was added and stirring continued for 15 mins while keeping the temperature below -10ºC.3-(Piperidin-4-yl) quinolin-2(1H)-one (Intermediate 2A, 6.99 g, 30.6 mmol), DIPEA (4.93 mL, 28.2 mmol) and DCM (20 mL) were then added in that order and the mixture was heated to 40ºC under N2 for 12 h. After cooling to rt, 2M HCl (aq) (38.7 mL) was added and the mixture was extracted twice with DCM. The combined organic extracts were washed three times with H₂O, dried (Na₂SO₄) and concentrated in vacuo. Purification by flash chromatography, eluting with MeOH/DCM (5:95), yielded methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoate (10.4 g, 21.3 mmol) as a light tan solid.

1H NMR: (400 MHz, CDCl3) δ: 1.40-1.60 (m, 2H), 1.95-1.97 (m, 2H), 2.46 (s, 3H), 2.90-3.00 (m, 2H), 3.11-3.26 (m, 3H), 3.76 (s, 3H), 4.07-4.12 (m, 2H), 4.86-4.91 (m, 1H), 5.18 (d, J=7.6, 1H), 6.93 (s, 1H), 7.17-7.21 (m, 1H), 7.24 (s, 1H), 7.32 (s, 1H), 7.43-7.54 (m, 3H), 7.95 (s, 1H), 10.70 (s, 2H). [0085] Step 2) To a solution of methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2- oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoate (9.79 g, 20.1 mmol) in 1,4-dioxane (150 mL) was added a solution of LiOH·H2O (1.26 g, 30.0 mmol) in H2O (150 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to near- dryness and re-dissolved in H2O before being acidified with aqueous 2M HCl (approximately 15 mL) whilst being rapidly stirred. The resulting thick white precipitate was isolated by filtration and washed with H₂O until the washings were near neutral pH. Drying in vacuo yielded the title compound (8.11 g, 17.1 mmol) as an off-white solid.

Data in Table 1A.

Preparation of amine intermediates

Intermediate 17A, tert-butyl 4-{(2S)-2-amino-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]prop l}piperidine-1-carbox late

I^{ntermediate 16 Intermediate 17}

[0086] Step 1) To a solution of

4-[(2S)-2-{[(benzyloxy)carbonyl]amino}-3- methoxy-3-oxopropyl]piperidine-1-carboxylate (Intermediate 16A, 4.29 g, 10.2 mmol) in 1,4- dioxane (50 mL) was added a solution of LiOH·H2O (856 mg, 20.4 mmol) in H2O (50 mL) and the mixture was stirred for 5 h. The reaction mixture was concentrated in vacuo to near-dryness and re-dissolved in H2O before being acidified with 0.5 M NaHSO4 (aq). The resulting thick white precipitate was extracted into EtOAc and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to yield N-[(benzyloxy)carbonyl]-3-[1-(tert- butoxycarbonyl)piperidin-4-yl]-L-alanine as a white foam (4.01 g, 9.87 mmol).

1H NMR: (400 MHz, DMSO-d₆) δ: 0.85-1.07 (m, 2H), 1.39 (s, 9H), 1.45-1.68 (m, 5H), 2.55- 2.71 (m, 2H), 3.86-3.94 (m, 1H), 4.85-4.98 (m, 2H), 5.04 (s, 2H), 7.28-7.39 (m, 5H), 7.53 (d, J=8.3, 1H), 12.5 (br s, 1H). [0087] Step 2) To a solution of N-[(benzyloxy)carbonyl]-3-[1-(tert- butoxycarbonyl)piperidin-4-yl]-L-alanine (4.00 g, 9.84 mmol) in DMF (80 mL) was added HBTU (4.10 g, 10.81 mmol) followed by DIPEA (3.74 mL, 21.47 mmol) and 1-(4- pyridyl)piperazine (Intermediate 15A, 1.69 g, 10.35 mmol) and the mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo to near-dryness and the residue dissolved in EtOAc, washed twice with H2O, twice with NaHCO3 (aq) and brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography, eluting with MeOH/DCM (5:95), yielded tert-butyl 4-{(2S)-2-{[(benzyloxy)carbonyl]amino}-3-oxo-3-[4-(pyridin-4-yl)piperazin- 1-yl]propyl}piperidine-1-carboxylate (4.51 g, 8.18 mmol) as an off-white foam.

1H NMR: (400 MHz, CDCl3) δ: 1.07-1.16 (br m, 2H), 1.44 (s, 9H), 1.54-1.60 (br m, 2H), 1.88- 1.91 (m, 1H), 2.62-2.65 (br m, 2H), 3.47-3.65 (br m, 6H), 3.81-3.86 (br m, 2H), 4.05 (br m, 2H), 4.26 (br m, 2H), 4.70-4.74 (m, 1H), 5.04-5.12 (m, 2H), 5.70 (d, J=8.8, 1H), 6.82 (d, J=6.0, 2H), 7.26-7.34 (m, 5H), 8.10 (br s, 2H).

[0088] Step 3) A solution of tert-butyl 4-{(2S)-2-{[(benzyloxy)carbonyl]amino}-3-oxo- 3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (557 mg, 1.01 mmol) in EtOH (20 mL) was eluted five times through a Pd/C cartridge at 50ºC using a continuous flow hydrogenation reactor (H-Cube, ThalesNano Nanotechnology Inc., Budapest, Hungary) in the presence of H2 (full H2 mode), monitoring conversion to desired product by LCMS. Upon > 95% conversion the reaction mixture was concentrated in vacuo to yield the title compound (455 mg, 1.09 mmol) as a yellow glassy solid.

Data in Table 1A. Intermediate 18A, methyl N-[(benzyloxy)carbonyl]-3-(1-propylpiperidin-4-yl)-L-alaninate

I^{ntermediate 16 Intermediate 18}

[0089] Step 1) HCl in 1,4-dioxane (4M, 10 mL, 40 mmol) was added to a solution of tert-butyl 4-[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxopropyl]piperidine-1- carboxylate (Intermediate 16A, 1.00 g, 2.38 mmol) in MeOH (10 mL). After stirring at rt for 2 h the reaction mixture was concentrated in vacuo to yield methyl N-[(benzyloxy)carbonyl]-3- piperidin-4-yl-L-alaninate hydrochloride (850 mg) which was used without purification in the subsequent step.

LCMS (Method C-1): m/z 321.2 (ES⁺) at 1.66 min. [0090] Step 2) A mixture of methyl N-[(benzyloxy)carbonyl]-3-piperidin-4-yl-L- alaninate hydrochloride (500 mg, 1.40 mmol), propionaldehyde (120 µL, 1.68 mmol) and glacial acetic acid (96 µL, 1.68 mmol) in DCM (10 mL) was stirred at rt for 1 h, before the addition of sodium triacetoxyborohydride (356 mg, 1.68 mmol). After stirring overnight at rt the mixture was concentrated in vacuo and purified by flash column chromatography, eluting with 0-10% MeOH in DCM to yield the title compound (400 mg, 1.10 mmol) as a colourless oil.

Data in Table 1A. Intermediate 19A, (2S)-2-amino-3-(1-propylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-1-one

Intermediate 18 Intermediate 19 [0091] Step 1) Aqueous sodium hydroxide (1M, 5 mL, 5.0 mmol) was added to a solution of methyl N-[(benzyloxy)carbonyl]-3-(1-propylpiperidin-4-yl)-L-alaninate (Intermediate 18A, 400 mg, 1.10 mmol) in MeOH (5 mL). After stirring at rt overnight the reaction mixture was partially concentrated in vacuo to remove MeOH and acidified to pH≤ 2 with 1M aqueous HCl. Concentration in vacuo yielded crude N-[(benzyloxy)carbonyl]-3-(1-propylpiperidin-4-yl)- L-alanine (385 mg) which was used without purification in the subsequent step.

LCMS (Method B): m/z 349.0 (ES⁺) at 0.79 min. [0092] Step 2) A mixture of crude N-[(benzyloxy)carbonyl]-3-(1-propylpiperidin-4-yl)- L-alanine (385 mg), 1-(4-pyridyl)piperazine (Intermediate 15, 215 mg, 1.32 mmol), HATU (505 mg, 1.33 mmol) and DIPEA (383 µL, 2.20 mmol) in DMF (5 mL) was stirred at rt for 3 h.

Concentration in vacuo yielded benzyl {(2S)-1-oxo-3-(1-propylpiperidin-4-yl)-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}carbamate (542 mg) as a pale orange, viscous oil which was used without purification in the subsequent step.

LCMS (Method B): m/z 493.9 (ES⁺) at 1.45 min. [0093] Step 3) Ammonium formate (643 mg, 11.0 mmol) was added to a solution of benzyl {(2S)-1-oxo-3-(1-propylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2- yl}carbamate (crude, 542 mg) in EtOH (40 mL) and H₂O (10 mL). Palladium on carbon (10%, 10 mg) was added and the mixture was heated at 70ºC under N2 overnight. After cooling to rt the mixture was filtered through celite and the filtrate concentrated in vacuo to yield the title compound as a yellow viscous oil (115 mg) which was used without purification in the formation of Example 4A.

Data in Table 1A. Intermediate 20A, 1-(4-{(2S)-2-amino-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]propyl}piperidin-1-yl)pentan-1-one

N O N

N H N O N NH₂

N N

O 1) HCl in 1,4-dioxane, EtOAc O

N 2) nBuCO₂H, HATU, Et₃N, DMF N

3) Pd/C, H₂, EtOH

O O O Intermediate 17, Step 2 product Intermediate 20

[0094] Step 1) HCl in 1,4-dioxane (4M, 2.30 mL, 9.20 mmol) was added to a solution of tert-butyl 4-{(2S)-2-{[(benzyloxy)carbonyl]amino}-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]propyl}piperidine-1-carboxylate (Intermediate 17A, Step 2 product) (1.30 g, 2.30 mmol) in EtOAc (23 mL) and the mixture was stirred at rt overnight. After concentration in vacuo purification by flash column chromatography eluting with DCM / MeOH / 7N NH₃ (90:5:5) in MeOH yielded benzyl {(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan- 2-yl}carbamate (740 mg, 1.64 mmol).

LCMS (Method B): m/z 452.2 (ES⁺) at 1.30 min. [0095] Step 2) A mixture of pentanoic acid (137 mg, 0.36 mmol), benzyl {(2S)-1-oxo- 3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}carbamate (146 mg, 0.32 mmol), triethylamine (209 µL, 1.50 mmol) and HATU (137 mg, 0.36 mmol) in DMF (3 mL) was stirred at rt overnight.1M aqueous sodium carbonate solution (20 mL) was added, the mixture was concentrated in vacuo and purified by gradient flash column chromatography, eluting with 0-10% (1:1 MeOH/7N NH₃ in MeOH) in DCM, to yield benzyl {(2S)-1-oxo-3-(1- pentanoylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}carbamate.

LCMS (Method B): m/z 536.2 (ES⁺) at 1.38 min. [0096] Step 3) A solution of benzyl {(2S)-1-oxo-3-(1-pentanoylpiperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}carbamate in EtOH was eluted through a Pd/C cartridge at 50ºC using a continuous flow hydrogenation reactor (H-Cube, ThalesNano

Nanotechnology Inc., Budapest, Hungary) in the presence of H₂ (full H₂ mode), monitoring conversion to desired product by LCMS. Upon > 95% conversion the reaction mixture was concentrated in vacuo to yield the title compound which was used in its entirety (assumed to be 0.32 mmol) without purification in the formation of Example 6A.

Data in Table 1A. Intermediate 21A, (2S)-2-amino-3-(1-ethylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-1-one

Intermediate 18 Intermediate 21

[0097] The title compound (286 mg, 0.83 mmol) was prepared over four steps from methyl N-[(benzyloxy)carbonyl]-3-piperidin-4-yl-L-alaninate hydrochloride (Intermediate 18A, Step 1 product) (320 mg, 0.90 mmol) and acetaldehyde (62 µL, 1.10 mmol) using the methods of Intermediates 18A and 19A.

Data in Table 1A. Intermediate 22A, (2S)-2-amino-3-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-1-one

Intermediate 18 Intermediate 22

[0098] The title compound (306 mg, used crude without purification in the formation of Example 12A) was prepared over four steps from methyl N-[(benzyloxy)carbonyl]-3-piperidin- 4-yl-L-alaninate hydrochloride (Intermediate 18A, Step 1 product) (1.0 g, 2.81 mmol) and 2- (dimethylamino)acetaldehyde sulfite (568 mg, 3.36 mmol) using the methods of Intermediates 18A and 19A.

Data in Table 1A. Intermediate 23A, ethyl 3-(4-{(2S)-2-amino-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]propyl}piperidin-1-yl)-3-oxopropanoate

Intermediate 17, Step 2 product Intermediate 23

[0099] Step 1) HCl in 1,4-dioxane (4M, 10.0 mL, 40.0 mmol) was added to a solution of tert-butyl 4-{(2S)-2-{[(benzyloxy)carbonyl]amino}-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]propyl}piperidine-1-carboxylate (Intermediate 17A, Step 2 product) (600 mg, 1.09 mmol) in MeOH (10 mL) and the mixture was stirred at rt overnight. Concentration in vacuo yielded benzyl {(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}carbamate dihydrochloride (570 mg, 1.09 mmol) as a sticky white solid.

LCMS (Method B): m/z 452.2 (ES⁺) at 1.72 min. [00100] Step 2) Ethyl 3-chloro-3-oxopropanoate (151 µL, 1.20 mmol) was added to a solution of Et3N (608 µL, 4.36 mmol) and benzyl {(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}carbamate dihydrochloride (570 mg, 1.09 mmol) in DCM (20 mL) and the mixture stirred at rt overnight. After concentration in vacuo purification by gradient flash column chromatography, eluting with 0-10% MeOH in DCM yielded the desired material (ethyl 3-(4-{(2S)-2-{[(benzyloxy)carbonyl]amino}-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]propyl}piperidin-1-yl)-3-oxopropanoate, pale yellow sticky solid, 510 mg), as an approximate 2:1 mixture with bis-acylated byproduct (ethyl 3-(4-{(2S)-2-{[(benzyloxy)carbonyl](3-ethoxy-3- oxopropanoyl)amino}-3-oxo-3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3- oxopropanoate). The mixture was used in the following step without further purification. LCMS (Method B): m/z 566.2 (ES⁺) at 1.18 min (desired material); m/z 680.2 (ES⁺) at 0.79 min (bis-acylated byproduct). [00101] Step 3) A mixture of crude ethyl 3-(4-{(2S)-2-{[(benzyloxy)carbonyl]amino}- 3-oxo-3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3-oxopropanoate (510 mg) and cyclohexa-1,4-diene (0.85 mL, 9.00 mmol) in EtOH (20 mL) was flushed with N₂ before the addition of 10% Pd/C (10 mg). After heating at 70ºC for 1 h, the reaction mixture was cooled to rt and ammonium formate (568 mg, 9.00 mmol) was added. The mixture was heated at 70ºC under N₂ overnight before cooling to rt and filtering. The filtrate was concentrated in vacuo to yield the crude title compound (194 mg) which was used without purification in the formation of Example 13a1.

Data in Table 1A. Table 1A. Intermediates

SYNTHESIS OF EXAMPLES

[00102] Typical procedures for the preparation of examples via amide coupling, and where appropriate, deprotection, as exemplified by the preparation of the below examples. Procedure 1A:

Example 11a.

[00103] Step 1: HATU (4.57 g, 12.0 mmol) was added to a solution of (2R)-3-(7- methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1-yl)carbonyl]amino}propanoic acid (Intermediate 7A, 4.65 g, 10.0 mmol) in DMF (150 mL), followed after 15 min by the addition of tert-butyl 4-{(2S)-2-amino-3-oxo-3-[4- (pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (Intermediate 17A, 4.60 g, 11.0 mmol) and DIPEA (6.86 mL, 40.1 mmol). The mixture was stirred at rt for 17 h before the addition of H₂O (600 mL). The resulting precipitate was isolated by filtration, washed with H₂O, and dissolved in a small amount of MeOH. Co-evaporation twice with toluene yielded crude tert- butyl 4-{(2S)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro-1H- spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoyl]amino}-3-oxo- 3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (7.82 g) which was used in the next step without further purification. A second batch of material (3.53 g) was prepared using this method.

LCMS (Method D-1): m/z 864.7 (ES⁺) at 0.88 min. [00104] Step 2: TFA (31 mL) was added to a solution of tert-butyl 4-{(2S)-2-{[(2R)-3- (7-methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1-yl)carbonyl]amino}propanoyl]amino}-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]propyl}piperidine-1-carboxylate (Step 1, Batch 1, 7.82 g) in DCM (150 mL) and the solution stirred at rt for 1 h. Toluene (50 mL) was added and the mixture was concentrated in vacuo. DCM (200 mL) and H₂O (50 mL) were added and the pH adjusted to approximately 12 with 2M (aq) NaOH solution. The phases were separated and the aqueous layer extracted with DCM/isopropanol (1:1, 5 x 200 mL). The combined organic phases were concentrated in vacuo. Purification by gradient flash column chromatography, eluting with 0-100% (DCM/MeOH/7N NH3 in MeOH (4:1:0.4)) in DCM yielded the title compound. A second batch of title compound was prepared using this method from Step 1, Batch 2 material. The purified title compound from both batches was combined, dissolved in a mixture of DCM, MeOH and diisopropyl ether, sonicated and concentrated in vacuo to yield the title compound (5.30 g, 6.94 mmol).

Data in Table 2A. [00105] A reversed-phase chiral method was used to separate the stereoisomers. A Chiralpak IF-3 column (250 x 4.6mm; 3 µm packing; Daicel Part Number: 86525) was used along with a binary gradient mobile phase of 0.1% trifluoroacetic acid in deionized water (Mobile Phase A) and 0.1% trifluoroacetic acid in methanol (Mobile Phase B). The mobile phase components were delivered using a binary high-pressure mixing pump along with a flow rate of 0.8 mL/minute (Agilent 1200 HPLC system). The gradient program was 35-50% B in 30 minutes. A solution was prepared at a concentration of 1.0 mg/mL in 50/50 pH 4.5, 10 mM ammonium acetate buffer/methanol, and was analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and a column temperature of 35 °C. The four diastereomers (11a1, 11a2, 11a3, and 11a4) were separated and isolated. The elution order of the diastereomers was established as follows:

[00106] R,R diastereomer (11a3): Retention Time=18.3 minutes, RRT = 0.83

[00107] S,S diastereomer (11a2): Retention Time=19.3 minutes, RRT=0.87

[00108] S,R diastereomer (11a4): Retention Time=20.3 minutes, RRT = 0.93

[00109] R,S diastereomer (11a1): Retention Time=22.0 minutes; RRT=1.00

Example 14a.

[00110] Step 1) A solution of HATU (7.84 g, 20.6 mmol) and 3,5-dibromo-N-[(2'-oxo- 1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]-D-tyrosine (Intermediate 14, 10.0 g, 17.2 mmol) in DMF (75 mL) was stirred at rt for 30 min before the addition of 4-{(2S)-2-amino-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]propyl}piperidine-1-carboxylate (Intermediate 17A, 7.72 g, 18.5 mmol) and DIPEA (11.8 mL, 68.8 mmol). The reaction mixture was stirred at rt overnight before cold H2O (500 mL), saturated aqueous NaHCO3 and DCM (200 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (3 x 200 mL). The combined organic phases were washed with brine (200 mL), concentrated in vacuo, and co-evaporated with toluene. Purification by gradient flash column chromatography, eluting with 0-100% solvent B in DCM (where solvent B = DCM/MeOH/7N NH₃ in MeOH (90:9:1.5) yielded 3,5-dibromo-Nα-{(2S)-3-[1-(tert- butoxycarbonyl)piperidin-4-yl]-1-oxo-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-N-[(2'- oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]-D- tyrosinamide (9.7 g, 9.86 mmol) as a white solid.

LCMS (Method D-1): m/z 984.5 (ES⁺) at 0.78 min. [00111] Step 2: 3,5-Dibromo-Nα-{(2S)-3-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1- oxo-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-Nα-[(2'-oxo-1',2'-dihydro-1H- spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]-D-tyrosinamide (9.7 g, 9.86 mmol) was dissolved in DCM (70 mL), cooled to 0ºC, and TFA (15 mL) was added dropwise. The mixture was stirred at rt for 10 min before the addition of toluene (50 mL) and concentration in vacuo. DCM (200 mL) and H₂O (100 mL) were added, the pH was adjusted to approximately 10 with 2N aqueous NaOH solution. The resulting precipitate was isolated by filtration, dissolved in DCM /MeOH (1:1, 300 mL), concentrated in vacuo, and co-evaporated several times with MeOH and toluene. Trituration from MeOH / methyl tert-butyl ether yielded the title compound (5.30 g, 6.00 mmol).

Data in Table 2A. Procedure 2A:

Example 1a.

Example 1

[00112] Step 1: DIPEA (0.12 mL, 0.66 mmol) was added to a solution of HATU (99 mg, 0.22 mmol), (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5- b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoic acid (Intermediate 8A, 100 mg, 0.22 mmol) and tert-butyl 4-{(2S)-2-amino-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]propyl}piperidine-1-carboxylate (Intermediate 17A, 92 mg, 0.22 mmol) in DMF (2 mL) and the reaction mixture was stirred at rt for 10 d before concentration in vacuo to yield crude tert- butyl 4-{(2S)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (190 mg, viscous brown oil) which was used without purification in the subsequent step.

LCMS (Method C-1): m/z 863.5 (ES⁺) at 1.89 min. [00113] Step 2: Crude tert-butyl 4-{(2S)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2- ({[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1- yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4-(pyridin-4-yl)piperazin-1- yl]propyl}piperidine-1-carboxylate (190 mg) was dissolved in MeOH (5 mL) and HCl in dioxane (4M, 5.0 mL, 20.0 mmol) was added. The reaction mixture was stirred at rt for 2 h before concentration in vacuo. Purification by preparative reversed phase HPLC (Phenomenex Gemini-NX 5µm C18 column, 100 x 30 mm, eluting with 15 to 90% MeCN/Solvent B over 26 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions by monitoring at 205 nm) yielded Example 1 (25 mg, 0.03 mmol) as a beige solid.

Data in Table 2A. Procedure 3A:

Example 13a.

[00114] Step 1: A mixture of DIPEA (0.27 mL, 1.52 mmol), HATU (172 mg, 0.45 mmol), (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5- b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoic acid (Intermediate 8, 176 mg, 0.38 mmol) and ethyl 3-(4-{(2S)-2-amino-3-oxo-3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin- 1-yl)-3-oxopropanoate (Intermediate 23A, 194 mg, 0.45 mmol) in DMF (10 mL) was stirred at rt overnight before concentration in vacuo. The crude material was filtered through a short plug of SiO2, eluting with MeOH, before further purification by preparative HPLC (Phenomenex Gemini-NX 5µm C18 column, 100 x 30 mm, eluting with 15 to 35% MeCN/Solvent B over 12.5 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O], collecting fractions by monitoring at 205 nm). During the purification, cleavage of the ethyl ester was observed.

Carboxylic acid containing fractions were combined and added to 10 mL of concentrated aqueous ammonia, and the mixture was allowed to stand at rt overnight before concentration in vacuo to yield the title compound (10 mg, 0.01 mmol) as a colourless solid.

Data in Table 2A. Further examples prepared by the above procedures are detailed in Table 2A.

Table 2A

Biological and biophysical methods and assay results [00115] Cloning, Baculovirus generation, large-scale infection of Sf21 cells and membrane preparation. Human Calcitonin Receptor Like Receptor (CRLR) and human RAMP1 were cloned into Invitrogen’s (ThermoFisher Scientific, UK) pFastBac dual expression vector. Transposition of CRLR/RAMP1 DNA was performed using Invitrogen’s Bac-to-Bac Baculovirus Expression Systems. P0 baculovirus was generated by transfecting SF9 cells with bacmid DNA using Cellfectin® II transfection reagent (ThermoFisher Scientific, UK, catalog number 10362-100). Following P0 generation P1 virus was then generated ready for large scale infection and membrane preparation. Sf21 cells were grown in expression medium ESF921 (Expression Systems, USA, catalog number 96-001-01) supplemented with 10% heat-inactivated FBS and 1% Pen/Strep and were infected at a cell density of 2.5x10⁶ cells/mL and an MOI of 2. Expression was carried out over 48 h in a shaking incubator set at 27°C. The cell culture was centrifuged at 2,500 rcf for 10 min at 4˚C. The pellets were resuspended in cold PBS

supplemented with Roche's Complete EDTA-free protease inhibitor cocktail tablets (Roche Applied Sciences, catalog number 05056489001), 1 mM PMSF and 1 mM EDTA. The resuspended cell paste was then centrifuged at 3,273 rcf for 12 min at 4˚C. The supernatant was discarded and the pellet frozen at -80^oC. The cell pellet from a 4 L culture was resuspended in buffer containing 50 mM Hepes pH 7.5, 150 mM NaCl, 8 Roche EDTA-free protease inhibitor cocktail tablets and 1 mM PMSF. The suspension was left stirring at rt for 1 h and then homogenised for 90 s at 9,500 rpm using a VDI 25 (VWR, USA) homogeniser. The cells were then lysed using a Microfluidizer processor M-110L Pneumatic (Microfluidics, USA). After lysis, the mixture was homogenised for 90 s at 9,500 rpm and then centrifuged at 335 rcf for 10 min. The supernatant was then further ultra-centrifuged at 42,000 rpm for 90 min. After ultra- centrifugation, the supernatant was discarded and the pellet was resuspended in 50 mL (25 mL for each 2 L culture) of buffer containing 50 mM Hepes pH 7.5, 150 mM NaCl, 3 Roche EDTA- free protease inhibitor cocktail tablets and 1 mM PMSF. The suspension was then homogenised for 90 s at 9,500 rpm. The resulting membranes were then stored at -80°C. [00116] Radioligand binding assay. Human CGRP receptors expressed (consisting of CRLR and RAMP1) in insect Sf21 cell membrane homogenates were re-suspended in the binding buffer (10 mM HEPES, pH 7.4, 5 mM MgCl2, 0.2% BSA) to a final assay concentration of 0.6 µg protein per well. Saturation isotherms were determined by the addition of various concentrations of ³H-telcagepant (Ho et al, The Lancet, 2008, 372, 2115) (in a total reaction volume of 250 µL) for 60 min at rt. At the end of the incubation, membranes were filtered onto a unifilter, a 96-well white microplate with bonded GF/B filter pre-incubated with 0.5% PEI, with a Tomtec cell harvester and washed 5 times with distilled water. Non-specific binding (NSB) was measured in the presence of 10 nM MK-3207 hydrochloride (CAS No.957116-20-0). Radioactivity on the filter was counted (1 min) on a microbeta counter after addition of 50 µL of scintillation fluid. For inhibition experiments, membranes were incubated with 0.5 nM ³H- telcagepant and 10 concentrations of the inhibitory compound (0.001-10 µM). IC₅₀ values were derived from the inhibition curve and the affinity constant (Ki) values were calculated using the Cheng-Prussoff equation (Cheng et al, Biochem. Pharmacol.1973, 22, 3099−3108). The pK_i values (where pK_i =−log₁₀ K_i) of certain compounds of the invention are tabulated below in Tables 3A, 3B, and 3C. [00117] cAMP functional assay. cAMP production following receptor activation was determined using the Homogeneous Time-Resolved Fluorescence (HTRF) cAMP dynamic-2 assay (Cisbio, France). The human neuroblastoma cell line SK-N-MC endogenously expressing the human CGRP receptor was seeded at a density of 12,500 cells/well in solid walled 96 well half area plates (Costar, Catalog Number 3688, Corning Life Sciences, Germany). After 16 h incubation at 37ºC media was removed and cells were incubated at 37°C for 30 min in serum free media containing 500 µM IBMX (Tocris, Abingdon, UK, Catalog Number 2845) and increasing concentrations of test antagonist. Following this cells were challenged with an EC₈₀ concentration of human CGRP (0.3 nM) for a further 30 min at 37°C and then cAMP production was determined as manufacturer’s instructions before plates were read on a PheraStar fluorescence plate reader (BMG LabTech, Germany). IC₅₀ values were derived from the inhibition curve. The pIC50 values (where pIC50 =−log10 IC50) were converted to a functional pKb value using a modified Cheng-Prussoff equation where Kd = agonist EC50 and L hot = agonist challenge concentration. The pK_b values of certain compounds of the invention are detailed in Tables 3A, 3B, and 3C. Table 3A.

[00118] Receptor Kinetic Profiling. It is appreciated that the kinetic profile of a small molecule at the relevant biological target can have an impact upon the pharmacodynamic effect of the molecule in vivo (Copeland, Expert Opin. Drug Discov., 2010, 5, 305). For example, olcegepant has slow kinetics at the CGRP receptor (Schindler, Doods, Eur. J. Pharmacol., 2002, 442, 187), a factor which may contribute to its prolonged efficacy in migraine treatment in humans (47% headache-free rate at 24 h after intravenous infusion of a 2.5 mg dose; Olesen et al, N. Eng. J. Med., 2004, 350, 1104). In a similar way, MK-3207 has also been shown to demonstrate relatively slow dissociation for the CGRP receptor (Salvatore et al, J. Pharmacol. Exp. Ther., 2010, 333, 152). The CGRP receptor kinetics of compounds of the invention and reference CGRP receptor antagonists have been profiled using the surface plasmon resonance technique below, and are detailed in Table 4A. [00119] Kinetic analyses were run on a Biacore T200 instrument (GE Healthcare Bio- Sciences AB, Uppsala, Sweden) at 25ºC using 0.05 mM EDTA, PBS (10 mM phosphate buffer, 2.7 mM KCl, 137 mM NaCl) pH 7.4, 0.005% v/v Surfactant P20, 5% DMSO as the running buffer. The purified CGRP receptor ectodomain complex containing a hexa-His tag (Moore et al, Structure, 2010, 18, 1083–1093) was immobilised on a sensor chip NTA (GE Healthcare Bio- Sciences AB) by the capture-couple technique (Rich et al, Anal. Biochem., 2011, 409, 267-272). The chip was loaded with Ni²⁺ and carboxyl groups of the dextran matrix were activated by EDC/NHS. The receptor ectodomain complex (100 nM in running buffer) was then injected and immobilised via the His-tag and amino groups. Two fold dilution series of each compound (five concentrations, in the range 25-40 nM) were injected. Blank-subtracted data were fitted to a 1:1 interaction model to obtain kinetic parameters which are expressed in Table 4A as dissociation half-life (t_1/2 = (ln 2/off-rate (k_d))/60).

[00120] The data presented indicates that each of the examples 2a1, 4a1, 6a1, 7a1, 8a1, 9a1, 11a1, 12a1 and 14a1 have the property of slow receptor dissociation that is comparable or slower in off-rate than olcegepant or MK-3207. Table 4A.

[00121] Pharmacokinetic profiling. The pharmacokinetic profiles of Examples and reference compounds have been assessed in male Sprague Dawley® rats via intravenous (iv), sub-cutaneous (sc) and intranasal (IN) routes of delivery, and in male Cynomolgus Monkeys via iv and sc routes of delivery. Pharmacokinetic data for Examples of the invention and a reference compound, olcegepant, are detailed in Tables 5A and 6A, 4B and 5B, 4C and 5C.

Methods: For rat studies, groups of three male Sprague Dawley® rats, typically ranging in weight between 180 and 300 g, were given a single dose of Example or reference compound via one of the following routes: iv, sc or IN, using doses, dose volumes and vehicles specified in Tables 5A, 4B, and 4C. Prior to IN dosing rats were anaesthetised with an intramuscular dose of 25-30 mg/kg ketamine cocktail (ketamine, xylazine hydrochloride and acepromazine maleate in saline) and the dose is introduced over 20-30 s via a polyethylene PE-10 tube inserted approximately 5 mm into the nasal cavity of the rat.

[00122] For cynomolgus monkey studies, groups of three male monkeys, typically ranging in weight between 3.0 and 4.5 kg, were given a single dose of Example or reference compound via one of the following routes: iv or sc, using doses, dose volumes and vehicles specified in Tables 6A, 5B, and 5C. Following dosing by the routes above blood samples were taken at several time points (typically pre-dose, 0.083, 0.25, 0.51, 2, 4, 8 and 24 h) via serial tail vein bleeds (rat) or cephalic or saphenous vein (monkey) from the animal and centrifuged to separate plasma for analysis by LC/MS/MS assay. WinNonlin v6.2 statistics software (Pharsight Corporation, California, USA) was used to generate pharmacokinetic parameters using the non- compartmental model. Table 5A.

[00123] Thermodynamic solubility profiling. A 50 mM DMSO stock solution of test compound was prepared, and from this, a working solution of 1 mM was prepared by dilution with DMSO. The UV absorbance of working solution was scanned from 220 nm to 1000 nm to identify the wavelength maxima of test compound. The 1 mM working solution was then serially diluted in DMSO to different concentrations to determine linearity/calibration curve. To ascertain the aqueous thermodynamic solubility of test compound, samples were added to a volume of PBS buffer (pH 7.4) or Sodium Phosphate Buffer (pH 6.0) which was appropriate to generate a final concentration of 1 mg/mL if all test compound dissolved. The resulting solution was then kept on a RotoSpin shaker at 50 rpm for 24 h at rt before the solution was filtered using 0.45 micron PVDF injector filters in order to remove the insoluble fraction of the compound. Subsequently, 150 uL of the filtrate is taken for quantification using a UV spectrophotometer, acquiring the optical density of standard solutions and test compound at the same wavelength maxima. From the optical density of test compound the thermodynamic solubility is calculated using the linearity/calibration curve and expressed as micromolar (µM). Solubility profiles of certain compounds of the invention are detailed in Tables 7A, 6B, and 6C. Table 7A.

[00124] Compounds of the invention having formula IB-1 of IB-2 may be prepared, for example, by routes including those depicted in Scheme 1B. Those of ordinary skill in the art readily understand that particular enantiomers and diastereomers not expressly set forth in Scheme 1B, or the following synthetic examples, can be prepared by using alternative chiral starting materials. Alternatively, the compounds can be prepared using racemic starting materials and the stereoisomers separated using techniques known in the art, for example chiral HPLC methods. Details of many of the standard transformations such as those in the routes below and others which could be used to perform the same transformations can be found in standard reference textbooks such as“Organic Synthesis”, M. B. Smith, McGraw-Hill (1994) or “Advanced Organic Chemistry”, 4^th edition, J. March, John Wiley & Sons (1992).

[00125] Urea formations between amino acid intermediates, for example methyl esters of amino acids, and amine intermediates can be formed under conditions using a coupling agent such as DSC in the presence of a base such as triethylamine or DIPEA in solvents such as DMF. The methyl ester portion of the subsequently formed urea derivatives can be saponified using aqueous bases such as lithium hydroxide in a suitable solvent such as THF, MeOH, 1,4-dioxane, EtOAc or a mixture thereof. The acid intermediates thus formed can be converted into amide examples under standard conditions, for example using a coupling agent such as HATU, in the presence of a base such as DIPEA in a suitable solvent such as DMF or DCM. The amine partners for such amide couplings can be prepared using an appropriate combination of standard transformations (for example reductive aminations using an amine, an aldehyde or ketone, and a reducing agent such as sodium triacetoxyborohydride in a solvent such as DCM in the presence of acetic acid; or amide formation under conditions such as those detailed above; or nucleophilic aromatic substitution (S_NAr) reactions). In the synthesis of compounds of the invention S_NAr reactions between an amine and a halogenated heterocycle are typically conducted at 80ºC, in a suitable solvent such as MeCN and in the presence of a base such as K2CO3. Following standard transformations such as the above, or during such a sequence of such transformations, removal of standard protecting groups may be necessary and can be undertaken using conditions which can be found in reference textbooks, for example“Protecting Groups”, 3^rd edition, P. J. Kocieński, Georg Thieme Verlag (2005). One such transformation is the removal of a tert-butoxycarbonyl group (commonly known as a Boc group) from an amine under acidic conditions such as HCl in a solvent such as 1,4-dioxane, MeOH, EtOH, DCM or combinations thereof. It can be appreciated that Boc deprotection of amine intermediates of the invention which possess additional basic centres may result in hydrochloride salts of different stoichiometries. For example the Boc deprotection of an intermediate with one additional basic centre will result in the formation of a new amine intermediate which is for example the mono-hydrochloride or di- hydrochloride salt, which will often be used without neutralisation of the hydrochloride salt to produce the free base of the intermediate, as it can be appreciated that in the subsequent amide formation an excess of a base such as DIPEA or triethylamine is typically used to neutralise the hydrochloride salt. Amine intermediates of the invention formed by Boc-deprotection which are used without neutralisation to the free base are named herein as the hydrochloride (x HCl), and the present invention extends to all salt forms of the said intermediates. Another such protecting group removal is the deprotection of a carbobenzyloxy-protected amine (commonly known as a CBZ or Z group) using reductive conditions such as catalysis by palladium on carbon in a solvent such as EtOH or aqueous EtOH in the presence of gaseous H₂. Alternative conditions for the removal of a CBZ-protecting group include transfer hydrogenation, for example using a palladium on carbon catalyst in the presence of or ammonium formate in a solvent such as EtOH or aqueous EtOH at an elevated temperature such as 70ºC.

[00126] In some cases, the general procedures described above will produce a mixture of stereoisomers. These stereoisomers can generally be separated using HPLC. In some cases, a reversed-phase chiral method is used to separate the stereoisomers. In such reversed-phase chiral method, a Chiralpak IF-3 column (250 x 4.6mm; 3 µm packing; Daicel Part Number: 86525) is used along with a binary gradient mobile phase of 0.1% trifluoroacetic acid in deionized water (Mobile Phase A) and 0.1% trifluoroacetic acid in methanol (Mobile Phase B). The chiral stationary phase is immobilized on the packing’s silica backbone, allowing for both normal- phase isocratic and reversed-phase gradient operation. The mobile phase components are delivered using a binary high-pressure mixing pump along with a flow rate of 0.8 mL/minute (Agilent 1200 HPLC system). The gradient program is 35-50% B in 30 minutes. Compound solutions are prepared at a concentration of 1.0 mg/mL in 50/50 pH 4.5, 10 mM ammonium acetate buffer/methanol, and analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and a column temperature of 35 °C.

[00127] In other cases, particularly with respect to several of the intermediates, a normal-phase chiral method is used to separate the stereoisomers. In such normal-phase method, a Chiralpak AD-H column (250 X 4.6 mm; 5 µm packing; Daicel Part Number: 19325) is used along with a binary isocratic mobile phase of 70% Heptane and 30% Isopropanol. The isopropanol mobile phase component is modified with 0.2% Diethylamine in order to facilitate elution of the basic analyte. The mobile phase components are delivered using a binary high- pressure mixing pump along with a flow rate of 1.0 mL/minute (Agilent 1200 HPLC system). If desired, the mobile phase components may be pre-mixed in the proper ratio (70:30 Heptane : 0.2% Diethylamine in Isopropanol), degassed, and delivered from a single container. Compound solutions with a concentration of 2 mg/mL in methanol are analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and ambient column temperature. If this normal-phase method is used to separate intermediates, the chiral intermediates can then be used to prepare chiral final compounds.

[00128] In still further cases, particularly with respect to several of the intermediates, a normal-phase chiral method is used to separate the stereoisomers. In such normal-phase method, a Chiralpak AD-H column (250 X 4.6 mm; 5 µm packing; Daicel Part Number: 19325) is used along with a binary isocratic mobile phase of 85% Heptane and 15% Isopropanol. The isopropanol mobile phase component is modified with 0.2% Diethylamine in order to facilitate elution of the basic analyte. The mobile phase components are delivered using a binary high- pressure mixing pump along with a flow rate of 1.0 mL/minute (Agilent 1200 HPLC system). If desired, the mobile phase components may be pre-mixed in the proper ratio (85:15 Heptane : 0.2% Diethylamine in Isopropanol), degassed, and delivered from a single container. Compound solutions with a concentration of 2 mg/mL in methanol are analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and ambient column temperature. If this normal-phase method is used to separate intermediates, the chiral intermediates can then be used to prepare chiral final compounds. SYNTHESIS OF INTERMEDIATES

Preparation of carboxylic acid intermediates

Typical procedure for the preparation of carboxylic acid intermediates via urea formation and subsequent saponification, as exemplified by the preparation of Intermediate 6B, (2R)- 3-(7-methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1- l)carbon l]amino}propanoic acid

[00129] Step 1) Et₃N (2.26 mL, 16.3 mmol) was added to a solution of (R)-methyl 2- amino-3-(7-methyl-1H-indazol-5-yl)propanoate dihydrochloride (Intermediate 5B, 995 mg, 3.3 mmol) and DSC (917 mg, 3.6 mmol) in DMF (20 mL) and the mixture stirred at rt for 30 min. Spiro[piperidine-4,4'-[4H]pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one (Intermediate 4B, 785 mg, 3.6 mmol) was then added portionwise and the reaction mixture stirred at rt for 18 h before concentration in vacuo. The residue was partitioned between H₂O and MeOH / DCM (1:9), the phases were separated and the aqueous layer was washed with H₂O. Residual solid from the separation step was dissolved in MeOH and the combined organic layers were concentrated in vacuo and purified by flash chromatography, eluting with EtOAc in MeOH (20:1), to yield methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'- pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoate (1.06 g, 2.22 mmol) as a white solid. LCMS (Method A): m/z 479.3 (ES+), at 2.61 min, 100%.

1H NMR: (400 MHz, DMSO-d₆) δ: 1.59-1.75 (m, 2H), 1.78-1.90 (m, 2H), 2.45 (s, 3H), 2.90- 3.08 (m, 4H), 3.59 (s, 3H), 3.86-3.96 (m, 2H), 4.28-4.38 (m, 1H), 6.94-7.06 (m, 3H), 7.32 (dd, J=7.4, 1.2, 1H), 7.39 (s, 1H), 7.95 (s, 1H), 8.18 (dd, J=5.1, 1.6, 1H), 10.79 (s, 1H), 13.04 (s, 1H). [00130] Step 2) Methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro- 1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoate (1.06 g, 2.22 mmol) was dissolved in THF (15 mL) and MeOH (3 mL) and an aqueous solution of LiOH (1M, 4.4 mL, 4.4 mmol) was added dropwise. After stirring at rt for 3.5 h further aqueous LiOH (1M, 2.2 mL, 2.2 mmol) was added dropwise and the mixture stirred for 1 h at rt before concentration under a stream of nitrogen. The residue was dissolved in a minimum volume of H₂O and cooled to 0ºC. Aqueous 1M HCl was added dropwise to adjust the pH to≤ 3 and the resulting precipitate was isolated by filtration, washed with cold H2O and Et2O to yield the title compound (877 mg, 1.89 mmol) as a pale yellow solid.

Data in Table 1B. Intermediate 7B, (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoic acid

[00131] The title compound (1.50 g, 3.2 mmol) was prepared over two steps from (R)- methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate (Intermediate 5B, 1.00 g, 4.3 mmol) and 1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Intermediate 1, 1.02 g, 4.7 mmol) using the methods of Intermediate 6B.

Data in Table 1B. Intermediate 9B, (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,4-dihydroquinazolin- 3(2H)-yl)piperidin-1- l]carbon l}amino)propanoic acid

[00132] The title compound (561 mg, 1.18 mmol) was prepared over two steps from (R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate (Intermediate 5B, 917 mg, 3.93 mmol) and 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (Intermediate 3B, 1.00 g, 4.32 mmol) using the methods of Intermediate 6B.

Data in Table 1B. Intermediate 8B, (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoic acid

[00133] Step 1) To a solution of (R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl) propanoate (Intermediate 5, 6.05 g, 25.9 mmol) in DMF (60 mL) under N₂ at approximately - 20°C was added CDI (8.40 g, 51.8 mmol) and the mixture was stirred for 15 min while keeping the temperature below -10°C. A solution of H2O (2.34 mL) in a few mL of DMF was added and stirring continued for 15 min while keeping the temperature below -10°C.3-(Piperidin-4-yl) quinolin-2(1H)-one (Intermediate 2B, 6.99 g, 30.6 mmol), DIPEA (4.93 mL, 28.2 mmol) and DCM (20 mL) were then added in that order and the mixture was heated to 40°C under N₂ for 12 hrs. After cooling to rt, 2M HCl (aq) (38.7 mL) was added and the mixture was extracted twice with DCM. The combined organic extracts were washed three times with H2O, dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography, eluting with MeOH/DCM (5:95), yielded methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoate (10.4 g, 21.3 mmol) as a light tan solid.

1H NMR: (400 MHz, CDCl3) δ: 1.40-1.60 (m, 2H), 1.95-1.97 (m, 2H), 2.46 (s, 3H), 2.90-3.00 (m, 2H), 3.11-3.26 (m, 3H), 3.76 (s, 3H), 4.07-4.12 (m, 2H), 4.86-4.91 (m, 1H), 5.18 (d, J=7.6, 1H), 6.93 (s, 1H), 7.17-7.21 (m, 1H), 7.24 (s, 1H), 7.32 (s, 1H), 7.43-7.54 (m, 3H), 7.95 (s, 1H), 10.70 (s, 2H).

[00134] Step 2) To a solution of methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2- oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoate (9.79 g, 20.1 mmol) in 1,4-dioxane (150 mL) was added a solution of LiOH·H2O (1.26 g, 30.0 mmol) in H2O (150 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to near- dryness and re-dissolved in H₂O before being acidified with aqueous 2M HCl (approximately 15 mL) whilst being rapidly stirred. The resulting thick white precipitate was isolated by filtration and washed with H2O until the washings were near neutral pH. Drying in vacuo yielded the title compound (8.11 g, 17.1 mmol) as an off-white solid.

Data in Table 1B. Preparation of amine intermediates

Intermediate 12B, benzyl 4-(2,8-diazaspiro[4.5]dec-8-yl)piperidine-1-carboxylate hydrochloride

[00135] Step 1) A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 10, 0.50 g, 2.08 mmol), benzyl 4-oxopiperidine-1-carboxylate (Intermediate 11B, 583 mg, 2.50 mmol), acetic acid (143 µL, 2.50 mmol) and sodium triacetoxyborohydride (530 mg, 2.50 mmol) in DCM (10 mL) was stirred at rt overnight. Further benzyl 4-oxopiperidine-1- carboxylate (Intermediate 11B, 600 mg, 2.57 mmol) and acetic acid (150 µL, 2.62 mmol) were added and the mixture stirred at rt for 1 h before addition of further sodium

triacetoxyborohydride (550 mg, 2.59 mmol). The mixture was stirred at rt overnight before concentration in vacuo and purification by gradient flash chromatography, eluting with 0-10% MeOH in DCM, yielded tert-butyl 8-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-2,8- diazaspiro[4.5]decane-2-carboxylate (620 mg, 1.35 mmol).

LCMS (Method B): m/z 458.2 (ES+), at 1.70 min.

1H NMR: (400 MHz, CDCl₃) δ: ppm 1.45 (s, 9H), 1.48-1.56 (m, 1H), 1.64-1.74 (m, 4H), 1.87- 1.96 (m, 2H), 2.51-1.85 (m, 10H), 3.30-3.43 (m, 4H), 4.19-4.32 (m, 2H), 5.11 (s, 2H), 7.30-7.40 (m, 5H). [00136] Step 2) HCl in 1,4-dioxane (4M, 5.0 mL, 20.0 mmol) was added to a solution of (tert-butyl 8-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-2,8-diazaspiro[4.5]decane-2- carboxylate (310 mg, 0.68 mmol) in MeOH (5 mL). The mixture was stirred at rt for 3 d before concentration in vacuo yielded the title compound (colourless solid, 290 mg).

Data in Table 1B. Intermediate 14B, benzyl [(2R)-1-(2,8-diazaspiro[4.5]dec-8-yl)-1-oxopropan-2- yl]methylcarbamate h drochloride

[00137] Step 1) A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 10, 865 mg, 3.60 mmol), N-[(benzyloxy)carbonyl]-N-methyl-D-alanine (Intermediate 13, 712 mg, 3.00 mmol), HATU (1.37 g, 3.60 mmol) and DIPEA (2.68 mL, 15.0 mmol) in DCM (25 mL) was stirred at rt overnight. Saturated aqueous NaHCO₃ solution was added, the phases were separated and the organic phases was concentrated in vacuo. Purification by gradient flash chromatography, eluting with 2-10% MeOH in DCM, followed by preparative HPLC (Phenomenex Gemini-NX 5µm C18 column, 100 x 30 mm, eluting with 50 to 80% MeCN/Solvent B over 12.5 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H2O], collecting fractions by monitoring at 205 nm), yielded

8-{N- [(benzyloxy)carbonyl]-N-methyl-D-alanyl}-2,8-diazaspiro[4.5]decane-2-carboxylate as a colourless foam (1.08 g, 2.19 mmol).

LCMS (Method A): m/z 460.5 (ES+), at 4.68 min.

1H NMR: (400 MHz, DMSO-d6) δ: 1.10-1.29 (m, 5H), 1.30-1.47 (m, 1H), 1.39 (s, 9H), 1.52- 1.77 (m, 2H), 2.67-2.77 (m, 3H), 2.87-3.12 (m, 3H), 3.12-3.35 (m, 5H), 3.46-3.76 (m, 1H), 4.88- 5.09 (m, 2H), 5.12-5.22 (m, 1H), 7.25-7.42 (m, 5H). [00138] Step 2) The title compound (white foam, 1.08 g) was prepared from Step 1 material (1.08 g, 2.19 mmol) and 4M HCl in 1,4-dioxane (15 mL, 60.0 mmol) in MeOH (15 mL) using the methods of Intermediate 12B.

Data in Table 1B. Intermediate 16B, 8-(p ridin-4- l)-2,8-diazaspiro[4.5]decane h drochloride

[00139] Step 1) A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 10, 1.00 g, 4.16 mmol), 4-fluoropyridine hydrochloride (Intermediate 15, 614 mg, 4.60 mmol) and K2CO3 (1.74 g, 12.6 mmol) in MeCN (80 mL) was heated at 80ºC overnight before cooling to rt and concentration in vacuo. The residue was partitioned between EtOAc and H2O, the organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo.

Purification by gradient flash chromatography, eluting with 0-100% solvent B in DCM (where solvent B is 7N NH3 in MeOH / DCM, 1:9) yielded tert-butyl 8-(pyridin-4-yl)-2,8- diazaspiro[4.5]decane-2-carboxylate (610 mg, 1.92 mmol) as a brown, viscous oil.

LCMS (Method B): m/z 318.2 (ES+), at 1.36 min.

1H NMR: (400 MHz, CD3OD) δ: 1.46 (s, 9H), 1.63-1.68 (m, 4H), 1.81-1.85 (m, 2H), 3.23 (s 2H), 3.36-3.54 (m, 6H), 6.82-6.83 (m, 2H), 8.07-8.09 (m, 2H). [00140] Step 2) The title compound (brown oil, 550 mg) was prepared from step 1) material (610 mg, 1.92 mmol) and 4M HCl in 1,4-dioxane (10 mL) using the methods of Intermediate 12B, and used without purification in the preparation of Example 7b1.

Data in Table 1B. Table 1B.

[00141] Typical procedures for the preparation of examples via amide coupling, and where appropriate, deprotection, as exemplified by the preparation of the below examples.

Procedure 1B:

Example 2b

[00142] Step 1) A mixture of (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoic acid (Intermediate 8, 100 mg, 0.21 mmol), benzyl [(2R)-1-(2,8-diazaspiro[4.5]dec-8-yl)-1-oxopropan-2-yl]methylcarbamate hydrochloride (Intermediate 14, 99 mg, 0.25 mmol), HATU (96 mg, 0.25 mL) and DIPEA (146 µL, 0.84 mmol) in DMF (5 mL) was stirred at rt overnight before concentration in vacuo.

Purification by gradient flash chromatography, eluting with 0-10% MeOH in DCM yielded benzyl methyl[(2R)-1-{2-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]-2,8-diazaspiro[4.5]dec-8-yl}-1- oxopropan-2-yl]carbamate (160 mg, 0.20 mmol) as a pale yellow solid.

LCMS (Method B): m/z 815.2 (ES+), at 1.41 min, 95%.

[00143] Step 2) Ammonium formate (126 mg, 2.0 mmol) was added to a mixture of benzyl methyl[(2R)-1-{2-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]-2,8-diazaspiro[4.5]dec-8-yl}-1- oxopropan-2-yl]carbamate (160 mg, 0.20 mmol) in EtOH (10 mL) and H2O (2 mL). Palladium on carbon (10%, 10 mg) was added and the reaction mixture was heated at 70ºC overnight. After cooling to rt further ammonium formate (126 mg, 2.0 mmol) and palladium on carbon (10%, 10 mg) were added and the mixture heated at 70ºC for 1 h before cooling to rt, filtration through celite, and concentration of the filtrate in vacuo. Purification by gradient flash chromatography eluting with 0-10% MeOH in DCM, followed by preparative HPLC (Phenomenex Gemini-NX 5µm C18 column, 100 x 30 mm, eluting with 20 to 40% MeCN/Solvent B over 12.5 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O], collecting fractions by monitoring at 205 nm), yielded the title compound (20 mg, 0.03 mmol) as a colourless solid. Data in Table 2B. Procedure 2B:

Example 5b.

[00144] Step 1) Benzyl methyl[(2R)-1-{2-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2'- oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1- yl)carbonyl]amino}propanoyl]-2,8-diazaspiro[4.5]dec-8-yl}-1-oxopropan-2-yl]carbamate (26 mg, 0.03 mg) was prepared from (2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2'-oxo-1',2'-dihydro- 1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoic acid

(Intermediate 6, 70 mg, 0.15 mmol), benzyl [(2R)-1-(2,8-diazaspiro[4.5]dec-8-yl)-1-oxopropan- 2-yl]methylcarbamate hydrochloride (Intermediate 14, 71 mg, 0.18 mmol), HATU (68 mg, 0.18 mmol) and DIPEA (0.13 mL, 0.18 mmol) in DMF (2 mL) using the methods of Example 2, Step 1.

LCMS (Method A): m/z 806.7 (ES+), at 3.64 min.

1H NMR: (400 MHz, CD3OD) δ: ppm 0.17-1.06 (m, 2H), 1.06-1.47 (m, 7H), 1.47-1.75 (m, 1H), 1.76-1.96 (m, 1H), 2.03 (d, J=5.1, 3H), 2.19-2.43 (m, 1H), 2.52 (s, 3H), 2.69-2.96 (m, 5H), 2.96- 3.24 (m, 7H), 3.40-3.55 (m, 1H), 3.55-3.97 (m, 1H), 4.07 (d, J=10.5, 2H), 4.52-4.74 (m, 1H), 4.97-5.12 (m, 1H), 5.13-5.33 (m, 1H), 6.93-7.19 (m, 3H), 7.20-7.65 (m, 9H), 7.89-8.06 (m, 1H), 8.20 (d, J=4.7, 1H). [00145] Step 2) A mixture of benzyl methyl[(2R)-1-{2-[(2R)-3-(7-methyl-1H-indazol- 5-yl)-2-{[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1- yl)carbonyl]amino}propanoyl]-2,8-diazaspiro[4.5]dec-8-yl}-1-oxopropan-2-yl]carbamate (26 mg, 0.03 mg) and palladium on carbon (10%, 10 mg) in EtOH (2.5 mL) and H₂O (0.5 mL) was stirred at rt overnight under an atmosphere of H2. After removal of the H2 atmosphere the mixture was filtered through celite and the filtrate concentrated in vacuo to yield the title compound (22 mg, 0.03 mmol).

Data in Table 2B. Further examples prepared by the above procedures are detailed in Table 2B. Table 2B.

[00146] Compounds of the invention having formula IC-1 and IC-2 may be prepared by routes including those in Scheme 1C. Those of ordinary skill in the art readily understand that particular enantiomers and diastereomers not expressly set forth in Scheme 1C, or the following synthetic examples, can be prepared by using alternative chiral starting materials. Alternatively, the compounds can be prepared using racemic starting materials and the stereoisomers separated using techniques known in the art, for example chiral HPLC methods. Details of many of the standard transformations such as those in the routes below and others which could be used to perform the same transformations can be found in standard reference textbooks such as“Organic Synthesis”, M. B. Smith, McGraw-Hill (1994) or“Advanced Organic Chemistry”, 4^th edition, J. March, John Wiley & Sons (1992).

Scheme 1C

[00147] Urea formations between amino acid intermediates, for example methyl esters of amino acids, and amine intermediates can be formed under conditions using a coupling agent such as DSC or CDI in the presence of a base such as triethylamine or DIPEA in solvents such as DMF and/or DCM. The methyl ester portion of the subsequently formed urea derivatives can be saponified using aqueous bases such as lithium hydroxide in a suitable solvent such as THF, MeOH, 1,4-dioxane, or a mixture thereof. The acid intermediates thus formed can be converted into amide examples under standard conditions, for example using a coupling agent such as HATU, in the presence of a base such as DIPEA or triethylamine in a suitable solvent such as DMF. The amine partners for such amide couplings can be prepared using an appropriate combination of standard transformations (for example reductive aminations using an amine, an aldehyde or ketone, and a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as MeOH or DCE, optionally in the presence of an additive such as acetic acid or zinc chloride; or alkylation using an alkyl halide and a strong base such as sodium hydride in a suitable solvent such as DMF). Following standard transformations such as the above, or during such a sequence of such transformations, removal of standard protecting groups may be necessary and can be undertaken using conditions which can be found in reference textbooks, for example“Protecting Groups”, 3^rd edition, P. J. Kocieński, Georg Thieme Verlag (2005). One such transformation is the removal of a tert-butoxycarbonyl group

(commonly known as a Boc group) from an amine under acidic conditions such as HCl in a solvent such as 1,4-dioxane, MeOH, EtOH, DCM or combinations thereof. It can be appreciated that Boc deprotection of amine intermediates of the invention which possess additional basic centres may result in hydrochloride salts of different stoichiometries. For example the Boc deprotection of an intermediate with one additional basic centre will result in the formation of a new amine intermediate which is for example the mono-hydrochloride or di-hydrochloride salt, which will often be used without neutralisation of the hydrochloride salt to produce the free base of the intermediate, as it can be appreciated that in the subsequent amide formation an excess of a base such as DIPEA or triethylamine is typically used to neutralise the hydrochloride salt. Amine intermediates of the invention formed by Boc-deprotection which are used without neutralisation to the free base are named herein as the hydrochloride (x HCl), and the present invention extends to all salt forms of the said intermediates. Examples of the invention may be transformed into further examples using standard transformations such as those detailed above, for example saponification of an ester using conditions such as those detailed above. [00148] In some cases, the general procedures described above will produce a mixture of stereoisomers. These stereoisomers can generally be separated using HPLC. In some cases, a reversed-phase chiral method is used to separate the stereoisomers. In such reversed-phase chiral method, a Chiralpak IF-3 column (250 x 4.6mm; 3 µm packing; Daicel Part Number: 86525) is used along with a binary gradient mobile phase of 0.1% trifluoroacetic acid in deionized water (Mobile Phase A) and 0.1% trifluoroacetic acid in methanol (Mobile Phase B). The chiral stationary phase is immobilized on the packing’s silica backbone, allowing for both normal- phase isocratic and reversed-phase gradient operation. The mobile phase components are delivered using a binary high-pressure mixing pump along with a flow rate of 0.8 mL/minute (Agilent 1200 HPLC system). The gradient program is 35-50% B in 30 minutes. Compound solutions are prepared at a concentration of 1.0 mg/mL in 50/50 pH 4.5, 10 mM ammonium acetate buffer/methanol, and analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and a column temperature of 35 °C.

[00149] In other cases, particularly with respect to several of the intermediates, a normal-phase chiral method is used to separate the stereoisomers. In such normal-phase method, a Chiralpak AD-H column (250 X 4.6 mm; 5 µm packing; Daicel Part Number: 19325) is used along with a binary isocratic mobile phase of 70% Heptane and 30% Isopropanol. The isopropanol mobile phase component is modified with 0.2% Diethylamine in order to facilitate elution of the basic analyte. The mobile phase components are delivered using a binary high- pressure mixing pump along with a flow rate of 1.0 mL/minute (Agilent 1200 HPLC system). If desired, the mobile phase components may be pre-mixed in the proper ratio (70:30 Heptane : 0.2% Diethylamine in Isopropanol), degassed, and delivered from a single container. Compound solutions with a concentration of 2 mg/mL in methanol are analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and ambient column temperature. If this normal-phase method is used to separate intermediates, the chiral intermediates can then be used to prepare chiral final compounds.

[00150] In still further cases, particularly with respect to several of the intermediates, a normal-phase chiral method is used to separate the stereoisomers. In such normal-phase method, a Chiralpak AD-H column (250 X 4.6 mm; 5 µm packing; Daicel Part Number: 19325) is used along with a binary isocratic mobile phase of 85% Heptane and 15% Isopropanol. The isopropanol mobile phase component is modified with 0.2% Diethylamine in order to facilitate elution of the basic analyte. The mobile phase components are delivered using a binary high- pressure mixing pump along with a flow rate of 1.0 mL/minute (Agilent 1200 HPLC system). If desired, the mobile phase components may be pre-mixed in the proper ratio (85:15 Heptane : 0.2% Diethylamine in Isopropanol), degassed, and delivered from a single container. Compound solutions with a concentration of 2 mg/mL in methanol are analyzed using an injection volume of 5 µL, a UV detection wavelength of 280 nm, and ambient column temperature. If this normal-phase method is used to separate intermediates, the chiral intermediates can then be used to prepare chiral final compounds. SYNTHESIS OF INTERMEDIATES

Preparation of carboxylic acid intermediates

Typical procedure for the preparation of carboxylic acid intermediates via urea formation and subsequent saponification, as exemplified by the preparation of Intermediate 4C, (2R)- 3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1- yl]carbon l}amino)propanoic acid

Intermediate 3 Intermediate 1 Intermediate 4

[00151] Step 1) To a solution of (R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl) propanoate (Intermediate 3C, 6.05 g, 25.9 mmol) in DMF (60 mL) under N₂ at approximately - 20ºC was added CDI (8.40 g, 51.8 mmol) and the mixture was stirred for 15 min while keeping the temperature below -10ºC. A solution of H2O (2.34 mL) in a few mL of DMF was added and stirring continued for 15 min while keeping the temperature below -10ºC.3-(Piperidin-4-yl) quinolin-2(1H)-one (Intermediate 1, 6.99 g, 30.6 mmol), DIPEA (4.93 mL, 28.2 mmol) and DCM (20 mL) were then added in that order and the mixture was heated to 40ºC under N2 for 12 h. After cooling to rt, 2M HCl (aq) (38.7 mL) was added and the mixture was extracted twice with DCM. The combined organic extracts were washed three times with H₂O, dried (Na₂SO₄) and concentrated in vacuo. Purification by flash chromatography, eluting with MeOH/DCM (5:95), yielded methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoate (10.4 g, 21.3 mmol) as a light tan solid.

1H NMR: (400 MHz, CDCl₃) δ: 1.40-1.60 (m, 2H), 1.95-1.97 (m, 2H), 2.46 (s, 3H), 2.90-3.00 (m, 2H), 3.11-3.26 (m, 3H), 3.76 (s, 3H), 4.07-4.12 (m, 2H), 4.86-4.91 (m, 1H), 5.18 (d, J=7.6, 1H), 6.93 (s, 1H), 7.17-7.21 (m, 1H), 7.24 (s, 1H), 7.32 (s, 1H), 7.43-7.54 (m, 3H), 7.95 (s, 1H), 10.70 (s, 2H). [00152] Step 2) To a solution of methyl (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2- oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoate (9.79 g, 20.1 mmol) in 1,4-dioxane (150 mL) was added a solution of LiOH·H₂O (1.26 g, 30.0 mmol) in H₂O (150 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to near- dryness and re-dissolved in H₂O before being acidified with aqueous 2M HCl (approximately 15 mL) whilst being rapidly stirred. The resulting thick white precipitate was isolated by filtration and washed with H2O until the washings were near neutral pH. Drying in vacuo yielded the title compound (8.11 g, 17.1 mmol) as an off-white solid.

Data in Table 1C. Intermediate 5C, (2R)-2-({[4-(7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1- yl]carbon l}amino)-3-(7-meth l-1H-indazol-5- l)propanoic acid

Intermediate 3 Intermediate 2 Intermediate 5

[00153] Step 1) Et3N (1.25 mL, 9.0 mmol) was added to a solution of (R)-methyl 2- amino-3-(7-methyl-1H-indazol-5-yl)propanoate (Intermediate 3C, 700 mg, 3.0 mmol) and DSC (845 mg, 3.3 mmol) in DMF (20 mL) and the mixture stirred at rt for 30 min.7-Fluoro-3- (piperidin-4-yl)quinolin-2(1H)-one hydrochloride (Intermediate 2, 933 mg, 3.3 mmol) was then added portionwise and the reaction mixture stirred at rt overnight before concentration in vacuo. The residue was partitioned between H₂O and DCM, with a small amount of MeOH added to aid dissolution, and the organic phase with washed with H₂O. After concentration in vacuo the residue was purified by flash chromatography, eluting with EtOAc in MeOH (20:1), to yield methyl (2R)-2-({[4-(7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)-3- (7-methyl-1H-indazol-5-yl)propanoate (462 mg, 0.91 mmol) as a yellow solid.

LCMS (Method A): m/z 506.3 (ES+), at 3.35 min.

1H NMR: (400 MHz, DMSO-d₆) ^ ^ ppm 1.22-1.37 (m, 2H), 1.73 (t, J=10.2, 2H), 2.47 (s, 3H), 2.64-2.80 (m, 2H), 2.82-2.94 (m, 1H), 2.95-3.11 (m, 2H), 3.59 (s, 3H), 4.08 (d, J=12.5, 2H), 4.21-4.33 (m, 1H), 6.85 (d, J=7.8, 1H), 6.97-7.10 (m, 3H), 7.41 (s, 1H), 7.59 (s, 1H), 7.70 (dd, J=8.2, 6.2, 1H), 7.87-8.10 (m, 1H), 11.85 (s, 1H), 13.04 (s, 1H) [00154] Step 2) Methyl (2R)-2-({[4-(7-fluoro-2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)-3-(7-methyl-1H-indazol-5-yl)propanoate (462 mg, 0.91 mmol) was dissolved in THF (6 mL) and MeOH (1.2 mL) and an aqueous solution of LiOH (1M, 1.82 mL, 1.82 mmol) was added dropwise. After stirring at rt for 4 h the reaction mixture was concentrated under a stream of nitrogen, the residue dissolved in a minimum volume of H₂O and acidified with 1M HCl. The resulting precipitate was isolated by filtration, washed with cold H2O and Et2O to yield the title compound (406 mg, 0.83 mmol) as a pale yellow solid.

Data in Table 1C. Preparation of amine intermediates

Intermediate 8C, 4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidine hydrochloride

Intermediate 6 Intermediate 8

[00155] Step 1) tert-Butyl 4-oxopiperidine-1-carboxylate (Intermediate 7, 2.09 g, 10.5 mmol) was added to a suspension of 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (Intermediate 6C, 1.66 g, 10.0 mmol) in DCE (60 mL). The mixture was stirred at rt for 30 min before the addition of sodium triacetoxyborohydride (2.97 g, 14.0 mmol). After stirring at rt overnight tert- butyl 4-oxopiperidine-1-carboxylate (Intermediate 7C, 210 mg, 1.05 mmol) was added and the mixture stirred for 8 h at rt, followed by the addition of 4-oxopiperidine-1-carboxylate (Intermediate 7C, 600 mg, 3.01 mmol) and sodium triacetoxyborohydride (900 mg, 4.25 mmol) and stirring at rt for 4 d. H2O (100 mL) was added, the mixture was stirred for 2 min before the phases were separated and the aqueous layer (adjusted to pH 4.7) was washed with DCM (2 x 30 mL). DCM (30 mL) was added to the aqueous phase, and the aqueous phase was adjusted to pH 7 by the addition of 1M NaOH before extraction with DCM (7 x 30 mL), adjusting the aqueous phase pH to 7 before each extraction. The aqueous phase was further extracted with DCM (5 x 30 mL), adjusting the pH to 7.5 before each extraction. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to yield

4-(4-methyl-4H-1,2,4-triazol-3- yl)-1,4'-bipiperidine-1'-carboxylate (2.27 g, 6.50 mmol) which was used without purification in the subsequent step.

LCMS (Method E): m/z 350.4 (ES+), at 3.91 min.

1H NMR: (500 MHz, CD3OD) ^ ^ ppm 1.43-1.48 (m, 1H), 1.46 (s, 9H), 1.87-2.02 (m, 6H), 2.39- 2.46 (m, 2H), 2.51-2.58 (m, 1H), 2.76 (br s, 2H), 2.81-2.92 (m, 1H), 3.10 (dt, J=12.4, 3.6, 2H), 3.71 (s, 3H), 4.14 (dt, J=13.4, 2.4, 2H), 4.59 (br s, 1H), 8.35 (s, 1H) [00156] Step 2) 4N HCl in 1,4-dioxane (16.0 mL, 64.0 mmol) was added to a solution of tert-butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidine-1'-carboxylate (2.27 g, 6.50 mmol) in DCM (120 mL) and the mixture stirred at rt for 2 h. Concentration in vacuo yielded the title compound (2.23 g) as the hydrochloride salt which was used without further purification. Data in Table 1C. Alternative synthesis of Intermediate 8C, 4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,4'- bipiperidine

Intermediate 6 Intermediate 8

[00157] Step 1) Benzyl 4-oxopiperidine-1-carboxylate (Intermediate 22, 23.6 g, 101.1 mmol) and sodium triacetoxyborohydride (28.6 g, 134.8 mmol) were added to a solution of 4-(4- methyl-4H-1,2,4-triazol-3-yl)piperidine (Intermediate 6C, 16.0 g, 96.3 mmol) in DCE (580 mL). After stirring at rt overnight acetic acid (5 mL) was added, and after stirring at rt for a further 2 h benzyl 4-oxopiperidine-1-carboxylate (Intermediate 22C, 2.35 g, 10.1 mmol) and sodium triacetoxyborohydride (2.86 g, 13.5 mmol) were added. After stirring at rt for 2 h benzyl 4- oxopiperidine-1-carboxylate (Intermediate 22, 7.05 g, 30.3 mmol) and sodium

triacetoxyborohydride (8.58 g, 40.4 mmol) were added, the mixture was stirred at rt for 2 h before the addition of benzyl 4-oxopiperidine-1-carboxylate (Intermediate 22C, 7.05 g, 30.3 mmol) and sodium triacetoxyborohydride (8.58 g, 40.4 mmol). After stirring at rt overnight H2O (1 L) was added, the phases were separated, and the aqueous phase was extracted with DCM (3 x 300 mL). The pH of the aqueous phase was adjusted to 7.5 with 6N aqueous NaOH and extracted with DCM (5 x 300 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to yield benzyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidine- 1'-carboxylate (23.2 g, 60.6 mmol).

LCMS (Method A): m/z 384.3 (ES+), at 3.29 min.

1H NMR: (400 MHz, CD₃OD) ^ ^ ppm 1.40-1.52 (m, 2H), 1.86-2.05 (m, 6H), 2.39-2.51 (m, 2H), 2.53-2.66 (m, 1H), 2.75-2.98 (m, 3H), 3.04-3.18 (m, 2H), 3.71 (s, 3H), 4.22 (d, J=13.4, 2H), 5.11 (s, 2H), 7.29-7.39 (m, 5H), 8.35 (s, 1H) [00158] Step 2) A mixture of 10% palladium on carbon (4.76 g) and benzyl 4-(4- methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidine-1'-carboxylate (17.2 g, 44.8 mmol) in EtOH (200 mL) was stirred under an atmosphere of H2 (1.5 bar) at rt for 90 min. The mixture was filtered through celite, concentrated in vacuo, re-dissolved in DCM (200 mL) and concentrated in vacuo. The re-dissolution and concentration process was repeated five times, and after further drying in vacuo the title compound (10.0 g, 40.1 mmol) was obtained as a white solid.

1H NMR: (400 MHz, DMSO-d6) ^ ^ ppm 1.40-1.51 (m, 2H), 1.63-1.77 (m, 4H), 1.80-1.87 (m, 3H), 2.21-2.32 (m, 2H), 2.35-2.45 (m, 1H), 2.52-2.63 (m, 2H), 2.66-2.80 (m, 1H), 2.87-2.99 (m, 2H), 3.09 (d, J=12.5, 2H), 3.59 (br s, 3H), 8.31 (s, 1H). Intermediate 10C, 4-(1H-imidazol-2-yl)-1,4'-bipiperidine hydrochloride

Intermediate 9 Intermediate 7 [00159] Step 1) A solution of 4-(1H-imidazol-2-yl)piperidine hydrochloride (Intermediate 9C, 2.30 g, 12.3 mmol), Et₃N (4.96 mL, 35.6 mmol), tert-butyl 4-oxopiperidine-1- carboxylate (Intermediate 7C, 2.44 g, 12.2 mmol) and ZnCl₂ (84.6 mg, 0.61 mmol) in MeOH (100 mL) was stirred at 60ºC for 5 h. After cooling to rt, sodium cyanoborohydride (3.09 g, 49.2 mmol) was added portionwise and the mixture stirred at rt for 16 h. After partitioning between MeOH/DCM (1:9, 300 mL) and H₂O (250 mL) the aqueous phase was extracted with

MeOH/DCM (1:9, 300 mL) and the combined organic phases were dried (Na2SO4) and concentrated in vacuo to yield tert-butyl 4-(1H-imidazol-2-yl)-1,4'-bipiperidine-1'-carboxylate (5.0 g, colourless oil) which was used without purification in the subsequent step.

TLC: Rf 0.5 (MeOH/DCM 1:9).

LCMS (Method D-2): m/z 335.2 (ES+), at 4.95 min. [00160] Step 2) Et₃N (4.16 mL, 29.8 mmol) was added to a solution of tert-butyl 4- (1H-imidazol-2-yl)-1,4'-bipiperidine-1'-carboxylate (5.0 g) in DCM (100 mL). After stirring for 15 min di-tert-butyl dicarbonate (4.85 g, 22.2 mmol) was added at 0ºC portion wise and the reaction mixture stirred at rt for 16 h. After partitioning between MeOH/DCM (1:9, 300 mL) and H2O (250 mL) the aqueous phase was extracted with MeOH/DCM (1:9, 300 mL) and the combined organic phases were dried (Na2SO4) and concentrated in vacuo. Purification by gradient flash chromatography, eluting with 0-3% MeOH in DCM yielded

4-[1-(tert- butoxycarbonyl)-1H-imidazol-2-yl]-1,4'-bipiperidine-1'-carboxylate (1.40 g, 3.22 mmol) as a colourless oil.

1H NMR: (400 MHz, DMSO-d₆) δ: ppm 1.22-1.32 (m, 3H), 1.39 (s, 9H), 1.57 (s, 9H), 1.69-1.72 (m, 4H), 1.85-1.91 (m, 2H), 2.20 (br s, 2H), 2.67 (br d, 3H), 2.99 (br s, 2H), 3.96 (dd, J=10.0, 2H), 6.85 (d, J=1.6, 1H), 7.42 (d, J=1.2, 1H). [00161] Step 3) 4M HCl in 1,4-dioxane (15 mL, 60 mmol) was added dropwise to a solution of tert-butyl 4-[1-(tert-butoxycarbonyl)-1H-imidazol-2-yl]-1,4'-bipiperidine-1'- carboxylate (1.40 g, 3.22 mmol) in 1,4-dioxane (20 mL) at 0ºC, and the mixture subsequently stirred at rt for 4 h. After concentration in vacuo trituration with Et₂O yielded the title compound (1.0 g) as an off-white solid.

Data in Table 1C. Intermediate 12C, 4-(4-meth l-1H-imidazol-5- l)-1,4'-bipiperidine h drochloride

Intermediate 11 Intermediate 12 [00162] Step 1) A mixture of 4-(4-methyl-1H-imidazol-5-yl)piperidine hydrochloride (Intermediate 11, 2.0 g, 9.9 mmol) and triethylamine (1.7 mL, 11.9 mmol) in DMF (40 mL) was stirred at rt. After 5 min tert-butyl 4-oxopiperidine-1-carboxylate (Intermediate 7C, 2.4 g, 11.9 mmol) and acetic acid (0.68 ml, 11.9 mmol) were added. After 30 min stirring at rt sodium triacetoxyborohydride (2.52 g, 11.9 mmol) was added. After stirring at rt overnight the reaction mixture was concentrated in vacuo and the residue partitioned between DCM (100 mL) and saturated aqueous NaHCO3 (100 ml). The aqueous phase was extracted with DCM (100 mL) and the combined organic phases were washed with brine and further dried by passing through a hydrophobic frit. The solvent was removed in vacuo and the product oil crystallised on standing for 3 d. After trituration with diethylether / isohexane the solid was collected by filtration and dried in vacuo to yield tert-butyl 4-(4-methyl-1H-imidazol-5-yl)-1,4'-bipiperidine-1'-carboxylate (1.64 g, 4.7 mmol).

LCMS (Method B): m/z 349.2 (ES+), at 1.24 min.

1H NMR: (400 MHz, CDCl3) ^ ^ ppm 1.39-1.51 (m, 11H), 1.68-1.91 (m, 6H), 2.20 (s, 3H), 2.24- 2.37 (m, 2H), 2.40-2.53 (m, 1H), 2.55-2.77 (m, 3H), 2.97-3.07 (m, 2H), 4.15 (br s, 2H), 7.45 (s, 1H) (1 exchangeable proton not observed) [00163] Step 2) 4N HCl in 1,4-dioxane (10.0 mL, 40.0 mmol) was added to a solution of tert-butyl 4-(4-methyl-1H-imidazol-5-yl)-1,4'-bipiperidine-1'-carboxylate (1.6 g, 4.6 mmol) in DCM (20 mL) and the mixture stirred at rt. After 2 h the reaction mixture was concentrated in vacuo, and the residue taken up and re-evaporated from DCM (x2) to yield the title compound (3.22 g, contains residual solvent) which was used without further purification in the synthesis of Example 2.

Data in Table 1C. [00164] A sample of Intermediate 12C (100 mg) was dissolved in DCM (5 mL) and a minimum amount of MeOH, solid NaCO₃ (200 mg) was added and the mixture stirred for 2 h. The reaction mixture was filtered and the filtrate concentrated under a flow of N2 then in vacuo to yield the title compound as the free base (31 mg, 0.12 mmol).

LCMS (Method A): m/z 249.3 (ES+), at 2.24 min.

1H NMR: (400 MHz, CD3OD) ^ ^ ppm 1.47 (qd, J=12.3, 4.1, 2H), 1.72-1.83 (m, 4H), 1.86-1.93 (m, 2H), 2.16 (s, 3H), 2.30-2.39 (m, 2H), 2.46 (tt, J=11.6, 3.5, 1H), 2.53-2.67 (m, 3H), 3.02-3.14 (m, 4H), 7.40 (s, 1H) (2 exchangeable protons not observed). Intermediate 14C, 4-(1-propyl-1H-imidazol-2-yl)piperidine hydrochloride

Intermediate 13 Intermediate 14

[00165] Step 1) Sodium hydride (60% in mineral oil, 478 mg, 12.0 mmol) was added to a solution of 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (Intermediate 13C, 2.50 g, 9.95 mmol) in DMF (50 mL) at 0ºC. After stirring at 0ºC for 20 min 1-iodopropane (1.16 mL, 11.9 mmol) was added and the reaction was stirred at rt for 2 h before partitioning between EtOAc (200 mL) and H₂O (150 mL). The aqueous phase was extracted with EtOAc (200 mL) and the combined organic phases were dried (Na₂SO₄), filtered, and concentrated in vacuo.

Purification by gradient flash chromatography, eluting with 0-10% MeOH in DCM yielded tert- butyl 4-(1-propyl-1H-imidazol-2-yl)piperidine-1-carboxylate (2.90 g, 9.89 mmol) as a yellow LCMS (Method C-2): m/z 294.5 (ES⁺), at 1.77 min.

1H NMR: (400 MHz, DMSO-d6) δ: ppm 0.81-0.92 (m, 3H), 1.41 (s, 9H), 1.51–1.70 (m, 6H), 2.89-2.97 (m, 3H), 3.81–3.88 (m, 2H), 3.97–4.00 (d, J=13.6, 2H), 6.78 (s, 1H), 7.04 (s, 1H). [00166] Step 2) The title compound (2.60 g) was prepared from tert-butyl 4-(1-propyl- 1H-imidazol-2-yl)piperidine-1-carboxylate (2.90 g, 9.89 mmol) and 4M HCl in 1,4-dioxane (15 mL, 60.0 mmol) using the methods of Intermediate 10C, Step 3. Data in Table 1C. Intermediate 15C, 4-(1-propyl-1H-imidazol-2-yl)-1,4'-bipiperidine hydrochloride

Intermediate 14 Intermediate 15

[00167] The title compound (0.70 g, 1.81 mmol) was prepared from 4-(1-propyl-1H- imidazol-2-yl)piperidine hydrochloride (Intermediate 14, 1.00 g) and tert-butyl 4-oxopiperidine- 1-carboxylate (Intermediate 7C, 868 mg, 4.36 mmol) using the methods of Intermediate 10C, Steps 1 and 3.

Data in Table 1C. Intermediate 17C, ethyl 5-(1,4'-bipiperidin-4-yl)-4H-1,2,4-triazole-3-carboxylate hydrochloride

Intermediate 16 Intermediate 17

[00168] The title compound was prepared over two steps from ethyl 5-(piperidin-4-yl)- 4H-1,2,4-triazole-3-carboxylate (Intermediate 16, 448 mg, 2.00 mmol), tert-butyl 4- oxopiperidine-1-carboxylate (Intermediate 7C, 478 mg, 2.40 mmol), sodium

triacetoxyborohydride (610 mg, 2.88 mmol) and acetic acid (137 µL, 2.39 mmol) using the methods of Intermediate 12C.

Data in Table 1C. Intermediate 19C, 4-(4H-1,2,4-triazol-3-yl)-1,4'-bipiperidine hydrochloride

Intermediate 18 Intermediate 19 [00169] Step 1) A mixture of 4-(1H-1,2,4-triazol-5-yl)piperidine hydrochloride (Intermediate 18C, 377 mg, 2.00 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (Intermediate 7C, 478 mg, 2.40 mmol), acetic acid (137 µL, 2.39 mmol) and Et₃N (279 µL, 2.00 mmol) was stirred at rt for 30 min before addition of sodium triacetoxyborohydride (610 mg, 2.88 mmol) and stirring at rt for 3 d. Further tert-butyl 4-oxopiperidine-1-carboxylate (Intermediate 7C, 300 mg, 1.51 mmol) and acetic acid (100 µL, 1.75 mmol) were added and the reaction mixture was stirred at rt for 30 min before addition of sodium triacetoxyborohydride (400 mg, 1.89 mmol) and stirring at rt overnight. After concentration in vacuo purification by gradient flash chromatography, eluting with 0-10% MeOH in DCM, followed by 10% (7N NH₃ in MeOH) in DCM yielded tert-butyl 4-(4H-1,2,4-triazol-3-yl)-1,4'-bipiperidine-1'-carboxylate (350 mg, 1.04 mmol) as a white solid.

LCMS (Method B): m/z 336.2 (ES⁺), at 0.94 min.

1H NMR: (400 MHz, CD₃OD) δ: ppm, 1.45 (s, 9H), 1.86-1.95 (m, 4H), 2.10-2.13 (m, 2H), 2.56- 2.61 (m, 2H), 2.69-2.81 (m, 3H), 2.88-2.94 (m, 1H), 3.03-3.19 (m, 4H), 4.15-4.18 (m, 2H), 8.16 (s, 1H) (one exchangeable proton not observed). [00170] Step 2) The title compound (320 mg) was prepared from tert-butyl 4-(4H- 1,2,4-triazol-3-yl)-1,4'-bipiperidine-1'-carboxylate (350 mg, 1.04 mmol) and 4M HCl in 1,4- dioxane (10 mL, 40.0 mmol) in MeOH (10 mL) using the methods of Intermediate 12C.

Data in Table 1C. Intermediate 21C, 4-(5-methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidine hydrochloride

Intermediate 20 Intermediate 21

[00171] Step 1) A mixture of 4-(3-methyl-1H-1,2,4-triazol-5-yl)piperidine

dihydrochloride (Intermediate 20C, 478 mg, 2.00 mmol), tert-butyl 4-oxopiperidine-1- carboxylate (Intermediate 7C, 478 mg, 2.40 mmol), acetic acid (137 µL, 2.39 mmol) and Et₃N (558 µL, 4.00 mmol) was stirred at rt for 30 min before addition of sodium

triacetoxyborohydride (610 mg, 2.88 mmol) and stirring at rt overnight. After concentration in vacuo purification by gradient flash chromatography, eluting with 0-10% (7N NH3 in MeOH) in DCM yielded tert-butyl 4-(5-methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidine-1'-carboxylate (310 mg, 0.89 mmol) as a colourless solid.

LCMS (Method B): m/z 350.2 (ES⁺), at 1.01 min.

1H NMR: (400 MHz, CD3OD) δ: ppm 1.45 (s, 9H), 1.48-1.55 (m, 2H), 1.91-1.99 (m, 7H), 2.11- 2.15 (m, 2H), 2.68-2.90 (m, 6H), 3.24-3.27 (m, 2H), 4.16-4.20 (m, 2H) (one exchangeable proton not observed). [00172] Step 2) The title compound (240 mg, 0.93 mmol) was prepared from tert-butyl 4-(5-methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidine-1'-carboxylate (310 mg, 0.89 mmol) and 4M HCl in 1,4-dioxane (5 mL, 20.0 mmol) in MeOH (5 mL) using the methods of Intermediate 12C. Data in Table 1C. Table 1C. Intermediates.

Intermediate Name Data

1H) (exchangeable protons not observed)

Commercially available,

4^{-(3-methyl-1H-1,2,4-triazol-5-yl)}

2_0C CAS No.933713-90-7 (free base), 1221724-59- p_iperidine

9 (dihydrochloride salt)

LCMS (Method B): m/z 250.2 (ES+), at 0.68min. ¹H NMR (400 MHz, CD₃OD) δ: ppm 4^{-(5-methyl-4H-1,2,4-triazol-3-yl)-} 2.02-2.14 (m, 2H), 2.21-2.31 (m, 2H), 2.42-2.49 2^1C

1_{,4'-bipiperidine hydrochloride} (m, 4H), 2.68 (s, 3H), 3.09-3.22 (m, 3H), 3.31- 3.40 (m, 2H), 3.58-3.67 (m, 3H), 3.70-3.78 (m, 2H) (exchangeable protons not observed)

b^{enzyl 4-oxopiperidine-1-} 2_{2C Commercially available, CAS No. 19099-93-5}

c_arboxylate SYNTHESIS OF EXAMPLES Typical procedures for the preparation of examples via amide coupling, as exemplified by the preparation of the below examples. Procedure 1C:

E

[00173] A mixture of 4-(4-methyl-1H-imidazol-5-yl)-1,4'-bipiperidine hydrochloride (Intermediate 12C, contaminated with solvent residues, assumed to be 21.0 mmol), (2R)-3-(7- methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1- yl]carbonyl}amino)propanoic acid (Intermediate 4, 9.93 g, 21.0 mmol), HATU (8.00 g, 20.9 mmol) and DIPEA (14.6 mL, 83.8 mmol) in DMF (150 mL) was stirred at room temperature overnight before concentration in vacuo. Purification by gradient flash chromatography, eluting with 0-100% solvent B in DCM (where solvent B is 7N NH3 in MeOH / DCM, 1:9) yielded the title compound (7.50 g, 10.7 mmol) as a white solid.

Data in Table 2C.

Example 5c.

[00174] The title compound (45 mg, 0.06 mmol) was prepared from (2R)-2-({[4-(7- fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)-3-(7-methyl-1H-indazol- 5-yl)propanoic acid (Intermediate 5C, 74 mg, 0.15 mmol), 4-(4-methyl-4H-1,2,4-triazol-3-yl)- 1,4'-bipiperidine hydrochloride (Intermediate 8C, 97 mg), HATU (69 mg, 0.18) and Et3N (0.21 mL, 1.51 mmol) in DMF (1.5 mL) using methods of Example 4. The title compound was purified by gradient flash column chromatography eluting with 0-100% solvent B in DCM (where solvent B is 7N NH3 in MeOH / DCM, 1:9), followed by preparative reversed phase HPLC (Phenomenex Gemini-NX 5µm C18 column, 100 x 30 mm, eluting with 10 to 40% MeCN/Solvent B over 12.5 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions by monitoring at 205 nm).

Data in Table 2C. Procedure 2C:

Exa

[00175] Lithium hydroxide monohydrate (9 mg, 0.21 mmol) was added to a solution of ethyl 5-{1'-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoyl]-1,4'-bipiperidin-4-yl}-4H-1,2,4-triazole-3- carboxylate (Example 6, 110 mg, 0.14 mmol) in MeOH (10 mL) and H2O (2 mL) and the reaction mixture was stirred at rt overnight. Further lithium hydroxide monohydrate (10 mg, 0.24 mmol) was added and after stirring at rt for 1 d the mixture was partially concentrated in vacuo to remove the MeOH.1N aqueous HCl was added to the residue, which was then concentrated in vacuo and purified by preparative reversed phase HPLC (Phenomenex Gemini-NX 5µm C18 column, 100 x 30 mm, eluting with 5 to 35% MeCN/Solvent B over 12.5 min at 30 mL/min [where solvent B is 0.2% of (28% NH3/H2O) in H2O] and collecting fractions by monitoring at 205 nm) to yield the title compound (10 mg, 0.01 mmol) as a colourless solid.

Data in Table 2C. [00176] Further examples prepared by the above procedures are detailed in Table 2C. Table 2C.

Biological and biophysical assay results Table 3C.

Table 4C.

[00177] The disclosure is directed to the following aspects: Aspect 1. A compound of formula IA-1, IA-2, IA-3, or IA-4,

or a salt thereof, wherein R¹ is H or Q-(C1-C6)alkyl; where Q is a bond, C(O) or C(O)O and where the (C₁-C₆)alkyl can be optionally substituted by N(C₁-C₃alkyl)₂ or CO₂H; R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H; and R⁴ is an optionally substituted aryl group which may be monocyclic or fused to a further ring. Aspect 2. The compound according to aspect 1, wherein R⁴ is a substituted phenyl group wherein the substituents are selected from halo or hydroxy. Aspect 3. The compound according to aspect 1, wherein R⁴ is a moiety according to formula (II)

wherein X is halo.

Aspect 4. The compound according to aspect 3, wherein X is Br.

Aspect 5. The compound according to aspect 1, wherein R⁴ is

. Aspect 6. The compound according to aspect 5, wherein R⁴ is

.

Aspect 7. The compound according to aspect 1, wherein R² is H and R³ is:

.

Aspect 8. The compound according to aspect 1 wherein R² forms a spirocyclic heterocyclic ring with R³ to form:

Aspect 9. The compound according to aspect 1, wherein R² is H or forms a spirocyclic heterocyclic ring with R³ to form:

.

and wherein when R² is H, R³ is:

Aspect 10. The compound according to aspect 1, wherein R¹ is H, CO ^t

2Bu, CH₂CH₃, CH2CH2CH3, COCH2CH2CH2CH3, CH2CH2N(CH3)2, COCH2CO2H.

Aspect 11. The compound according to aspect 10, wherein R¹ is H,

Aspect 12. The compound according to aspect 1, wherein the compound is selected from the group consisting of:

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (1a1); N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (1a3);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (1a4);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (1a2);

tert-butyl 4-{(2S)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (2a1);

tert-butyl 4-{(2R)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (2a3);

tert-butyl 4-{(2S)-2-{[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (2a2);

tert-butyl 4-{(2R)-2-{[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (2a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (3a1);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (3a3); N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (3a2);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (3a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(1-propylpiperidin-4-yl)- 1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (4a1);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(1-propylpiperidin-4-yl)- 1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (4a2);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(1-propylpiperidin-4-yl)- 1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (4a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(1-propylpiperidin-4-yl)- 1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (4a3);

3,5-dibromo-Nα-{[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}-N-{(2S)- 1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-D-tyrosinamide (5a1);

3,5-dibromo-Nα-{[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}-N-{(2S)- 1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-L-tyrosinamide (5a2);

3,5-dibromo-Nα-{[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}-N-{(2R)- 1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-D-tyrosinamide (5a3); 3,5-dibromo-Nα-{[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}-N-{(2R)- 1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-L-tyrosinamide (5a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(1-pentanoylpiperidin-4- yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (6a1);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(1-pentanoylpiperidin-4- yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (6a3);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(1-pentanoylpiperidin-4- yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (6a2);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(1-pentanoylpiperidin-4- yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (6a4);

N-[(2R)-1-({(2S)-3-(1-ethylpiperidin-4-yl)-1-oxo-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (7a1);

N-[(2R)-1-({(2R)-3-(1-ethylpiperidin-4-yl)-1-oxo-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (7a3);

N-[(2S)-1-({(2S)-3-(1-ethylpiperidin-4-yl)-1-oxo-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (7a2);

N-[(2S)-1-({(2R)-3-(1-ethylpiperidin-4-yl)-1-oxo-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (7a4); 3,5-dibromo-Nα-{[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1- yl]carbonyl}-N-{(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan- 2-yl}-D-tyrosinamide (8a1);

3,5-dibromo-Nα-{[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1- yl]carbonyl}-N-{(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan- 2-yl}-L-tyrosinamide (8a2);

3,5-dibromo-Nα-{[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1- yl]carbonyl}-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan- 2-yl}-D-tyrosinamide (8a3);

3,5-dibromo-Nα-{[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1- yl]carbonyl}-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan- 2-yl}-L-tyrosinamide (8a4);

3,5-dibromo-Nα-{[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1-yl]carbonyl}-N- {(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-D- tyrosinamide (9a1);

3,5-dibromo-Nα-{[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1-yl]carbonyl}-N- {(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-L- tyrosinamide (9a2);

3,5-dibromo-Nα-{[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1-yl]carbonyl}-N- {(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-D- tyrosinamide (9a3);

3,5-dibromo-Nα-{[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1-yl]carbonyl}-N- {(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-L- tyrosinamide (9a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,4- dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide (10a1); N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,4- dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide (10a2);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,4- dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide (10a3);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,4- dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide (10a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-1',2'-dihydro-1H- spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (11a1);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-1',2'-dihydro-1H- spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (11a3);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-1',2'-dihydro-1H- spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (11a2);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-1',2'-dihydro-1H- spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (11a4);

N-[(2R)-1-({(2S)-3-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1-oxo-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]- 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (12a1); N-[(2R)-1-({(2R)-3-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1-oxo-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]- 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (12a3); N-[(2S)-1-({(2S)-3-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1-oxo-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]- 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (12a2); N-[(2S)-1-({(2R)-3-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1-oxo-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]- 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (12a4); 3-(4-{(2S)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3- [4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3-oxopropanoic acid, ammonium salt (13a1);

3-(4-{(2R)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3- [4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3-oxopropanoic acid, ammonium salt (13a3);

3-(4-{(2S)-2-{[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3- [4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3-oxopropanoic acid, ammonium salt (13a2);

3-(4-{(2R)-2-{[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3- [4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3-oxopropanoic acid, ammonium salt (13a4);

3,5-dibromo-Nα-[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1-yl)carbonyl]-N-{(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}-D-tyrosinamide (14a1);

3,5-dibromo-Nα-[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1-yl)carbonyl]-N-{(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}-L-tyrosinamide (14a2); 3,5-dibromo-Nα-[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1-yl)carbonyl]-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}-D-tyrosinamide (14a3); and

3,5-dibromo-Nα-[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1-yl)carbonyl]-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}-L-tyrosinamide (14a4).

Aspect 13. The compound accordin to aspect 12, wherein the compound is:

. Aspect 14. A method for treating a cerebrovascular or vascular disorder in a subject

comprising administering to the subject a compound according to aspect 1.

Aspect 15. The method of aspect 14, wherein the cerebrovascular or vascular disorder is migraine without aura, chronic migraine, pure menstrual migraine, menstrually-related migraine, migraine with aura, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, status migrainosus, cluster headache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, hemicrania continua, cyclic vomiting syndrome, allergic rhinitis, rosacea, dental pain, earache, middle ear inflammation, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, pain associated with inflammatory bowel disease– Crohn’s disease, gout, complex regional pain syndrome, Behçet's disease, endometriosis pain, back pain, or cough. Aspect 16. The method of aspect 14, wherein the compound is administered via a non-oral route.

Aspect 17. The method of aspect 16, wherein the non-oral route of administration is an intranasal route, a sub-cutaneous route or an intravenous route.

Aspect 18. A method of synthesising a compound according to aspect 1.

Aspect 19. A compound of formula IB-1 or IB-2

a salt thereof, wherein R¹ is

, , or ;

R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H. Aspect 20. The compound according to aspect 19, wherein R¹ is

.

Aspect 21. The compound according to aspect 19, wherein R² is H and R³ is

.

Aspect 22. The compound according to aspect 21, wherein R³ is

.

Aspect 23. The compound according to aspect 19, wherein R² forms a spirocyclic

heterocyclic ring with R³ to form

.

Aspect 24. The compound according to aspect 19, wherein the compound is selected from the group consisting of:

N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8- diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)piperidine-1-carboxamide (1b1); N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8- diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)piperidine-1-carboxamide (1b2);

N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (2b1);

N-[(2S)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (2b2);

N-[(2R)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (2b3);

N-[(2S)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (2b4);

N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine- 1-carboxamide (3b1);

N-[(2S)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine- 1-carboxamide (3b2);

N-[(2R)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine- 1-carboxamide (3b3);

N-[(2S)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine- 1-carboxamide (3b4); N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8- diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-1,4-dihydroquinazolin-3(2H)- yl)piperidine-1-carboxamide (4b1);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8- diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-1,4-dihydroquinazolin-3(2H)- yl)piperidine-1-carboxamide (4b2);

N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazine]-1-carboxamide (5b1);

N-[(2S)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazine]-1-carboxamide (5b2);

N-[(2R)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazine]-1-carboxamide (5b3);

N-[(2S)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazine]-1-carboxamide (5b4);

N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1- carboxamide (6b1);

N-[(2S)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1- carboxamide (6b2);

N-[(2R)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1- carboxamide (6b3); N-[(2S)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1- carboxamide (6b4);

N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(pyridin-4-yl)-2,8-diazaspiro[4.5]dec- 2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1- carboxamide (7b1); and

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(pyridin-4-yl)-2,8-diazaspiro[4.5]dec- 2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1- carboxamide (7b2). Aspect 25. The compound according to aspect 19, wherein the compound is

. Aspect 26. A method for treating a cerebrovascular or vascular disorder in a subject

comprising administering to the subject a compound according to aspect 19.

Aspect 27. The method of aspect 26, wherein the cerebrovascular or vascular disorder is migraine without aura, chronic migraine, pure menstrual migraine, menstrually-related migraine, migraine with aura, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, status migrainosus, cluster headache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, hemicrania continua, cyclic vomiting syndrome, allergic rhinitis, rosacea, dental pain, earache, middle ear inflammation, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, pain associated with inflammatory bowel disease– Crohn’s disease, gout, complex regional pain syndrome, Behçet's disease, endometriosis pain, back pain, or cough.

Aspect 28. The method of aspect 26, wherein the compound is administered via a non-oral route.

Aspect 29. The method of aspect 28, wherein the non-oral route of administration is an intranasal route, a sub-cutaneous route or an intravenous route.

Aspect 30. A method of synthesizing a compound according to aspect 19.

Aspect 31. A compound of formula IC-1 or IC-2

, or a salt thereof, wherein R¹ is H or F and Ar¹ is an optionally substituted 5 membered heterocyclic ring containing at least two nitrogen atoms. Aspect 32. The compound according to aspect 31, wherein Ar¹ is an optionally substituted five-membered heterocyclic ring including at least two nitrogen atoms, wherein the optional substituents are selected from (C₁-C₆)alkyl, CO₂R² where R² is H or (C₁- C3)alkyl. Aspect 33. The compound according to aspect 31, wherein R¹ is H. Aspect 34. The compound according to aspect 31, wherein Ar¹ is a five-membered heterocyclic ring including two or three nitrogen atoms, optionally substituted with (C₁- C₆)alkyl. Aspect 35. The compound according to aspect 31, wherein Ar¹ is

or .

Aspect 36. The compound according to aspect 31, wherein Ar¹ is

.

Aspect 37. The compound according to aspect 31, wherein Ar¹ is

.

Aspect 38. The compound according to aspect 31, wherein the compound is selected from the group consisting of:

N-[(2R)-1-[4-(1H-imidazol-2-yl)-1,4'-bipiperidin-1'-yl]-3-(7-methyl-1H-indazol-5-yl)-1- oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (1c1); N-[(2S)-1-[4-(1H-imidazol-2-yl)-1,4'-bipiperidin-1'-yl]-3-(7-methyl-1H-indazol-5-yl)-1- oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (1c2); N-[(2R)-1-[4-(4-methyl-1H-imidazol-5-yl)-1,4'-bipiperidin-1'-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (2c1);

N-[(2S)-1-[4-(4-methyl-1H-imidazol-5-yl)-1,4'-bipiperidin-1'-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (2c2);

N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[4-(1-propyl-1H-imidazol-2-yl)-1,4'- bipiperidin-1'-yl]propan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (3c1);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[4-(1-propyl-1H-imidazol-2-yl)-1,4'- bipiperidin-1'-yl]propan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (3c2);

N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,4'- bipiperidin-1'-yl]-1-oxopropan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (4c1);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,4'- bipiperidin-1'-yl]-1-oxopropan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (4c2);

4-(7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-[4- (4-methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidin-1'-yl]-1-oxopropan-2-yl}piperidine-1- carboxamide (5c1);

4-(7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-[4- (4-methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidin-1'-yl]-1-oxopropan-2-yl}piperidine-1- carboxamide (5c2);

ethyl 5-{1'-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoyl]-1,4'-bipiperidin-4-yl}-4H-1,2,4-triazole-3- carboxylate (6c1); ethyl 5-{1'-[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoyl]-1,4'-bipiperidin-4-yl}-4H-1,2,4-triazole-3- carboxylate (6c2);

N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[4-(4H-1,2,4-triazol-3-yl)-1,4'- bipiperidin-1'-yl]propan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (7c1);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[4-(4H-1,2,4-triazol-3-yl)-1,4'- bipiperidin-1'-yl]propan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (7c2);

N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-1,4'- bipiperidin-1'-yl]-1-oxopropan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (8c1);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-1,4'- bipiperidin-1'-yl]-1-oxopropan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (8c2);

5-{1'-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoyl]-1,4'-bipiperidin-4-yl}-4H-1,2,4-triazole-3- carboxylic acid (9c1); and

5-{1'-[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoyl]-1,4'-bipiperidin-4-yl}-4H-1,2,4-triazole-3- carboxylic acid (9c2). Aspect 39. The compound according to aspect 31, wherein the compound is:

or

. Aspect 40. A method for treating a cerebrovascular or vascular disorder in a subject

comprising administering to the subject a compound according to aspect 31.

Aspect 41. The method of aspect 40, wherein the cerebrovascular or vascular disorder is migraine without aura, chronic migraine, pure menstrual migraine, menstrually-related migraine, migraine with aura, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, status migrainosus, cluster headache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, hemicrania continua, cyclic vomiting syndrome, allergic rhinitis, or rosacea, dental pain, earache, middle ear inflammation, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, pain associated with inflammatory bowel disease– Crohn’s disease, gout, complex regional pain syndrome, Behçet's disease, endometriosis pain, back pain, or cough.

Aspect 42. The method of aspect 40 wherein the compound is administered via a non-oral route.

Aspect 43. The method of aspect 42 wherein the non-oral route of administration is an intranasal route, a sub-cutaneous route or an intravenous route.

Aspect 44. A method of synthesizing a compound according to aspect 31.

Claims

Claims

1. A compound of formula IA-2, IA-3, IA-4, IB-2 or IC-2:

or a salt thereof, wherein; R¹ is H or Q-(C1-C6)alkyl; where Q is a bond, C(O) or C(O)O and where the (C1-C6)alkyl can be optionally substituted by N(C₁-C₃alkyl)₂ or CO₂H;

R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H; and R⁴ is an optionally substituted aryl group which may be monocyclic or fused to a further ring; R^1’ is

R^2’ is H or forms a spirocyclic heterocyclic ring with R^3’;

R^3’ forms a spirocyclic heterocyclic ring with R^2’ or is a heterocyclic ring if R^2’ is H; and R^1’’ is H or F and Ar¹ is an optionally substituted 5 membered heterocyclic ring containing at least two nitrogen atoms.

2. The compound according to claim 1 of formula IA-2, IA-3, or IA-4 or a salt thereof, wherein R¹ is H or Q-(C₁-C₆)alkyl; where Q is a bond, C(O) or C(O)O and where the (C₁- C₆)alkyl can be optionally substituted by N(C₁-C₃alkyl)₂ or CO₂H;

R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H; and R⁴ is an optionally substituted aryl group which may be monocyclic or fused to a further ring.

3. The compound according to claim 2, wherein R⁴ is a substituted phenyl group wherein the substituents are selected from halo or hydroxy.

4. The compound according to claim 2, wherein R⁴ is a moiety according to formula (II)

wherein X is halo.

5. The compound according to claim 4, wherein X is Br.

6. The compound according to claim 2, wherein R⁴ is

7. The compound according to claim 6, wherein R⁴ is

8. The compound according to claim 2, wherein R² is H and R³ is:

9. The compound according to claim 2 wherein R² forms a spirocyclic heterocyclic ring with R³ to form:

10. The compound according to claim 2, wherein R² is H or forms a spirocyclic heterocyclic ring with R³ to form:

and wherein when R² is H, R³ is:

R⁴ is:

11. The compound according to claim 2, wherein R¹ is H, CO ^t

2Bu, CH₂CH₃, CH₂CH₂CH₃, COCH2CH2CH2CH3, CH2CH2N(CH3)2, COCH2CO2H.

12. The compound according to claim 11, wherein R¹ is H,

13. The compound according to claim 2, wherein the compound is selected from the group consisting of: N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (1a3);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (1a4);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (1a2);

tert-butyl 4-{(2R)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (2a3);

tert-butyl 4-{(2S)-2-{[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (2a2);

tert-butyl 4-{(2R)-2-{[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate (2a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (3a3);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (3a2);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (3a4); N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(1-propylpiperidin-4- yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (4a2);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(1-propylpiperidin-4- yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (4a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(1-propylpiperidin-4- yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1-carboxamide (4a3);

3,5-dibromo-Nα-{[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}-N- {(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-L- tyrosinamide (5a2);

3,5-dibromo-Nα-{[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}-N- {(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-D- tyrosinamide (5a3);

3,5-dibromo-Nα-{[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}-N- {(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}-L- tyrosinamide (5a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(1- pentanoylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2- yl}amino)propan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (6a3);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(1-pentanoylpiperidin- 4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo- 1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (6a2);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(1- pentanoylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2- yl}amino)propan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (6a4); N-[(2R)-1-({(2R)-3-(1-ethylpiperidin-4-yl)-1-oxo-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo- 1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (7a3);

N-[(2S)-1-({(2S)-3-(1-ethylpiperidin-4-yl)-1-oxo-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo- 1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (7a2);

N-[(2S)-1-({(2R)-3-(1-ethylpiperidin-4-yl)-1-oxo-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo- 1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (7a4);

3,5-dibromo-Nα-{[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1- yl]carbonyl}-N-{(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}-L-tyrosinamide (8a2);

3,5-dibromo-Nα-{[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1- yl]carbonyl}-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}-D-tyrosinamide (8a3);

3,5-dibromo-Nα-{[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1- yl]carbonyl}-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}-L-tyrosinamide (8a4);

3,5-dibromo-Nα-{[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1- yl]carbonyl}-N-{(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}-L-tyrosinamide (9a2);

3,5-dibromo-Nα-{[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1- yl]carbonyl}-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}-D-tyrosinamide (9a3);

3,5-dibromo-Nα-{[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1- yl]carbonyl}-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1- yl]propan-2-yl}-L-tyrosinamide (9a4); N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,4- dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide (10a2);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,4- dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide (10a3);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,4- dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide (10a4);

N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-1',2'-dihydro- 1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (11a3);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-1',2'-dihydro- 1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (11a2);

N-[(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2R)-1-oxo-3-(piperidin-4-yl)-1-[4- (pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-1',2'-dihydro- 1H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (11a4);

N-[(2R)-1-({(2R)-3-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1-oxo-1-[4-(pyridin- 4-yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan- 2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (12a3);

N-[(2S)-1-({(2S)-3-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1-oxo-1-[4-(pyridin- 4-yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan- 2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (12a2);

N-[(2S)-1-({(2R)-3-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1-oxo-1-[4-(pyridin- 4-yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan- 2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (12a4);

3-(4-{(2R)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo- 3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3-oxopropanoic acid, ammonium salt (13a3);

3-(4-{(2S)-2-{[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo- 3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3-oxopropanoic acid, ammonium salt (13a2);

3-(4-{(2R)-2-{[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo- 3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3-oxopropanoic acid, ammonium salt (13a4);

3,5-dibromo-Nα-[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1-yl)carbonyl]-N-{(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}-L-tyrosinamide (14a2);

3,5-dibromo-Nα-[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1-yl)carbonyl]-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}-D-tyrosinamide (14a3); and

3,5-dibromo-Nα-[(2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazin]-1-yl)carbonyl]-N-{(2R)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}-L-tyrosinamide (14a4).

14. The compound according to claim 13, wherein the compound is selected from:

15. The compound according to claim 1 of formula IB-2 or a salt thereof, wherein R^1’ is

R^2’ is H or forms a spirocyclic heterocyclic ring with R^3’;

R^3’ forms a spirocyclic heterocyclic ring with R^2’ or is a heterocyclic ring if R^2’ is H.

16. The compound according to claim 15, wherein R^1’ is

17. The compound according to claim 16, wherein R^2’ is H and R^3’ is

18. The compound according to claim 17, wherein R^3’ is

.

19. The compound according to claim 15, wherein R^2’ forms a spirocyclic heterocyclic ring with R^3’ to form

20. The compound according to claim 19, wherein the compound is selected from the group consisting of: N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8- diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5- b]pyridin-1-yl)piperidine-1-carboxamide (1b2);

N-[(2S)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (2b2);

N-[(2R)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (2b3);

N-[(2S)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (2b4);

N-[(2S)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)piperidine-1-carboxamide (3b2);

N-[(2R)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)piperidine-1-carboxamide (3b3);

N-[(2S)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)piperidine-1-carboxamide (3b4);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8- diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-1,4-dihydroquinazolin-3(2H)- yl)piperidine-1-carboxamide (4b2);

N-[(2S)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'- pyrido[2,3-d][1,3]oxazine]-1-carboxamide (5b2); N-[(2R)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'- pyrido[2,3-d][1,3]oxazine]-1-carboxamide (5b3);

N-[(2S)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,4'- pyrido[2,3-d][1,3]oxazine]-1-carboxamide (5b4);

N-[(2S)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)- yl)piperidine-1-carboxamide (6b2);

N-[(2R)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)- yl)piperidine-1-carboxamide (6b3);

N-[(2S)-1-[8-(N-methyl-L-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)- yl)piperidine-1-carboxamide (6b4); and

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(pyridin-4-yl)-2,8- diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5- b]pyridin-1-yl)piperidine-1-carboxamide (7b2).

21. The compound according to claim 15, wherein the compound is

22. The compound according to claim 1 of formula IC-2 or a salt thereof, wherein R^1’’ is H or F and Ar¹ is an optionally substituted 5 membered heterocyclic ring containing at least two nitrogen atoms.

23. The compound according to claim 22, wherein Ar¹ is an optionally substituted five- membered heterocyclic ring including at least two nitrogen atoms, wherein the optional substituents are selected from (C1-C6)alkyl, CO2R^2’’ where R^2’’ is H or (C1-C3)alkyl.

24. The compound according to claim 22, wherein R^1’’ is H.

25. The compound according to claim 22, wherein Ar¹ is a five-membered heterocyclic ring including two or three nitrogen atoms, optionally substituted with (C₁-C₆)alkyl.

26. The compound according to claim 25, wherein Ar¹ is

or .

27. The compound according to claim 26, wherein Ar¹ is

.

28. The compound according to claim 26, wherein Ar¹ is

.

29. The compound according to claim 22, wherein the compound is selected from the group consisting of: N-[(2S)-1-[4-(1H-imidazol-2-yl)-1,4'-bipiperidin-1'-yl]-3-(7-methyl-1H-indazol-5-yl)-1- oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (1c2); N-[(2S)-1-[4-(4-methyl-1H-imidazol-5-yl)-1,4'-bipiperidin-1'-yl]-3-(7-methyl-1H- indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (2c2);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[4-(1-propyl-1H-imidazol-2-yl)-1,4'- bipiperidin-1'-yl]propan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (3c2);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,4'- bipiperidin-1'-yl]-1-oxopropan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (4c2);

4-(7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1- [4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,4'-bipiperidin-1'-yl]-1-oxopropan-2-yl}piperidine- 1-carboxamide (5c2);

ethyl 5-{1'-[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoyl]-1,4'-bipiperidin-4-yl}-4H-1,2,4-triazole- 3-carboxylate (6c2);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[4-(4H-1,2,4-triazol-3-yl)-1,4'- bipiperidin-1'-yl]propan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (7c2);

N-{(2S)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-1,4'- bipiperidin-1'-yl]-1-oxopropan-2-yl}-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (8c2); and

5-{1'-[(2S)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3- yl)piperidin-1-yl]carbonyl}amino)propanoyl]-1,4'-bipiperidin-4-yl}-4H-1,2,4-triazole- 3-carboxylic acid (9c2).

30. The compound according to claim 22, wherein the compound is:

or

31. A method for treating a cerebrovascular or vascular disorder in a subject comprising administering to the subject a compound according to claim 1.

32. The method according to claim 31, wherein the cerebrovascular or vascular disorder is migraine without aura, chronic migraine, pure menstrual migraine, menstrually-related migraine, migraine with aura, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, status migrainosus, cluster headache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, hemicrania continua, cyclic vomiting syndrome, allergic rhinitis, or rosacea, dental pain, earache, middle ear inflammation, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, pain associated with inflammatory bowel disease– Crohn’s disease, gout, complex regional pain syndrome, Behçet's disease, endometriosis pain, back pain, or cough.

33. The method according to claim 31 wherein the compound is administered via a non-oral route.

34. The method according to claim 33 wherein the non-oral route of administration is an intranasal route, a sub-cutaneous route or an intravenous route.

35. Use of a compound according to claim 1 for the treatment of a cerebrovascular or

vascular disorder in a subject.

36. The use according to claim 35, wherein the cerebrovascular or vascular disorder is

migraine without aura, chronic migraine, pure menstrual migraine, menstrually-related migraine, migraine with aura, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, status migrainosus, cluster headache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, hemicrania continua, cyclic vomiting syndrome, allergic rhinitis, or rosacea, dental pain, earache, middle ear inflammation, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, pain associated with inflammatory bowel disease– Crohn’s disease, gout, complex regional pain syndrome, Behçet's disease, endometriosis pain, back pain, or cough.

37. The use according to claim 35 wherein the compound is administered via a non-oral route.

38. The use according to claim 37 wherein the non-oral route of administration is an

intranasal route, a sub-cutaneous route or an intravenous route.

39. A method of synthesizing a compound according to claim 1.